Cole A. Giller

Transfer function analysis of dynamic cerebral autoregulation in humans

To test the hypothesis that spontaneous changes in cerebral blood flow are primarily induced by changes in arterial pressure and that cerebral autoregulation is a frequency-dependent phenomenon, we measured mean arterial pressure in the finger and mean blood flow velocity in the middle cerebral artery (V˙MCA) during supine rest and acute hypotension induced by thigh cuff deflation in 10 healthy subjects. Transfer function gain, phase, and coherence function between changes in arterial pressure andV˙MCA were estimated using the Welch method. The impulse response function, calculated as the inverse Fourier transform of this transfer function, enabled the calculation of transient changes inV˙MCA during acute hypotension, which was compared with the directly measured change in V˙MCA during thigh cuff deflation. Beat-to-beat changes inV˙MCA occurred simultaneously with changes in arterial pressure, and the autospectrum of V˙MCA showed characteristics similar to arterial pressure. Transfer gain increased substantially with increasing frequency from 0.07 to 0.20 Hz in association with a gradual decrease in phase. The coherence function was >0.5 in the frequency range of 0.07-0.30 Hz and <0.5 at <0.07 Hz. Furthermore, the predicted change inV˙MCA was similar to the measuredV˙MCA during thigh cuff deflation. These data suggest that spontaneous changes inV˙MCA that occur at the frequency range of 0.07-0.30 Hz are related strongly to changes in arterial pressure and, furthermore, that short-term regulation of cerebral blood flow in response to changes in arterial pressure can be modeled by a transfer function with the quality of a high-pass filter in the frequency range of 0.07-0.30 Hz.

Vagus nerve stimulation (VNS) for treatment-resistant depressions: A multicenter study

BACKGROUND Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.

Cerebral versus systemic hemodynamics during graded orthostatic stress in humans.

Orthostatic syncope is usually attributed to cerebral hypoperfusion secondary to systemic hemodynamic collapse. Recent research in patients with neurocardiogenic syncope has suggested that cerebral vasoconstriction may occur during orthostatic hypotension, compromising cerebral autoregulation and possibly contributing to the loss of consciousness. However, the regulation of cerebral blood flow (CBF) in such patients may be quite different from that of healthy individuals, particularly when assessed during the rapidly changing hemodynamic conditions associated with neurocardiogenic syncope. To be able to interpret the pathophysiological significance of these observations, a clear understanding of the normal responses of the cerebral circulation to orthostatic stress must be obtained, particularly in the context of the known changes in systemic and regional distributions of blood flow and vascular resistance during orthostasis. Therefore, the specific aim of this study was to examine the changes that occur in the cerebral circulation during graded reductions in central blood volume in the absence of systemic hypotension in healthy humans. We hypothesized that cerebral vasoconstriction would occur and CBF would decrease due to activation of the sympathetic nervous system. We further hypothesized, however, that the magnitude of this change would be small compared with changes in systemic or skeletal muscle vascular resistance in healthy subjects with intact autoregulation and would be unlikely to cause syncope without concomitant hypotension. Methods and ResultsTo test this hypothesis, we studied 13 healthy men (age, 27±7 years) during progressive lower body negative pressure (LBNP). We measured systemic flow (Qc is cardiac output; C2H2 rebreathing), regional forearm flow (FBF; venous occlusion plethysmography), and blood pressure (BP; Finapres) and calculated systemic (SVR) and forearm (FVR) vascular resistances. Changes in brain blood flow were estimated from changes in the blood flow velocity in the middle cerebral artery (VMcA) using transcranial Doppler. Pulsatility (systolic minus diastolic/mean velocity) normalized for systemic arterial pressure pulsatility was used as an index of distal cerebral vascular resistance. End-tidal PACO2 was closely monitored during LBNP. From rest to maximal LBNP before the onset of symptoms or systemic hypotension, Qc and FBF decreased by 29.9% and 34.4%, respectively. VMCA decreased less, by 15.5% consistent with a smaller decrease in CBF. Similarly, SVR and FVR increased by 62.8% and 69.8%, respectively, whereas pulsatility increased by 17.2%, suggestive of a mild degree of small-vessel cerebral vasoconstriction. Seven of 13 subjects had presyncope during LBNP, all associated with a sudden drop in BP (29±9%). By comparison, hyperventilation alone caused greater changes in VMCA (42±2%) and pulsatility but never caused presyncope. In a separate group of 3 subjects, superimposition of hyperventilation during highlevel LBNP caused a further decrease in VMCA (31±7%) but no change in BP or level of consciousness. ConclusionsWe conclude that cerebral vasoconstriction occurs in healthy humans during graded reductions in central blood volume caused by LBNP. However, the magnitude of this response is small compared with changes in SVR or FVR during LBNP or other stimuli known to induce cerebral vasoconstriction (hypocapnia). We speculate that this degree of cerebral vasoconstriction is not by itself sufficient to cause syncope during orthostatic stress. However, it may exacerbate the decrease in CBF associated with hypotension if hemodynamic instability develops.

The frequency-dependent behavior of cerebral autoregulation

Cerebral autoregulation is a complex physiological process composed of both fast and slow components that may respond differently to different rates and patterns of blood pressure variation. To assess the temporal nature of autoregulation, transcranial Doppler velocity recordings of the middle cerebral artery obtained over prolonged periods were compared with blood pressure recordings in 5 patients without cerebral disease and in 13 patients with intracranial pathological changes. Correlations between the velocity and pressure wave forms at various frequencies of variation were measured with systems analysis techniques. Patients with aneurysmal subarachnoid hemorrhage had high correlations indicating pressure-dependent flow and impaired autoregulation. Patients without cerebral disease had significantly lower correlations (P less than 0.01), indicating intact autoregulation. Examples of increasing correlations and correlations at new frequencies emerging as the clinical condition worsened are given. These preliminary examples suggest that the application of systems analysis techniques to velocity and pressure data allow measurement of the temporal nature of cerebral autoregulation.

Stereotactic Radiosurgery for Glomus Jugulare Tumors

Objectives/Hypothesis: Surgery is considered to be the mainstay of treatment for glomus jugulare tumors. A subset of patients are poor surgical candidates based on age, medical problems, tumor size, or prior treatment failure. The purpose of this study was to review our results with stereotactic radiosurgery (gamma knife treatment) in this group of patients, with particular attention to adverse reactions and symptom relief.

Tremor response to polarity, voltage, pulsewidth and frequency of thalamic stimulation

Background: Thalamic deep brain stimulation ameliorates essential and parkinsonian tremors refractory to medications. Stimulus voltage, polarity configuration, frequency, and pulsewidth can each be adjusted in order to optimize tremor control and maximize battery life. The relative impacts of these programmable variables have not previously been quantified. Methods: The thalamus of 11 patients (bilaterally in 2) was studied 4 to 59 months postoperatively. The stimulator was inactivated and medications withheld for 12 hours, and optimal electrode contacts were selected. Stimulation followed at a range of voltages (0, 1, 2, 3, or 4 V), pulsewidths (60, 90, or 120 μs), and frequencies (130, 160, or 185 Hz) for both monopolar and bipolar configurations. Seventy-eight combinations of variables were programmed in random sequence. Postural and action tremors were measured with an electromagnetic tracker, tremor was subjectively graded, and side effects were noted. Results: Voltage was consistently predictive of tremor response. Mean postural tremor amplitude in PD fell from 6.4 cm at 0 V to 2.6, 1.0, 0.3, and 0 cm at 1 through 4 V (bipolar configuration). The voltage response curve for essential tremor was flatter. The monopolar configuration was 10 to 25% more effective than bipolar. The longest pulsewidth tested was up to 30% more effective than the shortest, but frequency changes had little effect on tremor amplitude. Side effects occurred only with monopolar stimulation, and the only setting that was intolerable for the majority was 4 V, 120 μs, and 185 Hz. Conclusion: Bipolar deep brain stimulation at 90 μs, 130 Hz, adjusting the voltage up to 3 V, tends to be effective and well tolerated. Monopolar provides similar benefits for lower voltage, but side effects become common at 3 or 4 V.

Cognitive functioning in individuals with "benign" essential tremor.

Essential tremor (ET) is the most common type of movement disorder, although its etiology and neurophysiological substrates remain unclear. While thought to be a benign condition, it has yet to be studied from a neuropsychological perspective. We examined the neurocognitive functioning of 13 nondemented subjects with severe ET, including aspects of memory, cognitive flexibility, and attention. Results revealed that 12/13 subjects demonstrated impairment on 1 or more cognitive measures in comparison with published normative data. The pattern of findings was suggestive of relative dysfunction of frontal-mediated processes not unlike that seen in Parkinsons disease. These deficits were found in subjects irrespective of the presence of cognitive complaints, depression, or the existence of other potential neurocognitive risk factors. These findings suggest that mild cognitive deficits are not uncommon in association with severe ET and may be related to subcortical systems.

Linearity and non-linearity in cerebral hemodynamics

BACKGROUND Transcranial Doppler ultrasound has been extensively used to study cerebral hemodynamics, and yet the basic characteristics of the input/output system of blood pressure/velocity are little known. We examine whether this system can best be considered linear or non-linear. METHODS We assessed the adequacy of linear modeling in four ways: (1) Known properties of cerebral blood flow were reviewed and analyzed from a systems standpoint; (2) 1100 ARX & OE model types were tested with data from 29 normal subjects, with and without lowpass filtering; (3) time-frequency analysis was used to identify nonstationary behavior and markers of non-linearity (such as bifurcations, chirps, and intermittent autoregulatory impairment) in the same data sets; (4) simple computer models of autoregulation incorporating time delays and non-linear elements were tested for production of spontaneous oscillations. RESULTS (1) Several aspects of cerebral hemodynamics are poorly described by linear models, (2) the ARX & OE models performed poorly, (3) time-frequency analysis showed non-linear and nonstationary behavior, (4) the computer models produced spontaneous oscillations similar to those observed in humans. CONCLUSIONS There is strong evidence that the blood pressure/velocity system is non-linear.

Human cerebral autoregulation before, during and after spaceflight

Exposure to microgravity alters the distribution of body fluids and the degree of distension of cranial blood vessels, and these changes in turn may provoke structural remodelling and altered cerebral autoregulation. Impaired cerebral autoregulation has been documented following weightlessness simulated by head‐down bed rest in humans, and is proposed as a mechanism responsible for postspaceflight orthostatic intolerance. In this study, we tested the hypothesis that spaceflight impairs cerebral autoregulation. We studied six astronauts ∼72 and 23 days before, after 1 and 2 weeks in space (n= 4), on landing day, and 1 day after the 16 day Neurolab space shuttle mission. Beat‐by‐beat changes of photoplethysmographic mean arterial pressure and transcranial Doppler middle cerebral artery blood flow velocity were measured during 5 min of spontaneous breathing, 30 mmHg lower body suction to simulate standing in space, and 10 min of 60 deg passive upright tilt on Earth. Dynamic cerebral autoregulation was quantified by analysis of the transfer function between spontaneous changes of mean arterial pressure and cerebral artery blood flow velocity, in the very low‐ (0.02–0.07 Hz), low‐ (0.07–0.20 Hz) and high‐frequency (0.20–0.35 Hz) ranges. Resting middle cerebral artery blood flow velocity did not change significantly from preflight values during or after spaceflight. Reductions of cerebral blood flow velocity during lower body suction were significant before spaceflight (P < 0.05, repeated measures ANOVA), but not during or after spaceflight. Absolute and percentage reductions of mean (±s.e.m.) cerebral blood flow velocity after 10 min upright tilt were smaller after than before spaceflight (absolute, −4 ± 3 cm s−1 after versus−14 ± 3 cm s−1 before, P= 0.001; and percentage, −8.0 ± 4.8% after versus−24.8 ± 4.4% before, P < 0.05), consistent with improved rather than impaired cerebral blood flow regulation. Low‐frequency gain decreased significantly (P < 0.05) by 26, 23 and 27% after 1 and 2 weeks in space and on landing day, respectively, compared with preflight values, which is also consistent with improved autoregulation. We conclude that human cerebral autoregulation is preserved, and possibly even improved, by short‐duration spaceflight.

Evidence of redistribution of cerebral blood flow during treatment for an intracranial arteriovenous malformation.

The presence of an intracranial arteriovenous malformation has a dramatic impact on local circulatory dynamics. Treatment of some arteriovenous malformations can result in disastrous hyperemic states caused by redistribution of previously shunted blood. This report describes serial hemodynamic measurements of both cerebral blood flow and flow velocity in 3 patients during treatment for arteriovenous malformations. Measurements of cerebral blood flow were made by computed tomographic scan employing the stable xenon inhalation technique; flow velocity, including autoregulatory characteristics, was measured by transcranial Doppler ultrasonogram. Substantial hyperemia developed in one patient (Case 1) after resection and in another (Case 3) after embolization. Embolization resulted in restoration of normal regional cerebral blood flow in a patient who demonstrated hypoperfusion before treatment (Case 2). In Patient 1, postoperative hyperemia was associated with persistently elevated flow velocities, and may have been accompanied by hemispheric neurological deficits. Sequential hemodynamic measurements may predict patients at risk of perioperative complications, and may become useful clinical guidelines for the extent and timing of embolization and for the timing of surgery after intracranial hemorrhage or preoperative embolization procedures.