Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Functional MRI of the Brainstem for Assessing Its Autonomic Functions: From Imaging Parameters and Analysis to Functional Atlas.

BACKGROUND: The brainstem is a crucial component of the central autonomic nervous (CAN) system. Functional MRI (fMRI) of the brainstem remains challenging due to a range of factors, including diverse imaging protocols, analysis, and interpretation. PURPOSE: To develop an fMRI protocol for establishing a functional atlas in the brainstem. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Ten healthy subjects (four males, six females). FIELD STRENGTH/SEQUENCE: Using a 3.0 Tesla MR scanner, we acquired T1-weighted images and three different fMRI scans using fMRI protocols of the optimized functional Imaging of Brainstem (FIBS), the Human Connectome Project (HCP), and the Adolescent Brain Cognitive Development (ABCD) project. ASSESSMENT: The temporal signal-to-noise-ratio (TSNR) of fMRI data was compared between the FIBS, HCP, and ABCD protocols. Additionally, the main normalization algorithms (i.e., FSL-FNIRT, SPM-DARTEL, and ANTS-SyN) were compared to identify the best approach to normalize brainstem data using root-mean-square (RMS) error computed based on manually defined reference points. Finally, a functional autonomic brainstem atlas that maps brainstem regions involved in the CAN system was defined using meta-analysis and data-driven approaches. STATISTICAL TESTS: ANOVA was used to compare the performance of different imaging and preprocessing pipelines with multiple comparison corrections (P ≤ 0.05). Dice coefficient estimated ROI overlap, with 50% overlap between ROIs identified in each approach considered significant. RESULTS: The optimized FIBS protocol showed significantly higher brainstem TSNR than the HCP and ABCD protocols (P ≤ 0.05). Furthermore, FSL-FNIRT RMS error (2.1 ± 1.22 mm; P ≤ 0.001) exceeded SPM (1.5 ± 0.75 mm; P ≤ 0.01) and ANTs (1.1 ± 0.54 mm). Finally, a set of 12 final brainstem ROIs with dice coefficient ≥0.50, as a step toward the development of a functional brainstem atlas. DATA CONCLUSION: The FIBS protocol yielded more robust brainstem CAN results and outperformed both the HCP and ABCD protocols. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Oral ketamine effects on dynamics of functional network connectivity in patients treated for chronic suicidality.

The underlying brain mechanisms of ketamine in treating chronic suicidality and the characteristics of patients who will benefit from ketamine treatment remain unclear. To address these gaps, we investigated temporal variations of brain functional synchronisation in patients with suicidality treated with ketamine in a 6-week open-label oral ketamine trial. The trial's primary endpoint was the Beck Scale for Suicide Ideation (BSS). Patients who experienced greater than 50% improvement in BSS scores or had a BSS score less than 6 at the post-treatment and follow-up (10 weeks) visits were considered responders and persistent responders, respectively. The reoccurring and transient connectivity pattern (termed brain state) from 29 patients (45.6 years ± 14.5, 15 females) were investigated by dynamic functional connectivity analysis of resting-state functional MRI at the baseline, post-treatment, and follow-up. Post-treatment patients showed significantly more (FDR-Q = 0.03) transitions among whole brain states than at baseline. We also observed increased dwelling time (FDR-Q = 0.04) and frequency (FDR-Q = 0.04) of highly synchronised brain state at follow-up, which were significantly correlated with BSS scores (both FDR-Q = 0.008). At baseline, persistent responders had higher fractions (FDR-Q = 0.03, Cohen's d = 1.39) of a cognitive control network state with high connectivities than non-responders. These findings suggested that ketamine enhanced brain changes among different synchronisation patterns and enabled high synchronisation patterns in the long term, providing a possible biological pathway for its suicide-prevention effects. Moreover, differences in cognitive control states at baseline may be used for precise ketamine treatment planning.

Understanding Wellbeing Profiles According to White Matter Structural Connectivity Sub-types in Early Adolescents: The First Hundred Brains Cohort from the Longitudinal Adolescent Brain Study.

Wellbeing is protective against the emergence of psychopathology. Neurobiological markers associated with mental wellbeing during adolescence are important to understand. Limited research has examined neural networks (white matter tracts) and mental wellbeing in early adolescence specifically. A cross-sectional diffusion tensor imaging analysis approach was conducted, from the Longitudinal Adolescent Brain study, First Hundred Brains cohort (N = 99; 46.5% female; Mage = 13.01, SD = 0.55). Participants completed self-report measures including wellbeing, quality-of-life, and psychological distress. Potential neurobiological profiles using fractional anisotropy, axial, and radial diffusivity were determined via a whole brain voxel-wise approach, and hierarchical cluster analysis of fractional anisotropy values, obtained from 21 major white matter tracts. Three cluster groups with significantly different neurobiological profiles were distinguished. No significant differences were found between the three cluster groups and measures of wellbeing, but two left lateralized significant associations between white matter tracts and wellbeing measures were found. These results provide preliminary evidence for potential neurobiological markers of mental health and wellbeing in early adolescence and should be tracked longitudinally to provide more detailed and robust findings.

A longitudinal study of functional connectome uniqueness and its association with psychological distress in adolescence.

Each human brain has a unique functional synchronisation pattern (functional connectome) analogous to a fingerprint that underpins brain functions and related behaviours. Here we examine functional connectome (whole-brain and 13 networks) maturation by measuring its uniqueness in adolescents who underwent brain scans longitudinally from 12 years of age every four months. The uniqueness of a functional connectome is defined as its ratio of self-similarity (from the same subject at a different time point) to the maximal similarity-to-others (from a given subject and any others at a different time point). We found that the unique whole brain connectome exists in 12 years old adolescents, with 92% individuals having a whole brain uniqueness value greater than one. The cingulo-opercular network (CON; a long-acting 'brain control network' configuring information processing) demonstrated marginal uniqueness in early adolescence with 56% of individuals showing uniqueness greater than one (i.e., more similar to her/his own CON four months later than those from any other subjects) and this increased longitudinally. Notably, the low uniqueness of the CON correlates (ß = -18.6, FDR-Q < < 0.001) with K10 levels at the subsequent time point. This association suggests that the individualisation of CON network is related to psychological distress levels. Our findings highlight the potential of longitudinal neuroimaging to capture mental health problems in young people who are undergoing profound neuroplasticity and environment sensitivity period.

Subacute cytokine changes after a traumatic brain injury predict chronic brain microstructural alterations on advanced diffusion imaging in the male rat.

INTRODUCTION: The process of neuroinflammation occurring after traumatic brain injury (TBI) has received significant attention as a potential prognostic indicator and interventional target to improve patients' outcomes. Indeed, many of the secondary consequences of TBI have been attributed to neuroinflammation and peripheral inflammatory changes. However, inflammatory biomarkers in blood have not yet emerged as a clinical tool for diagnosis of TBI and predicting outcome. The controlled cortical impact model of TBI in the rodent gives reliable readouts of the dynamics of post-TBI neuroinflammation. We now extend this model to include a panel of plasma cytokine biomarkers measured at different time points post-injury, to test the hypothesis that these markers can predict brain microstructural outcome as quantified by advanced diffusion-weighted magnetic resonance imaging (MRI). METHODS: Fourteen 8-10-week-old male rats were randomly assigned to sham surgery (n = 6) and TBI (n = 8) treatment with a single moderate-severe controlled cortical impact. We collected blood samples for cytokine analysis at days 1, 3, 7, and 60 post-surgery, and carried out standard structural and advanced diffusion-weighted MRI at day 60. We then utilized principal component regression to build an equation predicting different aspects of microstructural changes from the plasma inflammatory marker concentrations measured at different time points. RESULTS: The TBI group had elevated plasma levels of IL-1ß and several neuroprotective cytokines and chemokines (IL-7, CCL3, and GM-CSF) compared to the sham group from days 3 to 60 post-injury. The plasma marker panels obtained at day 7 were significantly associated with the outcome at day 60 of the trans-hemispheric cortical map transfer process that is a frequent finding in unilateral TBI models. DISCUSSION: These results confirm and extend prior studies showing that day 7 post-injury is a critical temporal window for the reorganisation process following TBI. High plasma level of IL-1ß and low plasma levels of the neuroprotective IL-7, CCL3, and GM-CSF of TBI animals at day 60 were associated with greater TBI pathology.

Functional connectivity of brain associated with passive range of motion exercise: Proprioceptive input promoting motor activation?

Soft robotics have come to the forefront of devices available for rehabilitation following stroke; however, objective evaluation of the specific brain changes following rehabilitation with these devices is lacking. In this study, we utilized functional Magnetic Resonance Imaging (fMRI) and dynamic causal modeling (DCM) to characterize the activation of brain areas with a MRI compatible glove actuator compared to the conventional manual therapy. Thirteen healthy volunteers engaged in a motor-visual fMRI task under four different conditions namely active movement, manual passive movement, passive movement using a glove actuator, and crude tactile stimulation. Brain activity following each task clearly identified the somatosensory motor area (SMA) as a major hub orchestrating activity between the primary motor (M1) and sensory (S1) cortex. During the glove-induced passive movement, activity in the motor-somatosensory areas was reduced, but there were significant increases in motor cortical activity compared to manual passive movement. We estimated the modulatory signaling from within a defined sensorimotor network (SMA, M1, and S1), through DCM and highlighted a dual-gating of sensorimotor inputs to the SMA. Proprioceptive signaling from S1 to the SMA reflected positive coupling for the manually assisted condition, while M1 activity was positively coupled to the SMA during the glove condition. Importantly, both the S1 and M1 were shown to influence each other's connections with the SMA, with inhibitory nonlinear modulation by the M1 on the S1-SMA connection, and similarly S1 gated the M1-SMA connection. The work is one of the first to have applied effective connectivity to examine sensorimotor activity ensued by manual or robotic passive range of motion exercise, crude tactile stimulation, and voluntary movements to provide a basis for the mechanism by which soft actuators can alter brain activity.

Tauopathy in veterans with long-term posttraumatic stress disorder and traumatic brain injury.

PURPOSE: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) have emerged as independent risk factors for an earlier onset of Alzheimer's disease (AD), although the pathophysiology underlying this risk is unclear. Postmortem studies have revealed extensive cerebral accumulation of tau following multiple and single TBI incidents. We hypothesized that a history of TBI and/or PTSD may induce an AD-like pattern of tau accumulation in the brain of nondemented war veterans. METHODS: Vietnam War veterans (mean age 71.4 years) with a history of war-related TBI and/or PTSD underwent [18F]AV145 PET as part of the US Department of Defense Alzheimer's Disease Neuroimaging Initiative. Subjects were classified into the following four groups: healthy controls (n = 21), TBI (n = 10), PTSD (n = 32), and TBI+PTSD (n = 17). [18F]AV1451 reference tissue-normalized standardized uptake value (SUVr) maps, scaled to the cerebellar grey matter, were tested for differences in tau accumulation between groups using voxel-wise and region of interest approaches, and the SUVr results were correlated with neuropsychological test scores. RESULTS: Compared to healthy controls, all groups showed widespread tau accumulation in neocortical regions overlapping with typical and atypical patterns of AD-like tau distribution. The TBI group showed higher tau accumulation than the other clinical groups. The extent of tauopathy was positively correlated with the neuropsychological deficit scores in the TBI+PTSD and PTSD groups. CONCLUSION: A history of TBI and/or PTSD may manifest in neurocognitive deficits in association with increased tau deposition in the brain of nondemented war veterans decades after their trauma. Further investigation is required to establish the burden of increased risk of dementia imparted by earlier TBI and/or PTSD.

Hippocampal subfield volumes predict treatment response to oral ketamine in people with suicidality.

Ongoing stress results in hippocampal neuro-structural alterations which produce pathological consequences, including depression and suicidality. Ketamine may ameliorate stress related illnesses, including suicidality, via neuroplasticity processes. This novel study sought to determine whether oral ketamine treatment specifically affects hippocampal (whole and subfield) volumes in patients with chronic suicidality and MDD. It was hypothesised that oral ketamine treatment would differentially alter hippocampal volumes in trial participants categorised as ketamine responders, versus those who were non-responders. Twenty-eight participants received 6 single, weekly doses of oral ketamine (0.5-3 mg/kg) and underwent MRI scans at pre-ketamine (week 0), post-ketamine (week 6), and follow up (week 10). Hippocampal subfield volumes were extracted using the longitudinal pipeline in FreeSurfer. Participants were grouped according to ketamine response status and then compared in terms of grey matter volume (GMV) changes, among 10 hippocampal regions, over 6 and 10 weeks. Mixed ANOVAs were used to analyse interactions between time and group. Post treatment analysis revealed a significant main effect of group for three left hippocampal GMVs as well in the left and right whole hippocampus. Ketamine acute responders (Week 6) showed increased GMVs in both left and right whole hippocampus and in three subfields compared to acute non-responders, across all three timepoints, suggesting that pre-treatment increased hippocampal GMVs (particularly left hemisphere) may be predictive biomarkers of acute treatment response. Future studies should further investigate the potential of hippocampal volumes as a biomarker of ketamine treatment response.

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI.

Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS. This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated. In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.

Self-reported Fatigue was Associated with Increased White-matter Alterations in Long-term Traumatic Brain Injury and Posttraumatic Stress Disorder Patients.

Fatigue is a long-lasting problem in traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), with limited research that investigated the fatigue-related white-matter changes within TBI and/or PTSD cohorts. This exploratory cross-sectional study used diffusion tensor imaging (DTI) and neuropsychological data collected from 153 male Vietnam War veterans, as part of the Alzheimer's Disease Neuroimaging Initiative - Department of Defense, and were divided clinically into control veterans, PTSD, TBI, and with both TBI and PTSD (TBI + PTSD). The existence of fatigue was defined by the question "Do you often feel tired, fatigued, or sleepy during the daytime?". DTI data were compared between fatigue and non-fatigue subgroups in each clinical group using tract-based spatial statistics voxel-based differences. Fatigue was reported in controls (29.55%), slightly higher in TBI (52.17%, PBenf = 0.06), and significantly higher in both TBI + PTSD (66.67%, PBenf = 0.001) and PTSD groups (79.25%, PBenf < 0.001). Compared to non-fatigued subgroups, no white-matter differences were observed in the fatigued subgroups of control or TBI, while the fatigued PTSD subgroup only showed increased diffusivity measures (i.e., radial and axial), and the fatigued TBI + PTSD subgroup showed decreased fractional anisotropy and increased diffusivity measures (PFWE ≤ 0.05). The results act as preliminary findings suggesting fatigue to be significantly reported in TBI + PTSD and PTSD decades post-trauma with a possible link to white-matter microstructural differences in both PTSD and TBI + PTSD. Future studies with larger cohorts and detailed fatigue assessments would be required to identify the white-matter changes associated with fatigue in these cohorts.

Diffusion tensor imaging and plasma immunological biomarker panel in a rat traumatic brain injury (TBI) model and in human clinical TBI.

Introduction: Neuroinflammatory reactions play a significant role in the pathology and long-term consequences of traumatic brain injury (TBI) and may mediate salutogenic processes that white matter integrity. This study aimed to investigate the relationship between inflammatory markers and white matter integrity following TBI in both a rat TBI model and clinical TBI cases. Methods: In the rat model, blood samples were collected following a controlled cortical impact (CCI) to assess a panel of inflammatory markers; MR-based diffusion tensor imaging (DTI) was employed to evaluate white matter integrity 60 days post-injury. 15 clinical TBI patients were similarly assessed for a panel of inflammatory markers and DTI post-intensive care unit discharge. Blood samples from healthy controls were used for comparison of the inflammatory markers. Results: Time-dependent elevations in immunological markers were observed in TBI rats, with a correlation to preserved fractional anisotropy (FA) in white matter. Specifically, TBI-induced increased plasma levels of IL-1ß, IL-6, G-CSF, CCL3, CCL5, and TNF-α were associated with higher white matter integrity, as measured by FA. Clinical cases had similar findings: elevated inflammatory markers (relative to controls) were associated with preservation of FA in vulnerable white matter regions. Discussion: Inflammatory markers in post-TBI plasma samples are ambivalent with respect to prediction of favourable outcome versus a progression to more pervasive pathology and morbidity.

Treatment response with ketamine in chronic suicidality: An open label functional connectivity study.

BACKGROUND: Ketamine has recently been proposed as a treatment option for suicidality. Whilst its mechanism of action has been explored at molecular levels, the effect on the brain at the organ level remains unclear. Here we investigate immediate post-treatment and prolonged large-scale resting-state neural network changes to elucidate the neuronal underpinnings associated with ketamine's therapeutic effects. METHODS: Twenty-eight adults (aged 22-72 years) participated in the Oral Ketamine Trial On Suicidality, which is an open-label trial of weekly sub-anaesthetic doses of oral ketamine over 6 weeks. MRI was acquired at baseline, post-treatment, and follow-up. Functional connectivity changes at post-treatment and follow-up were examined using seed based and independent component analysis. RESULTS: The seed-based connectivity analysis revealed significantly reduced connectivity at post-treatment from the right hippocampus to both right and left superior frontal gyrus, from the left anterior parahippocampus to right superior frontal gyrus, left superior frontal gyrus, right middle frontal gyrus, and left frontal operculum cortex. Compared with baseline, the ICA showed reduced anterior default mode network connectivities to bilateral posterior cingulate cortex, middle and anterior cingulate cortex, lingual gyrus, and cuneus and increased connectivity of the frontoparietal network to the right superior parietal lobule at post-treatment. LIMITATIONS: Open label pilot study. CONCLUSIONS: We have shown sub-anaesthetic doses of ketamine alters connectivity in networks which have been shown to be aberrantly hyper-connected in numerous psychiatric conditions. These neurocircuitry changes are supported by significant reductions in suicide ideation. Our results provide support for the use of ketamine as a treatment for suicidality.

Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis.

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results. The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases. After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep. Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency, decreased stage 2 sleep, more Stage 3, and longer rapid eye movement sleep latency. However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency. The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.

Escalation of Tau Accumulation after a Traumatic Brain Injury: Findings from Positron Emission Tomography.

Traumatic brain injury (TBI) has come to be recognized as a risk factor for Alzheimer's disease (AD), with poorly understood underlying mechanisms. We hypothesized that a history of TBI would be associated with greater tau deposition in elders with high-risk for dementia. A Groups of 20 participants with self-reported history of TBI and 100 without any such history were scanned using [18F]-AV1451 positron emission tomography as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Scans were stratified into four groups according to TBI history, and by clinical dementia rating scores into cognitively normal (CDR = 0) and those showing cognitive decline (CDR ≥ 0.5). We pursued voxel-based group comparison of [18F]-AV1451 uptake to identify the effect of TBI history on brain tau deposition, and for voxel-wise correlation analyses between [18F]-AV1451 uptake and different neuropsychological measures and cerebrospinal fluid (CSF) biomarkers. Compared to the TBI-/CDR ≥ 0.5 group, the TBI+/CDR ≥ 0.5 group showed increased tau deposition in the temporal pole, hippocampus, fusiform gyrus, and inferior and middle temporal gyri. Furthermore, the extent of tau deposition in the brain of those with TBI history positively correlated with the extent of cognitive decline, CSF-tau, and CSF-amyloid. This might suggest TBI to increase the risk for tauopathies and Alzheimer's disease later in life.

Association of sub-acute changes in plasma amino acid levels with long-term brain pathologies in a rat model of moderate-severe traumatic brain injury.

Introduction: Traumatic brain injury (TBI) induces a cascade of cellular alterations that are responsible for evolving secondary brain injuries. Changes in brain structure and function after TBI may occur in concert with dysbiosis and altered amino acid fermentation in the gut. Therefore, we hypothesized that subacute plasma amino acid levels could predict long-term microstructural outcomes as quantified using neurite orientation dispersion and density imaging (NODDI). Methods: Fourteen 8-10-week-old male rats were randomly assigned either to sham (n = 6) or a single moderate-severe TBI (n = 8) procedure targeting the primary somatosensory cortex. Venous blood samples were collected at days one, three, seven, and 60 post-procedure and NODDI imaging were carried out at day 60. Principal Component Regression analysis was used to identify time dependent plasma amino acid concentrations after in the subacute phase post-injury that predicted NODDI metric outcomes at day 60. Results: The TBI group had significantly increased plasma levels of glutamine, arginine, alanine, proline, tyrosine, valine, isoleucine, leucine, and phenylalanine at days three-seven post-injury. Higher levels of several neuroprotective amino acids, especially the branched-chain amino acids (valine, isoleucine, leucine) and phenylalanine, as well as serine, arginine, and asparagine at days three-seven post-injury were also associated with lower isotropic diffusion volume fraction measures in the ventricles and thus lesser ventricular dilation at day 60. Discussion: In the first such study, we examined the relationship between the long-term post-TBI microstructural outcomes across whole brain and the subacute changes in plasma amino acid concentrations. At days three to seven post-injury, we observed that increased plasma levels of several amino acids, particularly the branched-chain amino acids and phenylalanine, were associated with lesser degrees of ventriculomegaly and hydrocephalus TBI neuropathology at day 60 post-injury. The results imply that altered amino acid fermentation in the gut may mediate neuroprotection in the aftermath of TBI.

Traumatic brain injury fast-forwards Alzheimer's pathology: evidence from amyloid positron emission tomorgraphy imaging.

PURPOSE: Traumatic brain injury (TBI) has been proposed as a risk factor for Alzheimer's disease (AD), although the mechanisms underlying the putative association are poorly understood. We investigated elderly individuals with a remote history of TBI, aiming to understand how this may have influenced amyloidosis, neurodegeneration, and clinical expression along the AD continuum. METHODS: Total of 241 individual datasets including amyloid beta (Aß) positron emission tomography ([18F]-AV45), structural MRI, and neuropsychological measures, were obtained from the Alzheimer's Disease Neuroimaging Initiative. The data were stratified into groups with (TBI +) or without (TBI -) history of head injury, and by clinical dementia rating (CDR) scores, into subgroups with normal cognition (CDR = 0) and those with symptomatic cognitive decline (CDR ≥ 0.5). We contrasted the TBI + and TBI - subgroups with respect to the onset age and extent of cognitive decline, cortical thickness changes, and Aß standard uptake value (SUVr). RESULTS: Compared to the TBI -/CDR ≥ 0.5 subgroup, the TBI + /CDR ≥ 0.5 subgroup showed a 3-4 year earlier age of cognitive impairment onset (ACIO, p = 0.005). Among those participants on the AD continuum (Aß + , as defined by a cortical SUVr ≥ 1.23), irrespective of current CDR, a TBI + history was associated with greater Aß deposition and more pronounced cortical thinning. When matched for severity of cognitive status, the TBI + /CDR ≥ 0.5 group showed greater Aß burden, but earlier ACIO as compared to the TBI -/CDR ≥ 0.5, suggesting a more indolent clinical AD progression in those with TBI history. CONCLUSION: Remote TBI history may alter the AD onset trajectory, with approximately 4 years earlier ACIO, greater amyloid deposition, and cortical thinning.

The effect of mindfulness training on resting-state networks in pre-adolescent children with sub-clinical anxiety related attention impairments.

Mindfulness training has been associated with improved attention and affect regulation in preadolescent children with anxiety related attention impairments, however little is known about the underlying neurobiology. This study sought to investigate the impact of mindfulness training on functional connectivity of attention and limbic brain networks in pre-adolescents. A total of 47 children with anxiety and/or attention issues (aged 9-11 years) participated in a 10-week mindfulness intervention. Anxiety and attention measures and resting-state fMRI were completed at pre- and post-intervention. Sustained attention was measured using the Conners Continuous Performance Test, while the anxiety levels were measured using the Spence Children's Anxiety Scale. Functional networks were estimated using independent-component analysis, and voxel-based analysis was used to determine the difference between the time-points to identify the effect of the intervention on the functional connectivity. There was a significant decrease in anxiety symptoms and improvement in attention scores following the intervention. From a network perspective, the results showed increased functional connectivity post intervention in the salience and fronto-parietal networks as well as the medial-inferior temporal component of the default mode network. Positive correlations were identified in the fronto-parietal network with Hit Response Time and the Spence Children's Anxiety Scale total and between the default mode network and Hit Response Time. A 10-week mindfulness intervention in children was associated with a reduction in anxiety related attention impairments, which corresponded with concomitant changes in functional connectivity.

Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: A cross-sectional neuroimaging study toward its neuropathophysiology and diagnosis.

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a debilitating illness affecting up to 24 million people worldwide but concerningly there is no known mechanism for ME/CFS and no objective test for diagnosis. A series of our neuroimaging findings in ME/CFS, including functional MRI (fMRI) signal characteristics and structural changes in brain regions particularly sensitive to hypoxia, has informed the hypothesis that abnormal neurovascular coupling (NVC) may be the neurobiological origin of ME/CFS. NVC is a critical process for normal brain function, in which glutamate from an active neuron stimulates Ca2+ influx in adjacent neurons and astrocytes. In turn, increased Ca2+ concentrations in both astrocytes and neurons trigger the synthesis of vascular dilator factors to increase local blood flow assuring activated neurons are supplied with their energy needs.This study investigates NVC using multimodal MRIs: (1) hemodynamic response function (HRF) that represents regional brain blood flow changes in response to neural activities and will be modeled from a cognitive task fMRI; (2) respiration response function (RRF) represents autoregulation of regional blood flow due to carbon dioxide and will be modeled from breath-holding fMRI; (3) neural activity associated glutamate changes will be modeled from a cognitive task functional magnetic resonance spectroscopy. We also aim to develop a neuromarker for ME/CFS diagnosis by integrating the multimodal MRIs with a deep machine learning framework. Methods and analysis: This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by consensus diagnosis made by two clinicians using the Canadian Consensus Criteria 2003. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI.The HRF, RRF, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, sex, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons.The data will be randomly divided into a training (N = 188) and a validation (N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator-regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group. Ethics and study registry: This study was reviewed and approved by University of the Sunshine Coast University Ethics committee (A191288) and has been registered with The Australian New Zealand Clinical Trials Registry (ACTRN12622001095752). Dissemination of results: The results will be disseminated through peer reviewed scientific manuscripts and conferences and to patients through social media and active engagement with ME/CFS associations.

Dataset of brain functional connectome and its maturation in adolescents.

We provided the dataset of brain connectome matrices, their similarities measures to self and others longitudinally, and Kessler's psychological distress scales (K10) including the response to each question. The dataset can be used to replicate the results of the manuscript titled "A longitudinal study of functional connectome uniqueness and its association with psychological distress in adolescence". The functional connectome (whole-brain and 13 networks) matrices were calculated from the resting-state functional MRIs (rs-fMRIs). We collected rs-fMRI and Kessler's psychological distress scale (K10) in 77 adolescents longitudinally up to 9 times from 12 years of age every four months. After removal of data with excessive motion, 262 functional connectome matrices were provided with this paper. The 300 regions of interest (ROIs) were defined using the Greene lab brain atlas. The functional connectome matrices were calculated as correlations between time series from any pair of ROIs extracted from pre-processed fMRIs. This dataset could be potentially used to1.Understand developmental changes in the functional brain connectivity,2.As a normal control database of functional connectome matrices,3.Develop and validate connectome and network-related analysing methods.