Zachary R. Messer

Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome

Neurocognition is impaired in chronic fatigue syndrome (CFS). We propose that the impairment relates to postural cerebral hemodynamics. Twenty-five CFS subjects and twenty control subjects underwent incremental upright tilt at 0, 15, 30, 45, 60, and 75° with continuous measurement of arterial blood pressure and cerebral blood flow velocity (CBFV). We used an n-back task with n ranging from 0 to 4 (increased n = increased task difficulty) to test working memory and information processing. We measured n-back outcomes by the number of correct answers and by reaction time. We measured CBFV, critical closing pressure (CCP), and CBFV altered by neuronal activity (activated CBFV) during each n value and every tilt angle using transcranial Doppler ultrasound. N-back outcome in control subjects decreased with n valve but was independent of tilt angle. N-back outcome in CFS subjects decreased with n value but deteriorated as orthostasis progressed. Absolute mean CBFV was slightly less than in control subjects in CFS subject at each angle. Activated CBFV in control subjects was independent of tilt angle and increased with n value. In contrast, activated CBFV averaged 0 in CFS subjects, decreased with angle, and was less than in control subjects. CCP was increased in CFS subjects, suggesting increased vasomotor tone and decreased metabolic control of CBFV. CCP did not change with orthostasis in CFS subjects but decreased monotonically in control subjects, consistent with vasodilation as compensation for the orthostatic reduction of cerebral perfusion pressure. Increasing orthostatic stress impairs neurocognition in CFS subjects. CBFV activation, normally tightly linked to cognitive neuronal activity, is unrelated to cognitive performance in CFS subjects; the increased CCP and vasomotor tone may indicate an uncoupling of the neurovascular unit during orthostasis.

Middle cerebral O2 delivery during the modified Oxford maneuver increases with sodium nitroprusside and decreases during phenylephrine

The modified Oxford maneuver is the reference standard for assessing arterial baroreflex function. The maneuver comprises a systemic bolus injection of 100 μg sodium nitroprusside (SNP) followed by 150 μg phenylephrine (PE). On the one hand, this results in an increase in oxyhemoglobin and total hemoglobin followed by a decrease within the cerebral sample volume illuminated by near-infrared spectroscopy (NIRS). On the other hand, it produces a decrease in cerebral blood flow velocity (CBFv) within the middle cerebral artery (MCA) during SNP and an increase in CBFv during PE as measured by transcranial Doppler ultrasound. To resolve this apparent discrepancy, we hypothesized that SNP dilates, whereas PE constricts, the MCA. We combined transcranial Doppler ultrasound of the right MCA with NIRS illuminating the right frontal cortex in 12 supine healthy subjects 18-24 yr old. Assuming constant O₂ consumption and venous saturation, as estimated by partial venous occlusion plethysmography, we used conservation of mass (continuity) equations to estimate the changes in arterial inflow (ΔQa) and venous outflow (ΔQv) of the NIRS-illuminated area. Oxyhemoglobin and total hemoglobin, respectively, increased by 13.6 ± 1.6 and 15.2 ± 1.4 μmol/kg brain tissue with SNP despite hypotension and decreased by 6 ± 1 and 7 ± 1 μmol/kg with PE despite hypertension. SNP increased ΔQa by 0.36 ± .03 μmol·kg(-1)·s(-1) (21.6 μmol·kg(-1)·min(-1)), whereas CBFv decreased from 71 ± 2 to 62 ± 2 cm/s. PE decreased ΔQa by 0.27 ± .2 μmol·kg(-1)·s(-1) (16.2 μmol·kg(-1)·min(-1)), whereas CBFv increased to 75 ± 3 cm/s. These results are consistent with dilation of the MCA by SNP and constriction by PE.

Spontaneous fluctuation indices of the cardiovagal baroreflex accurately measure the baroreflex sensitivity at the operating point during upright tilt

Spontaneous fluctuation indices of cardiovagal baroreflex have been suggested to be inaccurate measures of baroreflex function during orthostatic stress compared with alternate open-loop methods (e.g. neck pressure/suction, modified Oxford method). We therefore tested the hypothesis that spontaneous fluctuation measurements accurately reflect local baroreflex gain (slope) at the operating point measured by the modified Oxford method, and that apparent differences between these two techniques during orthostasis can be explained by a resetting of the baroreflex function curve. We computed the sigmoidal baroreflex function curves supine and during 70° tilt in 12 young, healthy individuals. With the use of the modified Oxford method, slopes (gains) of supine and upright curves were computed at their maxima (Gmax) and operating points. These were compared with measurements of spontaneous indices in both positions. Supine spontaneous analyses of operating point slope were similar to calculated Gmax of the modified Oxford curve. In contrast, upright operating point was distant from the centering point of the reset curve and fell on the nonlinear portion of the curve. Whereas spontaneous fluctuation measurements were commensurate with the calculated slope of the upright modified Oxford curve at the operating point, they were significantly lower than Gmax. In conclusion, spontaneous measurements of cardiovagal baroreflex function accurately estimate the slope near operating points in both supine and upright position.

Oscillatory Cerebral Blood Flow Is Associated With Impaired Neurocognition and Functional Hyperemia in Postural Tachycardia Syndrome During Graded Tilt

We hypothesize that upright cognitive impairment in patients with postural tachycardia syndrome (POTS) is caused by reduced cerebral blood flow (CBF). The CBF velocity (CBFv) measured by transcranial Doppler ultrasound decreased excessively during 70° tilt in a minority of patients with intermittent hyperpnea/hypocapnia. Incremental tilt showed no difference in mean CBFv. But N-back memory tasking indicated progressive compromised memory, reduced functional hyperemia, and reduced neurovascular coupling. Orthostasis caused slow oscillations in CBFv linked to oscillations in arterial pressure in patients with POTS. We also hypothesize that oscillatory CBFv degrades neurovascular coupling. We performed 2-back testing when subjects were in supine position and during incremental tilts to 15°, 30°, 45°, and 60° in 11 patients with POTS and 9 controls. Oscillatory arterial pressure, oscillatory CBFv, and neurovascular coupling were similar in supine position. The oscillatory arterial pressure increased by 31%, 45%, 67%, and 93% in patients with POTS during tilt and remained unchanged in the controls. Oscillatory CBFv increased by 61%, 82%, 161%, and 264% in patients with POTS during tilt and remained unchanged in the controls. Functional hyperemia decreased from 4.1% to 3.0%, 1.1%, 0.2%, and to 0.04% in patients with POTS, but it was unchanged at 4% in the controls. Percent correct N-back responses decreased from 78% to 33% in patients with POTS, whereas they remained at 89% in the controls. In patients with POTS, oscillatory CBFv was linearly correlated with functional hyperemia (r2=0.76). Increased oscillatory CBF is associated with reduced neurovascular coupling and diminished cognitive perf ormance in patients with POTS.

Altered oscillatory cerebral blood flow velocity and autoregulation in postural tachycardia syndrome

Decreased upright cerebral blood flow (CBF) with hyperpnea and hypocapnia is seen in a minority of patients with postural tachycardia syndrome (POTS). More often, CBF is not decreased despite upright neurocognitive dysfunction. This may result from time-dependent changes in CBF. We hypothesized that increased oscillations in CBF occurs in POTS (N = 12) compared to healthy controls (N = 9), and tested by measuring CBF velocity (CBFv) by transcranial Doppler ultrasound of the middle cerebral artery, mean arterial pressure (MAP) and related parameters, supine and during 70° upright tilt. Autospectra for mean CBFv and MAP, and transfer function analysis were obtained over the frequency range of 0.0078–0.4 Hz. Upright HR was increased in POTS (125 ± 8 vs. 86 ± 2 bpm), as was diastolic BP (74 ± 3 vs. 65 ± 3 mmHg) compared to control, while peripheral resistance, cardiac output, and mean CBFv increased similarly with tilt. Upright BP variability (BPV), low frequency (LF) power (0.04–0.13 Hz), and peak frequency of BPV were increased in POTS (24.3 ± 4.1, and 18.4 ± 4.1 mmHg2/Hz at 0.091 Hz vs. 11.8 ± 3.3, and 8.8 ± 2 mmHg2/Hz c at 0.071 Hz), as was upright overall CBFv variability, low frequency power and peak frequency of CBFv variability (29.3 ± 4.7, and 22.1 ± 2.7 [cm/s]2/Hz at.092 Hz vs. 14.7 ± 2.6, and 6.7 ± 1.2 [cm/s]2/Hz at 0.077Hz). Autospectra were sharply peaked in POTS. LF phase was decreased in POTS (-14 ± 4 vs. -25 ± 10 degrees) while upright. LF gain was increased (1.51 ± 0.09 vs. 0.86 ± 0.12 [cm/s]/ mmHg) while coherence was increased (0.96 ± 0.01 vs. 0.80 ± 0.04). Increased oscillatory BP in upright POTS patients is closely coupled to oscillatory CBFv over a narrow bandwidth corresponding to the Mayer wave frequency. Therefore combined increased oscillatory BP and increased LF gain markedly increases CBFv oscillations in a narrow bandwidth. This close coupling of CBF to MAP indicates impaired cerebral autoregulation that may underlie upright neurocognitive dysfunction in POTS.

Increased Pulsatile Cerebral Blood Flow, Cerebral Vasodilation, and Postsyncopal Headache in Adolescents

OBJECTIVE We hypothesize that, after a sudden decrease in cerebral blood flow velocity (CBFV) in adolescents, a faint, rapid hyperemic pulsatile CBFV occurs upon the patients return to the supine position and is associated with postsyncopal headache. STUDY DESIGN This case-control study involved 16 adolescent subjects with a history of fainting and headaches. We induced fainting during 70° tilt-table testing and measured mean arterial pressure, heart rate, end-tidal CO(2), and CBFV. Fifteen control subjects were similarly evaluated with a tilt but did not faint, and comparisons with fainters were made at equivalent defined time points. RESULTS Baseline values were similar between the groups. Upon fainting, mean arterial pressure decreased 49% in the patients who fainted vs 6% in controls (P < .001). The heart rate decreased 15% in fainters and increased 35% in controls (P < .001). In patients who fainted, cerebrovascular critical closing pressure increased markedly, which resulted in reduced diastolic (-66%) and mean CBFV (-46%) at faint; systolic CBFV was similar to controls. Pulsatile CBFV (systolic-diastolic CBFV) increased 38% in fainters, which caused flow-mediated dilatation of cerebral vessels. When the fainters returned to the supine position, CBFV exhibited increased systolic and decreased diastolic flows compared with controls (P < .02). CONCLUSION Increased pulsatile CBFV during and after faint may cause postsyncopal cerebral vasodilation and headache.

Phenylephrine Alteration of Cerebral Blood Flow During Orthostasis; Effect on N-Back Performance in Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) with orthostatic intolerance is characterized by neurocognitive deficits and impaired working memory, concentration, and information processing. In CFS, upright tilting [head-up tilt (HUT)] caused decreased cerebral blood flow velocity (CBFv) related to hyperventilation/hypocapnia and impaired cerebral autoregulation; increasing orthostatic stress resulted in decreased neurocognition. We loaded the baroreflex with phenylephrine to prevent hyperventilation and performed n-back neurocognition testing in 11 control subjects and 15 CFS patients. HUT caused a significant increase in heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decrease in end-tidal CO2 (ETCO2; 42.8 ± 1.2 vs. 33.9 ± 1.1 Torr, P < 0.05) in CFS vs. control. HUT caused CBFv to decrease 8.7% in control subjects but fell 22.5% in CFS. In CFS, phenylephrine prevented the HUT-induced hyperventilation/hypocapnia and the significant drop in CBFv with HUT (-8.1% vs. -22.5% untreated). There was no difference in control subject n-back normalized response time (nRT) comparing supine to HUT (106.1 ± 6.9 vs. 97.6 ± 7.1 ms at n = 4), and no difference comparing control to CFS while supine (97.1 ± 7.1 vs 96.5 ± 3.9 ms at n = 4). However, HUT of CFS subjects caused a significant increase in nRT (148.0 ± 9.3 vs. 96.4 ± 6.0 ms at n = 4) compared with supine. Phenylephrine significantly reduced the HUT-induced increase in nRT in CFS to levels similar to supine (114.6 ± 7.1 vs. 114.6 ± 9.3 ms at n = 4). Compared with control subjects, CFS subjects are more sensitive both to orthostatic challenge and to baroreflex/chemoreflex-mediated interventions. Increasing blood pressure with phenylephrine can alter CBFv. In CFS subjects, mitigation of the HUT-induced CBFv decrease with phenylephrine has a beneficial effect on n-back outcome.

Modulation of the axon-reflex response to local heat by reactive oxygen species in subjects with chronic fatigue syndrome.

Local cutaneous heating causes vasodilation as an initial first peak, a nadir, and increase to plateau. Reactive oxygen species (ROS) modulate the heat plateau in healthy controls. The initial peak, due to C-fiber nociceptor-mediated axon reflexes, is blunted with local anesthetics and may serve as a surrogate for the cutaneous response to peripheral heat. Chronic fatigue syndrome (CFS) subjects report increased perception of pain. To determine the role of ROS in this neurally mediated response, we evaluated changes in cutaneous blood flow from local heat in nine CFS subjects (16-22 yr) compared with eight healthy controls (18-26 yr). We heated skin to 42°C and measured local blood flow as a percentage of maximum cutaneous vascular conductance (%CVC(max)). Although CFS subjects had significantly lower baseline flow [8.75 ± 0.56 vs. 12.27 ± 1.07 (%CVC(max), CFS vs. control)], there were no differences between groups to local heat. We then remeasured this with apocynin to inhibit NADPH oxidase, allopurinol to inhibit xanthine oxidase, tempol to inhibit superoxide, and ebselen to reduce H(2)O(2). Apocynin significantly increased baseline blood flow (before heat, 14.91 ± 2.21 vs. 8.75 ± 1.66) and the first heat peak (69.33 ± 3.36 vs. 59.75 ± 2.75). Allopurinol and ebselen only enhanced the first heat peaks (71.55 ± 2.48 vs. 61.72 ± 2.01 and 76.55 ± 5.21 vs. 58.56 ± 3.66, respectively). Tempol had no effect on local heating. None of these agents changed the response to local heat in control subjects. Thus the response to heat may be altered by local levels of ROS, particularly H(2)O(2) in CFS subjects, and may be related to their hyperesthesia/hyperalgesia.

Cutaneous Nitric Oxide (NO) Modulates Noradrenergic Neurotransmission Pre-and Post-Synaptically; Excess Nitric Oxide (NO) Blunts Presynaptic Adrenergic Transduction in Orthostatic Intolerance (OI)

between a number of paired sound-HUT conditioning trials, in which HUT and sound always started together; the conditioned (CR) and unconditioned responses (UR) were compared. Arterial blood pressure (ABP), cerebral blood flow velocity (VMCA), end-tidal CO2, heart rate (HR) and cerebral blood volume and oxygenation indices by near infrared spectroscopy (NIRS), were continuously monitored during the procedure. Results: An anticipatory CR was observed in 6/9 subjects consisting of increased ABP (+3.3 ± 3.0 mmHg, P b 0.05), VMCA (+4.2 ± 3.6 cm*s, P b 0.05), and HR (+3.5 ± 7.1 bpm, P N 0.05) occurring in the first 6-10s from the beginning of the conditioned stimulus, with not significant changes in NIRS variables. The CR mimicked the beginning of the UR, although being slightly attenuated (by -34.2, -28.2 and -17.8% in the different variables, respectively). Conclusions: These preliminary results demonstrate the occurrence of a significant CR response to HUT. However, future studies are needed to investigate the possible contribution of an alertness response to the observed effects.