The "vestibular neuromatrix": A proposed, expanded vestibular network from graph theory in post-concussive vestibular dysfunction.

Convergent clinical and neuroimaging evidence suggests that higher vestibular function is subserved by a distributed network including visuospatial, cognitive-affective, proprioceptive, and integrative brain regions. Clinical vestibular syndromes may perturb this network, resulting in deficits across a variety of functional domains. Here, we leverage structural and functional neuroimaging to characterize this extended network in healthy control participants and patients with post-concussive vestibular dysfunction (PCVD). Then, 27 healthy control subjects (15 females) and 18 patients with subacute PCVD (12 female) were selected for participation. Eighty-two regions of interest (network nodes) were identified based on previous publications, group-wise differences in BOLD signal amplitude and connectivity, and multivariate pattern analysis on affective tests. Group-specific "core" networks, as well as a "consensus" network comprised of connections common to all participants, were then generated based on probabilistic tractography and functional connectivity between the 82 nodes and subjected to analyses of node centrality and community structure. Whereas the consensus network was comprised of affective, integrative, and vestibular nodes, PCVD participants exhibited diminished integration and centrality among vestibular and affective nodes and increased centrality of visual, supplementary motor, and frontal and cingulate eye field nodes. Clinical outcomes, derived from dynamic posturography, were associated with approximately 62% of all connections but best predicted by amygdalar, prefrontal, and cingulate connectivity. No group-wise differences in diffusion metrics or tractography were noted. These findings indicate that cognitive, affective, and proprioceptive substrates contribute to vestibular processing and performance and highlight the need to consider these domains during clinical diagnosis and treatment planning.

Eagle-449: A volumetric, whole-brain compilation of brain atlases for vestibular functional MRI research.

Human vestibular processing involves distributed networks of cortical and subcortical regions which perform sensory and multimodal integrative functions. These functional hubs are also interconnected with areas subserving cognitive, affective, and body-representative domains. Analysis of these diverse components of the vestibular and vestibular-associated networks, and synthesis of their holistic functioning, is therefore vital to our understanding of the genesis of vestibular dysfunctions and aid treatment development. Novel neuroimaging methodologies, including functional and structural connectivity analyses, have provided important contributions in this area, but often require the use of atlases which are comprised of well-defined a priori regions of interest. Investigating vestibular dysfunction requires a more detailed atlas that encompasses cortical, subcortical, cerebellar, and brainstem regions. The present paper represents an effort to establish a compilation of existing, peer-reviewed brain atlases which collectively afford comprehensive coverage of these regions while explicitly focusing on vestibular substrates. It is expected that this compilation will be iteratively improved with additional contributions from researchers in the field.

Characterization of visual processing in temporomandibular disorders using functional magnetic resonance imaging.

BACKGROUND AND PURPOSE: Many patients with chronic pain report hypersensitivity not only to noxious stimuli, but also to other modalities including innocuous touch, sound, and light, possibly due to differences in the processing of these stimuli. The goal of this study was to characterize functional connectivity (FC) differences between subjects with temporomandibular disorders (TMD) and pain-free controls during a visual functional magnetic resonance imaging (fMRI) task that included an unpleasant, strobing visual stimulus. We hypothesized the TMD cohort would exhibit maladaptations in brain networks consistent with multisensory hypersensitivities observed in TMD patients. METHODS: This pilot study included 16 subjects, 10 with TMD and 6 pain-free controls. Clinical pain was characterized using self-reported questionnaires. Visual task-based fMRI data were collected on a 3T MR scanner and used to determine differences in FC via group independent component analysis. RESULTS: Compared to controls, subjects with TMD exhibited abnormally increased FC between the default mode network and lateral prefrontal areas involved in attention and executive function, and impaired FC between the frontoparietal network and higher order visual processing areas. CONCLUSIONS: The results indicate maladaptation of brain functional networks, likely due to deficits in multisensory integration, default mode network function, and visual attention and engendered by chronic pain mechanisms.

Visuo-vestibular and cognitive connections of the vestibular neuromatrix are conserved across age and injury populations.

BACKGROUND AND PURPOSE: Given the prevalence of vestibular dysfunction in pediatric concussion, there is a need to better understand pathophysiological disruptions within vestibular and associated cognitive, affective, and sensory-integrative networks. Although current research leverages established intrinsic connectivity networks, these are nonspecific for vestibular function, suggesting that a pathologically guided approach is warranted. The purpose of this study was to evaluate the generalizability of the previously identified "vestibular neuromatrix" in adults with and without postconcussive vestibular dysfunction to young athletes aged 14-17. METHODS: This retrospective study leveraged resting-state functional MRI data from two sites. Site A included adults with diagnosed postconcussive vestibular impairment and healthy adult controls and Site B consisted of young athletes with preseason, postconcussion, and postseason time points (prospective longitudinal data). Adjacency matrices were generated from preprocessed resting-state data from each sample and assessed for overlap and network structure in MATLAB. RESULTS: Analyses indicated the presence of a conserved "core" network of vestibular regions as well as areas subserving visual, spatial, and attentional processing. Other vestibular connections were also conserved across samples but were not linked to the "core" subnetwork by regions of interest included in this study. CONCLUSIONS: Our results suggest that connections between central vestibular, visuospatial, and known intrinsic connectivity networks are conserved across adult and pediatric participants with and without concussion, evincing the significance of this expanded, vestibular-associated network. Our findings thus support this network as a workable model for investigation in future studies of dysfunction in young athlete populations.

Topology of pain networks in patients with temporomandibular disorder and pain-free controls with and without concurrent experimental pain: A pilot study.

Temporomandibular disorders (TMD) involve chronic pain in the masticatory muscles and jaw joints, but the mechanisms underlying the pain are heterogenous and vary across individuals. In some cases, structural, functional, and metabolic changes in the brain may underlie the condition. In the present study, we evaluated the functional connectivity between 86 regions of interest (ROIs), which were chosen based on previously reported neuroimaging studies of pain and differences in brain morphology identified in an initial surface-based morphometry analysis. Our main objectives were to investigate the topology of the network formed by these ROIs and how it differs between individuals with TMD and chronic pain (n = 16) and pain-free control participants (n = 12). In addition to a true resting state functional connectivity scan, we also measured functional connectivity during a 6-min application of a noxious cuff stimulus applied to the left leg. Our principal finding is individuals with TMD exhibit more suprathreshold correlations (higher nodal degree) among all ROIs but fewer "hub" nodes (i.e., decreased betweenness centrality) across conditions and across all pain pathways. These results suggest is this pain-related network of nodes may be "over-wired" in individuals with TMD and chronic pain compared to controls, both at rest and during experimental pain.

Multimodal magnetic resonance imaging reveals distinct sensitivity of hippocampal subfields in asymptomatic stage of Alzheimer's disease.

While hippocampal atrophy and its regional susceptibility to Alzheimer's disease (AD) are well reported at late stages of AD, studies of the asymptomatic stage of AD are limited but could elucidate early stage pathophysiology as well as provide predictive biomarkers. In this study, we performed multi-modal magnetic resonance imaging (MRI) to estimate morphometry, functional connectivity, and tissue microstructure of hippocampal subfields in cognitively normal adults including those with asymptomatic AD. High-resolution resting-state functional, diffusion and structural MRI, cerebral spinal fluid (CSF), and neuropsychological evaluations were performed in healthy young adults (HY: n = 40) and healthy older adults with negative (HO-: n = 47) and positive (HO+ : n = 25) CSF biomarkers of AD. Morphometry, functional connectivity, and tissue microstructure were estimated from the structural, functional, and diffusion MRI images, respectively. Our results indicated that normal aging affected morphometry, connectivity, and microstructure in all hippocampal subfields, while the subiculum and CA1-3 demonstrated the greatest sensitivity to asymptomatic AD pathology. Tau, rather than amyloid-ß, was closely associated with imaging-derived synaptic and microstructural measures. Microstructural metrics were significantly associated with neuropsychological assessments. These findings suggest that the subiculum and CA1-3 are the most vulnerable in asymptomatic AD and tau level is driving these early changes.

Percutaneous electric nerve field stimulation alters cortical thickness in a pilot study of veterans with fibromyalgia.

Objective: To evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS). Materials & methods: This was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-one veterans with fibromyalgia were randomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST with auricular PENFS (ST + PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2 weeks post-treatment.​ Clinical pain and physical function were also assessed at these timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness. Results: Both the ST + PENFS and ST groups reported a decrease in pain with treatment. Volumetric: Cortical thickness significantly decreased in the left middle posterior cingulate (p = 0.018) and increased in the left cuneus (p = 0.014) following ST + PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (p = 0.02) inversely correlated with pain scores. ST + PENFS group right hemisphere posterior dorsal cingulate size significantly (p = 0.044) positively correlated with pain scores. GABA: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (p = 0.083) using a linear mixed effects model. Conclusions: Results suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.

Alterations in Resting-State Functional Brain Connectivity and Correlations with Vestibular/Ocular-Motor Screening Measures in Postconcussion Vestibular Dysfunction.

BACKGROUND AND PURPOSE: Vestibular symptoms after concussion are common and associated with protracted recovery. The purpose of this study is to define resting-state functional MRI (rs-fMRI) brain connectivity alterations in patients with postconcussion vestibular dysfunction (PCVD) and correlations between rs-fMRI connectivity and symptoms provoked during Vestibular/Ocular-Motor Screening (VOMS) assessment. METHODS: Prospective IRB approved study. STUDY GROUP: 12 subjects with subacute PCVD (2-10 weeks); control group: 10 age-matched subjects without history of concussion or vestibular impairment. Both groups underwent clinical vestibular assessment. rs-fMRI was acquired on 3.0T Siemens Trio with a 12-channel head coil. rs-fMRI data analysis included independent component analysis-based functional connectivity group differences, graph theory analysis, and ROI-to-ROI connectivity correlation analysis with VOMS clinical derivatives. Group difference maps between resting-state networks were calculated using dual regression method and corrected for multiple comparisons. Correlation analysis between ROI-to-ROI rs-fMRI brain activation and VOMS assessment ratings was performed using Pearson correlation coefficient, with a significance threshold of P ≤ .05. RESULTS: Compared to controls, PCVD group demonstrated significantly increased rs-fMRI connectivity between the default-mode network and right middle frontal gyrus and right postcentral gyrus; and between a vestibular-sensorimotor network and right prefrontal cortex. Significant positive correlations were found between clinical derivative VOMS scores and components of the vestibular, visual networks, and multisensory processing cortical representations. CONCLUSION: Altered rs-fMRI brain connectivity with increased connectivity of visual input, multisensory processing, and spatial memory in PCVD is correlative with clinical derivative VOMS scores, suggesting maladaptive brain plasticity underlying vestibular symptomatology.

Changes in brain metabolites and resting-state connectivity in collegiate basketball players as a function of play time.

BACKGROUND AND PURPOSE: Magnetic resonance (MR) biomarkers are emerging for sports-related traumatic brain injury (TBI), but the effect of play time has not been characterized. Our goal was to characterize brain and inflammatory marker changes as a function of play time. METHODS: Nine male players (21±2 years old) from a single collegiate basketball team were included. MR imaging (MRI), MR spectroscopy, and plasma were collected pre, mid, and postseason. Game time played was calculated for each subject. Changes in brain volume, diffusion tensor imaging (DTI), metabolites (normalized to total creatine, tCr), temperature, structural and functional connectivity, and inflammatory markers were quantified. RESULTS: Myo-inositol/tCr in the left frontal white matter and brain temperature in the left frontal lobe varied significantly between time points. Glutamate (Glu/tCr) in the right frontal white matter and N-acetylaspartate in the posterior cingulate cortex (PCC) were negatively associated with minutes played. Midseason play time was associated with stronger blood-oxygen-level-dependent correlations between PCC and occipital areas, and weaker correlations between PCC and superior frontal connectivity. PCC Glu/tCr was positively associated with connectivity between the PCC and posterior supramarginal gyrus at preseason and with connectivity across time points among several right hemisphere regions. Volume, DTI, and inflammatory markers did not vary significantly. CONCLUSION: Given that MR parameters vary with game play time in the absence of diagnosed injury, play time should be considered as a factor in sports-related TBI research.

Impact of App-Delivered Mindfulness Meditation on Functional Connectivity, Mental Health, and Sleep Disturbances Among Physician Assistant Students: Randomized, Wait-list Controlled Pilot Study.

BACKGROUND: Health care provider and trainee burnout results in substantial national and institutional costs and profound social effects. Identifying effective solutions and interventions to cultivate resilience among health care trainees is critical. Although less is known about the mental health needs of physician assistants (PAs) or PA students, accumulating research indicates that they experience similarly alarming rates of burnout, depression, and emotional exhaustion. Mobile app-delivered mindfulness meditation may be an effective part of salubrious programming to bolster long-term resilience and health among PA students. OBJECTIVE: This study aims to examine the impact of app-delivered mindfulness meditation on self-reported mental health symptoms among PA students. A secondary aim is to investigate changes in brain connectivity to identify neurobiological changes related to changes in mental health symptoms. METHODS: We recruited PA students enrolled in their third semester of PA school and used a longitudinal, randomized, wait-list-controlled design. Participants randomized to the mindfulness group were provided 1-year subscriptions to the 10% Happier app, a consumer-based meditation app, and asked to practice every day for 8 weeks. Before randomization and again after completion of the 8-week program, all participants completed resting-state functional magnetic resonance imaging as well as self-report assessments of burnout, depression, anxiety, and sleep impairment. App use was acquired as a measure of mindfulness practice time. RESULTS: PA students randomized to the mindfulness group reported improvements in sleep impairment compared with those randomized to the wait-list control group (ηp2=0.42; P=.01). Sleep impairment decreased significantly in the mindfulness group (19% reduction; P=.006) but not in the control group (1% reduction; P=.71). There were no other significant changes in mental health for those randomized to app-delivered mindfulness. Across all students, changes in sleep impairment were associated with increased resting-state functional connectivity between the medial prefrontal cortex (a component of the default mode network) and the superior temporal gyrus, as well as between areas important for working memory. Changes in connectivity predicted categorical conversion from impaired to nonimpaired sleep in the mindfulness group. CONCLUSIONS: This pilot study is the first to examine app-based mindfulness for PA students' mental health and investigate the impact of mindfulness on PA students' brain function. These findings suggest that app-delivered mindfulness may be an effective tool to improve sleep dysfunction and that it may be an important part of the programming necessary to reduce the epidemic of suffering among health profession trainees.

The Impact of App-Delivered Mindfulness Meditation on Functional Connectivity and Self-Reported Mindfulness Among Health Profession Trainees.

Objectives: Previous research indicates that mindfulness meditation reduces anxiety and depression and enhances well-being. We examined the impact of app-delivered mindfulness meditation on resting state functional MRI (fMRI) connectivity among physician assistant (PA) students and surgery residents. Methods: PA students and residents were randomized to receive a popular meditation app or to wait-list control group. Before and after the 8-week meditation period, we acquired fMRI scans of participants' resting state, and participants completed a self-report measure of mindfulness. We used a 2 × 2, within- and between-group factorial design and leveraged a whole-brain connectome approach to examine changes in within- and between-network connectivity across the entire brain, and to examine whether changes in connectivity were associated with app use or to changes in self-reported mindfulness. Results: Meditation practitioners exhibited significantly stronger connectivity between the frontoparietal network and the left and right nucleus accumbens and between the default mode (DMN) and salience networks, among other regions. Mindfulness practice time was correlated with increased connectivity between the lateral parietal cortex and the supramarginal gyrus, which were also positively correlated with increased scores on the "Describing" subscale of the Five Facet Mindfulness Questionnaire between baseline and post-meditation. These findings are consistent with previous research indicating that mindfulness-based interventions alter functional connectivity within the DMN and between the DMN and other networks both during meditation and at rest, as well as increased connectivity in systems important for emotion and reward. Conclusions: Recent commentaries call for healthcare provider and trainee wellness programs that are sustainable and preventive in nature rather than reactive; these data indicate that even brief sessions of app-delivered mindfulness practice are associated with functional connectivity changes in a dose-dependent manner.

Ischemia and ischemic tolerance in the brain: an overview.

Stroke is the third leading cause of death and the leading cause of adult disability in the United States. This review outlines the pathways that lead to cell death following stroke, and also summarizes the current literature on the phenomenon of ischemic tolerance. Ischemic tolerance is an endogenous neuroprotective mechanism by which neurons are protected from the deleterious effects of brain ischemia that occur during and after stroke. A better understanding of the processes that lead to cell death after stroke and endogenous neuroprotective mechanisms like ischemic tolerance could help in the development of new treatment strategies for this devastating neurological disease.

Hippocampal subfields differentially correlate with chronic pain in older adults.

Although previous studies have demonstrated that the hippocampus plays a role in pain processing, the role of hippocampal subfields is uncertain. The goal of this study was to examine the relationship between hippocampal subfield volumes and chronic pain in nondemented older adults. The study sample included 86 community-residing adults age 70 or older who were free of dementia and recruited from the Einstein Aging Study. Chronic pain was defined as pain over the last 3 months, that was moderate or severe (minimum rating of 4 out of 10) most, or all of the time. Hippocampal subfield volumes were estimated using FreeSurfer software. We modeled the association between chronic pain and hippocampal and subfield volume using linear regression. The sample had a mean age of 80 and was 58% female. Chronic pain, present in 55% of the sample, was associated with smaller right and total hippocampal volumes, particularly in women, after adjusting for age, education, and intracranial volume (eTICV). In addition, in women, volume was significantly reduced in participants with chronic pain in right CA2-3 (ß=-0.35, p=0.010), right CA4-DG (ß=-0.35, p=0.011), left presubiculum (ß=-0.29, p=0.030), and left fimbria (ß=-0.30, p=0.023). In men, chronic pain was not associated with the volume of any of the hippocampal subfield volumes. Chronic pain in women is associated with a reduction in the volume of right hippocampus and also selected hippocampal subfields. Future studies should clarify the mechanisms underlying the association between regional hippocampal volumes and chronic pain, particularly in women.