Data-driven biomarkers better associate with stroke motor outcomes than theory-based biomarkers.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have associated motor outcomes with the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to model chronic motor outcomes after stroke and compares the accuracy of these associations to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients from the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Stroke Recovery Working Group. Using the explained variance metric to measure the strength of the association between chronic motor outcomes and imaging biomarkers, we compared theory-based biomarkers, like lesion load to known motor tracts, to three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had stronger associations with chronic motor outcomes accuracy than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R 2 = 0.210, P < 0.001), performing significantly better than the theory-based biomarkers of lesion load of the corticospinal tract (R 2 = 0.132, P < 0.001) and of multiple descending motor tracts (R 2 = 0.180, P < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R 2 = 0.200, P < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R 2 = 0.167, P < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved the strength of associations for theory-based and data-driven biomarkers. Combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R 2 = 0.241, P < 0.001. Overall, these results demonstrate that out-of-sample associations between chronic motor outcomes and data-driven imaging features, particularly when lesion data is represented in terms of structural disconnection, are stronger than associations between chronic motor outcomes and theory-based biomarkers. However, combining both theory-based and data-driven models provides the most robust associations.

Characterization of internal jugular vein region-specific distension and flow patterns during progressive volume shifting.

Blood volume shifts during postural adjustment lead to irregular distension of the internal jugular vein (IJV). In microgravity, distension may contribute to flow stasis and thromboembolism, though the regional implications and associated risk remain unexplored. We characterized regional differences in IJV volume distension and flow complexity during progressive head-down tilt (HDT) (0°, -6°, -15°, -30°) using conventional ultrasound and vector flow imaging. We also evaluated low-pressure thigh cuffs (40 mmHg) as a fluid shifting countermeasure during -6° HDT. Total IJV volume expanded 139 ± 95% from supine position (4.6 ± 2.7 mL) to -30° HDT (10.3 ± 5.0 mL). Blood flow profiles had greater vector uniformity at the cranial IJV region (P < 0.01) and became more dispersed with increasing tilt (P < 0.01). Qualitatively, flow was more uniform throughout the IJV during its early flow cycle phase and more disorganized during late flow phase. This disorganized flow was accentuated closer to the vessel wall, near the caudal region, and during greater HDT. Low-pressure thigh cuffs during -6° HDT decreased IJV volume at the cranial region (-12 ± 15%; P < 0.01) but not the caudal region (P = 0.20), although flow uniformity was unchanged (both regions, P > 0.25). We describe a distensible IJV accommodating large volume shifts along its length. Prominent flow dispersion was primarily found at the caudal region, suggesting multidirectional blood flow. Thigh cuffs appear effective for decreasing IJV volume but effects on flow complexity are minor. Flow complexity along the vessel length is likely related to IJV distension during chronic volume shifting and may be a precipitating factor for flow stasis and future thromboembolism risk.NEW & NOTEWORTHY The internal jugular vein (IJV) facilitates cerebral outflow and is sensitive to volume shifts. Concerns about IJV expansion and fluid flow behavior in astronauts have surfaced following thromboembolism reports. Our study explored regional volume distension and blood flow complexity in the IJV during progressive volume shifting. We observed stepwise volume distension and increasing flow dispersion with head-down tilting across all regions. Flow dispersion may pose a risk of future thromboembolism during prolonged volume shifts.

Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

Seated Elliptical Exercise, But Not Periodic Standing, Alleviates Sitting-Induced Changes to Arterial Wave Reflections.

PURPOSE: Sedentary behavior may contribute to increased central wave reflection due to associated peripheral vasoconstriction, yet its impact on central hemodynamics and the mitigating effects of interventional strategies have not been thoroughly investigated. We tested whether standing or seated elliptical breaks alleviate the deleterious effects of prolonged sitting on central wave reflections. METHODS: Eighteen healthy adults (9 9 females, 25 ± 3 yr) completed three 3-h protocols on separate days: uninterrupted sitting, sitting with periodic standing, and sitting with periodic seated elliptical activity. Central wave reflection, central pulse wave velocity, and lower-limb pulse wave velocity were measured before and after each intervention. RESULTS: Central relative wave reflection magnitude (RM) increased during sitting (0.31 ± 0.05 to 0.35 ± 0.05; P < 0.01) but did not change after standing (0.30 ± 0.05 to 0.32 ± 0.04; P = 0.19) or elliptical protocols (0.30 ± 0.05 to 0.30 ± 0.04; P > 0.99). The change in RM during prolonged sitting (ΔRM) was attenuated with elliptical activity (0.04 ± 0.05 vs 0.00 ± 0.03; P = 0.02) but not with periodic standing (0.04 ± 0.04 vs 0.02 ± 0.05; P = 0.54). In addition, augmentation index and central pulse wave velocity increased after sitting (both P < 0.01) and periodic standing (both P < 0.01) but were unchanged after elliptical activity. Lower limb pulse wave velocity did not change after sitting ( P = 0.73) or standing ( P = 0.21) but did decrease after elliptical activity ( P = 0.03). CONCLUSIONS: Prolonged sitting without interruptions increased central wave reflection, whereas elliptical but not standing interruptions were able to ameliorate multiple sitting-induced vascular consequences. More work is required to examine the long-term effectiveness of interruption strategies, as well as the optimal type, frequency, and duration for reducing vascular risk associated with sedentary behaviors.

Effect of High-Intensity Interval Training and Moderate-Intensity Continuous Training in People With Poststroke Gait Dysfunction: A Randomized Clinical Trial.

Background The exercise strategy that yields the greatest improvement in both cardiorespiratory fitness (V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$) and walking capacity poststroke has not been determined. This study aimed to determine whether conventional moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) have different effects on V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6-minute walk distance (6MWD). Methods and Results In this 24-week superiority trial, people with poststroke gait dysfunction were randomized to MICT (5 days/week) or HIIT (3 days/week with 2 days/week of MICT). MICT trained to target intensity at the ventilatory anaerobic threshold. HIIT trained at the maximal tolerable treadmill speed/grade using a novel program of 2 work-to-recovery protocols: 30:60 and 120:180 seconds. V̇O2 and heart rate was measured during performance of the exercise that was prescribed at 8 and 24 weeks for treatment fidelity. Main outcomes were change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ and 6MWD. Assessors were blinded to the treatment group for V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ but not 6MWD. Secondary outcomes were change in ventilatory anaerobic threshold, cognition, gait-economy, 10-meter gait-velocity, balance, stair-climb performance, strength, and quality-of-life. Among 47 participants randomized to either MICT (n=23) or HIIT (n=24) (mean age, 62±11 years; 81% men), 96% completed training. In intention-to-treat analysis, change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ for MICT versus HIIT was 2.4±2.7 versus 5.7±3.1 mL·kg-1·min-1 (mean difference, 3.2 [95% CI, 1.5-4.8]; P<0.001), and change in 6MWD was 70.9±44.3 versus 83.4±53.6 m (mean difference, 12.5 [95% CI, -17 to 42]; P=0.401). HIIT had greater improvement in ventilatory anaerobic threshold (mean difference, 2.07 mL·kg-1·min-1 [95% CI, 0.59-3.6]; P=0.008). No other between-group differences were observed. During V̇O2 monitoring at 8 and 24 weeks, MICT reached 84±14% to 87±18% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ while HIIT reached 101±22% to 112±14% of V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ (during peak bouts). Conclusions HIIT resulted in more than a 2-fold greater and clinically important change in V̇O2peak$$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ than MICT. Training to target (ventilatory anaerobic threshold) during MICT resulted in ~3 times the minimal clinically important difference in 6MWD, which was similar to HIIT. These findings show proof of concept that HIIT yields greater improvements in cardiorespiratory fitness than conventional MICT in appropriately screened individuals. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03006731.

Data-driven biomarkers outperform theory-based biomarkers in predicting stroke motor outcomes.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have predicted motor outcomes based on the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to predict chronic motor outcomes after stroke and compares the accuracy of these predictions to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients (293 female/496 male) from the ENIGMA Stroke Recovery Working Group (age 64.9±18.0 years; time since stroke 12.2±0.2 months; normalised motor score 0.7±0.5 (range [0,1]). The out-of-sample prediction accuracy of two theory-based biomarkers was assessed: lesion load of the corticospinal tract, and lesion load of multiple descending motor tracts. These theory-based prediction accuracies were compared to the prediction accuracy from three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had better prediction accuracy - as measured by higher explained variance in chronic motor outcomes - than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R2 = 0.210, p < 0.001), performing significantly better than predictions using the theory-based biomarkers of lesion load of the corticospinal tract (R2 = 0.132, p< 0.001) and of multiple descending motor tracts (R2 = 0.180, p < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R2 =0.200, p < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R2 =0.167, p < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved prediction accuracy for theory-based and data-driven biomarkers. Finally, combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R2 = 0.241, p < 0.001. Overall, these results demonstrate that models that predict chronic motor outcomes using data-driven features, particularly when lesion data is represented in terms of structural disconnection, perform better than models that predict chronic motor outcomes using theory-based features from the motor system. However, combining both theory-based and data-driven models provides the best predictions.

High-intensity exercise does not protect against orthostatic intolerance following bedrest in 55- to 65-yr-old men and women.

Prolonged bedrest provokes orthostatic hypotension and intolerance of upright posture. Limited data are available on the cardiovascular responses of older adults to head-up tilt following bedrest, with no studies examining the potential benefits of exercise to mitigate intolerance in this age group. This randomized controlled trial of head-down bedrest (HDBR) in 55- to 65-yr-old men and women investigated if exercise could avert post-HDBR orthostatic intolerance. Twenty-two healthy older adults (11 female) underwent a strict 14-day HDBR and were assigned to either an exercise (EX) or control (CON) group. The exercise intervention included high-intensity, aerobic, and resistance exercises. Head-up tilt-testing to a maximum of 15 minutes was performed at baseline (Pre-Bedrest) and immediately after HDBR (R1), as well as 6 days (R6) and 4 weeks (R4wk) later. At Pre-Bedrest, three participants did not complete the full 15 minutes of tilt. At R1, 18 did not finish, with no difference in tilt end time between CON (422 ± 287 s) and EX (409 ± 346 s). No differences between CON and EX were observed at R6 or R4wk. At R1, just 1 participant self-terminated the test with symptoms, while 12 others reported symptoms only after physiological test termination criteria were reached. Finishers on R1 protected arterial pressure with higher total peripheral resistance relative to Pre-Bedrest. Cerebral blood velocity decreased linearly with reductions in arterial pressure, end-tidal CO2, and cardiac output. High-intensity interval exercise did not benefit post-HDBR orthostatic tolerance in older adults. Multiple factors were associated with the reduction in cerebral blood velocity leading to intolerance.

Heating-induced peripheral limb microvascular vasodilation reduces arterial wave reflection.

Arterial wave reflection augments cardiac afterload increasing myocardial demands. Mathematical models and comparative physiology suggest that the lower limbs are the primary source of reflected waves; however, in vivo human evidence corroborating these observations is lacking. This study was designed to determine whether the vasculature of the lower or upper limbs contributes more to wave reflection. We hypothesized that lower limb heating will result in larger reductions in central wave reflection compared with upper limb heating due to local vasodilation of a larger microvascular bed. Fifteen healthy adults (8 females, 24 ± 3.6 yr) completed a within-subjects experimental crossover protocol with a washout period. The right upper and lower limbs were heated in a randomized order using 38°C water-perfused tubing with a 30-min break between protocols. Central wave reflection was calculated using pressure-flow relationships derived from aortic blood flow and carotid arterial pressure at baseline and after 30 min of heating. We observed a main effect of time for reflected wave amplitude (12.8 ± 2.7 to 12.2 ± 2.6 mmHg; P = 0.03) and augmentation index (-7.5 ± 8.9% to -4.5 ± 9.1%; P = 0.03). No significant main effects or interactions were noted for forward wave amplitude, reflected wave arrival time, or central relative wave reflection magnitude (all P values >0.23). Unilateral limb heating reduced reflected wave amplitude; however, the lack of a difference between conditions does not support the hypothesis that the lower limbs are the primary source of reflection. Future investigations should consider alternative vascular beds, such as splanchnic circulation.NEW & NOTEWORTHY Lower limb contributions to central wave reflections have been theorized without direct evidence in humans. In this study, mild passive heating was used to locally vasodilate either the right arm or leg to control local wave reflection sites. Heating in general reduced the reflected wave amplitude, but there were no differences between the arm or leg heating intervention, failing to provide support for the lower limbs as a primary contributor to wave reflection in humans.

Transfer function analysis of dynamic cerebral autoregulation: A CARNet white paper 2022 update.

Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.

Ambulatory Monitoring of Cerebrovascular Responses to Upright Posture and Walking in Older Adults With Heart Failure.

Background: Insufficient cardiac output in individuals with heart failure (HF) limits daily functioning and reduces quality of life. Although lower cerebral perfusion, secondary to limitations in cardiac output, has been observed during moderate-intensity efforts, individuals with HF also may be at risk for lower perfusion during even low-intensity ambulatory activities. Methods: We determined whether HF is associated with an altered cerebrovascular response to low-intensity activities representative of typical challenges of daily living. In this study, we monitored central hemodynamics and middle cerebral artery blood velocity (MCAv) and cerebral tissue oxygenation (near-infrared spectroscopy) in 10 individuals with HF (aged 78 ± 4 years; left ventricular ejection fraction 20%-61%) and 13 similar-aged controls (79 ± 8 years; 52%-73%) during 3 randomized transitions, as follows: (i) supine-to-standing; (ii) sitting-to-slow-paced over-ground walking; and (iii) sitting-to-normal-paced over-ground walking. Results: Throughout supine, sitting, standing, and both walking conditions, individuals with HF had lower cardiac index and cerebral tissue oxygenation than controls (P < 0.05), and MCAv was lower across the range of blood pressure in HF patients (P = 0.051) and during walking only (P = 0.011). Individuals with HF had an attenuated increase in stroke volume index and cardiac index during normal-paced walking, compared to controls (P < 0.01). Conclusions: The indices of cerebral perfusion from MCAv and cerebral oxygenation were lower during ambulatory activities in individuals with HF; however, relationships between MCAv and blood pressure were not different between those with HF and controls, indicating no difference in static cerebral autoregulation.

Contexte: Un débit cardiaque insuffisant chez les personnes atteintes d'insuffisance cardiaque limite les activités quotidiennes et affecte la qualité de vie. Par exemple, des efforts d'intensité modérée ont été associés à une perfusion cérébrale affaiblie chez ces personnes. Or, il semble que même des activités ambulatoires de faible intensité soient susceptibles d'avoir les mêmes conséquences. Méthodologie: Nous voulions déterminer si l'insuffisance cardiaque est associée à une altération de la réponse cérébrovasculaire à des activités de faible intensité qui sont typiques de la vie quotidienne. Dans le cadre de cette étude, nous avons surveillé l'hémodynamique centrale et la vitesse du sang dans l'artère cérébrale moyenne (VACM), ainsi que l'oxygénation tissulaire cérébrale (par spectroscopie dans le proche infrarouge) chez 10 personnes atteintes d'insuffisance cardiaque (âge : 78 ± 4 ans; fraction d'éjection du ventricule gauche de 20 à 61 %) et 13 témoins d'âge similaire (79 ± 8 ans; de 52 à 73 %) lors de 3 transitions réparties de façon aléatoire, soit : i) de la position couchée à debout; ii) de la position assise à une marche lente et iii) de la position assise à une marche à vitesse normale. Résultats: En position couchée, assise ou debout et avec les deux vitesses de marche, l'index cardiaque et l'oxygénation tissulaire cérébrale étaient plus faibles chez les personnes atteintes d'insuffisance cardiaque que chez les témoins (p < 0,05); la VACM était plus faible dans toutes les plages de pression artérielle chez les personnes atteintes d'insuffisance cardiaque (p = 0,051) et durant la marche seulement (p = 0,011). Les personnes atteintes d'insuffisance cardiaque présentaient une plus faible augmentation du volume d'éjection systolique et de l'index cardiaque durant la marche à vitesse normale, comparativement aux témoins (p < 0,01). Conclusions: Les indices de la perfusion cérébrale selon la VACM et l'oxygénation cérébrale étaient réduits durant les activités ambulatoires chez les personnes atteintes d'insuffisance cardiaque; cependant, les relations entre la VACM et la pression artérielle n'étaient pas différentes entre les personnes atteintes d'insuffisance cardiaque et les témoins, ce qui indique que l'autorégulation cérébrale statique n'est pas un facteur de différenciation.

Assessing jugular venous compliance with optical hemodynamic imaging by modulating intrathoracic pressure.

Significance: The internal jugular veins (IJV) are critical cerebral venous drainage pathways that are affected by right heart function. Cardiovascular disease and microgravity can alter central venous pressure (CVP) and venous return, which may contribute to increased intracranial pressure and decreased cardiac output. Assessing jugular venous compliance may provide insight into cerebral drainage and right heart function, but monitoring changes in vessel volume is challenging. Aim: We investigated the feasibility of quantifying jugular venous compliance from jugular venous attenuation (JVA), a noncontact optical measurement of blood volume, along with CVP from antecubital vein cannulation. Approach: CVP was progressively increased through a guided graded Valsalva maneuver, increasing mouth pressure by 2 mmHg every 2 s until a maximum expiratory pressure of 20 mmHg. JVA was extracted from a 1-cm segment between the clavicle and midneck. The contralateral IJV cross-sectional area (CSA) was measured with ultrasound to validate changes in the vessel size. Compliance was calculated using both JVA and CSA between four-beat averages over the duration of the maneuver. Results: JVA and CSA were strongly correlated (median and interquartile range) over the Valsalva maneuver across participants (r = 0.986, [0.983, 0.987]). CVP more than doubled on average between baseline and peak strain (10.7 ± 4.4 vs. 25.8 ± 5.4 cmH2O; p < 0.01). JVA and CSA increased nonlinearly with CVP, and both JVA- and CSA-derived compliance decreased progressively from baseline to peak strain (49% and 56% median reduction, respectively), with no significant difference in compliance reduction between the two measures (Z = - 1.24, p = 0.21). Pressure-volume curves showed a logarithmic relationship in both CSA and JVA. Conclusions: Optical jugular vein assessment may provide new ways to assess jugular distention and cardiac function.

Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis.

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; ß=0.16) but not contralesional (P=0.96; ß=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; ß=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; ß=-0.26) and contralesional (P=0.006; ß=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; ß=-0.21) and extent of sensorimotor damage (P=0.003; ß=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.

Cerebral Blood Flow and Core Mood Symptoms in Youth Bipolar Disorder: Evidence for Region-Symptom Specificity.

OBJECTIVE: Building on prior findings in adults, this study investigated regional cerebral blood flow (CBF) in relation to DSM-5 criterion A symptoms of depression and mania in youth with bipolar disorder (BD). METHOD: The study recruited 81 youths with BD and 75 healthy controls 13-20 years old. CBF was ascertained using pseudocontinuous arterial spin labeling magnetic resonance imaging. Region-of-interest analyses examined the amygdala, anterior cingulate cortex (ACC), middle frontal gyrus, and global gray matter CBF. The association of criterion A depression and mania symptoms with CBF was examined dimensionally in youth with BD in regression analyses with continuous symptom severity scores. Age and sex were included as covariates. False discovery rate (FDR) was used to correct for 28 tests (4 regions by 7 symptoms; α < .0017). CBF for BD and healthy control groups was compared to give context for findings. RESULTS: In youth with BD, depressed mood inversely correlated with ACC (ß = -0.31, puncorrected = .004, pFDR = .056) and global (ß = -0.27, puncorrected = .013, pFDR = .09) CBF. The same pattern was observed for anhedonia (ACC CBF: ß = -0.33, puncorrected = .004, pFDR = .056; global CBF: ß = -0.29, puncorrected = .008, pFDR = .07). There were no significant findings for manic symptoms or in BD vs healthy control contrasts. CONCLUSION: The present findings, while not significant after correction for multiple testing, highlight the potential value of focusing on ACC in relation to depressed mood and anhedonia, and demonstrate that CBF is sensitive to depression symptom severity in youth. Lack of findings regarding manic symptoms may relate to the exclusion of fully manic participants in this outpatient sample.

Sex-dependent jugular vein optical attenuation and distension during head-down tilt and lower body negative pressure.

Non-contact coded hemodynamic imaging (CHI) is a novel wide-field near-infrared spectroscopy system which monitors blood volume by quantifying attenuation of light passing through the underlying vessels. This study tested the hypothesis that CHI-based jugular venous attenuation (JVA) would be larger in men, and change in JVA would be greater in men compared to women during two fluid shift challenges. The association of JVA with ultrasound-based cross-sectional area (CSA) was also tested. Ten men and 10 women completed three levels of head-down tilt (HDT) and four levels of lower body negative pressure (LBNP). Both JVA and CSA were increased by HDT and reduced by LBNP (all p < 0.001). Main effects of sex indicated that JVA was higher in men than women during both HDT (p = 0.003) and LBNP (p = 0.011). Interaction effects of sex and condition were observed for JVA during HDT (p = 0.005) and LBNP (p < 0.001). We observed moderate repeated-measures correlations (rrm ) between JVA and CSA in women during HDT (rrm  = 0.57, p = 0.011) and in both men (rrm  = 0.74, p < 0.001) and women (rrm  = 0.66, p < 0.001) during LBNP. While median within-person correlation coefficients indicated an even stronger association between JVA and CSA, this association became unreliable for small changes in CSA. As hypothesized, JVA was greater and changed more in men compared to women during both HDT and LBNP. CHI provides a non-contact method of tracking large changes in internal jugular vein blood volume that occur with acute fluid shifts, but data should be interpreted in a sex-dependent manner.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Optical Hemodynamic Imaging of Jugular Venous Dynamics During Altered Central Venous Pressure.

OBJECTIVE: An optical imaging system is proposed for quantitatively assessing jugular venous response to altered central venous pressure. METHODS: The proposed system assesses sub-surface optical absorption changes from jugular venous waveforms with a spatial calibration procedure to normalize incident tissue illumination. Widefield frames of the right lateral neck were captured and calibrated using a novel flexible surface calibration method. A hemodynamic optical model was derived to quantify jugular venous optical attenuation (JVA) signals, and generate a spatial jugular venous pulsatility map. JVA was assessed in three cardiovascular protocols that altered central venous pressure: acute central hypovolemia (lower body negative pressure), venous congestion (head-down tilt), and impaired cardiac filling (Valsalva maneuver). RESULTS: JVA waveforms exhibited biphasic wave properties consistent with jugular venous pulse dynamics when time-aligned with an electrocardiogram. JVA correlated strongly (median, interquartile range) with invasive central venous pressure during graded central hypovolemia (r = 0.85, [0.72, 0.95]), graded venous congestion (r = 0.94, [0.84, 0.99]), and impaired cardiac filling (r = 0.94, [0.85, 0.99]). Reduced JVA during graded acute hypovolemia was strongly correlated with reductions in stroke volume (SV) (r = 0.85, [0.76, 0.92]) from baseline (SV: 79 ± 15 mL, JVA: 0.56 ± 0.10 a.u.) to -40 mmHg suction (SV: 59 ± 18 mL, JVA: 0.47 ± 0.05 a.u.; p 0.01). CONCLUSION: The proposed non-contact optical imaging system demonstrated jugular venous dynamics consistent with invasive central venous monitoring during three protocols that altered central venous pressure. SIGNIFICANCE: This system provides non-invasive monitoring of pressure-induced jugular venous dynamics in clinically relevant conditions where catheterization is traditionally required, enabling monitoring in non-surgical environments.

Cerebrovascular assessments to help understand brain-related changes associated with aerobic exercise after stroke.

Evidence suggests exercise is "good medicine" after stroke, yet consensus is lacking on the time to initiate, type, exertion level, and duration per session. It remains a challenge to identify outcome measures for stroke-exercise trials that are sufficiently sensitive to intervention parameters. Cerebrovascular assessments, namely cerebral blood flow and intracranial pulsatility, are herein discussed as examples of quantitative brain-specific measures that may be useful to monitor exercise-related brain changes and help to guide stroke rehabilitation interventions. Novelty: Cerebral blood flow and arterial stiffness are potential vascular targets for stroke exercise trials.

Sex differences in the autonomic and cerebrovascular responses to upright tilt.

Sex differences in the regulation of autonomic and cerebrovascular responses to orthostatic stress remain unclear. The objectives of this study were to concurrently investigate autonomic control and cerebrovascular resistance indices, including critical closing pressure (CrCP) and resistance area product (RAP), during upright tilt in men and women. In 13 women and 14 men (18-29 years), ECG, non-invasive blood pressure, middle cerebral artery blood velocity, and end-tidal CO2 (ETCO2) were continuously measured during supine rest and 70° tilt. Heart rate variability (HRV), cardiovagal baroreflex sensitivity (cBRS), and transfer function parameters of dynamic cerebral autoregulation were calculated. Compared to supine, upright tilt increased the low frequency-to-high frequency ratio of HRV in men only (P = 0.044), and decreased cBRS more in women (P = 0.001). Cerebrovascular resistance index (CVRi) increased during tilt only in men (sex-by-time interaction: P = 0.004). RAP was lower in women throughout tilt (main effect of sex: P = 0.022). CrCP decreased during tilt in both sexes (main effect of time: P < 0.001). Normalizing to ETCO2 did not alter the effect of tilt on cerebrovascular resistance. Men displayed a greater increase of sympathetic indices and CVRi during tilt while women had greater parasympathetic withdrawal. We hypothesize that increased sympathetic activity in men may drive sex differences in the cerebrovascular response to upright posture.