Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘Schizophrenia’


Mindful Discoveries

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Schizophrenia and the Synapse

Genetic evidence suggests that overactive synaptic pruning drives development of schizophrenia.

By Ruth Williams | January 27, 2016 … more follows)

http://www.the-scientist.com/?articles.view/articleNo/45189/title/Schizophrenia-and-the-Synapse/

http://www.the-scientist.com/images/News/January2016/Schizophrenia.jpg

C4 (green) at synapses of human neurons

Compared to the brains of healthy individuals, those of people with schizophrenia have higher expression of a gene called C4, according to a paper published inNature today (January 27). The gene encodes an immune protein that moonlights in the brain as an eradicator of unwanted neural connections (synapses). The findings, which suggest increased synaptic pruning is a feature of the disease, are a direct extension of genome-wide association studies (GWASs) that pointed to the major histocompatibility (MHC) locus as a key region associated with schizophrenia risk.

“The MHC [locus] is the first and the strongest genetic association for schizophrenia, but many people have said this finding is not useful,” said psychiatric geneticist Patrick Sullivan of the University of North Carolina School of Medicine who was not involved in the study. “The value of [the present study is] to show that not only is it useful, but it opens up new and extremely interesting ideas about the biology and therapeutics of schizophrenia.”

Schizophrenia has a strong genetic component—it runs in families—yet, because of the complex nature of the condition, no specific genes or mutations have been identified. The pathological processes driving the disease remain a mystery.

Researchers have turned to GWASs in the hope of finding specific genetic variations associated with schizophrenia, but even these have not provided clear candidates.

“There are some instances where genome-wide association will literally hit one base [in the DNA],” explained Sullivan. While a 2014 schizophrenia GWAS highlighted the MHC locus on chromosome 6 as a strong risk area, the association spanned hundreds of possible genes and did not reveal specific nucleotide changes. In short, any hope of pinpointing the MHC association was going to be “really challenging,” said geneticist Steve McCarroll of Harvard who led the new study.

Nevertheless, McCarroll and colleagues zeroed in on the particular region of the MHC with the highest GWAS score—the C4 gene—and set about examining how the area’s structural architecture varied in patients and healthy people.

The C4gene can exist in multiple copies (from one to four) on each copy of chromosome 6, and has four different forms: C4A-short, C4B-short, C4A-long, and C4B-long. The researchers first examined the “structural alleles” of the C4 locus—that is, the combinations and copy numbers of the different C4 forms—in healthy individuals. They then examined how these structural alleles related to expression of both C4Aand C4B messenger RNAs (mRNAs) in postmortem brain tissues.From this the researchers had a clear picture of how the architecture of the C4 locus affected expression ofC4A and C4B. Next, they compared DNA from roughly 30,000 schizophrenia patients with that from 35,000 healthy controls, and a correlation emerged: the alleles most strongly associated with schizophrenia were also those that were associated with the highest C4A expression. Measuring C4A mRNA levels in the brains of 35 schizophrenia patients and 70 controls then revealed that, on average, C4A levels in the patients’ brains were 1.4-fold higher.C4 is an immune system “complement” factor—a small secreted protein that assists immune cells in the targeting and removal of pathogens. The discovery of C4’s association to schizophrenia, said McCarroll, “would have seemed random and puzzling if it wasn’t for work . . . showing that other complement components regulate brain wiring.” Indeed, complement protein C3 locates at synapses that are going to be eliminated in the brain, explained McCarroll, “and C4 was known to interact with C3 . . . so we thought well, actually, this might make sense.”McCarroll’s team went on to perform studies in mice that revealed C4 is necessary for C3 to be deposited at synapses. They also showed that the more copies of the C4 gene present in a mouse, the more the animal’s neurons were pruned.Synaptic pruning is a normal part of development and is thought to reflect the process of learning, where the brain strengthens some connections and eradicates others. Interestingly, the brains of deceased schizophrenia patients exhibit reduced neuron density. The new results, therefore, “make a lot of sense,” said Cardiff University’s Andrew Pocklington who did not participate in the work. They also make sense “in terms of the time period when synaptic pruning is occurring, which sort of overlaps with the period of onset for schizophrenia: around adolescence and early adulthood,” he added.

“[C4] has not been on anybody’s radar for having anything to do with schizophrenia, and now it is and there’s a whole bunch of really neat stuff that could happen,” said Sullivan. For one, he suggested, “this molecule could be something that is amenable to therapeutics.”

A. Sekar et al., “Schizophrenia risk from complexvariation of complement component 4,”Nature,   http://dx.doi.com:/10.1038/nature16549, 2016.     

Tags schizophrenia, neuroscience, gwas, genetics & genomics, disease/medicine and cell & molecular biology

 

Schizophrenia: From genetics to physiology at last

Ryan S. Dhindsa& David B. Goldstein

Nature (2016)  http://dx.doi.org://10.1038/nature16874

The identification of a set of genetic variations that are strongly associated with the risk of developing schizophrenia provides insights into the neurobiology of this destructive disease.

http://www.nytimes.com/2016/01/28/health/schizophrenia-cause-synaptic-pruning-brain-psychiatry.html

 

Genetic study provides first-ever insight into biological origin of schizophrenia

Suspect gene may trigger runaway synaptic pruning during adolescence — NIH-funded study

NIH/NATIONAL INSTITUTE OF MENTAL HEALTH

IMAGE

http://media.eurekalert.org/multimedia_prod/pub/web/107629_web.jpg

The site in Chromosome 6 harboring the gene C4 towers far above other risk-associated areas on schizophrenia’s genomic “skyline,” marking its strongest known genetic influence. The new study is the first to explain how specific gene versions work biologically to confer schizophrenia risk.  CREDIT  Psychiatric Genomics Consortium

Versions of a gene linked to schizophrenia may trigger runaway pruning of the teenage brain’s still-maturing communications infrastructure, NIH-funded researchers have discovered. People with the illness show fewer such connections between neurons, or synapses. The gene switched on more in people with the suspect versions, who faced a higher risk of developing the disorder, characterized by hallucinations, delusions and impaired thinking and emotions.

“Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” explained Thomas Lehner, Ph.D., director of the Office of Genomics Research Coordination of the NIH’s National Institute of Mental Health (NIMH), which co-funded the study along with the Stanley Center for Psychiatric Research at the Broad Institute and other NIH components. “It could help explain schizophrenia’s delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain’s working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”

The gene, called C4 (complement component 4), sits in by far the tallest tower on schizophrenia’s genomic “skyline” (see graph below) of more than 100 chromosomal sites harboring known genetic risk for the disorder. Affecting about 1 percent of the population, schizophrenia is known to be as much as 90 percent heritable, yet discovering how specific genes work to confer risk has proven elusive, until now.

A team of scientists led by Steve McCarroll, Ph.D., of the Broad Institute and Harvard Medical School, Boston, leveraged the statistical power conferred by analyzing the genomes of 65,000 people, 700 postmortem brains, and the precision of mouse genetic engineering to discover the secrets of schizophrenia’s strongest known genetic risk. C4’s role represents the most compelling evidence, to date, linking specific gene versions to a biological process that could cause at least some cases of the illness.

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” said McCarroll. “The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that block box, peering inside and starting to see actual biological mechanisms.”

McCarroll’s team, including Harvard colleagues Beth Stevens, Ph.D., Michael Carroll, Ph.D., and Aswin Sekar, report on their findings online Jan. 27, 2016 in the journal Nature.

A swath of chromosome 6 encompassing several genes known to be involved in immune function emerged as the strongest signal associated with schizophrenia risk in genome-wide analyses by the NIMH-funded Psychiatric Genomics Consortium over the past several years. Yet conventional genetics failed to turn up any specific gene versions there linked to schizophrenia.

To discover how the immune-related site confers risk for the mental disorder, McCarroll’s team mounted a search for “cryptic genetic influences” that might generate “unconventional signals.” C4, a gene with known roles in immunity, emerged as a prime suspect because it is unusually variable across individuals. It is not unusual for people to have different numbers of copies of the gene and distinct DNA sequences that result in the gene working differently.

The researchers dug deeply into the complexities of how such structural variation relates to the gene’s level of expression and how that, in turn, might relate to schizophrenia. They discovered structurally distinct versions that affect expression of two main forms of the gene in the brain. The more a version resulted in expression of one of the forms, called C4A, the more it was associated with schizophrenia. The more a person had the suspect versions, the more C4 switched on and the higher their risk of developing schizophrenia. Moreover, in the human brain, the C4 protein turned out to be most prevalent in the cellular machinery that supports connections between neurons.

Adapting mouse molecular genetics techniques for studying synaptic pruning and C4’s role in immune function, the researchers also discovered a previously unknown role for C4 in brain development. During critical periods of postnatal brain maturation, C4 tags a synapse for pruning by depositing a sister protein in it called C3. Again, the more C4 got switched on, the more synapses got eliminated.

In humans, such streamlining/pruning occurs as the brain develops to full maturity in the late teens/early adulthood – conspicuously corresponding to the age-of-onset of schizophrenia symptoms.

Future treatments designed to suppress excessive levels of pruning by counteracting runaway C4 in at risk individuals might nip in the bud a process that could otherwise develop into psychotic illness, suggest the researchers. And thanks to the head start gained in understanding the role of such complement proteins in immune function, such agents are already in development, they note.

“This study marks a crucial turning point in the fight against mental illness. It changes the game,” added acting NIMH director Bruce Cuthbert, Ph.D. “Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments and even prevention.”

###

VIDEO: Opening Schizophrenia’s Black Box https://youtu.be/s0y4equOTLg

Reference: Sekar A, Biala AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K Presumey J Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4.Nature. Jan 27, 2016. DOI: 10.1038/nature16549.

 

Schizophrenia risk from complex variation of complement component 4

Aswin SekarAllison R. BialasHeather de RiveraAvery DavisTimothy R. Hammond, …., Michael C. CarrollBeth Stevens Steven A. McCarroll

Nature(2016)   http://dx.doi.org:/10.1038/nature16549

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

Figure 1: Structural variation of the complement component 4 (C4) gene.

http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature16549-f1.jpg

a, Location of the C4 genes within the major histocompatibility complex (MHC) locus on human chromosome 6. b, Human C4 exists as two paralogous genes (isotypes), C4A and C4B; the encoded proteins are distinguished at a key site

http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature16549-f3.jpg

http://www.nature.com/nature/journal/vaop/ncurrent/carousel/nature16549-sf8.jpg

Gene Study Points Toward Therapies for Common Brain Disorders

University of Edinburgh    http://www.dddmag.com/news/2016/01/gene-study-points-toward-therapies-common-brain-disorders

Scientists have pinpointed the cells that are likely to trigger common brain disorders, including Alzheimer’s disease, Multiple Sclerosis and intellectual disabilities.

It is the first time researchers have been able to identify the particular cell types that malfunction in a wide range of brain diseases.

Scientists say the findings offer a roadmap for the development of new therapies to target the conditions.

The researchers from the University of Edinburgh’s Centre for Clinical Brain Sciences used advanced gene analysis techniques to investigate which genes were switched on in specific types of brain cells.

They then compared this information with genes that are known to be linked to each of the most common brain conditions — Alzheimer’s disease, anxiety disorders, autism, intellectual disability, multiple sclerosis, schizophrenia and epilepsy.

Their findings reveal that for some conditions, the support cells rather than the neurons that transmit messages in the brain are most likely to be the first affected.

Alzheimer’s disease, for example, is characterised by damage to the neurons. Previous efforts to treat the condition have focused on trying to repair this damage.

The study found that a different cell type — called microglial cells — are responsible for triggering Alzheimer’s and that damage to the neurons is a secondary symptom of disease progression.

Researchers say that developing medicines that target microglial cells could offer hope for treating the illness.

The approach could also be used to find new treatment targets for other diseases that have a genetic basis, the researchers say.

Dr Nathan Skene, who carried out the study with Professor Seth Grant, said: “The brain is the most complex organ made up from a tangle of many cell types and sorting out which of these cells go wrong in disease is of critical importance to developing new medicines.”

Professor Seth Grant said: “We are in the midst of scientific revolution where advanced molecular methods are disentangling the Gordian Knot of the brain and completely unexpected new pathways to solving diseases are emerging. There is a pressing need to exploit the remarkable insights from the study.”

 

Quantitative multimodal multiparametric imaging in Alzheimer’s disease

Qian Zhao, Xueqi Chen, Yun Zhou      Brain Informatics  http://link.springer.com/article/10.1007/s40708-015-0028-9

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, causing changes in memory, thinking, and other dysfunction of brain functions. More and more people are suffering from the disease. Early neuroimaging techniques of AD are needed to develop. This review provides a preliminary summary of the various neuroimaging techniques that have been explored for in vivo imaging of AD. Recent advances in magnetic resonance (MR) techniques, such as functional MR imaging (fMRI) and diffusion MRI, give opportunities to display not only anatomy and atrophy of the medial temporal lobe, but also at microstructural alterations or perfusion disturbance within the AD lesions. Positron emission tomography (PET) imaging has become the subject of intense research for the diagnosis and facilitation of drug development of AD in both animal models and human trials due to its non-invasive and translational characteristic. Fluorodeoxyglucose (FDG) PET and amyloid PET are applied in clinics and research departments. Amyloid beta (Aβ) imaging using PET has been recognized as one of the most important methods for the early diagnosis of AD, and numerous candidate compounds have been tested for Aβ imaging. Besides in vivo imaging method, a lot of ex vivo modalities are being used in the AD researches. Multiphoton laser scanning microscopy, neuroimaging of metals, and several metal bioimaging methods are also mentioned here. More and more multimodality and multiparametric neuroimaging techniques should improve our understanding of brain function and open new insights into the pathophysiology of AD. We expect exciting results will emerge from new neuroimaging applications that will provide scientific and medical benefits.

Keywords –   Alzheimer’s disease Neuroimaging PET MRI Amyloid beta Multimodal

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that gradually destroys brain cells, causing changes in memory, thinking, and other dysfunction of brain functions [1]. AD is considered to a prolonged preclinical stage where neuropathological changes precede the clinical symptoms [2]. An estimation of 35 million people worldwide is living with this disease. If effective treatments are not discovered in a timely fashion, the number of AD cases is anticipated to rise to 113 million by 2050 [3].

Amyloid beta (Aβ) and tau are two of the major biomarkers of AD, and have important and different roles in association with the progression of AD pathophysiology. Jack et al. established hypothetical models of the major biomarkers of AD. By renewing and modifying the models, they found that the two major proteinopathies underlying AD biomarker changes, Aβ and tau, may be initiated independently in late onset AD where they hypothesize that an incident Aβ pathophysiology can accelerate an antecedent limbic and brainstem tauopathy [4]. MRI technique was used in the article, which revealed that the level of Aβ load was associated with a shorter time-to-progression of AD [5]. This warrants an urgent need to develop early neuroimaging techniques of AD neuropathology that can detect and predict the disease before the onset of dementia, monitor therapeutic efficacy in halting and slowing down progression in the earlier stage of the disease.

There have been various reports on the imaging assessments of AD. Some measurements reflect the pathology of AD directly, including positron emission tomography (PET) amyloid imaging and cerebrospinal fluid (CSF) beta-amyloid 42 (Aβ42), while others reflect neuronal injury associated with AD indirectly, including CSF tau (total and phosphorylated tau), fluorodeoxy-d-glucose (FDG)-PET, and MRI. AD Neuroimaging Initiative (ADNI) has been to establish the optimal panel of clinical assessments, MRI and PET imaging measures, as well as other biomarkers from blood and CSF, to inform clinical trial design for AD therapeutic development. At the same time, it has been highly productive in generating a wealth of data for elucidating disease mechanisms occurring during early stages of preclinical and prodromal AD [6].

Single neuroimaging often reflects limit information of AD. As a result, multimodal neuroimaging is widely used in neuroscience researches, as it overcomes the limitations of individual modalities. Multimodal multiparametric imaging mean the combination of different imaging techniques, such as PET, MRI, simultaneously or separately. The multimodal multiparametric imaging enables the visualization and quantitative analysis of the alterations in brain structure and function, such as PET/CT, and PET/MRI. [7]. In this review article, we summarize and discuss the main applications, findings, perspectives as well as advantages and challenges of different neuroimaging in AD, especially MRI and PET imaging.

2 Magnetic resonance imaging

MRI demonstrates specific volume loss or cortical atrophy patterns with disease progression in AD patients [810]. There are several MRI techniques and analysis methods used in clinical and scientific research of AD. Recent advances in MR techniques, such as functional MRI (fMRI) and diffusion MRI, depict not only anatomy and atrophy of the medial temporal lobe (MTL), but also microstructural alterations or perfusion disturbance within this region.

2.1 Functional MRI

Because of the cognitive reserve (CR), the relationship between severity of AD patients’ brain damage and corresponding clinical symptoms is not always paralleled [11, 12]. Recently, resting-state fMRI (RS-fMRI) is popular for its ability to map brain functional connectivity non-invasively [13]. By using RS-fMRI, Bozzali et al. reported that the CR played a role in modulating the effect of AD pathology on default mode network functional connectivity, which account for the variable clinical symptoms of AD [14]. Moreover, AD patients with higher educated experience were able to recruit compensatory neural mechanisms, which can be measured using RS-fMRI. Arterial spin-labeled (ASL) MRI is another functional brain imaging modality, which measures cerebral blood flow (CBF) by magnetically labeled arterial blood water following through the carotid and vertebral arteries as an endogenous contrast medium. Several studies have concluded the characteristics of CBF changes in AD patients using ASL-MRI [1517].

At some point in time, sufficient brain damage accumulates to result in cognitive symptoms and impairment. Mild cognitive impairment (MCI) is a condition in which subjects are usually only mildly impaired in memory with relative preservation of other cognitive domains and functional activities and do not meet the criteria for dementia [18], or as the prodromal state AD [19]. MCI patients are at a higher risk of developing AD and up to 15 % convert to AD per year [18]. Binnewijzend et al. have reported the pseudocontinuous ASL could distinguish both MCI and AD from healthy controls, and be used in the early diagnosis of AD [20]. In their continuous study, they used quantitative whole brain pseudocontinuous ASL to compare regional CBF (rCBF) distribution patterns in different types of dementia, and concluded that ASL-MRI could be a non-invasive and easily accessible alternative to FDG-PET imaging in the assessment of CBF of AD patients [21].

2.2 Structure MRI

Structural MRI (sMRI) has already been a reliable imaging method in the clinical diagnosis of AD, characterized as gray matter reduction and ventricular enlargement in standard T1-weighted sequences [9]. Locus coeruleus (LC) and substantia nigra (SN) degeneration was seen in AD. By using new quantitative calculating method, Chen et al. presented a new quantitative neuromelanin MRI approach for simultaneous measurement of locus LC and SN of brainstem in living human subjects [22]. The approach they used demonstrated advantages in image acquisition, pre-processing, and quantitative analysis. Numerous transgenic animal models of amyloidosis are available, which can manipulate a lot of neuropathological features of AD progression from the deposition of β-amyloid [23]. Braakman et al. demonstrated the dynamics of amyloid plaque formation and development in a serial MRI study in a transgenic mouse model [24]. Increased iron accumulation in gray matter is frequently observed in AD. Because of the paramagnetic nature of iron, MRI shows nice potential in the investigating iron levels in AD [25]. Quantitative MRI was shown high sensitivity and specificity in mapping cerebral iron deposition, and helped in the research on AD diagnosis [26].

The imaging patterns are always associated with the pathologic changes, such as specific protein markers. Spencer et al. manifested the relationship between quantitative T1 and T2 relaxation time changes and three immunohistochemical markers: β-amyloid, neuron-specific nuclear protein (a marker of neuronal cell load), and myelin basic protein (a marker of myelin load) in AD transgenic mice [27].

High-field MRI has been successfully applied to imaging plaques in transgenic mice for over a decade without contrast agents [24, 2830]. Sillerud et al. devised a method using blood–brain barrier penetrating, amyloid-targeted, superparamagnetic iron oxide nanoparticles (SPIONs) for better imaging of amyloid plaque [31]. Then, they successfully used this SPION-MRI to assess the drug efficacy on the 3D distribution of Aβ plaques in transgenic AD mouse [32].

2.3 Diffusion MRI

Diffusion-weighted imaging (DWI) is a sensitive tool that allows quantifying of physiologic alterations in water diffusion, which result from microscopic structural changes.

Diffusion tensor imaging (DTI) is a well-established and commonly employed diffusion MRI technique in clinical and research on neuroimaging studies, which is based on a Gaussian model of diffusion processes [33]. In general, AD is associated with widespread reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in several regions, most prominently in the frontal and temporal lobes, and along the cingulum, corpus callosum, uncinate fasciculus, superior longitudinal fasciculus, and MTL-associated tracts than healthy controls [3437]. Acosta-Cabronero et al. reported increased axial diffusivity and MD in the splenium, which were the earliest abnormalities in AD [38]. FA and radial diffusivity (DR) differences in the corpus callosum, cingulum, and fornix were found to separate individuals with MCI who converted to AD from non-converters [39]. DTI was also found to be a better predictor of AD-specific MTL atrophy when compared to CSF biomarkers [40]. These findings suggested the potential clinical utility of DTI as early biomarkers of AD and its progression. However, an increase in MD and DR and a decrease in FA with advancing age in selective brain regions have been previously reported [41, 42]. Diffusion MRI can be also used in the classifying of various stages of AD. Multimodal classification method, which combined fMRI and DTI, separated more MCI from healthy controls than single approaches [43].

In recent years, tau has emerged as a potential target for therapeutic intervention. Tau plays a critical role in the neurodegenerative process forming neurofibrillary tangles, which is a major hallmark of AD and correlates with clinical disease progression. Wells et al. applied multiparametric MRI, containing high-resolution structure MRI (sMRI), a novel chemical exchange saturation transfer (CEST) MRI, DTI, and ASL, and glucose CEST to measure changes of tau pathology in AD transgenic mouse [44].

Besides DWI MRI, perfusion-weighted imaging (PWI) is another advanced MR technique, which could measure the cerebral hemodynamics at the capillary level. Zimny et al. evaluated the correlation of MTL with both DWI and PWI in AD and MCI patients [45].

3 Positron emission tomography

PET is a specific imaging technique applying in researches of brain function and neurochemistry of small animals, medium-sized animals, and human subjects [4648]. As a particular brain imaging technique, PET imaging has become the subject of intense research for the diagnosis and facilitation of drug development of AD in both animal models and human trials due to its non-invasive and translational characteristic. PET with various radiotracers is considered as a standard non-invasive quantitative imaging technique to measure CBF, glucose metabolism, and β-amyloid and tau deposition.

3.1 FDG-PET

To date, 18F-FDG is one of the best and widely used neuroimaging tracers of PET, which employed for research and clinical assessment of AD [49]. Typical lower FDG metabolism was shown in the precuneus, posterior cingulate, and temporal and parietal cortex with progression to whole brain reductions with increasing disease progress in AD brains [50, 51]. FDG-PET imaging reflects the cerebral glucose metabolism, neuronal injury, which provides indirect evidence on cognitive function and progression that cannot be provided by amyloid PET imaging.

Schraml et al. [52] identified a significant association between hypometabolic convergence index and phenotypes using ADNI data. Some researchers also used 18F-FDG-PET to analyze genetic information with multiple biomarkers to classify AD status, predicting cognitive decline or MCI to AD conversion [5355]. Trzepacz et al. [56] reported multimodal AD neuroimaging study, using MRI, 11C-PiB PET, and 18F-FDG-PET imaging to predict MCI conversion to AD along with APOE genotype. Zhang et al. [57] compared the genetic modality single-nucleotide polymorphism (SNP) with sMRI, 18F-FDG-PET, and CSF biomarkers, which were used to differentiate healthy control, MCI, and AD. They found FDG-PET is the best modality in terms of accuracy.

3.2 Amyloid beta PET

Aβ, the primary constituent of senile plaques, and tau tangles are hypothesized to play a primary role in the pathogenesis of AD, but it is still hard to identify the fundamental mechanisms [5860]. Aβ plaque in brain is one of the pathological hallmarks of AD [61,62]. Accumulation of Aβ peptide in the cerebral cortex is considered one cause of dementia in AD [63]. Numerous studies have involved in vivo PET imaging assessing cortical β-amyloid burden [6466].

Aβ imaging using PET has been recognized as one of the most important methods for the early diagnosis of AD [67]. Numerous candidate compounds have been tested for Aβ imaging, such as 11C-PiB [68], 18F-FDDNP [69], 11C-SB-13 [70], 18F-BAY94-9172 [71], 18F-AV-45 [72], 18F-flutemetamol [73, 74], 11C-AZD2184 [75], and 18F-ADZ4694 [76], 11C-BF227 and 18F-FACT [77].

Several amyloid PET studies examined genotypes, phenotypes, or gene–gene interactions. Ramanan et al. [78] reported the GWAS results with 18F-AV-45 reflecting the cerebral amyloid metabolism in AD for the first time. Swaminathan et al. [79] revealed the association between plasma Aβ from peripheral blood and cortical amyloid deposition on 11C-PiB. Hohman et al. [80] reported the relationship between SNPs involved in amyloid and tau pathophysiology with 18F-AV-45 PET.

Among the PET tracers, 11C-PiB, which has a high affinity for fibrillar Aβ, is a reliable biomarker of underlying AD pathology [68, 81]. It shows cortical uptake well paralleled with AD pathology [82, 83], has recently been approved for use by the Food and Drug Administration (FDA, April 2012) and the European Medicines Agency (January 2013). 18F-GE-067 (flutemetamol) and 18F-BAY94-9172 (florbetaben) have also been approved by the US FDA in the last 2 years [84, 85].

18F-Florbetapir (also known as 18F-AV-45) exhibits high affinity specific binding to amyloid plaques. 18F-AV-45 labels Aβ plaques in sections from patients with pathologically confirmed AD [72].

It was reported in several research groups that 18F-AV-45 PET imaging showed a reliability of both qualitative and quantitative assessments in AD patients, and Aβ+ increased with diagnostic category (healthy control < MCI < AD) [82, 86, 87]. Johnson et al. used 18F-AV-45 PET imaging to evaluate the amyloid deposition in both MCI and AD patients qualitatively and quantitatively, and found that amyloid burden increased with diagnostic category (MCI < AD), age, and APOEε4 carrier status [88]. Payoux et al. reported the equivocal amyloid PET scans using 18F-AV-45 associated with a specific pattern of clinical signs in a large population of non-demented older adults more than 70 years old [89].

More and more researchers consider combination and comparison of multiple PET tracers targeting amyloid plaque imaging together. Bruck et al. compared the prognostic ability of 11C-PiB PET, 18F-FDG-PET, and quantitative hippocampal volumes measured with MR imaging in predicting MCI to AD conversion. They found that the FDG-PET and 11C-PiB PET imaging are better in predicting MCI to AD conversion [90]. Hatashita et al. used 11C-PiB and FDG-PET imaging to identify MCI due to AD, 11C-PiB showed a higher sensitivity of 96.6 %, and FDG-PET added diagnostic value in predicting AD over a short period [91].

Besides, new Aβ imaging agents were radiosynthesized. Yousefi et al. radiosynthesized a new Aβ imaging agent 18F-FIBT, and compared the three different Aβ-targeted radiopharmaceuticals for PET imaging, including 18F-FIBT, 18F-florbetaben, and 11C-PiB [92]. 11C-AZD2184 is another new PET tracer developed for amyloid senile plaque imaging, and the kinetic behavior of 11C-AZD2184 is suitable for quantitative analysis and can be used in clinical examination without input function [75,93, 94].

4 Multimodality imaging: PET/MRI

Several diagnostic techniques, including MRI and PET, are employed for the diagnosis and monitoring of AD [95]. Multimodal imaging could provide more information in the formation and key molecular event of AD than single method. It drives the progression of neuroimaging research due to the recognition of the clinical benefits of multimodal data [96], and the better access to hybrid devices, such as PET/MRI [97].

Maier et al. evaluated the dynamics of 11C-PiB PET, 15O-H2O-PET, and ASL-MRI in transgenic AD mice and concluded that the AD-related decline of rCBF was caused by the cerebral Aβ angiopathy [98]. Edison et al. systematically compared 11C-PiB PET and MRI in AD, MCI patients, and controls. They thought that 11C-PiB PET was adequate for clinical diagnostic purpose, while MRI remained more appropriate for clinical research [99]. Zhou et al. investigated the interactions between multimodal PET/MRI in elder patients with MCI, AD, and healthy controls, and confirmed the invaluable application of amyloid PET and MRI in early diagnosis of AD [100]. Kim et al. reported that Aβ-weighted cortical thickness, which incorporates data from both MRI and amyloid PET imaging, is a consistent and objective imaging biomarker in AD [101].

5 Other imaging modalities

Multiphoton non-linear optical microscope imaging systems using ultrafast lasers have powerful advantages such as label-free detection, deep penetration of thick samples, high sensitivity, subcellular spatial resolution, 3D optical sectioning, chemical specificity, and minimum sample destruction [102, 103]. Coherent anti-Stokes–Raman scattering (CARS), two-photon excited fluorescence (TPEF), and second-harmonic generation (SHG) microscopy are the most widely used biomedical imaging techniques [104106].

 

Quantitative electroencephalographic and neuropsychological investigation of an alternative measure of frontal lobe executive functions: the Figure Trail Making Test

 Paul S. Foster, Valeria Drago, Brad J. Ferguson, Patti Kelly Harrison,David W. Harrison 

Brain Informatis    http://dx.doi.org:/10.1007/s40708-015-0025-z    http://link.springer.com/article/10.1007/s40708-015-0025-z/fulltext.html

The most frequently used measures of executive functioning are either sensitive to left frontal lobe functioning or bilateral frontal functioning. Relatively little is known about right frontal lobe contributions to executive functioning given the paucity of measures sensitive to right frontal functioning. The present investigation reports the development and initial validation of a new measure designed to be sensitive to right frontal lobe functioning, the Figure Trail Making Test (FTMT). The FTMT, the classic Trial Making Test, and the Ruff Figural Fluency Test (RFFT) were administered to 42 right-handed men. The results indicated a significant relationship between the FTMT and both the TMT and the RFFT. Performance on the FTMT was also related to high beta EEG over the right frontal lobe. Thus, the FTMT appears to be an equivalent measure of executive functioning that may be sensitive to right frontal lobe functioning. Applications for use in frontotemporal dementia, Alzheimer’s disease, and other patient populations are discussed.

Keywords – Frontal lobes, Executive functioning, Trail making test, Sequencing, Behavioral speed, Designs, Nonverbal, Neuropsychological assessment, Regulatory control, Effortful control

A recent survey indicated that the vast majority of neuropsychologists frequently assess executive functioning as part of their neuropsychological evaluations [1]. Surveys of neuropsychologists have indicated that the Trail Making Test (TMT), Controlled Oral Word Association Test (COWAT), Wisconsin Card Sorting Test (WCST), and the Stroop Color-Word Test (SCWT) are among the most commonly used instruments [1,2]. Further, the Rabin et al. [1] survey indicated that these same tests are among the most frequently used by neuropsychologists when specifically assessing executive or frontal lobe functioning. The frequent use of the TMT, WCST, and the SCWT, as well as the assumption that they are measures of executive functioning, led Demakis (2003–2004) to conduct a series of meta-analyses to determine the sensitivity of these test to detect frontal lobe dysfunction, particularly lateralized frontal lobe dysfunction. The findings indicated that the SCWT and Part A of the TMT [3], as well as the WCST [4], were all sensitive to frontal lobe dysfunction. However, only the SCWT differentiated between left and right frontal lobe dysfunction, with the worst performance among those with left frontal lobe dysfunction [3].

The finding of the Demakis [4] meta-analysis, that the WCST was not sensitive to lateralized frontal lobe dysfunction, is not surprising given the equivocal findings that have been reported. Whereas performance on the WCST is sensitive to frontal lobe dysfunction [5, 6], demonstration of lateralized frontal dysfunction has been quite problematic. Unilateral left or right dorsolateral frontal dysfunction has been associated with impaired performance on the WCST [6]. Fallgatter and Strik [7] found bilateral frontal lobe activation during performance of the WCST. However, other imaging studies have found right lateralized frontal lobe activation [8] and left lateralized frontal activation [9] in response to performance on the WCST. Further, left frontal lobe alpha power is negatively correlated with performance on the WCST [10]. Finally, patients with left frontal lobe tumors exhibit more impaired performance on the WCST than those with right frontal tumors [11].

Unlike the data for the WCST, more consistent findings have been reported regarding lateralized frontal lobe functioning for the other commonly used measures of executive functioning. For instance, as with the Demakis [3] study, many investigations have found the SCWT to be sensitive to left frontal lobe functioning, although the precise localization within the left frontal lobe has varied. Impaired performance on the SCWT results from left frontal lesions [12] and specifically from lesions localized to the left dorsolateral frontal lobe [13, 14], though bilateral frontal lesions have also yielded impaired performance [13, 14]. Further, studies using neuroimaging to investigate the neural basis of performance on the SCWT have indicated involvement of the left anterior cingulated cortex [15], left lateral prefrontal cortex [16], left inferior precentral sulcus [17], and the left dorsolateral frontal lobe [18].

Wide agreement exists among investigations of the frontal lateralization of verbal or lexical fluency to confrontation. Specifically, patients with left frontal lobe lesions are known to exhibit impaired performance on lexical fluency to confrontation tasks, relative to either patients with right frontal lesions [12, 19, 20] or controls [21]. A recent meta-analysis also indicated that the largest deficits in performance on measures of lexical fluency are associated with left frontal lobe lesions [22]. Troster et al. [23] found that, relative to patients with right pallidotomy, patients with left pallidotomy exhibited more impaired lexical fluency. Several neuroimaging investigations have further supported the role of the left frontal lobe in lexical fluency tasks [15, 2427]. Performance on lexical fluency tasks also varies as a function of lateral frontal lobe asymmetry, as assessed by electroencephalography [28].

The Trail Making Test is certainly among the most widely used tests [1] and perhaps the most widely researched. Various norms exist for the TMT (see [29]), with Tombaugh [30] providing the most recent comprehensive set of normative data. Different methods of analyzing and interpreting the data have also been proposed and used, including error analysis [13, 14, 3133], subtraction scores [13, 14, 34], and ratio scores [13, 14, 35].

Several different language versions of the test have been developed and reported, including Arabic [36], Chinese [37, 38], Greek [39], and Hebrew [40]. Numerous alternative versions of the TMT have been developed to address perceived shortcomings of the original TMT. For instance, the Symbol Trail Making Test [41] was developed to reduce the cultural confounds associated with the use of the Arabic numeral system and English alphabet in the original TMT. The Color Trails Test (CTT; [42]) was also developed to control for cultural confounds, although mixed results have been reported regarding whether the CTT is indeed analogous to the TMT [4345]. A version of the TMT for preschool children, the TRAILS-P, has also been reported [46].

Additionally, the Comprehensive Trail Making Test [47] was developed to control for perceived psychometric shortcomings of the original TMT (for a review see [48] and the Oral Trail Making Test (OTMT; [49]) was developed to reduce confounds associated with motor speed and visual search abilities, with research supporting the OTMT as an equivalent measure [50, 51]. Alternate forms of the TMT have also been developed to permit successive administrations [32, 52] and to assess the relative contributions of the requisite cognitive skills [53].

Delis et al. [54] stated that the continued development of new instrumentation for improving diagnosis and treatment is a critical undertaking in all health-related fields. Further, in their view, the field of neuropsychology has recognized the importance of continually striving to develop new clinical measures. Delis and colleagues developed the extensive Delis-Kaplan Executive Functioning System (D-KEFS; [55]) in the spirit of advancing the instrumentation of neuropsychology. The D-KEFS includes a Trail Making Test consisting of five separate conditions. The Number-Letter Switching condition involves a sequencing procedure similar to that of the classic TMT. The other four conditions are designed to assess the component processes involved in completing the Number-Letter Switching condition so that a precise analysis of the nature of any underlying dysfunction may be accomplished. Specifically, these additional components include Visual Scanning, Number Sequencing, Letter Sequencing, and Motor Speed.

Given that the TMT comprises numbers and letters and is a measure of executive functioning, it may preferentially involve the left frontal lobe. Although the literature is somewhat controversial, neuropsychological and neuroimaging studies seem to provide support for the sensitivity of the TMT to detect left frontal dysfunction [56]. Recent clinically oriented studies investigating frontal lobe involvement of the TMT using transcranial magnetic stimulation (TMS) and near-infrared spectroscopy (NIRS) also support this localization [57]. Performance on Part B of the TMT improved following repetitive TMS applied to the left dorsolateral frontal lobe [57].

With 9–13-year-old boys performing TMT Part B, Weber et al. [58] found a left lateralized increase in the prefrontal cortex in deoxygenated hemoglobin, an indicator of increased oxygen consumption. Moll et al. [59] demonstrated increased activation specific to the prefrontal cortex, especially the left prefrontal region, in healthy controls performing Part B of the TMT. Foster et al. [60] found a significant positive correlation between performance on Part A of the TMT and low beta (13–21 Hz) magnitude (μV) at the left lateral frontal lobe, but not at the right lateral frontal lobe. Finally, Stuss et al. [13, 14] found that patients with left dorsolateral frontal dysfunction evidenced more errors than patients with lesions in other areas of the frontal lobes and those patients with left frontal lesions were the slowest to complete the test.

Taken together, the possibility exists that the aforementioned tests are largely associated with left frontal lobe activity and the TMT, in particular, provides information concerning mental processing speed as well as cognitive flexibility and set-shifting. While some studies have found that deficits in visuomotor set-shifting are specific to the frontal lobe damage [61], others investigators have reported such impairment in patients with posterior brain lesions and widespread cerebral dysfunctions, including cerebellar damage [62] and Alzheimer disease [63]. Thus, it remains unclear whether impairments in visuomotor set-shifting are specific to frontal lobe dysfunction or whether they are non-specific and can result from more posterior or widespread brain dysfunction.

Compared to the collective knowledge we have regarding the cognitive roles of the left frontal lobe, relatively little is known about right frontal lobe contributions to executive functioning. This is likely a result of the dearth of tests that are associated with right frontal activity. The Ruff Figural Fluency Test (RFFT; [64]) is among the few standardized tests of right frontal lobe functioning and was listed as the 14th most commonly used instrument to assess executive functioning in the Rabin et al. [1] survey. The RFFT is known to be sensitive to right frontal lobe functioning [65, 66]; see also [67] pp. 297–298), as is a measure based on the RFFT [19].

The present investigation, with the same intent and spirit as that reported by Delis et al. [54], sought to develop and initially validate a measure of right frontal lobe functioning in an effort to attain a greater understanding of right frontal contributions to executive functioning and to advance the instrumentation of neuropsychology. To meet this objective, a version of the Trail Making Test comprising figures, as opposed to numbers and letters, was developed. The TMT was used as a model for the new test, referred to as the Figure Trail Making Test (FTMT), due to the high frequency of use, the volume of research conducted, and the ease of administration of the TMT. Given that the TMT and the FTMT are both measuring executive functioning, we felt that a moderate correlation would exist between these two measures. Specifically, we hypothesized that performance on the FTMT would be positively correlated with performance on the TMT, in terms of the total time required to complete each part of the tests, an additive and subtractive score, and a ratio score. The total time required to complete each part of the FTMT was also hypothesized to be negatively correlated with the total number of unique designs produced on the RFFT and positively correlated with the number of perseverative errors committed on the RFFT and the perseverative error ratio. We also sought to determine whether the TMT and the FTMT were measuring different constructs by conducting a factor analysis, anticipating that the two tests would load on separate factors.

Additionally, we sought to obtain neurophysiological evidence that the FTMT is sensitive to right frontal lobe functioning. Specifically, we used quantitative electroencephalography (QEEG) to measure electrical activity over the left and right frontal lobes. A previous investigation we conducted found that performance on Part A of the TMT was related to left frontal lobe (F7) low beta magnitude [60]. For the present investigation, we predicted that significant negative correlations would exist between performance on Parts A and B of the TMT and both low and high beta magnitude at the F7 electrode site. We further predicted that significant negative correlations would exist between performance on Parts C and D of the FTMT and both low and high beta magnitude at the F8 electrode site.

3 Discussion

The need for additional measures of executive functions and especially instruments which may provide implications relevant to cerebral laterality is clear. There remains especially a void for neuropsychological instruments using a TMT format, which may provide information pertaining to the functional integrity of the right frontal region. Consistent with the hypotheses forwarded, significant correlations were found between performance on the TMT and the FTMT, in terms of the raw time required to complete each respective part of the tests as well as the additive and subtraction scores. The fact that the ratio scores were not significantly correlated is not surprising given that research has generally indicated a lack of clinical utility for this score [13, 14, 35]. Given the present findings, the TMT and the FTMT appear to be equivalent measures of executive functioning. Further, the present findings not only suggest that the FTMT may be a measure of executive functioning but also extend the realm of executive functioning to the sequencing and set-shifting of nonverbal stimuli.

However, the finding of significant correlations between the TMT and the FTMT represents somewhat of a caveat in that the TMT has been found to be sensitive to left frontal lobe functioning [13, 14, 57, 59]. This would seem to suggest the possibility that the FTMT is also sensitive to left frontal lobe functioning. The possibility that FTMT is related to left frontal lobe functioning is tempered, though, by the fact that the many of the hypothesized correlations between performance on the RFFT and the FTMT were also significant. Performance on the RFFT is related to right frontal lobe functioning [65,66]. Thus, the significant correlations between the RFFT and the FTMT suggest that the FTMT may also be sensitive to right frontal lobe functioning. Additionally, it should also be noted that the TMT was not significantly correlated with performance on the RFFT, with the exception of the significant correlation between performance on the TMT Part A and the total number of unique designs produced on the RFFT. Taken together, the results suggest that the FTMT may be a measure of right frontal executive functioning.

Additional support for the sensitivity of the FTMT to right frontal lobe functioning is provided by the finding of a significant negative correlation between performance on Part D of the FTMT and high beta magnitude. We have previously used QEEG to provide neurophysiological validation of the RFFT [65] and the Rey Auditory Verbal Learning Test [70] and the present findings provide further support for the use of QEEG in validating neuropsychological tests. The lack of significant correlations between the TMT and either low or high beta magnitude may be related to a restricted range of scores on the TMT. As a whole, performance on the FTMT was more variable than performance on the TMT and this relatively restricted range for the TMT may have impacted the obtained correlations. Given the present findings, together with those of the Foster et al. [65, 70] investigations, further support is also provided for the use of EEG in establishing neurophysiological validation for neuropsychological tests.

The results from the factor analysis provide support for the contention that the FMT may be a measure of right frontal lobe activity and also provide initial discriminant validity for the FTMT. Specifically, Parts C and D of the FTMT were found to load on the same factor as the number of designs generated on the RFFT, although the time required to complete Part A of the TMT is also included. Additionally, the number of errors committed on Parts C and D of the FTMT comprises a single factor, separate from either the TMT or the RFFT. Although these results support the FTMT as a measure of nonverbal executive functioning, it would be helpful to conduct an additional factor analysis including additional measures of right frontal functioning, and perhaps other measures of right hemisphere functioning as marker variables.

We sought to develop a measure sensitive to right frontal lobe functioning due to the paucity of such tests and the potentially important uses that right frontal lobe tests may have clinically. Tests of right frontal lobe functioning may, for instance, be useful in identifying and distinguishing left versus right frontotemporal dementia (FTD). Research has indicated that FTD is associated with cerebral atrophy at the right dorsolateral frontal and left premotor cortices [71]. Fukui and Kertesz [72] found right frontal lobe volume reduction in FTD relative to Alzheimer’s disease and progressive nonfluent aphasia. Some have suggested that FTD should not be considered as a unitary disorder and that neuropsychological testing may aid in differentially diagnosing left versus right FTD [73].

Whereas right FTD has been associated with more errors and perseverative responses on the Wisconsin Card Sorting Test (WCST), left FTD has been associated with significantly worse performance on the Boston Naming Test (BNT) and the Stroop Color-Word test [73]. Razani et al. [74] also distinguished between left and right FTD in finding that left FTD performed worse on the BNT and the right FTD patients performed worse on the WCST. However, as noted earlier, the WCST has been associated with left frontal activity [9], right frontal activation [8], and bilateral frontal activation [7]. Further, patients with left frontal tumors perform worse than those with right frontal tumors [11].

Patients with FTD that predominantly involves the right frontotemporal region have behavioral and emotional abnormalities and those with predominantly left frontotemporal region damage have a loss of lexical semantic knowledge. Patients, in whom neural degeneration begins on the left side, often present to the clinicians at an early stage of the disease due to the presence of language abnormalities, but maintain their emotion processing abilities, being preserved the right anterior temporal lobe. However, as this disease advances, the disease may progress to the right frontotemporal regions. Tests sensitive to right frontal lobe functioning may be useful tools to identify in advance the course of the disease, providing immediate and specific treatments and informing the caregivers on the possible prospective frame of the disease.

A potentially more important use of tests sensitive to right frontal lobe functioning, though, may be in predicting dementia patients that will develop significant and disruptive behavioral deficits. Research has found that approximately 92 % of right-sided FTD patients exhibit socially undesirable behaviors as their initial symptom, as compared to only 11 % of left-sided FTD patients [75]. Behavioral deficits in FTD are associated with gray matter loss at the dorsomedial frontal region, particularly on the right [76].

Alzheimer’s disease (AD) is also often associated with significant behavioral disturbances. Even AD patients with mild dementia are noted to exhibit behavioral deficits such as delusions, hallucinations, agitation, dysphoria, anxiety, apathy, and irritability [77]. Indeed, Shimabukuro et al. [77] found that regardless of dementia severity, over half of all AD patients exhibited apathy, delusions, irritability, dysphoria, and anxiety. Delusions in AD patients are associated with relative right frontal hypoperfusion as indicated by SPECT imaging [78, 79]. Further, positron emission tomography (PET) has indicated that AD patients exhibiting delusions exhibit hypometabolism at the right superior dorsolateral frontal and right inferior frontal pole [80].

Although research clearly implicates right frontal lobe dysfunction in the expression of behavioral deficits, data from neuropsychological testing are not as clear. Negative symptoms in patients with AD and FTD have been related to measures of nonverbal and verbal executive functioning as well as verbal memory [81]. Positive symptoms, in contrast, were related to constructional skills and attention. However, Staff et al. [78] failed to dissociate patients with delusions from those without delusions based on neuropsychological test performance, despite significant differences existing in right frontal and limbic functioning as revealed by functional imaging. The inclusion of other measures of right frontal lobe functioning may result in improved neuropsychological differentiation of dementia patients with and without significant behavioral disturbances. Further, it may be possible to predict early in the disease process those patients that will ultimately develop behavioral disturbances with improved measures of right frontal functioning. Predicting those that may develop behavioral problems will permit earlier treatment and will provide the family with more time to prepare for the potential emergence of such difficulties. Certainly, future research needs to be conducted that incorporates measures of right and left frontal lobe functioning in regression analyses to determine the plausibility of such prediction.

Tests sensitive to right frontal lobe functioning may also be useful in identifying more subtle right frontal lobe dysfunction and the cognitive and behavioral changes that follow. The right frontal lobe mediates language melody or prosody and forms a cohesive discourse, interprets abstract communication in spoken and written languages, and interprets the inferred relationships involved in communications. Subtle difficulties in interpreting abstract meaning in communication, comprehending metaphors, and even understanding jokes that are often seen in right frontal lobe stroke patients may not be detected by the family and may also be under diagnosed by clinicians [82]. Further, patients with right frontal lobe lesions are generally more euphoric and unconcerned, often minimizing their symptoms [82] or denying the illness, which may delay referral to a clinician and diagnosis.

Attention deficit hyperactivity disorder (ADHD) is a neurological disease characterized by motor inhibition deficit, problems with cognitive flexibility, social disruption, and emotional disinhibition [83, 84]. Functional MRI studies reveal reduced right prefrontal activation during “frontal tasks,” such as go/no go [85], Stroop [86], and attention task performance [87]. The right frontal lobe deficit hypothesis is further supported by structural studies [88, 89]. Tests of right frontal lobe functioning may be useful in further characterizing the nature of this deficit and in specifying the likely hemispheric locus of dysfunction.

To summarize, we feel that right frontal lobe functioning has been relatively neglected in neuropsychological assessment and that many uses for such tests exist. Our intent was to develop a test purportedly sensitive to right frontal functioning that would be easy and quick to administer in a clinical setting. However, we are certainly not meaning to assert that our FTMT would be applicable in all the aforementioned conditions. Additional research should be conducted to determine the precise clinical utility of the FTMT.

Further validation of the FTMT should also be undertaken. Establishing convergent validation may involve correlating tests measuring the same domain, such as executive functioning. This was initially accomplished in the present investigation through the significant correlations between the TMT and the FTMT. Additionally, convergent validation may also involve correlating tests that purportedly measure the same region of the brain. This was also initially accomplished in the present investigation through the significant correlations between the FTMT and the RFFT. However, additional convergent validation certainly needs to be obtained, as well as validation using patient populations and neurophysiological validation.

We are currently collecting data that hopefully will provide neurophysiological validation of the FTMT. Certainly, though, it is hoped that the present investigation will not only stimulate further research seeking to validate the FTMT and provide more comprehensive normative data, but also stimulate research investigating whether the FTMT or other measures of right frontal lobe functioning may be used to predict patients that will develop behavioral disturbances.

 

World’s Greatest Literature Reveals Multifractals, Cascades of Consciousness

http://www.scientificcomputing.com/news/2016/01/worlds-greatest-literature-reveals-multifractals-cascades-consciousness

http://www.scientificcomputing.com/sites/scientificcomputing.com/files/Worlds_Greatest_Literature_Reveals_Multifractals_Cascades_of_Consciousness_440.jpg

Multifractal analysis of Finnegan’s Wake by James Joyce. The ideal shape of the graph is virtually indistinguishable from the results for purely mathematical multifractals. The horizontal axis represents the degree of singularity, and the vertical axis shows the spectrum of singularity. Courtesy of IFJ PAN

Arthur Conan Doyle, Charles Dickens, James Joyce, William Shakespeare and JRR Tolkien. Regardless of the language they were working in, some of the world’s greatest writers appear to be, in some respects, constructing fractals. Statistical analysis, however, revealed something even more intriguing. The composition of works from within a particular genre was characterized by the exceptional dynamics of a cascading (avalanche) narrative structure. This type of narrative turns out to be multifractal. That is, fractals of fractals are created.

As far as many bookworms are concerned, advanced equations and graphs are the last things which would hold their interest, but there’s no escape from the math. Physicists from the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ) in Cracow, Poland, performed a detailed statistical analysis of more than one hundred famous works of world literature, written in several languages and representing various literary genres. The books, tested for revealing correlations in variations of sentence length, proved to be governed by the dynamics of a cascade. This means that the construction of these books is, in fact, a fractal. In the case of several works, their mathematical complexity proved to be exceptional, comparable to the structure of complex mathematical objects considered to be multifractal. Interestingly, in the analyzed pool of all the works, one genre turned out to be exceptionally multifractal in nature.

Fractals are self-similar mathematical objects: when we begin to expand one fragment or another, what eventually emerges is a structure that resembles the original object. Typical fractals, especially those widely known as the Sierpinski triangle and the Mandelbrot set, are monofractals, meaning that the pace of enlargement in any place of a fractal is the same, linear: if they at some point were rescaled x number of times to reveal a structure similar to the original, the same increase in another place would also reveal a similar structure.

Multifractals are more highly advanced mathematical structures: fractals of fractals. They arise from fractals ‘interwoven’ with each other in an appropriate manner and in appropriate proportions. Multifractals are not simply the sum of fractals and cannot be divided to return back to their original components, because the way they weave is fractal in nature. The result is that, in order to see a structure similar to the original, different portions of a multifractal need to expand at different rates. A multifractal is, therefore, non-linear in nature.

“Analyses on multiple scales, carried out using fractals, allow us to neatly grasp information on correlations among data at various levels of complexity of tested systems. As a result, they point to the hierarchical organization of phenomena and structures found in nature. So, we can expect natural language, which represents a major evolutionary leap of the natural world, to show such correlations as well. Their existence in literary works, however, had not yet been convincingly documented. Meanwhile, it turned out that, when you look at these works from the proper perspective, these correlations appear to be not only common, but in some works they take on a particularly sophisticated mathematical complexity,” says Professor Stanislaw Drozdz, IFJ PAN, Cracow University of Technology.

The study involved 113 literary works written in English, French, German, Italian, Polish, Russian and Spanish by such famous figures as Honore de Balzac, Arthur Conan Doyle, Julio Cortazar, Charles Dickens, Fyodor Dostoevsky, Alexandre Dumas, Umberto Eco, George Elliot, Victor Hugo, James Joyce, Thomas Mann, Marcel Proust, Wladyslaw Reymont, William Shakespeare, Henryk Sienkiewicz, JRR Tolkien, Leo Tolstoy and Virginia Woolf, among others. The selected works were no less than 5,000 sentences long, in order to ensure statistical reliability.

To convert the texts to numerical sequences, sentence length was measured by the number of words (an alternative method of counting characters in the sentence turned out to have no major impact on the conclusions). The dependences were then searched for in the data — beginning with the simplest, i.e. linear. This is the posited question: if a sentence of a given length is x times longer than the sentences of different lengths, is the same aspect ratio preserved when looking at sentences respectively longer or shorter?

“All of the examined works showed self-similarity in terms of organization of the lengths of sentences. Some were more expressive — here The Ambassadors by Henry James stood out — while others to far less of an extreme, as in the case of the French seventeenth-century romance Artamene ou le Grand Cyrus. However, correlations were evident and, therefore, these texts were the construction of a fractal,” comments Dr. Pawel Oswiecimka (IFJ PAN), who also noted that fractality of a literary text will, in practice, never be as perfect as in the world of mathematics. It is possible to magnify mathematical fractals up to infinity, while the number of sentences in each book is finite and, at a certain stage of scaling, there will always be a cut-off in the form of the end of the dataset.

Things took a particularly interesting turn when physicists from IFJ PAN began tracking non-linear dependence, which in most of the studied works was present to a slight or moderate degree. However, more than a dozen works revealed a very clear multifractal structure, and almost all of these proved to be representative of one genre, that of stream of consciousness. The only exception was the Bible, specifically the Old Testament, which has, so far, never been associated with this literary genre.

“The absolute record in terms of multifractality turned out to be Finnegan’s Wakeby James Joyce. The results of our analysis of this text are virtually indistinguishable from ideal, purely mathematical multifractals,” says Drozdz.

The most multifractal works also included A Heartbreaking Work of Staggering Genius by Dave Eggers, Rayuela by Julio Cortazar, The US Trilogy by John Dos Passos, The Waves by Virginia Woolf, 2666 by Roberto Bolano, and Joyce’sUlysses. At the same time, a lot of works usually regarded as stream of consciousness turned out to show little correlation to multifractality, as it was hardly noticeable in books such as Atlas Shrugged by Ayn Rand and A la recherche du temps perdu by Marcel Proust.

“It is not entirely clear whether stream of consciousness writing actually reveals the deeper qualities of our consciousness, or rather the imagination of the writers. It is hardly surprising that ascribing a work to a particular genre is, for whatever reason, sometimes subjective. We see, moreover, the possibility of an interesting application of our methodology: it may someday help in a more objective assignment of books to one genre or another,” notes Drozdz.

Multifractal analyses of literary texts carried out by the IFJ PAN have been published in Information Sciences, the journal of computer science. The publication has undergone rigorous verification: given the interdisciplinary nature of the subject, editors immediately appointed up to six reviewers.

Citation: “Quantifying origin and character of long-range correlations in narrative texts” S. Drożdż, P. Oświęcimka, A. Kulig, J. Kwapień, K. Bazarnik, I. Grabska-Gradzińska, J. Rybicki, M. Stanuszek; Information Sciences, vol. 331, 32–44, 20 February 2016; DOI: 10.1016/j.ins.2015.10.023

 

New Quantum Approach to Big Data could make Impossibly Complex Problems Solvable

David L. Chandler, MIT

http://www.scientificcomputing.com/news/2016/01/new-quantum-approach-big-data-could-make-impossibly-complex-problems-solvable

 

http://www.scientificcomputing.com/sites/scientificcomputing.com/files/New_Quantum_Approach_to_Big_Data_could_make_Impossibly_Complex_Problems_Solvable_440.jpg

This diagram demonstrates the simplified results that can be obtained by using quantum analysis on enormous, complex sets of data. Shown here are the connections between different regions of the brain in a control subject (left) and a subject under the influence of the psychedelic compound psilocybin (right). This demonstrates a dramatic increase in connectivity, which explains some of the drug’s effects (such as “hearing” colors or “seeing” smells). Such an analysis, involving billions of brain cells, would be too complex for conventional techniques, but could be handled easily by the new quantum approach, the researchers say. Courtesy of the researchers

From gene mapping to space exploration, humanity continues to generate ever-larger sets of data — far more information than people can actually process, manage or understand.

Machine learning systems can help researchers deal with this ever-growing flood of information. Some of the most powerful of these analytical tools are based on a strange branch of geometry called topology, which deals with properties that stay the same even when something is bent and stretched every which way.

Such topological systems are especially useful for analyzing the connections in complex networks, such as the internal wiring of the brain, the U.S. power grid, or the global interconnections of the Internet. But even with the most powerful modern supercomputers, such problems remain daunting and impractical to solve. Now, a new approach that would use quantum computers to streamline these problems has been developed by researchers at MIT, the University of Waterloo, and the University of Southern California.

The team describes their theoretical proposal this week in the journal Nature Communications. Seth Lloyd, the paper’s lead author and the Nam P. Suh Professor of Mechanical Engineering, explains that algebraic topology is key to the new method. This approach, he says, helps to reduce the impact of the inevitable distortions that arise every time someone collects data about the real world.

In a topological description, basic features of the data (How many holes does it have? How are the different parts connected?) are considered the same no matter how much they are stretched, compressed, or distorted. Lloyd explains that it is often these fundamental topological attributes “that are important in trying to reconstruct the underlying patterns in the real world that the data are supposed to represent.”

It doesn’t matter what kind of dataset is being analyzed, he says. The topological approach to looking for connections and holes “works whether it’s an actual physical hole, or the data represents a logical argument and there’s a hole in the argument. This will find both kinds of holes.”

Using conventional computers, that approach is too demanding for all but the simplest situations. Topological analysis “represents a crucial way of getting at the significant features of the data, but it’s computationally very expensive,” Lloyd says. “This is where quantum mechanics kicks in.” The new quantum-based approach, he says, could exponentially speed up such calculations.

Lloyd offers an example to illustrate that potential speedup: If you have a dataset with 300 points, a conventional approach to analyzing all the topological features in that system would require “a computer the size of the universe,” he says. That is, it would take 2300 (two to the 300th power) processing units — approximately the number of all the particles in the universe. In other words, the problem is simply not solvable in that way.

“That’s where our algorithm kicks in,” he says. Solving the same problem with the new system, using a quantum computer, would require just 300 quantum bits — and a device this size may be achieved in the next few years, according to Lloyd.

“Our algorithm shows that you don’t need a big quantum computer to kick some serious topological butt,” he says.

There are many important kinds of huge datasets where the quantum-topological approach could be useful, Lloyd says, for example understanding interconnections in the brain. “By applying topological analysis to datasets gleaned by electroencephalography or functional MRI, you can reveal the complex connectivity and topology of the sequences of firing neurons that underlie our thought processes,” he says.

The same approach could be used for analyzing many other kinds of information. “You could apply it to the world’s economy, or to social networks, or almost any system that involves long-range transport of goods or information,” Lloyd says. But the limits of classical computation have prevented such approaches from being applied before.

While this work is theoretical, “experimentalists have already contacted us about trying prototypes,” he says. “You could find the topology of simple structures on a very simple quantum computer. People are trying proof-of-concept experiments.”

Ignacio Cirac, a professor at the Max Planck Institute of Quantum Optics in Munich, Germany, who was not involved in this research, calls it “a very original idea, and I think that it has a great potential.” He adds “I guess that it has to be further developed and adapted to particular problems. In any case, I think that this is top-quality research.”

The team also included Silvano Garnerone of the University of Waterloo in Ontario, Canada, and Paolo Zanardi of the Center for Quantum Information Science and Technology at the University of Southern California. The work was supported by the Army Research Office, Air Force Office of Scientific Research, Defense Advanced Research Projects Agency, Multidisciplinary University Research Initiative of the Office of Naval Research, and the National Science Foundation.

 

Beyond Chess: Computer Beats Human in Ancient Chinese Game

http://www.rdmag.com/news/2016/01/beyond-chess-computer-beats-human-ancient-chinese-game

http://www.rdmag.com/sites/rdmag.com/files/rd1601_chess.jpg

A player places a black stone while his opponent waits to place a white one as they play Go, a game of strategy, in the Seattle Go Center, Tuesday, April 30, 2002. The game, which originated in China more than 2,500 years ago, involves two players who take turns putting markers on a grid. The object is to surround more area on the board with the markers than one’s opponent, as well as capturing the opponent’s pieces by surrounding them. A paper released Wednesday, Jan. 27, 2016 describes how a computer program has beaten a human master at the complex board game, marking significant advance for development of artificial intelligence. (AP Photo/Cheryl Hatch)

 

A computer program has beaten a human champion at the ancient Chinese board game Go, marking a significant advance for development of artificial intelligence.

The program had taught itself how to win, and its developers say its learning strategy may someday let computers help solve real-world problems like making medical diagnoses and pursuing scientific research.

The program and its victory are described in a paper released Wednesday by the journal Nature.

Computers previously have surpassed humans for other games, including chess, checkers and backgammon. But among classic games, Go has long been viewed as the most challenging for artificial intelligence to master.

Go, which originated in China more than 2,500 years ago, involves two players who take turns putting markers on a checkerboard-like grid. The object is to surround more area on the board with the markers than one’s opponent, as well as capturing the opponent’s pieces by surrounding them.

While the rules are simple, playing it well is not. It’s “probably the most complex game ever devised by humans,” Dennis Hassabis of Google DeepMind in London, one of the study authors, told reporters Tuesday.

The new program, AlphaGo, defeated the European champion in all five games of a match in October, the Nature paper reports.

In March, AlphaGo will face legendary player Lee Sedol in Seoul, South Korea, for a $1 million prize, Hassabis said.

Martin Mueller, a computing science professor at the University of Alberta in Canada who has worked on Go programs for 30 years but didn’t participate in AlphaGo, said the new program “is really a big step up from everything else we’ve seen…. It’s a very, very impressive piece of work.”

 

 

Biological Origin of Schizophrenia

Excessive ‘pruning’ of connections between neurons in brain predisposes to disease

http://hms.harvard.edu/sites/default/files/uploads/news/McCarroll_C4_600x400.jpg

Imaging studies showed C4 (in green) located at the synapses of primary human neurons. Image: Heather de Rivera, McCarroll lab

 PAUL GOLDSMITH    http://hms.harvard.edu/news/biological-origin-schizophrenia

The risk of schizophrenia increases if a person inherits specific variants in a gene related to “synaptic pruning”—the elimination of connections between neurons—according to a study from Harvard Medical School, the Broad Institute and Boston Children’s Hospital. The findings were based on genetic analysis of nearly 65,000 people.

The study represents the first time that the origin of this psychiatric disease has been causally linked to specific gene variants and a biological process.

Get more HMS news here

It also helps explain two decades-old observations: synaptic pruning is particularly active during adolescence, which is the typical period of onset for symptoms of schizophrenia, and the brains of schizophrenic patients tend to show fewer connections between neurons.

The gene, complement component 4 (C4), plays a well-known role in the immune system. It has now been shown to also play a key role in brain development and schizophrenia risk. The insight may allow future therapeutic strategies to be directed at the disorder’s roots, rather than just its symptoms.

The study, which appears online Jan. 27 in Nature, was led by HMS researchers at the Broad Institute’s Stanley Center for Psychiatric Research and Boston Children’s. They include senior author Steven McCarroll, HMS associate professor of genetics and director of genetics for the Stanley Center; Beth Stevens, HMS assistant professor of neurology at Boston Children’s and institute member at the Broad; Michael Carroll, HMS professor of pediatrics at Boston Children’s; and first author Aswin Sekar, an MD-PhD student at HMS.

The study has the potential to reinvigorate translational research on a debilitating disease. Schizophrenia afflicts approximately 1 percent people worldwide and is characterized by hallucinations, emotional withdrawal and a decline in cognitive function. These symptoms most frequently begin in patients when they are teenagers or young adults.

“These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”

First described more than 130 years ago, schizophrenia lacks highly effective treatments and has seen few biological or medical breakthroughs over the past half-century.

In the summer of 2014, an international consortium led by researchers at the Stanley Center identified more than 100 regions in the human genome that carry risk factors for schizophrenia.

The newly published study now reports the discovery of the specific gene underlying the strongest of these risk factors and links it to a specific biological process in the brain.

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” said McCarroll. “The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside and starting to see actual biological mechanisms.”

“This study marks a crucial turning point in the fight against mental illness,” said Bruce Cuthbert, acting director of the National Institute of Mental Health. “Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between. This study changes the game. Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments and even prevention.”

The path to discovery

The discovery involved the collection of DNA from more than 100,000 people, detailed analysis of complex genetic variation in more than 65,000 human genomes, development of an innovative analytical strategy, examination of postmortem brain samples from hundreds of people and the use of animal models to show that a protein from the immune system also plays a previously unsuspected role in the brain.

Over the past five years, Stanley Center geneticists and collaborators around the world collected more than 100,000 human DNA samples from 30 different countries to locate regions of the human genome harboring genetic variants that increase the risk of schizophrenia. The strongest signal by far was on chromosome 6, in a region of DNA long associated with infectious disease. This caused some observers to suggest that schizophrenia might be triggered by an infectious agent. But researchers had no idea which of the hundreds of genes in the region was actually responsible or how it acted.

Based on analyses of the genetic data, McCarroll and Sekar focused on a region containing the C4 gene. Unlike most genes, C4 has a high degree of structural variability. Different people have different numbers of copies and different types of the gene.

McCarroll and Sekar developed a new molecular technique to characterize the C4 gene structure in human DNA samples. They also measured C4 gene activity in nearly 700 post-mortem brain samples.

They found that the C4 gene structure (DNA) could predict the C4 gene activity (RNA) in each person’s brain. They then used this information to infer C4 gene activity from genome data from 65,000 people with and without schizophrenia.

These data revealed a striking correlation. People who had particular structural forms of the C4 gene showed higher expression of that gene and, in turn, had a higher risk of developing schizophrenia.

Connecting cause and effect through neuroscience

But how exactly does C4—a protein known to mark infectious microbes for destruction by immune cells—affect the risk of schizophrenia?

Answering this question required synthesizing genetics and neurobiology.

Stevens, a recent recipient of a MacArthur Foundation “genius grant,” had found that other complement proteins in the immune system also played a role in brain development. These results came from studying an experimental model of synaptic pruning in the mouse visual system.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics.”

Carroll had long studied C4 for its role in immune disease, and developed mice with different numbers of copies of C4.

The three labs set out to study the role of C4 in the brain.

They found that C4 played a key role in pruning synapses during maturation of the brain. In particular, they found that C4 was necessary for another protein—a complement component called C3—to be deposited onto synapses as a signal that the synapses should be pruned. The data also suggested that the more C4 activity an animal had, the more synapses were eliminated in its brain at a key time in development.

The findings may help explain the longstanding mystery of why the brains of people with schizophrenia tend to have a thinner cerebral cortex (the brain’s outer layer, responsible for many aspects of cognition) with fewer synapses than do brains of unaffected individuals. The work may also help explain why the onset of schizophrenia symptoms tends to occur in late adolescence.

The human brain normally undergoes widespread synapse pruning during adolescence, especially in the cerebral cortex. Excessive synaptic pruning during adolescence and early adulthood, due to increased complement (C4) activity, could lead to the cognitive symptoms seen in schizophrenia.

“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” Stevens said.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics,” she said. “We’re far from having a treatment based on this, but it’s exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk.”

Opening a path toward early detection and potential therapies

Beyond providing the first insights into the biological origins of schizophrenia, the work raises the possibility that therapies might someday be developed that could turn down the level of synaptic pruning in people who show early symptoms of schizophrenia.

This would be a dramatically different approach from current medical therapies, which address only a specific symptom of schizophrenia—psychosis—rather than the disorder’s root causes, and which do not stop cognitive decline or other symptoms of the illness.

The researchers emphasize that therapies based on these findings are still years down the road. Still, the fact that much is already known about the role of complement proteins in the immune system means that researchers can tap into a wealth of existing knowledge to identify possible therapeutic approaches. For example, anticomplement drugs are already under development for treating other diseases.

“In this area of science, our dream has been to find disease mechanisms that lead to new kinds of treatments,” said McCarroll. “These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”

This work was supported by the Broad Institute’s Stanley Center for Psychiatric Research and by the National Institutes of Health (grants U01MH105641, R01MH077139 and T32GM007753).

Adapted from a Broad Institute news release.

 

Scientists open the ‘black box’ of schizophrenia with dramatic genetic discovery

Amy Ellis Nutt    https://www.washingtonpost.com/news/speaking-of-science/wp/2016/01/27/scientists-open-the-black-box-of-schizophrenia-with-dramatic-genetic-finding/

 

Scientists Prune Away Schizophrenia’s Hidden Genetic Mechanisms

http://www.genengnews.com/gen-news-highlights/scientists-prune-away-schizophrenia-s-hidden-genetic-mechanisms/81252297/

https://youtu.be/s0y4equOTLg

A landmark study has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in a gene related to “synaptic pruning”—the elimination of connections between neurons. The findings represent the first time that the origin of this devastating psychiatric disease has been causally linked to specific gene variants and a biological process.

http://www.genengnews.com/Media/images/GENHighlight/thumb_107629_web2209513618.jpg

The site in Chromosome 6 harboring the gene C4 towers far above other risk-associated areas on schizophrenia’s genomic “skyline,” marking its strongest known genetic influence. The new study is the first to explain how specific gene versions work biologically to confer schizophrenia risk. [Psychiatric Genomics Consortium]

  • A new study by researchers at the Broad Institute’s Stanley Center for Psychiatric Research, Harvard Medical School, and Boston Children’s Hospital genetically analyzed nearly 65,000 people and revealed that an individual’s risk of schizophrenia is increased if they inherited distinct variants in a gene related to “synaptic pruning”—the elimination of connections between neurons. This new data represents the first time that the origin of this psychiatric disease has been causally linked to particular gene variants and a biological process.

The investigators discovered that versions of a gene commonly thought to be involved in immune function might trigger a runaway pruning of an adolescent brain’s still-maturing communications infrastructure. The researchers described a scenario where patients with schizophrenia show fewer such connections between neurons or synapses.

“Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” explained Thomas Lehner, Ph.D., director of the Office of Genomics Research Coordination at the NIH’s National Institute of Mental Health (NIMH), which co-funded the study along with the Stanley Center for Psychiatric Research at the Broad Institute and other NIH components. “It could help explain schizophrenia’s delayed age-of-onset of symptoms in late adolescence and early adulthood and shrinkage of the brain’s working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”

The gene the research team called into question, dubbed C4 (complement component 4), was associated with the largest risk for the disorder. C4’s role represents some of the most compelling evidence, to date, linking specific gene versions to a biological process that could cause at least some cases of the illness.

The findings from this study were published recently in Nature through an article entitled “Schizophrenia risk from complex variation of complement component 4.”

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” noted senior study author Steven McCarroll, Ph.D., director of genetics for the Stanley Center and an associate professor of genetics at Harvard Medical School. “The human genome is providing a powerful new way into this disease. Understanding these genetic effects on risk is a way of prying open that block box, peering inside and starting to see actual biological mechanisms.”

Dr. McCarroll and his colleagues found that a stretch of chromosome 6 encompassing several genes known to be involved in immune function emerged as the strongest signal associated with schizophrenia risk in genome-wide analyses. Yet conventional genetics failed to turn up any specific gene versions there that were linked to schizophrenia.

In order to uncover how the immune-related site confers risk for the mental disorder, the scientists mounted a search for cryptic genetic influences that might generate unconventional signals. C4, a gene with known roles in immunity, emerged as a prime suspect because it is unusually variable across individuals.

Upon further investigation into the complexities of how such structural variation relates to the gene’s level of expression and how that, in turn, might link to schizophrenia, the team discovered structurally distinct versions that affect expression of two main forms of the gene within the brain. The more a version resulted in expression of one of the forms, called C4A, the more it was associated with schizophrenia. The greater number of copies an individual had of the suspect versions, the more C4 switched on and the higher their risk of developing schizophrenia. Furthermore, the C4 protein turned out to be most prevalent within the cellular machinery that supports connections between neurons.

“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” remarked co-author Beth Stevens, Ph.D. a neuroscientist and assistant professor of neurology at Boston Children’s Hospital and institute member at the Broad. “This discovery enriches our understanding of the complement system in brain development and disease, and we could not have made that leap without the genetics. We’re far from having a treatment based on this, but it’s exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk.”

“This study marks a crucial turning point in the fight against mental illness. It changes the game,” added acting NIMH director Bruce Cuthbert, Ph.D. “Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between. This study changes the game. Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments, and even prevention.”

 

Connecting cause and effect through neuroscience

But how exactly does C4—a protein known to mark infectious microbes for destruction by immune cells—affect the risk of schizophrenia?

Answering this question required synthesizing genetics and neurobiology.

Stevens, a recent recipient of a MacArthur Foundation “genius grant,” had found that other complement proteins in the immune system also played a role in brain development. These results came from studying an experimental model of synaptic pruning in the mouse visual system.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics.”

Carroll had long studied C4 for its role in immune disease, and developed mice with different numbers of copies of C4.

The three labs set out to study the role of C4 in the brain.

They found that C4 played a key role in pruning synapses during maturation of the brain. In particular, they found that C4 was necessary for another protein—a complement component called C3—to be deposited onto synapses as a signal that the synapses should be pruned. The data also suggested that the more C4 activity an animal had, the more synapses were eliminated in its brain at a key time in development.

The findings may help explain the longstanding mystery of why the brains of people with schizophrenia tend to have a thinner cerebral cortex (the brain’s outer layer, responsible for many aspects of cognition) with fewer synapses than do brains of unaffected individuals. The work may also help explain why the onset of schizophrenia symptoms tends to occur in late adolescence.

The human brain normally undergoes widespread synapse pruning during adolescence, especially in the cerebral cortex. Excessive synaptic pruning during adolescence and early adulthood, due to increased complement (C4) activity, could lead to the cognitive symptoms seen in schizophrenia.

“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” Stevens said.

“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics,” she said. “We’re far from having a treatment based on this, but it’s exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk.”

Opening a path toward early detection and potential therapies

Beyond providing the first insights into the biological origins of schizophrenia, the work raises the possibility that therapies might someday be developed that could turn down the level of synaptic pruning in people who show early symptoms of schizophrenia.

This would be a dramatically different approach from current medical therapies, which address only a specific symptom of schizophrenia—psychosis—rather than the disorder’s root causes, and which do not stop cognitive decline or other symptoms of the illness.

The researchers emphasize that therapies based on these findings are still years down the road. Still, the fact that much is already known about the role of complement proteins in the immune system means that researchers can tap into a wealth of existing knowledge to identify possible therapeutic approaches. For example, anticomplement drugs are already under development for treating other diseases.

“In this area of science, our dream has been to find disease mechanisms that lead to new kinds of treatments,” said McCarroll. “These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”

This work was supported by the Broad Institute’s Stanley Center for Psychiatric Research and by the National Institutes of Health (grants U01MH105641, R01MH077139 and T32GM007753).

Adapted from a Broad Institute news release.

 

 

https://img.washingtonpost.com/wp-apps/imrs.php?src=https://img.washingtonpost.com/rf/image_908w/2010-2019/WashingtonPost/2011/09/27/Production/Sunday/SunBiz/Images/mental2b.jpg&w=1484

This post has been updated.

For the first time, scientists have pinned down a molecular process in the brain that helps to trigger schizophrenia. The researchers involved in the landmark study, which was published Wednesday in the journal Nature, say the discovery of this new genetic pathway probably reveals what goes wrong neurologically in a young person diagnosed with the devastating disorder.

The study marks a watershed moment, with the potential for early detection and new treatments that were unthinkable just a year ago, according to Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute at MIT. Hyman, a former director of the National Institute of Mental Health, calls it “the most significant mechanistic study about schizophrenia ever.”

“I’m a crusty, old, curmudgeonly skeptic,” he said. “But I’m almost giddy about these findings.”

The researchers, chiefly from the Broad Institute, Harvard Medical School and Boston Children’s Hospital, found that a person’s risk of schizophrenia is dramatically increased if they inherit variants of a gene important to “synaptic pruning” — the healthy reduction during adolescence of brain cell connections that are no longer needed.

[Schizophrenic patients have different oral bacteria than non-mentally ill individuals]

In patients with schizophrenia, a variation in a single position in the DNA sequence marks too many synapses for removal and that pruning goes out of control. The result is an abnormal loss of gray matter.

The genes involved coat the neurons with “eat-me signals,” said study co-author Beth Stevens, a neuroscientist at Children’s Hospital and Broad. “They are tagging too many synapses. And they’re gobbled up.

The Institute’s founding director, Eric Lander, believes the research represents an astonishing breakthrough. “It’s taking what has been a black box…and letting us peek inside for the first time. And that is amazingly consequential,” he said.

The timeline for this discovery has been relatively fast. In July 2014, Broad researchers published the results of the largest genomic study on the disorder and found more than 100 genetic locations linked to schizophrenia. Based on that research, Harvard and Broad geneticist Steven McCarroll analyzed data from about 29,000 schizophrenia cases, 36,000 controls and 700 post mortem brains. The information was drawn from dozens of studies performed in 22 countries, all of which contribute to the worldwide database called the Psychiatric Genomics Consortium.

[Influential government-appointed panel recommends depression screening for everyone]

One area in particular, when graphed, showed the strongest association. It was dubbed the “Manhattan plot” for its resemblance to New York City’s towering buildings. The highest peak was on chromosome 6, where McCarroll’s team discovered the gene variant. C4 was “a dark corner of the human genome,” he said, an area difficult to decipher because of its “astonishing level” of diversity.

C4 and numerous other genes reside in a region of chromosome 6 involved in the immune system, which clears out pathogens and similar cellular debris from the brain. The study’s researchers found that one of C4’s variants, C4A, was most associated with a risk for schizophrenia.

More than 25 million people around the globe are affected by schizophrenia, according to the World Health Organization, including 2 million to 3 million Americans. Highly hereditable, it is one of the most severe mental illnesses, with an annual economic burden in this country of tens of billions of dollars.

“This paper is really exciting,” said Jacqueline Feldman, associate medical director of the National Alliance on Mental Illness. “We as scientists and physicians have to temper our enthusiasm because we’ve gone down this path before. But this is profoundly interesting.”

There have been hundreds of theories about schizophrenia over the years, but one of the enduring mysteries has been how three prominent findings related to each other: the apparent involvement of immune molecules, the disorder’s typical onset in late adolescence and early adulthood, and the thinning of gray matter seen in autopsies of patients.

[A low-tech way to help treat young schizophrenic patients]

“The thing about this result,” said McCarroll, the lead author, ” it makes a lot of other things understandable. To have a result to connect to these observations and to have a molecule and strong level of genetic evidence from tens of thousands of research participants, I think that combination sets [this study] apart.”

The authors stressed that their findings, which combine basic science with large-scale analysis of genetic studies, depended on an unusual level of cooperation among experts in genetics, molecular biology, developmental neurobiology and immunology.

“This could not have been done five years ago,” said Hyman. “This required the ability to reference a very large dataset . …When I was [NIMH] director, people really resisted collaborating. They were still in the Pharaoh era. They wanted to be buried with their data.”

The study offers a new approach to schizophrenia research, which has been largely stagnant for decades.  Most psychiatric drugs seek to interrupt psychotic thinking, but experts agree that psychosis is just a single symptom — and a late-occurring one at that. One of the chief difficulties for psychiatric researchers, setting them apart from most other medical investigators, is that they can’t cut schizophrenia out of the brain and look at it under a microscope. Nor are there any good animal models.

All that now has changed, according to Stevens. “We now have a strong molecular handle, a pathway and a gene, to develop better models,” he said.

Which isn’t to say a cure is right around the corner.

“This is the first exciting  clue, maybe even the most important we’ll ever have, but it will be decades” before a true cure is found,” Hyman said. “Hope is a wonderful thing. False promise is not.”

Insight Pharma Report

Three neurodegenerative disorders that are heavily focused on in this report include: Alzheimer’s Disease/Mild Cognitive Impairment, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. Part II of the report will include all three of these disorders, highlighting specifics including background, history, and development of the disease. Deeper into the chapters, the report will unfold biomarkers under investigation, genetic targets, and an analysis of multiple studies investigating these elements.

Experts interviewed in these chapters include:

  • Dr. Jens Wendland, Head of Neuroscience Genetics, Precision Medicine, Clinical Research, Pfizer Worldwide R&D
  • Dr. Howard J. Federoff, Executive Vice President for Health Sciences, Georgetown University
  • Dr. Andrew West, Associate Professor of Neurology and Neurobiology and Co-Director, Center for Neurodegeneration and Experimental Therapeutics
  • Dr. Merit Ester Cudkowicz, Chief of Neurology at Massachusetts General Hospital

Part III of the report makes a shift from neurobiomarkers to neurodiagnostics. This section highlights several diagnostics in play and in the making from a number of companies, identifying company strategies, research underway, hypotheses, and institution goals. Elite researchers and companies highlighted in this part include:

  • Dr. Xuemei Huang, Professor and Vice Chair, Department of Neurology; Professor of Neurosurgery, Radiology,  Pharmacology, and Kinesiology Director; Hershey Brain Analysis Research Laboratory for Neurodegenerative Disorders, Penn State University-Milton, S. Hershey Medical Center Department of Neurology
  • Dr. Andreas Jeromin, CSO and President of Atlantic Biomarkers
  • Julien Bradley, Senior Director, Sales & Marketing, Quanterix
  • Dr. Scott Marshall, Head of Bioanalytics, and Dr. Jared Kohler, Head of Biomarker Statistics, BioStat Solutions, Inc.

Further analysis appears in Part IV. This section includes a survey exclusively conducted for this report. With over 30 figures and graphics and an in depth analysis, this part features insight into targets under investigation, challenges, advantages, and desired features of future diagnostic applications. Furthermore, the survey covers more than just the featured neurodegenerative disorders in this report, expanding to Multiple Sclerosis and Huntington’s Disease.

Finally, Insight Pharma Reports concludes this report with clinical trial and pipeline data featuring targets and products from over 300 companies working in Alzheimer’s Disease, Parkinson’s Disease and Amyotrophic Lateral Sclerosis.

 

Epigenome Tapped to Understand Rise of Subtype of Brain Medulloblastoma

http://www.genengnews.com/gen-news-highlights/epigenome-tapped-to-understand-rise-of-subtype-of-brain-medulloblastoma/81252294/

Scientists have identified the cells that likely give rise to the brain tumor subtype Group 4 medulloblastoma. [V. Yakobchuk/ Fotolia]

http://www.genengnews.com/Media/images/GENHighlight/thumb_Jan_28_2016_Fotolia_6761569_ColorfulBrain_4412824411.jpg

An international team of scientists say they have identified the cells that likely give rise to the brain tumor subtype Group 4 medulloblastoma. The believe their study (“Active medulloblastoma enhancers reveal subgroup-specific cellular origins”), published in Nature, removes a barrier to developing more effective targeted therapies against the brain tumor’s most common subtype.

Medulloblastoma occurs in infants, children, and adults, but it is the most common malignant pediatric brain tumor. The disease includes four biologically and clinically distinct subtypes, of which Group 4 is the most common. In children, about half of medulloblastoma patients are of the Group 4 subtype. Efforts to improve patient outcomes, particularly for those with high-risk Group 4 medulloblastoma, have been hampered by the lack of accurate animal models.

Evidence from this study suggests Group 4 tumors begin in neural stem cells that are born in a region of the developing cerebellum called the upper rhomic lip (uRL), according to the researchers.

“Pinpointing the cell(s) of origin for Group 4 medulloblastoma will help us to better understand normal cerebellar development and dramatically improve our chances of developing genetically faithful preclinical mouse models. These models are desperately needed for learning more about Group 4 medulloblastoma biology and evaluating rational, molecularly targeted therapies to improve patient outcomes,” said Paul Northcott, Ph.D., an assistant member of the St. Jude department of developmental neurobiology. Dr. Northcott, Stefan Pfister, M.D., of the German Cancer Research Center (DKFZ), and James Bradner, M.D., of Dana-Farber Cancer Institute, are the corresponding authors.

The discovery and other findings about the missteps fueling tumor growth came from studying the epigenome. Researchers used the analytic tool ChiP-seq to identify and track medulloblastoma subtype differences based on the activity of epigenetic regulators, which included proteins known as master regulator transcription factors. They bind to DNA enhancers and super-enhancers. The master regulator transcription factors and super-enhancers work together to regulate the expression of critical genes, such as those responsible for cell identity.

Those and other tools helped investigators identify more than 3,000 super-enhancers in 28 medulloblastoma tumors as well as evidence that the activity of super-enhancers varied by subtype. The super-enhancers switched on known cancer genes, including genes like ALK, MYC, SMO, and OTX2 that are associated with medulloblastoma, the researchers reported.

Knowledge of the subtype super-enhancers led to identification of the transcription factors that regulate their activity. Using computational methods, researchers applied that information to reconstruct the transcription factor networks responsible for medulloblastoma subtype diversity and identity, providing previously unknown insights into the regulatory landscape and transcriptional output of the different medulloblastoma subtypes.

The approach helped to discover and nominate Lmx1A as a master regulator transcription factor of Group 4 tumors, which led to the identification of the likely Group 4 tumor cells of origin. Lmx1A was known to play an important role in normal development of cells in the uRL and cerebellum. Additional studies performed in mice with and without Lmx1A in this study supported uRL cells as the likely source of Group 4 tumors.

“By studying the epigenome, we also identified new pathways and molecular dependencies not apparent in previous gene expression and mutational studies,” explained Dr. Northcott. “The findings open new therapeutic avenues, particularly for the Group 3 and 4 subtypes where patient outcomes are inferior for the majority of affected children.”

For example, researchers identified increased enhancer activity targeting the TGFbeta pathway. The finding adds to evidence that the pathway may drive Group 3 medulloblastoma, currently the subtype with the worst prognosis. The pathway regulates cell growth, cell death, and other functions that are often disrupted in cancer, but it’s role in medulloblastoma is poorly understood.

The analysis included samples from 28 medulloblastoma tumors representing the four subtypes. Researchers believe it is the largest epigenetic study yet for any single cancer type and, importantly, the first to use a large cohort of primary patient tumor tissues instead of cell lines grown in the laboratory. Previous studies have suggested that cell lines may be of limited use for studying the tumor epigenome. The three Group 3 medulloblastoma cell lines used in this study reinforced the observation, highlighting significant differences in epigenetic regulators at work in medulloblastoma cell lines versus tumor samples.

 

 

Advertisements

Read Full Post »


Identical Twin Brother Develops Schizophrenia

Author: Larry H. Bernstein, MD, FCAP

 

 

 

My identical twin brother develops schizophrenia

I graduated college as a chemistry undergraduate prior to entrance into medical school in 1973, and my brother had not exhibited signs of serious mental distress until that point.  He was dating a young woman who rejected him, and he was also under pressure from our father, who thought he did not have direction. The oldest daughter was married and was well prepared in piano and in mathematics, and she has prepared students in piano to the present day. The triplet sister was married to a medical student who went on to become a psychiatrist. The two sons were still living at home.  There was considerable pressure on my brother to complete his studies.   The trigger seemed to be the breakup of his relationship. It was in the months prior to my graduation that my mother was deeply concerned and our parents pursued a psychiatric evaluation.   He was put on chlorpromazine, but then developed jaundice. Schizophrenia was not understood in those years, and for many years was an illness that brought shame to the parents.  I shared a bedroom with my brother for all the years prior to this event and I only saw it develop at the surface.

We both had worked as waiters at a resort on Lake Michigan for some years prior to my entrance to medical school, and Leslie had an interest in biology.  He was closer to our younger sister, and I was trying to keep up with Sharon, who was 2 years older and had an infant that I visited often.  I had a close friend who was my buddy.  I could talk to him often, and we compared notes after a double date.  Leslie had a friend who we had played chess with in high school.  My brother showed no progress and his psychiatric visits were costly. My father was a dental technician who was skilled at making dentures.

It was the summer prior to my entry into medical school that I worked in a biochemistry research laboratory under the supervision of my brother in law.  The first year medical studies were pressured with anatomy, biochemistry, inborn errors of metabolism, neuroanatomy and embryology, and dissection of cadavers.  Leslie was admitted to the Lafayette Clinic at Wayne State University. He was now receiving the best care available. I visited him at that time, and he played chess with the attendant.
It was also during the first year of medical school that the progressive Rabbi Adler, at Rodeph Shalom who had a national reputation was shot in front of the Bima by Richard Wishnetsky, a troubled man our age who was mentally ill, probably with a mood disorder. My good friend was home from Berkeley and tried to avoid the problem, but he was released by a law school student. Richard’s parents were leaders in the congregation.  My friend and I knew there was a problem early because Richard had received a Woodrow Wilson scholarship, and he considered graduate studies under a faculty member at the Catholic University in Detroit, but he did go to the University of Michigan.

At the end of the first year, the triplets went to Washington, DC to participate in an ongoing Schizophrenia twin study.  I was engaged in studies of radiation on virus in an NIH lab during the study. Three years later, when I was rotating through psychiatry at Herman Kiefer Hospital in my third year having taking time out for a Master of Science degree in Anatomy (the evolution of the proteins of the eye lens), I found myself in the Detroit riots.

 

My brother grew a beard and became somewhat disheveled. He had hallucinations, and he could tell about his dreams.  For instance, so and so visited him.  He began living in an apartment on Woodward Avenue, the largest street in Detroit. He became very spiritual, and he wrote poetry.  One day he stood in the middle of Woodward Avenue wearing a tallis (prayer shawl) and directed traffic.  He did manage to finish his undergraduate studies, but when he took a job teaching biology, he just couldn’t. He also knew that a Croatian girl who graduated high school with us, who was a talented dancer, developed schizophrenia.

My mother was very stressed. She was helping to care for my older sister’s daughter, and she was grieving over her son.  She developed abdominal pain in 1978, when I graduated and went to my residency in Pathology at University of Kansas Medical Center in Kansas City, in what was to be a residency and PhD program. I had joined the Berry Plan during my medical school years and when I graduated I was randomly selected to go into the Navy, but got a deferment to complete my studies.

It was during that time that I learned that my mother had had an exploratory laparotomy for what turned out to be an infiltrating carcinoma of the stomach, through the wall and on the peritoneal surface (linitis plastic).  No biopsy was taken.  I flew home frequently until the end.  She was on morphine to ease the pain.  I began seeing a woman I had known in high school, who was now teaching. We were married in December of 1979, after my mother died.  My mother’s father had always been well and was a mechanic in Cleveland. I was told that he died of a broken heart with the loss of my mother.

I went to University of California, San Diego in January, 1980, to work in Enzymology, the inhibition of the pyridine nucleotide linked malate dehydrogenase reaction, under Nathan O. Kaplan, and there I also completed my residency.  It happens at that time, my brother had moved to San Diego, and he was looked after our triplet sister.  It was a fortunate circumstance for the triplets.

 

 

 

 

Read Full Post »


Schizophrenic hallucinations

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Update 11/23/2015

Brain Fold Tied to Hallucinations

A shorter crease in the medial prefrontal cortex is linked with a higher risk of schizophrenics experiencing hallucinations.

By Kerry Grens | November 19, 2015

http://www.the-scientist.com//?articles.view/articleNo/44547/title/Brain-Fold-Tied-to-Hallucinations/

WIKIMEDIA, DATABASE CENTER FOR LIFE SCIENCE

People with schizophrenia who experience hallucinations are more likely to have a certain contour to their brain—specifically, a shorter groove in the medial prefrontal cortex called the paracingulate sulcus (PCS). That’s according to a study published this week (November 17) in Nature Communications of 153 people, some of whom had schizophrenia with and without hallucinations and some who did not.

“We think that the PCS is involved in brain networks that help us recognize information that has been generated ourselves,” Jane Garrison, the lead author of the study and a researcher at the University of Cambridge, said in a press release. “People with a shorter PCS seem less able to distinguish the origin of such information, and appear more likely to experience it as having been generated externally.”

Garrison and her colleagues used MRI scans to gather PCS length. They found that schizophrenics who experienced hallucinations tended to have a shorter PCS, and a 1-cm reduction in the fold related to a 20 percent higher chance of having hallucinations. People with schizophrenia who did not have hallucinations and the healthy controls did not differ in their PCS length.

“We’ve known for some time that disorders like schizophrenia are not down to a single region of the brain. Changes are seen throughout various different areas. To be able to pin such a key symptom to a relatively specific part of the brain is quite unusual,” study coauthor Jon Simons of Cambridge told BBC News.

The study could not determine whether PCS length is a causal factor in hallucinations in schizophrenia.

 

Paracingulate sulcus morphology is associated with hallucinations in the human brain

Jane R. GarrisonCharles FernyhoughSimon McCarthy-JonesMark HaggardThe Australian Schizophrenia Research Bank & Jon S. Simons

Nature Communications  2015; 6(8956).      http://dx.doi.org:/10.1038/ncomms9956

 

Hallucinations are common in psychiatric disorders, and are also experienced by many individuals who are not mentally ill. Here, in 153 participants, we investigate brain structural markers that predict the occurrence of hallucinations by comparing patients with schizophrenia who have experienced hallucinations against patients who have not, matched on a number of demographic and clinical variables. Using both newly validated visual classification techniques and automated, data-driven methods, hallucinations were associated with specific brain morphology differences in the paracingulate sulcus, a fold in the medial prefrontal cortex, with a 1cm reduction in sulcal length increasing the likelihood of hallucinations by 19.9%, regardless of the sensory modality in which they were experienced. The findings suggest a specific morphological basis for a pervasive feature of typical and atypical human experience.

 

PCS measurement for two example images.

Figure 1: PCS measurement for two example images.

The paracingulate sulcus (PCS), marked in red, lies dorsal and parallel to the cingulate sulcus (CS), itself dorsal to the corpus callosum. (a) In this image, the PCS is continuous and is measured from its origin in the first quadrant (indicated by the cross-hairs at y=0 and z=0) to its end. (b) In this example, the PCS appears less distinct; it is measured from the point at which it runs in a posterior direction, dorsal to the cingulate sulcus.

 

PCS length by group.

Figure 2: PCS length by group

(a) Total PCS length across both hemispheres. (b) PCS length in the left hemisphere. (c) PCS length in the right hemisphere. ***P<0.001, **P<0.01, *P<0.05. Error bars represent standard error of the mean. Controls: 40 healthy control subjects; no hallucinations: 34 patients with schizophrenia who had not experienced hallucinations; hallucinations: 79 patients with schizophrenia who experienced hallucinations in any modality.

 

Hallucinations are a primary symptom of numerous mental health disorders, as well as featuring in the experience of many individuals within the healthy population. Previous attempts to characterize the brain mechanisms of hallucinations have often been confounded by designs relying on comparisons between patients and non-patients1. However, around 30% of patients who meet diagnostic criteria for schizophrenia never report such anomalous experiences, providing the potential for the discovery of brain structural markers that are specifically associated with the occurrence of hallucinations.

Undoubtedly, many neurobiological factors underlie hallucinations. In the present study, we focused on the paracingulate sulcus (PCS) in the medial prefrontal cortex (mPFC) given its previously established role in reality monitoring2, among other cognitive functions, defined as the ability to discriminate between real and imagined information3. Reality monitoring is impaired in patients with schizophrenia with hallucinations4, 5, 6 and in non-patients prone to hallucinations7. In the study by Buda et al.2, we previously identified that bilateral absence of the PCS was associated with reductions in reality monitoring performance in healthy individuals with no neurological damage. The PCS is one of the last sulci to develop in utero, providing the potential for individual differences in its morphology, such as sulcal length, to be particularly informative about functional variation in an area of the brain extensively implicated in reality monitoring judgments8, 9.

Here, we investigate PCS length in both hemispheres in three matched groups: schizophrenia patients with a history of hallucinations, schizophrenia patients with no history of hallucinations and healthy controls (see Table 1 for participant details). PCS length was measured from structural MRI scans using a newly validated visual classification technique and data-driven whole-brain analysis methods, carried out blind to diagnosis (see Methods section for details). Examples of long and short PCS images are displayed in Fig. 1. We report converging results from across methods indicating that hallucination status can be determined by specific brain morphology differences in the PCS.

Validation of PCS measurement protocol

To validate the new PCS measurement protocol, it was first applied to 53 healthy volunteer structural scans previously analysed by Buda et al.2, with the analysis undertaken blind to the ratings in the earlier study, to give 106 measurements of sulcal length across hemispheres. The left and right hemisphere PCS for each individual was classified as ‘prominent’ if the length was >40mm, ‘absent’ if PCS length was <20mm and ‘present’ if PCS length fell between these two limits, based on the earlier protocols2, 10. The PCS classifications obtained were then compared with the original ratings from the study by Buda et al.2 In all, 94 out of the 106 measurements matched precisely, resulting in a Cohen’s Kappa of 0.79 (P<0.001), 95% CI (0.68, 0.84), indicating ‘substantial agreement’11 between the two protocols.

To validate the measurement protocol further, and verify its sensitivity to morphological variations in schizophrenia, we measured PCS length in a small, locally acquired independent sample of 19 patients with schizophrenia, all of whom experienced hallucinations, as well as in 19 matched control participants. Informed consent was obtained from these participants in a manner approved by the UK National Research Ethics Service. Total PCS length was significantly reduced in the patients with schizophrenia (mean=84.1mm, s.d.=30.5mm) compared with controls (mean=110.2mm, s.d.=38.5mm), t(36)=2.31, P=0.027, d=0.77. These independent validations provide grounds for confidence about the reliability of our measurement protocol, and the likelihood that it will be sufficiently sensitive to identify morphological differences in our larger sample of 153 patients with schizophrenia and controls that may distinguish those who experienced hallucinations from those without hallucinations.

PCS measurement differences associated with hallucinations

Turning to the principal analysis of PCS morphology differences as a function of hallucination status, we compared PCS length between three large matched groups (patients with schizophrenia who had experienced hallucinations, patients with schizophrenia who had not experienced hallucinations and matched healthy controls; see Methods section for participant details and matching procedure). There was a main effect of group on total PCS length, summed across both hemispheres, F(2, 150)=8.90, P<0.001, ηp2=0.106, which survived the addition of cortical surface area as a covariate, F(2, 149)=7.03, P=0.001, ηp2=0.086. Other potential covariates such as age, IQ, intracranial volume and global brain gyrification index had no significant effect on PCS length and were removed from the model.

Planned comparisons revealed that patients with schizophrenia who experienced hallucinations exhibited significantly reduced PCS length compared with the patients without hallucinations (mean reduction=19.2mm), t(111)=2.531, P=0.013, d=0.519 and healthy controls (mean reduction=29.2mm), t(117)=4.149, P<0.001, d=0.805, whereas sulcal length between patients who did not experience hallucinations and healthy controls did not differ significantly, t(72)=1.07,P=0.288, d=0.246 (Fig. 2a).

With earlier research providing conflicting evidence of differential cortical-folding patterns between the two cerebral hemispheres in schizophrenia, we next investigated possible laterality effects on PCS length. There were main effects of hemisphere, F(1,150)=9.978, P=0.002, ηp2=0.062, and group, F(2,150)=8.900, P<0.001, ηp2=0.106, on PCS length, but no interaction between hemisphere and group. PCS length was greater in the left than the right hemisphere across all subject groups, t(152)=2.959, P=0.004, d=0.317 (Fig. 2b,c). Patients with schizophrenia who had experienced hallucinations exhibited reduced PCS length compared with the healthy controls in both hemispheres, t>2.636, P<0.01, d>0.546. The difference in PCS length between patients with schizophrenia who had experienced hallucinations and patients who had not experienced hallucinations was significant only in the left hemisphere, t(111)=2.464, P=0.015, d=0.505.

We tested the modality specificity of the observed relations by comparing PCS length between patients with auditory hallucinations and patients with hallucinations limited to other modalities (for example, visual, tactile, olfactory). The PCS reductions could not be differentiated according to hallucination modality, either summed across both hemispheres, t(77)=0.067, P=0.947, d=0.015, or within the left, t(77)=0.600, P=0.551, d=0.135, or right, t(77)=0.822, P=0.413, d=0.185, hemispheres alone, consistent with a generalized role for reality monitoring impairment in the formation of hallucinations, regardless of the sensory modality in which they occur.

……..

Data-driven whole-brain analyses

To further validate the PCS measurement protocol and to determine whether between-group differences in PCS length were accompanied by structural variations elsewhere in the brain, we conducted separate automated whole-brain analyses of surface-based cortical gyrification and of voxel-based grey matter volume (see Methods section for details). Confirming the results of the PCS measurement method, significant differences in local gyrification index were observed in the mPFC regions of interest surrounding the PCS, namely bilateral frontopolar, medial orbitofrontal, superior frontal and paracentral cortices, with patients with schizophrenia who experienced hallucinations exhibiting significantly reduced gyrification in these regions compared with patients without hallucinations, t(111)=2.165, P=0.033, d=0.448 (Fig. 3). No significant regional group differences elsewhere in the brain survived correction for multiple comparisons

 

Figure 3: Whole-brain cortical gyrification differences as a function of hallucination status.

Whole-brain cortical gyrification differences as a function of hallucination status.

http://www.nature.com/ncomms/2015/151117/ncomms9956/images_article/ncomms9956-f3.jpg

a) mPFC regions surrounding the PCS exhibiting significantly reduced gyrification in 79 patients who experienced hallucinations compared with 34 patients without hallucinations, rendered on a canonical pial cortical surface, viewed from the midline. (b) Local gyrification index in regions surrounding the PCS significantly differentiates patients with schizophrenia as a function of hallucination status, t(111)=2.165,P=0.033, d=0.448. Error bars represent standard error of the mean.

Consistent with reductions in mPFC cortical folding in hallucinations, grey matter volume was significantly greater in the functionally defined 8-mm sphere mPFC region of interest surrounding the anterior PCS in patients with schizophrenia who experienced hallucinations than in those who did not (x=6, y=54, z=−5; BA 10; Z=2.82; P=0.036 (small volume corrected), Fig. 4). The region identified as significant using this voxel-based method was smaller than the region that emerged in the surface-based gyrification analysis, which may be attributable to the different properties of cortical morphology measured, as well as any of numerous statistical and methodological differences between the two techniques (see Methods section for details). In any event, no significant grey matter volume differences elsewhere in the brain, associated with the occurrence of hallucinations, survived correction for multiple comparisons.

 

Figure 4: Grey matter volume differences measured with voxel-based morphometry.

Grey matter volume differences measured with voxel-based morphometry.

http://www.nature.com/ncomms/2015/151117/ncomms9956/images_article/ncomms9956-f4.jpg

(a) Significantly greater grey matter volume in 79 patients who experienced hallucinations than in 34 patients without hallucinations in the mPFC region of interest in the vicinity of the anterior PCS (circled), rendered on an inflated canonical cortical surface, viewed from the front. (b) Grey matter volume in PCS region significantly differentiates patients with schizophrenia as a function of hallucination status, Z=2.82;P=0.036 (small volume corrected). Error bars represent standard error of the mean.

 

Using newly validated visual classification techniques and automated, data-driven analysis methods, the present study identified that hallucinations were associated with specific brain morphology differences in the PCS region of the mPFC. Because the connection between PCS reduction and hallucinations was evident in participants who all had diagnoses of schizophrenia, our findings avoid confounding with patient status, as can occur in case–control comparisons. The hallucinating and non-hallucinating groups with schizophrenia in our study were matched for age, sex, handedness, IQ, duration of illness, antipsychotic medication and incidence of delusions and negative symptoms. In identifying that hallucinations can be distinguished by structural brain imaging data, we demonstrate that a multifactorial phenomenon which is defined experientially can be related to a single morphological change in the mPFC. As a tertiary sulcus forming around 36 weeks of gestation12, the 19.2mm mean reduction in PCS length that distinguished patients who hallucinated from those who did not hallucinate might arise from genetic factors that influence primary folding of the cortex through a disruption to neurodevelopmental pathways. Alternatively, the variability in PCS length might be a non-genetic consequence of some disturbance in primary sulcal development, or might represent extremes of normal statistical variation in the development of primary and secondary sulci.

Our results go beyond previous findings of changes in cortical-folding patterns associated with schizophrenia. Several previous studies have reported differences in PCS morphology in patients with schizophrenia compared with healthy controls13, 14, or investigated differences in global measures of cortical gyrification or sulcation associated with hallucination status15. The present study is the first to identify that PCS morphology changes can discriminate between hallucinating and non-hallucinating groups that are matched for overall brain volume, cortical surface area and global gyrification index, among other variables. The present findings are consistent with earlier research suggesting that leftward PCS hemispheric asymmetries in schizophrenia might be similar to those typically observed in healthy controls14, 16, though some previous studies have reported reduced PCS asymmetry in schizophrenia13, 17. In the present data, comparable laterality effects were observed in all subject groups, with significantly greater PCS length in the left than right hemisphere, and group differences evident across both hemispheres. Methodological differences might explain the discrepancies between previous studies, motivating the development of common measurement protocols, preferably incorporating both visual classification and automated, data-driven components, to optimize the identification and measurement of sometimes relatively indistinct or discontinuous anatomical landmarks such as the PCS.

Evidence from research in healthy individuals indicates that PCS reductions are associated with increased grey matter volume in the surrounding anterior cingulate cortex18, with Buda et al.2reporting that increased grey matter volume in the mPFC correlated negatively with an individual’s reality monitoring ability. Such findings fit with the present results, in which reduced mPFC surface-based gyrification and concomitant increased voxel-based grey matter volume were the only significant differences in the brain to be associated with the occurrence of hallucinations. Together with the results by Buda et al., these findings are consistent with a role for reality monitoring impairment in the generation of hallucinations, with a structural basis for that ability in the region of the PCS. An influence of reduced paracingulate folding and greater surrounding cortical volume may arise from weakened connectivity between the mPFC and both proximal and distal brain regions. Prominent theories of morphogenesis suggest that cortical folding in the human brain, which begins at around the 26th week of gestation19, 20, results either from differential mechanical tension along white matter axons linking disparate brain areas21, 22 or from variable tangential expansion of the cortical surface23.

Altered PCS morphology could thus lead to hallucinations through changes in connectivity between cortical regions involved in processing sensory representations and mPFC areas that support decision-making processes such as distinguishing real experiences from those that might have been imagined, among other cognitive functions8, 9, 24. This hypothesis has yet to be tested directly, although there is evidence of impaired anterior cingulate modulation of fronto–temporal connectivity in schizophrenia25. Investigating functional and structural connectivity between the broader mPFC and, for example, posterior auditory and language regions around the superior temporal gyrus, would further inform models of hallucination formation. Hallucinations are likely to be a multifactorial phenomenon5, and theoretical models implicate a range of cognitive and affective variables in their occurrence26, 27. It is possible that modality-general risk factors, such as reduced PCS length, may interact in some individuals with modality-specific risk factors, such as reduced arcuate fasciculus integrity in the case of auditory hallucinations28, to produce hallucinations in specific sensory modalities. Information on neurodevelopmental models of schizophrenia could also be gained by comparing PCS morphology in family studies and during disease development.

Our findings support modality-general views of hallucinations as stemming from atypicalities in reality monitoring. They raise important questions for cognitive models of hallucinations including how the internal ‘raw material’ of reality monitoring errors might be defined. In the case of auditory hallucinations, there is compelling evidence that hallucinations arise through the misattribution of internal events (for example, inner speech) as external auditory stimuli. A modality-general account would need to specify analogous internal events that could be misattributed as external ones in, for example, the visual or tactile modalities. A modality-general account would also have to explain considerable phenomenological variability in the experience as it is described in all modalities. Moreover, as with all theories proposing brain structural or functional changes associated with hallucinations, a reality monitoring account must explain why hallucinations are often transient phenomena rather than being experienced constantly. Susceptibility to hallucinations, and their triggering and maintenance by psychological and environmental factors, are likely to be multifactorial, complex processes. We show that a simple morphological variation is an important factor in determining why some individuals can have quasi-perceptual experience of entities that are not physically present.

 

How hallucinations emerge from trying to make sense of an ambiguous world

http://www.neuroscience.cam.ac.uk/news/article.php?permalink=edbb8aa287

Take a look at the black and white image. It probably looks like a meaningless pattern of black and white blotches. But now take a look at the image below and then return to the picture: it’s likely that you can now make sense of the black and white image. It is this ability that scientists at Cardiff University and the University of Cambridge believe could help explain why some people are prone to hallucinations.

http://www.cam.ac.uk/sites/www.cam.ac.uk/files/inner-images/press_twotone_sml.jpg

 

http://www.cam.ac.uk/sites/www.cam.ac.uk/files/inner-images/press_colour_smal.jpg

 

Adapted from University of Cambridge News
Press coverage: BBC News Cambridge News Daily Mail Motherboard ITV News Irish Examiner Belfast Telegraph

Posted on 10/13/2015

A bewildering and often very frightening experience in some mental illnesses is psychosis – a loss of contact with external reality. This often results in a difficulty in making sense of the world, which can appear threatening, intrusive and confusing. Psychosis is sometimes accompanied by drastic changes in perception, to the extent that people may see, feel, smell and taste things that are not actually there – so-called hallucinations. These hallucinations may be accompanied by beliefs that others find irrational and impossible to comprehend.

In research published today in the journal Proceedings of National Academy of Sciences (PNAS), a team of researchers based at Cardiff University and the University of Cambridge explore the idea that hallucinations arise due to an enhancement of our normal tendency to interpret the world around us by making use of prior knowledge and predictions.

In order to make sense of and interact with our physical and social environment, we need appropriate information about the world around us, for example the size or location of a nearby object. However, we have no direct access to this information and are forced to interpret potentially ambiguous and incomplete information from our senses. This challenge is overcome in the brain – for example in our visual system – by combining ambiguous sensory information with our prior knowledge of the environment to generate a robust and unambiguous representation of the world around us. For example, when we enter our living room, we may have little difficulty discerning a fast-moving black shape as the cat, even though the visual input was little more than a blur that rapidly disappeared behind the sofa: the actual sensory input was minimal and our prior knowledge did all the creative work.

“Vision is a constructive process – in other words, our brain makes up the world that we ‘see’,” explains first author Dr Christoph Teufel from the School of Psychology at Cardiff University. “It fills in the blanks, ignoring the things that don’t quite fit, and presents to us an image of the world that has been edited and made to fit with what we expect.”

“Having a predictive brain is very useful – it makes us efficient and adept at creating a coherent picture of an ambiguous and complex world,”adds senior author Professor Paul Fletcher from the Department of Psychiatry at the University of Cambridge. “But it also means that we are not very far away from perceiving things that aren’t actually there, which is the definition of a hallucination.

“In fact, in recent years we’ve come to realise that such altered perceptual experiences are by no means restricted to people with mental illness. They are relatively common, in a milder form, across the entire population. Many of us will have heard or seen things that aren’t there.”

In order to address the question of whether such predictive processes contribute to the emergence of psychosis, the researchers worked with 18 individuals who had been referred to a mental health service run by the NHS Cambridgeshire and Peterborough Foundation Trust, and led by Dr Jesus Perez, one of the co-authors on the study, and who suffered from very early signs of psychosis. They examined how these individuals, as well as a group of 16 healthy volunteers, were able to use predictions in order to make sense of ambiguous, incomplete black and white images, similar to the one shown above.

The volunteers were asked to look at a series of these black and white images, some of which contained a person, and then to say for a given image whether or not it contained a person. Because of the ambiguous nature of the images, the task was very difficult at first. Participants were then shown a series of full colour original images, including those from which the black and white images had been derived: this information could be used to improve the brain’s ability to make sense of the ambiguous image. The researchers reasoned that, since hallucinations may come from a greater tendency to superimpose one’s predictions on the world, people who were prone to hallucinations would be better at using this information because, in this task, such a strategy would be an advantage.

The researchers found a larger performance improvement in people with very early signs of psychosis in comparison to the healthy control group. This suggested that people from the clinical group were indeed relying more strongly on the information that they had been given to make sense of the ambiguous pictures.

When the researchers presented the same task to a larger group of 40 healthy people, they found a continuum in task performance that correlated with the participants’ scores on tests of psychosis-proneness. In other words, the shift in information processing that favours prior knowledge over sensory input during perception can be detected even before the onset of early psychotic symptoms.

“These findings are important because they tell us that the emergence of key symptoms of mental illness can be understood in terms of an altered balance in normal brain functions,” says Naresh Subramaniam from the Department of Psychiatry at the University of Cambridge. “Importantly, they also suggest that these symptoms and experiences do not reflect a ‘broken’ brain but rather one that is striving – in a very natural way – to make sense of incoming data that are ambiguous.”

The study was carried out in collaboration with Dr Veronika Dobler and Professor Ian Goodyer from the Department of Child and Adolescent Psychiatry at the University of Cambridge. The research was funded by the Wellcome Trust and the Bernard Wolfe Health Neuroscience Fund. It was carried out within the Cambridge and Peterborough NHS Foundation Trust. Additional support for the Behavioural and Clinical Neuroscience Institute at the University of Cambridge came from the Wellcome Trust and the Medical Research Council.

Shift toward prior knowledge confers a perceptual advantage in early psychosis and psychosis-prone healthy individuals

Christoph Teufela,b,1Naresh SubramaniambVeronika Doblerc,dJesus Perezc,dJohanna Finnemannb,ePuja R. Mehtab, et al.

PNAS 2013; 112(43): 13401–13406    http//dx.doi.org:/10.1073/pnas.1503916112

Significance

Perceiving things that are not there and holding unfounded, bizarre beliefs (hallucinations and delusions, respectively) are psychotic symptoms that occur in particular syndromes including affective psychoses, paranoid states, and schizophrenia. We studied the emergence of this loss of contact with reality based on current models of normal brain function. Working with clinical individuals experiencing early psychosis and nonclinical individuals with high levels of psychosis proneness, we show that their visual perception is characterized by a shift that favors prior knowledge over incoming sensory evidence. Given that these alterations in information processing are evident early on in psychosis and even in association with subtle perceptual changes indicating psychosis proneness, they may be important factors contributing to the emergence of severe mental illnesses.

 

Many neuropsychiatric illnesses are associated with psychosis, i.e., hallucinations (perceptions in the absence of causative stimuli) and delusions (irrational, often bizarre beliefs). Current models of brain function view perception as a combination of two distinct sources of information: bottom-up sensory input and top-down influences from prior knowledge. This framework may explain hallucinations and delusions. Here, we characterized the balance between visual bottom-up and top-down processing in people with early psychosis (study 1) and in psychosis-prone, healthy individuals (study 2) to elucidate the mechanisms that might contribute to the emergence of psychotic experiences. Through a specialized mental-health service, we identified unmedicated individuals who experience early psychotic symptoms but fall below the threshold for a categorical diagnosis. We observed that, in early psychosis, there was a shift in information processing favoring prior knowledge over incoming sensory evidence. In the complementary study, we capitalized on subtle variations in perception and belief in the general population that exhibit graded similarity with psychotic experiences (schizotypy). We observed that the degree of psychosis proneness in healthy individuals, and, specifically, the presence of subtle perceptual alterations, is also associated with stronger reliance on prior knowledge. Although, in the current experimental studies, this shift conferred a performance benefit, under most natural viewing situations, it may provoke anomalous perceptual experiences. Overall, we show that early psychosis and psychosis proneness both entail a basic shift in visual information processing, favoring prior knowledge over incoming sensory evidence. The studies provide complementary insights to a mechanism by which psychotic symptoms may emerge.

 

To interact successfully with our physical and social environment, we need appropriate information about relevant states of the world, such as the size, location, or distance of an object. However, there is no direct access to this information, only to sensory stimulation caused by the environment. This sensory information is inherently ambiguous and, on its own, rarely suffices to uniquely specify our surroundings (1). The human visual system overcomes this challenge by combining ambiguous sensory information with prior knowledge of the environment to generate a robust and unambiguous representation of the world around us (17). This insight has been formalized under the tenets of Bayesian decision theory and is typically modeled within a predictive coding framework. Here, the notion is that expectations based on prior knowledge are fed back from higher to lower levels of information processing, thereby shaping the way incoming signals are treated by lower-level mechanisms. This influence is labeled top-down processing. The present study tests the hypothesis that psychotic experiences arise from an increased use of prior knowledge in constructing meaningful percepts from ambiguous sensory inputs.

Psychosis—a loss of contact with external reality—is characterized by delusions (irrational, often bizarre beliefs) and hallucinations (perceptions in the absence of causative stimuli). Conceptual and computational models of psychosis have hypothesized that an imbalance in the combination of bottom-up sensory evidence and top-down prior knowledge is at the core of this altered state of mind (812). According to such models, at the perceptual level, an undue reliance on prior knowledge in perception may lead to the emergence of aberrant perceptions such as hallucinations. The current study tests this hypothesis in the visual domain by characterizing the impact of prior knowledge on the perception of ambiguous stimuli in two groups of people: a clinical group with early psychotic experiences (study 1) and healthy volunteers showing differing levels of proneness to such experiences (study 2). Although the conventional view focuses preferentially on auditory hallucinations in psychosis, epidemiological evidence indicates that hallucinations in the visual domain are very common in, for example, schizophrenia (13). In fact, vision seems to play a prominent role in the development of psychosis given that basic visual symptoms identified before illness onset are one of the most powerful predictors of the emergence of later psychotic disorders (14).

To determine mechanisms for the emergence of perceptual psychotic symptoms as purely as possible, we conducted two complementary studies. First, using a case-control study design, we characterized the balance between visual bottom-up and top-down processing in a group of patients with early psychotic experiences and matched healthy controls (SI Materials and Methods and Table S1). Individuals in our clinical group were recruited from a dedicated mental health service identifying help-seeking people who have low-level but measurable psychotic experiences. Although, at the time of testing, these individuals fell below the threshold for a categorical diagnosis, they already showed symptoms and have an increased risk for transitioning to a severe mental illness such as schizophrenia or an affective disorder (15). Importantly, working with such a group of patients and comparing them to controls enabled us to focus on the features of early psychosis before any formal categorical diagnosis. Moreover, and also critically, this comparison is not confounded by the effects of antipsychotic medication or the impact of chronic illness, allowing us, as purely as possible, to explore the mechanisms of early psychosis.

In a second study, we explored psychosis proneness in healthy participants characterized according to the presence of perceptual (16) and belief-related schizotypal features (17). Schizotypy refers to a personality measure that has established predictive value for psychotic and other mental illnesses (18). Although it has been traditionally considered a specific risk measure for schizophrenia, more recently it has been proposed to reflect a general psychosis proneness. A number of schizotypy scales have been devised to characterize various dimensions of psychosis. In the current study, we focused on individual variation in measures relating to perception and belief (16, 17) because they most clearly relate to the key features of psychosis. These measures provided us with a fine-grained index for relevant perceptual experience and beliefs, allowing us to characterize the bottom-up/top-down balance in relation to subtle, nonclinical but specific and measurable markers associated with psychosis proneness.

Characterizing these two situations enabled us to pursue our central aim of exploring information-processing mechanisms that are altered in association with the occurrence of early symptoms (study 1) and also identifiable even before such symptoms arise (study 2). As well as offering a purer assessment of the emergence of psychotic experiences, this approach is inspired by growing evidence suggesting that psychosis lies on a continuum with normality (19, 20) and is associated with a range of different psychiatric disorders (15, 21). According to this perspective, existing diagnostic categories group biologically heterogeneous syndromes with potentially different pathophysiological mechanisms into one disorder (22); this may obfuscate our attempts to understand the neurobiological underpinnings of mental illness. In keeping with a broader move within the field, the aim of this approach is therefore to characterize deeper dimensions in their own right, such as psychosis as in the current study, irrespective of diagnostic categorization to advance our mechanistic understanding of specific symptom clusters.

In summary, we explored how the use of prior knowledge in visual information processing is related to early psychosis and to psychosis proneness. Importantly, given our hypothesis, we predicted that the putative mechanism associated with the emergence of psychosis would confer a relative advantage in this task, given that successful performance required the use of prior knowledge to discriminate ambiguous stimuli. Together, the two studies provide evidence to suggest that early psychosis and psychosis proneness is associated with a shift in visual processing that favors prior knowledge over incoming sensory evidence. We also demonstrate that this relation is specific to atypical perceptual experiences rather than being linked to psychotic experiences more generally.

 

Our studies were designed to characterize, in complementary ways, the balance between visual bottom-up and top-down processing in clinical individuals with early psychosis and healthy people prone to developing psychotic symptoms. A relative advantage in using prior knowledge to discriminate between ambiguous images was observed in both situations. This finding is especially striking in the clinical group in study 1 given that performance in this group (as in psychiatrically ill individuals more generally) is typically impaired. Such a result is rare and revealing in that it highlights a specific information-processing atypicality rather than a general performance deficit. Study 2 allowed us to characterize these alterations in visual function more completely by adopting an individual differences approach with healthy participants and by capitalizing on subtle variations in perception and belief that exhibit graded similarity with psychotic experiences. In line with our clinical findings, we uncovered a relation between an individual’s visual performance benefit due to prior knowledge and their scores on two scales of psychosis proneness. Importantly, also, our data suggest that this relation is primarily driven by perceptual alterations rather than unusual beliefs. Taken together, these results indicate that visual function in early psychosis and in healthy people who are prone to such experiences is characterized by a basic information-processing shift that favors existing knowledge over incoming sensory evidence. Although, in the current experimental task, this shift conferred a performance benefit, under most natural viewing situations, it may provoke anomalous perceptual experiences. Specifically, it might impose prior expectations on inputs to the extent that, ultimately, formed percepts are generated that have no direct sensory cause: hallucinations.

These findings fit neatly with and support current conceptual and computational models of psychotic symptoms (812). For instance, it has been hypothesized that a single core disturbance relating to the balance between bottom-up and top-down processing can explain both the hallucinatory experiences and the bizarre delusional beliefs of psychotic patients (8, 11). Importantly, we show that, on the perceptual level, a shift in this balance toward prior knowledge is present both in a clinical group of individuals with early psychosis and even associated with psychosis proneness in the general population. Although schizotypy is a marker for psychosis proneness as ascertained by previous longitudinal studies (18), it is important to acknowledge that individuals in study 2 were not suffering from psychosis or even a diagnosed mental illness. Rather, those individuals scoring high on the scales identified a number of unusual perceptual experiences. It is therefore striking that the same information-processing shift was observed as was found in early psychosis. Indeed, even in the early psychosis group, no formal, categorical diagnosis was applicable (although it is known that such groups have a high risk of transition to full psychiatric illness) (15). The findings may therefore suggest that the altered balance is a fundamental trait that contributes to the emergence of psychosis rather than a reflection or consequence of the psychotic state.

The specificity of the relation between performance on our task and perceptual aspects of schizotypy is of particular interest. It has long been known that altered perceptual experiences form a key part of the emergence of psychosis (29). Given that the CAPS is selective for measuring schizotypal perceptual phenomena rather than targeting schizotypy in general (16), our findings indicate that a shift in visual information processing that favors prior knowledge over sensory evidence might be a marker for the mechanisms underlying this observation. The finding that healthy individuals that score high on this scale share this marker with our clinical group is in line with the growing belief that psychotic mental illnesses are part of a continuum with normality (19, 20). It supports the idea that the putative atypicality underlying the emergence of perceptual psychotic experiences relates directly to normal function of the system. In other words, the potential for psychotic experiences such as hallucinations might be a logical consequence of the way in which our brain deals with the inherent ambiguity of sensory information by incorporating prior knowledge into our perceptual processing. The current study uncovered an imbalance of this processing type that shows its effects at the perceptual level. However, within a hierarchical and recurrent information-processing system such as the human brain, an imbalance at any level will, in time, propagate up and down the hierarchy and affects the whole system (8, 30), a notion that might ultimately account for atypicalities in both lower-level perceptual processing and higher-level belief formation in severe mental illnesses and psychosis proneness (30).

 

Read Full Post »


Schizophrenia Brain

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

http://health-innovations.org/2015/10/27/neuroimaging-matches-specific-schizophrenia-behaviour-to-the-brains-anatomy/

Neuroimaging studies using fMRI and PET to examine functional differences in brain activity in patients with schizophrenia have shown that differences seem to most commonly occur in the frontal lobes, hippocampus, and temporal lobes. These differences are heavily linked to the neurocognitive deficits which often occur with schizophrenia, particularly in areas of memory, attention, problem solving, executive function and social cognition.

Earlier studies from the researchers reported evidence suggesting that schizophrenia is not a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. Results found that distinct sets of genes were strongly associated with particular clinical symptoms.

The current study investigates the brain’s anatomy and shows that there are distinct subgroups of patients with a schizophrenia diagnosis that correlates with symptoms.  This also explains the difficulty in past studies to identify a single set of biomarkers for a single type of schizophrenia.

The current study evaluated scans taken with magnetic resonance imaging (MRI) and a technique called diffusion tensor imaging in 36 healthy volunteers and 47 people with schizophrenia. Results show that the scans of patients with schizophrenia had various abnormalities in portions of the corpus callosum, a bundle of fibers that connects the left and right hemispheres of the brain and is considered critical to neural communication. Characteristics across the corpus callosum revealed in the brain scans matched specific symptoms of schizophrenia. Patients with specific features in one part of the corpus callosum typically displayed bizarre and disorganized behaviour. In other patients, irregularities in a different part of that structure were associated with disorganized thinking and speech and symptoms such as a lack of emotion; other brain abnormalities in the corpus callosum were associated with delusions or hallucinations.  The lab conclude that their findings provide further evidence that schizophrenia is a heterogeneous group of disorders rather than a single disorder.

The team surmise that they didn’t start with people who had certain symptoms and then look to see whether they had corresponding abnormalities in the brain. They note that they just looked at the data, and the patterns began to emerge. They go ony to add that this kind of granular information, combined with data about the genetics of schizophrenia, one day will help physicians treat the disorder in a more precise way.

Many genes responsible for the creation of synaptic proteins have previously shown to be strongly linked to schizophrenia and other brain disorders, however, until now the reasons have not been understood.  Now, researchers from Cardiff University have identified a critical function of what they believe to be schizophrenia’s ‘Rosetta Stone’ gene that could hold the key to decoding the function of all genes involved in the disease.  The team state that the breakthrough has revealed a vulnerable period in the early stages of the brain’s development that they hope can be targeted for future efforts in reversing schizophrenia.  The study is published in the journal Science.

The gene identified in the current study is known as ‘disrupted in schizophrenia-1’ (DISC-1). Earlier studies have shown that when mutated, the gene is a high risk factor for mental illness including schizophrenia, major clinical depression and bipolar disorder.  The aim of the current study was to determine whether DISC-1’s interactions with other proteins early on in the brain’s development had a bearing on the brain’s ability to adapt its structure and function, also known as ‘plasticity’, later on in adulthood.

In order for healthy development of the brain’s synapses to take place, the DISC-1 gene first needs to bind with two other molecules known as ‘Lis’ and ‘Nudel’.  The experiments in mice revealed that by preventing DISC-1 from binding with these molecules prevents cortical neurons in the brain’s largest region from being able to form synapses.  The ability to form coherent thoughts and to properly perceive the world is damaged as a consequence of this.

Preventing DISC-1 from binding with ‘Lis’ and ‘Nudel’ molecules when the brain was fully formed had no effect on its plasticity. However, the researchers were able to pinpoint a seven-day window early on in the brain’s development, one week after birth, where failure to bind had an irreversible effect on the brain’s plasticity later on in life.

The researchers hypothesize that DISC-1 is schizophrenia’s Rosetta Stone gene and could hold the master key to help unlock the understanding of the role played by all risk genes involved in the disease.  They go on to add that they have identified a critical period during brain development that will assist in testing whether other schizophrenia risk genes affecting different regions of the brain create their malfunction during their own critical period.

Read Full Post »


Outstanding Achievement in Schizophrenia Research

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

Series E. 2; 5.9

2014 Prizewinner:
David Braff, M.D.
 – University of California, San Diego School of Medicine – Watch Video

David Braff M.D. named Lieber Prize winner

David Braff MD, Distinguished Professor at UCSD’s Department of Psychiatry has been named this year’s Lieber Prize winner by the National Brain and Behavior Research Foundation (NBBRF) and the National Association for Research in Schizophrenia and Depression (NARSAD). This Prize is given to an outstanding neuropsychiatric researcher who has enhanced our fundamental understanding of schizophrenia, a devastating no fault heritable clinical brain disorder affecting 1% of the world’s population. Schizophrenia causes psychosis, cognitive dysfunction and profound disability in many patients. It also affects the families of the patients, since the disability-often strikes early in young adult life. Past Lieber Prize winners include two Nobel Laureates and many other world leading distinguished neuroscientists. The Award will be presented at a scientific meeting, ceremony and dinner in New York at the NBBRF-NARSAD Annual Gala at Lincoln Center in late October.

Dr. Braff has pursued and extended our understanding of schizophrenia via a number of major research projects. The Consortium on the Genomics of Schizophrenia (COGS) is a 30 million-dollar 10 year NIMH-funded consortium on the neurocognitive, neurophysiological, neural circuit and dysfunctional genomic architecture of schizophrenia. Dr Braff has been Principal Scientist and Director of this 7-site study: COGS 1 examined clinical features, neurocognitive and neurophysiological, and other familial endophenotypes or biomarkers in schizophrenia patients and their families as well as healthy control subjects. The follow up COGS 2 is studying 2500 schizophrenia patients and case-control subjects. Genomic and related methods include extensive behavioral, candidate gene, genome wide association, sequencing, methylation and stem cell projects from COGS and UCSD grants. This has led to an increased understanding of both the neural network and underlying genomic network bases of schizophrenia and has enhanced our understanding of risk and vulnerability markers which may provide targets for very early intervention and even, in the longer run, prevention. This neurodevelopmental psychotic process starts early in life but usually manifests itself in late teenagers and young adults. In addition, because of the underlying complex neural and genomic networks that have been identified by this work and the studies of other scientific projects, we have hope of finding novel therapeutic targets for pharmacological and sensory training- cognitive behavioral therapies for this devastating disorder.

Dr. Braff also has conducted longstanding translational (TRANS) and genomic studies over 30 years of continuously funded projects supported by NIMH, NARSAD and the Brain and Behavior Foundation. This research, conducted with many essential colleagues, including TRANS Co-PIs Mark Geyer, Ph.D. and Neal Swerdlow, M.D. Ph.D., has led to cross-species translational advances in understanding the neurobiology of schizophrenia and created powerful tools for screening candidate antipsychotic compounds to treat schizophrenia. Braff has also Directed the VA VISN 22 Mental Illness Research Center Clinical Neuroscience and Genomics Project, which provides crucial infrastructure and intellectual support for this work.

In recent years, Dr. Braff, a NARSAD Distinguished Investigator, has consistently been ranked by “ISI” in the top half of the top percent of all cited neuropsychiatric researchers based on the frequency with which his 300 publications are cited. He has also been awarded the Warren Award from the International Congress of Schizophrenia, the Inspiration Pioneer Research Award from NAMI, the Dean Award from the American College of Psychiatrists and the Marmor Award from the American Psychiatric Association, all given to honor an outstanding neuropsychiatric researcher. Dr. Braff’s colleagues at UCSD have included crucial contributions and context from TRANS Co-PIs, Mark Geyer Ph.D. and Neal Swerdlow MD Ph.D., Department Vice Chair (Also Deputy Director of COGS) as well as more recent faculty appointees Gregory Light, Ph.D (UCSD COGS Director and San Diego VA VISN 22 MIRECC Director) and Tiffany Greenwood, Ph.D. (Genetics And Statistical Genetics Lead Scientist) and many others.

Dr. Igor Grant, Chair of the Department commented, “Professor David Braff has been at the forefront of research into the neurobiology of schizophrenia. Beginning with observations on neurophysiologic biomarkers related to aberrant attentional and other cognitive mechanisms in those afflicted with schizophrenia, his work has progressed to linking such biomarkers to genetic underpinnings of this serious disorder, which affects 1% of our population, and causes great disruptions both for the person affected, and their families and loved ones. Professor Braff’s innovative work has opened better understanding of the interplay of genetic and neurodevelopmental factors in the evolution of schizophrenia, as well as promise of specific diagnostic markers that may help with early identification of people vulnerable to this disorder, at a time when preventive strategies may be most useful. As such his work will inform both improved treatment and prevention. Dr. Braff has also been a generative mentor to younger scientists, a fine educator, and helped the Department establish a modern inpatient psychiatric unit to care for people with severe mental disorders. The Department is very proud that Professor Braff was recognized with the Lieber Prize, reserved for the very finest psychiatrist scientists.”

https://youtu.be/c1_FtkMLJc4

“We are entering a new era of the neuropsychiatric and genomic revolutions, where advanced bioinformatics and other evolving technologies will help us to integrate brain, behavioral and genomic data about schizophrenia that we only imagined was possible in the past. Receiving this prize will serve to enhance all of our endeavors.”

 

Patrick F. Sullivan, M.D., Karolinska Institutet & University of North Carolina – Watch Video

Patrick F. Sullivan Awarded 2014 Lieber Prize for Outstanding Achievement in Schizophrenia Research

Patrick F. Sullivan, MD, FRANZCP, M. Hayworth & Family Distinguished Professor of Psychiatry and Professor of Genetics and Psychiatry at the University of North Carolina School of Medicine, is one of two researchers awarded the 2014 Lieber Prize for Outstanding Achievement in Schizophrenia Research.

The $50,000 cash award from the Brain & Behavior Research Foundation is given in recognition of a research scientist who has made distinguished contributions to the understanding of schizophrenia. It rewards past achievement and provides further incentive for an outstanding working scientist to continue to do exceptional research into the causes, prevention, and treatment of schizophrenia.

“The 2014 Outstanding Achievement Prize winners have dedicated their lives to solving some of the most intractable psychiatric problems in order to improve the lives of millions of people and their families,” said Jeffrey Borenstein, MD, CEO of the Brain & Behavior Research Foundation. “We applaud their past and future accomplishments.”

As a psychiatric geneticist, Dr. Sullivan works to decode the molecular and cellular consequences of genetic variations underlying schizophrenia. He heads large, multinational projects across a range of disorders, dividing his time between Sweden, where he is a Professor at the Karolinska Institutet, and UNC, where he is the Director of the Center for Psychiatric Genomics.

As founder and lead investigator of the Psychiatric Genomics Consortium (PGC), Dr. Sullivan directs 300 scientists from 70 institutions in 19 countries who are conducting mega-analyses, involving 90,000 participants, of genetic risk for schizophrenia, depression, autism, bipolar disorder and attention-deficit hyperactivity disorder. He is also the principal investigator for a Swedish genetic study of 10,000 patients with schizophrenia and bipolar disorder, one of the few projects looking into the impact of environmental factors in these disorders.

http://www.youtube.com/watch%3Fv%3DPzoEgKv5yKQ    Feb 5, 2015

A Stockholm Psychiatry Lecture held at Karolinska Institutet Feb 3 2015 by Prof. Patrick F Sullivan, UNC and KI.

http://www.dana.org/Briefing_Papers/Schizophrenia__Q_A_with_Patrick_F__Sullivan/Jul 14, 2015

Baby steps may become giant steps in the next ten years for schizophrenia, an illness which impacts an estimated 2.4 million Americans

 https://youtu.be/uJmA0gGTUnk 

“It is my deep hope that the work that led to my selection of this prize will continue so that we can greatly expand our knowledge of the genetic basis of schizophrenia so that these new findings will, in turn, lead to advances that improve the lives of people living with schizophrenia and other serious mental disorders.”

SIDNEY R. BAER, JR. PRIZE FOR INNOVATIVE AND PROMISING SCHIZOPHRENIA RESEARCH

Gregory Light, Ph.D.
University of California, San Diego

https://youtu.be/XqtcBkyz7vE

“This award strengthens my resolve to continue to develop treatment strategies that will ameliorate, prevent, and perhaps even cure schizophrenia and related psychotic illnesses in the next stages of my career.”

Stephan Ripke, M.D.
Broad Institute

https://youtu.be/nMfKsWFdM-k

“As a result of the immense collaborative efforts of the PGC, I believe that we are now on the path towards making seminal discoveries into the biology of this devastating disease. New therapeutic targets are imminent and the support of this prize will have a great impact on realizing this goal.”

 

Colvin Prize for Outstanding Achievement in Mood Disorders Research:

Wayne C. Drevets, M.D.
Janssen Pharmaceutica

https://youtu.be/xs7c3u3_pjk

“This prize not only affirms the significance of our past work, it also inspires and invigorates our current and future research, which we hope will improve the lives of people affected by bipolar disorder by leading to the discovery and development of new treatments.”

Fritz A. Henn, M.D., Ph.D.
Cold Spring Harbor Laboratory

https://youtu.be/-HVF-Lxpx14

“That my peers feel our work merits recognition is the greatest reward after a lifetime of work aimed at understanding and better treating major mental illness.”

2013 Marc G. Caron, Ph.D.
Video Clip
Duke University School of Medicine
2012 Michael J. Owen, M.D., Ph.D.
Video Clip
Cardiff University
2012 Michael O’Donovan, M.D., Ph.D.
Video Clip
Cardiff University
2011 Carol A. Tamminga, M.D.
Video Clip
UT Southwestern Medical Center at Dallas
2011 Joel E. Kleinman, M.D., Ph.D.
Video Clip
National Institute of Mental Health (NIMH)
2010 Ming T. Tsuang, M.D., Ph.D., D.Sc.
Video Clip

 

Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience

2014 Prizewinner:

Richard L. Huganir, Ph.D. – The Johns Hopkins University School of Medicine – Watch Video

Department Affiliation: Primary: Neuroscience; Secondary: Biological Chemistry; Howard Hughes Medical Institute
Degree: Ph.D., Cornell University
Rank: Professor/Director, Department of Neuroscience

Regulation of Neurotransmitter Receptors and Brain Function in Heath and Disease

Neurotransmitter receptors mediate signal transduction at the postsynaptic membrane of synaptic connections between neurons in the nervous system. We have been studying the molecular mechanisms in the regulation of neurotransmitter receptor function. Recently we have focused on glutamate receptors, the major excitatory receptors in the brain. Glutamate receptors can be divided into two major classes: AMPA and NMDA receptors. AMPA receptors mediate rapid excitatory synaptic transmission while NMDA receptors play important roles in neuronal plasticity and development. Studies in our laboratory have found that both AMPA and NMDA receptors are multiply phosphorylated by a variety of protein kinases. Phosphorylation regulates several functional properties of these receptors including conductance and membrane targeting. Recent studies in our lab have demonstrated that the phosphorylation of AMPA receptors is regulated during cellular models of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). Moreover, phosphorylation of the AMPA receptor GluR1 subunit is required for the expression of these forms of plasticity and for the retention of spatial memory and also regulates emotional memory formation and erasure.

We have also been examining the mechanisms of the subcellular targeting and clustering of glutamate receptors at synapses. We have recently identified a variety of proteins that directly or indirectly interact with AMPA and NMDA receptors. We have found a novel family of proteins that we call GRIPs (Glutamate Receptor Interacting Proteins) that directly bind to the C-termini of the GluR2/3 subunits of AMPA receptors. GRIPs contain seven PDZ domains, protein-protein interaction motifs, which crosslink AMPA receptors to each other or link them to other proteins. In addition, we have found that the C-termini of GluR2 also interacts with the PDZ domain of PICK1, a protein kinase C-binding protein that is found at excitatory synapses. The GluR2 subunit also interacts with the NSF protein, a protein involved in the regulation of membrane fusion events. These AMPA receptor interacting proteins are critical in the proper membrane trafficking and synaptic targeting of these receptors. We have shown that the binding of PICK1 and GRIP is required for a specific form of LTD in the cerebellum that is a cellular model for motor learning. Moreover, we have found that this receptor complex is critical for hippocampal LTP and LTD and spatial learning.

In addition to these studies on AMPA receptors, we have been characterizing a separate NMDA receptor associated protein complex that is important in synaptic targeting and downstream signaling of NMDA receptors. We have identified an excitatory synapse specific rasGAP, which we call synGAP that regulates synaptic Ras signaling and has profound effects on synaptic plasticity.

Importantly, recent evidence has implicated glutamate receptor associated complexes in several neurological and psychiatric disorders including Alzheimer’s disease, schizophrenia, autism, mental retardation as well as in chronic pain and drug addiction.

In summary, we have examined the molecular mechanisms underlying the regulation of neurotransmitter receptor function. Our studies have suggested that regulation of receptor function may be a major mechanism for the regulation of synaptic plasticity in the nervous system in health and disease and may be an important determinant of animal behavior.

Representative Publications:

  • Volk, L.J., Bachman, J.L., Johnson, R., Yu, Y., Huganir, R.L. (2013) PKM-Z is not required for hippocampal synaptic plasticity, learning and memory. Nature 493(7432): 420-3. Pub Med Reference
  • Thomas, G.M., Hayashi, T., Chiu, S.L., Chen, C.M., Huganir, R.L. (2012) Palmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking. Neuron73(3):482-96. Pub Med Reference
  • Makuch, L., Volk, L., Anggono, V., Johnson, R.C., Yu, Y., Duning, K., Kremerskothen, J., Xia, J., Takamiya, K., Huganir, R.L. (2011) Regulation of AMPA receptor function by the human memory-associated gene KIBRA. Neuron 71(6):1022-9. Pub Med Reference
  • Makino, Y., Johnson, R.C., Yu, Y., Takamiya, K., Huganir, R.L. (2011) Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor. Proc Natl Acad Sci USA. 108(20):8450-5. Epub 2011 May 2. Pub Med Reference
  • Mejias, R., Adamczyk, A., Anggono, V., Niranjan, T., Thomas, G.M., Sharma, K., Skinner, C., Schwartz, C.E., Stevenson, R.E., Fallin, M.D., Kaufmann, W., Pletnikov, M., Valle, D.,Huganir, R.L., Wang, T.  (2011) Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism. Proc Natl Acad Sci USA. 108(12):4920-5. Pub Med Reference 
  • Clem, R. and Huganir, R.L. (2010) Calcium-permeable AMPA receptor dynamics mediate fear memory erasure, Science 330(6007): 1108-12.  Pub Med Reference
  • Hayashi, T., Thomas, G., Huganir, R.L. (2009) Dual palmitoylation of NR2 subunits regulates NMDA receptor trafficking. Neuron 64(2): 213-226. Pub Med Reference
  • Lin, D.T., Makino, Y., Sharma, K., Hayashi, T., Neve, R., Takamiya, K., Huganir, R.L. (2009) Regulation of AMPA receptor GluR1 subunit extrasynaptic insertion events by 4.1N, phosphorylation and palmitoylation. Nat. Neurosci. 12(7): 879-87.� PMCID:� PMC2712131. Pub Med Reference
  • Sia, G.-M., Beique, J.-C., Rumbaugh, G., Cho, R., Worley, P.F., Huganir, R.L. (2007) Interaction of the N-terminal domain of the AMPA Receptor GluR4 subunit with the Neuronal Pentraxin NP1 mediates GluR4 synaptic recruitment. Neuron 55(1): 87-102. Pub Med Reference
  • Steinberg, J.P., Takamiya, K., Shen, Y., Xia, J., Rubio, M.E., Yu, S., Jin, W., Thomas, G.M., Linden, D.J., Huganir, R.L. (2006) Targeted In Vivo Mutations of the AMPA Receptor Subunit GluR2 and its Interacting Protein PICK1 Eliminate Cerebellar Long-Term Depression.Neuron. 49(6): 845-60. Pub Med Reference
  • Chung, H.J., Steinberg, J.P., Huganir, R.L. and Linden, D.J. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300:1751-1755, 2003.Pub Med Reference
  • Lee, H-K., Takamiya, K., Han, J-S., Man, H., Kim, C.-H., Rumbaugh, G., Yu, S., Ding, L., He, C., Petralia, R.S., Wenthold, R.J., Gallagher, M., and Huganir, R.L. (2003) Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112:631-643.  Pub Med Reference
  • Lee, H.K., Barbarosie, M., Kameyama, K., Bear, M.F., and Huganir, R.L. (2000) Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature405:955-959. Pub Med Reference
  • Ehlers, M.D., Zhang, S., Bernhardt, J.P., and Huganir R.L. (1996) Inactivation of NMDA receptors by direct interaction of calmodulin with NR1 subunit. Cell 84:745-755. Chung, H.J., Steinberg, J.P., Huganir, R.L. and Linden, D.J. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300:1751-1755, 2003. Pub Med Reference

GOLDMAN-RAKIC PRIZE FOR OUTSTANDING ACHIEVEMENT IN COGNITIVE NEUROSCIENCE

https://youtu.be/4alesBVcM3s

“This has been my life long career goal—to understand how memory is encoded in the brain and how these mechanisms are disrupted in cognitive disorders. I am honored to be associated with Dr. Goldman- Rakic’s legacy.”

2013 Karl Deisseroth, M.D., Ph.D.
Video Clip
Stanford University
2012 Larry R. Squire, Ph.D.
Video Clip
University of California, San Diego
2011 Michael E. Goldberg, M.D.
Video Clip
Columbia University/NYSPI
2010 Robert Malenka, M.D., Ph.D.
Video Clip
Stanford University

Read Full Post »


3:15PM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

 

3:15 p.m. Discussion Complex Disorders

Complex Disorders

During the past 30-40 years, it has become well established that most human disorders affecting large groups of individuals have a genetic basis. Based upon this information there are several efforts to conduct genetic analysis on very large populations of individuals to identify genetic factors that cause susceptibility to complex disorders. In this session, two examples where such studies are bearing fruit will be discussed.

Complex Disorders

Discussion Leader:

Anna Barker, Ph.D.
Director, Transformative Healthcare Knowledge Networks;
Co-Director, Complex Adaptive Systems Initiative:
Professor, School of Life Sciences, Arizona State University

World of Biomarkers following NIH Career – Molecular based Medicine

get all the facts right straight then distort them

Speakers:

Roy Perlis, MGH, Bipolar Specialty, Prof of Psychiatry

Specialist in Schizophrenia, Autism

  • Complexity – overlapping diseases, genomics discovery
  • Psychiatry Genomics – Susceptibility, variance explained by common variation, intervention studies for susceptibility
  • depression is hereditary
  • 2000 schizophrenics genome,
  • phenotype models is only partially indicative of help if you are on Klonopin, is this enough for the diagnosis
  • CRISPR — HOW to use it — not discovered yet for psychiatry disorder — it may be the solution, though

Joe Vockley

COO, Inova Health System

CSO, Inova Translational Medicine Institute

  • Preeclempsia – preterm Birth is a complex disease many factor can cause it, 12% of birth are Preterm birth
  • 10,000 genome vs full term birth, clinical phenotypes,
  • model 81% predictive — triage screening based on markers – genomics to follow phenotyping.
  • Genomics — indicative — not fully used from diagnostics to therapy
  • ancestor data (familial info) of the 10,000 in the cohort was done filter variant
  • whole genome sequencing, reimbursement does not support  to path to therapy based on genomics

Robert Plenge, M.D., Ph.D.   @rplenge
Vice President and Worldwide Head Genetics and Pharmacogenomics
Merck Research Laboratories – Specialist RA

ex- Pharmacogenetics at MGH

  • sample size 100,000 genomes completely sequenced  – PM is at present in Oncology – use Genetics to discover diagnostics markers, clinical diagnosis, protocols – worst in cancer
  • genetic effect are important component requires big cohort to identify large effect
  • dysfunctional variant
  • Proteomic predictors, in drug discovery not sufficient, marker of disease  it is helpful

 

 

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

@HarvardPMConf

#PMConf

@SachsAssociates

@WeillCornell

@ASU

@rplenge

@Merck

Read Full Post »


Social Behavior Traits Embedded in Gene Expression

Reviewer and Curator: Larry H. Bernstein, MD, FCAP

 

Social behavior traits embedded in gene expression

This article is a special piece on the anniversary of my brother’s death. It is special in the unique discoveries on social interaction and genetic mutations expressed early or in adolescence, with severe disabilities to the individual, and with a challenge to the families affected.  The first is about the genetic classification of schizophrenia variants.  The second is about a severe autism variant with insights into the protein expression in language development.

.

Schizophrenia is Actually 8 Genetic Disorders

09/15/2014    http://www.biosciencetechnology.com/news/2014/09/schizophrenia-actually-8-genetic-disorders

DNA variations matching schizophrenia symptoms

DNA variations matching schizophrenia symptoms

 

Igor Zwir, Ph.D., one of the senior investigators, helped match precise DNA variations in people with and without schizophrenia to symptoms in individual patients. (Source: WUSTL/Robert Boston)

 New research shows that schizophrenia isn’t a single disease but

  •  a group of eight genetically distinct disorders,
  • each with its own set of symptoms.

The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness.

The research at Washington University School of Medicine in St. Louis is reported online in The American Journal of Psychiatry.

About 80 percent of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition. Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to

  • eight different classes of schizophrenia.

Genes don’t operate by themselves,” said C. Robert Cloninger, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know

  • not just who the members of the orchestra are
  • but how they interact.”

Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations

  • in people with and without schizophrenia
  • to symptoms in individual patients.

In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 3,800 healthy controls,

  • learning how individual genetic variations
  • interacted with each other to produce the illness.

In some patients with hallucinations or delusions, for example, the researchers

  • matched distinct genetic features to patients’ symptoms,
  • demonstrating that specific genetic variations interacted
  • to create a 95 percent certainty of schizophrenia.

In another group, they found that

  • disorganized speech and behavior were specifically associated with
  • a set of DNA variations that carried a 100 percent risk of schizophrenia.

Cloninger said..  “What we’ve done here, after a decade of frustration in the field
of psychiatric genetics, is identify the way genes interact with each other, how

  • the ‘orchestra’ is either harmonious and leads to health, or
  • disorganized in ways that lead to distinct classes of schizophrenia,”

Although individual genes have only weak and inconsistent associations with schizophrenia, groups of interacting gene clusters

  • create an extremely high and consistent risk of illness,
  • on the order of 70 to 100 percent.

That makes it almost impossible for people with those genetic variations to avoid the condition. In all, the researchers identified

  • 42 clusters of genetic variations that
  • dramatically increased the risk of schizophrenia.

“In the past, scientists had been looking for associations between individual genes and schizophrenia,” explained Dragan Svrakic, a co-investigator and a professor of psychiatry at Washington University. “When one study would identify an association, no one else could replicate it. What was missing was the idea that

  • these genes don’t act independently.
  • They work in concert to disrupt the brain’s structure and function,
  • and that results in the illness.”

Svrakic said it was only when the research team

  1. was able to organize the genetic variations and
  2. the patients’ symptoms into groups that
  3. they could see that particular clusters of DNA variations
  4. acted together to cause specific types of symptoms.

Then they divided patients according to the type and severity of their symptoms, such as

  1. different types of hallucinations or delusions, and other symptoms, such as
  2. lack of initiative,
  3. problems organizing thoughts or a
  4. lack of connection between emotions and thoughts.

The results indicated that those symptom profiles describe

  • eight qualitatively distinct disorders
  • based on underlying genetic conditions.

The investigators also replicated their findings in two additional DNA databases of people with schizophrenia, an indicator that

  • identifying the gene variations that are working together
  • is a valid avenue to explore for improving diagnosis and treatment.
  1. By identifying groups of genetic variations and
  2. matching them to symptoms in individual patients,
  3. it soon may be possible to target treatments
  4. to specific pathways that cause problems,

according to co-investigator Igor Zwir, research associate in psychiatry at Washington University and associate professor in the Department of Computer Science and Artificial Intelligence at the University of Granada, Spain.

And Cloninger added it may be possible to use the same approach

  • to better understand how genes work together
  • to cause other common but complex disorders.

“People have been looking at genes to get a better handle on

  1. heart disease,
  2. hypertension and
  3. diabetes, and

it’s been a real disappointment,” he said. “Most of the variability in the severity of disease has not been explained, but we were able to find that

  • different sets of genetic variations
  • were leading to distinct clinical syndromes.

So I think this really could change the way people approach understanding the causes of complex diseases.”

Autism Caused by Spontaneous Mutations in Key Brain Gene

09/18/2014 –

TBR1 protein configurations

TBR1 protein configurations

Mutations in the TBR1 gene affect the location of the TBR1 protein in human cells. In normal cells the TBR1 protein, shown in red, is found alongside the DNA, shown in blue. In contrast, the mutant TBR1 protein is found throughout the cell. (Source: Source: Radboud University) Spontaneous mutations in the brain gene TBR1 disrupt the function of the encoded protein in children with severe autism. In addition, there is a direct link between TBR1 and FOXP2, a well-known language-related protein. These are the main findings of an article by Pelagia Deriziotis and colleagues at the Nijmegen Max Planck Institute for Psycholinguistics and published in Nature Communications.

Autism is a disorder of brain development which

  • leads to difficulties with social interaction and communication.

Disorders such as autism caused by gene mutation can change

  • the shape of protein molecules and
  • stop them from working properly during brain development.

Inherited genetic variants put some individuals at risk for autism.  Research in recent years has shown that

  • severe autism can result from
  • (germ-line?) mutations expressed in a child, not in either parent.

Scientists have sequenced the DNA code of thousands of unrelated children with severe autism and found a handful of genes involving independent de novo. One of these genes is

  • TBR1, a key gene in brain development.

Strong impact on protein function

In their study, Deriziotis and colleagues from the MPI’s Language and Genetics Department and the University of Washington investigated the

  • effects of autism risk mutations on TBR1 protein function.

They used several cutting-edge techniques to examine how these mutations affect the way the TBR1 protein works, using human cells grown in the laboratory.

“We directly compared de novo and inherited mutations, and found that the de novo mutations had much more

  • dramatic effects on TBR1 protein function,”

said Deriziotis, “This is a really striking confirmation of the strong impact that de novo mutations can have on early brain development.”

Social network for proteins

Since the human brain depends on many different genes and proteins working together, the researchers were interested in

  • identifying proteins that interact with TBR1.

They discovered that

  • TBR1 directly interacts with FOXP2,
  • an important protein in speech and language disorders,
  • pathogenic mutations affecting either of these proteins
    • abolish the mutual interaction.

FOXP2 is one of the few proteins to have been clearly implicated in speech and language disorders.

Simon Fisher, professor of Language and Genetics at Radboud University and director at the MPI, said that they are building

  • a picture of the neurogenetic pathways contributing to human traits
  • by coupling data from genome screening with functional analysis in the lab

Source: Radboud University

Read Full Post »

« Newer Posts - Older Posts »