Regional Cerebral Blood Flow Responses Research Articles

Mixed nut consumption improves brain insulin sensitivity: a randomized, single-blinded, controlled, crossover trial in older adults with overweight or obesity

BackgroundImproving brain insulin sensitivity, which can be assessed by measuring regional cerebral blood flow (CBF) responses to intranasal insulin, may prevent age-related metabolic and cognitive diseases. ObjectivesThis study aimed to investigate longer-term effects of mixed nuts on brain insulin sensitivity in older individuals with overweight/obesity. MethodsIn a randomized, single-blinded, controlled, crossover trial, 28 healthy adults (mean ± standard deviation: 65 ± 3 years; body mass index: 27.9 ± 2.3 kg/m2) received either daily 60-g mixed nuts (15 g of walnuts, pistachio, cashew, and hazelnuts) or no nuts (control) for 16 weeks, separated by an 8-week washout period. Throughout the study, participants were instructed to adhere to the Dutch food-based dietary guidelines. During follow-up, brain insulin action was assessed by quantifying acute effects of intranasal insulin on regional CBF using arterial spin labeling magnetic resonance imaging. Furthermore, effects on peripheral insulin sensitivity (oral glucose tolerance test), intrahepatic lipids, and cardiometabolic risk markers were assessed. ResultsBody weight and composition did not change. Compared with control, mixed nut consumption improved regional brain insulin action in 5 clusters located in the left (difference in CBF responses to intranasal insulin: −4.5 ± 4.7 mL/100 g/min; P < 0.001; −4.6 ± 4.8 mL/100 g/min; P < 0.001; and −4.3 ± 3.6 mL/100 g/min; P = 0.007) and right occipital lobes (−4.3 ± 5.6 mL/100 g/min; and −3.9 ± 4.9 mL/100 g/min; P = 0.028). A fifth cluster was part of the left frontal lobe (−5.0 ± 4.6 mL/100 g/min; P < 0.001). Peripheral insulin sensitivity was not affected. Intrahepatic lipid content (−0.7%-point; 95% CI: −1.3%-point to −0.1%-point; P = 0.027), serum low-density lipoprotein cholesterol concentration (−0.24 mmol/L; 95% CI: −0.44 to −0.04 mmol/L; P = 0.019), and systolic blood pressure (−5 mm Hg; 95% CI: −8 to −1 mm Hg; P = 0.006) were lower after the mixed nut intervention. ConclusionsLonger-term mixed nut consumption affected insulin action in brain regions involved in the modulation of metabolic and cognitive processes in older adults with overweight/obesity. Intrahepatic lipid content and different cardiometabolic risk markers also improved, but peripheral insulin sensitivity was not affected.This trial was registered at clinicaltrials.gov as NCT04210869.

Acute inorganic nitrate intake increases regional insulin action in the brain: Results of a double-blind, randomized, controlled cross-over trial with abdominally obese men

AimsImproving brain insulin sensitivity may be a promising approach in the prevention and treatment of metabolic and cognitive diseases. Our aim was to investigate acute effects of inorganic nitrate on regional cerebral blood flow (CBF) responses to intranasal insulin in abdominally obese men. MethodsEighteen apparently healthy men, aged 18–60 years and with a waist circumference ≥ 102 cm, participated in a randomized, double-blind, placebo-controlled cross-over trial. The study consisted of two test days separated by at least one week. Men received in random order a drink providing 10 mmol (i.e., 625 mg nitrate) potassium nitrate or an isomolar placebo drink with potassium chloride. Brain insulin action was assessed 120–150 min after the drinks by quantifying acute effects of nasal insulin on regional CBF using arterial spin labeling Magnetic Resonance Imaging. Glucose and insulin concentrations were measured at regular intervals, while blood pressure was determined fasted and at 240 min. ResultsInorganic nitrate intake increased regional insulin action in five brain clusters. The two largest clusters were located in the right temporal lobe (ΔCBF: 7.0 ± 3.8 mL/100 g/min, volume: 5296 mm3, P < 0.001; and ΔCBF: 6.5 ± 4.3 mL/100 g/min, volume: 3592 mm3, P < 0.001), while two other cortical clusters were part of the right frontal (ΔCBF: 9.0 ± 6.0 mL/100 g/min, volume: 1096 mm3, P = 0.007) and the left parietal lobe (ΔCBF: 6.1 ± 4.3 mL/100 g/min, volume: 1024 mm3, P = 0.012). One subcortical cluster was located in the striatum (ΔCBF: 5.9 ± 3.2 mL/100 g/min, volume: 1792 mm3, P < 0.001). No effects of nitrate were observed on CBF before administration. Following nitrate intake, circulating nitrate plus nitrite concentrations increased over time (P = 0.003), but insulin and glucose concentrations and blood pressure did not change. ConclusionAcute inorganic nitrate intake may improve regional brain insulin action in abdominally obese men. These regions are involved in the regulation of different metabolic and cognitive processes.The trial was registered on January 6th, 2021 at ClinicalTrials.gov as NCT04700241.

Hippocampus is more susceptible to hypoxic injury: has the Rosetta Stone of regional variation in neurovascular coupling been deciphered?

Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) are associated with cerebral hypoperfusion or reductions in baseline cerebral blood flow (CBF). The neurovascular coupling (NVC) response or functional hyperemia regulates brain perfusion via a retrograde (capillary-to-arteriole) pathway by increasing regional CBF in response to local neuron activation. The hippocampus plays a significant role in spatial and non-spatial memory. Functional MRI (fMRI) has not established a solid positive correlation between hippocampal blood oxygen level-dependent (BOLD) signal and local neuronal activity. The inconsistency of NVC in the hippocampus compared to the neocortex is possibly due to anatomical and methodological difficulties to accurately detect hippocampal blood flow. A recent study reported that NVC and oxygenation are reduced in the hippocampus compared to the cortex using a novel invasive surgical approach by creating a cranial window with and without removing the neocortex. Results from these studies suggest that the hippocampus is more susceptible to hypoxic injury in pathological conditions when NVC is impaired, such as AD/ADRD, stroke, and traumatic brain injury (TBI). The Rosetta Stone of regional variation in the NVC and its significance in AD/ADRD has not been fully deciphered based on these results without addressing remaining concerns; however, we are one step closer, indeed.

Low neuronal metabolism during isoflurane-induced burst suppression is related to synaptic inhibition while neurovascular coupling and mitochondrial function remain intact

Deep anaesthesia may impair neuronal, vascular and mitochondrial function facilitating neurological complications, such as delirium and stroke. On the other hand, deep anaesthesia is performed for neuroprotection in critical brain diseases such as status epilepticus or traumatic brain injury. Since the commonly used anaesthetic propofol causes mitochondrial dysfunction, we investigated the impact of the alternative anaesthetic isoflurane on neuro-metabolism. In deeply anaesthetised Wistar rats (burst suppression pattern), we measured increased cortical tissue oxygen pressure (ptiO2), a ∼35% drop in regional cerebral blood flow (rCBF) and burst-associated neurovascular responses. In vitro, 3% isoflurane blocked synaptic transmission and impaired network oscillations, thereby decreasing the cerebral metabolic rate of oxygen (CMRO2). Concerning mitochondrial function, isoflurane induced a reductive shift in flavin adenine dinucleotide (FAD) and decreased stimulus-induced FAD transients as Ca2+ influx was reduced by ∼50%. Computer simulations based on experimental results predicted no direct effects of isoflurane on mitochondrial complexes or ATP-synthesis. We found that isoflurane-induced burst suppression is related to decreased ATP consumption due to inhibition of synaptic activity while neurovascular coupling and mitochondrial function remain intact. The neurometabolic profile of isoflurane thus appears to be superior to that of propofol which has been shown to impair the mitochondrial respiratory chain.

Exercised state of mind: A perspective on ageing, cerebral blood flow and cognition.

Exercised state of mind: A perspective on ageing, cerebral blood flow and cognition.

Cerebrovascular function in hypertension: Does high blood pressure make you old?

The majority of individuals over an age of 60 have hypertension. Elevated blood pressure and older age are associated with very similar changes in brain structure and function. We review the parallel brain changes associated with increasing age and blood pressure. This review focuses on joint associations of aging and elevated blood pressure with neuropsychological function, regional cerebral blood flow responses to cognitive and metabolic challenges, white matter disruptions, grey matter volume, cortical thinning, and neurovascular coupling. Treatment of hypertension ameliorates many of these changes but fails to reverse them. Treatment of hypertension itself appears more successful with better initial brain function. We show evidence that sympathetic and renal influences known to increase blood pressure also impact brain integrity. Possible central mechanisms contributing to the course of hypertension and aging are then suggested. An emphasis is placed on psychologically relevant factors: stress, cardiovascular reactions to stress, and diet/obesity. The contribution of some of these factors to biological aging remains unclear and may provide a starting point for defining the independent and interacting effects of aging and increasing blood pressure on the brain.

Alterations in resting cerebrovascular regulation do not affect reactivity to hypoxia, hyperoxia or neurovascular coupling following a SCUBA dive.

What is the central question of this study? What are the characteristics of cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18m sea water with a 47min bottom time. What is the main finding and its importance? Acute alterations in CBF regulation at rest, including extra-cranial vasodilatation, reductions in shear patterns and elevations in intra-cranial blood velocity were observed at rest following a single SCUBA dive. These subtle changes in CBF regulation did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or neurovascular coupling following a single SCUBA dive. Reductions in vascular function during a SCUBA dive - due to hyperoxia-induced oxidative stress, arterial and venous gas emboli and altered endothelial integrity - may also extend to the cerebrovasculature following return to the surface. This study aimed to characterize cerebral blood flow (CBF) regulation following a single SCUBA dive to a depth of 18m sea water with a 47min bottom time. Prior to and following the dive, participants (n=11) completed (1) resting CBF in the internal carotid (ICA) and vertebral (VA) arteries (duplex ultrasound) and intra-cranial blood velocity (v) of the middle and posterior cerebral arteries (MCAv and PCAv, respectively) (transcranial Doppler ultrasound); (2) cerebrovascular reactivity to acute poikilocapnic hypoxia (i.e. , 0.10) and hyperoxia (i.e. , 1.0); and (3) neurovascular coupling (NVC; regional CBF response to local increases in cerebral metabolism). Global CBF, cerebrovascular reactivity to hypoxia and hyperoxia, and NVC were unaltered following a SCUBA dive (all P>0.05); however, there were subtle changes in other cerebrovascular metrics post-dive, including reductions in ICA (-13±8%, P=0.003) and VA (-11±14%, P=0.021) shear rate, lower ICAv (-10±9%, P=0.008) and VAv (-9±14%, P=0.028), increases in ICA diameter (+4±5%, P=0.017) and elevations in PCAv (+10±19%, P=0.047). Although we observed subtle alterations in CBF regulation at rest, these changes did not translate into any functional changes in cerebrovascular reactivity to hypoxia or hyperoxia, or NVC. Whether prolonged exposure to hyperoxia and hyperbaria during longer, deeper, colder and/or repetitive SCUBA dives would provoke changes to the cerebrovasculature requires further investigation.

Neurovascular Coupling Impairment in Acute Ischemic Stroke by Optogenetics and Optical Brain Imaging.

The coupling between neuronal activity and cerebral blood flow (CBF), known as neurovascular coupling, has been reported to be impaired after stroke. This study aims to investigate the neurovascular coupling impairment at the acute stage after ischemic stroke. Laser speckle contrast imaging (LSCI) was applied to measure the hemodynamic response to optogenetic excitation of sensorimotor neurons in healthy and ischemic brain. The results showed that the hemodynamic response to optogenetic stimulation decreased and the regional CBF response was correlated with the distance from the ischemic core at the acute stage, regardless of the change in resting CBF. Our results also demonstrated that excitatory neuronal stimulation of intact area could promote the recovery of neurovascular coupling, whereas peri-infarct neuronal excitation failed to restore neurovascular function 24 hrs after ischemia. These results suggested the intact periphery of penumbra as the target for excitatory stimulation in aspect of restoring the perfusion after ischemic stroke.

0011 The Influence of Obstructive Sleep Apnea Severity and Sex on Cerebral Perfusion

Abstract Introduction Obstructive Sleep Apnea (OSA) has been shown to initiate a pathological cascade negatively affecting the cardiovascular system, including cerebral circulation. There is limited data on OSA effects on regional brain function, though reduced global cerebral blood flow (CBF) has been observed among patients with OSA. However, there are few precise assessments. We hypothesized that regional CBF values are altered in OSA, and that sex influences the hypothesized relationship. Methods Participants from the NYU Center for Brain Health cohort (n=68; 57.4% female; mean age=66.32±6.84), representing cognitively healthy volunteers with OSA (AHI4% &amp;gt; 5/hr) and without, from several NIA-supported studies, completed evaluations including clinical, structural &amp; functional high-resolution arterial spin labeling 3 tesla MRI scans. Hippocampal and temporal cortex CBF was assessed at baseline and after CO2 challenge using a rebreathing protocol. Analyses were completed using one-way ANCOVA controlling for age and BMI. Results More men had OSA (82.8% vs 56.4%). Men without OSA showed a larger change in CBF after challenge in left (t=2.6, p=0.014) and right (t=2.4, p=0.021) hippocampus. Although the main analyses by severity level only boarded significance, pairwise comparisons indicated men with severe OSA (AHI4%&amp;gt;30/hr) exhibited a larger change in CBF after challenge in the hippocampus overall compared to those with mild OSA (AHI4%5–15/hr; p=0.015) and without OSA (p=0.017). Women with severe OSA showed a reduced change in CBF after challenge in the right hippocampus compared to those with mild (p=0.016), moderate (AHI4%16–29/hr; p=0.008), and without OSA (p=0.015). Conclusion This study suggests a possible differential effect of OSA severity and sex on regional CBF in response to a CO2 challenge, specifically in the hippocampus. Further studies will examine cognitive consequences of these sex-specific hippocampal perfusion abnormalities in OSA. Support NIH/NIA (1R01HL118624) Osorio, RS 07/01/13-04/30/17 Sleep Disordered Breathing in normal elderly and risk for Alzheimer’s disease (AD).NIH/NIA (R01AG056031S1) Osorio, RS 8/01/2019-7/31/2020 Sleep Aging and Risk for Alzheimer’s disease - Research Supplement to Promote Diversity in Health-Related Research

Impaired Awareness of Hypoglycemia Disrupts Blood Flow to Brain Regions Involved in Arousal and Decision Making in Type 1 Diabetes

Impaired awareness of hypoglycemia (IAH) affects one-quarter of adults with type 1 diabetes and significantly increases the risk of severe hypoglycemia. Differences in regional brain responses to hypoglycemia may contribute to the susceptibility of this group to problematic hypoglycemia. This study investigated brain responses to hypoglycemia in hypoglycemia aware (HA) and IAH adults with type 1 diabetes, using three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) functional MRI to measure changes in regional cerebral blood flow (CBF). Fifteen HA and 19 IAH individuals underwent 3D pCASL functional MRI during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global, and regional CBF responses to hypoglycemia (47 mg/dL [2.6 mmol/L]) were measured. In response to hypoglycemia, total symptom score did not change in those with IAH (P = 0.25) but rose in HA participants (P < 0.001). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were lower in the IAH group (P < 0.05). Hypoglycemia induced a rise in global CBF (HA P = 0.01, IAH P = 0.04) but was not different between groups (P = 0.99). IAH participants showed reduced regional CBF responses within the thalamus (P = 0.002), right lateral orbitofrontal cortex (OFC) (P = 0.002), and right dorsolateral prefrontal cortex (P = 0.036) and a lesser decrease of CBF in the left hippocampus (P = 0.023) compared with the HA group. Thalamic and right lateral OFC differences survived Bonferroni correction. Responses to hypoglycemia of brain regions involved in arousal, decision making, and reward are altered in IAH. Changes in these pathways may disrupt IAH individuals' ability to recognize hypoglycemia, impairing their capacity to manage hypoglycemia effectively and benefit fully from conventional therapeutic pathways to restore awareness.

Hypoglycemic thalamic activation in type 1 diabetes is associated with preserved symptoms despite reduced epinephrine

Brain responses to low plasma glucose may be key to understanding the behaviors that prevent severe hypoglycemia in type 1 diabetes. This study investigated the impact of long duration, hypoglycemia aware type 1 diabetes on cerebral blood flow responses to hypoglycemia. Three-dimensional pseudo-continuous arterial spin labeling magnetic resonance imaging was performed in 15 individuals with type 1 diabetes and 15 non-diabetic controls during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global cerebral blood flow and regional cerebral blood flow responses to hypoglycemia were measured. Epinephrine release during hypoglycemia was attenuated in type 1 diabetes, but symptom score rose comparably in both groups. A rise in global cerebral blood flow did not differ between groups. Regional cerebral blood flow increased in the thalamus and fell in the hippocampus and temporal cortex in both groups. Type 1 diabetes demonstrated lesser anterior cingulate cortex activation; however, this difference did not survive correction for multiple comparisons. Thalamic cerebral blood flow change correlated with autonomic symptoms, and anterior cingulate cortex cerebral blood flow change correlated with epinephrine response across groups. The thalamus may thus be involved in symptom responses to hypoglycemia, independent of epinephrine action, while anterior cingulate cortex activation may be linked to counterregulation. Activation of these regions may have a role in hypoglycemia awareness and avoidance of problematic hypoglycemia.

Effects of CO2 on Regional Cerebral Blood Flow Regulation During Lower‐Body Negative Pressure

Cerebrovascular CO2 reactivity (CVR) is differentially regulated between anterior and posterior cerebral circulations, where the cerebrovasculature is responsive to increases (dilation) or decreases (constriction) in arterial CO2. In addition, anterior and posterior cerebral blood flow (CBF) may be differentially regulated during lower body negative pressure (LNBP), where blood volume distribution is experimentally moved toward the lower extremities, imposing an acute hypovolemic and hypotensive challenge. However, the effects of steady‐state increases and decreases in CO2 on the CBF response to LBNP‐imposed hypotension has not been investigated systematically. The aim of this study was to investigate regional CBF responses to incremental (i.e., ramp) LBNP in steady‐state hypo‐ and hypercapnia in anterior and posterior cerebral circulations. We hypothesized that posterior CBF would be better maintained during LBNP at all levels of CO2 and that regional patterns of CBF regulation during LBNP would be unchanged by steady‐state CO2 perturbations. In 14 healthy participants, we measured cardiovascular and cerebrovascular variables, including heart rate (HR; ECG), mean arterial pressure (MAP; finometry), and using transcranial Doppler ultrasound, cerebral blood velocity (CBV) and cerebrovascular conductance (CVC; CBV/MAP) in the middle (MCA) and posterior cerebral artery (PCA). We carried out three separate incremental LBNP protocols (−20, −40, −60 and −80 mm Hg; 3‐min each) at three randomized steady‐state levels of CO2: (a) hypocapnia (−8 mm Hg; i.e., coached hyperventilation), (b) normocapnia (i.e., room air), and (c) hypercapnia (+8 mm Hg; 5% inspired CO2). We found that HR increased incrementally with LBNP in all CO2 conditions (P&lt;0.001). At −80mmHg LBNP, MAP decreased in hypo‐ (P=0.046) and normocapnia (P=0.002). MCA CBV decreased in normo‐ (P&lt;0.001) and hypercapnia (P&lt;0.001). PCA CBV also decreased in normo‐ (P=0.011) and hypercapnia (P=0.002). However, MCA CVC decreased in normo‐ (P=0.01) and hypercapnia (P&lt;0.001), whereas PCA CVC did not decrease during LBNP at all levels of CO2. These findings demonstrate greater sensitivity in anterior cerebral circulation compared to posterior during a moderate LBNP challenge with alterations in CO2. Our data elucidate a comprehensive understanding of regional CVR during LBNP‐induced hypovolemia, and may be applied to understanding preferential protection of posterior brain structures during hypovolemic shock.Support or Funding InformationNSERC Discovery and MRU Faculty of Science and TechnologyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Adrenoceptor blockade modifies regional cerebral blood flow responses to hyperbaric hyperoxia: protection against CNS oxygen toxicity.

Exposure to extreme hyperbaric oxygen (HBO2) >5-6 atmospheres absolute (ATA) produces baroreflex impairment, sympathetic hyperactivation, hypertension, tachycardia, and cerebral hyperemia, known as phase II, culminating in seizures. We hypothesized that attenuation of the effects of high sympathetic outflow would preserve regional cerebral blood flow (rCBF) and protect against HBO2-induced seizures. To explore this possibility, we tested four adrenoceptor antagonists in conscious and anesthetized rats exposed to HBO2 at 5 and 6 ATA, respectively: phentolamine (nonselective α1 and α2), prazosin (selective α1), propranolol (nonselective β1 and β2), and atenolol (selective β1). In conscious rats, four drug doses were administered to rats before HBO2 exposures, and seizure latencies were recorded. Drug doses that provided similar protection against seizures were administered before HBO2 exposures in anesthetized rats to determine the effects of adrenoceptor blockade on mean arterial pressure, heart rate, rCBF, and EEG spikes. All four drugs modified cardiovascular and rCBF responses in HBO2 that aligned with epileptiform discharges, but only phentolamine and propranolol effectively increased EEG spike latencies by ~20 and 36 min, respectively. When phentolamine and propranolol were delivered during HBO2 at the onset of phase II, only propranolol led to sustained reductions in heart rate and rCBF, preventing the appearance of epileptiform discharges. The enhanced effectiveness of propranolol may extend beyond β-adrenoceptor blockade, i.e., membrane stability and reduced metabolic activity. These results indicate that adrenoceptor drug pretreatment will minimize the effects of excessive sympathetic outflow on rCBF and extend HBO2 exposure time.NEW & NOTEWORTHY Blocking adrenergic receptors with phentolamine (nonselective α1 and α2), prazosin (selective α1), propranolol (nonselective β1 and β2), and atenolol (selective β1) modified cardiovascular and regional cerebral blood flow (rCBF) responses in hyperbaric oxygen (HBO2) at 6 atmospheres absolute (ATA); however, only phentolamine and propranolol extended EEG spike latencies. When these two agents were delivered at the onset of sympathetic hyperactivation, only propranolol reduced heart rate and rCBF throughout the exposure and prevented epileptiform discharges. These data validate the strong role of adrenergic control of cardiovascular function and rCBF in extreme HBO2 and the potential use of antiadrenergic drugs to prevent seizures.

Brain Regional Blood Flow and Working Memory Performance Predict Change in Blood Pressure Over 2 Years.

Hypertension is a presumptive risk factor for premature cognitive decline. However, lowering blood pressure (BP) does not uniformly reverse cognitive decline, suggesting that high BP per se may not cause cognitive decline. We hypothesized that essential hypertension has initial effects on the brain that, over time, manifest as cognitive dysfunction in conjunction with both brain vascular abnormalities and systemic BP elevation. Accordingly, we tested whether neuropsychological function and brain blood flow responses to cognitive challenges among prehypertensive individuals would predict subsequent progression of BP. Midlife adults (n=154; mean age, 49; 45% men) with prehypertensive BP underwent neuropsychological testing and assessment of regional cerebral blood flow (rCBF) response to cognitive challenges. Neuropsychological performance measures were derived for verbal and logical memory (memory), executive function, working memory, mental efficiency, and attention. A pseudo-continuous arterial spin labeling magnetic resonance imaging sequence compared rCBF responses with control and active phases of cognitive challenges. Brain areas previously associated with BP were grouped into composites for frontoparietal, frontostriatal, and insular-subcortical rCBF areas. Multiple regression models tested whether BP after 2 years was predicted by initial BP, initial neuropsychological scores, and initial rCBF responses to cognitive challenge. The neuropsychological composite of working memory (standardized beta, -0.276; se=0.116; P=0.02) and the frontostriatal rCBF response to cognitive challenge (standardized beta, 0.234; se=0.108; P=0.03) significantly predicted follow-up BP. Initial BP failed to significantly predict subsequent cognitive performance or rCBF. Changes in brain function may precede or co-occur with progression of BP toward hypertensive levels in midlife.

Regional Cerebral Blood Flow Responses to Graded Sympathetic Activation in Young Healthy Subjects

Numerous studies have investigated cerebral blood flow (CBF) responses during orthostatic stress, primarily using middle cerebral artery (MCA) blood velocity. Due to methodological limitations associated with this measurement, there has been a recent transition towards measuring blood flow in vertebral (VA), internal carotid (ICA) and external carotid arteries (ECA) using duplex Doppler ultrasound. Limited studies have simultaneously characterized the response of all these cerebral vessels to simulated orthostatic stress. Likewise, previous studies examining the influence of the sympathetic nervous system on the cerebral vasculature have also relied mainly on MCA velocity measures, primarily performed during infusion of α-adrenergic receptor agonists or antagonists. PURPOSE: To investigate regional CBF responses to a moderate and high level of reflex-mediated sympathetic activation via lower body negative pressure (LBNP) at -10 and -40 Torr, respectively. METHODS: In 8 young men, beat-to-beat arterial pressure (finger photoplethysmography), heart rate (ECG), VA, ICA, ECA and brachial artery blood flow (duplex Doppler ultrasound) and MCA blood velocity (transcranial Doppler) were measured at rest and during 5 min of -10 and -40 Torr LBNP performed in random order. Conductance was calculated as blood flow of the respective artery/mean arterial pressure. RESULTS: In both LBNP trials, there was a significant decrease in brachial artery blood flow and conductance (-10 Torr: -26.0±10.6 % baseline; -40 Torr: -42.3±4.4 % baseline, p=0.006). In contrast, VA, ICA and ECA blood flow and conductance were unaffected (e.g., VA conductance, -10 Torr: -5.8±4.6 % baseline; -40 Torr: -0.03±2.5 % baseline, p=0.654). MCA blood velocity was also unchanged by LBNP (p=0.648). CONCLUSION: Despite the large sympathetically-mediated reductions in brachial artery conductance, cerebral vascular conductance, assessed in multiple arteries, was unaffected by graded sympathetic activation with LBNP. These preliminary data suggest minimal direct effect of reflex-mediated elevations in sympathetic nerve activity on CBF. Supported by NIH grant 1 RO1 HL 127071.

Prehypertensive Blood Pressures and Regional Cerebral Blood Flow Independently Relate to Cognitive Performance in Midlife

BackgroundHigh blood pressure is thought to contribute to dementia in late life, but our understanding of the relationship between individual differences in blood pressure (BP) and cognitive functioning is incomplete. In this study, cognitive performance in nonhypertensive midlife adults was examined as a function of resting BP and regional cerebral blood flow (rCBF) responses during cognitive testing. We hypothesized that BP would be negatively related to cognitive performance and that cognitive performance would also be related to rCBF responses within areas related to BP control. We explored whether deficits related to systolic BP might be explained by rCBF responses to mental challenge.Methods and ResultsHealthy midlife participants (n=227) received neuropsychological testing and performed cognitive tasks in a magnetic resonance imaging scanner. A pseudocontinuous arterial spin labeling sequence assessed rCBF in brain areas related to BP in prior studies. Systolic BP was negatively related to 4 of 5 neuropsychological factors (standardized β>0.13): memory, working memory, executive function, and mental efficiency. The rCBF in 2 brain regions of interest was similarly related to memory, executive function, and working memory (standardized β>0.17); however, rCBF responses did not explain the relationship between resting systolic BP and cognitive performance.ConclusionsRelationships at midlife between prehypertensive levels of systolic BP and both cognitive and brain function were modest but suggested the possible value of midlife intervention.

Regional temperature and quantitative cerebral blood flow responses to cortical spreading depolarization in the rat

Regional temperature and quantitative regional cerebral blood flow responses to cortical spreading depolarization in the rat were continuously monitored in the same tissue using a microfabricated thermal diffusion sensor that recalibrates and measures in 5-s cycles. The regional cerebral blood flow response had four phases, including early hyperemia (peak: 226% of baseline; duration: 113.1 ± 14.4 s) and late oligemia (minimum: 57%, duration: 28.4 ± 3.7 min). Temperature rose with the start of the regional cerebral blood flow response to a peak increase of 0.28 ± 0.06℃ and returned to baseline near the start of oligemia. This technology may be useful for multimodal monitoring in both the laboratory and clinic.

Common functional pain syndromes

### Key points When a patient presents with pain of no obvious organic origin, they are often labelled as having ‘functional’ pain. The exact diagnosis is derived from the organ system displaying the predominant symptoms e.g. musculoskeletal pain in fibromyalgia (FM) or visceral pain in irritable bowel syndrome (IBS). The worldwide prevalence of all functional pain syndromes (FPS) is 15–20%. World Health Organization (WHO) surveys reveal that ∼10% of primary care patients develop a chronic pain condition within 12 months of initial registration. Of these, at least 50% continue to have symptoms beyond 1 yr. FPS cause enormous economic burden on society with concurrent ramifications for the individual's family in particular and society in general. FM alone has been estimated to cost around £4000 per patient per year. There has been a paradigm shift in the understanding of FPS. The old model of multiple discrete chronic pain conditions is being replaced by a more overarching, although no less complex, state of central sensitivity syndrome (CSS). Evidence is being accrued that FPS represent the phenotypic output of a complex interplay between genetic susceptibility, gene–environment interactions, and environmental triggers. Four common FPS will be reviewed in this article: FM, IBS, temporomandibular dysfunction (TMD), and chronic cardiac chest pain (CCCP). The pathophysiology and management of each will be examined and the case presented for a shared underlying mechanism called CSS. Once this new mechanism is adopted more widely, it will allow for future novel management options to be …

Altered hypermetabolic response to cortical spreading depolarizations after traumatic brain injury in rats

Spreading depolarizations are waves of near-complete breakdown of neuronal transmembrane ion gradients, free energy starving, and mass depolarization. Spreading depolarizations in electrically inactive tissue are associated with poor outcome in patients with traumatic brain injury. Here, we studied changes in regional cerebral blood flow and brain oxygen (PbtO2), glucose ([Glc]b), and lactate ([Lac]b) concentrations in rats, using minimally invasive real-time sensors. Rats underwent either spreading depolarizations chemically triggered by KCl in naïve cortex in absence of traumatic brain injury or spontaneous spreading depolarizations in the traumatic penumbra after traumatic brain injury, or a cluster of spreading depolarizations triggered chemically by KCl in a remote window from which spreading depolarizations invaded penumbral tissue. Spreading depolarizations in noninjured cortex induced a hypermetabolic response characterized by a decline in [Glc]b and monophasic increases in regional cerebral blood flow, PbtO2, and [Lac]b, indicating transient hyperglycolysis. Following traumatic brain injury, spontaneous spreading depolarizations occurred, causing further decline in [Glc]b and reducing the increase in regional cerebral blood flow and biphasic responses of PbtO2 and [Lac]b, followed by prolonged decline. Recovery of PbtO2 and [Lac]b was significantly delayed in traumatized animals. Prespreading depolarization [Glc]b levels determined the metabolic response to clusters. The results suggest a compromised hypermetabolic response to spreading depolarizations and slower return to physiological conditions following traumatic brain injury-induced spreading depolarizations.

Computational and experimental analysis of TMS-induced electric field vectors critical to neuronal activation

Objective. Transcranial magnetic stimulation (TMS) represents a powerful technique to noninvasively modulate cortical neurophysiology in the brain. However, the relationship between the magnetic fields created by TMS coils and neuronal activation in the cortex is still not well-understood, making predictable cortical activation by TMS difficult to achieve. Our goal in this study was to investigate the relationship between induced electric fields and cortical activation measured by blood flow response. Particularly, we sought to discover the E-field characteristics that lead to cortical activation. Approach. Subject-specific finite element models (FEMs) of the head and brain were constructed for each of six subjects using magnetic resonance image scans. Positron emission tomography (PET) measured each subject’s cortical response to image-guided robotically-positioned TMS to the primary motor cortex. FEM models that employed the given coil position, orientation, and stimulus intensity in experimental applications of TMS were used to calculate the electric field (E-field) vectors within a region of interest for each subject. TMS-induced E-fields were analyzed to better understand what vector components led to regional cerebral blood flow (CBF) responses recorded by PET. Main results. This study found that decomposing the E-field into orthogonal vector components based on the cortical surface geometry (and hence, cortical neuron directions) led to significant differences between the regions of cortex that were active and nonactive. Specifically, active regions had significantly higher E-field components in the normal inward direction (i.e., parallel to pyramidal neurons in the dendrite-to-axon orientation) and in the tangential direction (i.e., parallel to interneurons) at high gradient. In contrast, nonactive regions had higher E-field vectors in the outward normal direction suggesting inhibitory responses. Significance. These results provide critical new understanding of the factors by which TMS induces cortical activation necessary for predictive and repeatable use of this noninvasive stimulation modality.