Whole-brain Voxel-based Analysis Research Articles

Anatomically Standardized Detection of MRI Atrophy Patterns in Early-Stage Alzheimer's Disease.

MRI studies have consistently identified atrophy patterns in Alzheimer’s disease (AD) through a whole-brain voxel-based analysis, but efforts to investigate morphometric profiles using anatomically standardized and automated whole-brain ROI analyses, performed at the individual subject space, are still lacking. In this study we aimed (i) to utilize atlas-derived measurements of cortical thickness and subcortical volumes, including of the hippocampal subfields, to identify atrophy patterns in early-stage AD, and (ii) to compare cognitive profiles at baseline and during a one-year follow-up of those previously identified morphometric AD subtypes to predict disease progression. Through a prospectively recruited multi-center study, conducted at four Austrian sites, 120 patients were included with probable AD, a disease onset beyond 60 years and a clinical dementia rating of ≤1. Morphometric measures of T1-weighted images were obtained using FreeSurfer. A principal component and subsequent cluster analysis identified four morphometric subtypes, including (i) hippocampal predominant (30.8%), (ii) hippocampal-temporo-parietal (29.2%), (iii) parieto-temporal (hippocampal sparing, 20.8%) and (iv) hippocampal-temporal (19.2%) atrophy patterns that were associated with phenotypes differing predominately in the presentation and progression of verbal memory and visuospatial impairments. These morphologically distinct subtypes are based on standardized brain regions, which are anatomically defined and freely accessible so as to validate its diagnostic accuracy and enhance the prediction of disease progression.

Altered Brain Structure in Chronic Visceral Pain: Specific Differences in Gray Matter Volume and Associations With Visceral Symptoms and Chronic Stress.

Structural brain alterations in chronic pain conditions remain incompletely understood, especially in chronic visceral pain. Patients with chronic-inflammatory or functional bowel disorders experience recurring abdominal pain in concert with other gastrointestinal symptoms, such as altered bowel habits, which are often exacerbated by stress. Despite growing interest in the gut-brain axis and its underlying neural mechanisms in health and disease, abnormal brain morphology and possible associations with visceral symptom severity and chronic stress remain unclear. We accomplished parallelized whole-brain voxel-based morphometry analyses in two patient cohorts with chronic visceral pain, i.e., ulcerative colitis in remission and irritable bowel syndrome, and healthy individuals. In addition to analyzing changes in gray matter volume (GMV) in each patient cohort vs. age-matched healthy controls using analysis of covariance (ANCOVA), multiple regression analyses were conducted to assess correlations between GMV and symptom severity and chronic stress, respectively. ANCOVA revealed reduced GMV in frontal cortex and anterior insula in ulcerative colitis compared to healthy controls, suggesting alterations in the central autonomic and salience networks, which could however not be confirmed in supplemental analyses which rigorously accounted for group differences in the distribution of sex. In irritable bowel syndrome, more widespread differences from healthy controls were observed, comprising both decreased and increased GMV within the sensorimotor, central executive and default mode networks. Associations between visceral symptoms and GMV within frontal regions were altered in both patient groups, supporting a role of the central executive network across visceral pain conditions. Correlations with chronic stress, on the other hand, were only found for irritable bowel syndrome, encompassing numerous brain regions and networks. Together, these findings complement and expand existing brain imaging evidence in chronic visceral pain, supporting partly distinct alterations in brain morphology in patients with chronic-inflammatory and functional bowel disorders despite considerable overlap in symptoms and comorbidities. First evidence pointing to correlations with chronic stress in irritable bowel syndrome inspires future translational studies to elucidate the mechanisms underlying the interconnections of stress, visceral pain and neural mechanisms of the gut-brain axis.

The impact of COVID-19 lockdown on brain metabolism.

This study aims to evaluate the impact of French national lockdown of 55 days on brain metabolism of patients with neurological disorders. Whole‐brain voxel‐based PET analysis was used to correlate 18F‐FDG metabolism to the number of days after March 17, 2020 (in 95 patients; mean age: 54.3 years ± 15.7; 59 men), in comparison to the same period in 2019 before the SARS‐CoV‐2 outbreak (in 212 patients; mean age: 59.5 years ± 15.8; 114 men), and to the first 55 days of deconfinement (in 188 patients; mean age: 57.5 years ± 16.5; 93 men). Lockdown duration was negatively correlated to the metabolism of the sensory‐motor cortex with a prevailing effect on the left dominant pyramidal tract and on younger patients, also including the left amygdala, with only partial reversibility after 55 days of deconfinement. Weak overlap was found with the reported pattern of hypometabolism in long COVID (<9%). Restriction of physical activities, and possible related deconditioning, and social isolation may lead to functional disturbances of sensorimotor and emotional brain networks. Of note, this metabolic pattern seems distinct to those reported in long COVID. Further longitudinal studies with longer follow‐up are needed to evaluate clinical consequences and relationships on cognitive and mental health against functional deactivation hypothesis, and to extend these findings to healthy subjects in the context of lockdown.

Diffusion kurtosis imaging of white matter in bipolar disorder

White matter pathology likely contributes to the pathogenesis of bipolar disorder (BD). Most studies of white matter in BD have used diffusion tensor imaging (DTI), but the advent of more advanced multi-shell diffusion MRI imaging offers the possibility to investigate other aspects of white matter microstructure. Diffusion kurtosis imaging (DKI) extends the DTI model and provides additional measures related to diffusion restriction. Here, we investigated white matter in BD by applying whole-brain voxel-based analysis (VBA) and a network-based connectivity approach using constrained spherical deconvolution tractography to assess differences in DKI and DTI metrics between BD (n = 25) and controls (n = 24). The VBA showed lower mean kurtosis in the corona radiata and posterior association fibers in BD. Regional differences in connectivity were indicated by lower mean kurtosis and kurtosis anisotropy in streamlines traversing the temporal and occipital lobes, and lower mean axial kurtosis in the right cerebellar, thalamo-subcortical pathways in BD. Significant differences were not seen in DTI metrics following FDR-correction. The DKI findings indicate altered connectivity across cortical, subcortical and cerebellar areas in BD. DKI is sensitive to different microstructural properties and is a useful complementary technique to DTI to more fully investigate white matter in BD.

Insular interictal positron emission tomography hypometabolism in patients with ictal asystole.

We aimed to explore brain area(s) involved in the generation of ictal asystole (IA) by analyzing the interictal positron emission tomography (PET) metabolism of patients with IA recorded by video-electroencephalography or video-stereo-electroencephalography. We identified in our cohort of focal epilepsy patients who had undergone presurgical evaluation those who had a recorded period of IA of more than 3 s. We investigated the anatomometabolic changes (interictal 18 F-fluorodeoxyglucose PET) of these patients in comparison with (1) healthy subjects with similar age and sex distribution (n=19) using whole-brain voxel-based analysis (p-voxel < .001, p-cluster < .05, uncorrected) and (2) patients without IA with similar age and seizure onset zone (n=55). We found 12 patients with IA. Epilepsy was mainly temporal (four right temporal mesial, four bitemporal, two left temporal lateral, one right temporal lateral, and one right temporal "plus"). Seven patients had negative magnetic resonance imaging. Whole-brain statistical analysis of PET imaging was performed at the voxel level, showing that in comparison to healthy subjects and to epileptic patients without IA, a hypometabolism in the right posterior insula characterized epileptic patients with IA. Our study suggests involvement of the right posterior insula-a part of the central autonomic network-in the pathophysiological mechanism of IA.

Abnormalities of intrinsic brain activity in irritable bowel syndrome (IBS): A protocol for systematic review and meta analysis of resting-state functional imaging.

BackgroundIrritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders affecting up to 11.5% of the general global population. The brain–gut axis has been shown to play an important role in the pathogenesis of IBS. Several studies confirmed that intrinsic brain abnormalities existed in patients with IBS. But, studies of abnormal regional homogeneity (ReHo) in IBS have reported inconsistent results. The objective of this protocol is to conduct a meta-analysis using the Seed-based d mapping software package to identify the most consistent and replicable findings of ReHo in IBS patients.MethodWe will search the following three electronic databases: MEDLINE, EMBASE and Web of Science. The primary outcome will include the peak coordinates and effect sizes of differences in ReHo between patients with IBS and healthy controls from each dataset. The secondary outcomes will be the effects of age, illness severity, illness duration, and scanner field strength. The SDM approach was used to conduct voxel-wise meta-analysis. Whole-brain voxel-based jackknife sensitivity analysis was performed to conduct jackknife sensitivity analysis. A random effects model with Q statistics is used to conduct heterogeneity and publication bias between studies and meta-regression analyses were carried out to examine the effects of age, illness severity, illness duration, and scanner field strength.ResultsThe results of this paper will be submitted to a peer-reviewed journal for publication.ConclusionThis research will determine the consistent pattern of alterations in ReHo in IBS patients.

Decreased grey matter volumes in unaffected mothers of individuals with autism spectrum disorder reflect the broader autism endophenotype

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an early onset and a strong genetic origin. Unaffected relatives may present similar but subthreshold characteristics of ASD. This broader autism phenotype is especially prevalent in the parents of individuals with ASD, suggesting that it has heritable factors. Although previous studies have demonstrated brain morphometry differences in ASD, they are poorly understood in parents of individuals with ASD. Here, we estimated grey matter volume in 45 mothers of children with ASD (mASD) and 46 age-, sex-, and handedness-matched controls using whole-brain voxel-based morphometry analysis. The mASD group had smaller grey matter volume in the right middle temporal gyrus, temporoparietal junction, cerebellum, and parahippocampal gyrus compared with the control group. Furthermore, we analysed the correlations of these brain volumes with ASD behavioural characteristics using autism spectrum quotient (AQ) and systemizing quotient (SQ) scores, which measure general autistic traits and the drive to systemize. Smaller volumes in the middle temporal gyrus and temporoparietal junction correlated with higher SQ scores, and smaller volumes in the cerebellum and parahippocampal gyrus correlated with higher AQ scores. Our findings suggest that atypical grey matter volumes in mASD may represent one of the neurostructural endophenotypes of ASD.

Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia.

Much of human behaviour is motivated by the drive to experience pleasure. The capacity to envisage pleasurable outcomes and to engage in goal-directed behaviour to secure these outcomes depends upon the integrity of frontostriatal circuits in the brain. Anhedonia refers to the diminished ability to experience, and to pursue, pleasurable outcomes, and represents a prominent motivational disturbance in neuropsychiatric disorders. Despite increasing evidence of motivational disturbances in frontotemporal dementia (FTD), no study to date has explored the hedonic experience in these syndromes. Here, we present the first study to document the prevalence and neural correlates of anhedonia in FTD in comparison with Alzheimer's disease, and its potential overlap with related motivational symptoms including apathy and depression. A total of 172 participants were recruited, including 87 FTD, 34 Alzheimer's disease, and 51 healthy older control participants. Within the FTD group, 55 cases were diagnosed with clinically probable behavioural variant FTD, 24 presented with semantic dementia, and eight cases had progressive non-fluent aphasia (PNFA). Premorbid and current anhedonia was measured using the Snaith-Hamilton Pleasure Scale, while apathy was assessed using the Dimensional Apathy Scale, and depression was indexed via the Depression, Anxiety and Stress Scale. Whole-brain voxel-based morphometry analysis was used to examine associations between grey matter atrophy and levels of anhedonia, apathy, and depression in patients. Relative to controls, behavioural variant FTD and semantic dementia, but not PNFA or Alzheimer's disease, patients showed clinically significant anhedonia, representing a clear departure from pre-morbid levels. Voxel-based morphometry analyses revealed that anhedonia was associated with atrophy in an extended frontostriatal network including orbitofrontal and medial prefrontal, paracingulate and insular cortices, as well as the putamen. Although correlated on the behavioural level, the neural correlates of anhedonia were largely dissociable from that of apathy, with only a small region of overlap detected in the right orbitofrontal cortices whilst no overlapping regions were found between anhedonia and depression. This is the first study, to our knowledge, to demonstrate profound anhedonia in FTD syndromes, reflecting atrophy of predominantly frontostriatal brain regions specialized for hedonic tone. Our findings point to the importance of considering anhedonia as a primary presenting feature of behavioural variant FTD and semantic dementia, with distinct neural drivers to that of apathy or depression. Future studies will be essential to address the impact of anhedonia on everyday activities, and to inform the development of targeted interventions to improve quality of life in patients and their families.

Classification differentiates clinical and neuroanatomic features of cerebral small vessel disease.

Age-related cerebral small vessel disease involves heterogeneous pathogenesis, such as arteriosclerosis/lipohyalinosis and cerebral amyloid angiopathy. MRI can visualize the brain lesions attributable to small vessel disease pathologies, including white-matter hyperintensities, lacune and cerebral microbleeds. However, these MRI markers usually coexist in small vessel disease of different aetiologies. Currently, there is no available classification integrating these neuroimaging markers for differentiating clinical and neuroanatomic features of small vessel disease yet. In this study, we tested whether our proposed stratification scheme could characterize specific clinical, neuroanatomic and potentially pathogenesis/aetiologies in classified small vessel disease subtypes. Cross-sectional analyses from a community-based non-demented non-stroke cohort consisting of ≥50 years old individuals were conducted. All participants were scanned 3T brain MRI for small vessel disease detection and neuroanatomic measurements and underwent physical and cognitive assessments. Study population were classified into robust and four small vessel disease groups based on imaging markers indicating (i) bleeding or non-bleeding; (ii) specific location of cerebral microbleeds; and (iii) the severity and combination of white-matter hyperintensities and lacune. We used whole-brain voxel-based morphometry analyses and tract-based spatial statistics to evaluate the regional grey-matter volume and white-matter microstructure integrity for comparisons among groups. Among the 735 participants with eligible brain MRI images, quality screening qualified 670 for grey-matter volume analyses and 617 for white-matter microstructural analyses. Common and distinct patterns of the clinical and neuroimaging manifestations were found in the stratified four small vessel disease subgroups. Hierarchical clustering analysis revealed that small vessel disease type 4 had features distinct from the small vessel disease types 1, 2 and 3. Abnormal white-matter microstructures and cognitive function but preserved physical function and grey-matter volume were found in small vessel disease type 4. Among small vessel disease types 1, 2 and 3, there were similar characteristics but different severity; the clinical features showed both physical frail and cognitive impairment and the neuroanatomic features revealed frontal–subcortical white-matter microstructures and remote, diffuse cortical abnormalities. This novel stratification scheme highlights the distinct clinical and neuroanatomic features of small vessel disease and the possible underlying pathogenesis. It could have potential application in research and clinical settings.

Gradient of electro-convulsive therapy\u2019s antidepressant effects along the longitudinal hippocampal axis

Despite decades of successful treatment of therapy-resistant depression and major scientific advances in the field, our knowledge about electro-convulsive therapy’s (ECT) mechanisms of action is still scarce. Building on strong empirical evidence for ECT-induced hippocampus anatomy changes, we sought to test the hypothesis that ECT has a differential impact along the hippocampus longitudinal axis. We acquired behavioural and brain anatomy magnetic resonance imaging (MRI) data in patients with depressive episode undergoing ECT (n = 9) or pharmacotherapy (n = 24) and healthy controls (n = 30) at two time points 3 months apart. Using whole-brain voxel-based statistical parametric mapping and topographic analysis focused on the hippocampus, we observed ECT-induced gradient of grey matter volume increase along the hippocampal longitudinal axis with predominant impact on its anterior portion. Clinical outcome measures showed strong correlations with both baseline volume and rate of ECT-induced change exclusively for the anterior, but not posterior hippocampus. We interpret our findings confined to the anterior hippocampus and amygdala as additional evidence of the regional specific impact of ECT that unfolds its beneficial effect on depression via the “limbic” system. Main limitations of the study are patients’ polypharmacy, heterogeneity of psychiatric diagnosis, and long-time interval between scans.

Magnetisation transfer imaging revealed microstructural changes related to apathy symptoms after ischaemic stroke.

Apathy after stroke is common and has a negative impact on functional recovery. Neuroimaging correlates of poststroke apathy remain unclear. We aimed to investigate microstructural changes associated with the severity of poststroke apathy symptoms. We assessed 67 patients with cerebral ischaemia who underwent magnetisation transfer brain imaging 12-15 months after stroke. We used magnetisation transfer ratio (MTR) to represent microstructural integrity. We performed whole-brain voxel-based analysis and subsequent region of interest analysis to investigate the association between MTR and symptoms of poststroke apathy. To assess apathy symptoms, we used clinician-reported version of the Apathy Evaluation Scale. Voxel-based analysis showed the association between symptoms of apathy and decreased MTR in areas overlapping with structures located in both hemispheres: left thalamus, bilateral hippocampus, bilateral fornix/stria terminalis, right amygdala, splenium of the corpus callosum, the retrolenticular part of left internal capsule and left sagittal stratum. In the region of interest analysis, only lower MTR in right fornix/stria terminalis was associated with greater poststroke apathy symptoms in a multivariate logistic model (odds ratio: 1.25, 95% CI: 1.09-1.46, p=0.003). These associations were independent of depressive symptoms. Magnetisation transfer brain imaging 12-15 months after stroke revealed changes in microstructural integrity associated with apathy symptoms in brain areas related to processing emotional information and reward valuation.

Temporal trajectory of brain tissue property changes induced by electroconvulsive therapy

BackgroundAfter more than eight decades of electroconvulsive therapy (ECT) for pharmaco-resistant depression, the mechanisms governing its anti-depressant effects remain poorly understood. Computational anatomy studies using longitudinal T1-weighted magnetic resonance imaging (MRI) data have demonstrated ECT effects on hippocampus volume and cortical thickness, but they lack the interpretational specificity about underlying neurobiological processes. MethodsWe sought to fill in the gap of knowledge by acquiring quantitative MRI indicative for brain's myelin, iron and tissue water content at multiple time-points before, during and after ECT treatment. We adapted established tools for longitudinal spatial registration of MRI data to the relaxometry-based multi-parameter maps aiming to preserve the initial total signal amount and introduced a dedicated multivariate analytical framework. ResultsThe whole-brain voxel-based analysis based on a multivariate general linear model showed that there is no brain tissue oedema contributing to the predicted ECT-induced hippocampus volume increase neither in the short, nor in the long-term observations. Improvements in depression symptom severity over time were associated with changes in both volume estimates and brain tissue properties expanding beyond mesial temporal lobe structures to anterior cingulate cortex, precuneus and striatum. ConclusionThe obtained results stemming from multi-contrast MRI quantitative data provided a fingerprint of ECT-induced brain tissue changes over time that are contrasted against the background of established morphometry findings. The introduced data processing and statistical testing algorithms provided a reliable analytical framework for longitudinal multi-parameter brain maps. The results, particularly the evidence of lack of ECT impact on brain tissue water, should be considered preliminary considering the small sample size of the study.

18F-FDG brain PET hypometabolism in patients with long COVID.

PurposeIn the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as “long COVID.” We here present a retrospective analysis of 18F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection.MethodsPET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients’ characteristics and functional complaints.ResultsIn comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p < 0.001).ConclusionThis study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients’ symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.

Early brainstem [18F]THK5351 uptake is linked to cortical hyperexcitability in healthy aging.

BACKGROUNDNeuronal hyperexcitability characterizes the early stages of Alzheimer’s disease (AD). In animals, early misfolded tau and amyloid-β (Aβ) protein accumulation — both central to AD neuropathology — promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau — and its associated neuroinflammation — and cortical Aβ aggregations remains unknown.METHODSWe probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late-middle–aged individuals (50–69 years; 45 women and 19 men). We assessed whole-brain [18F]THK5351 PET uptake as a proxy measure of tau/neuroinflammation, and we assessed whole-brain Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers.RESULTSWe found that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment was associated with increased cortical excitability (r = 0.29, P = 0.02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (P value corrected for family-wise error [PFWE-corrected] < 0.001), was not significantly associated with cortical excitability (r = 0.14, P = 0.25). Importantly, no significant association was found between early Aβ cortical deposits and cortical excitability (r = –0.20, P = 0.11).CONCLUSIONThese findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGF.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.

Neuroanatomical correlates of reality monitoring in patients with schizophrenia and auditory hallucinations.

Reality-monitoring process enables to discriminate memories of internally generated information from memories of externally derived information. Studies have reported impaired reality-monitoring abilities in schizophrenia patients with auditory hallucinations (AHs), specifically with an exacerbated externalization bias, as well as alterations in neural activity within frontotemporoparietal areas. In healthy subjects, impaired reality-monitoring abilities have been associated with reduction of the paracingulate sulcus (PCS). The current study aimed to identify neuroanatomical correlates of reality monitoring in patients with schizophrenia. Thirty-five patients with schizophrenia and AHs underwent a reality-monitoring task and a 3D anatomical MRI scan at 1.5T. PCS lengths were measured separately for each hemisphere, and whole-brain voxel-based morphometry analyses were performed using the Computational Anatomy Toolbox (version 12.6) to evaluate the gray-matter volume (GMV). Partial correlation analyses were used to investigate the relationship between reality-monitoring and neuroanatomical outcomes (PCS length and GMV), with age and intracranial volume as covariates. The right PCS length was positively correlated with reality-monitoring accuracy (Spearman's ρ=0.431, p=0.012) and negatively with the externalization bias (Spearman's ρ=-0.379, p=0.029). Reality-monitoring accuracy was positively correlated with GMV in the right angular gyrus, whereas externalization bias was negatively correlated with GMV in the left supramarginal gyrus/superior temporal gyrus, in the right lingual gyrus and in the bilateral inferior temporal/fusiform gyri (voxel-level p<0.001 and cluster-level p<0.05, FDR-corrected). Reduced reality-monitoring abilities were significantly associated with shorter right PCS and reduced GMV in temporal and parietal regions of the reality-monitoring network in schizophrenia patients with AHs.

Macroscopic Structural and Connectome Mapping of the Mouse Brain Using Diffusion Magnetic Resonance Imaging.

Translational work in rodents elucidates basic mechanisms that drive complex behaviors relevant to psychiatric and neurological conditions. Nonetheless, numerous promising studies in rodents later fail in clinical trials, highlighting the need for improving the translational utility of preclinical studies in rodents. Imaging of small rodents provides an important strategy to address this challenge, as it enables a whole-brain unbiased search for structural and dynamic changes that can be directly compared to human imaging. The functional significance of structural changes identified using imaging can then be further investigated using molecular and genetic tools available for the mouse. Here, we describe a pipeline for unbiased search and characterization of structural changes and network properties, based on diffusion MRI data covering the entire mouse brain at an isotropic resolution of 100 µm. We first used unbiased whole-brain voxel-based analyses to identify volumetric and microstructural alterations in the brain of adult mice exposed to unpredictable postnatal stress (UPS), which is a mouse model of complex early life stress (ELS). Brain regions showing structural abnormalities were used as nodes to generate a grid for assessing structural connectivity and network properties based on graph theory. The technique described here can be broadly applied to understand brain connectivity in other mouse models of human disorders, as well as in genetically modified mouse strains. Graphic abstract: Pipeline for characterizing structural connectome in the mouse brain using diffusion magnetic resonance imaging. Scale bar = 1 mm.

Arterial spin labeling brain MRI study to evaluate the impact of deafness on cerebral perfusion in 79 children before cochlear implantation

Age at implantation is considered to be a major factor, influencing outcomes after pediatric cochlear implantation. In the absence of acoustic input, it has been proposed that cross-modal reorganization can be detrimental for adaptation to the new electrical input provided by a cochlear implant. Here, through a retrospective study, we aimed to investigate differences in cerebral blood flow (CBF) at rest prior to implantation in children with congenital deafness compared to normally hearing children. In addition, we looked at the putative link between pre-operative rest-CBF and the oral intelligibility scores at 12 months post-implantation. Finally, we observed the evolution of perfusion with age, within brain areas showing abnormal rest-CBF associated to deafness, in deaf children and in normally hearing children. In children older than 5 years old, results showed a significant bilateral hypoperfusion in temporal regions in deaf children, particularly in Heschl’s gyrus, and a significant hyperperfusion of occipital regions. Furthermore, in children older than 5 years old, whole brain voxel-by-voxel correlation analysis between pre-operative rest-CBF and oral intelligibility scores at 12 months post-implantation, showed significant negative correlation localized in the occipital regions: children who performed worse in the speech perception test one year after implantation were those presenting higher preoperative CBF values in these occipital regions. Finally, when comparing mean relative perfusion (extracted from the temporal regions found abnormal on whole-brain voxel-based analysis) across ages in patients and controls, we observed that the temporal perfusion evolution was significantly different in deaf children than in normally hearing children. Indeed, while temporal perfusion increased with age in normally hearing children, it remained stable in deaf children. We showed a critical period around 4 years old, where in the context of auditory deprivation, there is a lack of synaptic activity in auditory regions. These results support the benefits of early cochlear implantation to maximize the effectiveness of auditory rehabilitation and to avoid cross-modal reorganization.

Establishing two principal dimensions of cognitive variation in logopenic progressive aphasia.

Logopenic progressive aphasia is a neurodegenerative syndrome characterized by sentence repetition and naming difficulties arising from left-lateralized temporoparietal atrophy. Clinical descriptions of logopenic progressive aphasia largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits even on tasks with minimal language demands. Although non-linguistic cognitive deficits in logopenic progressive aphasia are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose the individual-level variation in cognitive performance in 43 well-characterized logopenic progressive aphasia patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected ‘speech production and verbal memory’ deficits which typify logopenic progressive aphasia. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably ‘logopenic’ patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralized temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, logopenic progressive aphasia patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralized temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in logopenic progressive aphasia, suggesting the presence of a genuine co-occurring cognitive impairment that is statistically independent of language function and disease severity.

Using a second-person approach to identify disease-specific profiles of social behavior in frontotemporal dementia and Alzheimer's disease

Changes in social behavior are recognized as potential symptoms of behavioral-variant frontotemporal dementia (bvFTD) and semantic dementia (SD), yet objective ways to assess these behaviors in natural social situations are lacking. This study takes a truly social (or second-person) approach and examines changes in real-world social behavior in different dementia syndromes, by analyzing non-scripted social interactions in bvFTD patients (n = 20) and SD patients (n = 20), compared to patients with Alzheimer's disease (AD) (n = 20). Video recordings of 10-min conversations between patients and behavioral neurologists were analyzed for the presence of socially engaging (e.g., nodding, smiling, gesturing) and disengaging behavior (e.g., avoiding eye contact, self-grooming, interrupting). Results demonstrated disease-specific profiles, with bvFTD patients showing less nodding and more looking away than AD, and SD patients showing more gesturing than AD. A principal components analysis revealed the presence of four unobserved components, showing atypical disengaging patterns of behavior. Whole-brain voxel-based morphometry analyses revealed distinct neurobiological bases for each of these components, with the brain regions identified previously associated with behavior selection, abstract mentalization and processing of multi-sensory and socially-relevant information, in mediating socially engaging and disengaging behavior. This study demonstrates the utility of systematic behavioral observation of social interactions in the differential diagnosis of dementia.

Neural Correlates of Adolescent Irritability and Its Comorbidity With Psychiatric Disorders

Irritable mood, a common and impairing symptom in psychopathology, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adulthood. We examined the neural correlates of adolescent irritability in IMAGEN, a sample of 2,024 14-year-old adolescents from 5 European countries. The Development and Well-Being Assessment (DAWBA) was used to assess attention-deficit/hyperactivity disorder, major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural magnetic resonance imaging was examined using whole-brain voxel-based morphometry analysis, and functional magnetic resonance imaging was examined during a stop signal task of inhibitory control. Imaging data were included in structural equation models to examine the direct and indirect associations between irritable mood and comorbid DSM diagnoses. Whole-brain voxelwise analysis showed that adolescent irritable mood was associated with less gray matter volume and less neural activation underlying inhibitory control in frontal and temporal cortical areas (cluster-correction at p< .05). Structural equation models suggested that part of the observed smaller gray matter volume was exclusively driven by irritability separate from direct relationships between generalized anxiety disorder (or attention-deficit/hyperactivity disorder, major depressive disorder, or oppositional defiant disorder) and gray matter volume. This study identifies adolescent irritability as an independent construct and points to a neurobiological correlate to irritability that is an important contributing feature to many psychopathological disorders.