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Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAAR expressed in oligodendroglia is strongly potentiated by n-butyl-β-carboline-3-carboxylate (β-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then β-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that β-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2+ and a decrease in CC1+ cell populations, alterations that were importantly retrieved by β-CCB treatment. Thus, the promyelinating character of β-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug. [ABSTRACT FROM AUTHOR]

Background: Violence in schizophrenia (SCZ) is a phenomenon associated with neurobiological factors. However, the neural mechanisms of violence in patients with SCZ are not yet sufficiently understood. Thus, this study aimed to explore the structural changes associated with the high risk of violence and its association with impulsiveness in patients with SCZ to reveal the possible neurobiological basis. Method: The voxel-based morphometry approach and whole-brain analyses were used to measure the alteration of gray matter volume (GMV) for 45 schizophrenia patients with violence (VSC), 45 schizophrenia patients without violence (NSC), and 53 healthy controls (HC). Correlation analyses were used to examine the association of impulsiveness and brain regions associated with violence. Results: The results demonstrated reduced GMV in the right insula within the VSC group compared with the NSC group, and decreased GMV in the right temporal pole and left orbital part of superior frontal gyrus only in the VSC group compared to the HC group. Spearman correlation analyses further revealed a positive correlation between impulsiveness and GMV of the left superior temporal gyrus, bilateral insula and left medial orbital part of the superior frontal gyrus in the VSC group. Conclusion: Our findings have provided further evidence for structural alterations in patients with SCZ who had engaged in severe violence, as well as the relationship between the specific brain alterations and impulsiveness. This work provides neural biomarkers and improves our insight into the neural underpinnings of violence in patients with SCZ. [ABSTRACT FROM AUTHOR]

Recent studies have shown that white–gray contrast (WGC) of either cortical or subcortical gray matter provides for accurate predictions of age in typically developing (TD) children, and that, at least for the cortex, it changes differently with age in subjects with autism spectrum disorder (ASD) compared to their TD peers. Our previous study showed different patterns of contrast change between ASD and TD in sensorimotor and association cortices. While that study was confined to the cortex, we hypothesized that subcortical structures, particularly the thalamus, were involved in the observed cortical dichotomy between lower and higher processing. The current paper investigates that hypothesis using the WGC measures from the thalamus in addition to those from the cortex. We compared age‐related WGC changes in the thalamus to those in the cortex. To capture the simultaneity of this change across the two structures, we devised a metric capturing the co‐development of the thalamus and cortex (CoDevTC), proportional to the magnitude of cortical and thalamic age‐related WGC change. We calculated this metric for each of the subjects in a large homogeneous sample taken from the Autism Brain Imaging Data Exchange (ABIDE) (N = 434). We used structural MRI data from the largest high‐quality cross‐sectional sample (NYU) as well as two other large high‐quality sites, GU and OHSU, all three using Siemens 3T scanners. We observed that the co‐development features in ASD and TD exhibit contrasting patterns; specifically, some higher‐order thalamic nuclei, such as the lateral dorsal nucleus, exhibited reduction in codevelopment with most of the cortex in ASD compared to TD. Moreover, this difference in the CoDevTC pattern correlates with a number of behavioral measures across multiple cognitive and physiological domains. The results support previous notions of altered connectivity in autism, but add more specific evidence about the heterogeneity in thalamocortical development that elucidates the mechanisms underlying the clinical features of ASD. [ABSTRACT FROM AUTHOR]

Background: Small-vessel disease (SVD) plays a crucial role in cardiac and brain ischemia, but little is known about potential interrelation between both. We retrospectively evaluated 370 patients, aiming at assessing the interrelation between cardiac and brain SVD by using quantitative 82Rb cardiac PET/CT and brain MRI. Results: In our population of 370 patients, 176 had normal myocardial perfusion, 38 had pure cardiac SVD and 156 had obstructive coronary artery disease. All underwent both a cardiac 82Rb PET/CT and a brain 1.5T or 3T MRI. Left-ventricle myocardial blood flow (LV-MBF) and flow reserve (LV-MFR) were recorded from 82Rb PET/CT, while Fazekas score, white matter lesion (WMab) volume, deep gray matter lesion (GMab) volume, and brain morphometry (for z-score calculation) using the MorphoBox research application were derived from MRI. Groups were compared with Kruskal–Wallis test, and the potential interrelation between heart and brain SVD markers was assessed using Pearson's correlation coefficient. Patients with cardiac SVD had lower stress LV-MBF and MFR (P < 0.001) than patients with normal myocardial perfusion; Fazekas scores and WMab volumes were similar in those two groups (P > 0.45). In patients with cardiac SVD only, higher rest LV-MBF was associated with a lower left-putamen (rho = − 0.62, P = 0.033), right-thalamus (rho = 0.64, P = 0.026), and right-pallidum (rho = 0.60, P = 0.039) z-scores and with a higher GMab volume. Lower stress LV-MBF was associated with lower left-caudate z-score (rho = 0.69, P = 0.014), while lower LV-MFR was associated with lower left (rho = 0.75, P = 0.005)- and right (rho = 0.59, P = 0.045)-putamen z-scores, as well as higher right-thalamus GMab volume (rho = − 0.72, P = 0.009). Conclusion: Significant interrelations between cardiac and cerebral SVD markers were found, especially regarding deep gray matter alterations, which supports the hypothesis of SVD as a systemic disease. [ABSTRACT FROM AUTHOR]

Background: Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality‐of‐life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS–FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied. Methods: A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language‐associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS–FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72‐negative ALS–FTD, C9orf72‐positive ALS–FTD, behavioral‐variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke' areas and FC along the FAT was also specifically assessed. Results: Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language‐associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS–FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72‐negative ALS–FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72‐positive ALS–FTD patients do not. Conclusions: Language‐associated tracts and networks are not only affected in language‐variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype. [ABSTRACT FROM AUTHOR]

Simple Summary: We studied cognitive (thinking) abilities and brain structure and function in older adults with multiple myeloma—a cancer of plasma cells—treated with high-dose chemotherapy and a stem cell transplant. The initial results suggested that after the chemotherapy and transplant, functional connectivity was diminished in regions involving the frontal and parietal lobes of the brain, while brain structure and cognitive function remained relatively stable. We also found increases in markers of inflammation after the transplant. The findings provide supporting evidence for the vulnerability of frontal and parietal brain regions to the side effects of chemotherapy. These preliminary findings would support the design of large future studies with the goal of developing therapeutic interventions. There is a paucity of research on treatment-related neurotoxicity in older adults with multiple myeloma (MM) treated with high-dose chemotherapy (HDC) and autologous SCT (HDC/ASCT), despite the increasing use of this regimen. We examined resting state functional connectivity (RSFC), gray matter (GM) volume, neurocognitive function (NF), and proinflammatory cytokines (PCy) in older patients with MM pre- and post-HDC/ASCT. Eighteen patients underwent MRI, NF tests, and serum PCy measurements prior to HDC/ASCT, and fifteen patients completed a follow up five-months post-HDC/ASCT. There were significant decreases in RSFC post-HDC/ASCT in (1) the central executive network (CEN) involving the left dorsolateral prefrontal cortex and right posterior parietal cortex (p = 0.022) and (2) the CEN involving the right posterior parietal cortex and the salience network involving the right dorsal anterior cingulate cortex (p = 0.029). There were no significant changes in GM or NF, except for improvements in attention (Digit Span Backward, p = 0.03). There were significant increases in several PCy post-HDC/ASCT (p ≤ 0.05). In conclusion, RSFC decreased in frontal, parietal, and cingulate cortices post-HDC/ASCT, NF was relatively stable, and several PCy increased. These findings are congruent with other studies in cancer patients and provide supporting evidence for the vulnerability of frontoparietal regions to chemotherapy's adverse effects. [ABSTRACT FROM AUTHOR]

Siponimod (Sp) is a Sphingosine 1-phosphate (S1P) receptor modulator, and it suppresses S1P- mediated autoimmune lymphocyte transport and inflammation. Theiler's murine encephalomyelitis virus (TMEV) infection mouse model of multiple sclerosis (MS) exhibits inflammation-driven acute and chronic phases, spinal cord lesions, brain and spinal cord atrophy, and white matter injury. The objective of the study was to investigate whether Sp treatment could attenuate inflammation-induced pathology in the TMEV model by inhibiting microglial activation and preventing the atrophy of central nervous tissue associated with neurodegeneration. Clinical disability score (CDS), body weight (BW), and rotarod retention time measures were used to assess Sp's impact on neurodegeneration and disease progression in 4 study groups of 102 animals, including 44 Sp-treated (SpT), 44 vehicle-treated, 6 saline-injected, and 8 age-matched healthy controls (HC). Next, 58 (22 SpT, 22 vehicle, 6 saline injected, and 8 HC) out of the 102 animals were further evaluated to assess the effect of Sp on brain region-specific and spinal cord volume changes, as well as microglial activation. Sp increased CDS and decreased BW and rotarod retention time in TMEV mice, but did not significantly affect most brain region volumes, except for lateral ventricle volume. Sp suppressed ventricular enlargement, suggesting reduced TMEV-induced inflammation in LV. No significant differences in spine volume changes were observed between Sp- and vehicle-treated animals, but there were differences between HC and TMEV groups, indicating TMEV-induced inflammation contributed to increased spine volume. Spine histology revealed no significant microglial density differences between groups in gray matter, but HC animals had higher type 1 morphology and lower type 2 morphology percentages in gray and white matter regions. This suggests that Sp did not significantly affect microglial density but may have modulated neuroinflammation in the spinal cord. Sp may have some effects on neuroinflammation and ventricular enlargement. However, it did not demonstrate a significant impact on neurodegeneration, spinal volume, or lesion volume in the TMEV mouse model. Further investigation is required to fully understand Sp's effect on microglial activation and its relevance to the pathophysiology of MS. The differences between the current study and previous research using other MS models, such as EAE, highlight the differences in pathological processes in these two disease models. [ABSTRACT FROM AUTHOR]

Objectives: Pre‐eclampsia has been associated with cardiovascular, cerebrovascular and/or psychological complaints. Signs of altered brain morphology and more white‐matter hyperintensities (WMHs) during and shortly after pre‐eclampsia have been observed in some, but not all, studies. We compared volumes of cerebral structures and the number of WMHs between formerly pre‐eclamptic women and those with normotensive gestational history and assessed the effect of age on brain volumes. Methods: Structural 7‐Tesla magnetic resonance imaging of the brain was performed in 59 formerly pre‐eclamptic women (aged 37 ± 6 years, 0.5–16 years postpartum) and 20 women with a history of normotensive pregnancy (aged 39 ± 5 years, 1–18 years postpartum). Fazekas scores were obtained to assess WMH load. Volumes of the whole brain, gray and white matter, brain lobes, and ventricular and pericortical cerebrospinal fluid (CSF) spaces were calculated after semiautomatic segmentation. Group differences were analyzed using ANCOVA and Bayes factors. Results were adjusted for age, educational attainment, presence of current hypertension and total intracranial volume. The effect of age on cerebral volumes was analyzed using linear regression analysis. Results: No changes in global and local brain volumes were observed between formerly pre‐eclamptic and control women. Also, no difference in WMH load was observed. Independent of pre‐eclamptic history, gray‐matter volume significantly decreased with age, while ventricular and pericortical CSF space volumes significantly increased with age. Conclusions: Volumetric changes of the cerebrum are age‐related but are independent of pre‐eclamptic history in the first two decades after childbirth. No evidence of greater WMH load after pre‐eclampsia was found. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Background and purpose: Although cognitive impairment (CI) is frequent in multiple sclerosis (MS) patients, few studies (and with conflicting results) have evaluated early predictors of CI in the long term. We aimed at determining associations between early clinical/neuroradiological variables with reference to CI after 20 years of MS. Methods: We investigated in 170 MS patients the relationship between clinical/magnetic resonance imaging (MRI) data at diagnosis and cognitive status almost 20 years after MS onset. Among others, number and volume of both white matter lesions (WMLs) and cortical lesions (CLs) were evaluated at diagnosis and after 2 years. All MS patients were followed over time and underwent a comprehensive neuropsychological assessment at the end of study. Advanced statistical methods (unsupervised cluster analysis and random forest model) were conducted. Results: CI patients showed higher focal cortical pathology at diagnosis compared to cognitively normal subjects (p < 0.001). Volumes of both WMLs and CLs emerged as the MRI metrics most associated with long‐term CI. Moreover, number of CLs (especially ≥3) was also strongly associated with long‐term CI (≥3 CLs: odds ratio [OR] = 3.7, 95% confidence interval = 1.8–7.5, p < 0.001), more than number of WMLs; the optimal cutoff of three CLs (area under the curve = 0.67, specificity = 75%, sensitivity = 55%) was estimated according to the risk of developing CI. Conclusions: These results highlight the impact of considering both white and gray matter focal damage from early MS stages. Given the low predictive value of WML number and the poor clinical applicability of lesion volume estimation in the daily clinical context, the evaluation of number of CLs could represent a reliable prognostic marker of CI. [ABSTRACT FROM AUTHOR]

Focal and generalized epilepsies are associated with robust differences in magnetic resonance imaging (MRI) measures of subcortical structures, gray matter, and white matter. However, it is unknown whether such structural brain differences reflect the cause or consequence of epilepsy or its treatment. Analyses of common genetic variants underlying both common epilepsy risk and variability in structural brain measures can give further insights, as such inherited variants are not influenced by disease or treatment. Here, we performed genetic correlation analyses using data from the largest genome‐wide association study (GWAS) on common epilepsy (n = 27 559 cases and 42 436 controls) and GWASs on MRI measures of white (n = 33 292) or gray matter (n = 51 665). We did not detect any significant genetic correlation between any type of common epilepsy and any of 280 measures of gray matter, white matter, or subcortical structures. These results suggest that there are distinct genetic bases underlying risk of common epilepsy and for structural brain measures. This would imply that the genetic basis of normal structural brain variation is unrelated to that of common epilepsy. Structural changes in epilepsy could rather be the consequence of epilepsy, its comorbidities, or its treatment, offering a cumulative record of disease. [ABSTRACT FROM AUTHOR]

Background: The NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort. Methods: We used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aβ42/Aβ40 (A+/−), CSF phospho-tau (T+/−), and adjusted hippocampal volume or CSF total-tau (N+/−). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A−T−N− towards A+T+N+ including also non-AD continuum ATN groups. Results: The ACH-based progression A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead. Conclusion: Using the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy. Trial registration: DRKS00007966, 04/05/2015, retrospectively registered. [ABSTRACT FROM AUTHOR]

Precise segmentation of infant brain magnetic resonance (MR) images into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) are essential for studying neuroanatomical hallmarks of early brain development. However, for 6‐month‐old infants, the extremely low‐intensity contrast caused by inherent myelination hinders accurate tissue segmentation. Existing convolutional neural networks (CNNs) based segmentation models for this task generally employ single‐scale symmetric convolutions, which are inefficient for encoding the isointense tissue boundaries in baby brain images. Here, we propose a 3D mixed‐scale asymmetric convolutional segmentation network (3D‐MASNet) framework for brain MR images of 6‐month‐old infants. We replaced the traditional convolutional layer of an existing to‐be‐trained network with a 3D mixed‐scale convolution block consisting of asymmetric kernels (MixACB) during the training phase and then equivalently converted it into the original network. Five canonical CNN segmentation models were evaluated using both T1‐ and T2‐weighted images of 23 6‐month‐old infants from iSeg‐2019 datasets, which contained manual labels as ground truth. MixACB significantly enhanced the average accuracy of all five models and obtained the most considerable improvement in the fully convolutional network model (CC‐3D‐FCN) and the highest performance in the Dense U‐Net model. This approach further obtained Dice coefficient accuracies of 0.931, 0.912, and 0.961 in GM, WM, and CSF, respectively, ranking first among 30 teams on the validation dataset of the iSeg‐2019 Grand Challenge. Thus, the proposed 3D‐MASNet can improve the accuracy of existing CNNs‐based segmentation models as a plug‐and‐play solution that offers a promising technique for future infant brain MRI studies. [ABSTRACT FROM AUTHOR]

Objective: Prematurity is associated with a high risk of long‐term behavioral problems. This study aimed to assess the prognostic utility of volumetric brain data at term‐equivalent‐age (TEA), clinical perinatal factors, and parental social economic risk in the prediction of the behavioral outcome at 5 years in a cohort of very preterm infants (VPT, <32 gestational weeks). Methods: T2‐weighted magnetic resonance brain images of 80 VPT children were acquired at TEA and automatically segmented into cortical gray matter, deep subcortical gray matter, white matter (WM), cerebellum (CB), and cerebrospinal fluid. The gray matter structure of the amygdala was manually segmented. Children were examined at 5 years of age with a behavioral assessment, using the strengths and difficulties questionnaire (SDQ). The utility of brain volumes at TEA, perinatal factors, and social economic risk for the prediction of behavioral outcome was investigated using support vector machine classifiers and permutation feature importance. Results: The predictive modeling of the volumetric data showed that WM, amygdala, and CB volumes were the best predictors of the SDQ emotional symptoms score. Among the perinatal factors, sex, sepsis, and bronchopulmonary dysplasia were the best predictors of the hyperactivity/inattention score. When combining the social economic risk with volumetric and perinatal factors, we were able to accurately predict the emotional symptoms score. Finally, social economic risk was positively correlated with the scores of conduct problems and peer problems. Conclusions: This study provides information on the relation between brain structure at TEA and clinical perinatal factors with behavioral outcome at age 5 years in VPT children. Nevertheless, the overall predictive power of our models is relatively modest, and further research is needed to identify factors associated with subsequent behavioral problems in this population. [ABSTRACT FROM AUTHOR]

The objective of this study was to analyze the neurostructural abnormalities of brain areas responsible for the acquisition and maintenance of fear in small animal phobia by comparing gray matter volume (GMV) in individuals with phobia and non-fearful controls. Structural magnetic resonance imaging was obtained from 62 adults (79% female) assigned to one of two groups: 31 were diagnosed with small animal phobia and 31 were non-fearful controls. To investigate structural alterations, a whole-brain voxel-based morphometry analysis was conducted to compare the GMV of the brain areas involved in fear between both groups. The results indicated that individuals with a small animal specific phobia showed smaller GMV in cortical regions, such as the orbitofrontal (OFC) and medial frontal cortex, and greater GMV in the putamen than non-fearful controls. These brain areas are responsible for avoidant behavior (putamen) and emotional regulation processes or inhibitory control (prefrontal cortex (PFC)), which might suggest a greater vulnerability of phobic individuals to acquiring non-adaptive conditioned responses and emotional dysregulation. The findings provide preliminary support for the involvement of structural deficits in OFC and medial frontal cortex in phobia, contributing to clarify the neurobiological substrates for phobias. [ABSTRACT FROM AUTHOR]

Many patients with multiple sclerosis (MS) experience information processing speed (IPS) deficits, and the Symbol Digit Modalities Test (SDMT) has been recommended as a valid screening test. Magnetic resonance imaging (MRI) has markedly improved the understanding of the mechanisms associated with cognitive deficits in MS. However, which structural MRI markers are the most closely related to cognitive performance is still unclear. We used the multicenter 3T‐MRI data set of the Italian Neuroimaging Network Initiative to extract multimodal data (i.e., demographic, clinical, neuropsychological, and structural MRIs) of 540 MS patients. We aimed to assess, through machine learning techniques, the contribution of brain MRI structural volumes in the prediction of IPS deficits when combined with demographic and clinical features. We trained and tested the eXtreme Gradient Boosting (XGBoost) model following a rigorous validation scheme to obtain reliable generalization performance. We carried out a classification and a regression task based on SDMT scores feeding each model with different combinations of features. For the classification task, the model trained with thalamus, cortical gray matter, hippocampus, and lesions volumes achieved an area under the receiver operating characteristic curve of 0.74. For the regression task, the model trained with cortical gray matter and thalamus volumes, EDSS, nucleus accumbens, lesions, and putamen volumes, and age reached a mean absolute error of 0.95. In conclusion, our results confirmed that damage to cortical gray matter and relevant deep and archaic gray matter structures, such as the thalamus and hippocampus, is among the most relevant predictors of cognitive performance in MS. [ABSTRACT FROM AUTHOR]

The human ventromedial prefrontal cortex (vmPFC) has been traditionally associated with decision-making under risk. Neuroimaging studies of such decision-making processes have largely focused on patients with vmPFC lesions or pathological gambling behavior, leading to a relative paucity of work focusing on the structural variability of the vmPFC in healthy individuals. To address this, we developed a decision-making task that allowed healthy players to choose to participate in either low stakes or high-stakes gambling on a trial-by-trial basis, and computed a metric that indexes the propensity for engaging in gambles with greater potential payoffs. We leveraged voxel-based morphometric analyses to examine the association between prefrontal gray matter volume and individual differences in the propensity for seeking high-risk/high-reward situations. Our analyses showed that vmPFC gray matter volume was inversely correlated with an increased tendency for engaging in high-stakes gambling. These results converge with findings from functional neuroimaging and brain lesion studies of vmPFC, and further extend them to show that normative variability in brain structure could also underpin risk-taking behavior. [ABSTRACT FROM AUTHOR]

Adolescents born preterm (<37 weeks of gestation) are at elevated risk for deficits in social cognition and peer relationships. Theory of Mind (ToM) is a complex form of social cognition important for regulating social interactions. ToM and the underlying mentalizing network continue to develop across adolescence. The present study recruited 48 adolescents (12–17 years old) who were either born extremely preterm (EPT; <28 weeks of gestation) or full-term (FT) at birth. Cortical thickness, gray matter volume and surface area were measured in four regions of the mentalizing network: the temporoparietal junction, anterior temporal cortex, posterior superior temporal sulcus and frontal pole (mBA10). We also assessed the adolescents' performance on a ToM task. Findings revealed both group differences and group-by-age interaction effects in the gray matter indices within the temporal lobe regions of the mentalizing network. The EPT group also performed significantly worse than the FT group on the ToM task. The cortical structural measures that discriminated the EPT and FT groups were not related to ToM performance. These results highlight altered developmental changes in brain regions underlying mentalizing functions in EPT adolescents relative to FT controls. [ABSTRACT FROM AUTHOR]

Introduction: Disruption of cortical gray matter and white matter tracts are well‐established markers of alcohol use disorder (AUD), but less is known about whether similar differences are present in intracortical myelin (ICM, i.e., highly myelinated gray matter in deeper cortical layers). The goal of this study was to provide initial proof‐of‐concept for using an optimized structural magnetic resonance imaging (MRI) sequence to detect differences in ICM in individuals with AUD compared to control participants reporting drinking within recommended guidelines. Methods: This study used an optimized 3T MRI sequence for high intracortical contrast to examine ICM‐related MRI signal in 30 individuals with AUD and 33 healthy social drinkers. Surface‐based analytic techniques were used to quantify ICM‐related MRI signal in 20 bilateral a priori regions of interest based on prior cortical thickness studies, and exploratory vertex‐wise analyses were examined using Cohen's d effect size. Results: The global distribution of ICM‐related signal was largely comparable between groups. Region of interest analysis indicated that AUD group exhibited greater ICM‐related MRI signal in precuneus, ventromedial prefrontal cortex, posterior cingulate, middle anterior cingulate, middle/posterior insula, and dorsolateral prefrontal cortex (Cohen's ds = 0.50–0.75). Four regions (right precuneus, ventromedial prefrontal cortex, posterior cingulate and left dorsolateral prefrontal cortex) remained significant (p <.05) after covarying for smoking status. Conclusion: These findings provide initial evidence of ICM differences in a moderately sized sample of individuals with AUD compared to controls, although the inflation of type 1 error rate necessitates caution in drawing conclusions. Robustly establishing these differences in larger samples is necessary. The cross‐sectional design cannot address whether the observed differences predate AUD or are consequences of heavy alcohol consumption. [ABSTRACT FROM AUTHOR]

Incidence of schizophrenia (SZ) has two predominant peaks, in adolescent and young adult. Early‐onset schizophrenia provides an opportunity to explore the neuropathology of SZ early in the disorder and without the confound of antipsychotic mediation. However, it remains unexplored what deficits are shared or differ between adolescent early‐onset (EOS) and adult‐onset schizophrenia (AOS) patients. Here, based on 529 participants recruited from three independent cohorts, we explored AOS and EOS common and unique co‐varying patterns by jointly analyzing three MRI features: fractional amplitude of low‐frequency fluctuations (fALFF), gray matter (GM), and functional network connectivity (FNC). Furthermore, a prediction model was built to evaluate whether the common deficits in drug‐naive SZ could be replicated in chronic patients. Results demonstrated that (1) both EOS and AOS patients showed decreased fALFF and GM in default mode network, increased fALFF and GM in the sub‐cortical network, and aberrant FNC primarily related to middle temporal gyrus; (2) the commonly identified regions in drug‐naive SZ correlate with PANSS positive significantly, which can also predict PANSS positive in chronic SZ with longer duration of illness. Collectively, results suggest that multimodal imaging signatures shared by two types of drug‐naive SZ are also associated with positive symptom severity in chronic SZ and may be vital for understanding the progressive schizophrenic brain structural and functional deficits. [ABSTRACT FROM AUTHOR]

Background: 23Na MRI correlates with tumor proliferation, and studies in pediatric patients are lacking. The purpose of the study: (1) to compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. Methods: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas (diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)). In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed. Results: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9–23.3 years) were scanned with 23Na MRI. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (p < 0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (p < 0.002 for LGG, and p < 0.02 for HGG). The dual echo 23Na MRI suppressed the sodium signal within both CSF and necrotic foci. Conclusion: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging. [ABSTRACT FROM AUTHOR]

Background and purpose: Currently, the extent of cholinergic basal forebrain atrophy in relatively pure limbic TAR DNA‐binding protein 43 (TDP‐43) pathology compared with relatively pure Alzheimer disease (AD) is unclear. Methods: We compared antemortem magnetic resonance imaging (MRI)‐based atrophy of the basal forebrain and medial and lateral temporal lobe volumes between 10 autopsy cases with limbic TDP‐43 pathology and 33 cases with AD pathology on postmortem neuropathologic examination from the Alzheimer's Disease Neuroimaging Initiative cohort. For reference, we studied MRI volumes from cognitively healthy, amyloid positron emission tomography‐negative subjects (n = 145). Group differences were assessed using Bayesian analysis of covariance. In addition, we assessed brain‐wide regional volume changes using partial least squares regression (PLSR). Results: We found extreme evidence (Bayes factor [BF]01 > 600) for a smaller basal forebrain volume in both TDP‐43 and AD cases compared with amyloid‐negative controls, and moderate evidence (BF01 = 4.9) that basal forebrain volume was not larger in TDP‐43 than in AD cases. The ratio of hippocampus to lateral temporal lobe volumes discriminated between TDP‐43 and AD cases with an accuracy of 0.78. PLSR showed higher gray matter in lateral temporal lobes and cingulate and precuneus, and reduced gray matter in precentral and postcentral gyri and hippocampus in TDP‐43 compared with AD cases. Conclusions: Atrophy of the cholinergic basal forebrain appears to be similarly pronounced in cases with limbic TDP‐43 pathology as in AD. This suggests that a clinical trial of the efficacy of cholinesterase inhibitors in amyloid‐negative cases with amnestic dementia and an imaging signature of TDP‐43 pathology may be warranted. [ABSTRACT FROM AUTHOR]

Background: There are gaps in our neurobiological understanding of functional movement disorder (FMD). Objectives: We investigated gray matter volumetric profiles in FMD, and related findings to resting‐state functional connectivity (rsFC) profiles using Human Connectome Project data. Methods: Volumetric differences between 53 FMD patients and 50 controls were examined, as well as relationships between individual differences in FMD symptom severity and volumetric profiles. Atrophy network mapping was also used to probe whether FMD‐related structural alterations preferentially impacted brain areas with dense rsFC. Results: Compared to controls without neurological comorbidities (albeit with mild depression and anxiety as a group), the FMD cohort did not show any volumetric differences. Across patients with FMD, individual differences in symptom severity negatively correlated with right supramarginal and bilateral superior temporal gyri volumes. These findings remained significant adjusting for FMD subtype or antidepressant use, but did not remain statistically significant adjusting for depression and anxiety scores. Symptom severity‐related structural alterations mapped onto regions with dense rsFC—identifying several disease epicenters in default mode, ventral attention, and salience networks. Conclusions: This study supports that FMD is a multinetwork disorder with an important role for the temporoparietal junction and its related connectivity in the pathophysiology of this condition. More research is needed to explore the intersection of functional neurological symptoms and mood. [ABSTRACT FROM AUTHOR]

We recently demonstrated that adolescents perinatally infected with HIV-1 (PHIV+) have accelerated aging as measured by a highly accurate epigenetic biomarker of aging known as the epigenetic clock. However, whether epigenetic age acceleration in PHIV+ impacts brain development at the macro- and microstructural levels of brain anatomy has not been studied. We report on a cross-sectional study of PHIV+ enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC). The Illumina Infinium Methylation EPIC array was used to generate DNA methylation data from the blood samples of 180 PHIV+ aged 9 to 12 years. The epigenetic clock software and method was used to estimate two measures, epigenetic age acceleration (AgeAccelerationResidual) and extrinsic epigenetic age acceleration (EEAA). Each participant underwent T1 structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). In order to investigate the associations of chronological age, sex, epigenetic age acceleration and treatment variables (CNS penetration effectiveness score (CPE)) of antiretroviral regimen on brain structure in PHIV+, we developed stepwise multiple regression models in R (version 3.4.3, 2017) including grey and white matter volumes, cortical thickness, cortical surface area and DTI measures of white matter microstructural integrity. The mean DNAm age (16.01 years) of the participants was higher than their mean chronological age (10.77 years). Epigenetic age acceleration contributed more to regional alterations of brain volumes, cortical thickness, cortical surface areas and neuronal microstructure than chronological age, in a range of regions. CPE positively contributed to volume of the brain stem. Understanding the drivers of epigenetic age acceleration could lead to valuable insights into structural brain alterations, and the persistence of neurocognitive disorders in seen in PHIV+ [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by both motor and non‐motor symptoms. A convergent pathophysiological hallmark of PD is an early selective vulnerability within the basal ganglia circuit. However, the causal interactions between basal ganglia atrophy and progressive structural network alterations in PD remain unaddressed. Here, we adopted voxel‐based morphometry method to measure gray matter (GM) volume for each participant (n = 84 PD patients and n = 70 matched healthy controls). Patients were first divided into three stages according to the Hoehn and Yahr (H&Y) and the Part III of Unified Parkinson's Disease Rating Scale scores respectively to analyze the stage‐specific GM atrophy patterns. Then, the modulation of early caudate atrophy over other brain structures was evaluated using the whole‐brain voxel‐wise and region‐of‐interest‐wise causal structural covariance network approaches. We found that GM atrophy progressively expands from the basal ganglia to the angular gyrus, temporal areas, and eventually spreads through the subcortical–cortical networks as PD progresses. Notably, we identified a shared caudate‐associated degeneration network including the basal ganglia, thalamus, cerebellum, sensorimotor cortex, and cortical association areas with the PD progressive factors. These findings suggest that the early structural vulnerability of basal ganglia in PD may play a pivotal role in the modulation of motor and non‐motor circuits at the structural level. Our work provides evidence for a novel mechanism of network degeneration that underlies the pathology of PD and may have potential clinical applications in the development of early predictors of PD onset and progress. [ABSTRACT FROM AUTHOR]

Background: Synthetic MRI (SyMRI) is a quantitative technique that allows measurements of T1 and T2 relaxation times (RTs). Brain RT evolution across lifespan is well described for the younger population. The aim was to study RTs of brain parenchyma in a healthy geriatric population in order to define the normal value of structures in this group population. Normal values for geriatric population could help find biomarker for age‐related brain disease. Materials and methods: Fifty‐four normal‐functioning individuals (22 females, 32 males) with mean age of 83 years (range 56–98) underwent SyMRI. RT values in manually defined ROIs (centrum semiovale, middle cerebellar peduncles, thalamus, and insular cortex) and in segmented whole‐brain components (brain parenchyma, gray matter, white matter, myelin, CSF, and stromal structures) were extracted from the SyMRI segmentation software. Patients' results were combined into the group age. Main ROI‐based and whole‐brain results were compared for the all dataset and for age group results as well. Results: For white matter, RTs between ROI‐based analyses and whole‐brain results for T2 and for T1 were statistically different and a trend of increasing T1 in centrum semiovale and cerebellar peduncle was observed. For gray matter, thalamic T1 was statistically different from insular T1. A difference was also found between left and right insula (p <.0001). T1 RTs of ROI‐based and whole‐brain‐based analyses were statistically different (p <.0001). No significant difference in T1 and T2 was found between age groups on ROI‐based analysis, but T1 in centrum semiovale and thalamus increased with age. No statistical difference between age groups was found for the various segmented volumes except for myelin between 65–74 years of age and the 95–105 years of age groups (p =.038). Conclusions: SyMRI is a new tool that allows faster imaging and permits to obtain quantitative T1 and T2. By defining RT values of different brain components of normal‐functioning elderly individuals, this technique may be used as a biomarker for clinical disorders like dementia. [ABSTRACT FROM AUTHOR]

Aim: To further investigate the neuroanatomical correlates of child sexual offending and disentangle them from the neural correlates of pedophilia, using a multivariate analytical approach in order to minimize loss of statistical power. Methods: This study presents structural MRI data on gray matter in an incarcerated, male population of 22 pedophilic and 21 non‐pedophilic child sexual offenders, and 20 violent non‐sexual offender controls, based on a multivariate whole‐brain approach using source‐based morphometry. Results: We identify a network of several neuroanatomical regions exhibiting interrelated reduced gray matter in both child sexual offender groups relative to controls, comprising extensive clusters in the bilateral cerebellum and frontal lobe, as well as smaller clusters in the bilateral parietal, temporal, and occipital lobes, the bilateral basal ganglia, the medial cingulate and the hippocampus. Conclusion: Our results speak to the interpretation that there are inter‐ and possibly connectivity‐related brain structural abnormalities in child sexual offenders that are not (only) pertaining to pedophilia per se. Interpretations and limitations of the present data are discussed and recommendations for future works are given. [ABSTRACT FROM AUTHOR]

Background: Migraine sufferers face difficulties getting appropriate care and treatment. Migraine is associated with reduced gray matter volume (GMV) in several brain regions, which could be related to various clinical characteristics of the disorder. Objectives: To examine differences in GMV in migraine patients with and without prior clinical care for migraine and examine differences in migraine clinical variables, psychosocial symptoms and their relationship with GMV. Methods: We utilized the baseline MRI scan and psychosocial symptom questionnaires from a longitudinal randomized controlled trial. Prior care of migraine was determined by diagnosis by a medical practitioner or prescription of migraine specific medication. Results: 117 patients were included in the study. Patients without prior care (n=23) had reduced GMV in the right dorsal medial prefrontal cortex (dMPFC) relative to patients who had prior care (p=0.034, FWE corrected). Both patient groups had reduced GMV compared to healthy controls (n=36). Patient groups did not differ in headache clinical variables. Regardless of care status, increasing scores on the stress (Perceived Stress Score) and depression questionnaires (Patient Health Questionnaire) were associated with increased GMV in the dMPFC. Conclusions: Clinical care may impact GMV in migraine patients. Patients may need different treatment options to address this baseline deficit. Trial registration: NCT02133209. [ABSTRACT FROM AUTHOR]

Primary education is the incubator for learning academic skills that help children to become a literate, communicative, and independent person. Over this learning period, nonlinear and regional changes in the brain occur, but how these changes relate to academic performance, such as reading ability, is still unclear. In the current study, we analyzed longitudinal T1 MRI data of 41 children in order to investigate typical cortical development during the early reading stage (end of kindergarten–end of grade 2) and advanced reading stage (end of grade 2–middle of grade 5), and to detect putative deviant trajectories in children with dyslexia. The structural brain change was quantified with a reliable measure that directly calculates the local morphological differences between brain images of two time points, while considering the global head growth. When applying this measure to investigate typical cortical development, we observed that left temporal and temporoparietal regions belonging to the reading network exhibited an increase during the early reading stage and stabilized during the advanced reading stage. This suggests that the natural plasticity window for reading is within the first years of primary school, hence earlier than the typical period for reading intervention. Concerning neurotrajectories in children with dyslexia compared to typical readers, we observed no differences in gray matter development of the left reading network, but we found different neurotrajectories in right IFG opercularis (during the early reading stage) and in right isthmus cingulate (during the advanced reading stage), which could reflect compensatory neural mechanisms. [ABSTRACT FROM AUTHOR]

Sensorimotor dysfunction has been previously reported in persons with cannabis dependence. Such individuals can exhibit increased levels of neurological soft signs (NSS), particularly involving motor coordination and sensorimotor integration. Whether such abnormalities may also apply to non‐dependent individuals with heavy cannabis use (HCU) is unknown, as much as the neural correlates underlying such deficits. In this study, we investigated associations between NSS and gray matter volume (GMV) in males with HCU and male controls. Twenty‐four persons with HCU and 17 controls were examined using standardized assessment of NSS and structural magnetic resonance imaging (MRI) at 3 T. GMV was calculated using voxel‐based morphometry algorithms provided by the Computational Anatomy Toolbox (CAT12). Individuals with HCU showed higher NSS total scores compared to controls. In particular, significant NSS‐subdomain effects were found for "motor coordination" (MoCo), "complex motor tasks" (CoMT), and "hard signs" (HS) expression in HCU (p < 0.05, Bonferroni‐corrected). Compared to controls, persons with HCU showed significant NSS/GMV interactions in putamen and inferior frontal cortex (MoCo), right cerebellum (CoMT) and middle and superior frontal cortices, and bilateral precentral cortex and thalamus (HS). In between‐group analyses, individuals with HCU showed lower GMV in the right anterior orbital and precentral gyrus, as well as higher GMV in the right superior frontal gyrus and left supplementary motor cortex compared to controls. The data support the notion of abnormal sensorimotor performance associated with HCU. The data also provide a neuromechanistic understanding of such deficits, particularly with respect to aberrant cortical–thalamic–cerebellar–cortical circuit. [ABSTRACT FROM AUTHOR]

Deep gray matter nuclei are the synaptic relays, responsible to route signals between specific brain areas. Dentate nuclei (DNs) represent the main output channel of the cerebellum and yet are often unexplored especially in humans. We developed a multimodal MRI approach to identify DNs topography on the basis of their connectivity as well as their microstructural features. Based on results, we defined DN parcellations deputed to motor and to higher‐order functions in humans in vivo. Whole‐brain probabilistic tractography was performed on 25 healthy subjects from the Human Connectome Project to infer DN parcellations based on their connectivity with either the cerebral or the cerebellar cortex, in turn. A third DN atlas was created inputting microstructural diffusion‐derived metrics in an unsupervised fuzzy c‐means classification algorithm. All analyses were performed in native space, with probability atlas maps generated in standard space. Cerebellar lobule‐specific connectivity identified one motor parcellation, accounting for about 30% of the DN volume, and two non‐motor parcellations, one cognitive and one sensory, which occupied the remaining volume. The other two approaches provided overlapping results in terms of geometrical distribution with those identified with cerebellar lobule‐specific connectivity, although with some differences in volumes. A gender effect was observed with respect to motor areas and higher‐order function representations. This is the first study that indicates that more than half of the DN volumes is involved in non‐motor functions and that connectivity‐based and microstructure‐based atlases provide complementary information. These results represent a step‐ahead for the interpretation of pathological conditions involving cerebro‐cerebellar circuits. [ABSTRACT FROM AUTHOR]

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [11C]raclopride and [18F]FE‐PE2I, respectively, were acquired along with T1‐weighted magnetic resonance imaging data in our previous studies, and were re‐analyzed in this work. We quantified the binding potentials (BPND) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BPND and regional GM volume were then examined by voxel‐based morphometry. In line with the functional and anatomical connectivity, [11C]raclopride BPND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BPND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BPND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18F]FE‐PE2I BPND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT. [ABSTRACT FROM AUTHOR]

Introduction: It is well established that cortical volume are decreased in patients with schizophrenia. One possible explanation is that the increased pro-inflammatory status in schizophrenia is related to volumetric decrease of gray matter. The aim of this study was to correlate interleukin 6 (IL-6) with cortical volume in patients with schizophrenia and controls. Methods: We selected 36 patients with schizophrenia and 35 controls. Interleukin 6 (IL-6) was correlated with cortical volume in patients with schizophrenia and controls. Results: IL-6 was negatively correlated with cortical volume (p = 0.027; rho = −0.370) in patients, but not in controls (p = 0.235). Discussion: Our results are in line with previous studies suggesting that chronic inflammatory activation in patients with schizophrenia could be one plausible mechanism that could contribute for the cortical volumetric decrease often seen in this population. However, this cross-sectional study with a small number of patients does not allow us to establish causal relations. [ABSTRACT FROM AUTHOR]

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results. [ABSTRACT FROM AUTHOR]

HIV‐infection has been associated with widespread alterations in brain structure and function, although few studies have examined whether such aberrations are co‐localized and the degree to which clinical and cognitive metrics are related. We examine this question in the somatosensory system using high‐resolution structural MRI (sMRI) and magnetoencephalographic (MEG) imaging of neural oscillatory activity. Forty‐four participants with HIV (PWH) and 55 demographically‐matched uninfected controls completed a paired‐pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. MEG data were transformed into the time‐frequency domain; significant sensor level responses were imaged using a beamformer. Virtual sensor time series were derived from the peak responses. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. The T1‐weighted sMRI data were processed using morphological methods to derive cortical thickness values across the brain. From these, the cortical thickness of the tissue coinciding with the peak response was estimated. Our findings indicated both PWH and control exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls. Follow‐up analyses indicated that the reduction in cortical thickness was significantly correlated with CD4 nadir and mediated the relationship between HIV and spontaneous cortical activity within the left postcentral gyrus. These data indicate that PWH have abnormally strong spontaneous cortical activity in the left postcentral gyrus and such elevated activity is driven by locally reduced cortical gray matter thickness. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated the promising capabilities of magnetic resonance imaging (MRI)-based quantitative susceptibility maps (QSM) in producing biomarkers of brain injury. The present study aims to further explore acute QSM changes in athletes after sports concussion and investigate prognostication capabilities of QSM-derived imaging metrics. The QSM were derived from neurological MRI data acquired on a cohort (n = 78) of concussed male American football athletes within 48 h of injury. The MRI-derived QSM values in subcortical gray and white matter compartments after concussion showed differences relative to a matched uninjured control group (white matter: z = 3.04, p = 0.002, subcortical gray matter: z = −2.07, p = 0.04). Subcortical gray matter QSM MRI measurements also correlated strongly with duration of symptoms (ρ = -0.46, p = 0.002) within a subcohort of subjects who had symptom durations for at least one week (n = 39). The acute QSM MRI metrics showed promising prognostication capabilities, with subcortical gray matter compartment QSM values yielding a mean classification area under the curve performance of 0.78 when predicting symptoms of more than two weeks in duration. The results of the study reproduce previous acute post-concussion group QSM findings and provide promising initial prognostication capabilities of acute QSM measurements in a post-concussion setting. [ABSTRACT FROM AUTHOR]

Objective: To examine the patterns of cortical gray matter thickness in multiple sclerosis (MS) patients. Methods: Seventy‐four MS patients—clinically isolated syndrome (4%), relapsing–remitting MS (79%), and progressive MS (17%)—and 21 healthy controls (HCs) underwent 1.5 Tesla T1‐weighted 3D MRI examinations to measure brain cortical thickness in a total of 68 regions of interest. Using hierarchical cluster analysis with multivariate cortical thickness data, cortical thickness reduction patterns were cross‐sectionally investigated in MS patients. Results: The MS patients were grouped into three major clusters (Clusters 1, 2, and 3). Most of the regional cortical thickness values were equivalent between the HCs and Cluster 1, but decreased in the order of Clusters 2 and 3. Only the thicknesses of the temporal lobe cortices (the bilateral superior and left middle temporal cortex, as well as the left fusiform cortex) were significantly different among Clusters 1, 2, and 3. In contrast, temporal pole thickness reduction was evident exclusively in Cluster 3, which was also characterized by increased lesion loads in the temporal pole and the adjacent juxtacortical white matter, dilatation of the inferior horn of the lateral ventricle, severe whole‐brain volume reduction, and longer disease duration. Although cortical atrophy was significantly more common in the progressive phase, approximately half of the MS patients with the severe cortical atrophy pattern had relapsing–remitting disease. Conclusion: Cortical thickness reduction patterns in MS are mostly characterized by the degree of temporal lobe cortical atrophy, which may start in the relapsing–remitting phase. Among the temporal lobe cortices, the neurodegenerative change may accelerate in the temporal pole in the progressive phase. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of changes in magnetic resonance imaging (MRI) detected after a seizure is not fully understood. Objective: To characterize and describe seizure‐induced changes detected by MRI. Animals Eighty‐one client‐owned dogs diagnosed with idiopathic epilepsy. Methods: Data collected retrospectively from medical records and included anatomical areas affected, T1‐, T2‐weighted and T2‐FLAIR (fluid‐attenuated inversion recovery) appearance, whether changes were unilateral or bilateral, symmetry, contrast enhancement, mass effect, and, gray and white matter distribution. Diffusion‐ and perfusion weighted maps were evaluated, if available. Results: Seizure‐induced changes were T2‐hyperintense with no suppression of signal on FLAIR. Lesions were T1‐isointense (55/81) or hypointense (26/81), local mass effect (23/81) and contrast enhancement (12/81). The majority of changes were bilateral (71/81) and symmetrical (69/71). The most common areas affected were the hippocampus (39/81) cingulate gyrus (33/81), hippocampus and piriform lobes (32/81). Distribution analysis suggested concurrence between cingulate gyrus and pulvinar thalamic nuclei, the cingulate gyrus and parahippocampal gyrus, hippocampus and piriform lobe, and, hippocampus and parahippocampal gyrus. Diffusion (DWI) characteristics were a mixed‐pattern of restricted, facilitated, and normal diffusion. Perfusion (PWI) showed either hypoperfusion (6/9) or hyperperfusion (3/9). Conclusions and Clinical Importance: More areas, than previously reported, have been identified that could incur seizure‐induced changes. Similar to human literature, DWI and PWI changes have been identified that could reflect the underlying metabolic and vascular changes. [ABSTRACT FROM AUTHOR]

Objective: It has been proposed that different stages of the bipolar disorder might have distinct neurobiological changes. However, the evidence for this has not been consistent, as the studies in early stages of the illness are limited by small sample sizes. The purpose of this study was to investigate the gray matter volume changes in bipolar patients who recently recovered from their first episode of mania (FEM). Methods: Using a whole-brain voxel-based analysis, we compared the regional gray matter volumes of 61 bipolar patients who have recovered from their FEM in the past 3 months with 43 age- and gender-matched healthy participants. We also performed a series of subgroup analyses to determine the effects of hospitalization during the FEM, history of depressive episodes, and exposure to lithium. Results: No statistically significant difference was found between gray matter volumes of FEM patients and healthy participants, even at a more liberal threshold (P < 0.001, uncorrected for multiple comparisons). Voxel-based subgroup analyses did not reveal significant gray matter differences except for a trend toward decreased gray matter volume in left lateral occipital cortex (P < 0.001, uncorrected) in patients with a previous history of depression. Conclusion: This study represents the largest structural neuroimaging investigation of FEM published to date. Early stage of bipolar disorder was not found to be associated with significant gray matter volume changes. Our findings suggest that there might be a window of opportunity for early intervention strategies to prevent or delay neuroprogression in bipolar disorder. [ABSTRACT FROM AUTHOR]

One of the major challenges in the diagnosis of Alzheimer's disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive AD marker, other measures are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at the clinical stage of AD. Our goal was therefore, (1) to evaluate the grey matter volume (GMV) of central olfactory processing regions in prodromal AD and (2) to assess its association with episodic memory. We included 34 cognitively normal healthy controls (HC), 92 individuals with subjective cognitive decline (SCD), and 40 with mild cognitive impairment (MCI). We performed regions of interest analysis (ROI) using two different approaches, allowing to extract GMV from (1) atlas-based anatomical ROIs and from (2) functional and non-functional subregions of these ROIs (olfactory ROIs and non-olfactory ROIs). Participants with MCI exhibited smaller olfactory ROIs GMV, including significant reductions in the piriform cortex, amygdala, entorhinal cortex, and left hippocampus compared to other groups (p ≤ 0.05, corrected). No significant effect was found regarding anatomical or non-olfactory ROIs GMV. The left hippocampus olfactory ROI GMV was correlated with episodic memory performance (p < 0.05 corrected). Limbic/medial-temporal olfactory processing areas are specifically atrophied at the MCI stage, and the degree of atrophy might predict cognitive decline in AD early stages. • Prior activated areas in fMRI studies determined olfactory processing ROIs. • Grey matter volume of olfactory areas is reduced in mild cognitive impairment. • Neurodegeneration is focused on limbic and medial-temporal olfactory areas. • Volume of central olfactory areas correlates with episodic memory performance. [ABSTRACT FROM AUTHOR]

Background: The memory impairments in mild cognitive impairment (MCI) can be classified into encoding (EF) and retrieval (RF) failure, which can be affected by underlying pathomechanism. We explored the differences structurally and functionally. Methods: We compared quantitative electroencephalography (qEEG) power spectra and connectivity between 87 MCI patients with EF and 78 MCI with RF using iSyncBrain® (iMediSync Inc., Republic of Korea) (https://isyncbrain.com/). Voxel-based morphometric analysis of the gray matter (GM) in the MCI groups and 71 cognitive normal controls was also done using the Computational Anatomy Toolbox 12 (http://www.neuro.uni-jena.de/cat/). Results: qEEG showed higher frontal theta and lower beta2 band power, and higher theta connectivity in the EF. There was no statistically significant difference in GM volume between the EF and RF. However, when compared to normal control, GM volume reductions due to EF in the left thalamus and bilateral hippocampi and reductions due to RF in the left thalamus, right superior frontal lobe, right superior temporal lobe, and right middle cingulum were observed (p < 0.05, family-wise error correction). Conclusions: MCI differs functionally and structurally according to their specific memory impairments. The EF findings are structurally and functionally more consistent with the prodromal Alzheimer's disease stage than the RF findings. Since this study is a cross-sectional study, prospective follow-up studies are needed to investigate whether different types of memory impairments can predict the underlying pathology of amnestic MCI. Additionally, insufficient sample size may lead to ambiguous statistical findings in direct comparisons, and a larger patient cohort could more robustly identify differences in GM volume reductions between the EF and the RF group. [ABSTRACT FROM AUTHOR]

No study has investigated red nucleus (RN) atrophy in multiple sclerosis (MS) despite cerebellum and its connections are elective sites of MS‐related pathology. In this study, we explore RN atrophy in early MS phases and its association with cerebellar damage (focal lesions and atrophy) and physical disability. Thirty‐seven relapse‐onset MS (RMS) patients having mean age of 35.6 ± 8.5 (18–56) years and mean disease duration of 1.1 ± 1.5 (0–5) years, and 36 age‐ and sex‐matched healthy controls (HC) were studied. Cerebellar and RN lesions and volumes were analyzed on 3 T‐MRI images. RMS did not differ from HC in cerebellar lobe volumes but significantly differed in both right (107.84 ± 13.95 mm3 vs. 99.37 ± 11.53 mm3, p =.019) and left (109.71 ± 14.94 mm3 vs. 100.47 ± 15.78 mm3, p =.020) RN volumes. Cerebellar white matter lesion volume (WMLV) inversely correlated with both right and left RN volumes (r = −.333, p =.004 and r = −.298, p =.010, respectively), while no correlation was detected between RN volumes and mean cortical thickness, cerebellar gray matter lesion volume, and supratentorial WMLV (right RN: r = −.147, p =.216; left RN: r = −.153, p =.196). Right, but not left, RN volume inversely correlated with midbrain WMLV (r = −.310, p =.008), while no correlation was observed between whole brainstem WMLV and either RN volumes (right RN: r = −.164, p =.164; left RN: r = −.64, p =.588). Finally, left RN volume correlated with vermis VIIb (r =.297, p =.011) and right interposed nucleus (r =.249, p =.034) volumes. We observed RN atrophy in early RMS, likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS. [ABSTRACT FROM AUTHOR]

The gray matter of the spinal cord is the seat of somata of various types of neurons devoted to the sensory and motor activities of the limbs and trunk as well as a part of the autonomic nervous system. The volume of the spinal gray matter is an indicator of the local neuronal processing, and this can decrease due to atrophy associated with degenerative diseases and injury. Nevertheless, the absolute volume of the human spinal cord has rarely been reported, if ever. Here, we use high-resolution magnetic resonance imaging, with a cross-sectional resolution of 50 × 50 μm and a voxel size of 0.0005 mm³ to estimate the total gray and white matter volume of a post mortem human female spinal cord. Segregation of gray and white matter was accomplished using deep learning image segmentation. Furthermore, we include data from a male spinal cord of a previously published study. The gray and white matter volumes were found to be 2.87 and 11.33 mL, respectively, for the female and 3.55 and 19.33 mL, respectively, for the male. The gray and white matter profiles along the vertebral axis were found to be strikingly similar, and the volumes of the cervical, thoracic, and lumbosacral sections were almost equal. [ABSTRACT FROM AUTHOR]

Introduction: We propose a method to evaluate quantitatively the longitudinal structural changes in brain atrophy to provide early detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Methods: We used existence probabilities obtained by segmenting magnetic resonance (MR) images at two different time points into four regions: gray matter, white matter, cerebrospinal fluid, and background. This method was applied to T1‐weighted MR images of 110 participants with normal cognition (NL), 165 with MCI, and 82 with AD, obtained from the Japanese Alzheimer's Disease Neuroimaging Initiative database. Results: We obtained the coefficients of probability change (CPC) for each dataset. We found high area under the receiver operating characteristic curve (ROC) values (up to 0.908 of the difference of ROCs) for some CPC regions that are considered indicators of atrophy. Additionally, we attempted to establish a machine‐learning algorithm to classify participants as NL or AD. The maximum accuracy was 92.1% for NL‐AD classification and 81.2% for NL‐MCI classification using CPC values between images acquired at first and sixth months, respectively. Conclusion: These results showed that the proposed method is effective for the early detection of AD and MCI. [ABSTRACT FROM AUTHOR]

Accurate and reliable measures of cortical thickness from magnetic resonance imaging are an important biomarker to study neurodegenerative and neurological disorders. Diffeomorphic registration‐based cortical thickness (DiReCT) is a known technique to derive such measures from non‐surface‐based volumetric tissue maps. ANTs provides an open‐source method for estimating cortical thickness, derived by applying DiReCT to an atlas‐based segmentation. In this paper, we propose DL+DiReCT, a method using high‐quality deep learning‐based neuroanatomy segmentations followed by DiReCT, yielding accurate and reliable cortical thickness measures in a short time. We evaluate the methods on two independent datasets and compare the results against surface‐based measures from FreeSurfer. Good correlation of DL+DiReCT with FreeSurfer was observed (r =.887) for global mean cortical thickness compared to ANTs versus FreeSurfer (r =.608). Experiments suggest that both DiReCT‐based methods had higher sensitivity to changes in cortical thickness than Freesurfer. However, while ANTs showed low scan‐rescan robustness, DL+DiReCT showed similar robustness to Freesurfer. Effect‐sizes for group‐wise differences of healthy controls compared to individuals with dementia were highest with the deep learning‐based segmentation. DL+DiReCT is a promising combination of a deep learning‐based method with a traditional registration technique to detect subtle changes in cortical thickness. [ABSTRACT FROM AUTHOR]

Background: We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer's disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. Methods: We retrospectively included 150 participants, including 29 bvAD, 28 "typical" amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. Results: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD

Although neuropsychological studies of human immunodeficiency virus (HIV)-infected patients have demonstrated heterogeneity in neurocognitive impairment and neuroimaging studies have reported diverse brain regions affected by HIV, it remains unclear whether individual differences in neurocognitive impairment are underpinned by their neural bases. Here, we investigated spatial distribution patterns of correlation between neurocognitive function and regional gray matter (GM) volume across patients with HIV. Thirty-one combination antiretroviral therapy-treated HIV-infected Japanese male patients and 33 age- and sex-matched healthy controls were included in the analysis after strict exclusion criteria, especially for substance use. Fifteen neurocognitive tests were used, and volumetric magnetic resonance imaging was performed. We used voxel-based morphometry to compare GM volume between groups and identify regional GM volumes that correlated with neurocognitive tests across patients. Using the Frascati criteria, 10 patients were diagnosed with asymptomatic neurocognitive impairment, while the others were not diagnosed with HIV-associated neurocognitive disorders. Patients showed a significantly lower performance in five neurocognitive tests as well as significantly reduced GM volume relative to controls, with volume-reduced regions spread diffusely across the whole brain. Different aspects of neurocognitive impairment (i.e., figural copy, finger tapping, and Pegboard) were associated with different GM regions. Our findings suggest a biological background constituting heterogeneity of neurocognitive impairment in HIV infection and support the clinical importance of considering individual differences for tailor-made medicine for people living with HIV. [ABSTRACT FROM AUTHOR]

Background: The increase of headache frequency is associated with higher headache related disability and lower quality of life in patients with migraine. However, the pathophysiology of migraine progression, persistence, or remission is elusive. The purpose of this study is to identify the brain signatures that are predictive of the long-term outcomes among patients with high-frequency migraine (HFM: 10–30 headache days/month). Methods: We prospectively enrolled patients with HFM and healthy controls and collected their baseline clinical profiles and brain-MRI data at first visit. We longitudinally followed the patients and determined their outcomes at 2-year follow-up. Good outcome was defined as ≥50% reduction of baseline headache days and poor outcome was defined as reduction < 50% or frequency increase. Voxel-based morphometry was used to study gray matter volume (GMV), and structural covariance was used to investigate structural connectivity. Results: Among 56 patients with HFM, 37 had good outcome and 19 poor outcome. Compared to the healthy controls (n = 37), patients with poor outcome had decreased GMV over the left posterior cingulate gyrus, and increased GMV over the bilateral cerebellum and the right precentral gyrus. Further, patients with poor outcome had greater GMV over the right and the left cerebella compared to patients with good outcome, and the GMVs of the cerebella were correlated to 2-year headache frequencies (right: r = 0.38, P = 0.005; left: r = 0.35, P = 0.009). Structural connectivity were increased between the cerebellum and the cuneus, the calcarine cortex, and the temporal lobe, respectively, in patients with poor outcome, and was decreased between the cerebellum and the prefrontal cortex in patients with poor outcome. The structural covariance integrities between the right cerebellum and the right cuneus were correlated to 2-year headache frequencies (r = 0.36, P = 0.008). Conclusions: Structural volume and connectivity changes of the cerebellum may underlie headache persistence in patients with HFM. [ABSTRACT FROM AUTHOR]

Background: Fluctuations are one of the core clinical features characterizing dementia with Lewy bodies (DLB). They represent a determining factor for its diagnosis and strongly impact the quality of life of patients and their caregivers. However, the neural correlates of this complex symptom remain poorly understood. This study aimed to investigate the structural and functional changes in DLB patients, compared to Alzheimer's disease (AD) patients and healthy elderly subjects, and their potential links with fluctuations. Methods: Structural and resting-state functional MRI data were collected from 92 DLB patients, 70 AD patients, and 22 control subjects, who also underwent a detailed clinical examination including the Mayo Clinic Fluctuation Scale. Gray matter volume changes were analyzed using whole-brain voxel-based morphometry, and resting-state functional connectivity was investigated using a seed-based analysis, with regions of interest corresponding to the main nodes of the salience network (SN), frontoparietal network (FPN), dorsal attention network (DAN), and default mode network (DMN). Results: At the structural level, fluctuation scores in DLB patients did not relate to the atrophy of insular, temporal, and frontal regions typically found in this pathology, but instead showed a weak correlation with more subtle volume reductions in different regions of the cholinergic system. At the functional level, the DLB group was characterized by a decreased connectivity within the SN and attentional networks, while the AD group showed decreases within the SN and DMN. In addition, higher fluctuation scores in DLB patients were correlated to a greater connectivity of the SN with the DAN and left thalamus, along with a decreased connectivity between the SN and DMN, and between the right thalamus and both the FPN and DMN. Conclusions: Functional connectivity changes, rather than significant gray matter loss, could play an important role in the emergence of fluctuations in DLB. Notably, fluctuations in DLB patients appeared to be related to a disturbed external functional connectivity of the SN, which may lead to less relevant transitions between different cognitive states in response to internal and environmental stimuli. Our results also suggest that the thalamus could be a key region for the occurrence of this symptom. [ABSTRACT FROM AUTHOR]

• Correcting gray matter boundary errors made by Freesurfer 7 has limited effects. • The investigated variables were volume, surface area, and thickness. • MRI images of males have more gray matter boundary errors compared to females. • Age or patient status (first-episode psychosis) has no effect on number of errors. • Baseline and 1-year images have significant correlation in number of errors. We have studied the effects of manual quality control of brain Magnetic Resonance Imaging (MRI) images processed with Freesurfer. T1 images of first episode psychosis patients (N = 60) and healthy controls (N = 41) were inspected for gray matter boundary errors. The errors were fixed, and the effects of error correction on brain volume, thickness, and surface area were measured. It is commonplace to apply quality control to Freesurfer MRI recordings to ensure that the edges of gray and white matter are detected properly, as incorrect edge detection leads to changes in variables such as volume, cortical thickness, and cortical surface area. We find that while Freesurfer v7.1.1. does regularly make mistakes in identifying the edges of cortical gray matter, correcting these errors yields limited changes in the commonly measured variables listed above. We further find that the software makes fewer gray matter boundary errors when processing female brains. The results suggest that manually correcting gray matter boundary errors may not be worthwhile due to its small effect on the measurements, with potential exceptions for studies that focus on the areas that are more commonly affected by errors: the areas around the cerebellar tentorium, paracentral lobule, and the optic nerves, specifically the horizontal segment of the middle cerebral artery. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms and cognitive impairment have been consistently reported in patients with hepatitis C virus (HCV) infection. Since the mechanisms behind remain to be established, the present study attempted to assess whether neuropsychological impairments in HCV-infected patients are accompanied by structural alterations in the brain. Therefore, 19 anti-HCV-antibody-positive women with mild liver disease and 16 healthy controls underwent extensive neuropsychological testing and cranial magnetic resonance imaging (MRI) examination. Nine of the patients and five controls were followed up after 6–7 years. Voxel-based morphometry and magnetization transfer imaging were utilized to study HCV-associated structural gray and white matter changes. The HCV-infected patients had significantly worse fatigue and depression scores and significantly poorer performance on attention and memory tests than controls. The patients displayed gray matter (GM) atrophy in the bilateral insula and thalamus and a profound GM volume increases in the cerebellum. Microstructural GM changes in the insula were also evident by a reduced magnetization transfer ratio. Structural white matter changes were observed along several descending and crossing fiber tracts. Follow-up at 7 years revealed increased GM atrophy in the left amygdala and left parahippocampal regions over time. We conclude that our data provide evidence for structural alterations in the brains of patients with chronic HCV infection. Disturbances of cerebellothalamocortical regions and circuits, linking cerebellar projections to the prefrontal cortex through the thalamus, underpin the emotional and cognitive dysfunction characteristically observed in these patients. [ABSTRACT FROM AUTHOR]