Genetic risk for schizophrenia is associated with increased proportion of indirect connections in brain networks revealed by a semi-metric analysis: evidence from population sample stratified for polygenic risk.

Research studies based on tractography have revealed a prominent reduction of asymmetry in some key white-matter tracts in schizophrenia (SCZ). However, we know little about the influence of common genetic risk factors for SCZ on the efficiency of routing on structural brain networks (SBNs). Here, we use a novel recall-by-genotype approach, where we sample young adults from a population-based cohort (ALSPAC:N genotyped = 8,365) based on their burden of common SCZ risk alleles as defined by polygenic risk score (PRS). We compared 181 individuals at extremes of low (N = 91) or high (N = 90) SCZ-PRS under a robust diffusion MRI-based graph theoretical SBN framework. We applied a semi-metric analysis revealing higher SMR values for the high SCZ-PRS group compared with the low SCZ-PRS group in the left hemisphere. Furthermore, a hemispheric asymmetry index showed a higher leftward preponderance of indirect connections for the high SCZ-PRS group compared with the low SCZ-PRS group (PFDR < 0.05). These findings might indicate less efficient structural connectivity in the higher genetic risk group. This is the first study in a population-based sample that reveals differences in the efficiency of SBNs associated with common genetic risk variants for SCZ.

Genetic risk for schizophrenia is associated with altered visually-induced gamma band activity: evidence from a population sample stratified polygenic risk.

Gamma oscillations (30-90 Hz) have been proposed as a signature of cortical visual information processing, particularly the balance between excitation and inhibition, and as a biomarker of neuropsychiatric diseases. Magnetoencephalography (MEG) provides highly reliable visual-induced gamma oscillation estimates, both at sensor and source level. Recent studies have reported a deficit of visual gamma activity in schizophrenia patients, in medication naive subjects, and high-risk clinical participants, but the genetic contribution to such a deficit has remained unresolved. Here, for the first time, we use a genetic risk score approach to assess the relationship between genetic risk for schizophrenia and visual gamma activity in a population-based sample drawn from a birth cohort. We compared visual gamma activity in a group (N = 104) with a high genetic risk profile score for schizophrenia (SCZ-PRS) to a group with low SCZ-PRS (N = 99). Source-reconstructed V1 activity was extracted using beamformer analysis applied to MEG recordings using individual MRI scans. No group differences were found in the induced gamma peak amplitude or peak frequency. However, a non-parametric statistical contrast of the response spectrum revealed more robust group differences in the amplitude of high-beta/gamma power across the frequency range, suggesting that overall spectral shape carries important biological information beyond the individual frequency peak. Our findings show that changes in gamma band activity correlate with liability to schizophrenia and suggest that the index changes to synaptic function and neuronal firing patterns that are of pathophysiological relevance rather than consequences of the disorder.

Sleep problems and associations with psychopathology and cognition in young people with 22q11.2 deletion syndrome (22q11.2DS).

BACKGROUND: Young people with 22q11.2 deletion syndrome (22q11.2DS) are at high risk for neurodevelopmental disorders. Sleep problems may play a role in this risk but their prevalence, nature and links to psychopathology and cognitive function remain undescribed in this population. METHOD: Sleep problems, psychopathology, developmental coordination and cognitive function were assessed in 140 young people with 22q11.2DS (mean age = 10.1, s.d. = 2.46) and 65 unaffected sibling controls (mean age = 10.8, s.d.SD = 2.26). Primary carers completed questionnaires screening for the children's developmental coordination and autism spectrum disorder. RESULTS: Sleep problems were identified in 60% of young people with 22q11.2DS compared to 23% of sibling controls (OR 5.00, p < 0.001). Two patterns best-described sleep problems in 22q11.2DS: restless sleep and insomnia. Restless sleep was linked to increased ADHD symptoms (OR 1.16, p < 0.001) and impaired executive function (OR 0.975, p = 0.013). Both patterns were associated with elevated symptoms of anxiety disorder (restless sleep: OR 1.10, p = 0.006 and insomnia: OR 1.07, p = 0.045) and developmental coordination disorder (OR 0.968, p = 0.0023, and OR 0.955, p = 0.009). The insomnia pattern was also linked to elevated conduct disorder symptoms (OR 1.53, p = 0.020). CONCLUSIONS: Clinicians and carers should be aware that sleep problems are common in 22q11.2DS and index psychiatric risk, cognitive deficits and motor coordination problems. Future studies should explore the physiology of sleep and the links with the neurodevelopment in these young people.

The impact of the COMT genotype and cognitive demands on facets of intra-subject variability.

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.

Preliminary evidence for genetic overlap between body mass index and striatal reward response.

The reward-processing network is implicated in the aetiology of obesity. Several lines of evidence suggest obesity-linked genetic risk loci (such as DRD2 and FTO) may influence individual variation in body mass index (BMI) through neuropsychological processes reflected in alterations in activation of the striatum during reward processing. However, no study has tested the broader hypotheses that (a) the relationship between BMI and reward-related brain activation (measured through the blood oxygenation-dependent (BOLD) signal) may be observed in a large population study and (b) the overall genetic architecture of these phenotypes overlap, an assumption critical for the progression of imaging genetic studies in obesity research. Using data from the Human Connectome Project (N = 1055 healthy, young individuals: average BMI = 26.4), we first establish a phenotypic relationship between BMI and ventral striatal (VS) BOLD during the processing of rewarding (monetary) stimuli (ß = 0.44, P = 0.013), accounting for potential confounds. BMI and VS BOLD were both significantly influenced by additive genetic factors (H2r = 0.57; 0.12, respectively). Further decomposition of this variance suggested that the relationship was driven by shared genetic (ρ g = 0.47, P = 0.011), but not environmental (ρ E = -0.07, P = 0.29) factors. To validate the assumption of genetic pleiotropy between BMI and VS BOLD, we further show that polygenic risk for higher BMI is also associated with increased VS BOLD response to appetitive stimuli (calorically high food images), in an independent sample (N = 81; P FWE-ROI < 0.005). Together, these observations suggest that the genetic factors link risk to obesity to alterations within key nodes of the brain's reward circuity. These observations provide a basis for future work exploring the mechanistic role of genetic loci that confer risk for obesity using the imaging genetics approach.

Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma.

The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects - using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re-uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function - and its response to pharmacological intervention - to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non-invasive (MEG) procedures.

Further support for association between GWAS variant for positive emotion and reward systems.

A recent genome-wide association study (GWAS) identified a significant single-nucleotide polymorphism (SNP) for trait-positive emotion at rs322931 on chromosome 1, which was also associated with brain activation in the reward system of healthy individuals when observing positive stimuli in a functional magnetic resonance imaging (fMRI) study. In the current study, we aimed to further validate the role of variation at rs322931 in reward processing. Using a similar fMRI approach, we use two paradigms that elicit a strong ventral striatum (VS) blood oxygen-level dependency (BOLD) response in a sample of young, healthy individuals (N=82). In the first study we use a similar picture-viewing task to the discovery sample (positive>neutral stimuli) to replicate an effect of the variant on emotion processing. In the second study we use a probabilistic reversal learning procedure to identify reward processing during decision-making under uncertainly (reward>punishment). In a region of interest (ROI) analysis of the bilateral VS, we show that the rs322931 genotype was associated with BOLD in the left VS during the positive>neutral contrast (PROI-CORRECTED=0.045) and during the reward>punishment contrast (PROI-CORRECTED=0.018), although the effect of passive picture viewing was in the opposite direction from that reported in the discovery sample. These findings suggest that the recently identified GWAS hit may influence positive emotion via individual differences in activity in the key hubs of the brain's reward system. Furthermore, these effects may not be limited to the passive viewing of positive emotional scenes, but may also be observed during dynamic decision-making. This study suggests that future studies of this GWAS locus may yield further insight into the biological mechanisms of psychopathologies characterised by deficits in reward processing and positive emotion.

Clinical improvements following bilateral anterior capsulotomy in treatment-resistant depression.

BACKGROUND: The purpose of this study was to evaluate a programme of lesion surgery carried out on patients with treatment-resistant depression (TRD). METHOD: This was a retrospective study looking at clinical and psychometric data from 45 patients with TRD who had undergone bilateral stereotactic anterior capsulotomy surgery over a period of 15 years, with the approval of the Mental Health Act Commission (37 with unipolar depression and eight with bipolar disorder). The Beck Depression Inventory (BDI) before and after surgery was used as the primary outcome measure. The Montgomery-Asberg Depression Rating Scale was administered and cognitive aspects of executive and memory functions were also examined. We carried out a paired-samples t test on the outcome measures to determine any statistically significant change in the group as a consequence of surgery. RESULTS: Patients improved on the clinical measure of depression after surgery by -21.20 points on the BDI with a 52% change. There were no significant cognitive changes post-surgery. Six patients were followed up in 2013 by phone interview and reported a generally positive experience. No major surgical complications occurred. CONCLUSIONS: With the limitations of an uncontrolled, observational study, our data suggest that capsulotomy can be an effective treatment for otherwise TRD. Performance on neuropsychological tests did not deteriorate.

A Hedonism Hub in the Human Brain.

Human values are abstract ideals that motivate behavior. The motivational nature of human values raises the possibility that they might be underpinned by brain structures that are particularly involved in motivated behavior and reward processing. We hypothesized that variation in subcortical hubs of the reward system and their main connecting pathway, the superolateral medial forebrain bundle (slMFB) is associated with individual value orientation. We conducted Pearson's correlation between the scores of 10 human values and the volumes of 14 subcortical structures and microstructural properties of the medial forebrain bundle in a sample of 87 participants, correcting for multiple comparisons (i.e.,190). We found a positive association between the value that people attach to hedonism and the volume of the left globus pallidus (GP).We then tested whether microstructural parameters (i.e., fractional anisotropy and myelin volume fraction) of the slMFB, which connects with the GP, are also associated to hedonism and found a significant, albeit in an uncorrected level, positive association between the myelin volume fraction within the left slMFB and hedonism scores. This is the first study to elucidate the relationship between the importance people attach to the human value of hedonism and structural variation in reward-related subcortical brain regions.

fMRI neurofeedback of higher visual areas and perceptual biases.

The self-regulation of brain activation via neurofeedback training offers a method to study the relationship between brain areas and perception in a more direct manner than the conventional mapping of brain responses to different types of stimuli. The current proof-of-concept study aimed to demonstrate that healthy volunteers can self-regulate activity in the parahippocampal place area (PPA) over the fusiform face area (FFA). Both areas are involved in higher order visual processing and are activated during the imagery of scenes and faces respectively. Participants (N=9) were required to upregulate PPA relative to FFA activity, and all succeeded at the task, with imagery of scenes being the most commonly reported mental strategy. A control group (N=8) underwent the same imagery and testing procedure, albeit without neurofeedback, in a mock MR scanner to account for any non-specific training effects. The upregulation of PPA activity occurred concurrently with activation of prefrontal and parietal areas, which have been associated with ideation and mental image generation. We tested whether successful upregulation of the PPA relative to FFA had consequences on perception by assessing bistable perception of faces and houses in a binocular rivalry task (before and after the scanning sessions) and categorisation of faces and scenes presented in transparent composite images (during scanning, interleaved with the self-regulation blocks). Contrary to our expectations, upregulation of the PPA did not alter the duration of face or house perception in the rivalry task and response speed and accuracy in the categorisation task. This conclusion was supported by the results of another control experiment (N=10 healthy participants) that involved intensive exposure to category-specific stimuli and did not show any behavioural or perceptual changes. We conclude that differential self-regulation of higher visual areas can be achieved, but that perceptual biases under conditions of stimulus rivalry are relatively robust against such internal modulation of localised brain activity. This study sets the basis for future investigations of perceptual and behavioural consequences of localised self-regulation of neural activity.

Common alleles contribute to schizophrenia in CNV carriers.

The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10(-17)) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.

CACNA1C risk variant is associated with increased amygdala volume.

Genome-wide association studies suggest that genetic variation within L-type calcium channel subunits confer risk to psychosis. The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology. Amongst others, it has been implicated in alterations in amygdala structure and function. In the present study, we show that the risk allele (A) is associated with increased amygdala volume in healthy individuals (n = 258). This observation reinforces a hypothesis that genetic variation may confer risk to psychosis via alterations in limbic structures. Further study of CACNA1C using intermediate phenotypes for psychosis will determine the mechanisms by which variation in this gene confers risk.

Replication study implicates COMT val158met polymorphism as a modulator of probabilistic reward learning.

Previous studies suggest that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (val158met) may modulate reward-guided decision making in healthy individuals. The polymorphism affects dopamine catabolism and thus modulates prefrontal dopamine levels, which may lead to variation in individual responses to risk and reward. We previously showed, using tasks that index reward responsiveness (measured by responses bias towards reinforced stimuli) and risk taking (measured by the Balloon Analogue Risk Task), that COMT met homozygotes had increased reward responsiveness and, thus, an increased propensity to seek reward. In this study, we sought to replicate these effects in a larger, independent cohort of Caucasian UK university students and staff with similar demographic characteristics (n = 101; 54 females, mean age: 22.2 years). Similarly to our previous study, we observed a significant trial × COMT genotype interaction (P = 0.047; η(2) = 0.052), which was driven by a significant effect of COMT on the incremental acquisition of response bias [response bias at block 3 - block 1 (met/met > val/val: P = 0.028) and block 3 - block 2 (met/met > val/val: P = 0.007)], suggesting that COMT met homozygotes demonstrated higher levels of reward responsiveness by the end of the task. However, we failed to see main effects of COMT genotype on overall response bias or risk-seeking behaviour. These results provide additional evidence that prefrontal dopaminergic variation may have a role in reward responsiveness, but not risk-seeking behaviour. Our findings may have implications for neuropsychiatric disorders characterized by clinical deficits in reward processing such as anhedonia.

CACNA1C risk variant affects reward responsiveness in healthy individuals.

The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia. We investigated whether this risk variant affects reward responsiveness because reward processing is one of the central cognitive-motivational domains implicated in both disorders. In a sample of 164 young, healthy individuals, we show a dose-dependent response, where the rs1006737 risk genotype was associated with blunted reward responsiveness, whereas discriminability did not significantly differ between genotype groups. This finding suggests that the CACNA1C risk locus may have a role in neural pathways that facilitate value representation for rewarding stimuli. Impaired reward processing may be a transdiagnostic phenotype of variation in CACNA1C that could contribute to anhedonia and other clinical features common to both affective and psychotic disorders.

COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures.

Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggests that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.

Pattern classification of valence in depression.

Neuroimaging biomarkers of depression have potential to aid diagnosis, identify individuals at risk and predict treatment response or course of illness. Nevertheless none have been identified so far, potentially because no single brain parameter captures the complexity of the pathophysiology of depression. Multi-voxel pattern analysis (MVPA) may overcome this issue as it can identify patterns of voxels that are spatially distributed across the brain. Here we present the results of an MVPA to investigate the neuronal patterns underlying passive viewing of positive, negative and neutral pictures in depressed patients. A linear support vector machine (SVM) was trained to discriminate different valence conditions based on the functional magnetic resonance imaging (fMRI) data of nine unipolar depressed patients. A similar dataset obtained in nine healthy individuals was included to conduct a group classification analysis via linear discriminant analysis (LDA). Accuracy scores of 86% or higher were obtained for each valence contrast via patterns that included limbic areas such as the amygdala and frontal areas such as the ventrolateral prefrontal cortex. The LDA identified two areas (the dorsomedial prefrontal cortex and caudate nucleus) that allowed group classification with 72.2% accuracy. Our preliminary findings suggest that MVPA can identify stable valence patterns, with more sensitivity than univariate analysis, in depressed participants and that it may be possible to discriminate between healthy and depressed individuals based on differences in the brain's response to emotional cues.

COMT val158met predicts reward responsiveness in humans.

A functional variant of the catechol-O-methyltransferase (COMT) gene [val158met (rs4680)] is frequently implicated in decision-making and higher cognitive functions. It may achieve its effects by modulating dopamine-related decision-making and reward-guided behaviour. Here we demonstrate that individuals with the met/met polymorphism have greater responsiveness to reward than carriers of the val allele and that this correlates with risk-seeking behaviour. We assessed performance on a reward responsiveness task and the Balloon analogue risk task, which measure how participants (N = 70, western European, university and postgraduate students) respond to reward and take risks in the presence of available reward. Individuals with the met/met genotype (n = 19) showed significantly higher reward responsiveness, F2,64 = 4.02, P = 0.02, and reward-seeking behaviour, F(2,68) = 4.52, P = 0.01, than did either val/met (n = 25) or val/val (n = 26) carriers. These results highlight a scenario in which genotype-dependent reward responsiveness shapes reward-seeking, therefore suggesting a novel framework by which COMT may modulate behaviour.

Cortical-basal ganglia imbalance in schizophrenia patients and unaffected first-degree relatives.

Structural brain changes are amongst the most robust biological alterations in schizophrenia, and their investigation in unaffected relatives is important for an assessment of the contribution of genetic factors. In this cross-sectional morphometry study we investigated whether volume changes in SZ are linked with genetic vulnerability and whether these effects are separated from secondary illness effects. We compared density of grey and white matter using high-resolution 3D-anatomical MRI imaging data in 31 SZ patients, 29 first-degree relatives and 38 matched healthy controls, using Voxel-Based Morphometry (VBM) with SPM8. Volume of basal ganglia was also compared by manual segmentation. We found increased grey matter in the striatum, globus pallidus internus and thalamus and decreased grey matter in the parahippocampal and cingulate gyri both in SZ patients and relatives. Additionally, SZ patients had decreased volume of temporal, frontal and limbic grey and white matter in comparison with relatives and controls. Relatives showed intermediate values in many of these areas. Increased volume in the thalamus and parts of the basal ganglia and decreased volume of cortical areas and underlying white matter were thus associated with schizophrenia and its genetic vulnerability. These results suggest that brain morphological changes associated with SZ are in part determined by genetic risk factors and are not entirely explained by effects of medication or changes secondary to illness.