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Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries (N= 14,877) using cognitive traits derived from the stop-signal task, namely – go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.

The substantial individual heterogeneity that characterizes people with mental illness is often ignored by classical case–control research, which relies on group mean comparisons. Here we present a comprehensive, multiscale characterization of the heterogeneity of gray matter volume (GMV) differences in 1,294 cases diagnosed with one of six conditions (attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive–compulsive disorder and schizophrenia) and 1,465 matched controls. Normative models indicated that person-specific deviations from population expectations for regional GMV were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience–ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia and attention-deficit/hyperactivity disorder. Phenotypic differences between cases assigned the same diagnosis may thus arise from the heterogeneous localization of specific regional deviations, whereas phenotypic similarities may be attributable to the dysfunction of common functional circuits and networks.

The anatomy of the brain necessarily constrains its function, but precisely how remains unclear. The classical and dominant paradigm in neuroscience is that neuronal dynamics are driven by interactions between discrete, functionally specialized cell populations connected by a complex array of axonal fibres1–3. However, predictions from neural field theory, an established mathematical framework for modelling large-scale brain activity4–6, suggest that the geometry of the brain may represent a more fundamental constraint on dynamics than complex interregional connectivity7,8. Here, we confirm these theoretical predictions by analysing human magnetic resonance imaging data acquired under spontaneous and diverse task-evoked conditions. Specifically, we show that cortical and subcortical activity can be parsimoniously understood as resulting from excitations of fundamental, resonant modes of the brain’s geometry (that is, its shape) rather than from modes of complex interregional connectivity, as classically assumed. We then use these geometric modes to show that task-evoked activations across over 10,000 brain maps are not confined to focal areas, as widely believed, but instead excite brain-wide modes with wavelengths spanning over 60 mm. Finally, we confirm predictions that the close link between geometry and function is explained by a dominant role for wave-like activity, showing that wave dynamics can reproduce numerous canonical spatiotemporal properties of spontaneous and evoked recordings. Our findings challenge prevailing views and identify a previously underappreciated role of geometry in shaping function, as predicted by a unifying and physically principled model of brain-wide dynamics.

Changes in brain volume are a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and numerous longitudinal studies suggest that volume deficits progress with illness duration. However, a major unresolved question concerns whether these changes are driven by the underlying illness or represent iatrogenic effects of antipsychotic medication. In this study, 62 antipsychotic-naïve patients with first-episode psychosis (FEP) received either a second-generation antipsychotic (risperidone or paliperidone) or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n= 27) was also recruited. Structural MRI scans were obtained at baseline, 3 months and 12 months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum (p< 0.05 FWE-corrected), such that patients receiving antipsychotic medication showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. Across the entire patient sample, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotic medications may be primarily mediated through their effects on the basal ganglia.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12–68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r= 0.067, pFDR= 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r= 0.285, pspin= 0.024), but not BD (r= 0.166, pspin= 0.205) or MDD (r= −0.274, pspin= 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, pspin= 0.006), BD (rho = −0.672, pspin= 0.009), and MDD (rho = −0.692, pspin= 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique with the capacity to modulate brain network connectivity and cognitive function. Recent studies have demonstrated long-lasting improvements in associative memory and resting-state connectivity following multi-day repetitive TMS (rTMS) to individualised parietal-hippocampal networks. We aimed to assess the reproducibility and network- and cognitive-specificity of these effects following multi-day rTMS. Participants received four days of 20 Hz rTMS to a subject-specific region of left lateral parietal cortex exhibiting peak functional connectivity to the left hippocampus. In a separate week, the same stimulation protocol was applied to a subject-specific region of pre-supplementary motor area (pre-SMA) exhibiting peak functional connectivity to the left putamen. We assessed changes to associative memory before and after each week of stimulation (N = 39), and changes to resting-state functional connectivity before and after stimulation in week one (N = 36). We found no evidence of long-lasting enhancement of associative memory or increased parieto-hippocampal connectivity following multi-day rTMS to the parietal cortex, nor increased pre-SMA-putamen connectivity following multi-day rTMS to pre-SMA. Instead, we observed some evidence of site-specific modulations of functional connectivity lasting ~24 h, with reduced connectivity within targeted networks and increased connectivity across distinct non-targeted networks. Our findings suggest a complex interplay between multi-day rTMS and network connectivity. Further work is required to develop reliable rTMS paradigms for driving changes in functional connectivity between cortical and subcortical regions.

Although major depressive disorder (MDD) is associated with altered functional coupling between disparate neural networks, the degree to which such measures are ameliorated by antidepressant treatment is unclear. It is also unclear whether functional connectivity can be used as a predictive biomarker of treatment response. Here, we used whole-brain functional connectivity analysis to identify neural signatures of remission following antidepressant treatment, and to identify connectomic predictors of treatment response. 163 MDD and 62 healthy individuals underwent functional MRI during pre-treatment baseline and 8-week follow-up sessions. Patients were randomized to escitalopram, sertraline or venlafaxine-XR antidepressants and assessed at follow-up for remission. Baseline measures of intrinsic functional connectivity between each pair of 333 regions were analyzed to identify pre-treatment connectomic features that distinguish remitters from non-remitters. We then interrogated these connectomic differences to determine if they changed post-treatment, distinguished patients from controls, and were modulated by medication type. Irrespective of medication type, remitters were distinguished from non-remitters by greater connectivity within the default mode network (DMN); specifically, between the DMN, fronto-parietal and somatomotor networks, the DMN and visual, limbic, auditory and ventral attention networks, and between the fronto-parietal and somatomotor networks with cingulo-opercular and dorsal attention networks. This baseline hypo-connectivity for non-remitters also distinguished them from controls and increased following treatment. In contrast, connectivity for remitters was higher than controls at baseline and also following remission, suggesting a trait-like connectomic characteristic. Increased functional connectivity within and between large-scale intrinsic brain networks may characterize acute recovery with antidepressants in depression.

Background: Several studies on 18F-FDG-PET/CT have investigated the prognostic role of this imaging modality in different tumors after treatment. Nevertheless, its role in restaging patients with recurrent CM still needs to be defined. Objective: The aim of this retrospective multicenter study was to evaluate the clinical and prognostic impact of 18F-FDG-PET/CT on the restaging process of cutaneous melanoma (CM) after surgery in patients with suspected distant recurrent disease or suspected metastatic progression disease. Materials and Methods: 74 patients surgically treated for CM underwent 18F-FDG-PET/CT for suspected distant recurrent disease or suspected metastatic progression disease. The diagnostic accuracy of visually interpreted 18F-FDG-PET/CT was obtained by considering histology (n=21 patients), other diagnostic imaging modalities performed within 2 months of PET/CT (CT in 52/74 patients and Whole-Body MRI in 18/74 patients) and clinical follow-up (n=74 patients) for at least 24 months containing all the clinical and diagnostic information useful for the PET performance assessment and outcome. Progression-free survival (PFS) and overall survival (OS) were assessed by using the Kaplan- Meier method. The risk of progression (Hazard Ratio-HR) was computed by the Cox regression analysis. Results: Suspicion of recurrent CM was confirmed in 24/27 patients with a positive 18F-FDG-PET/CT scan. Overall, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG-PET/CT were 82%, 93%, 88%, 89%, and 89%, respectively, with area under the curve being 0.87 (95%IC 0.78-0.97; p<0.05). 18F-FDG-PET/CT findings significantly influenced the therapeutic management in 18 patients (modifying therapy in 10 patients; guiding surgery in 8 patients). After 2 years of follow-up, PFS was significantly longer in patients with a negative vs. a positive 18F-FDG-PET/CT scan (90% vs 46%, p<0.05; Fig. 1). Moreover, a negative scan was associated with a significantly longer OS than a positive one (76% vs 39% after 2 years, p<0.05; Fig. 2). In addition, a positive 18F-FDG-PET/CT scan was associated with an increased risk of disease progression (HR=8.2; p<0,05). Conclusion: 18F-FDG-PET/CT showed a valuable diagnostic performance in patients with suspicion of recurrent CM. This imaging modality might have an important prognostic value in predicting the survival outcomes, assessing the risk of disease progression, and guiding treatment decision making.

Most major psychiatric disorders arise from disturbances of anatomically distributed neural systems rather than isolated dysfunction of circumscribed brain regions. The past decade has witnessed rapid advances in our capacity to measure, map, and model neural connectivity in diverse species and at different resolution scales, from the level of individual neurons and synapses to large-scale systems spanning the entire brain. In this review, we consider how these techniques, when grounded in the theory and methods of network science, can contribute to a biological understanding of mental illness. We focus in particular on attempts to accurately map brain network disturbances in clinical populations and to model the mechanistic causes of these changes. This work suggests that pathology within highly connected hub regions is a consistent finding across a broad array of phenotypically diverse disorders, and that disparate changes in brain network organization can sometimes be explained by a surprisingly small and simple set of mechanisms.

Disrupted motivational control is a common—but poorly treated—feature of psychiatric disorders, arising via aberrant mesolimbic dopaminergic signaling. GPR88 is an orphan G protein–coupled receptor that is highly expressed in the striatum and therefore well placed to modulate disrupted signaling. While the phenotype of Gpr88knockout mice suggests a role in motivational pathways, it is unclear whether GPR88 is involved in reward valuation and/or effort-based decision making in a sex-dependent manner and whether this involves altered dopamine function.

The cerebral cortex is organized hierarchically along an axis that spans unimodal sensorimotor to transmodal association areas. This hierarchy is often characterized using low-dimensional embeddings, termed gradients, of interregional functional coupling estimates measured with resting-state functional magnetic resonance imaging. Such analyses may offer insights into the pathophysiology of schizophrenia, which has been frequently linked to dysfunctional interactions between association and sensorimotor areas.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.

The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatment-resistance criteria.

We report a case of an ectopic/hypoplastic kidney removed by radio-guided surgery. A 7-year-old girl, with a history of vaginal drainage of urine, underwent renal scintigraphy with 99mTc-DMSA. SPECT/CT revealed a focal uptake in the pelvis, corresponding to hypoplastic kidney as confirmed by MRI. Based on SPECT/CT findings, the patient underwent laparoscopic surgery, using 99mTc-DMSA scan to help the surgeon to detect the small ectopic kidney. Intraoperatory histological report confirmed the renal origin of the specimen.

Cannabis is the most widely used illicit drug worldwide, though it is unclear whether its regular use is associated with persistent alterations in brain morphology. This review examines evidence from human structural neuroimaging investigations of regular cannabis users and focuses on achieving three main objectives. These include examining whether the literature to date provides evidence that alteration of brain morphology in regular cannabis users: i) is apparent, compared to non-cannabis using controls; ii) is associated with patterns of cannabis use; and with iii) measures of psychopathology and neurocognitive performance. The published findings indicate that regular cannabis use is associated with alterations in medial temporal, frontal and cerebellar brain regions. Greater brain morphological alterations were evident among samples that used at higher doses for longer periods. However, the evidence for an association between brain morphology and cannabis use parameters was mixed. Further, there is poor evidence for an association between measures of brain morphology and of psychopathology symptoms/neurocognitive performance. Overall, numerous methodological issues characterize the literature to date. These include investigation of small sample sizes, heterogeneity across studies in sample characteristics (e.g., sex, comorbidity) and in employed imaging techniques, as well as the examination of only a limited number of brain regions. These factors make it difficult to draw firm conclusions from the existing findings. Nevertheless, this review supports the notion that regular cannabis use is associated with alterations of brain morphology, and highlights the need to consider particular methodological issues when planning future cannabis research.

Resting-state functional MRI (rs-fMRI) is an increasingly popular technique for studying brain dysfunction in psychiatric patients, and is widely assumed to measure intrinsic properties of functional brain organization. Here, we review rs-fMRI studies of psychiatric populations and consider how recent evidence concerning the neuronal basis, behavioural relevance, and the stability of rs-fMRI measures can inform and constrain interpretation of findings obtained using case–control designs.

Although structural magnetic resonance imaging (sMRI) and neuropathological investigations offer complementary information that can be used to formulate and test hypotheses about pathophysiological mechanisms in psychiatric disorders, the findings from these two fields are seldom integrated in a systematic manner. In this study, we overview recent sMRI findings in schizophrenia and bipolar disorder and consider how they relate to neuropathological data.

Continuous theta burst stimulation (cTBS) is thought to reduce cortical excitability and modulate functional connectivity, possibly by altering cortical inhibition at the site of stimulation. However, most evidence comes from the motor cortex and it remains unclear whether similar effects occur following stimulation over other brain regions. We assessed whether cTBS over left dorsolateral prefrontal cortex altered gamma aminobutyric acid (GABA) concentration, functional connectivity and brain dynamics at rest, and brain activation and memory performance during a working memory task. Seventeen healthy individuals participated in a randomised, sham-controlled, cross-over experiment. Before and after either real or sham cTBS, magnetic resonance spectroscopy was obtained at rest to measure GABA concentrations. Functional magnetic resonance imaging (fMRI) was also recorded at rest and during an n-back working memory task to measure functional connectivity, regional brain activity (low-frequency fluctuations), and task-related patterns of brain activity. We could not find evidence for changes in GABA concentration (P = 0.66, Bayes factor [BF10] = 0.07), resting-state functional connectivity (P(FWE) > 0.05), resting-state low-frequency fluctuations (P = 0.88, BF10 = 0.04), blood-oxygen level dependent activity during the n-back task (P(FWE) > 0.05), or working memory performance (P = 0.13, BF10 = 0.05) following real or sham cTBS. Our findings add to a growing body of literature suggesting the effects of cTBS are highly variable between individuals and question the notion that cTBS is a universal ‘inhibitory’ paradigm.

The basic steady state heat transfer equations for convection, conduction, and radiant energy exchange were combined and adapted to the problem of modeling heat losses from small mammals and birds at rest in nesting cavities. The derived model describes heat loss rates in terms of a generalized heat transfer coefficient as a function of cavity height, diameter, wall thickness and thermal conductivity, and the radiative emissivity of interior cavity surfaces. The model was computerized and used to obtain 3125 unique solutions for combinations of a wide range of cavity characteristics; tabular data, graphical interpolations, and a statistical model were used to identify the most critical cavity features for any given set of animal-environmental conditions.

It has been hypothesized that there is an adrenal abnormality in the polycystic ovary syndrome (PCO). This study was undertaken to examine this hypothesis in a more physiological way, by enhancing the ACTH secretion in response to ovine corticotropin releasing hormone (oCRH) injection so that adrenal androgen and glucocorticoid responsiveness to endogenous stimulation could be examined. Plasma ACTH and the ACTH and Cortisol (F) response to oCRH were normal. The plasma T and dehydroepiandrosterone (DHEA) responses were also normal. The androstenedione (A) response, however, was exaggerated. This study supports the hypothesis that the adrenal gland in patients with PCO produces increased amounts of androstenedione in response to ACTH stimulation.

The basic steady state heat transfer equations for convection, conduction, and radiant energy exchange were combined and adapted to the problem of modeling heat losses from small mammals and birds at rest in nesting cavities. The derived model describes heat loss rates in terms of a generalized heat transfer coefficient as a function of cavity height, diameter, wall thickness and thermal conductivity, and the radiative emissivity of interior cavity surfaces. The model was computerized and used to obtain 3125 unique solutions for combinations of a wide range of cavity characteristics; tabular data, graphical interpolations, and a statistical model were used to identify the most critical cavity features for any given set of animal-environmental conditions.

Non-invasive neuroimaging is a powerful tool for quantifying diverse aspects of brain structure and function in vivo and has been used extensively to map the neural changes associated with different brain disorders. However, most neuroimaging techniques offer only indirect measures of underlying pathological mechanisms. The recent development of anatomically comprehensive gene-expression atlases has opened new opportunities for studying the transcriptional correlates of non-invasively measured neural phenotypes, offering a rich framework for evaluating pathophysiological hypotheses and putative mechanisms. Here, we overview some fundamental methods in imaging transcriptomics and outline their application to understanding brain disorders of neurodevelopment, adulthood, and neurodegeneration. Converging evidence indicates that spatial variations in gene expression are linked to normative changes in brain structure during age-related maturation and neurodegeneration that are in part associated with cell-specific gene expression markers of gene expression. Transcriptional correlates of disorder-related neuroimaging phenotypes are also linked to transcriptionally dysregulated genes identified in ex vivoanalyses of patient brains. Modeling studies demonstrate that spatial patterns of gene expression are involved in regional vulnerability to neurodegeneration and the spread of disease across the brain. This growing body of work supports the utility of transcriptional atlases in testing hypotheses about the molecular mechanism driving disease-related changes in macroscopic neuroimaging phenotypes.

Human brain networks undergo pronounced changes during development. The emergence of highly connected hub regions that can support integrated brain function is central to this maturational process, with these areas undergoing a particularly protracted period of development that extends into adulthood. The location of cortical network hubs emerges early but connections to and from hubs continue to strengthen throughout childhood and adolescence. Patterns of functional coupling in cortical association hubs are immature and incomplete at birth, but gradually strengthen during development. Early establishment of hub connectivity may provide a stable substrate that is refined by changes in tissue organization and microstructure, resulting in the emergence of complex functional dynamics by adulthood.

A radioiodine accumulation at Total Body Scan (TBS) in patient who has been thyroidectomized for a differentiated thyroid cancer is usually a reliable indicator of recurrent or metastatic functioning thyroid tissue. Radioiodine uptake may be usually observed at TBS in areas such as the intestinal tract, liver, salivary glands, bladder, and also in case of blood vessel ectasia. This report describes a patient with a bilaterally significant 131I uptake in upper abdomen. By ultrasound and radionuclide imaging the 131I uptake was proven to be due to radioiodine accumulation caused by bilateral polycystic renal disease.