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Impulsive and compulsive problem behaviours are associated with a variety of mental disorders. Latent phenotyping indicates the expression of impulsive and compulsive problem behaviours is predominantly governed by a transdiagnostic ‘disinhibition’ phenotype. In a cohort of 117 individuals, recruited as part of the Neuroscience in Psychiatry Network (NSPN), we examined how brain functional connectome and network properties relate to disinhibition. Reduced functional connectivity within a subnetwork of frontal (especially right inferior frontal gyrus), occipital and parietal regions was linked to disinhibition. Findings provide insights into neurobiological pathways underlying the emergence of impulsive and compulsive disorders.
Little is known about time perception, its putative role as cognitive endophenotype, and its neuroanatomical underpinnings in adults with attention deficit hyperactivity disorder (ADHD).
Twenty adults with ADHD, 20 unaffected first-degree relatives and 20 typically developing controls matched for age and gender undertook structural magnetic resonance imaging scans. Voxel-based morphometry with DARTEL was performed to obtain regional grey-matter volumes. Temporal processing was investigated as a putative cognitive endophenotype using a temporal reproduction paradigm. General linear modelling was employed to examine the relationship between temporal reproduction performances and grey-matter volumes.
ADHD participants were impaired in temporal reproduction and unaffected first-degree relatives performed in between their ADHD probands and typically developing controls. Increased grey-matter volume in the cerebellum was associated with poorer temporal reproduction performance.
Adults with ADHD are impaired in time reproduction. Performances of the unaffected first-degree relatives are in between ADHD relatives and controls, suggesting that time reproduction might be a cognitive endophenotype for adult ADHD. The cerebellum is involved in time reproduction and might play a role in driving time performances.
Abnormal brain connectivity or network dysfunction has been suggested as a paradigm to understand several psychiatric disorders. We here review the use of novel meta-analytic approaches in neuroscience that go beyond a summary description of existing results by applying network analysis methods to previously published studies and/or publicly accessible databases. We define this strategy of combining connectivity with other brain characteristics as ‘meta-connectomics’. For example, we show how network analysis of task-based neuroimaging studies has been used to infer functional co-activation from primary data on regional activations. This approach has been able to relate cognition to functional network topology, demonstrating that the brain is composed of cognitively specialized functional subnetworks or modules, linked by a rich club of cognitively generalized regions that mediate many inter-modular connections. Another major application of meta-connectomics has been efforts to link meta-analytic maps of disorder-related abnormalities or MRI ‘lesions’ to the complex topology of the normative connectome. This work has highlighted the general importance of network hubs as hotspots for concentration of cortical grey-matter deficits in schizophrenia, Alzheimer's disease and other disorders. Finally, we show how by incorporating cellular and transcriptional data on individual nodes with network models of the connectome, studies have begun to elucidate the microscopic mechanisms underpinning the macroscopic organization of whole-brain networks. We argue that meta-connectomics is an exciting field, providing robust and integrative insights into brain organization that will likely play an important future role in consolidating network models of psychiatric disorders.
Mentalizing deficits are a hallmark of the autism spectrum condition (ASC) and a potential endophenotype for atypical social cognition in ASC. Differences in performance and neural activation on the ‘Reading the Mind in the Eyes’ task (the Eyes task) have been identified in individuals with ASC in previous studies.
Performance on the Eyes task along with the associated neural activation was examined in adolescents with ASC (n = 50), their unaffected siblings (n = 40) and typically developing controls (n = 40). Based on prior literature that males and females with ASC display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotypes at the level of neural activation: (1) identifying and locating conjunctions of ASC–control and sibling–control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC–control and sibling–control differences across multiple thresholds.
Impaired behavioural performance on the Eyes task was observed in males with ASC compared to controls, but only at trend level in females; and no difference in performance was identified between sibling and same-sex control groups in both sexes. Neural activation showed a substantial endophenotype effect in the female groups but this was only modest in the male groups.
Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than an endophenotypic, marker of ASC. However, the neural response during the Eyes task is a potential endophenotypic marker for ASC, particularly in females.
Psychotic disorders are highly heritable such that the unaffected relatives of patients may manifest characteristics, or endophenotypes, that are more closely related to risk genes than the overt clinical condition. Facial affect processing is dependent on a distributed cortico-limbic network that is disrupted in psychosis. This study assessed facial affect processing and related brain structure as a candidate endophenotype of first-episode psychosis (FEP).
Three samples comprising 30 FEP patients, 30 of their first-degree relatives and 31 unrelated healthy controls underwent assessment of facial affect processing and structural magnetic resonance imaging (sMRI) data. Multivariate analysis (partial least squares, PLS) was used to identify a grey matter (GM) system in which anatomical variation was associated with variation in facial affect processing speed.
The groups did not differ in their accuracy of facial affect intensity rating but differed significantly in speed of response, with controls responding faster than relatives, who responded faster than patients. Within the control group, variation in speed of affect processing was significantly associated with variation of GM density in amygdala, lateral temporal cortex, frontal cortex and cerebellum. However, this association between cortico-limbic GM density and speed of facial affect processing was absent in patients and their relatives.
Speed of facial affect processing presents as a candidate endophenotype of FEP. The normal association between speed of facial affect processing and cortico-limbic GM variation was disrupted in FEP patients and their relatives.
Early Intervention in Psychosis Services (EIS) for young people in England experiencing first-episode psychosis (FEP) were commissioned in 2002, based on an expected incidence of 15 cases per 100 000 person-years, as reported by schizophrenia epidemiology in highly urban settings. Unconfirmed reports from EIS thereafter have suggested higher than anticipated rates. The aim of this study was to compare the observed with the expected incidence and delineate the clinical epidemiology of FEP using epidemiologically complete data from the CAMEO EIS, over a 6-year period in Cambridgeshire, for a mixed rural–urban population.
A population-based study of FEP (ICD-10, F10–39) in people aged 17–35 years referred between 2002 and 2007; the denominator was estimated from mid-year census statistics. Sociodemographic variation was explored by Poisson regression. Crude and directly standardized rates (for age, sex and ethnicity) were compared with pre-EIS rates from two major epidemiological FEP studies conducted in urban English settings.
A total of 285 cases met FEP diagnoses in CAMEO, yielding a crude incidence of 50 per 100 000 person-years [95% confidence interval (CI) 44.5–56.2]. Age- and sex-adjusted rates were raised for people from black ethnic groups compared with the white British [incidence rate ratio (IRR) 2.1, 95% CI 1.1–3.8]. Rates in our EIS were comparable with pre-EIS rates observed in more urban areas after age, sex and ethnicity standardization.
Our findings suggest that the incidence observed in EIS is far higher than originally anticipated and is comparable to rates observed in more urban settings prior to the advent of EIS. Sociodemographic variation due to ethnicity and other factors extend beyond urban populations. Our results have implications for psychosis aetiology and service planning.
Identification of facial emotions has been found to be impaired in schizophrenia but there are uncertainties about the neuropsychological specificity of the finding.
Twenty-two patients with schizophrenia and 20 healthy controls were given tests requiring identification of facial emotion, judgement of the intensity of emotional expressions without identification, familiar face recognition and the Benton Facial Recognition Test (BFRT). The schizophrenia patients were selected to be relatively intellectually preserved.
The patients with schizophrenia showed no deficit in identifying facial emotion, although they were slower than the controls. They were, however, impaired on judging the intensity of emotional expression without identification. They showed impairment in recognizing familiar faces but not on the BFRT.
When steps are taken to reduce the effects of general intellectual impairment, there is no deficit in identifying facial emotions in schizophrenia. There may, however, be a deficit in judging emotional intensity. The impairment found in naming familiar faces is consistent with other evidence of semantic memory impairment in the disorder.
Central to understanding of the behavioural consequences of depression has been the theory that the disorder is accompanied by an increased sensitivity to negative compared with positive reinforcement (negative bias), whereas other theorists have emphasized a global reduction in sensitivity to reinforcement in depression (blunting).
In this study, we used a probabilistic selection task that was designed to examine independently rates of learning to predict both positive and negative reinforcement. Twenty-three depressed out-patients and 23 healthy controls from the local population participated in the study.
No evidence for a negative bias was observed on the task, either during acquisition of the task or during generalization of the learned information. Depressed patients responded slower on the task than controls but showed a similar modulation of reaction times (RTs) as controls following reinforcement. Evidence for blunting was observed on the training phase, as reflected in reduced trial-by-trial adjustment during this phase. However, this effect was related specifically to the severity of anhedonia, as measured by the Snaith–Hamilton Pleasure Scale (SHAPS), and was independent of overall depression severity.
We argue that the observation of a negative bias or blunting in a group of depressed patients may be dependent on the neuropsychological task and the symptoms of the patients tested. Our results provide insight into how these theories might be further tested.
Substance use is implicated in the cause and course of psychosis.
To characterise substance and alcohol use in an epidemiologically representative treatment sample of people experiencing a first psychotic episode in south Cambridgeshire.
Current and lifetime substance use was recorded for 123 consecutive referrals to a specialist early intervention service. Substance use was compared with general population prevalence estimates from the British Crime Survey.
Substance use among people with first-episode psychosis was twice that of the general population and was more common in men than women. Cannabis abuse was reported in 51% of patients (n=62) and alcohol abuse in 43% (n=53). More than half (n=68, 55%) had used Class A drugs, and 38% (n=43) reported polysubstance abuse. Age at first use of cannabis, cocaine, ecstasy and amphetamine was significantly associated with age at first psychotic symptom.
Substance misuse is present in the majority of people with first-episode psychosis and has major implications for management. The association between age at first substance use and first psychotic symptoms has public health implications.
The psychosis-inducing effect of ketamine is important evidence
supporting the glutamate hypothesis of schizophrenia. However, the
symptoms the drug produces have not been described systematically.
To examine the effects of ketamine in healthy people using a structured
Ketamine (200 ng/ml) or placebo was administered by continuous infusion
to 15 healthy volunteers. Symptoms were rated using the Present State
Examination, the Thought, Language and Communication Scale and the Scale
for Assessment of Negative Symptoms.
Ketamine induced a range of perceptual distortions, but not
hallucinations. Referential ideas were seen in nearly half the sample.
There were only mild and infrequent ratings on the thought disorder
scale. Affective flattening and alogia were seen in some volunteers.
Ketamine does not reproduce the full picture of schizophrenia. The main
point of similarity concerns referential thinking. Phenomena resembling
negative symptoms are also seen, but the distinction of these from the
drug's sedative effects requires further elucidation.
Background. Demonstrating specific cognitive impairments in psychotic disorders is difficult. However, specific deficits in memory and executive functions have often been claimed. The Cambridge Neuropsychological Test Automated Battery (CANTAB) tasks of IDED attention-shifting (an executive task) and visuospatial paired associates learning (PAL, a memory task) require intact frontal and temporo-hippocampal functioning, respectively; both have been suggested as markers of disease progress in psychosis.
Method. Seventy-one subjects with a first-episode psychosis or at-risk mental state were assessed on these two tasks during referral to a specialist service, the Cambridge-based CAMEO early intervention team.
Results. Performance on the two tasks was dissociated. Poor performance on the PAL test was associated with increased symptom levels and poorer global function, while failure on the IDED executive test was not found to have significant clinical associations. Duration of illness was not associated with performance on either task.
Conclusions. Visuospatial PAL failure may be a marker of clinical severity at the onset of psychosis while IDED performance may reflect a more stable, trait-like impairment. Dissociated performance on the executive and associative learning tasks may reflect independent, neurally dissociated impairments that do not arise in a fixed order. This may explain some of the heterogeneity of cognitive function seen in early psychosis.
Background. In patients with schizophrenia, passivity delusions are characterized by a difficulty in determining the agency of purposive actions. Neuropsychological and functional neuroimaging data suggest that passivity delusions are associated with dysfunction of the parietal lobe association cortex.
Method. Cortical volume calculated from magnetic resonance imaging data in a group of 12 patients with schizophrenia characterized by motor passivity delusions was compared statistically with the cortical volume of 11 patients without passivity delusions.
Results. Reduced cortical volume was observed in parietal and frontal association cortices in the passivity group.
Conclusions. These data provide direct evidence for the involvement of the parietal lobe in the pathophysiology of passivity delusions in schizophrenia.
Background. The processing of facial emotion involves a distributed network of limbic and paralimbic brain structures. Many of these regions are also implicated in the pathophysiology of mood disorders. Behavioural data indicate that depressed subjects show a state-related positive recognition bias for faces displaying negative emotions. There are sparse data to suggest there may be an analogous, state-related negative recognition bias for negative emotions in mania. We used functional magnetic resonance imaging (fMRI) to investigate the behavioural and neurocognitive correlates of happy and sad facial affect recognition in patients with mania.
Method. Functional MRI and an explicit facial affect recognition task were used in a case-control design to measure brain activation and associated behavioural response to variable intensity of sad and happy facial expressions in 10 patients with bipolar I mania and 12 healthy comparison subjects.
Results. The patients with mania had attenuated subjective rating of the intensity of sad facial expressions, and associated attenuation of activation in the subgenual anterior cingulate and bilateral amygdala, with increased activation in the posterior cingulate and posterior insula. No behavioural or neurocognitive abnormalities were found in response to presentation of happy facial expressions.
Conclusions. Patients with mania showed a specific, mood-congruent, negative bias in sad facial affect recognition, which was associated with an abnormal profile of brain activation in paralimbic regions implicated in affect recognition and mood disorders. Functional imaging of facial emotion recognition may be a useful probe of cortical and subcortical abnormalities in mood disorders.
Background. Medically unexplained visual loss occurs in 1 to 5% of patients attending ophthalmology clinics and for many it runs a chronic course. A psychogenic aetiology is presumed in such cases, but little is known about the underlying neural mechanisms. Recent studies have established the value of functional magnetic resonance imaging (fMRI) in understanding the mechanisms of unexplained motor and sensory symptoms. The purpose of this study was to use a similar strategy (fMRI) to evaluate the cerebral responses to visual stimulation in a group of patients with medically unexplained visual loss, in an attempt to determine the underlying neural mechanisms.
Method. Brain activation induced by periodic (monocular) 8 Hz visual stimulation was detected by fMRI in five patients with unexplained visual loss who fulfilled DSM-IV criteria for conversion disorder, and seven normal volunteers. Between-group differences in mean power of activation were estimated by fitting a one-way analysis of variance (ANOVA) model at each intracerebral voxel in standard space.
Results. Compared with controls, patients showed reduced activation in visual cortices, but increased activation in left inferior frontal cortex, left insula-claustrum, bilateral striatum and thalami, left limbic structures, and left posterior cingulate cortex.
Conclusions. This preliminary study has identified novel neural correlates in patients with unexplained visual loss. The abnormal pattern of activation may reflect inhibition of primary visual cortex or a shift towards non-conscious (implicit) processing.
Background. There is considerable variability between patients in their expression of the diverse range of symptoms encompassed by the syndrome of schizophrenia, which may modulate functional activation to cognitive processing.
Method. Here we investigate associations between schizophrenic subsyndrome scores, identified by factor analysis, and experimentally controlled brain activation. Five factors were defined by rotated principal components analysis of PANSS rating scale measurements in 100 patients with schizophrenia. A subsample of 30 patients and a group of 27 comparison subjects were studied using functional magnetic resonance imaging (fMRI) during the performance of two periodically designed cognitive activation experiments: verbal working memory and psychomotor sequencing.
Results. Factor analysis replicated the five dimensions consistently reported. Within the patient group, power of activation by working memory was negatively associated with global symptom severity in left lingual and temporo-parietal cortices; negatively associated with positive subsyndrome scores in left inferior frontal and superior temporal cortices and basal ganglia; and positively associated with negative subsyndrome scores in lateral and medial premotor cortex. No relationship was observed between subsyndrome scores and functional activation during the motor task. Between-group comparisons demonstrated reduced power of response to the working memory task by patients in bilateral dorsolateral prefrontal and left pre- and post-central cortices.
Conclusions. In this study we observed task-specific modulation of functional response associated with symptom expression in schizophrenia. Our findings are compatible with previous empirical findings and theoretical conceptualization of human brain function, in terms of capacity constraints on activation in the face of competing demands from pathological and task-related cognitive activity.
Background. Neuroimaging studies of tuberous sclerosis complex (TSC) have previously focused mainly on tubers or subependymal nodules. Subtle pathological changes in the structure of the brain have not been studied in detail. Computationally intensive techniques for reliable morphometry of brain structure are useful in disorders like TSC, where there is little prior data to guide selection of regions of interest.
Methods. Dual-echo, fast spin-echo MRI data were acquired from 10 TSC patients of normal intelligence and eight age-matched controls. Between-group differences in grey matter, white matter and cerebrospinal fluid were estimated at each intracerebral voxel after registration of these images in standard space; a permutation test based on spatial statistics was used for inference. CSF-attenuated FLAIR images were acquired for neuroradiological rating of tuber number.
Results. Significant deficits were found in patients, relative to comparison subjects, of grey matter volume bilaterally in the medial temporal lobes, posterior cingulate gyrus, thalamus and basal ganglia, and unilaterally in right fronto-parietal cortex (patients −20%). We also found significant and approximately symmetrical deficits of central white matter involving the longitudinal fasciculi and other major intrahemispheric tracts (patients −21%); and a bilateral cerebellar region of relative white matter excess (patients +28%). Within the patient group, grey matter volume in limbic and subcortical regions of deficit was negatively correlated with tuber count.
Conclusions. Neuropathological changes associated with TSC may be more extensive than hitherto suspected, involving radiologically normal parenchymal structures as well as tubers, although these two aspects of the disorder may be correlated.
Background. Previous neuroimaging studies of children with attention deficit hyperactivity disorder (ADHD) have demonstrated anatomic and functional abnormalities predominantly in frontal and striatal grey matter. Here we report the use of novel image analysis methods, which do not require prior selection of regions of interest, to characterize distributed morphological deficits of both grey and white matter associated with ADHD.
Methods. Eighteen children with a refined phenotype of ADHD, who also met ICD-10 criteria for hyperkinetic disorder (mean age 10·4 years), and 16 normal children (mean age 10·3 years) were compared using magnetic resonance imaging. The groups were matched for handedness, sex, height, weight and head circumference. Morphological differences between groups were estimated by fitting a linear model at each voxel in standard space, applying a threshold to the resulting voxel statistic maps to generate clusters of spatially contiguous suprathreshold voxels, and testing cluster ‘mass’, or the sum of suprathreshold voxel statistics in each 2D cluster, by repeated random resampling of the data.
Results. The hyperkinetic children had significant grey matter deficits in right superior frontal gyrus (Brodmann area (BA) 8/9), right posterior cingulate gyrus (BA 30) and the basal ganglia bilaterally (especially right globus pallidus and putamen). They also demonstrated significant central white matter deficits in the left hemisphere anterior to the pyramidal tracts and superior to the basal ganglia.
Conclusions. This pattern of spatially distributed grey matter deficit in the right hemisphere is compatible with the hypothesis that ADHD is associated with disruption of a large scale neurocognitive network for attention. The left hemispheric white matter deficits may be due to dysmyelination.
Background. We used functional MRI to examine the functional anatomy of inner speech and different forms of auditory verbal imagery (imagining speech) in normal volunteers. We hypothesized that generating inner speech and auditory verbal imagery would be associated with left inferior frontal activation, and that generating auditory verbal imagery would involve additional activation in the lateral temporal cortices.
Methods. Subjects were scanned, while performing inner speech and auditory verbal imagery tasks, using a 1.5 Tesla magnet.
Results. The generation of inner speech was associated with activation in the left inferior frontal/insula region, the left temporo-parietal cortex, right cerebellum and the supplementary motor area. Auditory verbal imagery in general, as indexed by the three imagery tasks combined, was associated with activation in the areas engaged during the inner speech task, plus the left precentral and superior temporal gyri (STG), and the right homologues of all these areas.
Conclusions. These results are consistent with the use of the ‘articulatory loop' during both inner speech and auditory verbal imagery, and the greater engagement of verbal self-monitoring during auditory verbal imagery.
Background. Patients with obsessive–compulsive disorder (OCD) have symptoms that pre-dominantly concern washing (washers) or checking (checkers), or both. Functional neuroimaging has been used to identify the neural correlates of the urge to ritualize but has not distinguished between washing and checking symptoms in OCD. We used functional magnetic resonance imaging to compare the neural response to emotive pictures in washers and checkers.
Methods. In one of two 5-minute experiments, washers (N = 7), checkers (N = 7) and age-matched normal controls (N = 14) were scanned while viewing alternating blocks of normally disgusting (rated as disgusting by all subjects) and neutral pictures. In the other experiment, all patients and a normal subgroup (N = 8) viewed alternating blocks of washer-relevant (rated as more disgusting by washers than normal controls or checkers) and neutral pictures.
Results. In all subjects, normally disgusting pictures activated visual regions implicated in perception of aversive stimuli and the insula, important in disgust perception. Only in washers were similar regions activated by washer-relevant pictures. In checkers, these pictures activated fronto-striatal regions associated with the urge to ritualize in OCD. Normal controls were more similar in neural response to checkers than washers to these pictures. Both normal controls and checkers had frontal regions activated significantly more by washer-relevant than normally disgusting pictures, and had these regions activated significantly more than washers by washer-relevant pictures.
Conclusions. We demonstrate a differential neural response to washer-relevant disgust in washers and checkers: only washers demonstrate a neural response to washer-relevant disgust associated with emotion perception rather than attention to non-emotive visual detail.
Background. Many studies have separately reported abnormalities
of frontal and temporal lobe
structures in schizophrenia, but little is known of structural
fronto-temporal associations in this
condition. We investigated whether male patients with chronic schizophrenia
would show abnormal patterns of correlation between regional brain volumes.
Methods. Structural magnetic resonance images of the brain
42 patients were compared with
43 matched unaffected controls. We explored the pattern of association
between regional brain
volumes by correlational analyses, and non-parametrically tested for
significance of between-group differences by randomization.
Results. The schizophrenics demonstrated significant volume
several brain regions (left
temporal lobe and hippocampus, right dorsolateral prefrontal cortex), and
increases in the ventricular system (third ventricle and left temporal
of the lateral ventricle). Controls demonstrated large positive correlations
(r>0·4) between prefrontal and
temporal lobe regions. By contrast, inter-regional correlations significantly
reduced in schizophrenics included those between prefrontal, anterior
cingulate and temporal regions, and between
posterior cingulate and hippocampus (P<0·05). The
most salient abnormality in patients was a
dissociation between prefrontal and superior temporal gyrus volumes
Conclusions. These results support the existence of a relative
‘fronto-temporal dissociation’ in schizophrenia
which we suggest may be due to lack of mutually trophic influences during
temporal lobe development.
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