Uncovering the hidden effects of repetitive subconcussive head impact exposure: A mega-analytic approach characterizing seasonal brain microstructural changes in contact and collision sports athletes.

Repetitive subconcussive head impacts (RSHI) are believed to induce sub-clinical brain injuries, potentially resulting in cumulative, long-term brain alterations. This study explores patterns of longitudinal brain white matter changes across sports with RSHI-exposure. A systematic literature search identified 22 datasets with longitudinal diffusion magnetic resonance imaging data. Four datasets were centrally pooled to perform uniform quality control and data preprocessing. A total of 131 non-concussed active athletes (American football, rugby, ice hockey; mean age: 20.06 ± 2.06 years) with baseline and post-season data were included. Nonparametric permutation inference (one-sample t tests, one-sided) was applied to analyze the difference maps of multiple diffusion parameters. The analyses revealed widespread lateralized patterns of sports-season-related increases and decreases in mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across spatially distinct white matter regions. Increases were shown across one MD-cluster (3195 voxels; mean change: 2.34%), one AD-cluster (5740 voxels; mean change: 1.75%), and three RD-clusters (817 total voxels; mean change: 3.11 to 4.70%). Decreases were shown across two MD-clusters (1637 total voxels; mean change: -1.43 to -1.48%), two RD-clusters (1240 total voxels; mean change: -1.92 to -1.93%), and one AD-cluster (724 voxels; mean change: -1.28%). The resulting pattern implies the presence of strain-induced injuries in central and brainstem regions, with comparatively milder physical exercise-induced effects across frontal and superior regions of the left hemisphere, which need further investigation. This article highlights key considerations that need to be addressed in future work to enhance our understanding of the nature of observed white matter changes, improve the comparability of findings across studies, and promote data pooling initiatives to allow more detailed investigations (e.g., exploring sex- and sport-specific effects).

Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

Effects of cognitive behavioural therapy and exposure-response prevention on brain activation in obsessive-compulsive disorder patients: systematic review and meta-analysis.

Current psychotherapeutic treatments for OCD, while effective, have complex outcomes with mixed efficacy. Previous research has observed baseline brain activation patterns in OCD patients, elucidating some of the implications of this disorder. Observing the effects of evidence-based psychotherapeutics for OCD on brain activation (through MRI) may provide a more comprehensive outline of pathology. This systematic review and meta-analysis evaluated the effects of cognitive behavioural therapy (CBT) with exposure-response prevention (ERP) on brain activation in OCD patients. Academic databases were systematically searched, and the outcomes evaluated included changes in brain activation and symptom severity between baseline and post-treatment. Patients (n = 193) had confirmed OCD diagnosis and underwent protocolized CBT with ERP programs delivered by trained therapists. Participants in the CBT with ERP programs demonstrated significant improvements in symptom severity (Cohen's d = - 1.91). In general, CBT with ERP resulted in decreased activation post-treatment in the frontal (Cohen's d = 0.40), parietal (Cohen's d = 0.79), temporal (Cohen's d = 1.02), and occipital lobe (Cohen's d = 0.76), and cerebellum (Cohen's d = - 0.78). The findings support CBT with ERP's ability to improve brain activation abnormalities in OCD patients. By identifying regions that improved activation levels, psychotherapy programs may benefit from the addition of function-specific features that could improve treatment outcomes.

Effect of neurosurgical residency programs on neurosurgical patient outcomes in a single health care system: a cohort study.

BACKGROUND: The evidence on the benefits and drawbacks of involving neurosurgical residents in the care of patients who undergo neurosurgical procedures is heterogeneous. We assessed the effect of neurosurgical residency programs on the outcomes of such patients in a large single-payer public health care system. METHODS: Ten population-based cohorts of adult patients in Ontario who received neurosurgical care from 2013 to 2017 were identified on the basis of procedural codes, and the cohorts were followed in administrative health data sources. Patient outcomes by the status of the treating hospital (with or without a neurosurgical residency program) within each cohort were compared with models adjusted for a priori confounders and with adjusted multilevel models (MLMs) to also account for hospital-level factors. RESULTS: A total of 46 608 neurosurgical procedures were included. Operative time was 8%-30% longer in hospitals with neurosurgical residency programs in 9 out of 10 cohorts. Thirty-day mortality was lower in hospitals with neurosurgical residency programs for aneurysm repair (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.20-0.44), cerebrospinal fluid shunting (OR 0.52, 95% CI 0.34-0.79), intracerebral hemorrhage evacuation (OR 0.66, 95% CI 0.52-0.84), and posterior lumbar decompression (OR 0.32, 95% CI 0.15-0.65) in adjusted models. The mortality rates remained significantly different only for aneurysm repair (OR 0.19, 95% CI 0.05-0.69) and cerebrospinal shunting (OR 0.42, 95% CI 0.21-0.85) in MLMs. Length of stay was mostly shorter in hospitals with neurosurgical residents, but this finding did not persist in MLMs. Thirty-day reoperation rates did not differ between hospital types in MLMs. For 30-day readmission rates, only extracerebral hematoma decompression was significant in MLMs (OR 1.41, 95% CI 1.07-1.87). CONCLUSION: Hospitals with neurosurgical residents had longer operative times with similar to better outcomes. Most, but not all, of the differences between hospitals with and without residency programs were explained by hospital-level variables rather than direct effects of residents.

Maintained Representations of the Ipsilateral and Contralateral Limbs during Bimanual Control in Primary Motor Cortex.

Primary motor cortex (M1) almost exclusively controls the contralateral side of the body. However, M1 activity is also modulated during ipsilateral body movements. Previous work has shown that M1 activity related to the ipsilateral arm is independent of the M1 activity related to the contralateral arm. How do these patterns of activity interact when both arms move simultaneously? We explored this problem by training 2 monkeys (male, Macaca mulatta) in a postural perturbation task while recording from M1. Loads were applied to one arm at a time (unimanual) or both arms simultaneously (bimanual). We found 83% of neurons (n = 236) were responsive to both the unimanual and bimanual loads. We also observed a small reduction in activity magnitude during the bimanual loads for both limbs (25%). Across the unimanual and bimanual loads, neurons largely maintained their preferred load directions. However, there was a larger change in the preferred loads for the ipsilateral limb (∼25%) than the contralateral limb (∼9%). Lastly, we identified the contralateral and ipsilateral subspaces during the unimanual loads and found they captured a significant amount of the variance during the bimanual loads. However, the subspace captured more of the bimanual variance related to the contralateral limb (97%) than the ipsilateral limb (66%). Our results highlight that, even during bimanual motor actions, M1 largely retains its representations of the contralateral and ipsilateral limbs.SIGNIFICANCE STATEMENT Previous work has shown that primary motor cortex (M1) represents information related to the contralateral limb, its downstream target, but also reflects information related to the ipsilateral limb. Can M1 still represent both sources of information when performing simultaneous movements of the limbs? Here we record from M1 during a postural perturbation task. We show that activity related to the contralateral limb is maintained between unimanual and bimanual motor actions, whereas the activity related to the ipsilateral limb undergoes a small change between unimanual and bimanual motor actions. Our results indicate that two independent representations can be maintained and expressed simultaneously in M1.

Muting, not fragmentation, of functional brain networks under general anesthesia.

Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and a disruption of the brain's ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities - considered hallmarks of fragmentation - are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness.

Characterizing changes in network connectivity following chronic head trauma in special forces military personnel: a combined resting-fMRI and DTI study.

BACKGROUND: Soldiers are exposed to significant repetitive head trauma, which may disrupt functional and structural brain connectivity patterns. PURPOSE/HYPOTHESIS: Integrate resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) to characterize changes in connectivity biomarkers within Canadian Special Operations Forces (CANSOF), hypothesizing that alterations in architectural organization of cortical hubs may follow chronic repetitive head trauma. METHODS: Fifteen CANSOFs with a history of chronic exposure to sub-concussive head trauma and concussive injuries (1.9 ± 2.0 concussions (range: [0-6])), as well as an equal age-matched cohort of controls (CTLs) were recruited. BOLD-based rs-fMRI was combined with DTI to reconstruct functional and structural networks using independent component analyses and probabilistic tractography. Connectivity markers were computed based on the distance between functional seeds to assess for possible differences in injury susceptibility of short- and long-range connections. RESULTS/DISCUSSION: Significant hyper- and hypo-connectivity differences in cortical connections were observed suggesting that chronic head trauma may predispose soldiers to changes in the functional organization of brain networks. Significant structural alterations in axonal fibers directly connecting disrupted functional nodes were specific to hyper-connected long-range connections, suggesting a potential relationship between axonal injury and increases in neural recruitment following repetitive head trauma from high-exposure military duties.

The role of diffusion tensor imaging in characterizing injury patterns on athletes with concussion and subconcussive injury: a systematic review.

Traumatic brain injury (TBI) is a major public health problem. The majority of TBIs are in the form of mild TBI (also known as concussion) with sports-related concussion (SRC) receiving public attention in recent years.Here we have performed a systematic review of the literature on the use of Diffusion Tensor Imaging (DTI) on sports-related concussion and subconcussive injuries. Our review found different patterns of change in DTI parameters between concussed and subconcussed groups. The Fractional Anisotropy (FA) was either unchanged or increased for the concussion group, while the subconcussed group generally experienced a decrease in FA. A reverse pattern was observed for Mean Diffusivity (MD) - where the concussed group experienced a decrease in MD while the subconcussed group showed an increase in MD. However, in general, discrepancies were observed in the results reported in the literature - likely due to the huge variations in DTI acquisition parameters, and image processing and analysis methods used in these studies. This calls for more comprehensive and well-controlled studies in this field, including those that combine the advanced brain imaging with biomechancial modeling and kinematic sensors - to shed light on the underlying mechanisms behind the structural changes observed from the imaging studies.

A novel perspective to calibrate temporal delays in cerebrovascular reactivity using hypercapnic and hyperoxic respiratory challenges.

Redistribution of blood flow across different brain regions, arising from the vasoactive nature of hypercapnia, can introduce errors when examining cerebrovascular reactivity (CVR) response delays. In this study, we propose a novel analysis method to characterize hemodynamic delays in the blood oxygen level dependent (BOLD) response to hypercapnia, and hyperoxia, as a way to provide insight into transient differences in vascular reactivity between cortical regions, and across tissue depths. A pseudo-continuous arterial spin labeling sequence was used to acquire BOLD and cerebral blood flow simultaneously in 19 healthy adults (12 F; 20 ± 2 years) during boxcar CO2 and O2 gas inhalation paradigms. Despite showing distinct differences in hypercapnia-induced response delay times (P < 0.05; Bonferroni corrected), grey matter regions showed homogenous hemodynamic latencies (P > 0.05) once calibrated for bolus arrival time derived using non-vasoactive hyperoxic gas challenges. Longer hypercapnic temporal delays were observed as the depth of the white matter tissue increased, although no significant differences in response lag were found during hyperoxia across tissue depth, or between grey and white matter. Furthermore, calibration of hypercapnic delays using hyperoxia revealed that deeper white matter layers may be more prone to dynamic redistribution of blood flow, which introduces response lag times ranging between 1 and 3 s in healthy subjects. These findings suggest that the combination of hypercapnic and hyperoxic gas-inhalation MRI can be used to distinguish between differences in CVR that arise as a result of delayed stimulus arrival time (due to the local architecture of the cerebrovasculature), or preferential blood flow distribution. Calibrated response delays to hypercapnia provide important insights into cerebrovascular physiology, and may be used to correct response delays associated with vascular impairment.

Multi-parametric analysis reveals metabolic and vascular effects driving differences in BOLD-based cerebrovascular reactivity associated with a history of sport concussion.

Objective: Identify alterations in cerebrovascular reactivity (CVR) based on the history of sport-related concussion (SRC). Further explore possible mechanisms underlying differences in vascular physiology using hemodynamic parameters modeled using calibrated magnetic resonance imaging (MRI). Method: End-tidal targeting and dual-echo MRI were combined to probe hypercapnic and hyperoxic challenges in athletes with (n = 32) and without (n = 31) a history of SRC. Concurrent blood oxygenation level dependent (BOLD) and arterial spin labeling (ASL) data were used to compute BOLD-CVR, ASL-CVR, and other physiological parameters including resting oxygen extraction fraction (OEF0) and cerebral blood volume (CBV0). Multiple linear and logistic regressions were then used to identify dominant parameters driving group-differences in BOLD-CVR. Results: Robust evidence for elevated BOLD-CVR were found in athletes with SRC history spreading over parts of the cortical hemispheres. Follow-up analyses showed co-localized differences in ASL-CVR (representing modulation of cerebral blood flow) and hemodynamic factors representing static vascular (i.e., CBV0) and metabolic (i.e., OEF0) effects suggesting that group-based differences in BOLD-CVR may be driven by a mixed effect from factors with vascular and metabolic origins. Conclusion: These results emphasize that while BOLD-CVR offers promises as a surrogate non-specific biomarker for cerebrovascular health following SRC, multiple hemodynamic parameters can affect its relative measurements. Abbreviations: [dHb]: concentration of deoxyhemoglobin; AFNI: Analysis of Functional NeuroImages ( https://afni.nimh.nih.gov ); ASL: arterial spin labeling; BIG: position group: defensive and offensive linemen; BIG-SKILL: position group: full backs, linebackers, running backs, tight-ends; BOLD: blood oxygen level dependent; CBF: cerebral blood flow; CMRO2: cerebral metabolic rate of oxygen consumption; CTL: group of control subjects; CVR: cerebrovascular reactivity; fMRI: functional magnetic resonance imaging; FSL: FMRIB software library ( https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/ ); HC: hypercapnia; HO: hyperoxia; HX: group with history of concussion; M: maximal theoretical BOLD signal upon complete removal of venous dHb; pCASL: pseudo-continuous arterial spin labeling; PETCO2: end-tidal carbon dioxide; PETO2: end-tidal oxygen; SCAT: sport-concussion assessment tool; SKILL: position group: defensive backs, kickers, quarterbacks, safeties, wide-receivers; SRC: sport-related concussion.

Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain.

All attempts at treating strokes by pharmacologically reducing the human brain's vulnerability to ischaemia have failed, leaving stroke as a leading cause of death, disability and massive socioeconomic loss worldwide. Over decades, research has failed to translate over 1,000 experimental treatments from discovery in cells and rodents to use in humans, a scientific crisis that gave rise to the prevailing belief that pharmacological neuroprotection is not feasible or practicable in higher-order brains. To provide a strategy for advancing stroke therapy, we used higher-order gyrencephalic non-human primates, which bear genetic, anatomical and behavioural similarities to humans and tested neuroprotection by PSD-95 inhibitors--promising compounds that uncouple postsynaptic density protein PSD-95 from neurotoxic signalling pathways. Here we show that stroke damage can be prevented in non-human primates in which a PSD-95 inhibitor is administered after stroke onset in clinically relevant situations. This treatment reduced infarct volumes as gauged by magnetic resonance imaging and histology, preserved the capacity of ischaemic cells to maintain gene transcription in genome-wide screens of ischaemic brain tissue, and significantly preserved neurological function in neurobehavioural assays. The degree of tissue neuroprotection by magnetic resonance imaging corresponded strongly to the preservation of neurological function, supporting the intuitive but unproven dictum that integrity of brain tissue can reflect functional outcome. Our findings establish that tissue neuroprotection and improved functional outcome after stroke is unequivocally achievable in gyrencephalic non-human primates treated with PSD-95 inhibitors. Efforts must ensue to translate these findings to humans.

Rapid Online Corrections for Proprioceptive and Visual Perturbations Recruit Similar Circuits in Primary Motor Cortex.

An important aspect of motor function is our ability to rapidly generate goal-directed corrections for disturbances to the limb or behavioral goal. The primary motor cortex (M1) is a key region involved in processing feedback for rapid motor corrections, yet we know little about how M1 circuits are recruited by different sources of sensory feedback to make rapid corrections. We trained two male monkeys (Macaca mulatta) to make goal-directed reaches and on random trials introduced different sensory errors by either jumping the visual location of the goal (goal jump), jumping the visual location of the hand (cursor jump), or applying a mechanical load to displace the hand (proprioceptive feedback). Sensory perturbations evoked a broad response in M1 with ∼73% of neurons (n = 257) responding to at least one of the sensory perturbations. Feedback responses were also similar as response ranges between the goal and cursor jumps were highly correlated (range of r = [0.91, 0.97]) as were the response ranges between the mechanical loads and the visual perturbations (range of r = [0.68, 0.86]). Lastly, we identified the neural subspace each perturbation response resided in and found a strong overlap between the two visual perturbations (range of overlap index, 0.73-0.89) and between the mechanical loads and visual perturbations (range of overlap index, 0.36-0.47) indicating each perturbation evoked similar structure of activity at the population level. Collectively, our results indicate rapid responses to errors from different sensory sources target similar overlapping circuits in M1.

Consistent spatial lesion-symptom patterns: A comprehensive analysis using triangulation in lesion-symptom mapping in a cohort of stroke patients.

INTRODUCTION: The relationship between brain lesions and stroke outcomes is crucial for advancing patient prognosis and developing effective therapies. Stroke is a leading cause of disability worldwide, and it is important to understand the neurological basis of its varied symptomatology. Lesion-symptom mapping (LSM) methods provide a means to identify brain areas that are strongly associated with specific symptoms. However, inner variations in LSM methods can yield different results. To address this, our study aimed to characterize the lesion-symptom mapping variability using three different LSM methods. Specifically, we sought to determine a lesion symptom core across LSM approaches enhancing the robustness of the analysis and removing potential spatial bias. MATERIAL & METHODS: A cohort consisting of 35 patients with either right- or left-sided middle cerebral artery strokes were enrolled and evaluated using the NIHSS at 24 h post-stroke. Anatomical T1w MRI scans were also obtained 24 h post-stroke. Lesion masks were segmented manually and three distinctive LSM methods were implemented: ROI correlation-based, univariate, and multivariate approaches. RESULTS: The results of the LSM analyses showed substantial spatial differences in the extension of each of the three lesion maps. However, upon overlaying all three lesion-symptom maps, a consistent lesion core emerged, corresponding to the territory associated with elevated NIHSS scores. This finding not only enhances the spatial accuracy of the lesion map but also underscores its clinical relevance. CONCLUSION: This study underscores the significance of exploring complementary LSM approaches to investigate the association between brain lesions and stroke outcomes. By utilizing multiple methods, we can increase the robustness of our results, effectively addressing and neutralizing potential spatial bias introduced by each individual method. Such an approach holds promise for enhancing our understanding of stroke pathophysiology and optimizing patient care strategies.

Using electronically delivered therapy and brain imaging to understand OCD pathology: A pilot feasibility study.

Background: Obsessive-compulsive disorder (OCD) is a debilitating mental health disorder with current psychotherapeutic treatments, while somewhat effective, yielding low accessibility and scalability. A lack of knowledge regarding the neural pathology of OCD may be hindering the development of innovative treatments. Previous research has observed baseline brain activation patterns in OCD patients, elucidating some understanding of the implications. However, by using neuroimaging to observe the effects of treatment on brain activation, a more complete picture of OCD can be drawn. Currently, the gold standard treatment is cognitive behavioral therapy (CBT). However, CBT is often inaccessible, time-consuming, and costly. Fortunately, it can be effectively delivered electronically (e-CBT). Objectives: This pilot study implemented an e-CBT program for OCD and observed its effects on cortical activation levels during a symptom provocation task. It was hypothesized that abnormal activations could be attenuated following treatment. Methods: OCD patients completed a 16-week e-CBT program administered through an online platform, mirroring in-person content. Treatment efficacy was evaluated using behavioral questionnaires and neuroimaging. Activation levels were assessed at the resting state and during the symptom provocation task. Results: In this pilot, seven participants completed the program, with significant improvements (p < 0.05) observed between baseline and post-treatment for symptom severity and levels of functioning. No statistically significant (p = 0.07) improvement was observed in the quality of life. Participants had mostly positive qualitative feedback, citing accessibility benefits, comprehensive formatting, and relatable content. No significant changes in cortical activation were observed between baseline and post-treatment. Conclusion: This project sheds light on the application of e-CBT as a tool to evaluate the effects of treatment on cortical activation, setting the stage for a larger-scale study. The program showed great promise in feasibility and effectiveness. While there were no significant findings regarding changes in cortical activation, the trends were in agreeance with previous literature, suggesting future work could provide insight into whether e-CBT offers comparable cortical effects to in-person psychotherapy. Applying a greater knowledge of the neural mechanisms of action in OCD can help develop novel treatment plans in the future.

The physiological basis underlying functional connectivity differences in older adults: A multi-modal analysis of resting-state fMRI.

The purpose of this study was to determine if differences in functional connectivity strength (FCS) with age were confounded by vascular parameters including resting cerebral blood flow (CBF0), cerebrovascular reactivity (CVR), and BOLD-CBF coupling. Neuroimaging data were collected from 13 younger adults (24 ± 2 years) and 14 older adults (71 ± 4 years). A dual-echo resting state pseudo-continuous arterial spin labeling sequence was performed, as well as a BOLD breath-hold protocol. A group independent component analysis was used to identify networks, which were amalgamated into a region of interest (ROI). Within the ROI, FC strength (FCS) was computed for all voxels and compared across the groups. CBF0, CVR and BOLD-CBF coupling were examined within voxels where FCS was different between young and older adults. FCS was greater in old compared to young (P = 0.001). When the effect of CBF0, CVR and BOLD-CBF coupling on FCS was examined, BOLD-CBF coupling had a significant effect (P = 0.003) and group differences in FCS were not present once all vascular parameters were considered in the statistical model (P = 0.07). These findings indicate that future studies of FCS should consider vascular physiological markers in order to improve our understanding of aging processes on brain connectivity.

Spontaneous Behavioural Recovery Following Stroke Relates to the Integrity of Parietal and Temporal Regions.

Stroke is a devastating disease that results in neurological deficits and represents a leading cause of death and disability worldwide. Following a stroke, there is a degree of spontaneous recovery of function, the neural basis of which is of great interest among clinicians in their efforts to reduce disability following stroke and enhance rehabilitation. Conventionally, work on spontaneous recovery has tended to focus on the neural reorganization of motor cortical regions, with comparably little attention being paid to changes in non-motor regions and how these relate to recovery. Here we show, using structural neuroimaging in a macaque stroke model (N = 31) and by exploiting individual differences in spontaneous behavioural recovery, that the preservation of regions in the parietal and temporal cortices predict animal recovery. To characterize recovery, we performed a clustering analysis using Non-Human Primate Stroke Scale (NHPSS) scores and identified a good versus poor recovery group. By comparing the preservation of brain volumes in the two groups, we found that brain areas in integrity of brain areas in parietal, temporal and somatosensory cortex were associated with better recovery. In addition, a decoding approach performed across all subjects revealed that the preservation of specific brain regions in the parietal, somatosensory and medial frontal cortex predicted recovery. Together, these findings highlight the importance of parietal and temporal regions in spontaneous behavioural recovery.

Characterization of cerebrospinal fluid biomarkers associated with neurodegenerative diseases in healthy cynomolgus and rhesus macaque monkeys.

Monkeys are becoming important translational models of neurodegenerative disease. To facilitate model development, we measured cerebrospinal fluid (CSF) concentrations of key biomarkers in healthy male and female cynomolgus and rhesus macaques. Amyloid beta (Aß40, Aß42), tau (total tau [t-tau], phosphorylated tau [pThr181]), and neurofilament light (NfL) concentrations were measured in CSF of 82 laboratory-housed, experimentally naïve cynomolgus (n = 33) and rhesus (n = 49) macaques. Aß40 and Aß42 were significantly higher in rhesus, and female rhesus were higher than males. NfL and t-tau were higher in males, and NfL was higher in rhesus macaques. p-tau was not affected by species or sex. We also examined whether sample location (lumbar or cisterna puncture) affected concentrations. Sample acquisition site only affected NfL, which was higher in CSF from lumbar puncture compared to cisterna magna puncture. Establishing normative biomarker values for laboratory-housed macaque monkeys provides an important resource by which to compare to monkey models of neurodegenerative diseases.

Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor.

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether neuroprotection is feasible without cerebral blood flow augmentation in experimental permanent middle cerebral artery occlusion. METHODS: Rats were subjected to permanent middle cerebral artery occlusion by the suture occlusion method and were treated 1 hour thereafter with a single 5-minute intravenous infusion of the postsynaptic density-95 protein inhibitor Tat-NR2B9c (7.5 mg/kg) or saline (n=8/group). Arterial spin-labeled perfusion-weighted MRI and diffusion weighted MRI were obtained with a 4.7-T Bruker system at 30, 45, 70, 90, 120, 150, and 180 minutes postmiddle cerebral artery occlusion to determine cerebral blood flow and apparent diffusion coefficient maps, respectively. At 24 hours, animals were neurologically scored (0 to 5), euthanized, and the brains stained with 2-3-5-triphenyl tetrazolium chloride to ascertain infarct volumes corrected for edema. Additionally, the effects of Tat-NR2B9c on adenosine 5'-triphosphate levels were measured in vitro in neurons subjected to oxygen-glucose deprivation. RESULTS: Final infarct volume was decreased by 30.3% in the Tat-NR2B9c-treated animals compared with controls (P=0.028). There was a significant improvement in 24 hours neurological scores in the Tat-NR2B9c group compared with controls, 1.8±0.5 and 2.8±1.0, respectively (P=0.021). Relative to controls, Tat-NR2B9c significantly attenuated diffusion-weighted imaging lesion growth and preserved the diffusion-weighted imaging/perfusion-weighted imaging mismatch (ischemic penumbra) without affecting cerebral blood flow in the ischemic core or penumbra. Tat-NR2B9c treatment of primary neuronal cultures resulted in 26% increase in cell viability and 34% greater adenosine 5'-triphosphate levels after oxygen-glucose deprivation. CONCLUSIONS: Preservation of adenosine 5'-triphosphate levels in vitro and neuroprotection in permanent middle cerebral artery occlusion in rats is achievable without cerebral blood flow augmentation using a postsynaptic density-95 protein inhibitor.

Transient deactivation of dorsal premotor cortex or parietal area 5 impairs feedback control of the limb in macaques.

We can generate goal-directed motor corrections with surprising speed, but their neural basis is poorly understood. Here, we show that temporary cooling of dorsal premotor cortex (PMd) impaired both spatial accuracy and the speed of corrective responses, whereas cooling parietal area 5 (A5) impaired only spatial accuracy. Simulations based on optimal feedback control (OFC) models demonstrated that "deactivation" of the control policy (reduction in feedback gain) and state estimation (reduction in Kalman gain) caused impairments similar to that observed for PMd and A5 cooling, respectively. Furthermore, combined deactivation of both cortical regions led to additive impairments of individual deactivations, whereas reducing the amount of cooling to PMd led to impairments in response speed but not spatial accuracy, both also predicted by OFC models. These results provide causal support that frontoparietal circuits beyond primary somatosensory and motor cortices are involved in generating goal-directed motor corrections.

Compromised resting cerebral metabolism after sport-related concussion: A calibrated MRI study.

Altered resting cerebral blood flow (CBF0) in the acute phase post-concussion may contribute to neurobehavioral deficiencies, often reported weeks after the injury. However, in addition to changes in CBF0, little is known about other physiological mechanisms that may be disturbed within the cerebrovasculature. The aim of this study was to assess whether changes in baseline perfusion following sport-related concussion (SRC) were co-localized with changes in cerebral metabolic demand. Forty-two subjects (15 SRC patients 8.0 ± 4.6 days post-injury and 27 age-matched healthy control athletes) were studied cross-sectionally. CBF0, cerebrovascular reactivity (CVR), resting oxygen extraction (OEF0) and cerebral metabolic rate of oxygen consumption (CMRO2|0) were measured using a combination of hypercapnic and hyperoxic breathing protocols, and the biophysical model developed in calibrated MRI. Blood oxygenation level dependent and perfusion data were acquired simultaneously using a dual-echo arterial spin labelling sequence. SRC patients showed significant decreases in CBF0 spread across the grey-matter (P < 0.05, corrected), and these differences were also confounded by the effects of baseline end-tidal CO2 (P < 0.0001). Lower perfusion was co-localized with reductions in regional CMRO2|0 (P = 0.006) post-SRC, despite finding no group-differences in OEF0 (P = 0.800). Higher CVR within voxels showing differences in CBF was also observed in the SRC group (P = 0.001), compared to controls. Reductions in metabolic demand despite no significant changes in OEF0 suggests that hypoperfusion post-SRC may reflect compromised metabolic function after the injury. These results provide novel insight about the possible pathophysiological mechanisms underlying concussion that may affect the clinical recovery of athletes after sport-related head injuries.