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Posts Tagged ‘prefrontal cortex’


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).

 

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Recent Insights in Drug Development

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

A Better Class of Cancer Drugs
http://www.technologynetworks.com/medchem/news.aspx?ID=183124
An SDSU chemist has developed a technique to identify potential cancer drugs that are less likely to produce side effects.
A class of therapeutic drugs known as protein kinase inhibitors has in the past decade become a powerful weapon in the fight against various life-threatening diseases, including certain types of leukemia, lung cancer, kidney cancer and squamous cell cancer of the head and neck. One problem with these drugs, however, is that they often inhibit many different targets, which can lead to side effects and complications in therapeutic use. A recent study by San Diego State University chemist Jeffrey Gustafson has identified a new technique for improving the selectivity of these drugs and possibly decreasing unwanted side effects in the future.

Why are protein kinase–inhibiting drugs so unpredictable? The answer lies in their molecular makeup.

Many of these drug candidates possess examples of a phenomenon known as atropisomerism. To understand what this is, it’s helpful to understand a bit of the chemistry at work. Molecules can come in different forms that have exactly the same chemical formula and even the same bonds, just arranged differently. The different arrangements are mirror images of each other, with a left-handed and a right-handed arrangement. The molecules’ “handedness” is referred to as chirality. Atropisomerism is a form of chirality that arises when the spatial arrangement has a rotatable bond called an axis of chirality. Picture two non-identical paper snowflakes tethered together by a rigid stick.

Some axes of chirality are rigid, while others can freely spin about their axis. In the latter case, this means that at any given time, you could have one of two different “versions” of the same molecule.

Watershed treatment

As the name suggests, kinase inhibitors interrupt the function of kinases—a particular type of enzyme—and effectively shut down the activity of proteins that contribute to cancer.

“Kinase inhibition has been a watershed for cancer treatment,” said Gustafson, who attended SDSU as an undergraduate before earning his Ph.D. in organic chemistry from Yale University, then working there as a National Institutes of Health poctdoctoral fellow in chemical biology.

“However, it’s really hard to inhibit a single kinase,” he explained. “The majority of compounds identified inhibit not just one but many kinases, and that can lead to a number of side effects.”

Many kinase inhibitors possess axes of chirality that are freely spinning. The problem is that because you can’t control which “arrangement” of the molecule is present at a given time, the unwanted version could have unintended consequences.

In practice, this means that when medicinal chemists discover a promising kinase inhibitor that exists as two interchanging arrangements, they actually have two different inhibitors. Each one can have quite different biological effects, and it’s difficult to know which version of the molecule actually targets the right protein.

“I think this has really been under-recognized in the field,” Gustafson said. “The field needs strategies to weed out these side effects.”

Applying the brakes

So that’s what Gustafson did in a recently published study. He and his colleagues synthesized atropisomeric compounds known to target a particular family of kinases known as tyrosine kinases. To some of these compounds, the researchers added a single chlorine atom which effectively served as a brake to keep the atropisomer from spinning around, locking the molecule into either a right-handed or a left-handed version.

When the researchers screened both the modified and unmodified versions against their target kinases, they found major differences in which kinases the different versions inhibited. The unmodified compound was like a shotgun blast, inhibiting a broad range of kinases. But the locked-in right-handed and left-handed versions were choosier.

“Just by locking them into one or another atropisomeric configuration, not only were they more selective, but they  inhibited different kinases,” Gustafson explained.

If drug makers incorporated this technique into their early drug discovery process, he said, it would help identify which version of an atropisomeric compound actually targets the kinase they want to target, cutting the potential for side effects and helping to usher drugs past strict regulatory hurdles and into the hands of waiting patients.

 

Inroads Against Leukaemia
http://www.technologynetworks.com/medchem/news.aspx?ID=183594

 

Potential for halting disease in molecule isolated from sea sponges.
A molecule isolated from sea sponges and later synthesized in the lab can halt the growth of cancerous cells and could open the door to a new treatment for leukemia, according to a team of Harvard researchers and other collaborators led by Matthew Shair, a professor of chemistry and chemical biology.

“Once we learned this molecule, named cortistatin A, was very potent and selective in terms of inhibiting the growth of AML [acute myeloid leukemia] cells, we tested it in mouse models of AML and found that it was as efficacious as any other molecule we had seen, without having deleterious effects,” Shair said. “This suggests we have identified a promising new therapeutic approach.”

It’s one that could be available to test in patients relatively soon.

“We synthesized cortistatin A and we are working to develop novel therapeutics based on it by optimizing its drug-like properties,” Shair said. “Given the dearth of effective treatments for AML, we recognize the importance of advancing it toward clinical trials as quickly as possible.”

The drug-development process generally takes years, but Shair’s lab is very close to having what is known as a development candidate that could be taken into late-stage preclinical development and then clinical trials. An industrial partner will be needed to push the technology along that path and toward regulatory approval. Harvard’s Office of Technology Development (OTD) is engaged in advanced discussions to that end.

The molecule works, Shair explained, by inhibiting a pair of nearly identical kinases, called CDK8 and CDK19, that his research indicates play a key role in the growth of AML cells.

The kinases operate as part of a poorly understood, massive structure in the nucleus of cells called the mediator complex, which acts as a bridge between transcription factors and transcriptional machinery. Inhibiting these two specific kinases, Shair and colleagues found, doesn’t shut down all transcription, but instead has gene-specific effects.

“We treated AML cells with cortistatin A and measured the effects on gene expression,” Shair said. “One of the first surprises was that it’s affecting a very small number of genes — we thought it might be in the thousands, but it’s in the low hundreds.”

When Shair, Henry Pelish, a senior research associate in chemistry and chemical biology, and then-Ph.D. student Brian Liau looked closely at which genes were affected, they discovered many were associated with DNA regulatory elements known as “super-enhancers.”

“Humans have about 220 different types of cells in their body — they all have the same genome, but they have to form things like skin and bone and liver cells,” Shair explained. “In all cells, there are a relatively small number of DNA regulatory elements, called super-enhancers. These super-enhancers drive high expression of genes, many of which dictate cellular identity. A big part of cancer is a situation where that identity is lost, and the cells become poorly differentiated and are stuck in an almost stem-cell-like state.”

While a few potential cancer treatments have attacked the disease by down-regulating such cellular identity genes, Shair and colleagues were surprised to find that their molecule actually turned up the activity of those genes in AML cells.

“Before this paper, the thought was that cancer is ramping these genes up, keeping the cells in a hyper-proliferative state and affecting cell growth in that way,” Shair said. “But our molecule is saying that’s one part of the story, and in addition cancer is keeping the dosage of these genes in a narrow range. If it’s too low, the cells die. If they are pushed too high, as with cortistatin A, they return to their normal identity and stop growing.”

Shair’s lab became interested in the molecule several years ago, shortly after it was first isolated and described by other researchers. Early studies suggested it appeared to inhibit just a handful of kinases.

“We tested approximately 400 kinases, and found that it inhibits only CDK8 and CDK19 in cells, which makes it among the most selective kinase inhibitors identified to date,” Shair said. “Having compounds that precisely hit a specific target, like cortistatin A, can help reduce side effects and increase efficacy. In a way, it shatters a dogma because we thought it wasn’t possible for a molecule to be this selective and bind in a site common to all 500 human kinases, but this molecule does it, and it does it because of its 3-D structure. What’s interesting is that most kinase-inhibitor drugs do not have this type of 3-D structure. Nature is telling us that one way to achieve this level of specificity is to make molecules more like cortistatin A.”

Shair’s team successfully synthesized the molecule, which helped them study how it worked and why it affected the growth of a very specific type of cell. Later on, with funding and drug-development expertise provided by Harvard’s Blavatnik Biomedical Accelerator, Shair’s lab created a range of new molecules that may be better suited to clinical application.

“It’s a complex process to make [cortistatin A] — 32 chemical steps,” said Shair. “But we have been able to find less complex structures that act just like the natural compound, with better drug-like properties, and they can be made on a large scale and in about half as many steps.”

“Over the course of several years, we have watched this research progress from an intriguing discovery to a highly promising development candidate,” said Isaac Kohlberg, senior associate provost and chief technology development officer. “The latest results are a real testament to Matt’s ingenuity and dedication to addressing a very tough disease.”

While there is still much work to be done — in particular, to better understand how CDK8 and CDK19 regulate gene expression — the early results have been dramatic.

“This is the kind of thing you do science for,” Shair said, “the idea that once every 10 or 20 years you might find something this interesting, that sheds new light on important, difficult problems. This gives us an opportunity to generate a new understanding of cancer and also develop new therapeutics to treat it. We’re very excited and curious to see where it goes.”

 

Seeking A Better Way To Design Drugs

http://www.technologynetworks.com/medchem/news.aspx?ID=183338

NIH funds research at Worcester Polytechnic Institute to advance a new chemical process for more effective drug development and manufacturing.
The National Institutes of Health (NIH) has awarded $346,000 to Worcester Polytechnic Institute (WPI) for a three-year research project to advance development of a chemical process that could significantly improve the ability to design new pharmaceuticals and streamline the manufacturing of existing drugs.

Led by Marion Emmert, PhD, assistant professor of chemistry and biochemistry at WPI, the research program involves early-stage technology developed in her lab that may yield a more efficient and predictable method of bonding a vital class of structures called aromatic and benzylic amines to a drug molecule.

“Seven of the top 10 pharmaceuticals in use today have these substructures, because they are so effective at creating a biologically active compound,” Emmert said. “The current processes used to add these groups are indirect and not very efficient. So we asked ourselves, can we do it better? ”

For a drug to do its job in the body it must interact with a specific biological target and produce a therapeutic effect. First, the drug needs to physically attach or “bind” to the target, which is a specific part of a cell, protein, or molecule. As a result, designing a new drug is like crafting a three-dimensional jigsaw puzzle piece that fits precisely into an existing biological structure in the body. Aromatic and benzylic amines add properties to the drug that help it bind more efficiently to these biological structures.

Getting those aromatic and benzylic amines into the structure of a drug, however, is difficult. Traditionally, this requires a specialized chemical bond as precursor in a specific location of the drug’s molecular structure. “The current approach to making those bonds is indirect, requires several lengthy steps, and the outcome is not always precise or efficient,” Emmert said. “Only a small percentage of the bonds can be made in the proper place, and sometimes none at all.”

Emmert’s new approach uses novel reagents and metal catalysts to create a process that can attach amines directly, in the right place, every time. In early proof-of-principle experiments, Emmert has succeeded in making several amine bonds directly in one or two days, whereas the standard process can take two weeks with less accuracy. Over the next three years, with support from the NIH, Emmert’s team will continue to study the new catalytic processes in detail. They will also use the new process to synthesize Asacol, a common drug now in use for ulcerative colitis, and expect to significantly shorten its production.

“Some of our early data are promising, but we have a lot more work to do to understand the basic mechanisms involved in the new processes,” Emmert said. “We also have to adapt the process to molecules that could be used directly for drug development.”

 

Antiparasite Drug Developers Win Nobel

William Campbell, Satoshi Omura, and Youyou Tu have won this year’s Nobel Prize in Physiology or Medicine in recognition of their contributions to antiparasitic drug development.

By Karen Zusi and Tracy Vence | October 5, 2015

http://www.the-scientist.com//?articles.view/articleNo/44159/title/Antiparasite-Drug-Developers-Win-Nobel/

William Campbell, Satoshi Omura, and Youyou Tu have made significant contributions to treatments for river blindness, lymphatic filariasis, and malaria; today (October 5) these three scientists were jointly awarded the 2015 Nobel Prize in Physiology or Medicine in recognition of these advancements.

Tu is being recognized for her discoveries leading to the development of the antimalarial drug artemisinin. Campbell and Omura jointly received the other half of this year’s prize for their separate work leading to the discovery of the drug avermectin, which has been used to develop therapies for river blindness and lymphatic filariasis.

“These discoveries are now more than 30 years old,” David Conway, a professor of biology of the London School of Hygiene & Tropical Medicine, told The Scientist. “[These drugs] are still, today, the best two groups of compounds for antimalarial use, on the one hand, and antinematode worms and filariasis on the other.”

Omura, a Japanese microbiologist at Kitasato University in Tokyo, isolated strains of the soil bacteriaStreptomyces in a search for those with promising antibacterial activity. He eventually narrowed thousands of cultures down to 50.

Now research fellow emeritus at Drew University in New Jersey, Campbell spent much of his career at Merck, where he discovered effective antiparasitic properties in one of Omura’s cultures and purified the relevant compounds into avermectin (later refined into ivermectin).

“Bill Campbell is a wonderful scientist, a wonderful man, and a great mentor for undergraduate students,” said his colleague Roger Knowles, a professor of biology at Drew University. “His ability to speak about disease mechanisms and novel strategies to help [fight] these diseases. . . . that’s been a great boon to students.”

Tu began searching for a novel malaria treatment in the 1960s in traditional herbal medicine. She served as the head of Project 523, a program at the China Academy of Chinese Medical Sciences in Beijing aimed at finding new drugs for malaria. Tu successfully extracted a promising compound from the plant Artemisia annu that was highly effective against the malaria parasite. In recognition of her malaria research, Tu won a Lasker Award in 2011.

 

Optogenetics Advances in Monkeys

Researchers have selectively activated a specific neural pathway to manipulate a primate’s behavior.

By Kerry Grens | October 5, 2015

http://www.the-scientist.com//?articles.view/articleNo/44156/title/Optogenetics-Advances-in-Monkeys/

Scientists have used optogenetics to target a specific neural pathway in the brain of a macaque monkey and alter the animal’s behavior. As the authors reported in Nature Communications last month, such a feat had been accomplished only in rodents before.

Optogenetics relies on the insertion of a gene for a light-sensitive ion channel. When present in neurons, the channel can turn on or off the activity of a neuron, depending on the flavor of the channel. Previous attempts to use optogenetics in nonhuman primates affected brain regions more generally, rather than particular neural circuits. In this case, Masayuki Matsumoto of Kyoto University and colleagues delivered the channel’s gene specifically to one area of the monkey’s brain called the frontal eye field.

They found that not only did the neurons in this region respond to light shone on the brain, but the monkey’s behavior changed as well. The stimulation caused saccades—quick eye movements. “Our findings clearly demonstrate the causal relationship between the signals transmitted through the FEF-SC [frontal eye field-superior colliculus] pathway and saccadic eye movements,” Matsumoto and his colleagues wrote in their report.

“Over the decades, electrical microstimulation and pharmacological manipulation techniques have been used as tools to modulate neuronal activity in various brain regions, permitting investigators to establish causal links between neuronal activity and behaviours,” they continued. “These methodologies, however, cannot selectively target the activity (that is, the transmitted signal) of a particular pathway connecting two regions. The advent of pathway-selective optogenetic approaches has enabled investigators to overcome this issue in rodents and now, as we have demonstrated, in nonhuman primates.”

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Reported by: Dr. Venkat S. Karra, Ph.D.

 

Brain structures involved in dealing with fear...

 

Major depression or chronic stress can cause the loss of brain volume, a condition that contributes to both emotional and cognitive impairment. Now a team of researchers led by Yale University scientists has discovered one reason why this occurs—a single genetic switch that triggers loss of brain connections in humans and depression in animal models.

 

The findings, reported in Nature Medicine, show that the genetic switch known as a transcription factor represses the expression of several genes that are necessary for the formation of synaptic connections between brain cells, which in turn could contribute to loss of brain mass in the prefrontal cortex.

 

“We wanted to test the idea that stress causes a loss of brain synapses in humans,” said senior author Ronald Duman, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of neurobiology and of pharmacology. “We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated.”

 

The research team analyzed tissue of depressed and non-depressed patients donated from a brain bank and looked for different patterns of gene activation. The brains of patients who had been depressed exhibited lower levels of expression in genes that are required for the function and structure of brain synapses. Lead author and postdoctoral researcher H.J. Kang discovered that at least five of these genes could be regulated by a single transcription factor called GATA1. When the transcription factor was activated, rodents exhibited depressive-like symptoms, suggesting GATA1 plays a role not only in the loss of connections between neurons but also in symptoms of depression.

 

Duman theorizes that genetic variations in GATA1 may one day help identify people at high risk for major depression or sensitivity to stress.

 

“We hope that by enhancing synaptic connections, either with novel medications or behavioral therapy, we can develop more effective antidepressant therapies,” Duman said.

 

source:

 

http://www.rdmag.com/News/2012/08/Life-Sciences-Team-Discovers-How-Stress-Depression-Can-Shrink-The-Brain/

 

 

 

 

 

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