Atypical behaviour and connectivity in SHANK3-mutant macaques.

Mutation or disruption of the SH3 and ankyrin repeat domains 3 (SHANK3) gene represents a highly penetrant, monogenic risk factor for autism spectrum disorder, and is a cause of Phelan-McDermid syndrome. Recent advances in gene editing have enabled the creation of genetically engineered non-human-primate models, which might better approximate the behavioural and neural phenotypes of autism spectrum disorder than do rodent models, and may lead to more effective treatments. Here we report CRISPR-Cas9-mediated generation of germline-transmissible mutations of SHANK3 in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the SHANK3 gene and reduced levels of SHANK3 protein in these macaques. Analysis of data from functional magnetic resonance imaging revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits and increased repetitive behaviours, as well as social and learning impairments. Together, these results parallel some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioural phenotypes, that characterize autism spectrum disorder and Phelan-McDermid syndrome.

Data-driven MRI analysis reveals fitness-related functional change in default mode network and cognition following an exercise intervention.

Previous research has indicated that cardiorespiratory fitness (CRF) is structurally and functionally neuroprotective in older adults. However, questions remain regarding the mechanistic role of CRF on cognitive and brain health. The purposes of this study were to investigate if higher pre-intervention CRF was associated with greater change in functional brain connectivity during an exercise intervention and to determine if the magnitude of change in connectivity was related to better post-intervention cognitive performance. The sample included low-active older adults (n = 139) who completed a 6-month exercise intervention and underwent neuropsychological testing, functional neuroimaging, and CRF testing before and after the intervention. A data-driven multi-voxel pattern analysis was performed on resting-state MRI scans to determine changes in whole-brain patterns of connectivity from pre- to post-intervention as a function of pre-intervention CRF. Results revealed a positive correlation between pre-intervention CRF and changes in functional connectivity in the precentral gyrus. Using the precentral gyrus as a seed, analyses indicated that CRF-related connectivity changes within the precentral gyrus were derived from increased correlation strength within clusters located in the Dorsal Attention Network (DAN) and increased anti-correlation strength within clusters located in the Default Mode Network (DMN). Exploratory analysis demonstrated that connectivity change between the precentral gyrus seed and DMN clusters were associated with improved post-intervention performance on perceptual speed tasks. These findings suggest that in a sample of low-active and mostly lower-fit older adults, even subtle individual differences in CRF may influence the relationship between functional connectivity and aspects of cognition following a 6-month exercise intervention.

Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: a CAN-BIND-1 Study Report.

Neuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in major depressive disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 healthy controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI1 corresponded to default mode network (DMN)/inattentive processing; ROI2 corresponded to attentional networks, including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3. These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies. ClinicalTrials.gov TRN: NCT01655706; Date of Registration: August 2nd, 2012.

Treatment Response of Transcranial Magnetic Stimulation in Intellectually Capable Youth and Young Adults with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

To examine current clinical research on the use of transcranial magnetic stimulation (TMS) in the treatment of pediatric and young adult autism spectrum disorder in intellectually capable persons (IC-ASD). We searched peer-reviewed international literature to identify clinical trials investigating TMS as a treatment for behavioral and cognitive symptoms of IC-ASD. We identified sixteen studies and were able to conduct a meta-analysis on twelve of these studies. Seven were open-label or used neurotypical controls for baseline cognitive data, and nine were controlled trials. In the latter, waitlist control groups were often used over sham TMS. Only one study conducted a randomized, parallel, double-blind, and sham controlled trial. Favorable safety data was reported in low frequency repetitive TMS, high frequency repetitive TMS, and intermittent theta burst studies. Compared to TMS research of other neuropsychiatric conditions, significantly lower total TMS pulses were delivered in treatment and neuronavigation was not regularly utilized. Quantitatively, our multivariate meta-analysis results report improvement in cognitive outcomes (pooled Hedges' g = 0.735, 95% CI = 0.242, 1.228; p = 0.009) and primarily Criterion B symptomology of IC-ASD (pooled Hedges' g = 0.435, 95% CI = 0.359, 0.511; p < 0.001) with low frequency repetitive TMS to the dorsolateral prefrontal cortex. The results of our systematic review and meta-analysis data indicate that TMS may offer a promising and safe treatment option for pediatric and young adult patients with IC-ASD. However, future work should include use of neuronavigation software, theta burst protocols, targeting of various brain regions, and robust study design before clinical recommendations can be made.

Interaction Between Cerebellum and Cerebral Cortex, Evidence from Dynamic Causal Modeling.

The interaction of the cerebellum with cerebral cortical dynamics is still poorly understood. In this paper, dynamical causal modeling is used to examine the interaction between cerebellum and cerebral cortex as indexed by MRI resting-state functional connectivity in three large-scale networks on healthy young adults (N = 200; Human Connectome Project dataset). These networks correspond roughly to default mode, task positive, and motor as determined by prior cerebellar functional gradient analyses. We find uniform interactions within all considered networks from cerebellum to cerebral cortex, providing support for the notion of a universal cerebellar transform. Our results provide a foundation for future analyses to quantify and further investigate whether this is a property that is unique to the interactions from cerebellum to cerebral cortex.

A comprehensive data-driven analysis framework for detecting impairments in brain function networks with resting state fMRI in HIV-infected individuals on cART.

Central nervous system (CNS) sequelae continue to be common in HIV-infected individuals despite combination antiretroviral therapy (cART). These sequelae include HIV-associated neurocognitive disorder (HAND) and virologic persistence in the CNS. Resting state functional magnetic resonance imaging (rsfMRI) is a widely used tool to examine the integrity of brain function and pathology. In this study, we examined 16 HIV-positive (HIV+) subjects and 12 age, sex, and race matched HIV seronegative controls (HIV-) whole-brain high-resolution rsfMRI along with a battery of neurocognitive tests. A comprehensive data-driven analysis of rsfMRI revealed impaired functional connectivity, with very large effect sizes in executive function, language, and multisensory processing networks in HIV+ subjects. These results indicate the potential of high-resolution rsfMRI in combination with advanced data analysis techniques to yield biomarkers of neural impairment in HIV.

Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders.

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R2 = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program.

The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early-course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth.

Functional Territories of Human Dentate Nucleus.

Anatomical connections link the cerebellar cortex with multiple sensory, motor, association, and paralimbic cerebral areas. The majority of fibers that exit cerebellar cortex synapse in dentate nuclei (DN) before reaching extracerebellar structures such as cerebral cortex, but the functional neuroanatomy of human DN remains largely unmapped. Neuroimaging research has redefined broad categories of functional division in the human brain showing that primary processing, attentional (task positive) processing, and default-mode (task negative) processing are three central poles of neural macroscale functional organization. This broad spectrum of human neural processing categories is represented not only in the cerebral cortex, but also in the thalamus, striatum, and cerebellar cortex. Whether functional organization in DN obeys a similar set of macroscale divisions, and whether DN are yet another compartment of representation of a broad spectrum of human neural processing categories, remains unknown. Here, we show for the first time that human DN are optimally divided into three functional territories as indexed by high spatio-temporal resolution resting-state MRI in 77 healthy humans, and that these three distinct territories contribute uniquely to default-mode, salience-motor, and visual cerebral cortical networks. Our findings provide a systems neuroscience substrate for cerebellar output to influence multiple broad categories of neural control.

Improvising at rest: Differentiating jazz and classical music training with resting state functional connectivity.

Jazz improvisation offers a model for creative cognition, as it involves the real-time creation of a novel, information-rich product. Previous research has shown that when musicians improvise, they recruit regions in the Default Mode Network (DMN) and Executive Control Network (ECN). Here, we ask whether these findings from task-fMRI studies might extend to intrinsic differences in resting state functional connectivity. We compared Improvising musicians, Classical musicians, and Minimally Musically Trained (MMT) controls in seed-based functional connectivity and network analyses in resting state functional MRI. We also examined the functional correlates of behavioral performance in musical improvisation and divergent thinking. Seed-based analysis consistently showed higher connectivity in ventral DMN (vDMN) and bilateral ECN in both groups of musically trained individuals as compared to MMT controls, with additional group differences in primary visual network. In particular, primary visual network connectivity to DMN and ECN was highest in Improvisational musicians, as was connectivity between ECN and DMN; in contrast, connectivity between vDMN and frontal pole was highest in Classical musicians. Furthermore, graph-theoretical analysis indicated heightened network measures in both musician groups, with betweenness centrality, clustering, and local efficiency showing highest levels in Classical musicians, and degrees and strengths showing highest levels in Improvisational musicians. Taken together, results suggest that heightened functional connectivity among musicians can be explained by higher within-network connectivity (more tight-knit cortical networks) in Classical musicians, as opposed to more disperse, globally-connected cortical networks in Improvisational musicians.

Neurodevelopmental and Psychiatric Symptoms in Patients with a Cyst Compressing the Cerebellum: an Ongoing Enigma.

A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap-namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?

Water-fat separation imaging of the heart with standard magnetic resonance bSSFP CINE imaging.

PURPOSE: To study balanced steady-state free precession CINE phase-sensitive water-fat separation imaging in four cardiac imaging planes to determine the necessary phase correction and image artifacts particular to this technique. METHODS: Ten healthy volunteers and two subjects with known heart pathologies were studied with standard balanced steady-state free precession CINE imaging. Water-only and fat-only images were calculated using sign detection of the real part of the complex image after phase correction with constant and linear terms. Phase correction values were determined using both manual and automated methods. Differences in phase correction values between imaging planes, cardiac phases, coil elements, automated image reconstruction parameters as well as artifact scores between the automated and manual methods were studied with statistical tests. RESULTS: Water-fat separation performed well in the heart after constant and linear phase correction. Both constant (p = 0.8) and linear x (p = 1) and y (p = 1) phase correction values did not vary significantly across cardiac phases, but varied significantly among the coils (p < 0.001) and imaging planes (p < 0.001). False water-fat separation artifacts were most frequent in the chest/back and also were present at the mitral and aortic valves. CONCLUSION: Constant and linear phase correction is necessary to provide consistent results in standard imaging planes using a balanced steady-state free precession water-fat separation postprocessing algorithm applied to standard cardiac CINE imaging.

Physical activity-related individual differences in functional human connectome are linked to fluid intelligence in older adults.

The study examined resting state functional connectivity (rs-FC) associated with moderate-to-vigorous physical activity (MV-PA), sedentary time (ST), TV viewing, computer use, and their relationship to cognitive performance in older adults. We used pre-intervention data from 119 participants from the Fit & Active Seniors trial. Multivariate pattern analysis revealed two seeds associated with MV-PA: right superior frontal gyrus (SFG; spanning frontoparietal [FPN] and ventral attention networks [VAN]) and right precentral (PrG) and postcentral gyri (PoG) of the somatosensory network (SN). A positive correlation between the right SFG seed and a cluster spanning default mode (DMN), dorsal attention (DAN), FPN, and visual networks (VIS) was linked to higher fluid intelligence, as was FC between the right PrG/PoG seed and a cluster in VIS. No significant rs-FC patterns associated with ST, TV viewing, or computer use were found. Our findings suggest that greater functional integration within networks implementing top-down control and within those supporting visuospatial abilities, paired with segregation between networks critical and those not critical to top-down control, may help promote cognitive reserve in more physically active seniors.

Resting-state functional connectivity-based parcellation of the human dentate nucleus: new findings and clinical relevance.

For years, the cerebellum was left out of functional magnetic resonance imaging (fMRI) studies due to technological limitations. The advent of novel data acquisition and reconstruction strategies (e.g., whole-brain simultaneous multi-slice imaging) employing multi-channel array coils has overcome such limitations, ushering unprecedented improvements in temporal signal-to-noise ratio and spatiotemporal resolution. Here, we aim to provide a brief report on the deep cerebellar nuclei, specifically focusing on the dentate nuclei, the primary output nuclei, situated within both cognitive and motor cerebello-cerebral circuits. We highlight the importance of functional parcellation in refining our understanding of broad resting-state functional connectivity (RSFC) in both health and disease. First, we review work relevant to the functional topography of the dentate nuclei, including recent advances in functional parcellation. Next, we review RSFC studies using the dentate nuclei as seed regions of interest in neurological and psychiatric populations and discuss the potential benefits of applying functionally defined subdivisions. Finally, we discuss recent technological advances and underscore ultrahigh-field neuroimaging as a tool to potentiate functionally parcellated RSFC analyses in clinical populations.

Alterations of Functional Connectivity in Autism and Attention-Deficit/Hyperactivity Disorder Revealed by Multi-Voxel Pattern Analysis.

Background: Autism and attention-deficit/hyperactivity disorder (ADHD) are comorbid neurodevelopmental disorders that share common and distinct neurobiological mechanisms, with disrupted brain connectivity patterns being a hallmark feature of both conditions. It is challenging to gain a mechanistic understanding of the underlying disorder, because brain connectivity changes in autism and ADHD are heterogeneous. Objectives: The present resting state functional MRI (rs-fMRI) study focuses on investigating the shared and distinct resting state-fMRI connectivity (rsFC) patterns in autistic and ADHD adults using multi-voxel pattern analysis (MVPA). By identifying spatial patterns of fMRI activity across a given time course, MVPA is an innovative and powerful method for generating seed regions of interest (ROIs) without a priori hypotheses. Methods: We performed a data-driven, whole-brain, connectome-wide MVPA on rs-fMRI data collected from 15 autistic, 19 ADHD, and 15 neurotypical (NT) young adults. Results: MVPA identified cerebellar vermis 9, precuneus, and the right cerebellum VI for autistic versus NT, right inferior frontal gyrus and vermis 9 for ADHD versus NT, and right dorsolateral prefrontal cortex for autistic versus ADHD as significant clusters. Post hoc seed-to-voxel analyses using these clusters as seed ROIs were performed for further characterization of group differences. The cerebellum VI, vermis, and precuneus in autistic adults, and the vermis and frontal regions in ADHD showed different connectivity patterns in comparison with NT. Conclusions: The study characterizes the rsFC profile of cerebellum with key cortical areas in autism and ADHD, and it emphasizes the importance of studying the role of the functional connectivity of the cerebellum in neurodevelopmental disorders.

Resting-State Functional Connectivity in Relapsing-Remitting Multiple Sclerosis with Mild Disability: A Data-Driven, Whole-Brain Multivoxel Pattern Analysis Study.

Background: Multivoxel pattern analysis (MVPA) has emerged as a powerful unbiased approach for generating seed regions of interest (ROIs) in resting-state functional connectivity (RSFC) analysis in a data-driven manner. Studies exploring RSFC in multiple sclerosis have produced diverse and often incongruent results. Objectives: The aim of the present study was to investigate RSFC differences between people with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HC). Methods: We performed a whole-brain connectome-wide MVPA in 50 RRMS patients with expanded disability status scale ≤4 and 50 age and gender-matched HCs. Results: Significant group differences were noted in RSFC in three clusters distributed in the following regions: anterior cingulate gyrus, right middle frontal gyrus, and frontal medial cortex. Whole-brain seed-to-voxel RSFC characterization of these clusters as seed ROIs revealed network-specific abnormalities, specifically in the anterior cingulate cortex and the default mode network. Conclusions: The network-wide RSFC abnormalities we report agree with the previous findings in RRMS, the cognitive and clinical implications of which are discussed herein. Impact statement This study investigated resting-state functional connectivity (RSFC) in relapsing-remitting multiple sclerosis (RRMS) people with mild disability (expanded disability status scale ≤4). Whole-brain connectome-wide multivoxel pattern analysis was used for assessing RSFC. Compared with healthy controls, we were able to identify three regions of interest for significant differences in connectivity patterns, which were then extracted as a mask for whole-brain seed-to-voxel analysis. A reduced connectivity was noted in the RRMS group, particularly in the anterior cingulate cortex and the default mode network regions, providing insights into the RSFC abnormalities in RRMS.

Big contributions of the little brain for precision psychiatry.

Our previous work using 3T functional Magnetic Resonance Imaging (fMRI) parcellated the human dentate nuclei (DN), the primary output of the cerebellum, to three distinct functional zones each contributing uniquely to default-mode, salience-motor, and visual brain networks. In this perspective piece, we highlight the possibility to target specific functional territories within the cerebellum using non-invasive brain stimulation, potentially leading to the refinement of cerebellar-based therapeutics for precision psychiatry. Significant knowledge gap exists in our functional understanding of cerebellar systems. Intervening early, gauging severity of illness, developing intervention strategies and assessing treatment response, are all dependent on our understanding of the cerebello-cerebral networks underlying the pathology of psychotic disorders. A promising yet under-examined avenue for biomarker discovery is disruptions in cerebellar output circuitry. This is primarily because most 3T MRI studies in the past had to exclude cerebellum from the field of view due to limitations in spatiotemporal resolutions. Using recent technological advances in 7T MRI (e.g., parallel transmit head coils) to identify functional territories of the DN, with a focus on dentato-cerebello-thalamo-cortical (CTC) circuitry can lead to better characterization of brain-behavioral correlations and assessments of co-morbidities. Such an improved mechanistic understanding of psychiatric illnesses can reveal aspects of CTC circuitry that can aid in neuroprognosis, identification of subtypes, and generate testable hypothesis for future studies.

The Differential Effects of Adiposity and Fitness on Functional Connectivity in Preadolescent Children.

PURPOSE: Childhood obesity is a global health concern, with >340 million youth considered overweight or obese. In addition to contributing greatly to health care costs, excess adiposity associated with obesity is considered a major risk factor for premature mortality from cardiovascular and metabolic diseases and is also negatively associated with cognitive and brain health. A complementary line of research highlights the importance of cardiorespiratory fitness, a by-product of engaging in physical activity, on an abundance of health factors, including cognitive and brain health. METHODS: This study investigated the relationship among excess adiposity (visceral adipose tissue [VAT], subcutaneous abdominal adipose tissue), total abdominal adipose tissue, whole-body percent fat [WB%FAT], body mass index (BMI), and fat-free cardiorespiratory fitness (FF-V̇O 2max ) on resting-state functional connectivity (RSFC) in 121 ( f = 68) children (7-11 yr) using a data-driven whole-brain multivoxel pattern analysis. RESULTS: Multivoxel pattern analysis revealed brain regions that were significantly associated with VAT, BMI, WB%FAT, and FF-V̇O 2 measures. Yeo's (2011) RSFC-based seven-network cerebral cortical parcellation was used for labeling the results . Post hoc seed-to-voxel analyses found robust negative correlations of VAT and BMI with areas involved in the visual, somatosensory, dorsal attention, ventral attention, limbic, frontoparietal, and default mode networks. Further, positive correlations of FF-V̇O 2 were observed with areas involved in the ventral attention and frontoparietal networks. These novel findings indicate that negative health factors in childhood may be selectively and negatively associated with the 7 Yeo-defined functional networks, yet positive health factors (FF-V̇O 2 ) may be positively associated with these networks. CONCLUSIONS: These novel results extend the current literature to suggest that BMI and adiposity are negatively associated with, and cardiorespiratory fitness (corrected for fat-free mass) is positively associated with, RSFC networks in children.

Resting state functional connectivity provides mechanistic predictions of future changes in sedentary behavior.

Sedentary behaviors are increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths worldwide. Understanding the mechanistic predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. It has been posited that humans have an innate attraction towards effort minimization and that inhibitory control is required to overcome this prepotent disposition. Consequently, we hypothesized that individual differences in the functional connectivity of brain regions implicated in inhibitory control and physical effort decision making at the beginning of an exercise intervention in older adults would predict the change in time spent sedentary over the course of that intervention. In 143 healthy, low-active older adults participating in a 6-month aerobic exercise intervention (with three conditions: walking, dance, stretching), we aimed to use baseline neuroimaging (resting state functional connectivity of two a priori defined seed regions), and baseline accelerometer measures of time spent sedentary to predict future pre-post changes in objectively measured time spent sedentary in daily life over the 6-month intervention. Our results demonstrated that functional connectivity between (1) the anterior cingulate cortex and the supplementary motor area and (2) the right anterior insula and the left temporoparietal/temporooccipital junction, predicted changes in time spent sedentary in the walking group. Functional connectivity of these brain regions did not predict changes in time spent sedentary in the dance nor stretch and tone conditions, but baseline time spent sedentary was predictive in these conditions. Our results add important knowledge toward understanding mechanistic associations underlying complex out-of-session sedentary behaviors within a walking intervention setting in older adults.

Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies.

Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer's disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.