Cerebral Response Research Articles

The relationships between age, sex and exercise intensity on cerebral artery haemodynamics during isometric handgrip exercise.

Age and sex may alter the cerebral blood flow (CBF) responses to acute isometric exercise, via associated elevations in mean arterial pressure (MAP) and sympathetic activation. Our aim was to determine the relationships between age, sex and exercise intensity on cerebrovascular responses to isometric handgrip exercise. In 78 healthy adults (18-80 years, N=42 female), cerebrovascular responses were assessed during two minute isometric exercise bouts at three intensities (15, 30, 45% maximal voluntary contraction). Intracranial responses of the middle cerebral artery (MCA) and posterior cerebral artery (PCA) velocity (v) were measured using transcranial Doppler ultrasound. Extracranial responses of the internal carotid artery (ICA) and vertebral artery (VA) were assessed using Duplex ultrasound. Cardiopulmonary haemodynamic and neural parameters were measured throughout, including muscle sympathetic nerve activity, end-tidal carbon dioxide, and MAP. There were significant positive relationships between exercise intensity and the cerebral responses of the MCAv (P<0.001) and PCAv (P=0.005). There were no effects of intensity on ICA and VA responses (P>0.05), despite intensity-dependent increases in MAP (P<0.001). The increased MCAv response to exercise was blunted with advancing age (P=0.01) with no influence of sex (P=0.86). The present study provides data on age, sex and intensity specific relationships with intracranial and extracranial cerebrovascular responses to isometric exercise. Despite similar ICA, VA, and PCA responses, MCAv responses were attenuated with advancing age during handgrip exercise with no sex dependent influence. Further, intracranial responses were intensity dependent, whereas extracranial blood flow, shear-stress and velocity responses were similarly increased at all intensities during handgrip exercise.

Retinal and cerebral hemodynamics redistribute to favor thermoregulation in response to passive environmental heating and heated exercise in humans

ABSTRACT Core temperature (TC) changes, alongside exercise, affect hemodynamic responses across different conduit and microvascular beds. This study investigated impacts of ecologically valid environmental heat and exercise exposures on cerebral, skin and retinal vascular responses by combining physiological assessments alongside computational fluid dynamics (CFD) modeling. Young, healthy participants (n = 12) were exposed to environmental passive heating (PH), and heated exercise (HE) (ergometer cycling), in climate-controlled conditions (50 mins, 40°C, 50% relative humidity) while maintaining upright posture. Blood flow responses in the common carotid (CCA), internal carotid (ICA) and central retinal (CRA) arteries were assessed using Duplex ultrasound, while forearm skin microvascular blood flow responses were measured using optical coherence tomography angiography. Three-dimensional retinal hemodynamics (flow and pressure) were calculated via CFD simulation, enabling assessment of wall shear stress (WSS). TC rose following PH (+0.2°C, p = 0.004) and HE (+1.4°C, p < 0.001). PH increased skin microvascular blood flow (p < 0.001), whereas microvascular CRA flow decreased (p = 0.038), despite unchanged ICA flow. HE exacerbated these differences, with increased CCA flow (p = 0.007), unchanging ICA flow and decreased CRA flow (p < 0.001), and interactions between vascular (CCA vs. ICA p = 0.018; CCA vs. CRA p = 0.004) and microvascular (skin vs. retinal arteriolar p < 0.001) territories. Simulations revealed patterns of WSS and lumen pressure that uniformly decreased following HE. Under ecologically valid thermal challenge, different responses occur in distinct conduit and microvascular territories, with blood flow distribution favoring systemic thermoregulation, while flow may redistribute within the brain.

Cerebral Vasomotor Reactivity to Carbon Dioxide Using the Rebreathe Technique: Assessment of Within-day and Between-day Repeatability.

The cerebral vasodilator response to increased arterial carbon dioxide (CO2) concentration, termed cerebral vasomotor reactivity (CVMR), is used to assess cerebral vascular function. We sought to assess the within-day and between-day repeatability of CVMR to rebreathing-induced hypercapnia. Twelve healthy adults performed a within-day short interval protocol (17±2 minutes between trials), ten performed a within-day long interval protocol (145±16 minutes between trials), and seventeen performed a between-day protocol (5±2 days between visits). Repeatability of the slope of the percent change in middle cerebral artery mean blood velocity (%MCAvmean) and cerebral vascular conductance index (%CVCi), to the change in partial pressure of end-tidal CO2 (PETCO2) between the two trials/days was assessed. Within-day short interval %MCAvmean slope demonstrated fair to excellent repeatability (intraclass correlation, ICC=0.92 [95% confidence interval 0.72-0.98]; p<0.001) while %CVCi slope showed more variability (ICC=0.84 [0.47-0.95]; p=0.002]). Within-day long interval, %MCAvmean (ICC=0.95 [0.80-0.99]) and %CVCi (ICC=0.94 [0.71-0.99]) slopes showed good to excellent and fair to excellent repeatability respectively (p<0.001 for both). For between-day trials, better repeatability was observed for %CVCi (ICC=0.85 [0.57-0.95]; p<0.001) compared to %MCAvmean (ICC=0.76 [0.33-0.91]; p=0.004) slope. These findings indicate repeatable within- and between-day CVMR responses to rebreathe induced hypercapnia. However, a longer interval may be better for within-day repeat trials, particularly for CVCi measures.

Trial of the cerebral perfusion response to sodium nitrite infusion in patients with acute subarachnoid haemorrhage using arterial spin labelling MRI

Aneurysmal subarachnoid haemorrhage (SAH) is a devastating subset of stroke. One of the major determinants of outcome is an evolving multifactorial injury occurring in the first 72 hours, known as early brain injury. Reduced nitric oxide (NO) bioavailability and an associated disruption to cerebral perfusion is believed to play an important role in this process. We sought to explore this relationship, by examining the effect on cerebral perfusion of the in vivo manipulation of NO levels using an exogenous NO donor (sodium nitrite).We performed a double blind placebo controlled randomised experimental medicine study of the cerebral perfusion response to sodium nitrite infusion during the early brain injury period in 15 low grade (World Federation of Neurosurgeons grade 1–2) SAH patients. Patients were randomly assigned to receive sodium nitrite at 10 mcg/kg/min or saline placebo. Assessment occurred following endovascular aneurysm occlusion, mean time after ictus 66h (range 34–90h). Cerebral perfusion was quantified before infusion commencement and after 3 hours, using multi-post labelling delay (multi-PLD) vessel encoded pseudocontinuous arterial spin labelling (VEPCASL) magnetic resonance imaging (MRI).Administration of sodium nitrite was associated with a significant increase in average grey matter cerebral perfusion. Group level voxelwise analysis identified that increased perfusion occurred within regions of the brain known to exhibit enhanced vulnerability to injury. These findings highlight the role of impaired NO bioavailability in the pathophysiology of early brain injury.

Macrovascular blood flow and microvascular cerebrovascular reactivity are regionally coupled in adolescence.

Cerebrovascular imaging assessments are particularly challenging in adolescent cohorts, where not all modalities are appropriate, and rapid brain maturation alters hemodynamics at both macro- and microvascular scales. In a preliminary sample of healthy adolescents (n=12, 8-25 years), we investigated relationships between 4D flow MRI-derived blood velocity and blood flow in bilateral anterior, middle, and posterior cerebral arteries and BOLD cerebrovascular reactivity in associated vascular territories. As hypothesized, higher velocities in large arteries are associated with an earlier response to a vasodilatory stimulus (cerebrovascular reactivity delay) in the downstream territory. Higher blood flow through these arteries is associated with a larger BOLD response to a vasodilatory stimulus (cerebrovascular reactivity amplitude) in the associated territory. These trends are consistent in a case study of adult moyamoya disease. In our small adolescent cohort, macrovascular-microvascular relationships for velocity/delay and flow/CVR change with age, though underlying mechanisms are unclear. Our work emphasizes the need to better characterize this key stage of human brain development, when cerebrovascular hemodynamics are changing, and standard imaging methods offer limited insight into these processes. We provide important normative data for future comparisons in pathology, where combining macro- and microvascular assessments may better help us prevent, stratify, and treat cerebrovascular disease.

Effects of single- and bilateral limb immersion on systemic and cerebral hemodynamic responses to the cold pressor test.

The cold pressor test (CPT) involves cold water immersion of either the upper or lower limb(s) and elicits increases in sympathetic nervous activity (SNA), heart rate (HR), and mean arterial pressure (MAP) via stimulation of pain and cutaneous thermoreceptors. Greater pain perception during the CPT is associated with greater increases in SNA and more robust physiological responses. Due to potential differential sensitivity to both painful and thermal stimuli between upper and lower limbs, as well as potential effects of total exposure area, it is unclear whether the choice of limb(s) in CPT protocol design differentially affects systemic and cerebral hemodynamic responses. Our objective was to assess systemic and cerebral hemodynamic and ventilatory responses to different CPT protocols of the hand (CPTH), foot (CPTF), or bilateral feet (CPTBF). We hypothesized CPTBF would elicit greatest physiological responses due to increased exposure area to the cold stimulus. Twenty-eight (14 M, 14 F) healthy young adults [23.4 (SD: 2.4) yr] participated in three 3-min CPT protocols during a single visit. Blood pressure, HR, middle cerebral artery blood velocity (MCAv) and cerebrovascular conductance index, and end-tidal carbon dioxide ([Formula: see text]) were averaged over the final 30 s of each minute of the CPT for each protocol, and perceived pain was recorded at the end of each minute of the CPT. We found significant effects of the time-CPT protocol interaction on systolic blood pressure (P = 0.02), diastolic blood pressure (P < 0.01), MAP (P < 0.01), and HR (P < 0.001). There were no differences between CPT protocols on either MCAv (P = 0.4) or cerebrovascular conductance index (P = 0.1). HR responses peaked in the first minute of the CPT, and changes from baseline were greater in CPTBF [Δ14(16) beats/min] compared with CPTH [Δ5(13) beats/min; P = 0.01] and CPTF [Δ4.04(13.3) beats/min; P = 0.02]. MAP responses peaked in minute 2 of the CPT, and changes from baseline were greater in CPTH [Δ12(8) mmHg) and CPTBF (Δ13(9) mmHg] compared with CPTF [Δ8(7) mmHg; P < 0.01]. Perceived pain was significantly greater in the CPTBF [CPT1 7(2.3), CPT2 6.5(2.3), CPT3 6(3)] condition compared with CPTH [CPT1 6(1.3), CPT2 6(2.3), CPT3 6(2.3)] and CPTF [CPT1 6(3.0), CPT2 6(2.0), CPT3 5.5(3.0)] protocols at all three stages of the CPT (P ≤ 0.01). Our findings suggest choice of limb(s) in CPT protocols may lead to differences in systemic hemodynamic responses, with pain perception potentially influencing these responses. Based on our results, we suggest that choice of limb should be considered in future design of CPT studies, with hand CPT providing the best balance between participant tolerability and robust physiological responses.NEW & NOTEWORTHY Choice of limb(s) in cold pressor test (CPT) studies appears to influence systemic hemodynamics. Hand and bilateral feet induce more robust responses than single-foot CPT, potentially due to increased exposure area and pain perception. Despite no significant cerebrovascular effects, a sustained hyperventilatory response was noted in bilateral feet CPT. Hand CPTs may provide a balance between robust physiological responses and tolerability. These findings underscore the need for careful limb selection in future CPT studies.

Effect of the magnitude of abrupt change in sound pressure on the magnitude and phase synchrony of 40-Hz auditory steady state response

A periodic sound with a fixed inter-stimulus interval elicits an auditory steady-state response (ASSR). An abrupt change in a continuous sound is known to affect the brain’s ongoing neural oscillatory activity, but the underlying mechanism has not been fully clarified. We investigated whether and how an abrupt change in sound intensity affects the ASSR. The control stimulus was a train of 1-ms clicks with a sound pressure level (SPL) of 70 dB at 40 Hz for 1000 ms. In addition to the control stimulus, we applied six stimuli with changes consisting of a 500-ms train at 70 dB followed by a 500-ms similar train with louder clicks of 75, 80, or 85 dB or weaker clicks of 55, 60, or 65 dB. We obtained the magnetoencephalographic responses from 15 healthy subjects while presenting the seven stimuli randomly. The two-dipole model obtained for the 40-Hz ASSR in the control condition was applied to all of the stimulus conditions for each subject, and then the time–frequency analysis was conducted. We observed that both the amplitude and the inter-trial phase coherence of the 40-Hz ASSR transiently decreased and returned to the steady state after the change onset, i.e., the desynchronization of 40-Hz ASSR. The degree of desynchronization depended on the magnitude of the change regardless of whether the sound intensity increased or decreased, which might be a novel neurophysiological index of cerebral response driven by a change in the sensory environment.

Neurovascular coupling during dynamic upper body resistance exercise in healthy individuals.

During unilateral static and rhythmic handgrip exercise, middle cerebral artery blood velocity (MCAv) increases in the contralateral side to the exercising limb. However, whether this neurovascular coupling-mediated increase in contralateral MCAv is apparent against a background of fluctuating perfusion pressure produced by dynamic resistance exercise (RE) is unclear. We examined the cerebral haemodynamic response to unilateral dynamic RE in 30 healthy individuals (female=16, mean±SD: age, 26±6 years; height, 175±10cm; weight, 74±15kg; body mass index, 24±5kgm-2). Participants completed four sets of 10 paced repetitions (15 repetitionsmin-1) of unilateral bicep curl exercise at 60% of the predicted one-repetition maximum (7±3kg). Beat-to-beat blood pressure, bilateral MCAv and end-tidal carbon dioxide were measured throughout. One-way ANOVA was used to analyse cardiovascular variables and two-way ANOVA to analyse dependent cerebrovascular variables (side×sets, 2×5). A linear mixed model analysis was also performed to investigate the effects of end-tidal carbon dioxide and mean arterial blood pressure on MCAv. In comparison to baseline, within-exercise mean arterial blood pressure increased (P<0.001) across the sets, whereas bilateral MCAv decreased (P<0.001). However, no significant interaction effect was observed for any dependent variables (all P>0.787). The linear mixed model revealed that end-tidal carbon dioxide had the greatest effect on MCAv (estimate=1.019, t=8.490, P<0.001). No differences were seen in contralateral and ipsilateral MCAv during dynamic RE, suggesting that neurovascular coupling contributions during dynamic RE might be masked by other regulators, such as blood pressure.

The effect of multiband sequences on statistical outcome measures in functional magnetic resonance imaging using a gustatory stimulus

Recent technical developments have led to the invention of multiband functional magnetic resonance imaging (fMRI) sequences that allow for faster sampling rates. However, some studies have highlighted problems with these sequences, leading to a decreased temporal signal-to-noise ratio (tSNR). In addition, this temporal noise may interfere with detecting reward-related responses in mesolimbic regions. The blood-oxygen-level-dependent signal utilized in the majority of fMRI measurements is relatively slow. Furthermore, the cerebral response to gustatory stimuli would also be relatively slow. Therefore, given the temporal noise issues with multiband sequences, it is unclear whether multiband sequences are necessary for fMRI studies using gustatory stimuli. We thus conducted an fMRI experiment using a gustatory stimulus to investigate the effects of multiband sequences and increased sampling rates on statistical outcome measures. A single-band sequence with a repetition time (TR) of 2 s of phantom fMRI data and gustatory fMRI data from the gustatory regions exhibited the highest tSNR, although the tSNR of this sequence of gustatory fMRI was not statistically different from tSNR of multiband sequences with a TR of 2 s in any of the selected region of interests. Conventional general linear model analysis of fMRI showed that single-band sequences are more advantageous than multiband sequences for detecting brain responses to gustatory stimuli in the primary gustatory cortex. In addition, a Bayesian data comparison showed that data derived from a single-band sequence with a TR of 2 s was optimal for inferring neuronal connectivity in gustatory processing. Therefore, a conventional single-band sequence with a TR of 2 s is more appropriate for fMRI with gustatory stimuli. Image acquisition sequences should be selected aligned with the study objectives and target brain regions.

Effectiveness of a game-based high-intensity interval training on executive function and other health indicators of children with ADHD: A three-arm partially-blinded randomized controlled trial

BackgroundChildren with ADHD demand for effective intervention with minimum side effect to improve executive function (EF) and health well-being. MethodThis study used a three-arm partially-blinded randomized controlled trial to test the effects of two different kinds of 8-week game-based training programs (game-based HIIT program, GameHIIT; and game-based structured aerobic exercise program, GameSAE) on EF and other health indicators of children with ADHD, which was compared with a non-treatment control group. ResultsA total of 49 children with ADHD completed the program. Analyses of EF tests and parental survey indicated that (i) there is no significant intragroup difference among all measures between pre-/post-intervention tests for two game-based intervention groups. The only significant intergroup difference was observed in self-monitor score of parent-reported child's EF between GameSAE group and the control (large effect). Similarly, cerebral hemodynamic responses also found no significant group effect for all EF tests. However, the time effects were observed in several channels in the GameHIIT group in two EF tests (Color Words Stroop Test and Tower of London Test). No significant change of participants' overall ADHD symptoms was found in the pre-/post-tests for three groups. Nonetheless, further analyses revealed that both of two game-based training programs exhibited the significant positive effects on child's PA levels and the large effects on levels of physical fitness, when they were compared to the control. ConclusionBy this study, a significant enhancement in physical fitness and PA levels were found in both game-based PA interventions when they were compared with control group. However, the effectiveness of game-based PA interventions on improving EF or reducing ADHD symptoms remains unclear. This implies that a larger intervention dosage or a tailored intervention design may be warranted to improve the EF of children with ADHD.

Neuroimaging analysis reveals distinct cerebral perfusion responses to fasting-postprandial metabolic switching in Alzheimer's disease patients.

Extended fasting-postprandial switch intermitting time has been shown to affect Alzheimer's disease (AD). Few studies have investigated the cerebral perfusion response to fasting-postprandial metabolic switching (FMS) in AD patients. We aimed to evaluate the cerebral perfusion response to FMS in AD patients. In total, 30 AD patients, 32 mild cognitive impairment (MCI) patients, and 30 healthy control individuals (HCs) were included in the quantification of cerebral perfusion via cerebral blood flow (CBF). The cerebral perfusion response to FMS was defined as the difference (ΔCBF) between fasting and postprandial CBF. Patients with AD had a regional negative ΔCBF in the anterior temporal lobe, part of the occipital lobe and the parietal lobe under FMS stimulation, whereas HCs had no significant ΔCBF. The AD patients had lower ΔCBF values in the right anterior temporal lobe than the MCI patients and HCs. ΔCBF in the anterior temporal lobe was negatively correlated with cognitive severity and cognitive reserve factors in AD patients. AD patients exhibited a poor ability to maintain cerebral perfusion homeostasis under FMS stimulation. The anterior temporal lobe is a distinct area that responds to FMS in AD patients and negatively correlates with cognitive function.

Safety and Effectiveness of Acute Intermittent Hypoxia during a Single Treatment at Different Hypoxic Severities

PurposeExamine the cardiovascular, muscular function, cognitive, and neural plastic responses to determine the safety and effectiveness of acute Intermittent hypoxia (AIH) at a low, high, and control fractional inspired oxygen (FiO2) dosage MethodsThirteen human participants performed 30-min of AIH in 60-s intervals at FiO2’s of 0.21 (AIH21), 0.15 (AIH15), and 0.09 (AIH9). Heart rate variability (root mean squared of successive differences; RMSSD), heart rate, oxygen saturation (SpO2), blood pressure, muscular strength, neuromuscular activation, cerebral hemodynamic responses, cognition, symptomology, and brain-derived neurotrophic factor (BDNF) responses were measured before (Pre-AIH), after (post-AIH), and at 20-min of recovery (Recovery-AIH) ResultsThere were no differences between AIH protocols for heart rate, RMSSD, blood pressure, or SpO2. Muscular strength improved Post-AIH for AIH15 (10%) and AIH9 (14%) and remained elevated (6%) at Recovery-AIH. Neuromuscular activation increased Pre-AIH to Post-AIH for AIH15 (10%) and AIH9 (11%). Cerebral hemodynamic responses were not impacted between conditions. Both AIH15 and AIH9 increased BDNF Post-AIH (62%) and Recovery-AIH (63%) ConclusionAcute intermittent hypoxia is generally safe and effective at producing neural plastic responses, but further examination of co-occurring cardiovascular diseases is needed. This study provides safety focused findings which will widen the adoption and refinement of AIH protocols

In vivo optical assessment of cerebral and skeletal muscle microvascular response to phenylephrine.

This study aimed to investigate the simultaneous response of the cerebral and skeletal muscle microvasculature to the same phenylephrine (PE) boluses. A hybrid optical system that combines hyperspectral near-infrared spectroscopy (hs-NIRS) and diffuse correlation spectroscopy (DCS) was used to monitor changes in tissue oxygenation and perfusion. Data were collected from the head and hind limb of seven male Sprague-Dawley rats while administering intravenous (IV) injections of PE or saline to all animals. The response to saline was used as a control. Skeletal muscle oxygenation decreased significantly after PE injection, while a statistically underpowered decrease in perfusion was observed, followed by an increase beyond baseline. Vascular conductance also decreased in the muscle reflecting the drug's vasoconstrictive effects. Tissue oxygenation and perfusion increased in the brain in response to PE. Initially, there was a sharp increase in cerebral perfusion but no changes in cerebral vascular conductance. Subsequently, cerebral flow and vascular conductance decreased significantly below baseline, likely reflecting autoregulatory mechanisms to manage the excess flow. Further, fitting an exponential function to the secondary decrease in cerebral perfusion and increase in muscular blood flow revealed a quicker kinetic response in the brain to adjust blood flow. In the skeletal muscle, PE caused a transient decrease in blood volume due to vasoconstriction, which resulted in an overall decrease in hemoglobin content and tissue oxygen saturation. Since PE does not directly affect cerebral vessels, this peripheral vasoconstriction shunted blood into the brain, resulting in an initial increase in oxygenated hemoglobin and oxygen saturation.

Abstract 65: Postpartum Alterations of Middle Cerebral Artery Reactivity and Hemodynamics in a Transgenic Rat Model of Preeclampsia

Evidence suggests that cerebrovascular disease is a leading cause of morbidity and mortality in women with preeclampsia (PE), however the mechanisms are unknown. In a transgenic rat displaying PE-like syndrome (TGA-PE: female transgenic for angiotensinogen mated to male transgenic for renin), we have shown postpartum alterations in cerebrovascular hemodynamics suggesting dysfunctional autoregulation. We hypothesize that impaired middle cerebral artery (MCA) reactivity contributes to the cerebrovascular dysfunction in this model. High frequency ultrasound was used to determine the pulsatility index (PI) of left MCA (LMCA). Vascular responses were studied in isolated segments of LMCA from SD (n= 12) and TGA-PE (n=8) two months post-delivery. Arteries were mounted on a Multi-Wire Myograph for determination of isometric force (USA-DMT). The contractile responses to K + 75 mM and endothelin-1 (ET-1, 10 -11 -10 -7 M) were measured in basal tone. Vasodilatory responses to acetylcholine (ACh, 10 -11 -10 -4 M) were determined in arteries pre-constricted with the thromboxane agonist U46619 (10 -7 M); the maximal response ( R MAX ) and sensitivity (pD 2 =-Log[EC 50 ]) were analyzed. Our data show that systolic blood pressures were elevated in TGA-PE versus SD at 2 months post-delivery (144.9±2.7 vs. 118.4±2.5, p&lt;0.05; n=10-19). However, the PI was lower in TGA-PE vs. SD (0.96±0.05 vs. 1.31±0.06; p&lt;0.05, n=8-13). No differences in basal tone of MCA segments were observed, whereas TGA-PE arteries displayed a lower optimal diameter (175±4 μm vs. 217±4 μm; p&lt;0.05) and a lower response to K + (0.85±0.11 vs. 1.29±0.1 mN/mm; p&lt;0.05) compared to SD. Vasodilatation to acetylcholine was similar (ACh MAX : 79±8 vs. 70±9%) with a lower sensitivity (pD 2 : 5.2±0.1 vs. 6.7±0.4; p&lt;0.05) in TGA-PE. The contractile response to ET-1 was increased in TGA-PE arteries (ET-1 MAX : 159±7 vs. 129±6 % K MAX ; p&lt;0.05) with no differences in sensitivity (pD 2 : 8.8±0.1 vs. 8.9±0.1). Our data demonstrate structural and functional differences in MCA from TGA-PE vs. SD at 2 months postpartum. In addition to a smaller functional diameter, a lower non-receptor dependent contraction may explain the lower resistance of MCA observed in the preeclamptic model. We conclude that attenuated vasodilatory and increased contractile responses of MCA could promote cerebrovascular dysfunction in this model, and that these adaptations may contribute to cerebrovascular pathology in postpartum preeclamptic state. Supported by NIH 1R01HL155420

Oxygen-Based Autoregulation Indices Associated with Clinical Outcomes and Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage.

Impairment in cerebral autoregulation has been proposed as a potentially targetable factor in patients with aneurysmal subarachnoid hemorrhage (aSAH); however, there are different continuous measures that can be used to calculate the state of autoregulation. In addition, it has previously been proposed that there may be an association of impaired autoregulation with the occurrence of spreading depolarization (SD) events. Study participants with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10s moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In study participants with subdural electrocorticography (ECoG) monitoring, SD was also scored. Associations between clinical outcomes using the modified Rankin scale and occurrence of either isolated or clustered SD were assessed. A total of 320 study participants were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors, such as modified Fisher scale score and World Federation of Neurosurgical Societies scale grade, were strongly associated with the clinical outcome. SD probability was related to blood pressure in a triphasic pattern, with a linear increase in probability below MAP of ~ 100 mm Hg. Multiple autoregulation indices were available for review based on moving correlations between mean arterial pressure (MAP) and various surrogates of cerebral blood flow (CBF). We calculated the pressure reactivity (PRx) using two different sources for intracranial pressure (ICP). We calculated the oxygen reactivity (ORx) using the partial pressure of brain tissue oxygen (PbtO2) from the Licox probe. We calculated the cerebral blood flow reactivity (CBFRx) using perfusion measurements from the Bowman perfusion probe. Finally, we calculated the cerebral oxygen saturation reactivity (OSRx) using regional cerebral oxygen saturation measured by near-infrared spectroscopy from the INVOS sensors. Only worse ORx and OSRx were associated with worse clinical outcomes. Both ORx and OSRx also were found to increase in the hour prior to SD for both sporadic and clustered SD. Impairment in autoregulation in aSAH is associated with worse clinical outcomes and occurrence of SD when using ORx and OSRx. Impaired autoregulation precedes SD occurrence. Targeting the optimal MAP or cerebral perfusion pressure in patients with aSAH should use ORx and/or OSRx as the input function rather than intracranial pressure.

Ultrafast Cooling With Total Liquid Ventilation Mitigates Early Inflammatory Response and Offers Neuroprotection in aPorcine Model of Cardiac Arrest.

Brain injury is one of the most serious complications after cardiac arrest (CA). To prevent this phenomenon, rapid cooling with total liquid ventilation (TLV) has been proposed in small animal models of CA (rabbits and piglets). Here, we aimed to determine whether hypothermic TLV can also offer neuroprotection and mitigate cerebral inflammatory response in large animals. Anesthetized pigs were subjected to 14 minutes of ventricular fibrillation followed by cardiopulmonary resuscitation. After return of spontaneous circulation, animals were randomly subjected to normothermia (control group, n=8) or ultrafast cooling with TLV (TLV group, n=8). In the latter group, TLV was initiated within a window of 15 minutes after return of spontaneous circulation and allowed to reduce tympanic, esophageal, and bladder temperature to the 32 to 34 °C range within 30 minutes. After 45 minutes of TLV, gas ventilation was resumed, and hypothermia was maintained externally until 3 hours after CA, before rewarming using heat pads (0.5 °C-1 °C/h). After an additional period of progressive rewarming for 3 hours, animals were euthanized for brain withdrawal and histological analysis. At the end of the follow-up (ie, 6 hours after CA), histology showed reduced brain injury as witnessed by the reduced number of Fluroro-Jade C-positive cerebral degenerating neurons in TLV versus control. IL (interleukin)-1ra and IL-8 levels were also significantly reduced in the cerebrospinal fluid in TLV versus control along with cerebral infiltration by CD3+ cells. Conversely, circulating levels of cytokines were not different among groups, suggesting a discrepancy between local and systemic inflammatory levels. Ultrafast cooling with TLV mitigates neuroinflammation and attenuates acute brain lesions in the early phase following resuscitation in large animals subjected to CA.

Is Nasal Dysbiosis a Required Component for Neuroinflammation in Major Depressive Disorder?

Human microbiota is known to influence immune and cerebral responses by direct and/or indirect mechanisms, including hypothalamic-pituitary-adrenal axis signaling, activation of neural afferent circuits to the brain, and by altering the peripheral immune responses (cellular and humoral immune function, circulatory inflammatory cells, and the production of several inflammatory mediators, such as cytokines, chemokines, and reactive oxygen species). The inflammatory responses in the nasal mucosa (rhinitis) or paranasal sinuses (chronic rhinosinusitis) are dual conditions related with a greater risk for developing depression. In the nasal cavity, anatomic components of the olfactive function are in direct contact with the CNS through the olfactory receptors, neurons, and axons that end in the olfactory bulb and the entorhinal cortex. Local microbiome alterations (dysbiosis) are linked to transepithelial translocation of microorganisms and their metabolites, which disrupts the epithelial barrier and favors vascular permeability, increasing the levels of several inflammatory molecules (both cytokines and non-cytokine mediators: extracellular vesicles (exosomes) and neuropeptides), triggering local inflammation (rhinitis) and the spread of these components into the central nervous system (neuroinflammation). In this review, we discuss the role of microbiota-related immunity in conditions affecting the nasal mucosa (chronic rhinosinusitis and allergic rhinitis) and their relevance in major depressive disorders, focusing on the few mechanisms known to be involved and providing some hypothetical proposals on the pathophysiology of depression.

Plasminogen activator inhibitor-1 mediates cerebral ischemia-induced astrocytic reactivity.

Although ischemia increases the abundance of plasminogen activator inhibitor-1 (PAI-1), its source and role in the ischemic brain remain unclear. We detected PAI-1-immunoreactive cells with morphological features of reactive astrocytes in the peri-ischemic cortex of mice after an experimentally-induced ischemic lesion, and of a chimpanzee that suffered a naturally-occurring stroke. We found that although the abundance of PAI-1 increases 24 hours after the onset of the ischemic injury in a non-reperfusion murine model of ischemic stroke, at that time-point there is no difference in astrocytic reactivity and the volume of the ischemic lesion between wild-type (Wt) animals and in mice either genetically deficient (PAI-1-/-) or overexpressing PAI-1 (PAI-1Tg). In contrast, 72 hours later astrocytic reactivity and the volume of the ischemic lesion were decreased in PAI-1-/- mice and increased in PAI-1Tg animals. Our immunoblottings and fractal analysis studies show that the abundance of astrocytic PAI-1 rises during the recovery phase from a hypoxic injury, which in turn increases the abundance of glial fibrillary acidic protein (GFAP) and triggers morphological features of reactive astrocytes. These studies indicate that cerebral ischemia-induced release of astrocytic PAI-1 triggers astrocytic reactivity associated with enlargement of the necrotic core.

Influence of gestational window on offspring vascular health in rodents with in utero exposure to electronic cigarettes.

Studies have shown cerebrovascular dysfunction in offspring with full-gestational electronic cigarette (Ecig) exposure, but little is known about how individual trimester exposure impacts offspring health. This study aimed to determine if there is a critical window during gestation that contributes to vascular and anxiety-like behavioural changes seen with full-term exposure. To test this, rats were time-mated, and the pregnant dams were randomly assigned to Ecig exposure during first trimester (gestational day, GD2-7), second trimester (GD8-14), third trimester (GD15-21) or full-term gestation (GD2-21). We also assessed the effect of maternal preconception exposure. Both male and female offspring from all maternal exposure conditions were compared to offspring from dams under ambient air (control) conditions. Ecig exposure consisted of 60-puffs/day (5days/week) using either 5 or 30watts for each respective exposure group. We found that maternal exposure to Ecig in the second and third trimesters resulted in a decrease (23-38%) in vascular reactivity of the middle cerebral artery (MCA) reactivity in 3- and 6-month-old offspring compared to Air offspring. Further, the severity of impairment was comparable to the full-term exposure (31-46%). Offspring also displayed changes in body composition, body mass, anxiety-like behaviour and locomotor activity, indicating that Ecigs influence neurodevelopment and metabolism. Maternal preconception exposure showed no impact on offspring body mass, anxiety-like behaviour, or vascular function. Thus, the critical exposure window where Ecig affects vascular development in offspring occurs during mid- to late-gestation in pregnancy, and both 5W and 30W exposure produce significant vascular dysfunction compared to Air. KEY POINTS: Exposure to electronic cigarettes (Ecigs) is known to increase risk factors for cardiovascular disease in both animals and humans. Maternal Ecig use during pregnancy in rodents is found to impair the vascular health of adolescent and adult offspring, but the critical gestation window for Ecig-induced vascular impairment is not known. This study demonstrates Ecig exposure during mid- and late-gestation (i.e. second or third trimester) results in impaired endothelial cell-mediated dilatation (i.e. middle cerebral artery reactivity) and alters anxiety-like behaviour in offspring. Maternal exposure prior to conception did not impact offspring's vascular or anxiety-like behavioural outcomes. Rodent models have been a reliable and useful predictor of inhalation-induced harm to humans. These data indicate maternal use of Ecigs during pregnancy should not be considered safe, and begin to inform clinicians and women about potential long-term harm to their offspring.

Effects of sodium bicarbonate ingestion on ventilatory and cerebrovascular responses in resting heated humans.

Hyperthermia stimulates ventilation in humans. This hyperthermia-induced hyperventilation may be mediated by the activation of peripheral chemoreceptors implicated in the regulation of respiration in reaction to various chemical stimuli, including reductions in arterial pH. Here, we investigated the hypothesis that during passive heating at rest, the increases in arterial pH achieved with sodium bicarbonate ingestion, which could attenuate peripheral chemoreceptors activity, mitigate hyperthermia-induced hyperventilation. We also assessed that the effect of sodium bicarbonate ingestion on cerebral blood flow responses, which are associated with hyperthermia-induced hyperventilation. Twelve healthy men ingested a sodium bicarbonate (0.3 g/kg body weight) or sodium chloride (0.208 g/kg). One hundred minutes after the ingestion, the participants were passively heated using hot-water immersion (42°C) combined with a water-perfused suit. Increases in esophageal temperature (an index of core temperature) and minute ventilation (VE) during the heating were similar in the two trials. Moreover, when VE is expressed as a function of esophageal temperature, there were no between-trial differences in the core temperature threshold for hyperventilation (37.9 ± 0.3 vs. 38.0 ± 0.4°C, P = 0.338), and sensitivity of hyperthermia-induced hyperventilation as assessed by the slope of the core temperature-VE relation (13.7 ± 14.9 vs. 15.8 ± 15.6 L/min/°C, P = 0.748). Furthermore, middle cerebral artery mean blood velocity (an index of cerebral blood flow) decreased similarly with heating duration in both trials. These results suggest that sodium bicarbonate ingestion does not mitigate hyperthermia-induced hyperventilation and the reductions in cerebral blood flow index in resting heated humans.