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Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient.
Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology.
Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions.
These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the ‘dysconnectivity hypothesis’ of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations.
The 22q11.2 deletion syndrome (22q11DS) is caused by a deletion on chromosome 22 locus q11.2. This copy number variant results in haplo-insufficiency of the catechol-O-methyltransferase (COMT) gene, and is associated with a significant increase in the risk for developing cognitive impairments and psychosis. The COMT gene encodes an enzyme that primarily modulates clearance of dopamine (DA) from the synaptic cleft, especially in the prefrontal cortical areas. Consequently, extracellular DA levels may be increased in prefrontal brain areas in 22q11DS, which may underlie the well-documented susceptibility for cognitive impairments and psychosis in affected individuals. This study aims to examine DA D2/3 receptor binding in frontal brain regions in adults with 22q11DS, as a proxy of frontal DA levels.
The study was performed in 14 non-psychotic, relatively high functioning adults with 22q11DS and 16 age- and gender-matched healthy controls (HCs), who underwent DA D2/3 receptor [18F]fallypride PET imaging. Frontal binding potential (BPND) was used as the main outcome measure.
BPND was significantly lower in adults with 22q11DS compared with HCs in the prefrontal cortex and the anterior cingulate gyrus. After Bonferroni correction significance remained for the anterior cingulate gyrus. There were no between-group differences in BPND in the orbitofrontal cortex and anterior cingulate cortex.
This study is the first to demonstrate lower frontal D2/3 receptor binding in adults with 22q11DS. It suggests that a 22q11.2 deletion affects frontal dopaminergic neurotransmission.
22q11.2 deletion syndrome (22q11DS), one of the most common recurrent copy number variant disorders, is associated with dopaminergic abnormalities and increased risk for psychotic disorders.
Given the elevated prevalence of substance use and dopaminergic abnormalities in non-deleted patients with psychosis, we investigated the prevalence of substance use in 22q11DS, compared with that in non-deleted patients with psychosis and matched healthy controls.
This cross-sectional study involved 434 patients with 22q11DS, 265 non-deleted patients with psychosis and 134 healthy controls. Psychiatric diagnosis, full-scale IQ and COMT Val158Met genotype were determined in the 22q11DS group. Substance use data were collected according to the Composite International Diagnostic Interview.
The prevalence of total substance use (36.9%) and substance use disorders (1.2%), and weekly amounts of alcohol and nicotine use, in patients with 22q11DS was significantly lower than in non-deleted patients with psychosis or controls. Compared with patients with 22q11DS, healthy controls were 20 times more likely to use substances in general (P < 0.001); results were also significant for alcohol and nicotine use separately. Within the 22q11DS group, there was no relationship between the prevalence of substance use and psychosis or COMT genotype. Male patients with 22q11DS were more likely to use substances than female patients with 22q11DS.
The results suggest that patients with 22q11DS are at decreased risk for substance use and substance use disorders despite the increased risk of psychotic disorders. Further research into neurobiological and environmental factors involved in substance use in 22q11DS is necessary to elucidate the mechanisms involved.
Depression has been associated with abnormalities in neural underpinnings of Reward Learning (RL). However, inconsistencies have emerged, possibly owing to medication effects. Additionally, it remains unclear how neural RL signals relate to real-life behaviour. The current study, therefore, examined neural RL signals in young, mildly to moderately depressed – but non-help-seeking and unmedicated – individuals and how these signals are associated with depressive symptoms and real-life motivated behaviour.
Individuals with symptoms along the depression continuum (n = 87) were recruited from the community. They performed an RL task during functional Magnetic Resonance Imaging and were assessed with the Experience Sampling Method (ESM), completing short questionnaires on emotions and behaviours up to 10 times/day for 15 days. Q-learning model-derived Reward Prediction Errors (RPEs) were examined in striatal areas, and subsequently associated with depressive symptoms and an ESM measure capturing (non-linearly) how anticipation of reward experience corresponds to actual reward experience later on.
Significant RPE signals were found in the striatum, insula, amygdala, hippocampus, frontal and occipital cortices. Region-of-interest analyses revealed a significant association between RPE signals and (a) self-reported depressive symptoms in the right nucleus accumbens (b = −0.017, p = 0.006) and putamen (b = −0.013, p = .012); and (b) the quadratic ESM variable in the left (b = 0.010, p = .010) and right (b = 0.026, p = 0.011) nucleus accumbens and right putamen (b = 0.047, p < 0.001).
Striatal RPE signals are disrupted along the depression continuum. Moreover, they are associated with reward-related behaviour in real-life, suggesting that real-life coupling of reward anticipation and engagement in rewarding activities might be a relevant target of psychological therapies for depression.
Abnormalities in reward learning in psychotic disorders have been proposed to be linked to dysregulated subcortical dopaminergic (DA) neurotransmission, which in turn is a suspected mechanism for predisposition to psychosis. We therefore explored the striatal dopaminergic modulation of reward processing and its behavioral correlates in individuals at familial risk for psychosis.
We performed a DA D2/3 receptor [18F]fallypride positron emission tomography scan during a probabilistic reinforcement learning task in 16 healthy first-degree relatives of patients with psychosis and 16 healthy volunteers, followed by a 6-day ecological momentary assessment study capturing reward-oriented behavior in the everyday life.
We detected significant reward-induced DA release in bilateral caudate, putamen and ventral striatum of both groups, with no group differences in its magnitude nor spatial extent. In both groups alike, greater extent of reward-induced DA release in all regions of interest was associated with better performance in the task, as well as in greater tendency to be engaged in reward-oriented behavior in the daily life.
These findings suggest intact striatal dopaminergic modulation of reinforcement learning and reward-oriented behavior in individuals with familial predisposition to psychosis. Furthermore, this study points towards a key link between striatal reward-related DA release and pursuit of ecologically relevant rewards.
There has been much debate as to whether the association between cannabis and subclinical expression of psychosis is causal, or whether psychotic experiences may prompt cannabis use in individuals at genetic risk for psychosis as a means of self-medication. The Genetic Risk and Outcome in Psychosis (GROUP) study investigated the association between familial liability for psychosis and sensitivity to cannabis, using patient sibling and sibling-control pairs analyses. This study focused on gene-environment interactions relevant to psychotic disorders, and included patients with psychotic disorder, their siblings and community controls. Caspi and colleagues highlighted the importance of individual genetic vulnerability when they reported an interaction between cannabis use and variation in the gene that encodes catecholamine-O-methyl transferase (COMT). Given that different types of cannabis clearly affect mental health differentially, more research is needed to understand how genetic liability may increase sensitivity to, or preference for, the specific constituents of cannabis.
Lack of social interaction, which is characteristically seen in people
with autistic-spectrum disorder, may be caused by malfunctioning of the
frontostriatal reward systems. However, no reported in
vivo brain imaging studies have investigated reward
mechanisms in autistic-spectrum disorder.
To investigate functional brain activation during reward feedback in
people with autistic-spectrum disorder and control individuals.
We used event-related functional magnetic resonance imaging to examine
the neural substrates of monetary reward in individuals with
autistic-spectrum disorder and matched controls.
When rewarded, individuals with autism compared with control individuals
showed significantly greater brain activation in the left anterior
cingulate gyrus. In addition, activation of this region was negatively
correlated with social interaction as measured by the Autism Diagnostic
In people with autistic-spectrum disorder, achieving reward is associated
with significant differences in the activation of areas known to be
responsible for attention and arousal, and this may partially underpin
some deficits in social behaviour.
We studied the functional neuroanatomy of social behaviour in
velo-cardio-facial syndrome (VCFS) using a facial emotional processing task
and functional magnetic resonance imaging in adults with this syndrome and
controls matched for age and IQ. The VCFS group had less activation in the
right insula and frontal brain regions and more activation in occipital
regions. Genetically determined abnormalities in pathways including those
involved in emotional processing may underlie deficits in social cognition
in people with VCFS.
Stephan Eliez, Division of Child and Adolescent Psychiatry, Geneva University School of Medicine, Switzerland,
Therese van Amelsvoort, Department of Psychiatry, Academic Medical Centre, Amsterdam, Holland
Kieran C. Murphy, Education and Research Centre, Royal College of Surgeons of Ireland,Peter J. Scambler, Institute of Child Health, University College London
This chapter discusses the currently available neuroimaging literature in people with velo-cardio-facial syndrome (VCFS), and explains how this contributes to our understanding of the neurobiology of schizophrenia in the general population. Several publications have investigated quantitative volumetric changes in VCFS children and adolescents. Structural alteration of the cerebellum in children and adolescents with VCFS was congruent with several qualitative studies reporting reduction in posterior fossa, cerebellum, or vermis. Using cross-sectional data analysis, changes of temporal and mesio-temporal lobe structures in individuals with VCFS compared with typically developing subjects were investigated. Imprinting is a genetic mechanism in which gene expression is modulated by the parental origin of the chromosome on which the gene is located. Research on imprinting has shown that parental origin of a genomic deletion can affect the physical and cognitive phenotype of individuals with the genetic disorder.
Velo-cardio-facial syndrome (VCFS) is associated with deletions in the q11 band of chromosome 22, learning disability and psychosis, but the neurobiological basis is poorly understood.
To investigate brain anatomy in adults with VCFS.
Magnetic resonance imaging was used to study 10 patients with VCFS and 13 matched controls. We carried out three analyses: qualitative; traced regional brain volume; and measurement of grey and white matter volume.
The subjects with VCFS had: a high prevalence of white matter hyperintensities and abnormalities of the septum pellucidum; a significantly smaller volume of cerebellum; and widespread differences in white matter bilaterally and regional specific differences in grey matter in the left cerebellum, insula, and frontal and right temporal lobes.
Deletion at chromosome 22q11 is associated with brain abnormalities that are most likely neurodevelopmental and may partially explain the high prevalence of learning disability and psychiatric disorder in VCFS.