Postmortem Brain Imaging in Alzheimer's Disease and Related Dementias: The South Texas Alzheimer's Disease Research Center Repository.

BACKGROUND: Neuroimaging bears the promise of providing new biomarkers that could refine the diagnosis of dementia. Still, obtaining the pathology data required to validate the relationship between neuroimaging markers and neurological changes is challenging. Existing data repositories are focused on a single pathology, are too small, or do not precisely match neuroimaging and pathology findings. OBJECTIVE: The new data repository introduced in this work, the South Texas Alzheimer's Disease research center repository, was designed to address these limitations. Our repository covers a broad diversity of dementias, spans a wide age range, and was specifically designed to draw exact correspondences between neuroimaging and pathology data. METHODS: Using four different MRI sequences, we are reaching a sample size that allows for validating multimodal neuroimaging biomarkers and studying comorbid conditions. Our imaging protocol was designed to capture markers of cerebrovascular disease and related lesions. Quantification of these lesions is currently underway with MRI-guided histopathological examination. RESULTS: A total of 139 postmortem brains (70 females) with mean age of 77.9 years were collected, with 71 brains fully analyzed. Of these, only 3% showed evidence of AD-only pathology and 76% had high prevalence of multiple pathologies contributing to clinical diagnosis. CONCLUSION: This repository has a significant (and increasing) sample size consisting of a wide range of neurodegenerative disorders and employs advanced imaging protocols and MRI-guided histopathological analysis to help disentangle the effects of comorbid disorders to refine diagnosis, prognosis and better understand neurodegenerative disorders.

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

BACKGROUND: White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. OBJECTIVE: Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. METHODS: The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. RESULTS: ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. CONCLUSIONS: The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial.

Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. Five participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study. D and Q levels in blood increased in all participants (12.7-73.5 ng ml-1 for D and 3.29-26.3 ng ml-1 for Q). In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) ranging from 0.281 to 0.536 ml-1 with a CSF to plasma ratio of 0.422-0.919%; Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile. CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased (t(4) = 3.913, P = 0.008 and t(4) = 3.354, P = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aß42 levels (t(4) = -2.338, P = 0.079). In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies. ClinicalTrials.gov identifier: NCT04063124 .

Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease.

Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aß) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aß42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aß may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.

Co-alteration Network Architecture of Major Depressive Disorder: A Multi-modal Neuroimaging Assessment of Large-scale Disease Effects.

Major depressive disorder (MDD) exhibits diverse symptomology and neuroimaging studies report widespread disruption of key brain areas. Numerous theories underpinning the network degeneration hypothesis (NDH) posit that neuropsychiatric diseases selectively target brain areas via meaningful network mechanisms rather than as indistinct disease effects. The present study tests the hypothesis that MDD is a network-based disorder, both structurally and functionally. Coordinate-based meta-analysis and Activation Likelihood Estimation (CBMA-ALE) were used to assess the convergence of findings from 92 previously published studies in depression. An extension of CBMA-ALE was then used to generate a node-and-edge network model representing the co-alteration of brain areas impacted by MDD. Standardized measures of graph theoretical network architecture were assessed. Co-alteration patterns among the meta-analytic MDD nodes were then tested in independent, clinical T1-weighted structural magnetic resonance imaging (MRI) and resting-state functional (rs-fMRI) data. Differences in co-alteration profiles between MDD patients and healthy controls, as well as between controls and clinical subgroups of MDD patients, were assessed. A 65-node 144-edge co-alteration network model was derived for MDD. Testing of co-alteration profiles in replication data using the MDD nodes provided distinction between MDD and healthy controls in structural data. However, co-alteration profiles were not distinguished between patients and controls in rs-fMRI data. Improved distinction between patients and healthy controls was observed in clinically homogenous MDD subgroups in T1 data. MDD abnormalities demonstrated both structural and functional network architecture, though only structural networks exhibited between-groups differences. Our findings suggest improved utility of structural co-alteration networks for ongoing biomarker development.

Metabolic syndrome predictors of brain gray matter volume in an age-stratified community sample of 776 Mexican- American adults: Results from the genetics of brain structure image archive.

Introduction: This project aimed to investigate the association between biometric components of metabolic syndrome (MetS) with gray matter volume (GMV) obtained with magnetic resonance imaging (MRI) from a large cohort of community-based adults (n = 776) subdivided by age and sex and employing brain regions of interest defined previously as the "Neural Signature of MetS" (NS-MetS). Methods: Lipid profiles, biometrics, and regional brain GMV were obtained from the Genetics of Brain Structure (GOBS) image archive. Participants underwent T1-weighted MR imaging. MetS components (waist circumference, fasting plasma glucose, triglycerides, HDL cholesterol, and blood pressure) were defined using the National Cholesterol Education Program Adult Treatment Panel III. Subjects were grouped by age: early adult (18-25 years), young adult (26-45 years), and middle-aged adult (46-65 years). Linear regression modeling was used to investigate associations between MetS components and GMV in five brain regions comprising the NS-MetS: cerebellum, brainstem, orbitofrontal cortex, right insular/limbic cluster and caudate. Results: In both men and women of each age group, waist circumference was the single component most strongly correlated with decreased GMV across all NS-MetS regions. The brain region most strongly correlated to all MetS components was the posterior cerebellum. Conclusion: The posterior cerebellum emerged as the region most significantly associated with MetS individual components, as the only region to show decreased GMV in young adults, and the region with the greatest variance between men and women. We propose that future studies investigating neurological effects of MetS and its comorbidities-namely diabetes and obesity-should consider the NS-MetS and the differential effects of age and sex.

Invariant structural and functional brain regions associated with tinnitus: A meta-analysis.

Tinnitus is a common, functionally disabling condition of often unknown etiology. Neuroimaging research to better understand tinnitus is emerging but remains limited in scope. Voxel-based physiology (VBP) studies detect tinnitus-associated pathophysiology by group-wise contrast (tinnitus vs controls) of resting-state indices of hemodynamics, metabolism, and neurovascular coupling. Voxel-based morphometry (VBM) detects tinnitus-associated neurodegeneration by group-wise contrast of structural MRI. Both VBP and VBM studies routinely report results as atlas-referenced coordinates, suitable for coordinate-based meta-analysis (CBMA). Here, 17 resting-state VBP and 8 VBM reports of tinnitus-associated regional alterations were meta-analyzed using activation likelihood estimation (ALE). Acknowledging the need for data-driven insights, ALEs were performed at two levels of statistical rigor: corrected for multiple comparisons and uncorrected. The corrected ALE applied cluster-level inference thresholding by intensity (z-score > 1.96; p < 0.05) followed by family-wise error correction for multiple comparisons (p < .05, 1000 permutations) and fail-safe correction for missing data. The corrected analysis identified one significant cluster comprising five foci in the posterior cingulate gyrus and precuneus, that is, not within the primary or secondary auditory cortices. The uncorrected ALE identified additional regions within auditory and cognitive processing networks. Taken together, tinnitus is likely a dysfunction of regions spanning multiple canonical networks that may serve to increase individuals' interoceptive awareness of the tinnitus sound, decrease capacity to switch cognitive sets, and prevent behavioral and cognitive attention to other stimuli. It is noteworthy that the most robust tinnitus-related abnormalities are not in the auditory system, contradicting collective findings of task-activation literature in tinnitus.

Immediate and long-term effects of speech treatment targets and intensive dosage on Parkinson's disease dysphonia and the speech motor network: Randomized controlled trial.

This study compared acoustic and neural changes accompanying two treatments matched for intensive dosage but having two different treatment targets (voice or articulation) to dissociate the effects of treatment target and intensive dosage in speech therapies. Nineteen participants with Parkinsonian dysphonia (11 F) were randomized to three groups: intensive treatment targeting voice (voice group, n = 6), targeting articulation (articulation group, n = 7), or an untreated group (no treatment, n = 6). The severity of dysphonia was assessed by the smoothed cepstral peak prominence (CPPS) and neuronal changes were evaluated by cerebral blood flow (CBF) recorded at baseline, posttreatment, and 7-month follow-up. Only the voice treatment resulted in significant posttreatment improvement in CPPS, which was maintained at 7 months. Following voice treatment, increased activity in left premotor and bilateral auditory cortices was observed at posttreatment, and in the left motor and auditory cortices at 7-month follow-up. Articulation treatment resulted in increased activity in bilateral premotor and left insular cortices that were sustained at a 7-month follow-up. Activation in the auditory cortices and a significant correlation between the CPPS and CBF in motor and auditory cortices was observed only in the voice group. The intensive dosage resulted in long-lasting behavioral and neural effects as the no-treatment group showed a progressive decrease in activity in areas of the speech motor network out to a 7-month follow-up. These results indicate that dysphonia and the speech motor network can be differentially modified by treatment targets, while intensive dosage contributes to long-lasting effects of speech treatments.

Hemodynamic and metabolic correspondence of resting-state voxel-based physiological metrics in healthy adults.

Voxel-based physiological (VBP) variables derived from blood oxygen level dependent (BOLD) fMRI time-course variations include: amplitude of low frequency fluctuations (ALFF), fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity (ReHo). Although these BOLD-derived variables can detect between-group (e.g. disease vs control) spatial pattern differences, physiological interpretations are not well established. The primary objective of this study was to quantify spatial correspondences between BOLD VBP variables and PET measurements of cerebral metabolic rate and hemodynamics, being well-validated physiological standards. To this end, quantitative, whole-brain PET images of metabolic rate of glucose (MRGlu; 18FDG) and oxygen (MRO2; 15OO), blood flow (BF; H215O) and blood volume (BV; C15O) were obtained in 16 healthy controls. In the same subjects, BOLD time-courses were obtained for computation of ALFF, fALFF and ReHo images. PET variables were compared pair-wise with BOLD variables. In group-averaged, across-region analyses, ALFF corresponded significantly only with BV (R = 0.64; p < 0.0001). fALFF corresponded most strongly with MRGlu (R = 0.79; p < 0.0001), but also significantly (p < 0.0001) with MRO2 (R = 0.68), BF (R = 0.68) and BV (R=0.68). ReHo performed similarly to fALFF, with significant strong correspondence (p < 0.0001) with MRGlu (R = 0.78), MRO2 (R = 0.54), and, but less strongly with BF (R = 0.50) and BV (R=0.50). Mutual information analyses further clarified these physiological interpretations. When conditioned by BV, ALFF retained no significant MRGlu, MRO2 or BF information. When conditioned by MRGlu, fALFF and ReHo retained no significant MRO2, BF or BV information. Of concern, however, the strength of PET-BOLD correspondences varied markedly by brain region, which calls for future investigation on physiological interpretations at a regional and per-subject basis.

Combined PET and whole-tissue imaging of lymphatic-targeting vaccines in non-human primates.

Antigen accumulation in lymph nodes (LNs) is critical for vaccine efficacy, but understanding of vaccine biodistribution in humans or large animals remains limited. Using the rhesus macaque model, we employed a combination of positron emission tomography (PET) and fluorescence imaging to characterize the whole-animal to tissue-level biodistribution of a subunit vaccine comprised of an HIV envelope trimer protein nanoparticle (trimer-NP) and lipid-conjugated CpG adjuvant (amph-CpG). Following immunization in the thigh, PET imaging revealed vaccine uptake primarily in inguinal and iliac LNs, reaching distances up to 17 cm away from the injection site. Within LNs, trimer-NPs exhibited striking accumulation on the periphery of follicular dendritic cell (FDC) networks in B cell follicles. Comparative imaging of soluble Env trimers (not presented on nanoparticles) in naïve or previously-immunized animals revealed diffuse deposition of trimer antigens in LNs following primary immunization, but concentration on FDCs in pre-immunized animals with high levels of trimer-specific IgG. These data demonstrate the capacity of nanoparticle or "albumin hitchhiking" technologies to concentrate vaccines in genitourinary tract-draining LNs, which may be valuable for promoting mucosal immunity.

Changes in Brain Volume Associated with Trauma-Focused Cognitive Behavioral Therapy Among Youth with Posttraumatic Stress Disorder.

This study investigated group differences and longitudinal changes in brain volume before and after trauma-focused cognitive behavioral therapy (TF-CBT) in 20 unmedicated youth with maltreatment-related posttraumatic stress disorder (PTSD) and 20 non-trauma-exposed healthy control (HC) participants. We collected MRI scans of brain anatomy before and after 5 months of TF-CBT or the same time interval for the HC group. FreeSurfer software was used to segment brain images into 95 cortical and subcortical volumes, which were submitted to optimal scaling regression with lasso variable selection. The resulting model of group differences at baseline included larger right medial orbital frontal and left posterior cingulate corticies and smaller right midcingulate and right precuneus corticies in the PTSD relative to the HC group, R2 = .67. The model of group differences in pre- to posttreatment change included greater longitudinal changes in right rostral middle frontal, left pars triangularis, right entorhinal, and left cuneus corticies in the PTSD relative to the HC group, R2 = .69. Within the PTSD group, pre- to posttreatment symptom improvement was modeled by longitudinal decreases in the left posterior cingulate cortex, R2 = .45, and predicted by baseline measures of a smaller right isthmus (retrosplenial) cingulate and larger left caudate, R2 = .77. In sum, treatment was associated with longitudinal changes in brain regions that support executive functioning but not those that discriminated PTSD from HC participants at baseline. Additionally, results confirm a role for the posterior/retrosplenial cingulate as a correlate of PTSD symptom improvement and predictor of treatment outcome.

Disruption of the Atrophy-based Functional Network in Multiple Sclerosis Is Associated with Clinical Disability: Validation of a Meta-Analytic Model in Resting-State Functional MRI.

Background In multiple sclerosis (MS), gray matter (GM) atrophy exhibits a specific pattern, which correlates strongly with clinical disability. However, the mechanism of regional specificity in GM atrophy remains largely unknown. Recently, the network degeneration hypothesis (NDH) was quantitatively defined (using coordinate-based meta-analysis) as the atrophy-based functional network (AFN) model, which posits that localized GM atrophy in MS is mediated by functional networks. Purpose To test the NDH in MS in a data-driven manner using the AFN model to direct analyses in an independent test sample. Materials and Methods Model fit testing was conducted with structural equation modeling, which is based on the computation of semipartial correlations. Model verification was performed in coordinate-based data of healthy control participants from the BrainMap database (https://www.brainmap.org). Model validation was conducted in prospectively acquired resting-state functional MRI in participants with relapsing-remitting MS who were recruited between September 2018 and January 2019. Correlation analyses of model fit indices and volumetric measures with Expanded Disability Status Scale (EDSS) scores and disease duration were performed. Results Model verification of healthy control participants included 80 194 coordinates from 9035 experiments. Model verification in healthy control data resulted in excellent model fit (root mean square error of approximation, 0.037; 90% CI: 0.036, 0.039). Twenty participants (mean age, 36 years ± 9 [standard deviation]; 12 women) with relapsing-remitting MS were evaluated. Model validation in resting-state functional MRI in participants with MS resulted in deviation from optimal model fit (root mean square error of approximation, 0.071; 90% CI: 0.070, 0.072), which correlated with EDSS scores (r = 0.68; P = .002). Conclusion The atrophy-based functional network model predicts functional network disruption in multiple sclerosis (MS), thereby supporting the network degeneration hypothesis. On resting-state functional MRI scans, reduced functional network integrity in participants with MS had a strong positive correlation with clinical disability. © RSNA, 2021 Online supplemental material is available for this article.

Validation of T2 -based oxygen extraction fraction measurement with 15 O positron emission tomography.

PURPOSE: To evaluate the accuracy of T2 -based whole-brain oxygen extraction fraction (OEF) estimation by comparing it with gold standard 15 O-PET measurements. METHODS: Sixteen healthy adult subjects underwent MRI and 15 O-PET OEF measurements on the same day. On MRI, whole-brain OEF was quantified by T2 -relaxation-under-spin-tagging (TRUST) MRI, based on subject-specific hematocrit. The TRUST OEF was compared to the whole-brain averaged OEF produced by 15 O-PET. Agreement between TRUST and 15 O-PET whole-brain OEF measurements was examined in terms of intraclass correlation coefficient (ICC) and in absolute OEF values. In a subset of 10 subjects, test-retest reproducibility of whole-brain OEF was also evaluated and compared between the two modalities. RESULTS: Across the 16 subjects, the mean whole-brain OEF of TRUST and 15 O-PET were 36.44 ± 4.07% and 36.45 ± 3.65%, respectively, showing no difference between the two modalities (P = .99). TRUST whole-brain OEF strongly correlated with that of 15 O-PET (N = 16, ICC = 0.90, P = 4 × 10-7 ). The coefficient-of-variation of TRUST and 15 O-PET whole-brain OEF measurements were 1.79 ± 0.67% and 2.06 ± 1.55%, respectively, showing no difference between the two modalities (N = 10, P = .64). Further analyses on the effect of hematocrit revealed that correlation between PET OEF and TRUST OEF with assumed hematocrit remained significant (ICC = 0.8, P < 2 × 10-5 ). CONCLUSION: Whole-brain OEF measured by TRUST was in excellent agreement with gold standard 15 O-PET, with highly comparable accuracy and reproducibility. These findings suggest that TRUST MRI can provide accurate quantification of whole-brain OEF noninvasively.

Using the Schmahmann Syndrome Scale to Assess Cognitive Impairment in Young Adults with Metabolic Syndrome: a Hypothesis-Generating Report.

The posterior cerebellum is the most significantly compromised brain structure in individuals with metabolic syndrome (MetS) (Hum Brain Mapp 40(12):3575-3588, 2019). In light of this, we hypothesized that cognitive decline reported in patients with MetS is likely related to posterior cerebellar atrophy. In this study, we performed a post hoc analyses using T1-weighted magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) in the form of voxel-wise tract-based spatial statistics (TBSS), biometric, and psychometric data from young participants with (n = 52, aged 18-35 years) and without MetS (n = 52, aged 18-35 years). To test the predictive value of components of the Schmahmann syndrome scale (SSS), also known as the cerebellar cognitive affective syndrome scale, we used structural equation modeling to adapt available psychometric scores in our participant sample to the SSS and compare them to the composite score of all psychometric data available. Our key findings point to a statistically significant correlation between TBSS fractional anisotropy (FA) values from DTI and adapted SSS psychometric scores in individuals with MetS (r2 = .139, 95% CI = 0.009, .345). This suggests that the SSS could be applied to assess cognitive and likely neuroanatomical effects associated with MetS. We strongly suggest that future work aimed at investigating the neurocognitive effects of MetS and related comorbidities (i.e., dyslipidemia, diabetes, obesity) would benefit from implementing and further exploring the validity of the SSS in this patient population.

Mapping typical and hypokinetic dysarthric speech production network using a connected speech paradigm in functional MRI.

We developed a task paradigm whereby subjects spoke aloud while minimizing head motion during functional MRI (fMRI) in order to better understand the neural circuitry involved in motor speech disorders due to dysfunction of the central nervous system. To validate our overt continuous speech paradigm, we mapped the speech production network (SPN) in typical speakers (n = 19, 10 females) and speakers with hypokinetic dysarthria as a manifestation of Parkinson disease (HKD; n = 21, 8 females) in fMRI. We then compared it with the SPN derived during overt speech production by 15O-water PET in the same group of typical speakers and another HKD cohort (n = 10, 2 females). The fMRI overt connected speech paradigm did not result in excessive motion artifacts and successfully identified the same brain areas demonstrated in the PET studies in the two cohorts. The SPN derived in fMRI demonstrated significant spatial overlap with the corresponding PET derived maps (typical speakers: r = 0.52; speakers with HKD: r = 0.43) and identified the components of the neural circuit of speech production belonging to the feedforward and feedback subsystems. The fMRI study in speakers with HKD identified significantly decreased activity in critical feedforward (bilateral dorsal premotor and motor cortices) and feedback (auditory and somatosensory areas) subsystems replicating previous PET study findings in this cohort. These results demonstrate that the overt connected speech paradigm is feasible during fMRI and can accurately localize the neural substrates of typical and disordered speech production. Our fMRI paradigm should prove useful for study of motor speech and voice disorders, including stuttering, apraxia of speech, dysarthria, and spasmodic dysphonia.

A resting-state network comparison of combat-related PTSD with combat-exposed and civilian controls.

Resting-state functional connectivity (rsFC) is an emerging means of understanding the neurobiology of combat-related post-traumatic stress disorder (PTSD). However, most rsFC studies to date have limited focus to cognitively related intrinsic connectivity networks (ICNs), have not applied data-driven methodologies or have disregarded the effect of combat exposure. In this study, we predicted that group independent component analysis (GICA) would reveal group-wise differences in rsFC across 50 active duty service members with PTSD, 28 combat-exposed controls (CEC), and 25 civilian controls without trauma exposure (CC). Intranetwork connectivity differences were identified across 11 ICNs, yet combat-exposed groups were indistinguishable in PTSD vs CEC contrasts. Both PTSD and CEC demonstrated anatomically diffuse differences in the Auditory Vigilance and Sensorimotor networks compared to CC. However, intranetwork connectivity in a subset of three regions was associated with PTSD symptom severity among executive (left insula; ventral anterior cingulate) and right Fronto-Parietal (perigenual cingulate) networks. Furthermore, we found that increased temporal synchronization among visuospatial and sensorimotor networks was associated with worse avoidance symptoms in PTSD. Longitudinal neuroimaging studies in combat-exposed cohorts can further parse PTSD-related, combat stress-related or adaptive rsFC changes ensuing from combat.

A neural signature of metabolic syndrome.

That metabolic syndrome (MetS) is associated with age-related cognitive decline is well established. The neurobiological changes underlying these cognitive deficits, however, are not well understood. The goal of this study was to determine whether MetS is associated with regional differences in gray-matter volume (GMV) using a cross-sectional, between-group contrast design in a large, ethnically homogenous sample. T1-weighted MRIs were sampled from the genetics of brain structure (GOBS) data archive for 208 Mexican-American participants: 104 participants met or exceeded standard criteria for MetS and 104 participants were age- and sex-matched metabolically healthy controls. Participants ranged in age from 18 to 74 years (37.3 ± 13.2 years, 56.7% female). Images were analyzed in a whole-brain, voxel-wise manner using voxel-based morphometry (VBM). Three contrast analyses were performed, a whole sample analysis of all 208 participants, and two post hoc half-sample analyses split by age along the median (35.5 years). Significant associations between MetS and decreased GMV were observed in multiple, spatially discrete brain regions including the posterior cerebellum, brainstem, orbitofrontal cortex, bilateral caudate nuclei, right parahippocampus, right amygdala, right insula, lingual gyrus, and right superior temporal gyrus. Age, as shown in the post hoc analyses, was demonstrated to be a significant covariate. A further functional interpretation of the structures exhibiting lower GMV in MetS reflected a significant involvement in reward perception, emotional valence, and reasoning. Additional studies are needed to characterize the influence of MetS's individual clinical components on brain structure and to explore the bidirectional association between GMV and MetS.

Assessment of chiropractic care on strength, balance, and endurance in active-duty U.S. military personnel with low back pain: a protocol for a randomized controlled trial.

BACKGROUND: Low back pain (LBP) is a common cause of disability among U.S. military personnel. Approximately 20% of all diagnoses resulting in disability discharges are linked to back-related conditions. Because LBP can negatively influence trunk muscle strength, balance, and endurance, the military readiness of active-duty military personnel with LBP is potentially compromised. Chiropractic care may facilitate the strengthening of trunk muscles, the alteration of sensory and motor signaling, and a reduction in pain sensitivity, which may contribute to improving strength, balance, and endurance for individuals with LBP. This trial will assess the effects of chiropractic care on strength, balance, and endurance for active-duty military personnel with LBP. METHODS/DESIGN: This randomized controlled trial will allocate 110 active-duty military service members aged 18-40 with non-surgical acute, subacute, or chronic LBP with pain severity of ≥2/10 within the past 24 h. All study procedures are conducted at a single military treatment facility within the continental United States. Participants are recruited through recruitment materials approved by the institutional review board, such as posters and flyers, as well as through provider referrals. Group assignment occurs through computer-generated random allocation to either the study intervention (chiropractic care) or the control group (waiting list) for a 4-week period. Chiropractic care consists primarily of spinal manipulation at a frequency and duration determined by a chiropractic practitioner. Strength, balance, and endurance outcomes are obtained at baseline and after 4 weeks. The primary outcome is a change between baseline and 4 weeks of peak isometric strength, which is measured by pulling on a bimanual handle in a semi-squat position. Secondary outcomes include balance time during a single-leg standing test and trunk muscle endurance with the Biering-Sorensen test. Patient-reported outcomes include pain severity, disability measured with the Roland Morris Disability Questionnaire, symptom bothersomeness, PROMIS-29, Fear Avoidance Beliefs Questionnaire, expectations of care, physical activity, and global improvement. DISCUSSION: This trial may help inform further research on biological mechanisms related to manual therapies employed by chiropractic practitioners. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02670148 Registered on 1 February 2016.

Functional integrity in children with anoxic brain injury from drowning.

Drowning is a leading cause of accidental injury and death in young children. Anoxic brain injury (ABI) is a common consequence of drowning and can cause severe neurological morbidity in survivors. Assessment of functional status and prognostication in drowning victims can be extremely challenging, both acutely and chronically. Structural neuroimaging modalities (CT and MRI) have been of limited clinical value. Here, we tested the utility of resting-state functional MRI (rs-fMRI) for assessing brain functional integrity in this population. Eleven children with chronic, spastic quadriplegia due to drowning-induced ABI were investigated. All were comatose immediately after the injury and gradually regained consciousness, but with varying ability to communicate their cognitive state. Eleven neurotypical children matched for age and gender formed the control group. Resting-state fMRI and co-registered T1-weighted anatomical MRI were acquired at night during drug-aided sleep. Network integrity was quantified by independent components analysis (ICA), at both group- and per-subject levels. Functional-status assessments based on in-home observations were provided by families and caregivers. Motor ICNs were grossly compromised in ABI patients both group-wise and individually, concordant with their prominent motor deficits. Striking preservations of perceptual and cognitive ICNs were observed, and the degree of network preservation correlated (ρ = 0.74) with the per-subject functional status assessments. Collectively, our findings indicate that rs-fMRI has promise for assessing brain functional integrity in ABI and, potentially, in other disorders. Furthermore, our observations suggest that the severe motor deficits observed in this population can mask relatively intact perceptual and cognitive capabilities. Hum Brain Mapp 38:4813-4831, 2017. © 2017 Wiley Periodicals, Inc.

Methylene blue modulates functional connectivity in the human brain.

Methylene blue USP (MB) is a FDA-grandfathered drug used in clinics to treat methemoglobinemia, carbon monoxide poisoning and cyanide poisoning that has been shown to increase fMRI evoked blood oxygenation level dependent (BOLD) response in rodents. Low dose MB also has memory enhancing effect in rodents and humans. However, the neural correlates of the effects of MB in the human brain are unknown. We tested the hypothesis that a single low oral dose of MB modulates the functional connectivity of neural networks in healthy adults. Task-based and task-free fMRI were performed before and one hour after MB or placebo administration utilizing a randomized, double-blinded, placebo-controlled design. MB administration was associated with a reduction in cerebral blood flow in a task-related network during a visuomotor task, and with stronger resting-state functional connectivity in multiple regions linking perception and memory functions. These findings demonstrate for the first time that low-dose MB can modulate task-related and resting-state neural networks in the human brain. These neuroimaging findings support further investigations in healthy and disease populations.