The Role of the Anterior Thalamic Nuclei in the Genesis of Memory Disorders in Alzheimer's Disease: An Exploratory Study.

BACKGROUND: Increasing evidence is demonstrating that degeneration of specific thalamic nuclei, in addition to the hippocampus, may occur in Alzheimer's disease (AD) from the prodromal stage (mild cognitive impairment - MCI) and contribute to memory impairment. OBJECTIVE: Here, we evaluated the presence of macro and micro structural alterations at the level of the anterior thalamic nuclei (ATN) and medio-dorsal thalamic nuclei (MDTN) in AD and amnestic MCI (aMCI) and the possible relationship between such changes and the severity of memory impairment. METHODS: For this purpose, a sample of 50 patients with aMCI, 50 with AD, and 50 age- and education-matched healthy controls (HC) were submitted to a 3-T MRI protocol with whole-brain T1-weighted and diffusion tensor imaging and a comprehensive neuropsychological assessment. RESULTS: At macro-structural level, both the ATN and MDTN were found significantly smaller in patients with aMCI and AD when compared to HC subjects. At micro-structural level, instead, diffusion alterations that significantly differentiated aMCI and AD patients from HC subjects were found only in the ATN, but not in the MDTN. Moreover, diffusion values of the ATN were significantly associated with poor episodic memory in the overall patients' group. CONCLUSIONS: These findings represent the first in vivo evidence of a relevant involvement of ATN in the AD-related neurodegeneration and memory profile and strengthen the importance to look beyond the hippocampus when considering neurological conditions characterized by memory decline.

Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

INTRODUCTION: Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool. METHODS: 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables. RESULTS: Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges' g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses. CONCLUSION: EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence.

Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

Two neurostructural subtypes: results of machine learning on brain images from 4,291 individuals with schizophrenia.

Machine learning can be used to define subtypes of psychiatric conditions based on shared clinical and biological foundations, presenting a crucial step toward establishing biologically based subtypes of mental disorders. With the goal of identifying subtypes of disease progression in schizophrenia, here we analyzed cross-sectional brain structural magnetic resonance imaging (MRI) data from 4,291 individuals with schizophrenia (1,709 females, age=32.5 years±11.9) and 7,078 healthy controls (3,461 females, age=33.0 years±12.7) pooled across 41 international cohorts from the ENIGMA Schizophrenia Working Group, non-ENIGMA cohorts and public datasets. Using a machine learning approach known as Subtype and Stage Inference (SuStaIn), we implemented a brain imaging-driven classification that identifies two distinct neurostructural subgroups by mapping the spatial and temporal trajectory of gray matter (GM) loss in schizophrenia. Subgroup 1 (n=2,622) was characterized by an early cortical-predominant loss (ECL) with enlarged striatum, whereas subgroup 2 (n=1,600) displayed an early subcortical-predominant loss (ESL) in the hippocampus, amygdala, thalamus, brain stem and striatum. These reconstructed trajectories suggest that the GM volume reduction originates in the Broca's area/adjacent fronto-insular cortex for ECL and in the hippocampus/adjacent medial temporal structures for ESL. With longer disease duration, the ECL subtype exhibited a gradual worsening of negative symptoms and depression/anxiety, and less of a decline in positive symptoms. We confirmed the reproducibility of these imaging-based subtypes across various sample sites, independent of macroeconomic and ethnic factors that differed across these geographic locations, which include Europe, North America and East Asia. These findings underscore the presence of distinct pathobiological foundations underlying schizophrenia. This new imaging-based taxonomy holds the potential to identify a more homogeneous sub-population of individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Data-driven biomarkers outperform theory-based biomarkers in predicting stroke motor outcomes.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have predicted motor outcomes based on the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to predict chronic motor outcomes after stroke and compares the accuracy of these predictions to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients (293 female/496 male) from the ENIGMA Stroke Recovery Working Group (age 64.9±18.0 years; time since stroke 12.2±0.2 months; normalised motor score 0.7±0.5 (range [0,1]). The out-of-sample prediction accuracy of two theory-based biomarkers was assessed: lesion load of the corticospinal tract, and lesion load of multiple descending motor tracts. These theory-based prediction accuracies were compared to the prediction accuracy from three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had better prediction accuracy - as measured by higher explained variance in chronic motor outcomes - than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R2 = 0.210, p < 0.001), performing significantly better than predictions using the theory-based biomarkers of lesion load of the corticospinal tract (R2 = 0.132, p< 0.001) and of multiple descending motor tracts (R2 = 0.180, p < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R2 =0.200, p < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R2 =0.167, p < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved prediction accuracy for theory-based and data-driven biomarkers. Finally, combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R2 = 0.241, p < 0.001. Overall, these results demonstrate that models that predict chronic motor outcomes using data-driven features, particularly when lesion data is represented in terms of structural disconnection, perform better than models that predict chronic motor outcomes using theory-based features from the motor system. However, combining both theory-based and data-driven models provides the best predictions.

Cortical morphology in patients with the deficit and non-deficit syndrome of schizophrenia: a worldwide meta- and mega-analyses.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

Brain Network Topology in Deficit and Non-Deficit Schizophrenia: Application of Graph Theory to Local and Global Indices.

Patients with deficit schizophrenia (SZD) suffer from primary and enduring negative symptoms. Limited pieces of evidence and neuroimaging studies indicate they differ from patients with non-deficit schizophrenia (SZND) in neurobiological aspects, but the results are far from conclusive. We applied for the first time, graph theory analyses to discriminate local and global indices of brain network topology in SZD and SZND patients compared with healthy controls (HC). High-resolution T1-weighted images were acquired for 21 SZD patients, 21 SZND patients, and 21 HC to measure cortical thickness from 68 brain regions. Graph-based metrics (i.e., centrality, segregation, and integration) were computed and compared among groups, at both global and regional networks. When compared to HC, at the regional level, SZND were characterized by temporoparietal segregation and integration differences, while SZD showed widespread alterations in all network measures. SZD also showed less segregated network topology at the global level in comparison to HC. SZD and SZND differed in terms of centrality and integration measures in nodes belonging to the left temporoparietal cortex and to the limbic system. SZD is characterized by topological features in the network architecture of brain regions involved in negative symptomatology. Such results help to better define the neurobiology of SZD (SZD: Deficit Schizophrenia; SZND: Non-Deficit Schizophrenia; SZ: Schizophrenia; HC: healthy controls; CC: clustering coefficient; L: characteristic path length; E: efficiency; D: degree; CCnode: CC of a node; CCglob: the global CC of the network; Eloc: efficiency of the information transfer flow either within segregated subgraphs or neighborhoods nodes; Eglob: efficiency of the information transfer flow among the global network; FDA: Functional Data Analysis; and Dmin: estimated minimum densities).

In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis.

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Preoperative Navigated Transcranial Magnetic Stimulation: New Insight for Brain Tumor-Related Language Mapping.

Preoperative brain mapping methods are particularly important in modern neuro-oncology when a tumor affects eloquent language areas since damage to parts of the language circuits can cause significant impairments in daily life. This narrative review examines the literature regarding preoperative and intraoperative language mapping using repetitive navigated transcranial magnetic stimulation (rnTMS) with or without direct electrical stimulation (DES) in adult patients with tumors in eloquent language areas. The literature shows that rnTMS is accurate in detecting preexisting language disorders and positive intraoperative mapping regions. In terms of the region extent and clinical outcomes, rnTMS has been shown to be accurate in identifying positive sites to guide resection, reducing surgery duration and craniotomy size and thus improving clinical outcomes. Before incorporating rnTMS into the neurosurgical workflow, the refinement of protocols and a consensus within the neuro-oncology community are required.

Internal clock variability, mood swings and working memory in bipolar disorder.

BACKGROUND: Distortions in time processing may be regarded as an endophenotypic marker of neuropsychiatric diseases; however, investigations addressing Bipolar Disorder (BD) are still scarce. METHODS: The present study compared timing abilities in 30 BD patients and 30 healthy controls (HC), and explored the relationship between time processing and affective-cognitive symptoms in BD, with the aim to determine whether timing difficulties are primary in bipolar patients or due to comorbid cognitive impairment. Four tasks measuring external timing were administered: a temporal and spatial orienting of attention task and a temporal and colour discrimination task, for assessing the ability to evaluate temporal properties of external events; two other tasks assessed the speed of the internal clock (i.e. temporal bisection and temporal production tasks). Attentional, executive and working memory (WM) demands were equated for controlling additional cognitive processes. RESULTS: BD patients did not show differences in external timing accuracy compared to HC; conversely, we found increased variability of the internal clock in BD and this performance was related to Major Depressive Episodes recurrence and WM functioning. Hence, variability of the internal clock is influenced by the progressive course of BD and impacted by variations in WM. LIMITATIONS: Future studies including BD patients stratified by mood episode will further specify timing alterations conditional to the current affective state. CONCLUSIONS: Our results shed new light on the clinical phenotypes of BD, suggesting that timing might be used as a model system of the ongoing pathophysiological process.

Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis.

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; ß=0.16) but not contralesional (P=0.96; ß=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; ß=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; ß=-0.26) and contralesional (P=0.006; ß=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; ß=-0.21) and extent of sensorimotor damage (P=0.003; ß=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.

Corpus callosum morphology in major mental disorders: a magnetic resonance imaging study.

Mental disorders diagnosis is based on specific clinical criteria. However, clinical studies found similarities and overlapping phenomenology across a variety of disorders, which suggests a common neurobiological substrate. Thus, there is a need to measure disease-related neuroanatomical similarities and differences across conditions. While structural alterations of the corpus callosum have been investigated in obsessive-compulsive disorder, schizophrenia, major depressive disorder and bipolar disorder, no study has addressed callosal aberrations in all diseases in a single study. Moreover, results from pairwise comparisons (patients vs. controls) show some inconsistencies, possibly related to the parcellation methods to divide the corpus callosum into subregions. The main aim of the present paper was to uncover highly localized callosal characteristics for each condition (i.e. obsessive-compulsive disorder, schizophrenia, major depressive disorder and bipolar disorder) as compared either to healthy control subjects or to each other. For this purpose, we did not rely on any sub-callosal parcellation method, but applied a well-validated approach measuring callosal thickness at 100 equidistant locations along the whole midline of the corpus callosum. One hundred and twenty patients (30 in each disorder) as well as 30 controls were recruited for the study. All groups were closely matched for age and gender, and the analyses were performed controlling for the impact of antipsychotic treatment and illness duration. There was a significant main effect of group along the whole callosal surface. Pairwise post hoc comparisons revealed that, compared to controls, patients with obsessive-compulsive disorder had the thinnest corpora callosa with significant effects almost on the entire callosal structure. Patients with schizophrenia also showed thinner corpora callosa than controls but effects were confined to the isthmus and the anterior part of the splenium. No significant differences were found in both major depressive disorder and bipolar disorder patients compared to controls. When comparing the disease groups to each other, the corpus callosum was thinner in obsessive-compulsive disorder patients than in any other group. The effect was evident across the entire corpus callosum, with the exception of the posterior body. Altogether, our study suggests that the corpus callosum is highly changed in obsessive-compulsive disorder, selectively changed in schizophrenia and not changed in bipolar disorder and major depressive disorder. These results shed light on callosal similarities and differences among mental disorders providing valuable insights regarding the involvement of the major brain commissural fibre tract in the pathophysiology of each specific mental illness.

Macro- and micro-structural cerebellar and cortical characteristics of cognitive empathy towards fictional characters in healthy individuals.

Few investigations have analyzed the neuroanatomical substrate of empathic capacities in healthy subjects, and most of them have neglected the potential involvement of cerebellar structures. The main aim of the present study was to investigate the associations between bilateral cerebellar macro- and micro-structural measures and levels of cognitive and affective trait empathy (measured by Interpersonal Reactivity Index, IRI) in a sample of 70 healthy subjects of both sexes. We also estimated morphometric variations of cerebral Gray Matter structures, to ascertain whether the potential empathy-related peculiarities in cerebellar areas were accompanied by structural differences in other cerebral regions. At macro-structural level, the volumetric differences were analyzed by Voxel-Based Morphometry (VBM)- and Region of Interest (ROI)-based approaches, and at a micro-structural level, we analyzed Diffusion Tensor Imaging (DTI) data, focusing in particular on Mean Diffusivity and Fractional Anisotropy. Fantasy IRI-subscale was found to be positively associated with volumes in right cerebellar Crus 2 and pars triangularis of inferior frontal gyrus. The here described morphological variations of cerebellar Crus 2 and pars triangularis allow to extend the traditional cortico-centric view of cognitive empathy to the cerebellar regions and indicate that in empathizing with fictional characters the cerebellar and frontal areas are co-recruited.

Transcranial Direct Current Stimulation and Cognition in Neuropsychiatric Disorders: Systematic Review of the Evidence and Future Directions.

Transcranial direct current stimulation (tDCS) has been implemented in neuropsychiatric disorders characterized by cognitive impairment. However, methodological heterogeneity challenges conclusive remarks. Through a critical analysis of previous conflicting findings and in the light of current neurobiological models of pathophysiology, we qualitatively assessed the effects of tDCS in neuropsychiatric disorders that share neurobiological underpinnings, as to evaluate whether stimulation can improve cognitive deficits in patients' cohorts. We performed a systematic review of tDCS studies targeting cognitive functions in mental disorders and pathological cognitive aging. Data from 41 studies, comprising patients with diagnosis of mood disorders, schizophrenia-spectrum disorders, Alzheimer's disease (AD), and mild cognitive impairment (MCI), were included. Results indicate that tDCS has the capacity to enhance processing speed, working memory, and executive functions in patients with mood and schizophrenia-spectrum disorders. The evidence of a positive effect on general cognitive functioning and memory is either inconclusive in AD, or weak in MCI. Future directions are discussed for developing standardized stimulation protocols and for translating the technique therapeutic potential into effective clinical practice.

Cerebellar GABA Levels and Cognitive Interference in Parkinson's disease and Healthy Comparators.

The neuroanatomical and molecular substrates for cognitive impairment in Parkinson Disease (PD) are far from clear. Evidence suggests a non-dopaminergic basis, and a crucial role for cerebellum in cognitive control in PD. We investigated whether a PD cognitive marker (response inhibition) was differently controlled by g-amino butyric acid (GABA) and/or by glutamate-glutamine (Glx) levels in the cerebellum of idiopathic PD patients, and healthy comparators (HC). Magnetic resonance spectroscopy of GABA/Glx (MEGA-PRESS acquisition sequence) was performed at 3 Tesla, and response inhibition assessed by the Stroop Word-Color Test (SWCT) and the Wisconsin Card Sorting Test (WCST). Linear correlations between cerebellar GABA/Glx levels, SWCT time/error interference effects and WCST perseverative errors were performed to test differences between correlation coefficients in PD and HC. Results showed that higher levels of mean cerebellar GABA were associated to SWCT increased time and error interference effects in PD, and the contrary in HC. Such effect dissociated by hemisphere, while correlation coefficients differences were significant in both right and left cerebellum. We conclude that MRS measured levels of cerebellar GABA are related in PD patients with decreased efficiency in filtering task-irrelevant information. This is crucial for developing pharmacological treatments for PD to potentially preserve cognitive functioning.

Subclinical Cognitive and Neuropsychiatric Correlates and Hippocampal Volume Features of Brain White Matter Hyperintensity in Healthy People.

White matter hyperintensities (WMH) are associated with brain aging and behavioral symptoms as a possible consequence of disrupted white matter pathways. In this study, we investigated, in a cohort of asymptomatic subjects aged 50 to 80, the relationship between WMH, hippocampal atrophy, and subtle, preclinical cognitive and neuropsychiatric phenomenology. Thirty healthy subjects with WMH (WMH+) and thirty individuals without (WMH-) underwent comprehensive neuropsychological and neuropsychiatric evaluations and 3 Tesla Magnetic Resonance Imaging scan. The presence, degree of severity, and distribution of WMH were evaluated with a semi-automated algorithm. Volumetric analysis of hippocampal structure was performed through voxel-based morphometry. A multivariable logistic regression analysis indicated that phenomenology of subclinical apathy and anxiety was associated with the presence of WMH. ROI-based analyses showed a volume reduction in the right hippocampus of WMH+. In healthy individuals, WMH are associated with significant preclinical neuropsychiatric phenomenology, as well as hippocampal atrophy, which are considered as risk factors to develop cognitive impairment and dementia.

Sense of external agency is sustained by multisensory functional integration in the somatosensory cortex.

"Sense of agency" (SoA), the feeling of control for events caused by one's own actions, is deceived by visuomotor incongruence. Sensorimotor networks are implicated in SoA, however little evidence exists on brain functionality during agency processing. Concurrently, it has been suggested that the brain's intrinsic resting-state (rs) activity has a preliminary influence on processing of agency cues. Here, we investigated the relation between performance in an agency attribution task and functional interactions among brain regions as derived by network analysis of rs functional magnetic resonance imaging. The action-effect delay was adaptively increased (range 90-1,620 ms) and behavioral measures correlated to indices of cognitive processes and appraised self-concepts. They were then regressed on local metrics of rs brain functional connectivity as to isolate the core areas enabling self-agency. Across subjects, the time window for self-agency was 90-625 ms, while the action-effect integration was impacted by self-evaluated personality traits. Neurally, the brain intrinsic organization sustaining consistency in self-agency attribution was characterized by high connectiveness in the secondary visual cortex, and regional segregation in the primary somatosensory area. Decreased connectiveness in the secondary visual area, regional segregation in the superior parietal lobule, and information control within a primary visual cortex-frontal eye fields network sustained self-agency over long-delayed effects. We thus demonstrate that self-agency is grounded on the intrinsic mode of brain function designed to organize information for visuomotor integration. Our observation is relevant for current models of psychopathology in clinical conditions in which both rs activity and sense of agency are altered.

Lithium treatment impacts nucleus accumbens shape in bipolar disorder.

The effects of lithium treatment duration on deep grey matter structures in bipolar disorder are not well known. In this cross-sectional neuroimaging case-control study, we tested the hypothesis that shape characteristics of deep grey matter structures in bipolar disorder are associated with the duration of lithium treatment and with clinical phenomenology. In a setting of neuropsychiatry outpatient clinic, we included 74 patients with bipolar disorder (BD) and 74 matched healthy control subjects (HC). Both groups underwent a Magnetic Resonance Imaging acquisition and an exhaustive assessment of clinical and psychiatrics dimensions. Shape measures of seven deep grey matter structures (hippocampus, amygdala, caudate, nucleus accumbens, putamen, globus pallidus and thalamus) were obtained from T1 weighted images in both groups, using FSL FIRST segmentation tool. The segmented structures were then analysed vertex-by-vertex with FSL Randomise tool. First, we investigated the presence of significant associations between the duration of lithium treatment and shape measures in BD sample. Then, for structures that resulted significantly associated with the duration of lithium treatment, comparisons between BD and HC were performed either considering the BD group as a whole or dividing it in three groups based on the duration of treatment (lithium drug-naïve, short and long treated). Any deformation uncovered by group comparisons was subsequently associated with depressive and hypomanic/manic symptoms. The relationship between structures shape and the duration of lithium treatment in BD sample was significant for bilateral nucleus accumbens. Specifically, significant bilateral extroflection effects, related to longer duration of lithium treatment, were found bilaterally over the surface shape of core accumbens nuclei (r2R-Accu-Core = 0.12, p = 0.016, r2L-Accu-Core = 0.1, p = 0.031). Moreover, introflection effect related to longer duration of treatment resulted over the shell of right accumbens (r2R-Accu-Shell = 0.17, p = 0.002). Nucleus accumbens shape did not differ between BD and HC considering BD group as a whole. By contrast, categorizing BD in subgroups as a function of the duration of lithium treatment revealed significant inward deformation on the core of left accumbens nucleus and outward deformation on the shell of the right accumbens nucleus in lithium-naive patients, compared to both patients with long duration of lithium treatment (pL-Accu-Core = 0.016, pR-Accu-Shell = 0.005) and HC (pL-Accu-Core = 0.002; pR-Accu-Shell = 0.005). Moreover, compared to HC, inward deformation on the core of the left accumbens surface was found for patients with short duration of treatment (pLAccu-Core = 0.027). Finally, measures of surface deformation on the core of left accumbens observed in the group comparison showed significant positive correlations with depressive symptoms severity, as assessed by the Hamilton Depression Rating Scale (total score: r2L-AccuCore = 0.07, p = 0.02, somatic score: r2L-Accu-Core = 0.1, p = 0.005) and Beck Hopelessness Scale (r2LAccu-Core = 0.05, p = 0.03). Findings demonstrate that lithium untreated BD patients are characterised by localized shape abnormalities in the nucleus accumbens. Lithium treatment could act modulating these morphometric features as part of its mechanism of action in mood stabilizing.

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

BACKGROUND: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. METHOD: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. RESULTS: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. CONCLUSION: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Segregation of Brain Structural Networks Supports Spatio-Temporal Predictive Processing.

The ability to generate probabilistic expectancies regarding when and where sensory stimuli will occur, is critical to derive timely and accurate inferences about updating contexts. However, the existence of specialized neural networks for inferring predictive relationships between events is still debated. Using graph theoretical analysis applied to structural connectivity data, we tested the extent of brain connectivity properties associated with spatio-temporal predictive performance across 29 healthy subjects. Participants detected visual targets appearing at one out of three locations after one out of three intervals; expectations about stimulus location (spatial condition) or onset (temporal condition) were induced by valid or invalid symbolic cues. Connectivity matrices and centrality/segregation measures, expressing the relative importance of, and the local interactions among specific cerebral areas respect to the behavior under investigation, were calculated from whole-brain tractography and cortico-subcortical parcellation. Results: Response preparedness to cued stimuli relied on different structural connectivity networks for the temporal and spatial domains. Significant covariance was observed between centrality measures of regions within a subcortical-fronto-parietal-occipital network -comprising the left putamen, the right caudate nucleus, the left frontal operculum, the right inferior parietal cortex, the right paracentral lobule and the right superior occipital cortex-, and the ability to respond after a short cue-target delay suggesting that the local connectedness of such nodes plays a central role when the source of temporal expectation is explicit. When the potential for functional segregation was tested, we found highly clustered structural connectivity across the right superior, the left middle inferior frontal gyrus and the left caudate nucleus as related to explicit temporal orienting. Conversely, when the interaction between explicit and implicit temporal orienting processes was considered at the long interval, we found that explicit processes were related to centrality measures of the bilateral inferior parietal lobule. Degree centrality of the same region in the left hemisphere covaried with behavioral measures indexing the process of attentional re-orienting. These results represent a crucial step forward the ordinary predictive processing description, as we identified the patterns of connectivity characterizing the brain organization associated with the ability to generate and update temporal expectancies in case of contextual violations.