Fluctuating arterial blood pressure during high-intensity interval exercise (HIIE) may challenge dynamic cerebral autoregulation (dCA), specifically after stroke after an injury to the cerebrovasculature. We hypothesized that dCA would be attenuated at rest and during a sit-to-stand transition immediately after and 30 min after HIIE in individuals poststroke compared with age- and sex-matched control subjects (CON). HIIE switched every minute between 70% and 10% estimated maximal watts for 10 min. Mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) were recorded. dCA was quantified during spontaneous fluctuations in MAP and MCAv via transfer function analysis. For sit-to-stand, time delay before an increase in cerebrovascular conductance index (CVCi = MCAv/MAP), rate of regulation, and % change in MCAv and MAP were measured. Twenty-two individuals poststroke (age 60 ± 12 yr, 31 ± 16 mo) and twenty-four CON (age 60 ± 13 yr) completed the study. Very low frequency (VLF) gain (P = 0.02, η2 = 0.18) and normalized gain (P = 0.01, η2 = 0.43) had a group × time interaction, with CON improving after HIIE whereas individuals poststroke did not. Individuals poststroke had lower VLF phase (P = 0.03, η2 = 0.22) after HIIE compared with CON. We found no differences in the sit-to-stand measurement of dCA. Our study showed lower dCA during spontaneous fluctuations in MCAv and MAP following HIIE in individuals poststroke compared with CON, whereas the sit-to-stand response was maintained.NEW & NOTEWORTHY This study provides novel insights into poststroke dynamic cerebral autoregulation (dCA) following an acute bout of high-intensity interval exercise (HIIE). In people after stroke, dCA appears attenuated during spontaneous fluctuations in mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) following HIIE. However, the dCA response during a single sit-to-stand transition after HIIE showed no significant difference from controls. These findings suggest that HIIE may temporarily challenge dCA after exercise in individuals with stroke.

A multi-center study in Los Angeles (USC), Kansas City (KUMC) and Dallas (UT-SWMC) has been quantifying the dynamics of CO2 vasoreactivity in MCI/AD patients and cognitively normal controls under spontaneous resting conditions. The goal is to develop effective vasoreactivity physio-markers for early diagnosis of MCI and pre-clinical AD, based on previous findings of significantly reduced vasoreactivity in MCI patients [ Marmarelis et al., J. Alzh. Dis. 56:89-105, 2017 ]. Here, we report on the effects of slow-paced breathing upon these physio-markers. Spontaneous changes in arterial blood pressure (ABP), end-tidal CO2 (etCO2), and cerebral blood flow velocity (CBFV) in middle cerebral arteries were recorded under resting conditions over two 6-8 min sessions, separated by session of slow-paced breathing (6 breaths/minute), in 47 MCI and 25 AD patients and 58 age-matched cognitively normal controls. Using our novel methodology, we obtained predictive models of the dynamic effects of ABP and etCO2 upon CBFV using the universal convolutional form of linear dynamic models, which are defined by the respective “kernels” estimated from time-series data. The etCO2-to-CBFV kernel is used to compute indices (physio-markers) that quantify the vasoreactivity in each participant. The vasoreactivity index for each participant is computed from the integrated etCO2-to-CBFV kernel as the time-average over the first 30 sec. The average kernels for patients and controls are shown in Figures 1-2 for the two sessions respectively. Note the smaller kernel values for patients – while the difference is reduced after slow-paced breathing. The obtained vasoreactivity indices are significantly smaller for 72 patients (MCI and AD taken together) vs 58 controls for the first session [p = 0.018; mean (SD): 0.057 (0.539) vs 0.424 (1.076)] but NOT for the session after slow-paced breathing [p = 0.237; mean (SD): 0.193 (0.731) vs 0.361 (0.863)]. Average etCO2 was lower after paced-breathing [p = 10 −6 ; mean (SD): 36.23 (6.18) vs 33.44 (6.36)]. Quantitative analysis of cerebral CO2 vasoreactivity under resting spontaneous conditions in 72 MCI/AD patients vs 58 age-matched controls, before and after slow-paced breathing, revealed that the significant vasoreactivity deficit in MCI/AD patients is mitigated (at least temporarily) after slow-paced breathing. This effect may be due to observed hypocapnia induced by slow-paced breathing.

During aerobic exercise, central hemodynamics and CO2 partial pressure are central to middle cerebral artery blood velocity (MCAv) response. Still, the extent of their contribution is unknown. The purpose of this study was to characterize and utilize statistical modeling to determine the contribution of heart rate (HR), mean arterial pressure (MAP), and end-tidal CO2 (PETCO2) dynamics to MCAv dynamics. Three randomized exercise bouts were completed on a recumbent stepper at 30-40% (Low), 45-55% (Mod1), and 60-70% (Mod2) of estimated HRmax. A 90-s resting period was followed by 6-min of continuous exercise within the estimated HR ranges. HR, MAP, PETCO2, and MCAv exercise dynamics were modeled with a monoexponential curve. From this modeling, the baseline (BL), time delay (TD), time constant (τ), and steady-state (SS) responses were determined. Backward AIC linear regression models determined contributing dynamics. Seventeen healthy adults completed all exercise bouts (28 ± 6 yrs, 8 females). The time from initiation of exercise to an exponential increase in HR (HRTD) was significantly longer for Low than Mod2 (p=0.047). The time constant for the rise in HR (HRτ) was significantly shorter for Low than Mod1 and Mod2 (p=0.01). The absolute change in HR from baseline to steady-state (HRSS) was significantly lower for Low than Mod1 and Mod2 (p<0.001), and Mod1 was significantly lower than Mod2 (p<0.001). MAPSS was significantly lower for Low than Mod1 (p=0.01) and Mod2 (p<0.001). Exercise intensity, HRTD, and MAPTD accounted for 17% of variation for MCAvTD (p=0.01). HRTD, PETCO2TD, and MCAvTD accounted for 21% of variation MCAvτ (p<0.01). MCAvτ, MAPSS, and PETCO2SS accounted for 60% of variation for MCAvSS (p<0.001). Throughout the MCAv dynamic response pathway central hemodynamics and end-tidal CO2 do not account for most MCAv response until the steady-state phase. Thus, other physiological factors should be considered with assessing cerebrovascular function during aerobic exercise.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThe authors disclosed receipt of the following financial support for the research, authorship, and publication of this article. SA was supported by a Clinical and Translational Science Award (CTSA) from the National Center for Advancing Translational Sciences (NCATS), which was awarded to the University of Kansas for Frontiers: the University of Kansas Clinical and Translational Science Institute (# TL1TR002368). AW was supported by the American Heart Association Predoctoral Fellowship Grant (898190), the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (T32HD057850) and the National Heart, Lung, and Blood Institute (T32HL134643). Additional support was provided by the National Institute on Aging P30 AG072973 grant. The contents are solely the authors' responsibility and do not necessarily represent the official views of the NCATS or the National Institutes of Health.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The protocol was reviewed and approved by the University of Kansas Medical Center's institutional review board (IRB number STUDY00003176). Research was conducted in accordance with the principles embodied in the Declaration of Helsinki and in accordance with local statutory requirements.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe data underlying the results presented in the study are available upon reasonable request from the corresponding author.

An ongoing multi-center study of a consortium of Alzheimer’s Disease Centers in Los Angeles (USC), Dallas (UT-SWMC) and Kansas City (KUMC) has explored quantitatively the dynamics of the homeostatic mechanism that maintains adequate cortical tissue oxygenation during a rise in blood CO2 tension. The results from cognitively normal subjects and MCI/AD patients were compared to assess differences in the dynamics of this important homeostatic mechanism. Quantification of the dynamics of cortical tissue oxygenation was achieved through extraction of predictive models from five-minute data-records of spontaneous fluctuations in cortical tissue oxygenation (CTO), measured non-invasively via near infrared spectroscopy at the prefrontal cortex, and the associated fluctuations in arterial blood pressure (ABP) and end-tidal CO2 (etCO2). Using a novel kernel-based modeling methodology, we analyzed the time-series data from 25 MCI patients, 7 AD patients and 45 age-matched cognitively normal controls (NC) and obtained predictive models of the dynamic effects of ABP and etCO2 (viewed as a proxy for blood CO2 tension) upon CTO. These predictive models were used to quantify the dynamics of cortical CO2 reactivity (CCR) in each participant, as the time-average of the model-predicted CTO response to unit-step etCO2 change over the first 30 sec. The obtained CCR indices were used to evaluate the differences between NC and MCI/AD patients. The obtained CCR indices were significantly different for the 32 patients (MCI and AD lumped together due to small number of AD) vs. 45 age-matched controls (p= 0.0083), with respective mean (SD): 0.014 (0.108) vs -0.059 (0.119). This is illustrated in Figure 1, where the average model-predicted CTO responses to a unit-step change of etCO2 are shown for 32 MCI/AD patients (red line) and 45 controls (blue line). Note the negative values of the average CTO response for patients (red line) to unit-step increase of etCO2 that indicates polarity reversal of the normal CO2 vasomotor reactivity (blue line). Quantitative analysis of cortical oxygenation dynamics under resting spontaneous conditions in 32 MCI/AD patients relative to 45 age-matched controls revealed a significant impairment of the homeostatic mechanism that maintains adequate oxygenation of cortical tissue during a rise in blood CO2 tension.

There is a positive association between cardiorespiratory fitness and cognitive health, but the interaction between cardiorespiratory fitness and aging on cerebral hemodynamics is unclear. These potential interactions are further influenced by sex differences. The purpose of this study was to determine the sex-specific relationships between cardiorespiratory fitness, age, and cerebral hemodynamics in humans. Measurements of unilateral middle cerebral artery blood velocity (MCAv) and cerebral pulsatility index obtained using transcranial Doppler ultrasound and cardiorespiratory fitness [maximal oxygen consumption ((V) over doto(2max))] obtained from maximal incremental exercise tests were retrieved from study records at three institutions. A total of 153 healthy participants were included in the analysis (age = 42 +/- 20 yr, range = 18-83 yr). There was no association between (V) over doto(2max) and MCAv in all participants (P = 0.20). The association between (V) over doto(2max) and MCAv was positive in women, but no longer significant after age adjustment (univariate: P = 0.01; age-adjusted: P = 0.45). In addition, there was no association between (V) over doto(2max) and MCAv in men (univariate: P = 0.25, age-adjusted: P = 0.57). For (V) over doto(2max) and cerebral pulsatility index, there were significant negative associations in all participants (P < 0.001), in men (P < 0.001) and women (P < 0.001). This association remained significant when adjusting for age in women only (P = 0.03). In summary, higher cardiorespiratory fitness was associated with a lower cerebral pulsatility index in all participants, and the significance remained only in women when adjusting for age. Future studies are needed to determine the sex-specific impact of cardiorespiratory fitness improvements on cerebrovascular health. NEW & NOTEWORTHY We present data pooled from three institutions to study the impact of age, sex, and cardiorespiratory fitness on cerebral hemodynamics. Cardiorespiratory fitness was positively associated with middle cerebral artery blood velocity in women, but not in men. Furthermore, cardiorespiratory fitness was inversely associated with cerebral pulsatility index in both men and women, which remained significant in women when adjusting for age. These data suggest a sex-specific impact of cardiorespiratory fitness on resting cerebral hemodynamics.

It is plausible that statins could improve cerebral blood flow through pleiotropic mechanisms. The purpose of this investigation was to assess the contribution of statins to cerebrovascular variables in older adults with dyslipidemia and familial history of dementia. Furthermore, we explored the interaction between statin use and sex due to prevalent bias in statin trials. Middle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler ultrasound. Continuous supine rest recordings lasted 8 min. Participants included in analyses were statin (n = 100) or non-statin users (n = 112). MCAv and cerebrovascular conductance were significantly higher in statin users (p = 0.047; p = 0.04), and pulsatility index (PI) was significantly lower in statin users (p < 0.01). An interaction effect between statin use and sex was present for PI (p = 0.02); female statin users had significantly lower cerebrovascular resistance than the other three groups. In this cross-sectional analysis, statin use was positively associated with cerebrovascular variables in older adults at risk for dementia. Female statin users had significantly higher resting MCAv and cerebrovascular conductance than female non-statin users. The greatest contribution of statin use was the association with reduced cerebrovascular resistance. Given that cerebrovascular dysregulation is one of the earliest changes in Alzheimer’s disease and related dementia pathology, targeting the cerebrovasculature with statins may be a promising prevention strategy.

Abstract Current sit‐to‐stand methods measuring dynamic cerebral autoregulation (dCA) do not capture the precise onset of the time delay (TD) response. Reduced sit‐to‐stand reactions in older adults and individuals post‐stroke could inadvertently introduce variability, error, and imprecise timing. We applied a force sensor during a sit‐to‐stand task to more accurately determine how TD before the onset of dCA may be altered. Middle cerebral artery blood velocity (MCAv) and mean arterial pressure (MAP) were measured during two sit‐to‐stands separated by 15 min. Recordings started with participants sitting on a force‐sensitive resistor for 60 s, then asked to stand for 2 min. Upon standing, the force sensor voltage immediately dropped and marked the exact moment of arise‐and‐off (AO). Time from AO until an increase in cerebrovascular conductance (CVC = MCAv/MAP) was calculated as TD. We tested the sensor in four healthy young adults, two older adults, and two individuals post‐stroke. Healthy young adults stood quickly and the force sensor detected a small change in TD compared to classically estimated AO, from verbal command to stand. When compared to the estimated AO, older adults had a delayed measured AO and TD decreased up to ~53% while individuals post‐stroke had an early AO and TD increased up to ~14%. The stance time during the sit‐to‐stand has the potential to influence the TD before the onset of dCA metric. As observed in the older adults and participants with stroke, this response may drastically vary and influence TD.

We are the first, to our knowledge, to characterize the cerebrovascular and hemodynamic response to low-volume high-intensity interval exercise (HIIT, 1-min intervals) in young healthy adults. Middle cerebral artery blood velocity (MCAv) decreased during the HIIT bout and rebounded during active recovery. Women demonstrated a significantly higher resting MCAv than men and the difference remained during HIIT. Here, we report a novel protocol and characterized the MCAv response during an acute bout of low-volume HIIT.

Objective: To examine the association between postconcussion exercise volume and changes in depression, anxiety, dizziness, and postural stability. Design: Secondary analysis of a single-site prospective clinical trial. Setting: Cerebrovascular research laboratory. Participants: Participants completed questionnaires and underwent tests of gait and balance within 2 weeks of a concussion (mean = 11 ± 3 days postconcussion) and approximately 1 month later (mean = 41 ± 7 days postconcussion). Exercise volume was tracked by weekly exercise logs. Interventions: On the basis of a previous work classifying exercise volume following concussion, we grouped participants according to self-reported exercise volume between visits as high exercise volume (≥150 min/wk) or low exercise volume (<150 min/wk). Main Outcome Measures: Participants completed assessments evaluating anxiety and depression (Hospital Anxiety and Depression Scale), dizziness (Dizziness Handicap Inventory), and postural stability (tandem gait and modified Balance Error Scoring System). Results: Thirty-eight participants completed the study, of which 22 were in the high exercise volume group (mean = 71 ± 40 min/wk; 16.8 ± 2.1 years; 59% female) and 16 were in the low exercise volume group (mean = 379 ± 187 min/wk; 17.5 ± 2.1 years; 31% female). Although depression symptoms were not significantly different initially (mean difference = 1.5; 95% CI, −0.68 to 3.68; P = .24), the high exercise volume group had significantly lower depression symptom scores at follow-up (mean difference = 3.0; 95% CI, 1.40 to 4.47; P < .001). Anxiety symptoms (mean difference = 2.8; 95% CI, 0.3 to 5.4; P = 0.03), dizziness symptoms (mean difference = 10.9; 95% CI, 0.2 to 21.5; P = .047), single-task tandem gait (mean difference = 3.1 seconds; 95% CI, 0.2 to 6.0; P = .04), and dual-task tandem gait (mean difference = 4.2 seconds; 95% CI, 0.2 to 8.2; P = .04) were significantly better among the high exercise volume group. Conclusion: Greater exercise volumes were associated with lower depression, anxiety, and dizziness symptoms, and faster tandem gait performance. These preliminary findings suggest a potentially beneficial role for exercise within several different domains commonly affected by concussion.

OBJECTIVES/GOALS: Reduced cerebral blood flow (CBF) along with vascular risk factors (e.g., dyslipidemia) are prevalent in Alzheimers disease (AD) and related dementias. Statins are one of the most effective pharmacologic treatments for vascular risk reduction, which may contribute to CBF in individuals with an increased risk for AD. METHODS/STUDY POPULATION: Cross-sectional analysis of 212 older adults with a family history of dementia. Heart rate via electrocardiogram, mean arterial pressure (MAP) via brachial sphygmomanometers, end-tidal CO2 via capnograph, and CBF velocity at the middle cerebral artery (MCAv) via transcranial Doppler ultrasound were collected following 20-minutes of supine rest. Mean MCAv (cm/s) was measured within each cardiac cycle and averaged over an 8-minute duration. Cerebrovascular conductance was calculated by dividing mean MCAv by MAP. Pulsatility Index was calculated by subtracting systolic MCAv from diastolic MCAv and then dividing by mean MCAv. RESULTS/ANTICIPATED RESULTS: 125 females (68 ± 6 years; 49 statin) and 87 males (70 ± 6 years; 47 statin) were included in analyses. There were no significant differences between heart rate, MAP, or end-tidal CO2 between statin and non-statin users. After controlling for age, sex, and low-density and high-density lipoprotein, statin use did not significantly contribute to MCAv (p = 0.09). However, statin use did significantly contribute to cerebrovascular conductance (MCAv/MAP; p = 0.03) as well as Pulsatility Index (assessment of cerebral health, p < 0.01). DISCUSSION/SIGNIFICANCE: Our findings suggest statin use significantly and positively contributes to resting cerebral blood flow velocity and cerebrovascular health. Further investigation is warranted into statin interventions with other components of cerebrovascular function, as differences may have implications for brain health and disease pathogenesis.

Hemodynamic control during exercise is critical for cerebral perfusion during activity. It is not well understood, however, how initial hemodynamic responses contribute to the cerebrovascular response during steady-state exercise. PURPOSE: Determine the contribution of heart rate (HR) and mean arterial pressure (MAP) on the middle cerebral artery blood flow velocity (MCAv) within three different exercise intensities. METHODS: Three randomized bouts of exercise were performed on a recumbent stepper at 30-40% (LO), 45-55% (MOD1), and 60-70% (MOD2) of age-predicted max HR (HRmax). 90-sec of rest followed by 6-minutes of continuous exercise at the HRmax intensities was recorded. HR, MAP, and MCAv kinetics were modeled with a mono-exponential equation. The kinetics determined were: baseline (average 90 seconds of rest), time delay (seconds proceeding the exponential increase), time constant (time-to-63% of amplitude), and response (steady-state at 3-4.5 min of exercise). A stepwise AIC regression model selection was completed for each exercise bout. RESULTS: Seventeen adults completed all exercise bouts (28 ± 6 years of age, 8 females). The MCAv steady-state response between bouts was trending to a difference (p = 0.07). Within LO, the HR time constant and baseline MAP contributed to 29% of the MCAv response. Within MOD1, baseline HR, HR time constant, and MAP time constant contributed to 24% of the MCAv response. Lastly, within MOD2, HR time delay and baseline MAP contributed to 57% of the MCAv response. CONCLUSIONS: During lower intensity exercise, initial HR and MAP hemodynamics contributed to only about a third of the MCAv response. However, within the highest intensity exercise bout assessed (MOD2), initial hemodynamics contributed to almost two-thirds of the MCAv response. Therefore, HR and MAP kinetics play a significant role in the MCAv response to exercise at 60-70% HRmax. Future investigations are needed in populations with cardiovascular diseases.

Reduced cerebral blood flow (CBF) along with vascular risk factors (e.g., dyslipidemia) are prevalent in Alzheimer’s disease (AD) and related dementias. Considering the lack of disease-modifying therapies, targeting modifiable vascular risk factors is imperative. Statins are one of the most effective pharmacologic treatments for vascular risk reduction, which may increase CBF in individuals with an increased risk for AD. Despite widespread statin use in both sexes, sex specific statin effects on CBF is not completely understood. Cross-sectional analysis of 194 older adults with a family history of dementia. Heart rate via electrocardiogram, mean arterial pressure (MAP) via plethysmograph, end-tidal CO 2 via capnograph, and CBF velocity at the middle cerebral artery (MCAv) via transcranial Doppler ultrasound were collected following 20-minutes of supine rest. Mean MCAv (cm/s) was measured within each cardiac cycle and averaged over an 8-minute duration. 114 females (68 ± 5 years; 49 statin) and 80 males (70 ± 6 years; 46 statin) were included in analyses. There were no significant differences between vasodilator medication use, heart rate, end-tidal CO 2 , or MAP between sexes. MCAv was significantly higher in females compared to males. There was a significant interaction effect between statin use and sex (p = 0.03). Post-hoc analyses suggest that the female statin group had significantly higher MCAv than female non-statin group (59.0 ± 12.1 vs. 52.7 ± 12.1; p = 0.02) and female statin group had significantly higher MCAv than male statin group (59.0 ± 12.1 vs. 47.5 ± 10.4 cm/s; p < 0.001). Males were significantly older than females; however, we report that age was not a significant covariate in the model. Our findings suggest a sex specific statin effect on MCAv, with females having had a significantly higher MCAv from statin use. Further investigation is warranted into other components of cerebrovascular function, as differences between sexes may have implications for brain health and disease pathogenesis.

Background: Aerobic exercise has emerged as a useful treatment to improve outcomes among individuals who experience a concussion. However, compliance with exercise recommendations and the effect of exercise volume on symptom recovery require further investigation. Purpose: To examine (1) if an 8-week aerobic exercise prescription, provided within 2 weeks of concussion, affects symptom severity or exercise volume; (2) whether prescription adherence, rather than randomized group assignment, reflects the actual effect of aerobic exercise in postconcussion recovery; and (3) the optimal volume of exercise associated with symptom resolution after 1 month of study. Study Design: Cohort study; Level of evidence, 2. Methods: Individuals randomized to an exercise intervention (n = 17; mean age, 17.2 ± 2.0 years; 41% female; initially tested a mean of 11.3 ± 2.8 days after injury) or standard of care (n = 20; mean age, 16.8 ± 2.2 years; 50% female; initially tested a mean of 10.7 ± 3.2 days after injury) completed an aerobic exercise test within 14 days of injury. They returned for assessments 1 month and 2 months after the initial visit. The aerobic exercise group was instructed to exercise 5 d/wk, 20 min/d (100 min/wk), at a target heart rate based on an exercise test at the initial visit. Participants reported their exercise volume each week over the 8-week study period and reported symptoms at each study visit (initial, 1 month, 2 months). Because of low compliance in both groups, there was no difference in the volume of exercise between the 2 groups. Results: There were no significant symptom severity differences between the intervention and standard-of-care groups at the initial (median Post-Concussion Symptom Inventory, 15 [interquartile range = 10, 42] vs 20 [11, 35.5]; P = .26), 1-month (4 [0, 28] vs 5.5 [0.5, 21.5]; P = .96), or 2-month (6.5 [0, 27.5] vs 0 [0, 4]; P = .11) study visits. Exercise volume was similar between groups (median, 115 [54, 225] vs 88 [28, 230] min/wk for exercise intervention vs standard of care; P = .52). Regardless of group, those who exercised <100 min/wk reported significantly higher symptom severity at the 1-month evaluation compared with those who exercised ≥100 min/wk (median, 1.5 [0, 7.5] vs 12 [4, 28]; P = .03). Exercising ≥160 min/wk successfully discriminated between those with and those without symptoms 1 month after study commencement (classification accuracy, 81%; sensitivity, 90%; specificity, 78%). Conclusion: Greater exercise volume was associated with lower symptom burden after 1 month of study, and an exercise volume >160 min/wk in the first month of the study was the threshold associated with symptom resolution after the first month of the study. Because our observation on the association between exercise volume and symptom level is a retrospective and secondary outcome, it is possible that participants who were feeling better were more likely to exercise more, rather than the exercise itself driving the reduction in symptom severity.

We present the largest dataset ( n = 524) pooled from three institutions to study how age and sex affect middle cerebral artery blood velocity (MCAv) and flow pulsatility index (PI) across the adult lifespan. We report the rate of MCAv decline and flow PI rise is significantly greater in females compared with in males. These data suggest that sex-specific trajectories with aging and therapeutic interventions to promote healthy brain aging should consider these findings.

Background: Dizziness after concussion can be detrimental to both the physical and psychosocial wellbeing of patients. Vestibular symptoms, in particular, can amplify postural instability, which may create a greater sense of mental and physical abnormality post-concussion. Purpose: To examine the three-way association between self-reported dizziness with concussion symptoms, depression and anxiety severity, and gait deficits within two weeks post-concussion. We hypothesized that participants who endorsed a moderate/severe level of dizziness would report a more severe concussion symptom burden, more severe depression and anxiety, and worse postural stability. Methods: For this cross-sectional study, participants ages 14-21, were recruited from either a regional sports concussion clinic or emergency department, and tested within 14 days of a diagnosed concussion. Participants completed the Dizziness Handicap Inventory (DHI), Post-Concussion Symptom Inventory (PSCI), and Hospital Anxiety and Depression Scale (HADS).They also completed an instrumented single/dual-task gait assessment (three trials per condition). The gait assessment included walking at a self-selected pace towards a target 8m ahead, then returning to the start line. Dual task trials included a cognitive task (months in reverse order, serial 7’s, and spelling a 5-letter word backwards) while walking. Descriptive statistics, independent t-tests, and Mann Whitney U tests were used to compare between those with moderate/severe dizziness (DHI score ≥36) and those with mild/no dizziness (DHI score <36), p<0.05. Results: 40 participants completed the study. 19 self-reported moderate/severe dizziness (63% female, 17.1±2.4 years of age, average DHI score 48.4±12.6) and 21 mild/no dizziness (38% females, 16.5±1.9 years of age, average DHI score 18.7±9.3). Those with moderate/severe dizziness reported significantly more severe symptoms (PSCI: 43.0±20.6 vs. 22.8±15.7, p=0.001), and had higher median HADS anxiety (6 vs. 2, p<0.001) and depression (6 vs. 1, p=0.001) scores than those with no/minimal dizziness. During steady-state gait, the moderate/severe dizziness group walked with significantly lower single-task cadence (Figure 1B) and dual-task cadence (Figure 1E) than the no/mild dizziness group. Conclusion: Participants who self-reported a moderate to severe level of dizziness within 14 days of a concussion reported worse symptom severity, anxiety, and depression than those with no/mild dizziness. Further, cadence during gait is negatively affected by the level of dizziness reported. Clinicians should be aware of the psychosocial and physical effects dizziness symptoms may play in a patient’s recovery. Gait deficits in the moderate/severe dizziness group further indicate the importance of evaluating how the feeling of postural instability affects gait following concussion. Word Count: 389/400 Figure 1. Single-task (A,B,C) and dual-task (D,E,F) steady-state gait performance comparisons between the moderate/severe and no/mild dizziness groups.

Background: Current recommendations for sport-related concussion uniformly emphasize the importance of physical activity. However, specifics of this recommendation remain vague and do not account for an exercise dosage or compliance. Purposes: First, we examined if an 8-week individualized sub-symptom threshold aerobic exercise prescription, initiated within the first two weeks of concussion, alleviates symptom severity or affects the amount of exercise performed during the study. Second, we examined whether prescription adherence, rather than randomized group assignment, reflects the actual impact of aerobic exercise in post-concussion recovery. Methods: For this single-site prospective randomized clinical trial, participants completed an aerobic exercise test within 14 days of injury, and were randomized to an individualized aerobic exercise program or standard-of-care, and returned for assessments 1 month and 2 months after the initial visit (Table 1). The aerobic exercise group was instructed to exercise 5 days/week, 20 minutes/day, at a target heart rate based on an exercise test at the initial visit. Participants reported their symptom exercise volume each week over the 8-week study period, and reported symptoms at each study visit (initial, 1 month, 2 month). Results: Initial symptom severity was not different between randomized groups (Figure 1A), and no significant differences in symptom severity were found at the 4-week (Figure 1B) or 8-week (Figure 1C) assessment. In addition, there was no significant differences between groups for average weekly exercise volume during the first four weeks (Figure 2A) or second four weeks (Figure 2B) of the study. During the first four weeks of the study, 65% (n=11/17) of the exercise intervention participants were compliant with their exercise recommendation (≥100 min/week), compared to 45% (n=9/20) of the standard-of-care group (p=0.33). During the second four weeks of the study, 71% (n=12/17) of the exercise prescription group exercised ≥100 min/week, compared to 55% (n=11/20) of the standard-of-care group (p=0.50). When grouped by exercise volume, the group who exercised ≥100 minutes/week during the first month of the study reported significantly lower symptom severity scores than those who exercised <100 minutes/week (Figure 3B), despite similar initial symptom severity scores (Figure 3A). Conclusion: Participant randomization within 14 days of concussion did not lead to a significant reduction in symptoms, or greater exercise volume. Given that greater exercise volume was associated with lower symptoms after one month of the study, researchers and clinicians should pay particular attention to adherence to aerobic exercise programs for the treatment of concussion. Figure 1. Individual data points describing the distribution of symptom severity for those randomized to the exercise intervention and standard-of-care groups at (A) the initial evaluation (≤14 days post-injury), (B) the 1 month evaluation, and (C) the 2 month evaluation. The solid black line represents the median value for each group. Note: No significant differences were identified between groups at the initial (p=0.26), one month (p=0.96), or two month (p=0.11) evaluations. Figure 2. Individual data points describing the distribution of average weekly exercise volume (mins/week) for those randomized to the exercise intervention and standard-of-care groups (A) during the first 4 weeks of the study, and (B) the second 4 weeks of the study. The solid black line represents the group median value. Note: There were no significant differences between groups during the first 4 weeks (p=0.52) or second 4 weeks (p=0.59) of the study. Figure 3. Individual data points describing the distribution of symptom severity, compared between those who did and did not report an average exercise volume ≥100 minutes per week during the first month of the study. The solid black line represents the median value for each group. Note: Those who exercised <100 min/week reported significantly higher symptom severity (p=0.034) at the 1 month evaluation compared to those who exercised ≥100 min/week. No significant differences were identified at the initial (p=0.14) or 2 month (p=0.66) evaluations.

Introduction: High intensity interval exercise (HIIE) is performed widely. However, the field possesses limited knowledge regarding the acute HIIE cerebrovascular response. Our objective was to characterize the middle cerebral artery blood velocity (MCAv) response during an acute bout of short interval HIIE in healthy adults. We hypothesized MCAv would decrease below BL 1) during HIIE, 2) following HIIE, 3) and 30-minutes after HIIE. As a secondary objective, we investigated sex differences in the MCAv response during HIIE. Methods: Fourteen healthy adults (7 male) completed the HIIE session. The 10-minute HIIE session included alternating 1-minute bouts of high-intensity and low-intensity intervals. MCAv, mean arterial pressure (MAP), heart rate (HR), and expired end tidal carbon dioxide (PETCO2), were recorded at BL, during HIIE, following HIIE, and 30-minutes after HIIE. Results: Contrary to our hypothesis, MCAv remained above BL for the HIIE duration. MCAv peaked at the third minute then decreased concomitantly with PETCO2. MCAv was lower than BL after HIIE (p=0.03). Thirty minutes after HIIE, MCAv returned to near BL values (p = 0.47). Women showed higher BL MCAv (x = 70.9 {+/-} 8.1 cm/s) compared to men (x = 59.3 {+/-} 5.8 cm/s, p = 0.01). A greater magnitude of MCAv response was observed in men resulting in non-significant differences during HIIE secondary to higher workload (p = 0.03). Conclusions: Collectively, these findings show that in healthy adults, MCAv remained above BL during a 10-minute short-interval HIIE and returned to resting values 30 minutes after exercise.

Background and Objectives Aerobic exercise has become a useful method to assist with postconcussion management. Exercise can exacerbate concussion symptoms even when symptoms are not apparent at rest. Few studies have examined the reasons for symptom exacerbation during exercise following a concussion. We had 2 primary objectives: (1) to delineate cardiopulmonary and cerebrovascular responses to exercise in adolescents and young adults with a concussion and healthy controls and (2) to determine the association between cerebrovascular responses and symptom burden. Methods We recruited participants with a recent concussion from a sport concussion clinic between September 1, 2018, and February 22, 2020. They were included if their concussion occurred <3 weeks before initial testing and if they were symptomatic at rest. Participants were excluded if they sustained a concussion in the past year (excluding index injury), reported history of neurologic disorders, or were using medications/devices that may alter neurologic function. Participants completed a progressive, symptom-limited, submaximal exercise protocol on a stationary bicycle. We assessed heart rate, blood pressure, fraction of end tidal CO2 (FETCO2), and middle cerebral artery blood flow velocity (CBF) and cerebrovascular function (vasoactivity and autoregulation) at seated rest and during exercise. Results We conducted 107 exercise tests (40 concussed, 37 healthy participants initially; 30 concussed at follow-up). Concussed participants were tested initially (mean 17.6 ± 2.2 [SD] years of age; 55% female; mean 12.5 ± 4.7 days postconcussion) and again 8 weeks later (mean 73.3 ± 9.5 days postconcussion). Control participants (mean 18.3 ± 2.4 years; 62% female) were tested once. FETCO2 increased throughout the exercise protocol as heart rate increased, reached a plateau, and declined at higher exercise intensities. CO2 explained >25% of the variation in resting CBF (R2 > 0.25; p < 0.01) in most (73% individuals). Within the concussion group, resting symptom severity and the heart rate at which FETCO2 reached a plateau explained ∼2/3s of variation in exercise-induced symptom exacerbation (R2 = 0.65; FETCO2 β = −1.210 ± 0.517 [SE], p < 0.05). There was a moderate, statistically significant relationship between cerebrovascular responses to CO2 at rest (cerebral vasoactivity) and cerebrovascular responses to exercise-induced changes in FETCO2 (R2 = 0.13, p = 0.01). Discussion The arterial CO2 response and symptom exacerbation relationship during postconcussion aerobic exercise may be mediated by increased sensitivity of cerebral vasculature to exercise-related increase in CO2.

Objective To assess acute cerebrovascular function in concussed adolescents (14–21 years of age), whether it is related to resting cerebral hemodynamics, and whether it recovers chronically. Methods Cerebral vasoreactivity and autoregulation, based on middle cerebral artery blood flow velocity, was assessed in 28 concussed participants (≤14 days of injury) and 29 matched controls. The participants in the concussion group returned for an 8‐week follow‐up assessment. Over the course of those 8‐weeks, participants recorded aerobic exercise frequency and duration. Results Between groups, demographic, clinical, and hemodynamic variables were not significantly different. Vasoreactivity was significantly higher in the concussed group ( p = 0.02). Within the concussed group, 60% of the variability in resting cerebral blood flow velocity was explained by vasoreactivity and two components of autoregulation – falling slope and effectiveness of autoregulation (adjusted R 2 = 0.60, p < 0.001). Moreover, lower mean arterial pressure, lower responses to increases in arterial pressure, and lower vasoreactivity were significantly associated with larger symptom burden (adjusted R 2 = 0.72, p < 0.01). By the 8‐week timepoint, symptom burden, but not vasoreactivity, improved in all but four concussed participants ( p < 0.01). 8‐week change in vasoreactivity was positively associated with aerobic exercise volume (adjusted R 2 = 0.19, p = 0.02). Interpretation Concussion resulted in changes in cerebrovascular regulatory mechanisms, which in turn explained the variability in resting cerebral blood flow velocity and acute symptom burden. Furthermore, these alterations persisted chronically despite symptom resolution, but was positively modified by aerobic exercise volume. These findings provide a mechanistic framework for further investigation into underlying cerebrovascular related symptomatology. ANN NEUROL 2021;90:43–51

Objective: To examine if self-reported dizziness is associated with concussion symptoms, depression and/or anxiety symptoms, or gait performance within 2 weeks of postconcussion. Design: Cross-sectional study. Setting: Research laboratory. Participants: Participants were diagnosed with a concussion within 14 days of initial testing (N = 40). Participants were divided into 2 groups based on their Dizziness Handicap Inventory (DHI) score: 36 to 100 = moderate/severe dizziness and 0 to 35 = mild/no dizziness. Interventions: Participants were tested on a single occasion and completed the DHI, hospital anxiety and depression scale (HADS), Patient Health Questionnaire-9 (PHQ-9), and Post-Concussion Symptom Inventory (PCSI). Three different postural control tests were use: modified Balance Error Scoring System, single-/dual-task tandem gait, and a single-/dual-task instrumented steady-state gait analysis. Main Outcome Measures: Comparison of patient-reported outcomes and postural control outcomes between moderate/severe (DHI ≥ 36) and mild/no (DHI < 36) dizziness groups. Results: Participants with moderate/severe dizziness (n = 19; age = 17.1 ± 2.4 years; 63% female) reported significantly higher symptom burden (PSCI: 43.0 ± 20.6 vs 22.8 ± 15.7; P = 0.001) and had higher median HADS anxiety (6 vs 2; P < 0.001) and depression (6 vs 1; P = 0.001) symptom severity than those with no/minimal dizziness (n = 21; age = 16.5 ± 1.9; 38% female). During steady-state gait, moderate/severe dizziness group walked with significantly slower single-task cadence (mean difference = 4.8 steps/minute; 95% confidence interval = 0.8, 8.8; P = 0.02) and dual-task cadence (mean difference = 7.4 steps/minute; 95% confidence interval = 0.7, 14.0; P = 0.04) than no/mild dizziness group. Conclusion: Participants who reported moderate/severe dizziness reported higher concussion symptom burden, higher anxiety scores, and higher depression scores than those with no/mild dizziness. Cadence during gait was also associated with the level of dizziness reported.