Trajectories and Milestones of Cortical and Subcortical Development of the Marmoset Brain From Infancy to Adulthood.

With increasing attention on the developmental causes of neuropsychiatric disorders, appropriate animal models are crucial to identifying causes and assessing potential interventions. The common marmoset is an ideal model as it has sophisticated social/emotional behavior, reaching adulthood within 2 years of birth. Magnetic resonance imaging was used in an accelerated longitudinal cohort (n = 41; aged 3-27 months; scanned 2-7 times over 2 years). Splines were used to model nonlinear trajectories of grey matter volume development in 53 cortical areas and 16 subcortical nuclei. Generally, volumes increased before puberty, peaked, and declined into adulthood. We identified 3 milestones of grey matter development: I) age at peak volume; II) age at onset of volume decline; and III) age at maximum rate of volume decline. These milestones differentiated growth trajectories of primary sensory/motor cortical areas from those of association cortex but also revealed distinct trajectories between association cortices. Cluster analysis of trajectories showed that prefrontal cortex was the most heterogenous of association regions, comprising areas with distinct milestones and developmental trajectories. These results highlight the potential of high-field structural MRI to define the dynamics of primate brain development and importantly to identify when specific prefrontal circuits may be most vulnerable to environmental impact.

Structural Covariance Networks in Children with Autism or ADHD.

Background: While autism and attention-deficit/hyperactivity disorder (ADHD) are considered distinct conditions from a diagnostic perspective, clinically they share some phenotypic features and have high comorbidity. Regardless, most studies have focused on only one condition, with considerable heterogeneity in their results. Taking a dual-condition approach might help elucidate shared and distinct neural characteristics. Method: Graph theory was used to analyse topological properties of structural covariance networks across both conditions and relative to a neurotypical (NT; n = 87) group using data from the ABIDE (autism; n = 62) and ADHD-200 datasets (ADHD; n = 69). Regional cortical thickness was used to construct the structural covariance networks. This was analysed in a theoretical framework examining potential differences in long and short-range connectivity, with a specific focus on relation between central graph measures and cortical thickness. Results: We found convergence between autism and ADHD, where both conditions show an overall decrease in CT covariance with increased Euclidean distance between centroids compared with a NT population. The 2 conditions also show divergence. Namely, there is less modular overlap between the 2 conditions than there is between each condition and the NT group. The ADHD group also showed reduced cortical thickness and lower degree in hub regions than the autism group. Lastly, the ADHD group also showed reduced wiring costs compared with the autism groups. Conclusions: Our results indicate a need for taking an integrated approach when considering highly comorbid conditions such as autism and ADHD. Furthermore, autism and ADHD both showed alterations in the relation between inter-regional covariance and centroid distance, where both groups show a steeper decline in covariance as a function of distance. The 2 groups also diverge on modular organization, cortical thickness of hub regions and wiring cost of the covariance network. Thus, on some network features the groups are distinct, yet on others there is convergence.

Relationship Between Cortical Gyrification, White Matter Connectivity, and Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, which is accompanied by differences in gray matter neuroanatomy and white matter connectivity. However, it is unknown whether these differences are linked or reflect independent aetiologies. Using a multimodal neuroimaging approach, we therefore examined 51 male adults with ASD and 48 neurotypical controls to investigate the relationship between gray matter local gyrification (lGI) and white matter diffusivity in associated fiber tracts. First, ASD individuals had a significant increase in gyrification around the left pre- and post-central gyrus. Second, white matter fiber tracts originating and/or terminating in the cluster of increased lGI had a significant increase in axial diffusivity. This increase in diffusivity was predominantly observed in tracts in close proximity to the cortical sheet. Last, we demonstrate that the increase in lGI was significantly correlated with increased diffusivity of short tracts. This relationship was not significantly modulated by a main effect of group (i.e., ASD), which was more closely associated with gray matter gyrification than white matter diffusivity. Our findings suggest that differences in gray matter neuroanatomy and white matter connectivity are closely linked, and may reflect common rather than distinct aetiological pathways.

Validation of non-REM sleep stage decoding from resting state fMRI using linear support vector machines.

A growing body of literature suggests that changes in consciousness are reflected in specific connectivity patterns of the brain as obtained from resting state fMRI (rs-fMRI). As simultaneous electroencephalography (EEG) is often unavailable, decoding of potentially confounding sleep patterns from rs-fMRI itself might be useful and improve data interpretation. Linear support vector machine classifiers were trained on combined rs-fMRI/EEG recordings from 25 subjects to separate wakefulness (S0) from non-rapid eye movement (NREM) sleep stages 1 (S1), 2 (S2), slow wave sleep (SW) and all three sleep stages combined (SX). Classifier performance was quantified by a leave-one-subject-out cross-validation (LOSO-CV) and on an independent validation dataset comprising 19 subjects. Results demonstrated excellent performance with areas under the receiver operating characteristics curve (AUCs) close to 1.0 for the discrimination of sleep from wakefulness (S0|SX), S0|S1, S0|S2 and S0|SW, and good to excellent performance for the classification between sleep stages (S1|S2:~0.9; S1|SW:~1.0; S2|SW:~0.8). Application windows of fMRI data from about 70 s were found as minimum to provide reliable classifications. Discrimination patterns pointed to subcortical-cortical connectivity and within-occipital lobe reorganization of connectivity as strongest carriers of discriminative information. In conclusion, we report that functional connectivity analysis allows valid classification of NREM sleep stages.

Increased body mass index is associated with specific regional alterations in brain structure.

BACKGROUND: Although obesity is associated with structural changes in brain grey matter, findings have been inconsistent and the precise nature of these changes is unclear. Inconsistencies may partly be due to the use of different volumetric morphometry methods, and the inclusion of participants with comorbidities that exert independent effects on brain structure. The latter concern is particularly critical when sample sizes are modest. The purpose of the current study was to examine the relationship between cortical grey matter and body mass index (BMI), in healthy participants, excluding confounding comorbidities and using a large sample size. SUBJECTS: A total of 202 self-reported healthy volunteers were studied using surface-based morphometry, which permits the measurement of cortical thickness, surface area and cortical folding, independent of each other. RESULTS: Although increasing BMI was not associated with global cortical changes, a more precise, region-based analysis revealed significant thinning of the cortex in two areas: left lateral occipital cortex (LOC) and right ventromedial prefrontal cortex (vmPFC). An analogous region-based analysis failed to find an association between BMI and regional surface area or folding. Participants' age was also found to be negatively associated with cortical thickness of several brain regions; however, there was no overlap between the age- and BMI-related effects on cortical thinning. CONCLUSIONS: Our data suggest that the key effect of increasing BMI on cortical grey matter is a focal thinning in the left LOC and right vmPFC. Consistent implications of the latter region in reward valuation, and goal control of decision and action suggest a possible shift in these processes with increasing BMI.

Meta-connectomics: human brain network and connectivity meta-analyses.

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.

Temporal reproduction and its neuroanatomical correlates in adults with attention deficit hyperactivity disorder and their unaffected first-degree relatives.

BACKGROUND: Little is known about time perception, its putative role as cognitive endophenotype, and its neuroanatomical underpinnings in adults with attention deficit hyperactivity disorder (ADHD). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Disorders of compulsivity: a common bias towards learning habits.

Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.

'Reading the Mind in the Eyes': an fMRI study of adolescents with autism and their siblings.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥ 30 kg m(-2) and binge eating scale scores ≥ 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day(-1) GSK1521498, 5 mg day(-1) GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day(-1) caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day(-1) on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

Speed of facial affect intensity recognition as an endophenotype of first-episode psychosis and associated limbic-cortical grey matter systems.

BACKGROUND: 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). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the µ-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-ß-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

Administrative incidence of psychosis assessed in an early intervention service in England: first epidemiological evidence from a diverse, rural and urban setting.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

The relationship between motor deficit and primary motor cortex hemispheric activation balance after stroke: longitudinal fMRI study.

BACKGROUND: In the chronic stage of stroke, previous work has shown that the worse the hand motor deficit, the greater the shift of primary motor cortex (M(1)) activation towards the contralesional hemisphere (ie, unphysiological) balance. Whether the same relationship applies at earlier stages of recovery in serially studied patients is not known. METHODS: fMRI of fixed-rate auditory-cued affected index-thumb tapping was obtained at two time points (mean 36 and 147 days poststroke) in a cohort of nine patients with ischaemic stroke (age: 56+/-9 years; three women/six men; seven subcortical, one medullary and one cortical). On each fMRI day, the unaffected/affected ratio of maximal index tapping rate (IT-R) was obtained. To assess the M(1) hemispheric activation balance, the authors computed the classic Laterality Index (LI). The correlation between LI and IT-R was computed for each time point separately. RESULTS: The expected correlation between LI-M(1) and IT-R, that is, motor performance worse with more unphysiological LI, prevailed at both time points (Kendall p=0.008 and 0.058, respectively), with no statistically significant difference between the two regressions. The same analysis for the dorsal premotor cortex and the supplementary motor area showed no significant correlation at either time-point. CONCLUSION: These results from a small cohort of longitudinally assessed patients suggest that the relationship between M(1) laterality index and hand motor performance appears independent of time since onset of stroke. This in turn may suggest that attempting to restore the hemispheric balance by enhancing ipsilesional M(1) and/or constraining contralesional M(1) activity may have consistent efficacy throughout recovery.

Facial emotion processing in schizophrenia: a non-specific neuropsychological deficit?

BACKGROUND: Identification of facial emotions has been found to be impaired in schizophrenia but there are uncertainties about the neuropsychological specificity of the finding. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Approach and avoidance learning in patients with major depression and healthy controls: relation to anhedonia.

BACKGROUND: 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). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Reorganisation of Brain Hubs across Altered States of Consciousness.

Patterns of functional interactions across distributed brain regions are suggested to provide a scaffold for the conscious processing of information, with marked topological alterations observed in loss of consciousness. However, establishing a firm link between macro-scale brain network organisation and conscious cognition requires direct investigations into neuropsychologically-relevant architectural modifications across systematic reductions in consciousness. Here we assessed both global and regional disturbances to brain graphs in a group of healthy participants across baseline resting state fMRI as well as two distinct levels of propofol-induced sedation. We found a persistent modular architecture, yet significant reorganisation of brain hubs that formed parts of a wider rich-club collective. Furthermore, the reduction in the strength of rich-club connectivity was significantly associated with the participants' performance in a semantic judgment task, indicating the importance of this higher-order topological feature for conscious cognition. These results highlight a remarkable interplay between global and regional properties of brain functional interactions in supporting conscious cognition that is relevant to our understanding of clinical disorders of consciousness.

Substantia nigra/ventral tegmental reward prediction error disruption in psychosis.

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.

Activation of auditory cortex during silent lipreading.

Watching a speaker's lips during face-to-face conversation (lipreading) markedly improves speech perception, particularly in noisy conditions. With functional magnetic resonance imaging it was found that these linguistic visual cues are sufficient to activate auditory cortex in normal hearing individuals in the absence of auditory speech sounds. Two further experiments suggest that these auditory cortical areas are not engaged when an individual is viewing nonlinguistic facial movements but appear to be activated by silent meaningless speechlike movements (pseudospeech). This supports psycholinguistic evidence that seen speech influences the perception of heard speech at a prelexical stage.