Cerebral Blood Flow Response Research Articles

Higher body mass index is associated with worse hippocampal vasoreactivity to carbon dioxide.

Background and objectivesObesity is a risk factor for cognitive decline. Probable mechanisms involve inflammation and cerebrovascular dysfunction, leading to diminished cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). The hippocampus, crucially involved in memory processing and thus relevant to many types of dementia, poses a challenge in studies of perfusion and CVR, due to its location, small size, and complex shape. We examined the relationships between body mass index (BMI) and hippocampal resting CBF and CVR to carbon dioxide (CVRCO2) in a group of cognitively normal middle-aged and older adults.MethodsOur study was a retrospective analysis of prospectively collected data. Subjects were enrolled for studies assessing the role of hippocampal hemodynamics as a biomarker for AD among cognitively healthy elderly individuals (age > 50). Participants without cognitive impairment, stroke, and active substance abuse were recruited between January 2008 and November 2017 at the NYU Grossman School of Medicine, former Center for Brain Health. All subjects underwent medical, psychiatric, and neurological assessments, blood tests, and MRI examinations. To estimate CVR, we increased their carbon dioxide levels using a rebreathing protocol. Relationships between BMI and brain measures were tested using linear regression.ResultsOur group (n = 331) consisted of 60.4% women (age 68.8 ± 7.5 years; education 16.8 ± 2.2 years) and 39.6% men (age 70.4 ± 6.4 years; education 16.9 ± 2.4 years). Approximately 22% of them (n = 73) were obese. BMI was inversely associated with CVRCO2 (β = −0.12, unstandardized B = −0.06, 95% CI −0.11, −0.004). A similar relationship was observed after excluding subjects with diabetes and insulin resistance (β = −0.15, unstandardized B = −0.08, 95% CI −0.16, −0.000). In the entire group, BMI was more strongly related to hippocampal CVRCO2 in women (β = −0.20, unstandardized B = −0.08, 95% CI −0.13, −0.02).DiscussionThese findings lend support to the notion that obesity is a risk factor for hippocampal hemodynamic impairment and suggest targeting obesity as an important prevention strategy. Prospective studies assessing the effects of weight loss on brain hemodynamic measures and inflammation are warranted.

Orthostatic stress response in pediatric Fontan patients and the effect of ACE inhibition.

Many cardiocirculatory mechanisms are involved in the adaptation to orthostatic stress. While these mechanisms may be impaired in Fontan patients. However, it is yet unclear how Fontan patients, who exhibit a critical fluid balance, respond to orthostatic stress. Angiotensin converting enzyme inhibitors are often prescribed to Fontan patients, but they may negatively influence orthostatic tolerance. Therefore, we evaluated the response to orthostatic stress in pediatric Fontan patients before and after treatment with enalapril. Thirty-five Fontan patients (aged 14 years) with moderate-good systolic ventricular function without pre-existent enalapril treatment were included. Before and after a three-month enalapril treatment period, the hemodynamic response to head-up tilt test was evaluated by various parameters including cardiac index, blood pressure, cerebral blood flow, aortic stiffness and cardiac autonomous nervous activity. Thirty-four healthy subjects (aged 13 years) served as controls. Fontan patients had a decreased cerebral blood flow and increased aortic stiffness in the supine position compared to controls, while all other factors did not differ. Patients and controls showed a comparable response to head-up tilt test for most parameters. Twenty-seven patients completed the enalapril study with a mean dosage of 0.3±0.1mg/kg/day. Most parameters were unaffected by enalapril, only the percent decrease in cardiac index to tilt was higher after treatment, but the cardiac index during tilt was not lower (3.0L/min/m2 pre-enalapril versus 2.8L/min/m2 after treatment; P = 0.15). Pediatric Fontan patients adequately respond to orthostasis with maintenance of blood pressure and cerebral blood flow and sufficient autonomic response. Enalapril treatment did not alter the response. Scientific title: ACE inhibition in Fontan patients: its effect on body fluid regulation (sAFE-study). The Netherlands National Trial Register: Trail NL6415. Registered 2017-07-20. Trial information: https://www.trialregister.nl/trial/6415.

Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Quantification of hypoxic regions distant from occlusions in cerebral penetrating arteriole trees.

The microvasculature plays a key role in oxygen transport in the mammalian brain. Despite the close coupling between cerebral vascular geometry and local oxygen demand, recent experiments have reported that microvascular occlusions can lead to unexpected distant tissue hypoxia and infarction. To better understand the spatial correlation between the hypoxic regions and the occlusion sites, we used both in vivo experiments and in silico simulations to investigate the effects of occlusions in cerebral penetrating arteriole trees on tissue hypoxia. In a rat model of microembolisation, 25 μm microspheres were injected through the carotid artery to occlude penetrating arterioles. In representative models of human cortical columns, the penetrating arterioles were occluded by simulating the transport of microspheres of the same size and the oxygen transport was simulated using a Green's function method. The locations of microspheres and hypoxic regions were segmented, and two novel distance analyses were implemented to study their spatial correlation. The distant hypoxic regions were found to be present in both experiments and simulations, and mainly due to the hypoperfusion in the region downstream of the occlusion site. Furthermore, a reasonable agreement for the spatial correlation between hypoxic regions and occlusion sites is shown between experiments and simulations, which indicates the good applicability of in silico models in understanding the response of cerebral blood flow and oxygen transport to microemboli.

Close association between spreading depolarization and development of infarction under experimental ischemia in anesthetized male mice

Clinical and experimental evidence suggests that spreading depolarizations (SD) usually occur in patients with ischemic or hemorrhagic stroke when the gray matter of the brain is affected. In this study, we evaluated spatiotemporal changes of cerebral blood flow (CBF) during middle cerebral artery (MCA) occlusion and examined the relationship between SD occurrence and cerebral infarct development. In male isoflurane-anesthetized C57BL/6J mice, CBF changes over the ipsilateral parietal bone were recorded by laser speckle flowgraphy during and after transient (45 min, n = 22) or permanent occlusion (n = 22) of the distal MCA. Infarct volume was evaluated 24 hr after the operation. Upon MCA occlusion, CBF decreased by −55.6 ± 8.5 % in the lowest CBF and linearly recovered with increasing distance from the region. At 1–10 min after onset of occlusion, SD occurred and concentrically propagated from the core region, showing a decrease of CBF in the whole observed area along with a transient hyperemia and oligemia in the normal region. SD spontaneously re-occurred and propagated around the ischemic area in 37 % of mice, accompanied with a marked decrease of CBF in the core or a marked increase of CBF in the normal region. The CBF response to SDs gradually changed from the core to the normal area, depending upon the distance from the core region. Infarction was not observed in transiently (n = 2) or permanently (n = 4) occluded mice without SD. The infarct area tended to be larger with increasing number of SDs in transiently occluded mice. In conclusion, our findings suggest that the occurrence of SD during ischemia might elicit infarct formation and/or influence infarct development.

Is there a role of proinflammatory cytokines on degenerin-mediated cerebrovascular function in preeclampsia?

Preeclampsia (PE) is associated with adverse cerebrovascular effects during and following parturition including stroke, small vessel disease, and vascular dementia. A potential contributing factor to the cerebrovascular dysfunction is the loss of cerebral blood flow (CBF) autoregulation. Autoregulation is the maintenance of CBF to meet local demands with changes in perfusion pressure. When perfusion pressure rises, vasoconstriction of cerebral arteries and arterioles maintains flow and prevents the transfer of higher systemic pressure to downstream microvasculature. In the face of concurrent hypertension, loss of autoregulatory control exposes small delicate microvessels to injury from elevated systemic blood pressure. While placental ischemia is considered the initiating event in the preeclamptic cascade, the factor(s) mediating cerebrovascular dysfunction are poorly understood. Elevated plasma proinflammatory cytokines, such as tumor necrosis factor α (TNF‐α) and interleukin‐17 (IL‐17), are potential mediators of autoregulatory loss. Impaired CBF responses to increases in systemic pressure are attributed to the impaired pressure‐induced (myogenic) constriction of small cerebral arteries and arterioles in PE. Myogenic vasoconstriction is initiated by pressure‐induced vascular smooth muscle cell (VSMC) stretch. Recent studies from our laboratory group indicate that proinflammatory cytokines impair the myogenic mechanism of CBF autoregulation via inhibition of vascular degenerin proteins, putative mediators of myogenic constriction in VSMCs. This brief review links studies showing the effect of proinflammatory cytokines on degenerin expression and CBF autoregulation to the pathological cerebral consequences of preeclampsia.

Dynamic Measurements of Cerebral Blood Flow Responses to Cortical Spreading Depolarization in the Murine Endovascular Perforation Subarachnoid Hemorrhage Model.

Delayed cerebral ischemia (DCI) is the most severe complication after subarachnoid hemorrhage (SAH), and cortical spreading depolarization (CSD) is believed to play a vital role in it. However, the dynamic changes in cerebral blood flow (CBF) in response to CSD in typical SAH models have not been well investigated. Here, SAH was established in mice with endovascular perforation. Subsequently, the spontaneous CBF dropped instantly and then returned to baseline rapidly. After KCl application to the cortex, subsequent hypoperfusion waves occurred across the groups, while a lower average perfusion level was found in the SAH groups (days 1-7). Moreover, in the SAH groups, the number of CSD decreased within day 7, and the duration and spreading velocity of the CSD increased within day 3 and day 14, respectively. Next, we continuously monitored the local field potential (LFP) in the prefrontal cortex. The results showed that the decrease in the percentage of gamma oscillations lasted throughout the whole process in the SAH group. In the chronic phase after SAH, we found that the mice still had cognitive deficits but experienced no obvious tissue damage. In summary, SAH negatively affects the CBF responses to CSD and the spontaneous LFP activity and causes long-term cognitive deficits in mice. Based on these findings, in the specific phase after SAH, DCI is induced or exacerbated more easily by potential causers of CSD in clinical practice (edema, erythrocytolysis, inflammation), which may lead to neurological deterioration.

Dynamic cerebral blood flow changes with FOXOs stimulation are involved in neuronal damage associated with high-altitude cerebral edema in mice

Acute hypobaric hypoxia (AHH) exposure causes altitude mountain sickness (AMS) and life-threatening high altitude cerebral edema (HACE). Despite decades of research, the role of cerebral blood flow (CBF) changes in the pathophysiology of severe AMS remains unclear. The current study evaluated spatiotemporal responses of CBF associated with HACE in mice during the early stages of ascent to high altitudes. First, mice were exposed to AHH to test their tolerance to increasing altitudes (3000–8000 m). Because of its significant influence on both locomotor activity and rotarod behavior tests in mice, further observations were initiated at an altitude of 6000 m to investigate the specific pathophysiology of AMS. Compared with controls, laser speckle contrast imaging (LSCI) revealed a significant decrease in CBF during the early stage (0.5–24 h) at an altitude of 6000 m that was accompanied by a significant increase in brain water content (BWC). Moreover, observations of brain lipid oxidative damage and oxidative stress during the early stage of AHH exposure revealed DNA and cellular damage in cortical and hippocampal regions. Transcriptome profiling of the hippocampus revealed upregulation of forkhead box transcription factors. Similarly, western blot assays revealed upregulation of FOXO1a, FOXO3a, caspase-3 and Bax, and downregulation of Bcl-2, indicating a temporal influence of AHH on mitochondrial function and neuronal apoptosis. Thus, we found that the pathophysiology of HACE occurred with dynamic CBF changes, which triggered oxidative stress and neuronal damage in the mouse brain after AHH exposure. Our findings provide potential strategies for treatment of AHH in the future.

Playing a musical instrument increases blood flow in the middle cerebral artery.

PurposeStudies using functional magnetic resonance imaging and positron-emission tomography suggest that many regions of the brain are activated by such complex muscle activity. Although these studies demonstrated relative increases in blood flow in some brain regions with increased neural activity, whether or not the absolute value of cerebral blood flow increases has yet to be elucidated. It also remains unknown whether playing musical instruments affects cerebral blood flow. The aim of this study was to determine the impact of playing a musical instrument on blood flow velocity in the middle cerebral artery (MCAv) by using Doppler ultrasound to measure absolute values of arterial flow velocity.MethodsThirteen musicians performed three pieces of music with different levels of difficulty: play for the first time (FS), music in practice (PR) and already mastered (MS) on either piano or violin. MCAv was recorded continuously from 10 min before until 10 min after playing. Associations between the cerebral blood flow response and blood pressure and gas-exchange variables were examined.ResultsPR and MS significantly increased the MCAv. The blood pressure increased significantly in performances of all difficulty levels except for MS. There were no significant changes in exhaled gas variables during the performance.ConclusionThese findings suggest that playing a musical instrument increases MCAv, and that this change is influenced by the difficulty of the performance.

1310-P: Effects of Insulin Resistance on Brain Responses to Caloric Sugars and Nonnutritive Sweetener

Evidence suggests that insulin resistance (IR) affects feeding behavior by modulating neural responses to post-ingestive signals, including nutrients and taste. We examined associations between IR and activation of the hypothalamus and insula, brain regions involved in homeostasis and taste processing, to ingestion of sugars and the non-nutritive sweetener (NNS) , sucralose. Seventy-four participants (23.4±4 years; 42%male; BMI 27.2±5; HOMA-IR 5.3±5) completed 4 MRI visits with ingestion of drinks containing 75g sucrose, 75g glucose, sucralose, or water in a randomized cross-over design. Arterial spin labeling MRI was performed before, 15min and 30min after drink ingestion to measure cerebral blood flow (CBF) . Primary outcomes were associations between HOMA-IR and hypothalamic and insular CBF responses to glucose vs. sucrose, sucralose vs. water, and sucrose vs. sucralose. Mixed effects models included the following factors: drink contrasts, sex, time point, and BMI and HOMA-IR as continuous variables. Bonferroni-Holm was used to adjust for multiple comparisons. In the hypothalamus, HOMA-IR, independent of BMI, was associated with a greater hypothalamic CBF response to sucralose vs. water (p&amp;lt;0.03) , but there was no association between HOMA-IR and hypothalamic response to sugar. In the insula, there was a drink by HOMA-IR interaction in the insular response to sucralose vs. water (p&amp;lt;0.02) ; persons with IR showed greater increases in CBF after sucralose vs. water. We also found a main effect of HOMA-IR; persons with higher IR had greater insular CBF increases to sugar (p&amp;lt;0.05) , and a drink by HOMA-IR interaction revealed a stronger association between IR and insular response to glucose vs. sucrose (p&amp;lt;0.03) . There was no association between HOMA-IR and brain responses to sucralose vs. sucrose. These findings show that IR is associated with greater activation of brain regions involved in taste and energy homeostasis to ingestion of sugar and NNS, which may promote eating behavior. Disclosure S. Kullmann: Other Relationship; Novo Nordisk. R. Veit: None. K. Jann: None. S.H. Luo: None. B.C. Angelo: None. J.M. Alves: None. J.R. Monterosso: None. K.A. Page: None. Funding NIDDK R01DK102794

Assaying activity-dependent arteriole and capillary responses in brain slices.

.SignificanceNeurovascular coupling (NVC) is the process that increases cerebral blood flow in response to neuronal activity. NVC is orchestrated by signaling between neurons, glia, and vascular cells. Elucidating the mechanisms underlying NVC at different vascular segments and in different brain regions is imperative for understanding of brain function and mechanisms of dysfunction.AimOur goal is to describe a protocol for concurrently monitoring stimulation-evoked neuronal activity and resultant vascular responses in acute brain slices.ApproachWe describe a step-by-step protocol that allows the study of endogenous NVC mechanisms engaged by neuronal activity in a controlled, reduced preparation.ResultsThis ex vivo NVC assay allows researchers to disentangle the mechanisms regulating the contractile responses of different vascular segments in response to neuronal firing independent of flow and pressure mediated effects from connected vessels. It also enables easy pharmacological manipulations in a simplified, reduced system and can be combined with imaging or broader electrophysiology techniques to obtain multimodal data during NVC.ConclusionsThe ex vivo NVC assay will facilitate investigations of cellular and molecular mechanisms that give rise to NVC and should serve as a valuable complement to in vivo imaging methods.

FGF21 response to sucrose is associated with BMI and dorsal striatal signaling in humans.

This study examined associations between BMI and dietary sugar intake with sucrose-induced fibroblast growth factor 21 (FGF21) and whether circulating FGF21 is associated with brain signaling following sucrose ingestion in humans. A total of 68 adults (29 male; mean [SD), age 23.2 [3.8] years; BMI 27.1 [4.9] kg/m2 ) attended visits after a 12-hour fast. Plasma FGF21 was measured at baseline and at 15, 30, and 120 minutes after sucrose ingestion (75 g in 300 mL of water). Brain cerebral blood flow responses to sucrose were measured using arterial spin labeling magnetic resonance imaging. Higher circulating FGF21 levels were associated with reduced blood flow in the striatum in response to sucrose (β = -7.63, p = 0.03). This association was greatest among persons with healthy weight (β = -15.70, p = 0.007) and was attenuated in people with overweight (β = -4.00, p = 0.63) and obesity (β = -12.45, p = 0.13). BMI was positively associated with FGF21 levels in response to sucrose (β = 0.53, p = 0.02). High versus low dietary sugar intake was associated with greater FGF21 responses to acute sucrose ingestion in individuals with healthy weight (β = 8.51, p = 0.04) but not in individuals with overweight or obesity (p > 0.05). These correlative findings support evidence in animals showing that FGF21 acts on the brain to regulate sugar consumption through a negative feedback loop.

Cerebrovascular Dynamics During Light Exercise

Cerebral blood flow (CBF) dynamic response to moderate‐intensity exercise has a time delay (TD) of ~ 40s. This is dramatically longer compared to other physiological responses to exercise (e.g. skeletal muscle blood flow &lt;10 s) and CBF response to other stimuli (e.g. hypercapnia, thigh cuff occlusion, ~ 10‐20 s). A possible explanation is that a rest‐to‐exercise transition induces a brief hypotensive response due to intensity dependent rapid vasodilation of the periphery (exercise‐onset hypotension, EoH).PurposeTo determine if the magnitude and timing of EoH, effectively reduces CBF at exercise onset causing the longer observed TD. To test this, we modelled CBF kinetic response to light‐intensity exercise to mitigate the magnitude of EoH and determine if components of the CBF response were quickened in young healthy adults.Methods26 young healthy adults (13 Women, 23.8 ± 4 yrs; 23.9 ± 2.9 kg/m2) completed a rest (2min seated quietly, BL) to exercise (3 minutes at 50W, EX) transition on a recumbent cycle ergometer. Middle cerebral artery velocity (MCAv; transcranial doppler) and mean arterial pressure (MAP; finger photoplethysmography) were measured on a heartbeat‐by‐heartbeat basis. End‐tidal CO2 (EtCO2) was measured using breath‐by‐breath capnography. Cerebral vascular conductance index (CVCi) was calculated as (CVCi = MCAv/MAP *100 mmHg). Change in MCAv data (ΔMCAv = MCAvEX‐MCAvBL) were averaged into 2 s bins and fit to a monoexponential model (ΔMCAv(t)= Amp(1‐e‐(t‐TD)/ τ)). Time delay (TD), tau (τ), and mean response time (MRT = TD + τ) were obtained from the model. Several subjects (N=11) exhibited little to no TD (TD &lt; 1 s), these subjects (FAST) were separated out and compared to individuals with longer TDs (TD ≥ 3 s; SLOW). Comparisons were made using an independent t‐test.ResultsAll data is mean±SD. In total, subjects exhibited a TD of 15.4 ± 18.2 s, τ of 79.8 ± 139.7, and MRT of 95.3 ± 134.9 s. This coincided with a ΔMAPNADIR (‐14.5 ± 8.2 mmHg), ΔMCAvNADIR (‐5.7 ± 5.8 cm/s) which occurred at similar times (14.0 ± 17.2 vs. 18.6 ± 14.4 s; p=0.30 MAPNADIR vs. MCAvNADIR), and ΔCVCiMAX (25.3 ± 34.0 cm/s/100mmHg). When data were split, the FAST group experienced a faster TD compared to SLOW (0.01 ± 0.01 vs. 26.8 ± 16.4 s; p&lt;0.001). ΔMCAvNADIR although different (‐1.0 ± 4.0 vs. ‐9.1 ± 4.2 cm/s; p&lt;0.001, FAST vs. SLOW), occurred at similar times (20.5 ± 17.3 vs. 17.3 ± 12.5 s; p=0.59, FAST vs. SLOW). ΔMAPNADIR (‐14.4 ± 10.4 vs. ‐14.6 ± 6.5 mmHg; p=0.97) and CVCiMAX (22.1 ± 25.4 vs. 27.6 ± 39.9 cm/s/100mmHg; p=0.56 FAST vs. SLOW) were not different between groups. There were no other differences between groups regrading demographic, EtCO2, or other kinetic variables.DiscussionOur data indicates EoH is related to the initial drop in CBF and TD during light‐exercise is faster (15.9 s) when compared to previous research during moderate‐intensity exercise (~40 s). However, our data identifies fast responders who have minimal TD and MCAvNADIR responses without differing EoH at the same absolute exercise intensity. Therefore, these data reveal monoexponential CBF models ignore initial perturbances to CBF and disregard potentially important cerebrovascular mechanisms occurring prior to model predicted blood flow increases.

Central Command Related Changes in Anterior Cerebral Artery Blood Velocity and Prefrontal Oxygenation at the Onset of Moderate Voluntary Hand‐Grip Exercise

Recently, it has been identified that volitionally initiated finger tapping, which is a “very light motor effort” physical activity, elicits greater increases in mean anterior cerebral artery blood velocity (ACAmean), ACA vascular conductance index (ACAvci) and prefrontal oxygenation (Oxy‐Hb) responses compared to a cued start. These findings suggest that differences in ACAmean and prefrontal Oxy‐Hb responses between the exercise initiation modes may be related to central command. However, it remains unknown if similar responses are observed at the onset of voluntary exercise of a “moderate motor effort”. Therefore, the purpose of this study was to determine ACAmean, ACAvci and prefrontal Oxy‐Hb responses during dynamic hand grip exercise at 40% of maximal voluntary contraction (MVC) during two exercise initiation modes (voluntary or cued start). ACAmean, ACAvci, and prefrontal Oxy‐Hb were measured in seven participants (4 females and 3 males; aged 26 ± 3 years) at baseline (‐30 sec to ‐20 sec prior to initiation of exercise), pre‐exercise (‐20 sec to 0 sec) and the onset of exercise (0 sec to 15 sec) of each exercise initiation condition. Participants perceived exertion Borg Scale rating for the 40%‐MVC was 11.5 (median). A two‐way repeated measures ANOVA was conducted for the variables of interests. A significant factor interactions was identified for ACAmean ((F(2,12) = 5.02, p=0.03)) and Oxy‐Hb ((F(2,12) = 5.86, p= 0.02)). Post hoc test revealed that a voluntary start to hand grip exercise increased ACAmean by 2.6±1.0 cm/s (p=0.002) v.s. 0.7± 2.0 cm/s for a cued start (p=0.3) and increased Oxy‐Hb by 11.6±10.7 µM (p=0.02) v.s. 2.9±9.5 µM for a cued start (p=0.7) at the onset of exercise when compared to baseline. Furthermore, there was tendency in ACAvci to also increase with voluntary start by 3.9%±6.0 (p=0.06) vs. cued start 0.43% ± 6.0 p=0.57 from baseline to the initial onset of exercise. These primary findings suggest that moderate dynamic hand grip exercise elicits similar anterior cerebral blood flow and prefrontal oxygenation responses previously observed and thus, showing similar metabolic demands as finger‐tapping.

Cerebrovascular Carbon Dioxide Reactivity with Hyperoxia and Hypoxia in Humans with Treated Hypertension

Hypertension increases the risk of cerebrovascular diseases such as stroke and dementia, but the underlying mechanisms are currently unclear. While chronic hypertension can lead to anatomical and functional adaptations within the cerebral circulation, its effect on cerebral blood flow (CBF) control remains poorly understood. We tested the hypothesis that the CBF responses to CO2 with either high or low oxygen levels are impaired in treated hypertensive patients compared to normotensive aged‐matched controls.In 14 treated hypertensive patients (age: 68±5 years, mean±SD) and 8 normotensive age‐matched controls (age: 66±6 years), we assessed cardiorespiratory and cerebrovascular variables at rest, during voluntary hyperventilation (partial pressure of end‐tidal CO2 [PETCO2] ~25 mmHg), and hyperoxic and hypoxic rebreathing. Using transcranial Doppler ultrasound and finger photoplethysmography, we measured beat‐to‐beat middle cerebral artery blood velocity (MCAv: index of CBF) and BP, respectively, while PETCO2 was assessed using a gas analyzer. Linear regression was used to determine the MCAv‐CO2 slope (i.e., cerebrovascular CO2 reactivity).At rest, mean BP was higher in the hypertensive patients (108±9 mmHg) compared to normotensive controls (93±10 mmHg, p=0.001), while MCAv (46.8±11.4 vs. 53.3±10.4 cm/s) and PETCO2 (41±4 vs. 42±3 mmHg) were not different between groups (p&lt;0.05). Hyperventilation‐induced hypocapnia elicited similar reductions in MCAv in the hypertensive and normotensive groups (Δ14.8±4.7 vs. Δ16.5±5.7 cm/s, p=0.484). Similarly, the MCAv‐CO2slope was not different between the hypertensive and normotensive groups during either hyperoxic rebreathing (1.53±1.05 vs. 1.98±0.56 cm/s/mmHg, p=0.320) or hypoxic rebreathing (1.94±1.04 vs. 2.21±1.13 cm/s/mmHg, p=0.815).These preliminary findings indicate that in treated hypertensive patients, the MCAv responses to hypocapnia, and hypercapnia administrated with either high or low oxygen levels, do not differ from that observed in age‐matched normotensive controls.

What are the effects of acute exercise and exercise training on cerebrovascular hemodynamics following stroke? A systematic review and meta-analysis

Limited data exist regarding the effects of acute exercise and exercise training on cerebrovascular hemodynamic variables after stroke. This systematic review and meta-analysis 1) examined the effects of acute exercise and exercise training on cerebrovascular hemodynamic variables reported in the stroke exercise literature and 2) synthesized the peak middle cerebral artery blood velocity (MCAv) achieved during an acute bout of moderate-intensity exercise in individuals after stroke. Six databases (Medline, Embase, Web of Science, CINAHL, PsycINFO, AMED) were searched from inception to December 1st, 2021 for studies that examined the effect of acute exercise or exercise training on cerebrovascular hemodynamics in adults after stroke. Two reviewers conducted title and abstract screening, full-text evaluation, data extraction, and quality appraisal. Random-effects models were used in meta-analysis. Nine studies, including four acute exercise (n = 61) and five exercise training studies (n = 193), were included. Meta-analyses were not statistically feasible for several cerebrovascular hemodynamic variables. Descriptive analysis reveals that exercise training may increase cerebral blood flow and cerebrovascular reactivity to carbon dioxide among individuals after stroke. Meta-analysis of three acute exercise studies revealed no significant changes in MCAv during acute moderate-intensity exercise [n = 48 participants, mean difference = 5.2 cm/s, 95% confidence interval (CI) [-0.6, 11.0], P = 0.08] compared with resting MCAv values. This review suggests that individuals after stroke may have attenuated cerebrovascular hemodynamics as measured by the MCAv during acute moderate-intensity exercise. Aerobic exercise training is beneficial for improving cardiovascular health and function after stroke; higher-quality research utilizing agreed-upon hemodynamic variables is needed to synthesize the effects of exercise training on poststroke cerebrovascular hemodynamics.

Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Cerebral hemodynamic response to caffeine: effect of dietary caffeine consumption.

Caffeine has a significant effect on cerebrovascular systems, and the dual action of caffeine on both neural and vascular responses leads to concerns for the interpretation of blood oxygenation level-dependent (BOLD) functional MRI. However, potential differences in the brain response to caffeine with regard to consumption habits have not been fully elucidated, as BOLD responses may vary with the dietary caffeine consumption history. The main aim of this study was to characterize the acute effect of caffeine on cerebral hemodynamic responses in participants with different patterns of caffeine consumption habits. Fifteen non-habitual and 11 habitual volunteers were included in this study. The cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to the breath-hold challenge were measured before and after 200 mg caffeine administration. The non-habitual individuals exhibited a pattern of progressive reduction in CBF with time. The CVR was diminished in the caffeinated condition (P < 0.05). In the habitual group, the pattern of CBF decrease was smaller and homogeneous across the brain, and reached steady state rapidly. The CVR was not affected in the presence of caffeine (P > 0.05). Our results demonstrated that the cerebral hemodynamic response to caffeine was subject to the habitual consumption patterns of the participants. The compromised CVR following caffeine administration in the non-habitual group may partially explain the suppressed BOLD response to a visual stimulation in low-caffeine-level users.

Assessing Cerebrovascular Resistance in Patients With Sickle Cell Disease.

In patients with sickle cell disease (SCD) the delivery of oxygen to the brain is compromised by anemia, abnormal rheology, and steno-occlusive vascular disease. Meeting demands for oxygen delivery requires compensatory features of brain perfusion. The cerebral vasculature’s regulatory function and reserves can be assessed by observing the flow response to a vasoactive stimulus. In a traditional approach we measured voxel-wise change in Blood Oxygen-Level Dependent (BOLD) MRI signal as a surrogate of cerebral blood flow (CBF) in response to a linear progressive ramping of end-tidal partial pressure of carbon dioxide (PETCO2). Cerebrovascular reactivity (CVR) was defined as ΔBOLD/ΔPETCO2. We used a computer model to fit a virtual sigmoid resistance curve to the progressive CBF response to the stimulus, enabling the calculation of resistance parameters: amplitude, midpoint, range response, resistance sensitivity and vasodilatory reserve. The quality of the resistance sigmoid fit was expressed as the r 2 of the fit. We tested 35 patients with SCD, as well as 24 healthy subjects to provide an indication of the normal ranges of the resistance parameters. We found that gray matter CVR and resistance amplitude, range, reserve, and sensitivity are reduced in patients with SCD compared to healthy controls, while resistance midpoint was increased. This study is the first to document resistance measures in adult patients with SCD. It is also the first to score these vascular resistance measures in comparison to the normal range. We anticipate these data will complement the current understanding of the cerebral vascular pathophysiology of SCD, identify paths for therapeutic interventions, and provide biomarkers for monitoring the progress of the disease.

Impaired Cerebral Autoregulation in Parkinson's Disease: An Orthostatic Hypotension Analysis.

Orthostatic hypotension (OH) is an early non-motor manifestation of Parkinson's disease (PD). However, the underlying mechanism of hemodynamic changes in patients with PD and OH remains unclear. This study aimed to investigate the dynamic cerebral autoregulation changes in patients with PD with OH. Ninety patients with PD and 20 age- and sex-matched healthy controls (HCs) were recruited. The patients' non-invasive blood pressure (BP) and cerebral blood flow velocity were simultaneously recorded at supine and orthostatic positions during the active standing test (AST). Transfer function analysis was used to determine autoregulatory parameters including gain [i.e., damping effect of dynamic cerebral autoregulation (dCA) on the magnitude of BP oscillation] and phase difference (i.e., the time delay of the cerebral blood flow response to BP). Sixteen patients (17.8%) in the PD population were diagnosed with OH (PD-OH). The AST results were normal for 74 patients (82.2%) (PD-NOR). In the supine position, the PD-OH group had a lower phase degree than the PD-NOR group (50.3 ± 23.4 vs. 72.6 ± 32.2 vs. 68.9 ± 12.1, p = 0.020); however, no significant difference was found upon comparing with the HC group. In the orthostatic position, the normalized gain was significantly higher for the symptomatic OH group than for the asymptomatic OH group and HC group (1.50 ± 0.58 vs. 0.97 ± 0.29 vs. 1.10 ± 0.31, p = 0.019). A symptomatic OH in the PD population indicates an impaired cerebral autoregulation ability in the orthostatic position. Cerebral autoregulation tends to be impaired in the supine position in the OH population.