Threshold-free Cluster Enhancement Research Articles

Cerebellar functional connectivity relates to lower urinary tract function: A 7 Tesla study.

The objective of this study is to explore the functional connectivity (FC) of the cerebellum during the storage phase of micturition, through detecting spontaneous blood-oxygen-level dependent signal between the cerebellum and different brain regions using a high-resolution 7 Tesla magnetic resonance imaging (MRI) scanner. We recruited healthy individuals with no reported history of neurological disease or lower urinary tract (LUT) symptoms. Participants were asked to drink 500 mL of water and then empty their bladders before entering the MRI scanner. They underwent a T1-weighted anatomical scan, followed by an initial (8 min) empty bladder resting state functional MRI (rs-fMRI) acquisition. Once subjects felt the desire to void, a second rs-fMRI scan was obtained, this time with a full bladder state. We established a priori cerebellar regions of interest from the literature to perform seed-to-voxel analysis using nonparametric statistics based on the Threshold Free Cluster Enhancement method and utilized a voxel threshold of p < 0.05. Twenty individuals (10 male and 10 female) with a median age of 25 years (IQR [3.5]) participated in the study. We placed 31 different 4-mm spherical seeds throughout the cerebellum and assessed their FC with the remainder of the brain. Three of these (left cerebellar tonsil, right posterolateral lobe, right posterior lobe) showed significant differences in connectivity when comparing scans conducted with a full bladder to those with an empty bladder. Additionally, we observed sex differences in FC, with connectivity being higher in women during the empty bladder condition. Our initial findings reveal, for the first time, that the connectivity of the cerebellar network is modulated by bladder filling and is associated with LUT function. Unraveling the cerebellum's role in bladder function lays the foundation for a more comprehensive understanding of urinary pathologies affecting this area.

Emotion-related impulsivity and suicidal ideation and behavior in schizophrenia spectrum disorder: a pilot fMRI study.

Suicidal ideation and behavior (SIB) are serious problems in people with schizophrenia spectrum disorders (SSD). Nevertheless, relatively little is known about the circuitry underlying SIB in SSD. Recently, we showed that elevated emotional impulsivity (urgency) was associated with SIB in SSD. Here we examined brain activity in people with SSD and elevated SIB. We tested 16 people with SSD who had low SIB and 14 people with high SIB on a task in which emotion regulation in response to affective pictures was implicitly manipulated using spoken sentences. Thus, there were neutral pictures preceded by neutral statements (NeutNeut condition), as well as negative pictures preceded by either negative (NegNeg) or neutral (NeutNeg) statements. After each picture, participants rated how unpleasant each picture was for them. The latter two conditions were compared to the NeutNeut condition. We compared the emotion-regulated condition (NeutNeg) to the unregulated condition (NeutNeut). Statistics were threshold using threshold free cluster enhancement (TFCE). People in the low SIB group showed higher activation in this contrast in medial frontal gyrus, right rostral anterior cingulate, bilateral superior frontal gyrus/DLPFC, and right middle cingulate gyrus, as well as right superior temporal gyrus. This study provides clues to the neural basis of SIB in SSD as well as underlying mechanisms.

Acute neural effects of the mood stabiliser lamotrigine on emotional processing in healthy volunteers: a randomised control trial.

Lamotrigine is an effective mood stabiliser, largely used for the management and prevention of depression in bipolar disorder. The neuropsychological mechanisms by which lamotrigine acts to relieve symptoms as well as its neural effects on emotional processing remain unclear. The primary objective of this current study was to investigate the impact of an acute dose of lamotrigine on the neural response to a well-characterised fMRI task probing implicit emotional processing relevant to negative bias. 31 healthy participants were administered either a single dose of lamotrigine (300 mg, n = 14) or placebo (n = 17) in a randomized, double-blind design. Inside the 3 T MRI scanner, participants completed a covert emotional faces gender discrimination task. Brain activations showing significant group differences were identified using voxel-wise general linear model (GLM) nonparametric permutation testing, with threshold free cluster enhancement (TFCE) and a family wise error (FWE)-corrected cluster significance threshold of p < 0.05. Participants receiving lamotrigine were more accurate at identifying the gender of fearful (but not happy or angry) faces. A network of regions associated with emotional processing, including amygdala, insula, and the anterior cingulate cortex (ACC), was significantly less activated in the lamotrigine group compared to the placebo group across emotional facial expressions. A single dose of lamotrigine reduced activation in limbic areas in response to faces with both positive and negative expressions, suggesting a valence-independent effect. However, at a behavioural level lamotrigine appeared to reduce the distracting effect of fear on face discrimination. Such effects may be relevant to the mood stabilisation effects of lamotrigine.

Dynamic Mechanism of Cerebral Venous Disruption: Longitudinal Evidence From a Community-Based Cohort.

This study aims to investigate the temporal and spatial patterns of structural brain injury related to deep medullary veins (DMVs) damage. This is a longitudinal analysis of the population-based Shunyi cohort study. Baseline DMVs numbers were identified on susceptibility-weighted imaging. We assessed vertex-wise cortex maps and diffusion maps at both baseline and follow-up using FSL software and the longitudinal FreeSurfer analysis suite. We performed statistical analysis of global measurements and voxel/vertex-wise analysis to explore the relationship between DMVs number and brain structural measurements. A total of 977 participants were included in the baseline, of whom 544 completed the follow-up magnetic resonance imaging (age 54.97±7.83 years, 32% men, mean interval 5.56±0.47 years). A lower number of DMVs was associated with a faster disruption of white matter microstructural integrity, presented by increased mean diffusivity and radial diffusion (β=0.0001 and SE=0.0001 for both, P=0.04 and 0.03, respectively), in extensive deep white matter (threshold-free cluster enhancement P<0.05, adjusted for age and sex). Of particular interest, we found a bidirectional trend association between DMVs number and change in brain volumes. Specifically, participants with mild DMVs disruption showed greater cortical enlargement, whereas those with severe disruption exhibited more significant brain atrophy, primarily involving clusters in the frontal and parietal lobes (multiple comparison corrected P<0.05, adjusted for age, sex, and total intracranial volume). Our findings posed the dynamic pattern of brain parenchymal lesions related to DMVs injury, shedding light on the interactions and chronological roles of various pathological mechanisms.

Cortical grey matter volume differences in children with developmental coordination disorder compared to typically developing children.

The cause of Developmental Coordination Disorder (DCD) is unknown, but neuroimaging evidence suggests that DCD may be related to altered brain development. Children with DCD show less structural and functional connectivity compared to typically developing (TD) children, but few studies have examined cortical volume in children with DCD. The purpose of this study was to investigate cortical grey matter volume using voxel-based morphometry (VBM) in children with DCD compared to TD children. This cross-sectional study was part of a larger randomized-controlled trial (ClinicalTrials.gov ID: NCT02597751) that involved various MRI scans of children with/without DCD. This paper focuses on the anatomical scans, performing VBM of cortical grey matter volume in 30 children with DCD and 12 TD children. Preprocessing and VBM data analysis were conducted using the Computational Anatomy Tool Box-12 and a study-specific brain template. Differences between DCD and TD groups were assessed using a one-way ANOVA, controlling for total intracranial volume. Regression analyses examined if motor and/or attentional difficulties predicted grey matter volume. We used threshold-free cluster enhancement (5,000 permutations) and set an alpha level of 0.05. Due to the small sample size, we did not correct for multiple comparisons. Compared to the TD group, children with DCD had significantly greater grey matter in the left superior frontal gyrus. Lower motor scores (meaning greater impairment) were related to greater grey matter volume in left superior frontal gyrus, frontal pole, and right middle frontal gyrus. Greater grey matter volume was also significantly correlated with higher scores on the Conners 3 ADHD Index in the left superior frontal gyrus, superior parietal lobe, and precuneus. These results indicate that greater grey matter volume in these regions is associated with poorer motor and attentional skills. Greater grey matter volume in the left superior frontal gyrus in children with DCD may be a result of delayed or absent healthy cortical thinning, potentially due to altered synaptic pruning as seen in other neurodevelopmental disorders. These findings provide further support for the hypothesis that DCD is related to altered brain development.

Altered functional-structural coupling may predict Parkinson's patient's depression.

We aimed to elucidate the neurobiological basis of depression in Parkinson's disease and identify potential imaging markers for depression in patients with Parkinson's disease. We recruited 43 normal controls (NC), 46 depressed Parkinson's disease patients (DPD) and 56 non-depressed Parkinson's disease (NDPD). All participants underwent routine T2-weighted, T2Flair, and resting-state scans on the same 3.0T magnetic resonance imaging (MRI) scanner at our hospital. Pre-processing includes calculating surface-based Regional Homogeneity (2DReHo) and cortical thickness. Then we defined the correlation coefficient between 2DReHo and cortical thickness as the functional-structural coupling index. Between-group comparisons were conducted on the Fisher's Z-transformed correlation coefficients. To identify specific regions of decoupling, the 2DReHo for each participant were divided by cortical thickness at each vertex, followed by threshold-free cluster enhancement (TFCE) multiple comparison correction. Binary logistic regression analysis was performed with DPD as the dependent variable, and significantly altered indicators as the independent variables. Receiver operating characteristic curves were constructed to compare the diagnostic performance of individual predictors and combinations using R and MedCalc software. DPD patients exhibited a significantly lower whole-brain functional-structural coupling index than NDPD patients and NC. Abnormal functional-structural coupling was primarily observed in the left inferior parietal lobule and right primary and early visual cortices in DPD patients. Receiver operating characteristic analysis revealed that the combination of cortical functional-structural coupling, surface-based ReHo, and thickness had the best diagnostic performance, achieving a sensitivity of 65% and specificity of 77.7%. This is the first study to explore the relationship between functional and structural changes in DPD patients and evaluate the diagnostic performance of these altered correlations to predict depression in Parkinson's disease patients. We posit that these changes in functional-structural relationships may serve as imaging biomarkers for depression in Parkinson's disease patients, potentially aiding in the classification and diagnosis of Parkinson's disease. Additionally, our findings provide functional and structural imaging evidence for exploring the neurobiological basis of depression in Parkinson's disease.

Efficacy Assessment of Cerebral Perfusion Augmentation Through Functional Connectivity in an Acute Canine Stroke Model.

Ischemic stroke disrupts functional connectivity within the brain's resting-state networks (RSNs), impacting recovery. This study evaluates the effects of NEH (Norepinephrine and Hydralazine), a cerebral perfusion augmentation therapy, on RSN integrity in a hyper-acute canine stroke model. Fifteen adult purpose-bred mongrel canines, divided into treatment and control (natural history) groups, underwent endovascular induction of acute middle cerebral artery occlusion (MCAO). Post-occlusion, the treatment group received intra-arterial Norepinephrine (0.1-1.52 μg/kg/min, adjusted for 25-45 mmHg above baseline mean arterial pressure) and Hydralazine (20mg). Resting-state fMRI data were acquired with a 3.0 T scanner using a BOLD-sensitive EPI sequence (TR/TE=1400 ms/20ms, 2.5 mm slices, 300 temporal positions). Preprocessing included motion correction, spatial smoothing (2.5 mm FWHM), and high-pass filtering (0.01 Hz cutoff). Functional connectivity within RSNs were analyzed through group-level independent component analysis (ICA) and weighted whole-brain ROI-to-ROI connectome, pre-and post-MCAO. NEH therapy significantly maintained connectivity post-MCAO in the Higher-order Visual and Parietal RSNs, as evidenced by thresholded statistical mapping (TFCE p-corr > 0.95). However, this preservation was network-dependent, with no significant changes in the Primary Visual and Sensorimotor networks. NEH demonstrates potential as a proof-of-concept therapy for maintaining RSN functional connectivity following ischemic stroke, emphasizing the therapeutic promise of perfusion augmentation. These insights reinforce the role of functional connectivity as a measurable endpoint for stroke intervention efficacy, suggesting clinical translatability for patients with insufficient collateral circulation. NEH＝ Norepinephrine and Hydralazine; RSN＝ Resting-State Network; ICA = Independent Component Analysis; rsfMRI = resting-state Functional Magnetic Resonance Imaging; MCAO = Middle Cerebral Artery Occlusion; TFCE = Threshold-Free Cluster Enhancement.

Resting-state functional magnetic resonance imaging: features of statistical processing of ROI-analysis data

BACKGROUND: In many works, to study intra- and inter-network connections, a method for constructing networks is used — ROI-analysis (region of interest analysis). The conflicting results obtained when assessing brain connectivity using ROI-analysis can be explained by methodological differences associated with the statistical processing of fMRI data. In this regard, it is relevant to conduct a study with a comparative assessment of various statistical methods of ROI-analysis in processing resting state fMRI data.&#x0D; AIM: to assess the functional connectivity of the main resting state networks of the brain using ROI-analysis using various statistical approaches.&#x0D; MATERIALS AND METHODS: We analyzed data from 15 resting-state fMRI studies of the brain of patients without neurological and mental pathology. fMRI scanning was performed on a Phillips Ingenia 1.5 T scanner using a gradient echo-planar imaging (EPI-BOLD) sequence. ROI-analysis was used to build networks. Statistical data processing was performed using methods: functional network connectivity, randomization/permutation spatial pairwise clustering statistics, and threshold-free cluster enhancement.&#x0D; RESULTS: The number of connections between the structures of brain networks recorded using the method of functional network connectivity is 280, spatial pairwise clustering — 186, threshold-free cluster enhancement — 182. An interesting fact is that negative connections were identified only when using parametric statistics.&#x0D; CONCLUSION: A comparative assessment of methods for statistical processing of fMRI data during ROI-analysis was carried out. The functional network connectivity method based on multivariate parametric statistics turned out to be more informative than randomization/permutation spatial pairwise clustering statistics and the method based on threshold-free cluster enhancement. Despite the growing popularity in recent years of resting-state fMRI in the study of functional activity and connectivity of the brain, there are no standardized algorithms for constructing networks of the brain.

207 Intraoperative Functional Re-mapping Unveils Evolving Patterns of Cortical Plasticity

INTRODUCTION: Diffuse low-grade gliomas (DLGG) induce a compensatory modulation of the anatomo-functional architecture, making this kind of brain tumours an ideal lesion model to study the dynamics of neuroplasticity. Direct electrostimulation (DES) mapping is a well-tried procedure used during awake resection surgeries to spare cortical epicenters which are critical for a range of functions. Because DLGG is a chronic disease, it inevitably relapses years after the initial surgery, and thus requires a second surgery to reduce tumour volume again. METHODS: We capitalized on a series of 101 DLGG patients who benefited from two DES-guided neurosurgeries usually spaced several years apart, resulting in a DES dataset of 2082 cortical sites. We used a multi-step approach to generate probabilistic neuroplasticity maps that reflected the dynamic rearrangements of cortical mappings from one surgery to another, both at the population and individual-level. RESULTS: Voxel-wise neuroplasticity maps revealed regions with a high potential of evolving reorganizations, including the supplementary motor area (SMA), the dorsolateral prefrontal cortex (dlPFC), the anterior ventral premotor cortex (vPMC) and the middle superior temporal gyrus (STG). Parcel-wise neuroplasticity maps confirmed this potential for the dlPFC, the anterior and the ventral precentral gyrus. A series of clustering analyses revealed a topological migration of clusters, especially within the left dlPFC and STG (language sites); the left vPMC (speech arrest/dysarthria sites) and the right SMA (negative motor response sites). At the individual level, these dynamic changes were confirmed for the dlPFC (bilateral), the left vPMC and the anterior left STG (threshold free cluster enhancement, 5000 permutations, family-wise-error-corrected). CONCLUSIONS: Our results provide a critical insight into the dynamic potential of DLGG-induced continuing rearrangements of the cerebral cortex, with considerable implications for re-operations.

Microstructural abnormality of white matter tracts in rheumatoid arthritis

BackgroundStructural and functional brain imaging studies have reported abnormalities of gray matter morphology and functional activities in patients with rheumatoid arthritis (RA). However, it is largely unknown whether patients with RA show alterations of white matter microstructural organization. ObjectivesTo automatically identify alteration of white matter microstructure in patients with RA and further examine how this alteration associates with clinical characteristics. MethodsThis single-institutional prospective study included 66 participants (33 patients with RA [52 ± 9 years, 29 women] and 33 sex/age-matched healthy controls [53 ± 12 years, 27 women]), who underwent diffusion MRI scan from January 2021 to December 2021. The white matter microstructure was assessed using fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Voxelwise analyses were conducted on white matter skeleton using an automated, observer-independent tract-based spatial statistics analysis. The relationship between white matter microstructural alterations and clinical and neuropsychological variables was evaluated using correlation analysis. ResultsCompared with healthy controls, patients with RA exhibited lower fractional anisotropy in several major white matter tracts (threshold-free cluster enhancement at P < 0.05 for multiple comparison correction, permutation test), involving the forceps minor, bilateral inferior fronto-occipital fasciculus, bilateral anterior thalamic radiation, and bilateral uncinate fasciculus. Lower fractional anisotropy values in the patients with RA were significantly associated with pain-related assessments, including tender joint count (r = -0.43, P = 0.015), Clinical Disease Activity Index score (r = -0.36, P = 0.049), pain severity rated through visual analogue scale (r = -0.45, P = 0.012), and Simplified Disease Activity Index score (r = -0.36, P = 0.045). No significant group difference was found in mean diffusivity, axial diffusivity, and radial diffusivity. ConclusionsWe report the first anatomical evidence for aberrant microstructure organization of several major white matter tracts and its associations with pain processing in patients with rheumatoid arthritis.

Plasma Apo-E mediated corticospinal tract abnormalities and suicidality in patients with major depressive disorder.

This study aims to explore the link between Apo-E, brain white matter, and suicide in patients with major depressive disorder (MDD) to investigate the potential neuroimmune mechanisms of Apo-E that may lead to suicide. Thirty-nine patients with MDD (22 patients with suicidality) and 57 age, gender, and education-matched healthy controls participated in this study, provided plasma Apo-E samples, and underwent diffusion tensor imaging scans. Plasma Apo-E levels and white matter microstructure were analyzed among the MDD with suicidality, MDD without suicidality, and HC groups using analysis of variance with post hoc Bonferroni correction and tract-based spatial statistics (TBSS) with threshold-free cluster enhancement correction. Mediation analysis investigated the relationship between Apo-E, brain white matter, and suicidality in MDD. The MDD with suicidality subgroup had higher depressive and suicide scores, longer disease course, and lower plasma Apo-E levels than MDD without suicidality. TBSS revealed that the MDD non-suicide subgroup showed significantly increased mean diffusivity in the left corticospinal tract and body of the left corpus callosum, as well as increased axial diffusivity in the left anterior corona radiata and the right posterior thalamic radiation compared to the suicidal MDD group. The main finding was that the increased MD of the left corticospinal tract contributed to the elevated suicide score, with Apo-E mediating the effect. Preliminary result that Apo-E's mediating role between the left corticospinal tract and the suicide factor suggests the neuroimmune mechanism of suicide in MDD. The study was registered on ClinicalTrials.gov (NCT03790085).

MRI Assessment of Cerebral White Matter Microvascular Hemodynamics Across the Adult Lifespan.

Changes in cerebral hemodynamics with aging are important for understanding age-related variation in neuronal health. While many prior studies have focused on gray matter, less is known regarding white matter due in part to measurement challenges related to the lower vascular density in white matter. To investigate the impact of age and sex on white matter hemodynamics in a Human Connectome Project in Aging (HCP-A) cohort using tract-based spatial statistics (TBSS). Retrospective cross-sectional. Six hundred seventy-eight typically aging individuals (381 female), aged 36-100 years. Multi-delay pseudo-continuous arterial spin labeling (ASL) and diffusion-weighted pulsed-gradient spin-echo echo planar imaging sequences at 3.0 T. A skeleton of mean fractional anisotropy (FA) was produced using TBSS. This skeleton was used to project ASL-derived cerebral blood flow (CBF) and arterial transit time (ATT) measures onto white matter tracts. General linear models were applied to white matter FA, CBF, and ATT maps, while covarying for age and sex. Threshold-free cluster enhancement multiple comparisons correction was performed for the effects of age and sex, thresholded at PFWE < 0.05. CBF, ATT, and FA were compared between sex for each tract using analysis of covariance, with multiple comparisons correction for the number of tracts at PFDR < 0.05. Significantly lower white matter CBF and significantly prolonged white matter ATTs were associated with older age. These effects were widespread across tracts for ATT. Significant (PFDR < 0.05) sex differences in ATT were observed across all tracts, and significant sex differences in CBF were observed in all tracts except the bilateral uncinate fasciculus. Females demonstrated significantly higher CBF compared to males across the lifespan. Few tracts demonstrated significant sex differences in FA. This study identified significant sex- and age-associated differences in white matter hemodynamics across tracts. 3 TECHNICAL EFFICACY: Stage 3.

The effects of cannabis abstinence on cognition and resting state network activity in people with multiple sclerosis: A preliminary study

We previously reported that people with multiple sclerosis (pwMS) who have been using cannabis frequently over many years can have significant cognitive improvements accompanied by concomitant task-specific changes in brain activation following 28 days of cannabis abstinence. We now hypothesize that the default Mode Network (DMN), known to modulate cognition, would also show an improved pattern of activation align with cognitive improvement following 28 days of drug abstinence. Thirty three cognitively impaired pwMS who were frequent cannabis users underwent a neuropsychological assessment and fMRI at baseline. Individuals were then assigned to a cannabis continuation (CC, n = 15) or withdrawal (CW, n = 18) group and the cognitive and imaging assessments were repeated after 28 days. Compliance with cannabis withdrawal was checked with regular urine monitoring. Following acquisition of resting state fMRI (rs-fMRI), data were processed using independent component analysis (ICA) to identify the DMN spatial map. Between and within group analyses were carried out using dual regression for voxel-wise comparisons of the DMN. Clusters of voxels were considered statistically significant if they survived threshold-free cluster enhancement (TFCE) correction at p < 0.05. The two groups were well matched demographically and neurologically at baseline. The dual regression analysis revealed no between group differences at baseline in the DMN. By day 28, the CW group in comparison to the CC group had increased activation in the left posterior cingulate, and right, angular gyrus (p < 0.05 for both, TFCE). A within group analysis for the CC group revealed no changes in resting state (RS) networks. Within group analysis of the CW group revealed increased activation at day 28 versus baseline in the left posterior cingulate, right angular gyrus, left hippocampus (BA 36), and the right medial prefrontal cortex (p < 0.05). The CW group showed significant improvements in multiple cognitive domains. In summary, our study revealed that abstaining from cannabis for 28 days reverses activation of DMN activity in pwMS in association with improved cognition across several domains.

Characterization of dynamic patterns of human fetal to neonatal brain asymmetry with deformation-based morphometry.

Despite established knowledge on the morphological and functional asymmetries in the human brain, the understanding of how brain asymmetry patterns change during late fetal to neonatal life remains incomplete. The goal of this study was to characterize the dynamic patterns of inter-hemispheric brain asymmetry over this critically important developmental stage using longitudinally acquired MRI scans. Super-resolution reconstructed T2-weighted MRI of 20 neurotypically developing participants were used, and for each participant fetal and neonatal MRI was acquired. To quantify brain morphological changes, deformation-based morphometry (DBM) on the longitudinal MRI scans was utilized. Two registration frameworks were evaluated and used in our study: (A) fetal to neonatal image registration and (B) registration through a mid-time template. Developmental changes of cerebral asymmetry were characterized as (A) the inter-hemispheric differences of the Jacobian determinant (JD) of fetal to neonatal morphometry change and the (B) time-dependent change of the JD capturing left-right differences at fetal or neonatal time points. Left-right and fetal-neonatal differences were statistically tested using multivariate linear models, corrected for participants' age and sex and using threshold-free cluster enhancement. Fetal to neonatal morphometry changes demonstrated asymmetry in the temporal pole, and left-right asymmetry differences between fetal and neonatal timepoints revealed temporal changes in the temporal pole, likely to go from right dominant in fetal to a bilateral morphology in neonatal timepoint. Furthermore, the analysis revealed right-dominant subcortical gray matter in neonates and three clusters of increased JD values in the left hemisphere from fetal to neonatal timepoints. While these findings provide evidence that morphological asymmetry gradually emerges during development, discrepancies between registration frameworks require careful considerations when using DBM for longitudinal data of early brain development.

Effects of Physical Activity, Vascular Burden and Clinical Diagnosis on White Matter Integrity

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. Both degenerative and vascular pathology tend to contribute to dementia as AD coexists with single or multiple cardiovascular risk factors (vascular burden). Modifiable lifestyle factor such as physical activity has been associated with lower vascular burden (VB) and a lower risk of dementia. To test whether physical activity characterised as being inactive or active helped preserve white matter microstructure in a sample consisting of healthy controls and patients from the clinical AD continuum (mild cognitive impairment to dementia) with either low or high VB.Method213 participants were recruited from three memory clinics and were classified as being either physically active (n = 113) or inactive (n = 100) based on the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) questionnaire. Voxel‐wise tract‐based spatial statistics (TBSS) was carried out using a set of 5000 permutations and threshold‐free cluster enhancement (TFCE) to find significant clusters for fractional anisotropy (FA), axial diffusivity (AxD), mean diffusivity (MD) and radial diffusivity (RD).ResultParticipants who were physically active had higher FA and lower AxD, MD and RD values relative to the inactive participants. Changes in indices of WM integrity were widespread across the brain covering mainly association and projection tracts but a few commissural tracts. A three‐way interaction effect between Group × Physical Activity × VB was found for FA that was present in mainly projection tracts with a rightward asymmetry along with some association and commissural tracts. Post hocs revealed greater FA in physically active patients with high VB compared with inactive patients with high VB in projection and association/limbic tracts with a rightward asymmetry. Furthermore, the patients with high VB showed higher FA in bilateral projection fibers and cerebellar regions compared with inactive controls with high VB.ConclusionTBSS analysis revealed that high risk patients such as those with high VB achieved the maximum benefit by being physically active as it led to a much greater preservation of white microstructure relative to controls with high VB. This preservation of white matter microstructure was only observed in patients but not in controls.

Lower locus coeruleus integrity in older COVID‐19 survivors: initial findings from an international 7T MRI consortium

AbstractBackgroundThe SARS‐CoV‐2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID‐19 survivors and controls.MethodParticipants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR‐imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID‐19 survivors, 6 controls; Figure 1). COVID‐19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID‐19. Healthy controls were required to have no significant pre‐existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT‐TFL sequence (0.4×0.4×0.5mm). A site‐specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel‐wise integrity values were compared between COVID‐19 survivors and controls using a robust linear regression (age‐controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman’s rank correlation.ResultAverage LC integrity was not correlated with age, sex, or Hispanic ethnicity (p&gt;0.3). COVID‐19 survivors did not differ from Controls when examining the entire LC (p = 0.54). Voxel‐wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID‐19 survivors exhibited lower LC integrity than controls (p = 0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p = 0.9). LC integrity did not correlate with cognitive performance within the COVID‐19 survivors (Trail Making Test B: p = 0.43; Craft Story delayed recall p = 0.47; MoCA p = 0.84).ConclusionConsistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS‐CoV‐2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID‐19.

Low bone mineral density is associated with gray matter volume decrease in UK Biobank.

Previous research has found an association of low bone mineral density (BMD) and regional gray matter (GM) volume loss in Alzheimer's disease (AD). We were interested whether BMD is associated with GM volume decrease in brains of a healthy elderly population from the UK Biobank. T1-weighted images from 5,518 women (MAge = 70.20, SD = 3.54; age range: 65-82 years) and 7,595 men (MAge = 70.84, SD = 3.68; age range: 65-82 years) without neurological or psychiatric impairments were included in voxel-based morphometry (VBM) analysis in CAT12 with threshold-free-cluster-enhancement (TFCE) across the whole brain. We found a significant decrease of GM volume in women in the superior frontal gyri, middle temporal gyri, fusiform gyri, temporal poles, cingulate gyri, precunei, right parahippocampal gyrus and right hippocampus, right ventral diencephalon, and right pre- and postcentral gyrus. Only small effects were found in men in subcallosal area, left basal forebrain and entorhinal area. BMD is associated with low GM volume in women but less in men in regions afflicted in the early-stages of AD even in a sample without neurodegenerative diseases.

18 Vascular Risk, Cerebral White Matter, and Executive Functioning in Vietnam-Era Veterans with Traumatic Brain Injury and/or Post-Traumatic Stress Disorder: A Department of Defense Alzheimer’s Disease Initiative (DoD-ADNI) Study

Objective:Research indicates that Veterans with a history of traumatic brain injury (TBI) are at increased risk for dementia. Although the precise mechanisms underlying this relationship are poorly understood, remote TBI may exacerbate normal age-related changes to cerebral white matter (WM) and result in cognitive decline. However, Veterans commonly experience a constellation of mental (e.g., post-traumatic stress disorder [PTSD] and depression) and vascular (e.g., diabetes, hypertension, obesity) health conditions that have also been implicated in pathologic cerebral WM and cognitive aging trajectories. Therefore, the present study sought to (1) clarify the effects of remote TBI within the context of PTSD, depression, and vascular risk on WM micro- and macrostructure, and (2) explore if WM integrity is associated with cognition in a sample of Vietnam-Era Veterans.Participants and Methods:The sample consisted of 195 male Veterans ages 60-80 (mean age=69.3) enrolled in the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI) study. 102 Veterans met criteria for TBI by sustaining a head-injury that resulted in a loss of consciousness, alteration of consciousness, or post-traumatic amnesia. Current and/or lifetime PTSD was designated by scores &gt;30 on the Clinician-Administered PTSD Scale. The Geriatric Depression Scale was used as a continuous measure of depression. A vascular risk score (0-3) was calculated based on diabetes, hypertension, and obesity (BMI &gt;30 kg/m2). An executive functioning composite was created by averaging sample-specific z-scores for Trail Making Tests (A and B), with higher scores indicating worse performance. Voxelwise analysis of WM microstructure (fractional anisotropy [FA]) was conducted with Tract-Based Spatial Statistics (TBSS), using non-parametric permutation testing with threshold-free cluster enhancement. SPM’s Lesion Segmentation Tool was used to investigate WM macrostructure (WM hyperintensity [WMH] volume). Lesion probability maps were masked to restrict WMH volume calculations to WM. Robust regression using M-estimation and predictive R2 calculated using 10-fold cross-validation examined WMH volume, predictor, and cognitive associations. Age was a covariate in all WM analyses, and education was a covariate in all cognitive analyses.Results:TBSS analysis revealed widespread, significant negative relationships between vascular risk and FA across numerous WM tracts (p’s&lt;0.05). These associations remained significant after adjusting for TBI history, PTSD, and depression. TBSS identified significant positive relationships between executive functioning performance and FA across similar brain regions (p’s&lt;0.05). Robust regressions revealed that vascular risk significantly predicted WMH volume (p=0.006; ß=0.161; R2=0.093), whereas TBI history, PTSD, and depression did not (p’s=0.107-0.166; ß's=-0.089-0.101). WMH volume significantly predicted executive functioning (p=0.002; ß=0.216; R2=0.105), whereas TBI history, PTSD, depression, and vascular risk did not (p’s=0.123-0.888; ß's=-0.012-0.125).Conclusions:Our results suggest that vascular health, relative to remote TBI, PTSD, and depression, may be more robustly associated with cerebral WM micro- and macrostructure in older Veterans. Furthermore, poorer WM integrity is associated with poorer cognitive performance. These findings underscore the importance of vascular health interventions in preventing negative brain and cognitive aging outcomes in Veterans, independent of TBI history. Future studies might leverage other neuroimaging modalities (e.g., functional MRI) to further investigate the effects of vascular health on aging in Veterans with a history of TBI.

TMS of parietal and occipital cortex locked to spontaneous transient large-scale brain states enhances natural oscillations in EEG

BackgroundFluctuating neuronal network states influence brain responses to transcranial magnetic stimulation (TMS). Our previous studies revealed that transient spontaneous bihemispheric brain states in the EEG, driven by oscillatory power, information flow and regional domination, modify cortical EEG responses to TMS. However, the impact of ongoing fluctuations of large-scale brain network states on TMS-EEG responses has not been explored. ObjectivesTo determine the effects of large-scale brain network states on TMS-EEG responses. MethodsResting-state EEG and structural MRI from 24 healthy subjects were recorded to infer large-scale brain states. TMS-EEG was acquired with TMS at state-related targets, identified by the spatial distribution of state activation power from resting-state EEG. TMS-induced oscillations were measured by event-related spectral perturbations (ERSPs), and classified with respect to the brain states preceding the TMS pulses. State-locked ERSPs with TMS at specific state-related targets and during state activation were compared with state-unlocked ERSPs. ResultsIntra-individual comparison of ERSPs by threshold free cluster enhancement (TFCE) revealed that posterior and visual state-locked TMS, respectively, increased beta and alpha responses to TMS of parietal and occipital cortex compared to state-unlocked TMS. Also, the peak frequencies of ERSPs were increased with state-locked TMS. In addition, inter-individual correlation analyses revealed that posterior and visual state-locked TMS-induced oscillation power (ERSP clusters identified by TFCE) positively correlated with state-dependent oscillation power preceding TMS. ConclusionsSpontaneous transient large-scale brain network states modify TMS-induced natural oscillations in specific brain regions. This significantly extends our knowledge on the critical importance of instantaneous state on explaining the brain's varying responsiveness to external perturbation.

Resting-State Functional Connectivity Difference in Alzheimer's Disease and Mild Cognitive Impairment Using Threshold-Free Cluster Enhancement.

The disruption of functional connectivity is one of the early events that occurs in the brains of Alzheimer's disease (AD) patients. This paper reports a study on the clustering structure of functional connectivity in eight important brain networks in healthy, AD, and prodromal stage subjects. We used the threshold-free cluster enhancement (TFCE) method to explore the connectivity from resting-state functional MR images (rs-fMRIs). We conducted the study on a total of 32 AD, 32 HC, and 31 MCI subjects. We modeled the brain as a graph-based network to study these impairments, and pairwise Pearson's correlation-based functional connectivity was used to construct the brain network. The study found that connections in the sensory motor network (SMN), dorsal attention network (DAN), salience network (SAN), default mode network (DMN), and cerebral network were severely affected in AD and MCI. The disruption in these networks may serve as potential biomarkers for distinguishing AD and MCI from HC. The study suggests that alterations in functional connectivity in these networks may contribute to cognitive deficits observed in AD and MCI. Additionally, a negative correlation was observed between the global clinical dementia rating (CDR) score and the Z-score of functional connectivity within identified clusters in AD subjects. These findings provide compelling evidence suggesting that the neurodegenerative disruption of functional magnetic resonance imaging (fMRI) connectivity is extensively distributed across multiple networks in individuals diagnosed with AD.