Posts Tagged ‘neurobiology’

Neuron clearing with age

Larry H. Bernstein, MD, FCAP, Curator



Brain Guardians Remove Dying Neurons

Salk scientists show how immune receptors clear dead and dysfunctional brain cells and how they might be targets for treating neurodegenerative diseases

By Salk Institute for Biological Studies

By adolescence, your brain already contains most of the neurons that you’ll have for the rest of your life. But a few regions continue to grow new nerve cells—and require the services of cellular sentinels, specialized immune cells that keep the brain safe by getting rid of dead or dysfunctional cells.

Now, Salk scientists have uncovered the surprising extent to which both dying and dead neurons are cleared away, and have identified specific cellular switches that are key to this process. The work was detailed in Nature on April 6, 2016.

Video courtesy of the Salk Institute

“We discovered that receptors on immune cells in the brain are vital for both healthy and injured states,” says Greg Lemke, senior author of the work, a Salk professor of molecular neurobiology and the holder of the Françoise Gilot-Salk Chair. “These receptors could be potential therapeutic targets for neurodegenerative conditions or inflammation-related disorders, such as Parkinson’s disease.”

death in the brain

An accumulation of dead cells (green spots) is seen in the subventricular zone (SVZ)—a neurogenic region—of the brain in a mouse lacking the receptors Mer and Axl. (Blue staining marks all cells.) No green spots are seen in the SVZ from a normal mouse. IMAGE CREDIT: SALK INSTITUTE

Two decades ago, the Lemke lab discovered that immune cells express critical molecules called TAM receptors, which have since become a focus for autoimmune and cancer research in many laboratories. Two of the TAM receptors, dubbed Mer and Axl, help immune cells called macrophages act as garbage collectors, identifying and consuming the over 100 billion dead cells that are generated in a human body every day.

For the current study, the team asked if Mer and Axl did the same job in the brain. Specialized central nervous system macrophages called microglia make up about 10 percent of cells in the brain, where they detect, respond to and destroy pathogens. The researchers removed Axl and Mer in the microglia of otherwise healthy mice. To their surprise, they found that the absence of the two receptors resulted in a large pile-up of dead cells, but not everywhere in the brain. Cellular corpses were seen only in the small regions where the production of new neurons—neurogenesis—is observed.

Many cells die normally during adult neurogenesis, but they are immediately eaten by microglia. “It is very hard to detect even a single dead cell in a normal brain, because they are so efficiently recognized and cleared by microglia,” says Paqui G. Través, a co-first author on the paper and former Salk research associate. “But in the neurogenic regions of mice lacking Mer and Axl, we detected many such cells.”

When the researchers more closely examined this process by tagging the newly growing neurons in mice’s microglia missing Mer and Axl, they noticed something else interesting. New neurons that migrate to the olfactory bulb, or smell center, increased dramatically without Axl and Mer around. Mice lacking the TAM receptors had a 70 percent increase in newly generated cells in the olfactory bulb than normal mice.

Video courtesy of the Salk Institute

How—and to what extent—this unchecked new neural growth affects a mouse’s sense of smell is not yet known, according to Lemke, though it is an area the lab will explore. But the fact that so many more living nerve cells were able to migrate into the olfactory bulb in the absence of the receptors suggests that Mer and Axl have another role aside from clearing dead cells—they may actually also target living, but functionally compromised, cells.

“It appears as though a significant fraction of cell death in neurogenic regions is not due to intrinsic death of the cells but rather is a result of the microglia themselves, which are killing a fraction of the cells by engulfment,” says Lemke. “In other words, some of these newborn neuron progenitors are actually being eaten alive.”

This isn’t necessarily a bad thing in the healthy brain, Lemke adds. The brain produces more neurons than it can use and then prunes back the cells that aren’t needed. However, in an inflamed or diseased brain, the destruction of living cells may backfire.

Greg Lemke and Lawrence Fourgeaud

Greg Lemke and Lawrence Fourgeaud PHOTO CREDIT: SALK INSTITUTE

The Lemke lab did one more series of experiments to understand the role of TAM receptors in disease: they looked at the activity of Axl and Mer in a mouse model of Parkinson’s disease. This model produces a human protein present in an inherited form of the disease that results in a slow degeneration of the brain. The team saw that Axl was far more active in this setting, consistent with other studies showing that increased Axl is a reliable indicator of inflammation in tissues.

the area of a brain lacking Mer and Axl

In the area of a brain lacking Mer and Axl a ‘trail of death’ is apparent from the migratory pathway from the neurogenic region to the olfactory bulb (smell center of the brain). Blue staining marks all cells, and green spots are dead cells. No green spots are seen in the same section from a normal mouse. IMAGE CREDIT: SALK INSTITUTE

“It seems that we can modify the course of the disease in an animal model by manipulating Axl and Mer,” says Lawrence Fourgeaud, a co-first author on the paper and former Salk research associate. The team cautions that more research needs to be done to determine if modulating the TAM receptors could be a viable therapy for neurodegenerative disease involving microglia.

Other researchers on the paper were Yusuf Tufail, Humberto Leal-Bailey, Erin D. Lew, Patrick G. Burrola, Perri Callaway, Anna Zagórska and Axel Nimmerjahn of the Salk Institute; and Carla V. Rothlin of the Yale University School of Medicine.

The work was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Howard Hughes Medical Institute, and the NomisH.N. and Frances C. Berger, Fritz B. Burns, HKT, WaittRita Allen, and Hearst foundations.

Related Article: How Neurons Lose Their Connections

Related Article: Beer Compound Could Help Fend Off Alzheimer’s and Parkinson’s Diseases


TAM receptors regulate multiple features of microglial physiology

Lawrence FourgeaudPaqui G. TravésYusuf TufailHumberto Leal-Bailey, …., Axel Nimmerjahn Greg Lemke
Nature 532:240–244 (14 April 2016).

Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells1. Here we show that the TAM receptor tyrosine kinases Mer and Axl2 regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis3, 4 is normally driven by both TAM receptor ligands Gas6 and protein S5. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson’s disease6. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.




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Schizophrenic hallucinations

Larry H. Bernstein, MD, FCAP, Curator


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


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).


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.

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.

(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

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.


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//


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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