Gray Matter Changes Research Articles

Increased thalamic gray matter volume induced by repetitive transcranial magnetic stimulation treatment in patients with major depressive disorder.

Repetitive transcranial magnetic stimulation (rTMS) is an effective therapy in improving depressive symptoms in MDD patients, but the intrinsic mechanism is still unclear. In this study, we investigated the influence of rTMS on brain gray matter volume for alleviating depressive symptoms in MDD patients using structural magnetic resonance imaging (sMRI) data. Patients with first episode, unmedicated patients with MDD (n = 26), and healthy controls (n = 31) were selected for this study. Depressive symptoms were assessed before and after treatment by using the HAMD-17 score. High-frequency rTMS treatment was conducted in patients with MDD over 15 days. The rTMS treatment target is located at the F3 point of the left dorsolateral prefrontal cortex. Structural magnetic resonance imaging (sMRI) data were collected before and after treatment to compare the changes in brain gray matter volume. Before treatment, patients with MDD had significantly reduced gray matter volumes in the right fusiform gyrus, left and right inferior frontal gyrus (triangular part), left inferior frontal gyrus (orbital part), left parahippocampal gyrus, left thalamus, right precuneus, right calcarine fissure, and right median cingulate gyrus compared with healthy controls (P < 0.05). After rTMS treatment, significant growth in gray matter volume of the bilateral thalamus was observed in depressed patients (P < 0.05). Bilateral thalamic gray matter volumes were enlarged in the thalamus of MDD patients after rTMS treatment and may be the underlying neural mechanism for the treatment of rTMS on depression.

Longitudinal changes in gray matter correspond to changes in cognition across the lifespan: implications for theories of cognition

The present study examines the association between gray matter volume and cognition. Studies that have examined this issue have focused primarily on older adults, whereas the present study examines the issue across the entire adult lifespan. A total of 463 adults, ages 20–88 at first assessment, were followed longitudinally across three assessments over 8–10years. Significant individual differences in a general cognition measure comprised of measures of speed of processing, working memory, and episodic memory were observed, as well as in measures of cortical and subcortical gray matter. Parallel process latent growth curve modeling showed a reliable relationship between decreases in cortical matter and cognitive decline across the entire adult lifespan, which persisted after controlling for age effects. Implications of these findings in relation to progression toward dementia, risk assessment, cognitive intervention, and environmental factors are discussed, as well as implications for theories of cognitive aging.

Detection of grey matter microstructural substrates of neurodegeneration in multiple sclerosis.

Multiple sclerosis features complex pathological changes in grey matter that begin early and eventually lead to diffuse atrophy. Novel approaches to image grey-matter microstructural alterations in vivo are highly sought after and would enable more sensitive monitoring of disease activity and progression. This cross-sectional study aimed to assess the sensitivity of high-gradient diffusion MRI for microstructural tissue damage in cortical and deep grey matter in people with multiple sclerosis and test the hypothesis that reduced cortical cell body density is associated with cortical and deep grey-matter volume loss. Forty-one people with multiple sclerosis (age 24-72, 14 females) and 37 age- and sex-matched healthy controls were scanned on a 3 T Connectom MRI scanner equipped with 300 mT/m gradients using a multi-shell diffusion MRI protocol. The soma and neurite density imaging model was fitted to high-gradient diffusion MRI data to obtain estimates of intra-neurite, intra-cellular and extra-cellular signal fractions and apparent soma radius. Cortical and deep grey-matter microstructural imaging metrics were compared between multiple sclerosis and healthy controls and correlated with grey-matter volume, clinical disability and cognitive outcomes. People with multiple sclerosis showed significant cortical and deep grey-matter volume loss compared with healthy controls. People with multiple sclerosis showed trends towards lower cortical intra-cellular signal fraction and significantly lower intra-cellular and higher extra-cellular signal fractions in deep grey matter, especially the thalamus and caudate, compared with healthy controls. Changes were most pronounced in progressive disease and correlated with the Expanded Disability Status Scale, but not the Symbol Digit Modalities Test. In multiple sclerosis, normalized thalamic volume was associated with thalamic microstructural imaging metrics. Whereas thalamic volume loss did not correlate with cortical volume loss, cortical microstructural imaging metrics were significantly associated with thalamic volume, and not with cortical volume. Compared with the short diffusion time (Δ = 19 ms) achievable on the Connectom scanner, at the longer diffusion time of Δ = 49 ms attainable on clinical scanners, multiple sclerosis-related changes in imaging metrics were generally less apparent with lower effect sizes in cortical and deep grey matter. Soma and neurite density imaging metrics obtained from high-gradient diffusion MRI data provide detailed grey-matter characterization beyond cortical and thalamic volumes and distinguish multiple sclerosis-related microstructural pathology from healthy controls. Cortical cell body density correlates with thalamic volume, appears sensitive to the microstructural substrate of neurodegeneration and reflects disability status in people with multiple sclerosis, becoming more pronounced as disability worsens.

White Matter and Gray Matter Changes Related to Cognition in Community populations (P12-6.008)

<h3>Objective:</h3> To investigate the global and topographic changes of white matter integrity and cortical structure related to cognitive impairments in a community-based population. <h3>Background:</h3> Further studies in associations of cortical and subcortical changes with cognitive function would better explain the pathology of cognitive impairment. <h3>Design/Methods:</h3> A cross-sectional analysis was performed based on 995 subjects (aged 56.8±9.1 years, 34.8% males) from the Shunyi study, a community-dwelling cohort. Cognitive status was accessed by a series of neurocognitive tests including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), category Verbal Fluency Test (VFT), Digit Span Test (DST), and Trail Making Tests A and B (TMT-A and TMT-B). Structural and diffusional MRI data were acquired. White matter integrity was assessed using fractional anisotropy (FA), mean diffusivity (MD), and peak width of skeletonized mean diffusivity (PSMD). Cortical surface area, thickness, and volume were measured using Freesurfer. Probabilistic tractography was further conducted to track the white matter fibers connecting to the cortical regions related to cognition. General linear models were used to investigate the association between brain structure and cognition. <h3>Results:</h3> Global mean FA and MD were associated with VFT performances (FA, β=0.119, p&lt;0.001; MD, β=−0.128, p&lt;0.001). Global cortical surface area, thickness, and volume were not related to cognitive scores. In tract-based spatial statistics, disrupted white matter integrity was related to cognitive impairment mainly in visuomotor processing speed and executive function (TMT-A and VFT), rather than short-term memory (DST). In the whole brain vertex-wise analysis, surface area in the left orbitofrontal cortex and left central sulcus were positively associated with MMSE and MoCA scores. These associations were independent of the connecting white matter tract. <h3>Conclusions:</h3> Disrupted white matter integrity and regional cortical surface area were related to cognition in community-dwelling populations. The associations of cortical surface area and cognition were independent of the connecting white matter tract. <b>Disclosure:</b> Mrs. Li has nothing to disclose. Jing Yuan has nothing to disclose. Fei Han has nothing to disclose. Lixin Zhou has nothing to disclose. Jun Ni has nothing to disclose. Ming Yao has nothing to disclose. Shuyang Zhang has nothing to disclose. Zhengyu Jin has nothing to disclose. Liying Cui has nothing to disclose. Feifei Zhai has nothing to disclose. Yi-Cheng Zhu has nothing to disclose.

Gray Matter Microstructure Alterations in People with Multiple Sclerosis Based on Cell Body and Neurite Density Imaging (P10-3.007)

<h3>Objective:</h3> To evaluate a novel compartment-based model for apparent cell body and neurite density imaging (SANDI) in gray matter (GM) in people with multiple sclerosis (MS) compared to healthy controls (HC) and its correlation with brain atrophy. <h3>Background:</h3> MS features focal cortical lesions and microstructural changes in normal-appearing GM, which can impact clinical function and disability. High gradient diffusion MRI has potential to optimize GM tissue microstructure characterization by overcoming challenges due to the complexity of underlying components. <h3>Design/Methods:</h3> 41 people with MS and 37 age- and sex-matched HC were scanned on a 3T Connectom MRI scanner equipped with 300mT/m gradients using a multi-shell acquisition protocol consisting of eight b-values at 19msec diffusion time. Microstructural metrics of SANDI, including a measure of soma density (f_soma) in the cortex and deep GM, were compared between MS and HC and correlated with cortical and thalamic atrophy, correcting for multiple comparisons. <h3>Results:</h3> Cortical cell body signal fraction (f_soma) was decreased in MS compared to HC (0.56 vs. 0.58, <i>p</i>=0.027, not surviving FDR-correction). In deep GM, f_soma and extra-cellular signal fraction were significantly decreased in MS compared to HC (<i>FDR-p</i>=0.045 in both), which was most pronounced in progressive MS. Based on spatial analysis, f_soma of caudate nucleus and thalamus were significantly decreased in MS compared to HC (<i>FDR-p</i>=0.003 and <i>FDR-p</i>=0.027, respectively). Whereas cortical atrophy in MS was poorly correlated with cortical f_soma, thalamic atrophy in MS demonstrated moderate correlation with decreased thalamic f_soma (r=0.311, <i>p</i>=0.054) and decreased cortical f_soma (r=0.474, <i>p</i>=0.008). <h3>Conclusions:</h3> SANDI metrics, in particular f_soma, provide detailed GM characterization beyond cortical and thalamic volumes and are able to characterize MS-related microstructural pathology. Decreased cortical cell density correlates with declining thalamic volume and may precede volumetric measures of cortical atrophy in people with MS. <b>Disclosure:</b> Ms. Krijnen has nothing to disclose. Andrew Russo has nothing to disclose. Dr. Salim Karam has nothing to disclose. The institution of Menno M Schoonheim has received research support from Dutch MS Research Foundation. The institution of Menno M Schoonheim has received research support from Eurostars-EUREKA. The institution of Menno M Schoonheim has received research support from ARSEP. The institution of Menno M Schoonheim has received research support from Amsterdam Neuroscience. The institution of Menno M Schoonheim has received research support from MAGNIMS. The institution of Menno M Schoonheim has received research support from ZonMW. The institution of Menno M Schoonheim has received research support from Atara Biotherapeutics. The institution of Menno M Schoonheim has received research support from Biogen. The institution of Menno M Schoonheim has received research support from Celgene/Bristol Meyers Squibb. The institution of Menno M Schoonheim has received research support from Genzyme. The institution of Menno M Schoonheim has received research support from MedDay. The institution of Menno M Schoonheim has received research support from Merck. Dr. Huang has received personal compensation in the range of $0-$499 for serving as a Consultant for Siemens Healthineers. The institution of Dr. Huang has received research support from Siemens Healthineers. The institution of Dr. Huang has received research support from Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Galen/Atlantica. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Banner Life Sciences. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Greenwich Biosciences. Dr. Klawiter has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for OM1. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. The institution of Dr. Klawiter has received research support from Biogen. The institution of Dr. Klawiter has received research support from Abbvie. The institution of Dr. Klawiter has received research support from Genentech.

Quantitative Evaluation of Oxygen Extraction Fraction Changes in the Monkey Brain during Acute Stroke by Using Quantitative Susceptibility Mapping.

The oxygen extraction fraction (OEF) indicates the brain's oxygen consumption and can be estimated by using the quantitative susceptibility mapping (QSM) MRI technique. Recent studies have suggested that OEF alteration following stroke is associated with the viability of at-risk tissue. In the present study, the temporal evolution of OEF in the monkey brain during acute stroke was investigated using QSM. Ischemic stroke was induced in adult rhesus monkeys (n = 8) with permanent middle cerebral artery occlusion (pMCAO) by using an interventional approach. Diffusion-, T2-, and T2*-weighted images were conducted on day 0, day 2, and day 4 post-stroke using a clinical 3T scanner. Progressive changes in magnetic susceptibility and OEF, along with their correlations with the transverse relaxation rates and diffusion indices, were examined. The magnetic susceptibility and OEF in injured gray matter of the brain significantly increased during the hyperacute phase, and then decreased significantly on day 2 and day 4. Moreover, the temporal changes of OEF in gray matter were moderately correlated with mean diffusivity (MD) (r = 0.52; p = 0.046) from day 0 to day 4. Magnetic susceptibility in white matter progressively increased (from negative values to near zero) during acute stroke, and significant increases were seen on day 2 (p = 0.08) and day 4 (p = 0.003) when white matter was significantly degenerated. However, significant reduction of OEF in white matter was not seen until day 4 post-stroke. The preliminary results demonstrate that QSM-derived OEF is a robust approach to examine the progressive changes of gray matter in the ischemic brain from the hyperacute phase to the subacute phase of stroke. The changes of OEF in gray matter were more prominent than those in white matter following stroke insult. The findings suggest that QSM-derived OEF may provide complementary information for understanding the neuropathology of the brain tissue following stroke and predicting stroke outcomes.

Magnetic Resonance Imaging Characteristics of Brain Structure and Neuroendocrine Changes in Patients with First-Episode Schizophrenia

This research was aimed to investigate the magnetic resonance imaging (MRI) features of brain structure and neuroendocrine levels in patients with first-episode schizophrenia. 25 hospitalized patients with first-episode schizophrenia were selected as the observation group, while 25 healthy people were selected as the control group. All the objects underwent MRI examination, and the images as well as gray matter density of the original image data were analyzed under voxel-based morphometry (VBM). The cortisol and prolactin in the observation group were detected, and the levels were compared. The Pearson correlation analysis was adopted to analyze the correlation between cortisol and prolactin levels and the total score of the Positive and Negative Syndrome Scale (PANSS). The results showed that the gray matter volume of the precentral gyrus, superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, postcentral gyrus, inferior parietal lobule, superior parietal lobule, and anterior cingulate cortex of the observation group decreased, while the volume of cerebellar gray matter increased. The levels of cortisol and prolactin in the observation group (387.54 ± 117.69 μg/L and 804.16 ± 267.13 μIU/mL, respectively) were significantly higher than those in the control group (138.46 ± 62.47 μg/L and 397.54 ± 203.82 μIU/mL, respectively), and the differences were statistically significant ( P &lt; 0.05 ). The results of the Pearson correlation test showed that the higher the cortisol level, the more severe the schizophrenia (r = 0.421 and P = 0.013 ), while the prolactin level was not directly related to the severity of schizophrenia (r = 0.019 and P = 0.568 ). In conclusion, the MRI features based on the VBM technology can accurately assess the changes of gray matter; the levels of cortisol and prolactin in patients with first-episode schizophrenia were significantly higher than those in healthy people; and the higher the cortisol level, the more severe the schizophrenia symptoms. This study provided a certain research basis for MRI features of brain structure and neuroendocrine changes in patients with first-episode schizophrenia.

Microstructural and Microvascular Alterations in Psychotic Spectrum Disorders: A Three-Compartment Intravoxel Incoherent Imaging and Free Water Model.

Microvascular and inflammatory mechanisms have been hypothesized to be involved in the pathophysiology of psychotic spectrum disorders (PSDs). However, data evaluating these hypotheses remain limited. We applied a three-compartment intravoxel incoherent motion free water imaging (IVIM-FWI) technique that estimates the perfusion fraction (PF), free water fraction (FW), and anisotropic diffusion of tissue (FAt) to examine microvascular and microstructural changes in gray and white matter in 55 young adults with a PSD compared to 37 healthy controls (HCs). We found significantly increased PF, FW, and FAt in gray matter regions, and significantly increased PF, FW, and decreased FAt in white matter regions in the PSD group versus HC. Furthermore, in patients, but not in the HC group, increased PF, FW, and FAt in gray matter and increased PF in white matter were significantly associated with poor performance on several cognitive tests assessing memory and processing speed. We additionally report significant associations between IVIM-FWI metrics and myo-inositol, choline, and N-acetylaspartic acid magnetic resonance spectroscopy imaging metabolites in the posterior cingulate cortex, which further supports the validity of PF, FW, and FAt as microvascular and microstructural biomarkers of PSD. Finally, we found significant relationships between IVIM-FWI metrics and the duration of psychosis in gray and white matter regions. The three-compartment IVIM-FWI model provides metrics that are associated with cognitive deficits and may reflect disease progression.

White matter and gray matter changes related to cognition in community populations.

Further studies are needed to improve the understanding of the pathological process underlying cognitive impairments. The purpose of this study is to investigate the global and topographic changes of white matter integrity and cortical structure related to cognitive impairments in a community-based population. A cross-sectional analysis was performed based on 995 subjects (aged 56.8 ± 9.1 years, 34.8% males) from the Shunyi study, a community-dwelling cohort. Cognitive status was accessed by a series of neurocognitive tests including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), category Verbal Fluency Test (VFT), Digit Span Test (DST), and Trail Making Tests A and B (TMT-A and TMT-B). Structural and diffusional MRI data were acquired. White matter integrity was assessed using fractional anisotropy (FA), mean diffusivity (MD), and peak width of skeletonized mean diffusivity (PSMD). Cortical surface area, thickness, and volume were measured using Freesurfer. Probabilistic tractography was further conducted to track the white matter fibers connecting to the cortical regions related to cognition. General linear models were used to investigate the association between brain structure and cognition. Global mean FA and MD were significantly associated with performances in VFT (FA, β 0.119, p < 0.001; MD, β -0.128, p < 0.001). Global cortical surface area, thickness, and volume were not related to cognitive scores. In tract-based spatial statistics analysis, disruptive white matter integrity was related to cognition impairment, mainly in visuomotor processing speed, semantic memory, and executive function (TMT-A and VFT), rather than verbal short-term memory and working memory (DST). In the whole brain vertex-wise analysis, surface area in the left orbitofrontal cortex, right posterior-dorsal part of the cingulate gyrus, and left central sulcus were positively associated with MMSE and MoCA scores, and the association were independent of the connecting white matter tract. Disrupted white matter integrity and regional cortical surface area were related to cognition in community-dwelling populations. The associations of cortical surface area and cognition were independent of the connecting white matter tract.

Behavioral variant frontotemporal dementia in patients with primary psychiatric disorder: A magnetic resonance imaging study.

The clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD) in patients with a history of primary psychiatric disorder (PPD) is challenging. PPD shows the typical cognitive impairments observed in patients with bvFTD. Therefore, the correct identification of bvFTD onset in patients with a lifetime history of PPD is pivotal for an optimal management. Twenty-nine patients with PPD were included in this study. After clinical and neuropsychological evaluations, 16 patients with PPD were clinically classified as bvFTD (PPD-bvFTD+), while in 13 cases clinical symptoms were associated with the typical course of the psychiatric disorder itself (PPD-bvFTD-). Voxel- and surface-based investigations were used to characterize gray matter changes. Volumetric and cortical thickness measures were used to predict the clinical diagnosis at a single-subject level using a support vector machine (SVM) classification framework. Finally, we compared classification performances of magnetic resonance imaging (MRI) data with automatic visual rating scale of frontal and temporal atrophy. PPD-bvFTD+ showed a gray matter decrease in thalamus, hippocampus, temporal pole, lingual, occipital, and superior frontal gyri compared to PPD-bvFTD- (p<.05, family-wise error-corrected). SVM classifier showed a discrimination accuracy of 86.2% in differentiating PPD patients with bvFTD from those without bvFTD. Our study highlights the utility of machine learning applied to structural MRI data to support the clinician in the diagnosis of bvFTD in patients with a history of PPD. Gray matter atrophy in temporal, frontal, and occipital brain regions may represent a useful hallmark for a correct identification of dementia in PPD at a single-subject level.

Altered Grey Matter-Brain Healthcare Quotient: Interventions of Olfactory Training and Learning of Neuroplasticity

Recent studies revealed that grey matter (GM) changes due to various training and learning experiences, using magnetic resonance imaging. In this study, we investigate the effect of psychological characteristics and attitudes toward training and learning on GM changes. Ninety participants were recruited and distributed into three groups: an olfactory training group that underwent 40 olfactory training sessions designed for odour classification tasks, a group classified for learning of neuroplasticity and brain healthcare using a TED Talk video and 28 daily brain healthcare messages, and a control group. Further, we assessed psychological characteristics, such as curiosity and personal growth initiatives. In the olfactory training group, we conducted a questionnaire survey on olfactory training regarding their interests and sense of accomplishment. In the olfactory training group, the GM change was significantly correlated with the sense of achievement and interest in training. The learning of neuroplasticity and brain healthcare group showed a significantly smaller 2-month GM decline than did the control group. The Curiosity and Exploration Inventory-II scores were significantly correlated with GM changes in both intervention groups only. In conclusion, our result suggested that training or learning with a sense of accomplishment, interest, and curiosity would lead to greater GM changes.

Neuroimaging features of depression-frailty phenotype in older adults: a pilot study.

Frailty and late-life depression (LLD) often coexist and share several structural brain changes. We aimed to study the joint effect LLD and frailty have on brain structure. Cross-sectional study. Academic Health Center. Thirty-one participants (14 LLD+Frail and 17 Never-depressed+Robust). LLD was diagnosed by a geriatric psychiatrist according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition for single episode or recurrent major depressive disorder without psychotic features. Frailty was assessed using the FRAIL scale (0-5), classifying subjects as robust (0), prefrail (1-2), and frail (3-5). Participants underwent T1-weighted magnetic resonance imaging in which covariance analysis of subcortical volumes and vertex-wise analysis of cortical thickness values were performed to access changes in grey matter. Participants also underwent diffusion tensor imaging in which tract-based spatial statistics was used with voxel-wise statistical analysis on fractional anisotropy and mean diffusion values to assess changes in white matter (WM). We found a significant difference in mean diffusion values (48,225 voxels; peak voxel: pFWER=0.005, MINI coord. (X,Y,Z) = -26,-11,27) between the LLD-Frail group and comparison group. The corresponding effect size (f=0.808) was large. We showed the LLD+Frailty group is associated with significant microstructural changes within WM tracts compared to Never-depressed+Robust individuals. Our findings indicate the possibility of a heightened neuroinflammatory burden as a potential mechanism underlying the co-occurrence of both conditions and the possibility of a depression-frailty phenotype in older adults.

The characteristics of brain structural remodeling in patients with unilateral vestibular schwannoma.

Brain structural remodeling alters related brain function. However, few studies have assessed morphological alterations of unilateral vestibular schwannoma (VS) patients. Therefore, this study examined the characteristics of brain structural remodeling in unilateral VS patients. We recruited 39 patients with unilateral VS (19 left, 20 right) and 24 matched normal controls (NCs). We obtained brain structural imaging data using 3T T1-weighted anatomical and diffusion tensor imaging scans. Then, we evaluated both gray and white matter (WM) changes using FreeSurfer software and tract-based spatial statistics, respectively. Furthermore, we constructed a structural covariance network to assess brain structural network properties and the connectivity strength between brain regions. Compared with NCs, VS patients showed cortical thickening in non-auditory areas (e.g., the left precuneus), especially left VS patients, along with reduced cortical thickness in the right superior temporal gyrus (auditory areas). VS patients also showed increased fractional anisotropy in extensive non-auditory-related WM (e.g., the superior longitudinal fasciculus), especially right VS patients. Both left and right VS patients showed increased small-worldness (more efficient information transfer). Left VS patients had a single reduced-connectivity subnetwork in contralateral temporal regions (right-side auditory areas), but increased connectivity between some non-auditory regions (e.g., left precuneus and left temporal pole). VS patients exhibited greater morphological alterations in non-auditory than auditory areas, with structural reductions seen in related auditory areas and a compensatory increase in non-auditory areas. Left and right VS patients show differential patterns of brain structural remodeling. These findings provide a new perspective on the treatment and postoperative rehabilitation of VS.

Transcranial direct current stimulation (tDCS) in depression induces structural plasticity

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique involving administration of well-tolerated electrical current to the brain through scalp electrodes. TDCS may improve symptoms in neuropsychiatric disorders, but mixed results from recent clinical trials underscore the need to demonstrate that tDCS can modulate clinically relevant brain systems over time in patients. Here, we analyzed longitudinal structural MRI data from a randomized, double-blind, parallel-design clinical trial in depression (NCT03556124, N = 59) to investigate whether serial tDCS individually targeted to the left dorso-lateral prefrontal cortex (DLPFC) can induce neurostructural changes. Significant (FWEc p < 0.05) treatment-related gray matter changes were observed with active high-definition (HD) tDCS relative to sham tDCS within the left DLPFC stimulation target. No changes were observed with active conventional tDCS. A follow-up analysis within individual treatment groups revealed significant gray matter increases with active HD-tDCS in brain regions functionally connected with the stimulation target, including the bilateral DLPFC, bilateral posterior cingulate cortex, subgenual anterior cingulate cortex, and the right hippocampus, thalamus and left caudate brain regions. Integrity of blinding was verified, no significant differences in stimulation-related discomfort were observed between treatment groups, and tDCS treatments were not augmented by any other adjunct treatments. Overall, these results demonstrate that serial HD-tDCS leads to neurostructural changes at a predetermined brain target in depression and suggest that such plasticity effects may propagate over brain networks.

Local synchronicity in dopamine-rich caudate nucleus influences Huntington's disease motor phenotype.

Structural grey and white matter changes precede the manifestation of clinical signs of Huntington's disease by many years. Conversion to clinically manifest disease therefore likely reflects not merely atrophy but a more widespread breakdown of brain function. Here, we investigated the structure-function relationship close to and after clinical onset, in important regional brain hubs, particularly caudate nucleus and putamen, which are central to maintaining normal motor behaviour. In two independent cohorts of patients with premanifest Huntington's disease close to onset and very early manifest Huntington's disease (total n = 84; n = 88 matched controls), we used structural and resting state functional MRI. We show that measures of functional activity and local synchronicity within cortical and subcortical regions remain normal in the premanifest Huntington's disease phase despite clear evidence of brain atrophy. In manifest Huntington's disease, homeostasis of synchronicity was disrupted in subcortical hub regions such as caudate nucleus and putamen, but also in cortical hub regions, for instance the parietal lobe. Cross-modal spatial correlations of functional MRI data with receptor/neurotransmitter distribution maps showed that Huntington's disease-specific alterations co-localize with dopamine receptors D1 and D2, as well as dopamine and serotonin transporters. Caudate nucleus synchronicity significantly improved models predicting the severity of the motor phenotype or predicting the classification into premanifest Huntington's disease or motor manifest Huntington's disease. Our data suggest that the functional integrity of the dopamine receptor-rich caudate nucleus is key to maintaining network function. The loss of caudate nucleus functional integrity affects network function to a degree that causes a clinical phenotype. These insights into what happens in Huntington's disease could serve as a model for what might be a more general relationship between brain structure and function in neurodegenerative diseases in which other brain regions are vulnerable.

White and gray matter alterations in de novo PD patients: which matter most?

This paper aimed to identify white matter (WM) and gray matter (GM) abnormalities in a sample of early PD patients, and their correlations with motor and non-motor symptom severity. We enrolled 62 de novo PD patients and 31 healthy subjects. Disease severity and non-motor symptom burden were assessed by the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale, respectively. Cognitive performance was assessed using Montreal Cognitive Assessment and Frontal Assessment Battery. All subjects underwent a 3-Tesla MRI protocol. MRI analyses included tract-based spatial statistics, cortical thickness, and subcortical and cerebellar volumetry. In comparison to control subjects, PD patients exhibited lower fractional anisotropy and higher mean, axial, and radial diffusivity in most WM bundles, including corticospinal tracts, the internal and external capsule, the anterior and posterior thalamic radiations, the genu and body of the corpus callosum, cerebellar peduncles, and superior and inferior longitudinal and fronto-occipital fasciculi. Correlations between Montreal Cognitive Assessment scores and fractional anisotropy values in the right posterior thalamic radiation, left superior corona radiata, right inferior-fronto-occipital fasciculus, left inferior longitudinal fasciculus, bilateral anterior thalamic radiations, and bilateral superior longitudinal fasciculi were found. Smaller cerebellar volumes in early PD patients in the left and right crus I were also found. No GM changes were present in subcortical or cortical regions. The combined evaluation of WM and GM in the same patient sample demonstrates that WM microstructural abnormalities precede GM structural changes in early PD patients.

Apathy is associated with striatal atrophy and cognitive impairment in cerebral small vessel disease

BackgroundApathy has been considered a common neuropsychiatric symptom and an important contributor to cognitive impairment in cerebral small vessel disease (SVD). However, the mechanism leading to apathy in SVD and the process whereby apathy promotes cognitive impairments remain largely unknown. We aimed to explore the relationship between apathy, cognition, and structural changes of deep grey matter (DGM) in SVD patients. MethodsParticipants were screened for SVD, completed assessments of apathy cognition, underwent magnetic resonance imaging (MRI) scanning, and then stratified into apathy and non-apathy groups. We used region of interest (ROI)-based, voxel-based volume, and vertex-based shape analyses to compare DGM structures between study groups. Using linear regression analysis, we examined the association between apathy, structural changes, and cognition, followed by a mediation analysis of these factors. ResultsA total of sixty-four SVD participants were included, with thirty in the apathy group and thirty-four in the non-apathy group. Intergroup comparison showed significantly lower volumes in bilateral caudate, right putamen, and pallidum and smaller vertex-based shapes in the right caudate and pallidum in participants with apathy compared to those without apathy. Apathy was associated with the striatal atrophy (i.e., lower volumes and smaller shape) and independently contributed to cognitive impairments in SVD. However, the above structural differences did not mediate the association between apathy and cognitive impairments. ConclusionThese results highlight the important role of striatal atrophy in apathy in SVD and call for additional studies to explore the relationship between apathy, cognition, and DGM.

Diffusion MRI approaches for investigating microstructural complexity in a rat model of traumatic brain injury

Our study explores the potential of conventional and advanced diffusion MRI techniques including diffusion tensor imaging (DTI), and single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD) to investigate complex microstructural changes following severe traumatic brain injury in rats at a chronic phase. Rat brains after sham-operation or lateral fluid percussion (LFP) injury were scanned ex vivo in a 9.4 T scanner. Our region-of-interest-based approach of tensor-, and SS3T-CSD derived fixel-, 3-tissue signal fraction maps were sensitive to changes in both white matter (WM) and grey matter (GM) areas. Tensor-based measures, such as fractional anisotropy (FA) and radial diffusivity (RD), detected more changes in WM and GM areas as compared to fixel-based measures including apparent fiber density (AFD), peak FOD amplitude and primary fiber bundle density, while 3-tissue signal fraction maps revealed distinct changes in WM, GM, and phosphate-buffered saline (PBS) fractions highlighting the complex tissue microstructural alterations post-trauma. Track-weighted imaging demonstrated changes in track morphology including reduced curvature and average pathlength distal from the primary lesion in severe TBI rats. In histological analysis, changes in the diffusion MRI measures could be associated to decreased myelin density, loss of myelinated axons, and increased cellularity, revealing progressive microstructural alterations in these brain areas five months after injury. Overall, this study highlights the use of combined conventional and advanced diffusion MRI measures to obtain more precise insights into the complex tissue microstructural alterations in chronic phase of severe brain injury.

Changes in brain gray matter volume in nasopharyngeal carcinoma patients after radiotherapy in long-term follow-up

ObjectivesThe aim of this study was to examine the changes in gray matter in nasopharyngeal carcinoma patients with normal hearing (Group 1) and nasopharyngeal carcinoma patients with hearing loss (Group 2) after radiotherapy using voxel-based morphological analysis and to analyze the relationship with the radiation doses of the temporal lobe. Methods21 patients in Group 1, 14 patients in Group 2, and 21 healthy volunteers were selected. All participants underwent an otologic examination and three-dimensional magnetization preparatory rapid acquisition gradient echo sequence scan. The correlation between the variation of whole brain gray matter volume and the doses of the temporal lobe was analyzed by Data Processing & Analysis for Brain Imaging software. ResultsCompared with the normal control group, the brain areas with reduced gray matter volume in nasopharyngeal carcinoma patients after radiotherapy were mainly in the left posterior cerebellar lobe (T = −8.797), left insular lobe (T = −7.96), and the right insular lobe (T = −6.632). Compared to Group 1, the brain areas of Group 2 patients with reduced gray matter volume were mainly in the left superior temporal gyrus (T = −2.366), left olfactory bulb (T = −2.52), left Rolandic operculum (T = −2.431), and right olfactory bulb (T = −3.100). Compared with Group 1, the brain areas of Group 2 patients with increased gray matter volume were mainly in the left calcarine sulcus (T=3.425) and right calcarine sulcus (T=3.169). There were no correlations between the changes of brain gray matter volume and the radiation doses of the temporal lobe in both Group 1 and Group 2. ConclusionsThe radiotherapy may cause the changes of brain areas associated with cognitive function in nasopharyngeal carcinoma in a long-term follow-up. At the same time, nasopharyngeal carcinoma patients with the radiation-induced hearing loss had abnormal gray matter volumes in the auditory center and other sensory centers. Our findings might provide new understanding into the pathogenesis of radiation-induced brain damage in normal-appearing brain tissue. Yet this exploratory study should be taken with caution.

Age-dependent changes in brain iron deposition and volume in deep gray matter nuclei using quantitative susceptibility mapping

BackgroundMicrostructural changes in deep gray matter (DGM) nuclei are related to physiological behavior, cognition, and memory. Therefore, it is critical to study age-dependent trajectories of biomarkers in DGM nuclei for understanding brain development and aging, as well as predicting cognitive or neurodegenerative diseases. ObjectivesWe aimed to (1) characterize age-dependent trajectories of mean susceptibility, adjusted volume, and total iron content simultaneously in DGM nuclei using quantitative susceptibility mapping (QSM); (2) examine potential contributions of sex related effects to the different age-dependence trajectories of volume and iron deposition; and (3) evaluate the ability of brain age prediction by combining mean magnetic susceptibility and volume of DGM nuclei. MethodsMagnetic susceptibilities and volumetric values of DGM nuclei were obtained from 220 healthy participants (aged 10–70 years) scanned on a 3T MRI system. Regions of interest (ROIs) were drawn manually on the QSM images. Univariate regression analysis between age and each of the MRI measurements in a single ROI was performed. Pearson correlation coefficients were calculated between magnetic susceptibility and adjusted volume in a single ROI. The statistical significance of sex differences in age-dependent trajectories of magnetic susceptibilities and adjusted volumes were determined using one-way ANCOVA. Multiple regression analysis was used to evaluate the ability to estimate brain age using a combination of the mean susceptibilities and adjusted volumes in multiple DGM nuclei. ResultsMean susceptibility and total iron content increased linearly, quadratically, or exponentially with age in all six DGM nuclei. Negative linear correlation was observed between adjusted volume and age in the head of the caudate nucleus (CN; R2 = 0.196, p < 0.001). Quadratic relationships were found between adjusted volume and age in the putamen (PUT; R2 = 0.335, p < 0.001), globus pallidus (GP; R2 = 0.062, p = 0.001), and dentate nucleus (DN; R2 = 0.077, p < 0.001). Males had higher mean magnetic susceptibility than females in the PUT (p = 0.001), red nucleus (RN; p = 0.002), and substantia nigra (SN; p < 0.001). Adjusted volumes of the CN (p < 0.001), PUT (p = 0.030), GP (p = 0.007), SN (p = 0.021), and DN (p < 0.001) were higher in females than those in males throughout the entire age range (10–70 years old). The total iron content of females was higher than that of males in the CN (p < 0.001), but lower than that of males in the PUT (p = 0.014) and RN (p = 0.043) throughout the entire age range (10–70 years old). Multiple regression analyses revealed that the combination of the mean susceptibility value of the PUT, and the volumes of the CN and PUT had the strongest associations with brain age (R2 = 0.586). ConclusionsQSM can be used to simultaneously investigate age- and sex- dependent changes in magnetic susceptibility and volume of DGM nuclei, thus enabling a comprehensive understanding of the developmental trajectories of iron accumulation and volume in DGM nuclei during brain development and aging.