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Highlights • There are no quantitative markers of major depression that associates with brain. • Switching strategy during verbal fluency can be calculated via machine learning. • Switching between semantic clusters is related to cognitive function in depression. • It is associated with cortical thickness in frontal, temporal and occipital regions. • It is associated with fractional anisotropy in right long antero-posterior tracts., Background The search of biomarkers in the field of depression requires easy implementable tests that are biologically rooted. Qualitative analysis of verbal fluency tests (VFT) are good candidates, but its cerebral correlates are unknown. Methods We collected qualitative semantic and phonemic VFT scores along with grey and white matter anatomical MRI of depressed (n = 26) and healthy controls (HC, n = 25) women. Qualitative VFT variables are the “clustering score” (i.e. the ability to produce words within subcategories) and the “switching score” (i.e. the ability to switch between clusters). The clustering and switching scores were automatically calculated using a data-driven approach. Brain measures were cortical thickness (CT) and fractional anisotropy (FA). We tested for associations between CT, FA and qualitative VFT variables within each group. Results Patients had reduced switching VFT scores compared to HC. Thicker cortex was associated with better switching score in semantic VFT bilaterally in the frontal (superior, rostral middle and inferior gyri), parietal (inferior parietal lobule including the supramarginal gyri), temporal (transverse and fusiform gyri) and occipital (lingual gyri) lobes in the depressed group. Positive association between FA and the switching score in semantic VFT was retrieved in depressed patients within the corpus callosum, right inferior fronto-occipital fasciculus, right superior longitudinal fasciculus extending to the anterior thalamic radiation (all p

The insula is important for the processing of pleasant aspects of touch whereas its role in the processing of emotionally neutral touch has been less explored. Here, we used a network approach to investigate the insular processing of pleasant stroking touch and emotionally neutral vibratory touch, analysing functional magnetic resonance imaging data from 23 healthy adult participants. Vibration and skin stroking activated areas in the posterior, middle and anterior insula. Psychophysiological interaction analyses suggested that skin stroking increased functional connectivity between the posterior and ventral anterior insula. Vibration instead increased functional connectivity between the posterior and dorsal anterior insula, and induced a stronger decrease of the default mode network activity compared to stroking. These results confirmed findings from previous studies showing that the posterior insula processes affective touch information. We suggest that this is accomplished by relaying tactile information from the posterior insula to ventral anterior insula, an area tightly connected to the emotional parts of the brain. However, our results also suggested that the insula processes tactile information with less emotional valence. A central hub in this processing seemed to be the right dorsal anterior insula. Keywords: Touch, fMRI, Insula, Resting state networks

Graphical abstract, Highlights • Cerebral palsy adolescents had stronger proprioceptive BOLD-responses. • Cerebral palsy adolescents had worse sensorimotor performance. • Stronger BOLD-responses were associated with worse sensorimotor performance., Cerebral palsy (CP) is a motor disorder where the motor defects are partly due to impaired proprioception. We studied cortical proprioceptive responses and sensorimotor performance in adolescents with CP and their typically-developed (TD) peers. Passive joint movements were used to stimulate proprioceptors during functional magnetic resonance imaging (fMRI) session to quantify the proprioceptive responses whose associations to behavioral sensorimotor performance were also examined. Twenty-three TD (15 females, age: mean ± standard deviation 14.2 ± 2.4 years) and 18 CP (12 females, age: mean ± standard deviation, 13.8 ± 2.3 years; 12 hemiplegic, 6 diplegic) participants were included in this study. Participants’ index fingers and ankles were separately stimulated at 3 Hz and 1 Hz respectively with pneumatic movement actuators. Regions-of-interest were used to quantify BOLD-responses from the primary sensorimotor (SM1) and secondary (SII) somatosensory cortices and were compared across the groups. Associations between responses strengths and sensorimotor performance measures were also examined. Proprioceptive responses were stronger for the individuals with CP compared to their TD peers in SM1 (p

Highlights • Posterior cortices, hippocampus and amygdala track atrophy in EOAD over two years. • The medial temporal cortex is unaltered in EOAD at early stages. • EOAD exhibited a posterior-to-anterior gradient of cortical loss after two years. • EOAD subcortical volume loss extends beyond hippocampus and amygdala after two years. • Cerebrospinal fluid biomarkers might predict atrophy rates in EOAD., There is evidence longitudinal atrophy in posterior brain areas in early-onset Alzheimer’s disease (EOAD; aged

Background The 2019 novel coronavirus disease pandemic (COVID-19) is one of the most serious health risks facing the global population. Teachers’ responses are important in the management of the outbreak in schools. The purpose of this study is to examine teachers’ risk perception, self-efficacy, response efficacy, and approach to disease prevention during the COVID-19 outbreak in Taiwan. Methods A descriptive, cross-sectional online survey was completed by 344 teachers across four levels of education. Pearson correlations between major variables were calculated. General linear model with a posthoc test was used to estimate the least squares means for each level of the independent variables and test the mean differences between the response scores. Results The teachers with a higher risk perception showed a stronger adoption of disease prevention measures, but they also showed lower self-efficacy. In addition, teachers with higher self-efficacy had higher response efficiency. Female teachers had relatively stronger adoption of disease prevention measures than their male colleagues, and age was associated with a 0.040 point increase in adoption scores. Elementary school teachers were significantly stronger in this regard than teachers at junior high schools, high schools and universities in terms of behavior scores. Conclusions High implementation rate of Taiwanese teachers’ disease prevention measures came from their higher risk perceptions. Among them, older female teachers, especially those who teach at elementary schools, are key to implementing disease prevention measures.

Highlights • The effect of first dopaminergic treatment on the reward circuit in PD is unclear. • Many ON/OFF designs suffer from long-lasting dopaminergic effects (multiple days). • We tested reward processing in dopa-naive PD before and after treatment initiation. • Dopaminergic drugs increased reward-related hippocampus activity in PD. • The relationship with development of neuropsychiatric symptoms remains unknown., Background Parkinson’s disease is associated with severe nigro-striatal dopamine depletion, leading to motor dysfunction and altered reward processing. We previously showed that drug-naïve patients with Parkinson’s disease had a consistent attenuation of reward signalling in the mesolimbic and mesocortical system. Here, we address the neurobiological effects of dopaminergic therapy on reward sensitivity in the mesolimbic circuitry, and how this may contribute to neuropsychiatric symptoms. Objectives We tested the hypothesis that (1) dopaminergic treatment would restore the attenuated, mesolimbic and mesocortical responses to reward; and (2) restoration of reward responsivity by dopaminergic treatment would predict motor performance and the emergence of impulse control symptoms. Methods In 11 drug-naïve Parkinson patients, we prospectively assessed treatment-induced changes in reward processing before, and eight weeks after initiation of monotherapy with dopamine agonists. They were compared to 10 non-medicated healthy controls who were also measured longitudinally. We used whole-brain functional magnetic resonance imaging at 3 Tesla to assess the reward responsivity of the brain to monetary gains and losses, while participants performed a simple consequential gambling task. Results In patients, dopaminergic treatment improved clinical motor symptoms without significantly changing task performance. Dopamine agonist therapy induced a stronger reward responsivity in the right hippocampus with higher doses being less effective. None of the patients developed impulse control disorders in the follow-up period of four years. Conclusions Short-term treatment with first-ever dopaminergic medication partially restores deficient reward-related processing in the hippocampus in de novo Parkinson’s disease.

International audience; Heterogeneity in cognitive and academic abilities is a prominent feature of autism spectrum disorder (ASD), yet little is known about its underlying causes. Here we combine functional brain imaging during numerical problem-solving with hierarchical drift-diffusion models of behavior and standardized measures of numerical abilities to investigate neural mechanisms underlying cognitive variability in children with ASD, and their IQ-matched Typically Developing (TD) peers. Although the two groups showed similar levels of brain activation, the relation to individual abilities differed markedly in ventral temporal-occipital, parietal and prefrontal regions important for numerical cognition: children with ASD showed a positive correlation between functional brain activation and numerical abilities, whereas TD children showed the opposite pattern. Despite similar accuracy and response times, decision thresholds were significantly higher in the ASD group, suggesting greater evidence required for problem-solving. Critically, the relationship between individual abilities and engagement of prefrontal control systems anchored in the anterior insula was differentially moderated by decision threshold in subgroups of children with ASD. Our findings uncover novel cognitive and neural sources of variability in academically-relevant cognitive skills in ASD and suggest that multilevel measures and latent decision-making dynamics can aid in characterization of cognitive variability and heterogeneity in neurodevelopmental disorders.; Autism Spectrum Disorder; Individual differences; Numerical problem-solving; Decision-making; Brain imaging

Highlights • Fronto-temporal white matter tracts relate to social network size. • Specific limbic and temporal regions are larger in people with larger social networks. • Functional coupling of the default mode network varies with social network size., Social skills rely on a specific set of cognitive processes, raising the possibility that individual differences in social networks are related to differences in specific brain structural and functional networks. Here, we tested this hypothesis with multimodality neuroimaging. With diffusion MRI (DMRI), we showed that differences in structural integrity of particular white matter (WM) tracts, including cingulum bundle, extreme capsule and arcuate fasciculus were associated with an individual’s social network size (SNS). A voxel-based morphology analysis demonstrated correlations between gray matter (GM) volume and SNS in limbic and temporal lobe regions. These structural changes co-occured with functional network differences. As a function of SNS, dorsomedial and dorsolateral prefrontal cortex showed altered resting-state functional connectivity with the default mode network (DMN). Finally, we integrated these three complementary methods, interrogating the relationship between social GM clusters and specific WM and resting-state networks (RSNs). Probabilistic tractography seeded in these GM nodes utilized the SNS-related WM pathways. Further, the spatial and functional overlap between the social GM clusters and the DMN was significantly closer than other control RSNs. These integrative analyses provide convergent evidence of the role of specific circuits in SNS, likely supporting the adaptive behavior necessary for success in extensive social environments.

Objective Metabolic syndrome (MetS) refers to a cluster of risk factors for cardiovascular disease, including obesity, hypertension, dyslipidemia, and hyperglycemia. While sizable prior literature has examined associations between individual risk factors and quantitative measures of cortical thickness (CT), only very limited research has investigated such measures in MetS. Furthermore, the relative contributions of these risk factors to MetS-related effects on brain morphology have not yet been studied. The primary goal of this investigation was to examine how MetS may affect CT. A secondary goal was to explore the relative contributions of individual risk factors to regional alterations in CT, with the potential to identify risk factor combinations that may underlie structural changes. Methods Eighteen participants with MetS (mean age = 59.78 years) were age-matched with 18 healthy control participants (mean age = 60.50 years). CT measures were generated from T1-weighted images and groups were contrasted using whole-brain general linear modeling. A follow-up multivariate partial least squares correlation (PLS) analysis, including the full study sample with complete risk factor measurements (N = 53), was employed to examine which risk factors account for variance in group structural differences. Results Participants with MetS demonstrated significantly reduced CT in left hemisphere inferior parietal, rostral middle frontal, and lateral occipital clusters and in a right hemisphere precentral cluster. The PLS analysis revealed that waist circumference, high-density lipoprotein cholesterol (HDL-C), triglycerides, and glucose were significant contributors to reduced CT in these clusters. In contrast, diastolic blood pressure showed a significantly positive association with CT while systolic blood pressure did not emerge as a significant contributor. Age was not associated with CT. Conclusion These results indicate that MetS can be associated with regionally specific reductions in CT. Importantly, a novel link between a risk factor profile comprising indices of obesity, hyperglycemia, dyslipidemia and diastolic BP and localized alterations in CT emerged. While the pathophysiological mechanisms underlying these associations remain incompletely understood, these findings may be relevant for future investigations of MetS and might have implications for treatment approaches that focus on specific risk factor profiles with the aim to reduce negative consequences on the structural integrity of the brain., Highlights • Cortical thickness is reduced bilaterally in metabolic syndrome. • Five out of six risk factor components contribute to altered cortical thickness. • Particular risk factor combination may be an important target for intervention.

Individuals with schizophrenia exhibit problems with understanding the figurative meaning of language. This study evaluates neural correlates of diminished humor comprehension observed in schizophrenia. The study included chronic schizophrenia (SCH) outpatients (n = 20), and sex, age and education level matched healthy controls (n = 20). The fMRI punchline based humor comprehension task consisted of 60 stories of which 20 had funny, 20 nonsensical and 20 neutral (not funny) punchlines. After the punchlines were presented, the participants were asked to indicate whether the story was comprehensible and how funny it was. Three contrasts were analyzed in both groups reflecting stages of humor processing: abstract vs neutral stories - incongruity detection; funny vs abstract - incongruity resolution and elaboration; and funny vs neutral – complete humor processing. Additionally, parametric modulation analysis was performed using both subjective ratings separately. Between-group comparisons revealed that the SCH subjects had attenuated activation in the right posterior superior temporal gyrus (BA 41) in case of irresolvable incongruity processing of nonsensical puns; in the left dorsomedial middle and superior frontal gyri (BA 8/9) in case of incongruity resolution and elaboration processing of funny puns; and in the interhemispheric dorsal anterior cingulate cortex (BA 24) in case of complete processing of funny puns. Additionally, during comprehensibility ratings the SCH group showed a suppressed activity in the left dorsomedial middle and superior frontal gyri (BA 8/9) and revealed weaker activation during funniness ratings in the left dorsal anterior cingulate cortex (BA 24). Interestingly, these differences in the SCH group were accompanied behaviorally by a protraction of time in both types of rating responses and by indicating funny punchlines less comprehensible. Summarizing, our results indicate neural substrates of humor comprehension processing impairments in schizophrenia, which is accompanied by fronto-temporal hypoactivation., Highlights • Schizophrenia outpatients revealed impairments in humor comprehension processing. • Neural processing was impaired at three stages of the humor comprehension process. • Incongruity detection - hypofunction in the right temporal lobe in schizophrenia. • Resolution & Elaboration - hypofunction in the left frontal lobe in schizophrenia. • Complete process - hypofunction in the anterior cingulate cortex in schizophrenia.

Conventional MRI studies showed that radiation-induced brain necrosis in patients with nasopharyngeal carcinoma (NPC) in years after radiotherapy (RT) could involve brain gray matter (GM) and impair brain function. However, it is still unclear the radiation-induced brain morphological changes in NPC patients with normal-appearing GM in the early period after RT. In this study, we acquired high-resolution brain structural MRI data from three groups of patients, 22 before radiotherapy (pre-RT) NPC patients with newly diagnosed but not yet medically treated, 22 NPC patients in the early-delayed stage after radiotherapy (post-RT-ED), and 20 NPC patients in the late-delayed stage after radiotherapy (post-RT-LD), and then analyzed the radiation-induced cortical thickness alteration in NPC patients after RT. Using a vertex-wise surface-based morphometry (SBM) approach, we detected significantly decreased cortical thickness in the precentral gyrus (PreCG) in the post-RT-ED group compared to the pre-RT group. And the post-RT-LD group showed significantly increased cortical thickness in widespread brain regions, including the bilateral inferior parietal, left isthmus of the cingulate, left bank of the superior temporal sulcus and left lateral occipital regions, compared to the pre-RT group, and in the bilateral PreCG compared to the post-RT-ED group. Similar analysis with ROI-wise SBM method also found the consistent results. These results indicated that radiation-induced brain injury mainly occurred in the post-RT-LD group and the cortical thickness alterations after RT were dynamic in different periods. Our findings may reflect the pathogenesis of radiation-induced brain injury in NPC patients with normal-appearing GM and an early intervention is necessary for protecting GM during RT., Highlights • Found radiation-induced abnormal cortical thickness in NPC patients with normal-appearing GM after RT • Only in the PreCG, the post-RT-ED showed decreased cortical thickness compared to pre-RT group. • The post-RT-LD had widespread abnormal cortical thickness than either the pre-RT or post-RT-ED groups. • Alterations of cortical thickness in NPC patients after RT are dynamic in different periods.

The brain underpinnings of schizophrenia and bipolar disorders are multidimensional, reflecting complex pathological processes and causal pathways, requiring multivariate techniques to disentangle. Furthermore, little is known about the complementary clinical value of brain structural phenotypes when combined with data on cognitive performance and genetic risk. Using data-driven fusion of cortical thickness, surface area, and gray matter density maps (GMD), we found six biologically meaningful patterns showing strong group effects, including four statistically independent multimodal patterns reflecting co-occurring alterations in thickness and GMD in patients, over and above two other independent patterns of widespread thickness and area reduction. Case-control classification using cognitive scores alone revealed high accuracy, and adding imaging features or polygenic risk scores increased performance, suggesting their complementary predictive value with cognitive scores being the most sensitive features. Multivariate pattern analyses reveal distinct patterns of brain morphology in mental disorders, provide insights on the relative importance between brain structure, cognitive and polygenetic risk score in classification of patients, and demonstrate the importance of multivariate approaches in studying the pathophysiological substrate of these complex disorders., Highlights • Linked ICA showed six independent multivariate morphology patterns sensitive to SZ. • Machine learning used to compare brain structure, cognitive and genetic scores. • Cognition showed highest prediction of SZ, boosted by brain structure or genetics.

Kabuki syndrome (KS) is a rare congenital disorder (1/32000 births) characterized by distinctive facial features, intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities. In the last decade, mutations in KMT2D and KDM6A were identified as a major cause of kabuki syndrome. Although genetic abnormalities have been highlighted in KS, brain abnormalities have been little explored. Here, we have investigated brain abnormalities in 6 patients with KS (4 males; Mage = 10.96 years, SD = 2.97 years) with KMT2D mutation in comparison with 26 healthy controls (17 males; Mage = 10.31 years, SD = 2.96 years). We have used MRI to explore anatomical and functional brain abnormalities in patients with KS. Anatomical abnormalities in grey matter volume were assessed by cortical and subcortical analyses. Functional abnormalities were assessed by comparing rest cerebral blood flow measured with arterial spin labeling-MRI. When compared to healthy controls, KS patients had anatomical alterations characterized by grey matter decrease localized in the bilateral precentral gyrus and middle frontal gyrus. In addition, KS patients also presented functional alterations characterized by cerebral blood flow decrease in the left precentral gyrus and middle frontal gyrus. Moreover, subcortical analyses revealed significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus in patients with KS. Our results strongly indicate anatomical and functional brain abnormalities in KS. They suggest a possible neural basis of the cognitive symptoms observed in KS, such as fine motor impairment, and indicate the need to further explore the consequences of such brain abnormalities in this disorder. Finally, our results encourage further imaging-genetics studies investigating the link between genetics, anatomical and functional brain alterations in KS., Highlights • Kabuki syndrome children show decreased grey matter in precentral and frontal areas • Decreased rest cerebral blood flow is also observed in the same regions • Hippocampus and dentate gyrus volumes are reduced • Brain abnormalities, so far understudied, could underpin clinical deficits

Highlights • We measured brain activity patterns for recognizing newly trained words in children. • Retrieval related activation in the hippocampus decreased a week after training. • Lexical integration effect was not observed even after a delay of 1 week. • Younger group used right hemisphere more whereas teens used left hemisphere more., Memory representations of words are thought to undergo changes with consolidation: Episodic memories of novel words are transformed into lexical representations that interact with other words in the mental dictionary. Behavioral studies have shown that this lexical integration process is enhanced when there is more time for consolidation. Neuroimaging studies have further revealed that novel word representations are initially represented in a hippocampally-centered system, whereas left posterior middle temporal cortex activation increases with lexicalization. In this study, we measured behavioral and brain responses to newly-learned words in children. Two groups of Dutch children, aged between 8–10 and 14–16 years, were trained on 30 novel Japanese words depicting novel concepts. Children were tested on word-forms, word-meanings, and the novel words’ influence on existing word processing immediately after training, and again after a week. In line with the adult findings, hippocampal involvement decreased with time. Lexical integration, however, was not observed immediately or after a week, neither behaviorally nor neurally. It appears that time alone is not always sufficient for lexical integration to occur. We suggest that other factors (e.g., the novelty of the concepts and familiarity with the language the words are derived from) might also influence the integration process.

Traditional models of left hemisphere stroke recovery propose that reactivation of remaining ipsilesional tissue is optimal for language processing whereas reliance on contralesional right hemisphere homologues is less beneficial or possibly maladaptive in the chronic recovery stage. However, neuroimaging evidence for this proposal is mixed. This study aimed to elucidate patterns of effective connectivity in patients with chronic aphasia in light of healthy control connectivity patterns and in relation to damaged tissue within left hemisphere regions of interest and according to performance on a semantic decision task. Using fMRI and dynamic causal modeling, biologically-plausible models within four model families were created to correspond to potential neural recovery patterns, including Family A: Left-lateralized connectivity (i.e., no/minimal damage), Family B: Bilateral anterior-weighted connectivity (i.e., posterior damage), Family C: Bilateral posterior-weighted connectivity (i.e., anterior damage) and Family D: Right-lateralized connectivity (i.e., extensive damage). Controls exhibited a strong preference for left-lateralized network models (Family A) whereas patients demonstrated a split preference for Families A and C. At the level of connections, controls exhibited stronger left intrahemispheric task-modulated connections than did patients. Within the patient group, damage to left superior frontal structures resulted in greater right intrahemispheric connectivity whereas damage to left ventral structures resulted in heightened modulation of left frontal regions. Lesion metrics best predicted accuracy on the fMRI task and aphasia severity whereas left intrahemispheric connectivity predicted fMRI task reaction times. These results are discussed within the context of the hierarchical recovery model of chronic aphasia., Highlights • The semantic network in neurologically-intact, healthy controls was characterized by left-lateralized connectivity. • Patient connectivity was split between left-lateralized and bilateral, posterior-weighted (i.e., anterior damage) models. • Controls solely recruited LITG-driven connections whereas patients recruited a distributed network of connections. • Within the patient group, intra- and inter-hemispheric connections were related to lesion site and/or size. Lesion size predicted aphasia severity and fMRI task accuracy, and effective connectivity predicted task reaction times.

Structural brain networks derived from diffusion magnetic resonance imaging data have been used extensively to describe the human brain, and graph theory has allowed quantification of their network properties. Schemes used to construct the graphs that represent the structural brain networks differ in the metrics they use as edge weights and the algorithms they use to define the network topologies. In this work, twenty graph construction schemes were considered. The schemes use the number of streamlines, the fractional anisotropy, the mean diffusivity or other attributes of the tracts to define the edge weights, and either an absolute threshold or a data-driven algorithm to define the graph topology. The test-retest data of the Human Connectome Project were used to compare the reproducibility of the graphs and their various attributes (edges, topologies, graph theoretical metrics) derived through those schemes, for diffusion images acquired with three different diffusion weightings. The impact of the scheme on the statistical power of the study and on the number of participants required to detect a difference between populations or an effect of an intervention was also calculated. The reproducibility of the graphs and their attributes depended heavily on the graph construction scheme. Graph reproducibility was higher for schemes that used thresholding to define the graph topology, while data-driven schemes performed better at topology reproducibility (mean similarities of 0.962 and 0.984 respectively, for graphs derived from diffusion images with b=2000 s/mm2). Additionally, schemes that used thresholding resulted in better reproducibility for local graph theoretical metrics (intra-class correlation coefficients (ICC) of the order of 0.8), compared to data-driven schemes. Thresholded and data-driven schemes resulted in high (0.86 or higher) ICCs only for schemes that use exclusively the number of streamlines to construct the graphs. Crucially, the number of participants required to detect a difference between populations or an effect of an intervention could change by a factor of two or more depending on the scheme used, affecting the power of studies to reveal the effects of interest., Highlights • The reproducibility of graphs depends on the graph-construction scheme. • The reproducibility of graph theoretical metrics also depends on the scheme used. • The reproducibility of edge weights depends on the graph-construction scheme. • Structural network graphs are fairly consistent across diffusion weightings.

Background Cerebral microbleeds (CMBs) are considered to be risk factors for cognitive dysfunction. The specific pathology and clinical manifestations of CMBs are different based on their locations. We investigated the association between CMBs at different locations and cognitive dysfunction and explored the potential underlying pathways in a rural Han Chinese population. Methods We used baseline data from 562 community-dwelling adults (55–65 years old) in the Taizhou Imaging Study between 2013 and 2015. All individuals underwent multimodal brain magnetic resonance imaging (MRI) and 444 subjects completed neuropsychological tests: the Mini-Mental Status Examination and the Montreal Cognitive Assessment. Multinomial logistic regression was used to estimate the association between CMBs and cognitive dysfunction. The volume of brain regions and white matter microstructure were analyzed using Freesurfer and tract-based spatial statistics, respectively. Results CMBs were detected in 104 individuals (18.5%) in our study. Multinomial logistic regression found deep/mixed CMBs were associated with global cognitive dysfunction (OR 3.52; 95% CI 1.21 to 10.26), whereas lobar CMBs (OR 1.76; 95% CI 0.56 to 5.53) were not. Quantification of multimodal brain MRI showed that deep/mixed CMBs were accompanied by decreased thalamic volume and loss of fractional anisotropy of bilateral anterior thalamic radiations. Conclusion Deep/mixed CMBs were associated with cognitive dysfunction in this Chinese cross-sectional study. Disruption of thalamocortical connectivity might be a potential pathway underlying this relationship., Highlights • Cerebral microbleeds (CMBs) are found in 18.5% of middle-aged Chinese population. • Deep/mixed CMBs, not lobar CMBs, are associated with cognitive dysfunction. • Atrophy and fiber connectivity disruption might be the underlying neural pathways.

Olfactory dysfunction is an early manifestation of Parkinson's disease (PD). The present study aimed to illustrate potential differences between PD patients and healthy controls in terms of neural activity and functional connectivity within the olfactory brain network. Twenty PD patients and twenty healthy controls were examined with olfactory fMRI and resting-state fMRI. Data analysis of olfactory fMRI included data-driven tensorial independent component (ICA) and task-driven general linear model (GLM) analyses. Data analysis of resting-state fMRI included probabilistic ICA based on temporal concatenation and functional connectivity analysis within the olfactory network. ICA of olfactory fMRI identified an olfactory network consisting of the posterior piriform cortex, insula, right orbitofrontal cortex and thalamus. Recruitment of this network was less significant for PD patients. GLM analysis revealed significantly lower activity in the insula bilaterally and the right orbitofrontal cortex in PD compared to healthy controls but no significant differences in the olfactory cortex itself. Analysis of resting-state fMRI did not reveal any differences in the functional connectivity within the olfactory, default mode, salience or central executive networks between the two groups. In conclusion, olfactory dysfunction in PD is associated with less significant recruitment of the olfactory brain network. ICA could demonstrate differences in both the olfactory cortex and its main projections, compared to GLM that revealed differences only on the latter. Resting-state fMRI did not reveal any significant differences in functional connectivity within the olfactory, default mode, salience and central executive networks in this cohort., Highlights • Less significant recruitment of the olfactory brain network was found in Parkinson's disease. • Independent component analysis reveals differences in both olfactory cortex and its projections. • Differences in functional connectivity within the olfactory network were not significant.

Highlights • IBS and Ulcerative Colitis (UC) patients have changes in brain network organization. • Changes in brain network organization correlate with disease symptomatology. • In UC, brain network organization changes correlate with disease duration. • Chronic gut inflammation as well as pain have neuroplastic effects on the brain., Objective We aimed to identify differences in network properties of white matter microstructure between asymptomatic ulcerative colitis (UC) participants who had a history of chronic gut inflammation, healthy controls (HCs) and a disease control group without gut inflammation (irritable bowel syndrome; IBS). Design Diffusion weighted imaging was conducted in age and sex-matched participants with UC, IBS, and HCs (N = 74 each), together with measures of gastrointestinal and psychological symptom severity. Using streamline connectivity matrices and graph theory, we aimed to quantify group differences in brain network connectivity. Regions showing group connectivity differences were correlated with measures showing group behavioral and clinical differences. Results UC participants exhibited greater centrality in regions of the somatosensory network and default mode network, but lower centrality in the posterior insula and globus pallidus compared to HCs (q

Highlights • The Brain/MINDS beyond project plans to collect multi-site/scanner brain MRI data. • Prospective harmonization of MRI was achieved by standardizing scanning protocols. • The preliminary data showed moderate reliability of brain connectome data. • Completing traveling subject plan will allow robust statistical harmonization. • Scanning protocols are publicly available and data will also be shared by 2024., Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

Is motor response inhibition supported by a specialised neuronal inhibitory control mechanism, or by a more general system of action updating? This pre-registered study employed a context-cueing paradigm requiring both inhibitory and non-inhibitory action updating in combination with functional magnetic resonance imaging to test the specificity of responses under different updating conditions, including the cancellation of actions. Cortical regions of activity were found to be common to multiple forms of action updating. However, functional specificity during response inhibition was observed in the anterior right inferior frontal gyrus. In addition, fronto-subcortical activity was explored using a novel contrast method. These exploratory results indicate that the specificity for response inhibition observed in right prefrontal cortex continued downstream and was observed in right hemisphere subcortical activity, while left hemisphere activity was associated with right-hand response execution. Overall, our findings reveal both common and distinct correlates of response inhibition in prefrontal cortex, with exploratory analyses supporting putative models of subcortical pathways and extending them through the demonstration of lateralisation., Highlights • Anterior specificity in cortical activity to response inhibition was identified. • Methodological development of a compound contrast methodology optimising data usage. • Exploratory demonstration of lateralised subcortical action control pathways.

Highlights • We usied a rtfMRI neurofeedback to modulate interhemispheric IPS activity balance. • Six healthy individuals healthy hea were recruited for a proof-of-concept study. • Two of the six successfully learnt to modulate this balance using rtfMRI neurofeedback. • Neurofeedback did not change the behavioural distribution of attention in the learners. • The results have implications for the rehabilitation of post-stroke hemineglect., The intraparietal sulcus (IPS) plays a key role in the distribution of attention across the visual field. In stroke patients, an imbalance between left and right IPS activity has been related to a spatial bias in visual attention characteristic of hemispatial neglect. In this study, we describe the development and implementation of a real-time functional magnetic resonance imaging neurofeedback protocol to noninvasively and volitionally control the interhemispheric IPS activity balance in neurologically healthy participants. Six participants performed three neurofeedback training sessions across three weeks. Half of them trained to voluntarily increase brain activity in left relative to right IPS, while the other half trained to regulate the IPS activity balance in the opposite direction. Before and after the training, we estimated the distribution of attention across the visual field using a whole and partial report task. Over the course of the training, two of the three participants in the left-IPS group increased the activity in the left relative to the right IPS, while the participants in the right-IPS group were not able to regulate the interhemispheric IPS activity balance. We found no evidence for a decrease in resting-state functional connectivity between left and right IPS, and the spatial distribution of attention did not change over the course of the experiment. This study indicates the possibility to voluntarily modulate the interhemispheric IPS activity balance. Further research is warranted to examine the effectiveness of this technique in the rehabilitation of post-stroke hemispatial neglect.

Background Idiopathic cervical dystonia (CD) is a chronic movement disorder characterized by impressive clinical symptoms and the lack of clear pathological findings in clinical diagnostics and imaging. At present, the injection of botulinum toxin (BNT) in dystonic muscles is an effective therapy to control motor symptoms and pain in CD. Objectives We hypothesized that, although it is locally injected to dystonic muscles, BNT application leads to changes in brain and network activity towards normal brain function. Methods Using 3 T functional MR imaging along with advanced analysis techniques (functional connectivity, Granger causality, and regional homogeneity), we aimed to characterize brain activity in CD (17 CD patients vs. 17 controls) and to uncover the effects of BNT treatment (at 6 months). Results In CD, we observed an increased information flow within the basal ganglia, the thalamus, and the sensorimotor cortex. In parallel, some of these structures became less responsive to regulating inputs. Furthermore, our results suggested an altered somatosensory integration. Following BNT administration, we noted a shift towards normal brain function in the CD patients, especially within the motor cortex, the somatosensory cortex, and the basal ganglia. Conclusion The changes in brain function and network activity in CD can be interpreted as related to the underlying cause, the effort to compensate or a mixture of both. Although BNT is applied in the last stage of the cortico-neuromuscular pathway, brain patterns are shifted towards those of healthy controls., Highlights • we characterized brain activity in CD and the effects of BNT using 3T fMR imaging and network analysis techniques • following treatment with botulinum toxin (BNT), abnormal brain activity patterns in primary dystonia are attenuated • critical key regions for both the pathophysiology and BNT-induced improvement in cervical dystonia are the BG

Background Numerous cognitive and emotional functions are executed asymmetrically between the left and right hemispheres. Right hemisphere hyperactivity/left hemisphere hypoactivity often appears to be a feature in neuroimaging studies of depression. However, few studies have evaluated abnormalities in structural asymmetry in untreated patients with major depressive disorder (MDD). Methods In this study, 3-dimensional high-resolution structural magnetic resonance images were acquired from 35 treatment-naïve patients with MDD (mean age = 28.9 years, 22 females) and 35 normal controls. The asymmetry index in cortical thickness and subcortical volume were calculated based on an automated surface-based technique. Results Abnormalities in structural asymmetry in patients with MDD were mainly located in the cortical-striatal-pallidal-thalamic circuit, including the superior frontal cortex, rostral middle frontal cortex, caudal middle frontal cortex, nucleus accumbens, pallidum and thalamus. No significant correlation was observed between symptom severity and asymmetric measurements. Conclusion These findings provide further evidence for the altered morphological interhemispheric imbalances in depression and these alterations were independent of depressive symptom severity, suggesting that cerebral asymmetry could be an appropriate indicator of morphological variations in mental disease., Highlights • Cortical asymmetric changes in depression mainly involved the frontal cortex. • Clinical variables were not associated with cerebral asymmetry. • Cerebral asymmetry could be an indicator of morphological variations in depression.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a characteristic overeating disorder, mild to moderate intellectual disability, and a variable range of social and behavioral difficulties. Consequently, widespread alterations in neural structure and developmental and maturational trajectory would be expected. To date, there have been few quantitative and systematic studies of brain morphology in PWS, although alterations of volume and of cortical organisation have been reported. This study aimed to investigate, in detail, the structure of grey matter and cortex in the brain in a sample of young adults with PWS in a well-matched case-controlled analysis. 20 young adults with PWS, aged 19–27 years, underwent multiparameter mapping magnetic resonance imaging sequences, from which measures of grey matter volume, cortical thickness and magnetisation transfer saturation, as a proxy measure of myelination, were examined. These variables were investigated in comparison to a control group of 40 typically developing young adults, matched for age and sex. A voxel-based morphometry analysis identified large and widespread bilateral clusters of both increased and decreased grey matter volume in the brain in PWS. In particular, widespread areas of increased volume encompassed parts of the prefrontal cortex, especially medially, the majority of the cingulate cortices, from anterior to posterior aspects, insula cortices, and areas of the parietal and temporal cortices. Increased volume was also reported in the caudate, putamen and thalamus. The most ventromedial prefrontal areas, in contrast, showed reduced volume, as did the parts of the medial temporal lobe, bilateral temporal poles, and a small cluster in the right lateral prefrontal cortex. Analysis of cortical structure revealed that areas of increased volume in the PWS group were largely driven by greater cortical thickness. Conversely, analysis of myelin content using magnetisation transfer saturation indicated that myelination of the cortex was broadly similar in the PWS and control groups, with the exception of highly localised areas, including the insula. The bilateral nature of these abnormalities suggests a systemic biological cause, with possible developmental and maturational mechanisms discussed, and may offer insight into the contribution of imprinted genes to neural development., Highlights • Twenty young adults with PWS and forty age and sex-matched control participants underwent multiparameter mapping MRI. • Large and widespread bilateral clusters of both increased and decreased grey matter volume were identified in PWS. • Volumetric increases in PWS were largely driven by greater cortical thickness. • Myelination of the cortex in PWS was broadly similar to the typically-developing control group. • Potential developmental and maturational explanations are considered, including insights into the of the role of imprinted genes.

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing., Highlights • The thalamic target for surgery for tremor is not readily visible on conventional MRI. • Probabilistic tractography is used to segment the thalamus based on connectivity. • The best target area is connected to the contralateral dentate cerebellar nucleus. • GPU processing is used to segment the thalamus in a clinically feasible timescale. • This technique can map out the DRT tract with clear mesencephalic crossing.

Shwachman–Diamond syndrome is a rare recessive genetic disease caused by mutations in SBDS gene, at chromosome 7q11. Phenotypically, the syndrome is characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal dysplasia and variable cognitive impairments. Structural brain abnormalities (smaller head circumference and decreased brain volume) have also been reported. No correlation studies between brain abnormalities and neuropsychological features have yet been performed. In this study we investigate neuroanatomical findings, neurofunctional pathways and cognitive functioning of Shwachman–Diamond syndrome subjects compared with healthy controls. To be eligible for inclusion, participants were required to have known SBDS mutations on both alleles, no history of cranial trauma or any standard contraindication to magnetic resonance imaging. Appropriate tests were used to assess cognitive functions. The static images were acquired on a 3 × 0 T magnetic resonance scanner and blood oxygen level-dependent functional magnetic resonance imaging data were collected both during the execution of the Stroop task and at rest. Diffusion tensor imaging was used to assess brain white matter. The Tract-based Spatial Statistics package and probabilistic tractography were used to characterize white matter pathways. Nine participants (5 males), half of all the subjects aged 9–19 years included in the Italian Shwachman–Diamond Syndrome Registry, were evaluated and compared with nine healthy subjects, matched for sex and age. The patients performed less well than norms and controls on cognitive tasks (p = 0.0002). Overall, cortical thickness was greater in the patients, both in the left (+10%) and in the right (+15%) hemisphere, significantly differently increased in the temporal (left and right, p = 0.04), and right parietal (p = 0.03) lobes and in Brodmann area 44 (p = 0.04) of the right frontal lobe. The greatest increases were observed in the left limbic-anterior cingulate cortex (≥43%, p, Highlights • We correlate brain structure and connectivity with cognition in Shwachman–Diamond patients. • Cortical thickness was greater in the patients than in controls. • Six abnormal clusters of white matter fibres were identified in patients. • Brain areas activated during a Stroop task and at rest were different in patients. • Cognitive impairment in patients is associated with diffuse brain anomalies.

Chronic itch, a highly debilitating condition, has received relatively little attention in the neuroimaging literature. Recent studies suggest that brain regions supporting itch in chronic itch patients encompass sensorimotor and salience networks, and corticostriatal circuits involved in motor preparation for scratching. However, how these different brain areas interact with one another in the context of itch is still unknown. We acquired BOLD fMRI scans in 14 atopic dermatitis patients to investigate resting-state functional connectivity before and after allergen-induced itch exacerbated the clinical itch perception in these patients. A seed-based analysis revealed decreased functional connectivity from baseline resting state to the evoked-itch state between several itch-related brain regions, particularly the insular and cingulate cortices and basal ganglia, where decreased connectivity was significantly correlated with increased levels of perceived itch. In contrast, evoked itch increased connectivity between key nodes of the frontoparietal control network (superior parietal lobule and dorsolateral prefrontal cortex), where higher increase in connectivity was correlated with a lesser increase in perceived itch, suggesting that greater interaction between nodes of this executive attention network serves to limit itch sensation via enhanced top-down regulation. Overall, our results provide the first evidence of itch-dependent changes in functional connectivity across multiple brain regions., Highlights • Atopic dermatitis patients were subjected to allergen-induced itch. • Evoked itch reduced functional connectivity between itch-related brain regions. • Evoked itch increased functional connectivity within frontoparietal control network. • The above changes in functional connectivity correlated with perceived itch level. • Itch sensation may be top-down regulated by frontoparietal control network.

Background Alterations in the hedonic component of ingestive behaviors have been implicated as a possible risk factor in the pathophysiology of overweight and obese individuals. Neuroimaging evidence from individuals with increasing body mass index suggests structural, functional, and neurochemical alterations in the extended reward network and associated networks. Aim To apply a multivariate pattern analysis to distinguish normal weight and overweight subjects based on gray and white-matter measurements. Methods Structural images (N = 120, overweight N = 63) and diffusion tensor images (DTI) (N = 60, overweight N = 30) were obtained from healthy control subjects. For the total sample the mean age for the overweight group (females = 32, males = 31) was 28.77 years (SD = 9.76) and for the normal weight group (females = 32, males = 25) was 27.13 years (SD = 9.62). Regional segmentation and parcellation of the brain images was performed using Freesurfer. Deterministic tractography was performed to measure the normalized fiber density between regions. A multivariate pattern analysis approach was used to examine whether brain measures can distinguish overweight from normal weight individuals. Results 1. White-matter classification: The classification algorithm, based on 2 signatures with 17 regional connections, achieved 97% accuracy in discriminating overweight individuals from normal weight individuals. For both brain signatures, greater connectivity as indexed by increased fiber density was observed in overweight compared to normal weight between the reward network regions and regions of the executive control, emotional arousal, and somatosensory networks. In contrast, the opposite pattern (decreased fiber density) was found between ventromedial prefrontal cortex and the anterior insula, and between thalamus and executive control network regions. 2. Gray-matter classification: The classification algorithm, based on 2 signatures with 42 morphological features, achieved 69% accuracy in discriminating overweight from normal weight. In both brain signatures regions of the reward, salience, executive control and emotional arousal networks were associated with lower morphological values in overweight individuals compared to normal weight individuals, while the opposite pattern was seen for regions of the somatosensory network. Conclusions 1. An increased BMI (i.e., overweight subjects) is associated with distinct changes in gray-matter and fiber density of the brain. 2. Classification algorithms based on white-matter connectivity involving regions of the reward and associated networks can identify specific targets for mechanistic studies and future drug development aimed at abnormal ingestive behavior and in overweight/obesity., Highlights • Multivariate analysis can be used to classify overweight from normal weight individuals. • Anatomical connectivity achieved 97% accuracy in the classification algorithm. • Greater connectivity was observed in extended reward and somatosensory regions. • Morphological gray-matter achieved 69% accuracy in the classification algorithm. • Lower morphological values were observed in regions of the extended reward network.

Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE: rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: − 5.3 ppb, right: − 6.7 ppb, p, Highlights • Magnetic susceptibility and common gene variants linked to iron were investigated. • The C282Y and H63D alleles were associated with putamen and thalamus susceptibility changes. • Dependent on allele status, men and women differed in deep GM susceptibility in MS.

Highlights • Stroke patients show a reduced response of the ventral striatum to rewarding feedback. • The strong hypoactivation of nucleus accumbens could not be explained by structural damage. • Striatal hypoactivation in stroke survivors may cause impaired consolidation of motor skills., Introduction Motor skill learning can help stroke survivors to cope with motor function deficits but requires many repetitions. One factor that keeps patients motivated is obtaining reward upon successfully completing a motor task. It has been suggested that stroke survivors have deficits in reward processing which may negatively impact skill learning. Objective To test the hypothesis that stroke survivors have deficient reward processing during motor skill learning evident in reduced activation in the striatum and its subdivisions in functional magnetic resonance imaging as compared with healthy, age-matched control subjects. Methods Striatal activity in response to performance dependent feedback and monetary reward was measured in 28 subacute stroke patients and 18 age-matched healthy control subjects during the training of visuomotor tracking an arc-shaped trajectory using the wrist (unimpaired side in patients, dominant side in controls) in an fMRI scanner. Results Despite comparable monetary rewards, stroke patients showed reduced activation in the ventral part (p

Understanding brain reserve in preclinical stages of neurodegenerative disorders allows determination of which brain regions contribute to normal functioning despite accelerated neuronal loss. Besides the recruitment of additional regions, a reorganisation and shift of relevance between normally engaged regions are a suggested key mechanism. Thus, network analysis methods seem critical for investigation of changes in directed causal interactions between such candidate brain regions. To identify core compensatory regions, fifteen preclinical patients carrying the genetic mutation leading to Huntington's disease and twelve controls underwent fMRI scanning. They accomplished an auditory paced finger sequence tapping task, which challenged cognitive as well as executive aspects of motor functioning by varying speed and complexity of movements. To investigate causal interactions among brain regions a single Dynamic Causal Model (DCM) was constructed and fitted to the data from each subject. The DCM parameters were analysed using statistical methods to assess group differences in connectivity, and the relationship between connectivity patterns and predicted years to clinical onset was assessed in gene carriers. In preclinical patients, we found indications for neural reserve mechanisms predominantly driven by bilateral dorsal premotor cortex, which increasingly activated superior parietal cortices the closer individuals were to estimated clinical onset. This compensatory mechanism was restricted to complex movements characterised by high cognitive demand. Additionally, we identified task-induced connectivity changes in both groups of subjects towards pre- and caudal supplementary motor areas, which were linked to either faster or more complex task conditions. Interestingly, coupling of dorsal premotor cortex and supplementary motor area was more negative in controls compared to gene mutation carriers. Furthermore, changes in the connectivity pattern of gene carriers allowed prediction of the years to estimated disease onset in individuals. Our study characterises the connectivity pattern of core cortical regions maintaining motor function in relation to varying task demand. We identified connections of bilateral dorsal premotor cortex as critical for compensation as well as task-dependent recruitment of pre- and caudal supplementary motor area. The latter finding nicely mirrors a previously published general linear model-based analysis of the same data. Such knowledge about disease specific inter-regional effective connectivity may help identify foci for interventions based on transcranial magnetic stimulation designed to stimulate functioning and also to predict their impact on other regions in motor-associated networks., Highlights • Connectivity of a motor network is altered in preclinical neurodegeneration. • Dynamic Causal Modelling reveals task-dependent recruitment of pre- and caudal SMA. • Connectivity of the dorsal premotor cortex reveals compensatory mechanisms. • DCM allows prediction of years to clinical onset in preclinical patients.

Sickle cell disease (SCD) is a red blood cell disorder that causes many complications including life-long pain. Treatment of pain remains challenging due to a poor understanding of the mechanisms and limitations to characterize and quantify pain. In the present study, we examined simultaneously recording functional MRI (fMRI) and electroencephalogram (EEG) to better understand neural connectivity as a consequence of chronic pain in SCD patients. We performed independent component analysis and seed-based connectivity on fMRI data. Spontaneous power and microstate analysis was performed on EEG-fMRI data. ICA analysis showed that patients lacked activity in the default mode network (DMN) and executive control network compared to controls. EEG-fMRI data revealed that the insula cortex's role in salience increases with age in patients. EEG microstate analysis showed patients had increased activity in pain processing regions. The cerebellum in patients showed a stronger connection to the periaqueductal gray matter (involved in pain inhibition), and negative connections to pain processing areas. These results suggest that patients have reduced activity of DMN and increased activity in pain processing regions during rest. The present findings suggest resting state connectivity differences between patients and controls can be used as novel biomarkers of SCD pain., Highlights • Simultaneous EEG-fMRI recordings revealed altered connectivity in sickle cell patients. • Reduced activity observed in default mode network and executive control network. • Patients' salience network strength increases with age; opposite seen in controls. • EEG-fMRI parameters reflect disease severity in sickle cell patients.

Highlights • Healthy adults performed movements while receiving neurofeedback from real-time fMRI. • Two experiments were performed, one with younger and one with older adults. • Neurofeedback (NF) represented the laterality of activation in the motor cortices. • The NF groups produced more lateralized activity than the sham group., Neurofeedback training involves presenting an individual with a representation of their brain activity and instructing them to alter the activity using the feedback. One potential application of neurofeedback is for patients to alter neural activity to improve function. For example, there is evidence that greater laterality of movement-related activity is associated with better motor outcomes after stroke; so using neurofeedback to increase laterality may provide a novel route for improving outcomes. However, we must demonstrate that individuals can control relevant neurofeedback signals. Here, we performed two proof-of-concept studies, one in younger (median age: 26 years) and one in older healthy volunteers (median age: 67.5 years). The purpose was to determine if participants could manipulate laterality of activity between the motor cortices using real-time fMRI neurofeedback while performing simple hand movements. The younger cohort trained using their left and right hand, the older group trained using their left hand only. In both studies participants in a neurofeedback group were able to achieve more lateralized activity than those in a sham group (younger adults: F(1,23) = 4.37, p

Highlights • The increased functional connectivity between the SMA and aMCC indicates a mediator role of the aMCC in NFB learning. • Successful regulation of the targeted SMC is correlated with its functional connectivity with the non-targeted SMA. • The involvement of the aMCC and frontal areas and the path of influence support the skill-learning concept of NFB. • The investigation into the intrinsic property of the system to be trained is helpful to understand how NFB works., Neurofeedback (NFB) allows subjects to learn self-regulation of neuronal brain activation based on information about the ongoing activation. The implementation of real-time functional magnetic resonance imaging (rt-fMRI) for NFB training now facilitates the investigation into underlying processes. Our study involved 16 control and 16 training right-handed subjects, the latter performing an extensive rt-fMRI NFB training using motor imagery. A previous analysis focused on the targeted primary somato-motor cortex (SMC). The present study extends the analysis to the supplementary motor area (SMA), the next higher brain area within the hierarchy of the motor system. We also examined transfer-related functional connectivity using a whole-volume psycho-physiological interaction (PPI) analysis to reveal brain areas associated with learning. The ROI analysis of the pre- and post-training fMRI data for motor imagery without NFB (transfer) resulted in a significant training-specific increase in the SMA. It could also be shown that the contralateral SMA exhibited a larger increase than the ipsilateral SMA in the training and the transfer runs, and that the right-hand training elicited a larger increase in the transfer runs than the left-hand training. The PPI analysis revealed a training-specific increase in transfer-related functional connectivity between the left SMA and frontal areas as well as the anterior midcingulate cortex (aMCC) for right- and left-hand trainings. Moreover, the transfer success was related with training-specific increase in functional connectivity between the left SMA and the target area SMC. Our study demonstrates that NFB training increases functional connectivity with non-targeted brain areas. These are associated with the training strategy (i.e., SMA) as well as with learning the NFB skill (i.e., aMCC and frontal areas). This detailed description of both the system to be trained and the areas involved in learning can provide valuable information for further optimization of NFB trainings.

Major depressive disorder (MDD) and bipolar disorder (BD) are severe psychiatric diseases with overlapping symptomatology. Although previous studies reported abnormal brain structures in MDD or BD patients, the disorder-specific underlying neural mechanisms remain poorly understood. The purpose of this study was to investigate the whole-brain gray matter morphological patterns in unmedicated patients with MDD or BD and to identify the shared and disease-specific brain morphological alterations in these two disorders. We acquired high-resolution brain structural MRI data from a sample of 36 MDD patients, 32 BD patients, and 30 healthy controls. Using FreeSurfer, we estimated their brain cortical thickness (CT) and compared between-group difference in multiple locations across the continuous cortical surface. Compared to the healthy controls, both the MDD and BD patient groups showed significantly reduced CT in the left inferior temporal cortex (ITC). However, compared to the MDD patients, the BD patients showed a significantly thinner CT in the left rostral middle frontal region. In addition, compared to the healthy controls, the BD patients displayed thinner CT in the left ITC, left frontal pole (FPO), left superior frontal, right lateral occipital, right pars triangularis (PTRI) and right lateral orbitofrontal regions. Further analysis revealed a significantly positive correlation between the mean CT in the left FPO and the onset age, but a negative correlation between the mean CT in the right PTRI and the number of episodes, in the BD patients. Our findings revealed that the BD and MDD patients had variations in CT that were in common, but many more that were distinct, suggesting potential differences in their neural mechanisms., Highlights • We found thinner CT in the left ITC in both MDD and BD groups compared to controls. • We detected thinner CT in the left rMFC in the BD group compared to the MDD group. • The BD group had more pronounced abnormality in CT primarily in the PFC than the MDD group. • Clinical variables of BD group were associated with decreased CT in the left FPO and right PTRI. This study aims to detect abnormal cortical thickness in patients with major depressive disorder (MDD) or bipolar disorder (BD), and to identify the shared and disease-specific brain morphological alterations in these two disorders. The two patient groups showed several common but more distinct variation patterns in cortical thickness, and the BD patients had lower cortical thickness in widespread brain areas than the MDD and the controls. These findings may have potential clinical implications for distinguishing BD from MDD patients.

Objective To evaluate whether placental transfusion influences brain myelination at 4 months of age. Study design A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC

The purpose of the present study was to detail the childhood developmental course of different white matter (WM) characteristics. In a longitudinal diffusion tensor imaging (DTI) study of 159 healthy children between 4 and 11 years scanned twice, we used tract-based spatial statistics as well as delineation of 15 major WM tracts to characterize the regional pattern of change in fractional anisotropy (FA), mean (MD), radial (RD) and axial diffusivity (AD). We tested whether there were decelerations of change with increasing age globally and tract-wise, and also illustrated change along medial-to-lateral, posterior-to-anterior and inferior-to-superior gradients. We found a significant linear increase in global FA, and decrease in MD and RD over time. For mean AD, a weak decrease was observed. The developmental changes in specific WM tracts showed regional differences. Eight WM tracts showed non-linear development patterns for one or several DTI metrics, with a deceleration in change with age. Sex did not affect change in any DTI metric. Overall, greater rate of change was found in the left hemisphere. Spatially, there was a posterior-to-anterior gradient of change with greater change in frontal regions for all metrics. The current study provides a comprehensive characterization of the regional patters of change in WM microstructure across pre-adolescence childhood., Highlights • We explore longitudinal change in white matter (WM) microstructure in children. • Using TBSS to delineate 15 WM tracts and several gradients in the brain • Global WM change show linear developmental patterns from age 4 to 11 years. • Greater WM change in the anterior compared to the posterior brain region. • The developmental patterns for WM tracts show regional differences.

Voice and speech in Parkinson's disease (PD) patients are classically affected by a hypophonia, dysprosody, and dysarthria. The underlying pathomechanisms of these disabling symptoms are not well understood. To identify functional anomalies related to pathophysiology and compensation we compared speech-related brain activity and effective connectivity in early PD patients who did not yet develop voice or speech symptoms and matched controls. During fMRI 20 PD patients ON and OFF levodopa and 20 control participants read 75 sentences covertly, overtly with neutral, or with happy intonation. A cue-target reading paradigm allowed for dissociating task preparation from execution. We found pathologically reduced striato-prefrontal preparatory effective connectivity in early PD patients associated with subcortical (OFF state) or cortical (ON state) compensatory networks. While speaking, PD patients showed signs of diminished monitoring of external auditory feedback. During generation of affective prosody, a reduced functional coupling between the ventral and dorsal striatum was observed. Our results suggest three pathomechanisms affecting speech in PD: While diminished energization on the basis of striato-prefrontal hypo-connectivity together with dysfunctional self-monitoring mechanisms could underlie hypophonia, dysarthria may result from fading speech motor representations given that they are not sufficiently well updated by external auditory feedback. A pathological interplay between the limbic and sensorimotor striatum could interfere with affective modulation of speech routines, which affects emotional prosody generation. However, early PD patients show compensatory mechanisms that could help improve future speech therapies., Highlights • Speech networks are altered in PD patients before they develop speech symptoms. • Hypophonia relates to reduced energization due to reduced striato-prefrontal coupling. • PD patients show signatures of reduced monitoring of auditory feedback. • Dysarthria may result from imprecise shaping of motor representations by feedback. • External therapeutic models help normalizing speech-related neural anomalies.

Background Binge consumption of alcohol is a major societal problem associated with important cognitive, physiological and neurotoxic consequences. Converging evidence highlights the need to assess binge drinking (BD) and its effects on the developing brain while taking into account gender differences. Here, we compared the brain volumetric differences between genders in college-aged binge drinkers and healthy volunteers. Method T1-weighted magnetic resonance imaging (MRI) images of 30 binge drinkers (18 males) and 46 matched healthy volunteers (23 males) were examined using voxel-based morphometry. The anatomical scans were covaried with Alcohol Use Disorders Identification Test (AUDIT) scores. Whole brain voxel-wise group comparisons were performed using a cluster extent threshold correction. Results Several large clusters qualified with group-by-gender interactions were observed in prefrontal, striatal and medial temporal areas, whereby BD females had more volume than non-BD females, while males showed the inverse pattern of decreased volume in BD males and increased volume in non-BD males. AUDIT scores negatively correlated with volume in the right superior frontal cortex and precentral gyrus. Conclusions These findings dovetail with previous studies reporting that a state effect of BD in college-aged drinkers and the severity of alcohol use are associated with volumetric alterations in the cortical and subcortical areas of the brain. Our study indicates that these widespread volumetric changes vary differentially by gender, suggesting either sexual dimorphic endophenotypic risk factors, or differential neurotoxic sensitivities for males and females., Highlights • We examined brain volumetric differences between genders in college-aged binge drinkers and healthy volunteers. • Gender significantly moderated brain volumetric differences in prefrontal, striatal and medial temporal areas. • The severity of alcohol use in binge drinkers is associated with brain volumetric changes in the superior frontal cortex and precentral gyrus.