Shigehiko Ogoh

Cerebral blood flow during exercise: mechanisms of regulation

The response of cerebral vasculature to exercise is different from other peripheral vasculature; it has a small vascular bed and is strongly regulated by cerebral autoregulation and the partial pressure of arterial carbon dioxide (Pa(CO(2))). In contrast to other organs, the traditional thinking is that total cerebral blood flow (CBF) remains relatively constant and is largely unaffected by a variety of conditions, including those imposed during exercise. Recent research, however, indicates that cerebral neuronal activity and metabolism drive an increase in CBF during exercise. Increases in exercise intensity up to approximately 60% of maximal oxygen uptake produce elevations in CBF, after which CBF decreases toward baseline values because of lower Pa(CO(2)) via hyperventilation-induced cerebral vasoconstriction. This finding indicates that, during heavy exercise, CBF decreases despite the cerebral metabolic demand. In contrast, this reduced CBF during heavy exercise lowers cerebral oxygenation and therefore may act as an independent influence on central fatigue. In this review, we highlight methodological considerations relevant for the assessment of CBF and then summarize the integrative mechanisms underlying the regulation of CBF at rest and during exercise. In addition, we examine how CBF regulation during exercise is altered by exercise training, hypoxia, and aging and suggest avenues for future research.

The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise

We examined the relationship between changes in cardiac output and middle cerebral artery mean blood velocity (MCA Vmean) in seven healthy volunteer men at rest and during 50% maximal oxygen uptake steady‐state submaximal cycling exercise. Reductions in were accomplished using lower body negative pressure (LBNP), while increases in were accomplished using infusions of 25% human serum albumin. Heart rate (HR), arterial blood pressure and MCA Vmean were continuously recorded. At each stage of LBNP and albumin infusion was measured using an acetylene rebreathing technique. Arterial blood samples were analysed for partial pressure of carbon dioxide tension (P  a,CO 2. During exercise HR and were increased above rest (P < 0.001), while neither MCA Vmean nor P  a,CO 2 was altered (P > 0.05). The MCA Vmean and were linearly related at rest (P < 0.001) and during exercise (P= 0.035). The slope of the regression relationship between MCA Vmean and at rest was greater (P= 0.035) than during exercise. In addition, the phase and gain between MCA Vmean and mean arterial pressure in the low frequency range were not altered from rest to exercise indicating that the cerebral autoregulation was maintained. These data suggest that the associated with the changes in central blood volume influence the MCA Vmean at rest and during exercise and its regulation is independent of cerebral autoregulation. It appears that the exercise induced sympathoexcitation and the change in the distribution of between the cerebral and the systemic circulation modifies the relationship between MCA Vmean and .

Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function

There is considerable utility in the use of transcranial Doppler ultrasound (TCD) to assess cerebrovascular function. The brain is unique in its high energy and oxygen demand but limited capacity for energy storage that necessitates an effective means of regional blood delivery. The relative low cost, ease-of-use, non-invasiveness, and excellent temporal resolution of TCD make it an ideal tool for the examination of cerebrovascular function in both research and clinical settings. TCD is an efficient tool to access blood velocities within the cerebral vessels, cerebral autoregulation, cerebrovascular reactivity to CO(2), and neurovascular coupling, in both physiological states and in pathological conditions such as stroke and head trauma. In this review, we provide: (1) an overview of TCD methodology with respect to other techniques; (2) a methodological synopsis of the cerebrovascular exam using TCD; (3) an overview of the physiological mechanisms involved in regulation of the cerebral blood flow; (4) the utility of TCD for assessment of cerebrovascular pathology; and (5) recommendations for the assessment of four critical and complimentary aspects of cerebrovascular function: intra-cranial blood flow velocity, cerebral autoregulation, cerebral reactivity, and neurovascular coupling. The integration of these regulatory mechanisms from an integrated systems perspective is discussed, and future research directions are explored.

Arterial baroreflex resetting during exercise: a current perspective

Within the past 20 years numerous animal and human experiments have provided supportive evidence of arterial baroreflex resetting during exercise. In addition, it has been demonstrated that both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex) play both independent and interactive roles in the resetting of the arterial baroreflex with exercise. A fundamental alteration associated with baroreflex resetting during exercise is the movement of the operating point of the reflex away from the centring point and closer to the threshold, thereby increasing the ability of the reflex to buffer hypertensive stimuli. Recent studies suggest that central command and the cardiopulmonary baroreceptors may play a role in this movement of the operating point on the baroreflex–heart rate and baroreflex–blood pressure curve, respectively. Current research is focusing on the investigation of central neural mechanisms involved in cardiovascular control, including use of electrophysiological and molecular biological techniques in rat and mouse models to investigate baroreflex resetting as well as use of state of the art brain imaging techniques in humans. However, the purpose of this review is to describe the role of the arterial baroreflex in the regulation of arterial blood pressure during physical activity from a historical perspective with a particular emphasis on human investigations.

Influence of Changes in Blood Pressure on Cerebral Perfusion and Oxygenation

Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation. Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of “normal” CA has not been clearly identified. While controlling for the influence of arterial Pco2, we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal Pco2, and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: ≈40 to ≈125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAvmean was altered by 0.82±0.35% per millimeter of mercury change in mean blood pressure (R2=0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slope=−0.18%/mm Hg; R2=0.60) and MCAvmean (slope=−0.26%/cm · s−1; R2=0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAvmean.

The distribution of blood flow in the carotid and vertebral arteries during dynamic exercise in humans

Non‐technical summary  The mechanism underlying the plateau or relative decrease in cerebral blood flow during maximal incremental dynamic exercise remains unclear. We show that during graded dynamic exercise, the regulation of internal carotid artery blood flow was limited by a large increase in external carotid artery blood flow, one function of which is thermoregulation during heavy exercise. The mechanism of the plateau or decrease in internal carotid artery blood flow appears to be partly due to exercise‐induced redistribution of arterial blood flow to the head and brain.

Autonomic Neural Control of the Cerebral Vasculature Acute Hypotension

Background and Purpose— The effect of antihypertensive drugs on autonomic neural control of the cerebral circulation remains unclear. This study was designed to compare middle cerebral artery mean blood velocity responses to acute hypotension with and without &agr;1-adrenoreceptor blockade (Prazosin) in young, healthy humans. Methods— Acute hypotension was induced nonpharmacologically in 6 healthy subjects (mean±SE; 28±2 years) by releasing bilateral thigh cuffs after 9 minutes of suprasystolic resting ischemia before and after an oral dose of Prazosin (1 mg/20 kg body weight). Results— Prazosin had no effect on thigh cuff release-induced reductions in mean arterial pressure and middle cerebral artery mean blood velocity. However, Prazosin attenuated the amount of peripheral vasoconstriction through the arterial baroreflex as evidenced by a slower return of mean arterial pressure to baseline (P=0.03). Immediately after cuff release, cerebral vascular conductance index increased through cerebral autoregulation and returned to resting values as a result of an increased perfusion pressure mediated through arterial baroreflex mechanisms. The rate of regulation, an index of cerebral autoregulation, was attenuated with Prazosin (control versus Prazosin; rate of regulation=0.204±0.020 versus 0.006±0.053/s, P=0.037). In addition, as mean arterial pressure was returning to resting values, the rate of change in cerebral vascular conductance index was decreased with Prazosin (0.005±0.006/s) compared with control (0.025±0.005/s; P=0.010). Conclusions— These data suggest that during recovery from acute hypotension, decreases in cerebral vascular conductance index were mediated by increases in arterial blood pressure and sympathetically mediated cerebral vasoconstriction.

Baroreflex‐Mediated Changes in Cardiac Output and Vascular Conductance in Response to Alterations in Carotid Sinus Pressure during Exercise in Humans

We sought to quantify the contribution of cardiac output (Q) and total vascular conductance (TVC) to carotid baroreflex (CBR)‐mediated changes in mean arterial pressure (MAP) during mild to heavy exercise. CBR function was determined in eight subjects (25 ± 1 years) at rest and during three cycle exercise trials at heart rates (HRs) of 90, 120 and 150 beats min−1 performed in random order. Acute changes in carotid sinus transmural pressure were evoked using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr (+5.33 to −10.67 kPa). Beat‐to‐beat changes in HR and MAP were recorded throughout. In addition, stroke volume (SV) was estimated using the Modelflow method, which incorporates a non‐linear, three‐element model of the aortic input impedance to compute an aortic flow waveform from the arterial pressure wave. The application of NP and NS did not cause any significant changes in SV either at rest or during exercise. Thus, CBR‐mediated alterations in Q were solely due to reflex changes in HR. In fact, a decrease in the carotid‐HR response range from 26 ± 7 beats min−1 at rest to 7 ± 1 beats min−1 during heavy exercise (P= 0.001) reduced the contribution of Q to the CBR‐mediated change in MAP. More importantly, at the time of the peak MAP response, the contribution of TVC to the CBR‐mediated change in MAP was increased from 74 ± 14 % at rest to 118 ± 6 % (P= 0.017) during heavy exercise. Collectively, these findings indicate that alterations in vasomotion are the primary means by which the CBR regulates blood pressure during mild to heavy exercise.

Autonomic nervous system influence on arterial baroreflex control of heart rate during exercise in humans

A combination of sympathoexcitation and vagal withdrawal increases heart rate (HR) during exercise, however, their specific contribution to arterial baroreflex sensitivity remains unclear. Eight subjects performed 25 min bouts of exercise at a HR of 90, 120, and 150 beats min−1, respectively, with and without metoprolol (0.16 ± 0.01 mg kg−1; mean ±s.e.m.) or glycopyrrolate (12.6 ± 1.6 μg kg−1). Carotid baroreflex (CBR) function was determined using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr, while transfer function gain (GTF) was calculated to assess the linear dynamic relationship between mean arterial pressure and HR. Spontaneous baroreflex sensitivity (SBR) was evaluated as the slope of sequences of three consecutive beats in which systolic blood pressure and the R–R interval of the ECG either increased or decreased, in a linear fashion. The β‐1 adrenergic blockade decreased and vagal cardiac blockade increased HR both at rest and during exercise (P < 0.05). The gain at the operating point of the modelled reflex function curve (GOP) obtained using NP and NS decreased with workload independent of β‐1 adrenergic blockade. In contrast, vagal blockade decreased GOP from −0.40 ± 0.04 to −0.06 ± 0.01 beats min−1 mmHg−1 at rest (P < 0.05). Furthermore, as workload increased both GOP and SBR, and GOP and GTF were correlated (P < 0.001), suggesting that the two dynamic methods applied to evaluate arterial baroreflex (ABR) function provide the same information as the modelled GOP. These findings suggest that during exercise the reduction of arterial baroreceptor reflex sensitivity at the operating point was a result of vagal withdrawal rather than an increase in sympathetic activity.

Differential blood flow responses to CO2 in human internal and external carotid and vertebral arteries

•  Arterial CO2 serves as a mediator of cerebral blood flow, and its relative influence on the regulation of cerebral blood flow is defined as cerebral CO2 reactivity. •  Because of methodological limitations, almost all previous studies have evaluated the response of blood flow velocity in the middle cerebral artery to changes in CO2 as a measure of CO2 reactivity across the whole brain. •  We found that the vertebral artery has lower CO2 reactivity than the internal carotid artery. Moreover, CO2 reactivity in the external carotid artery was markedly lower than in the cerebral circulation. •  These results demonstrate regional differences in CO2 regulation of blood flow between the internal carotid, external carotid, and vertebro‐basilar circulation.