Brain, Vol. 124, No. 6, 1208-1217,
June 2001
© 2001 Oxford University Press
Recovery of brain function during induced cerebral hypoperfusion
1 Departments of Neurology, 2 Radiology, 3 Neurological Surgery and 4 Anesthesiology, New York-Presbyterian Medical Center, Columbia University, New York and 5 Departments of Anesthesia and Perioperative Care, Neurological Surgery and Neurology, University of California, San Francisco, California, USA
Correspondence to:
Randolph S. Marshall, MD, New York-Presbyterian Medical Center, Columbia University, 710 W. 168th Street, New York, NY 10032, USA E-mail: rsm2{at}columbia.edu
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Abstract |
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We used the setting of clinically indicated internal carotid artery balloon test occlusions in 44 patients with inoperable carotid cavernous aneurysms or head and neck tumours to examine real-time changes in higher cerebral function that correlate with specific levels of cerebral blood flow. By making detailed haemodynamic and neurobehavioural measurements during the 30 min the carotid artery was occluded, we were able to quantify higher cerebral function patterns in relation to absolute cerebral blood flow (CBF) levels. We found that once the carotid artery was occluded, patients whose CBF averaged 47 ml/100 g/min (no different from baseline) maintained consistent performance on a sustained attention task; those whose CBF dropped to an average 37 ml/100 g/min had a reversible deterioration of sustained attention, and those whose CBF fell to 27 ml/100 g/min had impaired sustained attention that persisted until the carotid occlusion was reversed. The relevance of these results to the pathological state of clinical stroke is discussed with respect to the haemodynamic and physiological mechanisms that may determine how brain function is lost and regained in the setting of acute cerebral hypoperfusion.
cerebral blood flow; carotid artery occlusion; stroke; recovery; sustained attention
CBF = cerebral blood flow; ICA = internal carotid artery; IRT = inter-response time; MAP = mean arterial pressure; MCA = middle cerebral artery; TCD = transcranial Doppler ultrasound
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Introduction |
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Sudden occlusion of the carotid artery may produce symptoms of hemispheric ischaemia or may go unnoticed by the patient (Hennerici et al., 1987
; Powers et al., 2000). The ability of the brain to tolerate carotid occlusion is thought to depend on the adequacy of collateral circulation across the circle of Willis, collaterals via leptomeningeal branches and the autoregulatory capacity of cerebral arterioles to dilate in response to a drop in cerebral perfusion pressure (Schomer et al., 1994; van Everdingen et al., 1998). Because a carotid occlusion is generally not imaged until minutes to hours after a patient has had a stroke or TIA (transient ischaemic attack), or even later in patients who are asymptomatic for the occlusion (Norris et al., 1991), real-time correlation between clinical state and the cerebral haemodynamics of carotid occlusion has not been well delineated. There is a group of patients, however, who may undergo intentional occlusion of the carotid artery for treatment of their condition, i.e. those with inoperable carotid artery aneurysms or head and neck tumours, who may need to have their carotid arteries sacrificed in the course of treatment. These patients typically first undergo internal carotid artery `test occlusions' to determine whether there is adequate collateral blood flow to allow permanent occlusion of the carotid artery to be done safely. Test occlusions are done in an angiography suite with a neuroanaesthesiologist and neurologist monitoring the patient's vital signs and neurological status. We have taken advantage of the highly controlled environment of the clinical carotid artery balloon test occlusion to study the real-time haemodynamic and behavioural effects of carotid occlusion. By monitoring haemodynamic and behavioural responses during the 30 min of the test occlusion, we had the chance to investigate the immediate effects of acute internal carotid artery (ICA) occlusion such as might happen in the first few minutes after a carotid artery is blocked pathologically by a thrombus, embolus or dissection. We were particularly interested in how real-time changes in cerebral blood flow (CBF) correlated with changes in higher cerebral function.
Prior studies showed that there was a significant association between performance on a sustained attention task and the level of ipsilateral cerebral blood flow during temporary carotid artery occlusion (Marshall et al., 1999). Specifically, CBF below 30 ml/100 g/min was associated with a deterioration in sustained attention at some point during the test occlusion. More detailed inspection of the data, however, suggested that in some patients behavioural performance deteriorated but then recovered within the test occlusion period. We now present the performance of 44 test occlusion patients (including 22 new patients) with increased time resolution, to investigate the hypothesis that deterioration and recovery of sustained attention can occur rapidly even while the carotid artery remains occluded. Using quantitative CBF data in 26 of the patients, we further investigated the hypothesis that the deterioration and recovery pattern of behaviour is associated with a CBF level distinct from the CBF level in those whose sustained attention does not recover and from the level in those in whom an attentional deficit does not appear at all.
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Method |
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Subjects
We studied 44 patients with inoperable pericavernous carotid aneurysms (30 patients) or head and neck tumours (14 patients) who underwent test occlusion of the internal carotid artery. There were 13 men and 31 women with mean age 54.4 years (SD 6.9 years). Sixteen left ICAs and 28 right ICAs were tested. All patients underwent diagnostic angiograms prior to test occlusions. The study was approved by the Columbia–Presbyterian Medical Center Institutional Review Board (CPMC IRB). Signed, informed consent was obtained for all procedures.
Procedures
Details of the test occlusion protocol have been published elsewhere (Marshall et al., 1999). Briefly, under systemic heparinization, a 5 French catheter with a balloon tip was inserted via a 5.5 French femoral artery introducer sheath into the midcervical portion of the ICA. A distal lumen in the balloon catheter allowed measurement of ICA pressures and enabled injection of 133Xe for CBF measurements during occlusion. Mean systemic arterial pressure (MAP) was measured with a strain gauge in the femoral introducer sheath. Cortical CBF was determined by intracarotid 133Xe injection, using two cadmium telluride scintillation detectors placed over the lateral frontal and parietal cortex ipsilateral to the carotid occlusion. CBF was calculated with tracer data collected between 20 and 80 s after injection, which provided a value weighted towards the grey matter (Young et al., 1990). Arterial partial pressure of carbon dioxide (PaCO2) and haematocrit were measured with each hemispheric CBF determination. Neurological function and performance on a sustained attention task were assessed at the time of baseline CBF measurement. Then, while the patient performed the behavioural task, the balloon was inflated, pressures were recorded and CBF was determined again. As the test occlusion proceeded, standard neurological examinations were done 5 min after occlusion, and then every 4–5 min between the 2- to 5-min blocks of the sustained attention assessments. The neurological examination, performed by a neurologist, tested motor and sensory function in the face and limbs, visual fields, verbal fluency and comprehension, and visual extinction to double simultaneous stimuli. As a further test of the adequacy of haemodynamic reserve, if the patient remained clinically stable with initial occlusion, sodium nitroprusside was given intravenously, beginning at a dose of 0.5 µg/kg/min and gradually increasing the dose to 1–2 µg/kg/min to achieve a MAP of 60–70% of the patient's pre-occlusion baseline MAP (Young and Pile-Spellman, 1994; Standard et al., 1995; Tanaka et al., 1995). Neurological and sustained attention assessments were continued during the hypotensive phase. CBF was recorded again in most patients at the maximum hypotensive stage. For patients in whom CBF measurements were not obtained because of the unavailability of equipment or personnel, detailed neurological and sustained attention testing alone was used to monitor the patient's status. In 14 patients, blood flow velocities in the ipsilateral middle cerebral artery (MCA) were monitored by transcranial Doppler ultrasound (TCD) at a depth of 45–55 mm. The balloon was deflated if either (i) the patient tolerated carotid occlusion for 30 min, including hypotension (considered to be a pass of the test occlusion), or (ii) the patient developed dysarthria, aphasia, field cut, or weakness or sensory loss in the contralateral face, arm or leg during the procedure. Angiography was repeated after balloon deflation to ensure no embolic arterial occlusions or vasospasm had occurred.
Sustained attention task
Patients were taught one of two sustained attention tasks prior to beginning the test occlusion. One task, the inter-response time (IRT) task, required that the patient make responses with a computer mouse to estimate repeatedly an interval of 10–13 s (Lazar et al., 1996). The computer recorded the intervals the patients actually achieved, and gave a positive or negative feedback signal as to whether they were inside or outside the target interval. Blocks of 20 time estimations, each block lasting 3–5 min, were performed by the patient throughout the test occlusion period. A second, similar time-estimation task required that the patient press a computer mouse button synchronously with metronomic tones generated by the computer every 1500 ms. Blocks of 60 tones were given repeatedly throughout the test occlusion period, giving a total time of 1.5 min per block. Patients were trained on either of these tasks prior to the test occlusion until further trials did not improve performance. Once in the angiography suite, baseline performance was established with the catheter in place but prior to balloon inflation. The balloon was then inflated and assessments of performance on the task were obtained during ICA occlusion and under the condition of occlusion plus hypotension as described above. We used the synchrony task in the later test occlusions because the greater number of responses per block and the shorter block time required for this task provided finer time resolution. The synchrony task has been tested in a variety of psychophysical experiments in normal subjects and in neurological diseases (Ivry and Keele, 1989; Nichelli et al., 1995).
In both tasks, sustained attention performance was assessed from the variability in the precision of time estimation, a behavioural parameter which is thought to reflect internal clock mechanisms and sustained attention, both of which are required for normal cognitive function (Gibbon et al., 1997). Better performance was thus represented by more precise responses (lower variance) and poorer performance by less precise responses (higher variance). Initial deterioration in performance was defined as an increase in variance greater than 2.5-fold, a threshold that has been shown to achieve 75% sensitivity for a state of low blood flow (Marshall et al., 1999). Recovery in performance during the occlusion period was operationalized as at least a 2-fold decrease in variance following the deterioration.
Data analysis
Patients were grouped according to their pattern of sustained attention during carotid occlusion: unchanged in performance throughout the test occlusion (U group), deterioration in performance followed by recovery (D–R group), and deterioration with no recovery until the occlusion was reversed (D–NoR group). Figure 1 depicts examples of the three patterns. For patients in whom CBF was measured at the precise time of worst attentional performance, one-way analysis of variance (ANOVA) was used to compare average CBF among the three groups of patients. Patients whose CBF was not obtained at the time of worst attentional performance were not included in the ANOVA. CBF values were not known at the time of the behavioural testing, so no observer bias could be introduced.
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Results |
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All patients were able to perform the sustained attention tasks according to instructions during the test occlusion. Table 1
shows patient characteristics, behavioural performance data and hemispheric CBF values at baseline and at the time point of worst performance. None of the 44 patients had any irreversible neurological deficits or complications from the procedure.
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Behavioural patterns
Five of the 44 patients showed no change in sustained attention during the 30 min of carotid occlusion, including 15–20 min of induced hypotension in four of them (U group). Twenty-two of the 44 showed deterioration in attention that did not recover until the balloon was deflated (D–NoR group). In five of these 22 patients, the deterioration occurred during normotension and in 17 it occurred at the final hypotensive stage, when the mean arterial pressure had been lowered to 33–72% of baseline.
The third group (D–R), in whom there was a deterioration in sustained attention followed by spontaneous recovery to baseline or near-baseline performance within 5–10 min of the deterioration, comprised 14 patients. Four of these 14 later went on to have a second deterioration in sustained attention in the late hypotensive phase of the test occlusion. In nine of the 14, the transient deterioration occurred in the first few minutes of the normotensive period, and in the other five it occurred at the time of the initial induction of hypotension. Three patients of the total number of 44 were eliminated from analysis because an adequate baseline could not be established, making uncertain the interpretation of subsequent performance. Hemiparesis was observed in 12 patients as a terminating event in the test occlusion (10 patients in the D–NoR group and two in the D–R group). All 12 patients with hemiparesis demonstrated deterioration in sustained attention prior to the onset of weakness, eight of them showing the change in sustained attention within the first 5 min of occlusion. There was no difference in the distribution of patients in the behavioural groups among those doing the IRT versus the synchrony attentional tasks. Neither age of patient nor side of carotid occlusion correlated with behavioural pattern.
CBF and behavioural change
Of the 44 patients who underwent carotid artery balloon test occlusion, 36 had repeated 133Xe-CBF measurements during the test occlusion procedure. Of these, 26 had CBF measurements at the precise time of the worst performance on the sustained attention task: three out of five in the U group, five out of 14 in the D–R group and 18 out of 22 in the D–NoR group. Average baseline CBF among all patients was 45 ± 11 ml/100 g/min. There was no statistical difference in baseline CBF between groups.
The mean CBF for the U group during the test occlusion was 47 ml/100 g/min; the mean CBF for the D–R group during the worsened performance was 37 ml/100 g/min; the mean CBF for the D–NoR group was 27 ml/100 g/min. The difference in CBF among the three groups was statistically significant by one-way ANOVA [F(2,23) = 7.13, P = 0.004] (Fig. 2). The degree of loss of timing performance in the two deterioration groups did not differ significantly between the two groups (an average 5.0-fold increase in variance in time estimation for the D–R group and a 9.6-fold increase for the D–NoR group; P = 0.20).
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Three patterns of MCA mean flow velocity were identified. In five patients MCA flow velocity fell to 57–71% of the pre-occlusion baseline immediately after ICA occlusion then returned gradually to 82–100% of baseline over 3–6 min. In five patients there was no drop in MCA flow or a modest increase. In four patients there was a decrease to a mean of 54% (range 33–71%) of baseline with no subsequent recovery. In all five patients who showed the first TCD pattern and in two of three others in whom the MCA flow velocity dropped to and remained at 50% of baseline throughout the test occlusion, sustained attention remained unchanged in the immediate postocclusion period. Thus, although the mean flow velocity in the MCA measured by TCD in 14 patients correlated reasonably well with absolute CBF measurements (r2 = 0.69), the pattern of change in TCD signal did not correlate well with changes in CBF in real-time. There were not enough patients per group to draw conclusions about the correlation between MCA flow velocity and behavioural pattern, as was done for the Xe-CBF measurements.
Case example
Figure 3 depicts an example of simultaneous neurological and haemodynamic monitoring in a single patient who demonstrated deterioration and recovery of sustained attention, followed by a second deterioration that recovered only when the balloon was deflated. Performance on the IRT attentional task in her case at low SA remained unchanged immediately upon occlusion, deteriorated with the initial drop in blood pressure, then recovered again despite lower blood pressure and a CBF that remained lower than baseline.
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As shown in the figure, the acute drop in MCA flow velocity measured by TCD as a result of ICA occlusion did not produce an immediate change in brain function. The TCD pattern showed a rapid fall in MCA flow velocity followed by a return to near baseline over 3–6 min, as was seen in four other patients.
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Discussion |
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We have demonstrated that specific levels of CBF correlate with performance on a sustained attention task when blood flow to the cerebral hemisphere is compromised acutely by occlusion of the carotid artery. In those in whom CBF data were available, carotid occlusion in patients who maintained consistent performance on the sustained attention task was associated with an average CBF of 47 ml/100 g/min (no different from baseline); those who had impaired sustained attention that persisted until normal flow through the carotid artery had been restored by deflating the balloon had CBF which fell to 27 ml/100 g/min. Most notable, however, was a group of patents who had a reversible deterioration of sustained attention even while the carotid remained occluded. This D–R group's CBF dropped to an average 37 ml/100 g/min. By making detailed neurobehavioural measurements during these clinically indicated carotid artery test occlusions, we were able for the first time to document functional recovery during the hyperacute phase of ICA occlusion. We were further able to quantify patterns of higher cerebral function in relation to absolute CBF levels in humans. Although the average CBF levels for the three behavioural groups were statistically distinguishable, there was substantial variability in the absolute CBF level within groups. The variability during ICA occlusion may have been due to baseline CBF differences across all patients, or to focal CBF differences that were below the anatomical or time resolution achieved by our CBF technique. As demonstrated by the patient represented in Fig. 3
, however, recovery of function appears to occur in some cases without restoration of CBF, suggesting that absolute CBF is not the only factor to govern functional recovery.
Given the recent intense efforts to treat cerebrovascular occlusive disease with rapid arterial recanalization and reperfusion (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995; Furlan et al., 1999), surprisingly few studies in the literature correlate absolute CBF levels with clinical brain function during cerebral hypoperfusion, and no studies to date have addressed the reversal of clinical deficits during hypoperfusion. Part of the reason for the lack of such information is the paucity of clinical situations in which both cerebral function and cerebral blood flow can be measured simultaneously during hyperacute cerebral hypoperfusion. In an operating room setting, it has been shown that patients undergoing carotid cross-clamping during carotid endarterectomy have EEG flattening when CBF drops to 17–18 ml/100 g/min (Trojaberg and Boysen, 1973; Sundt et al., 1974), but the clinical state could not be assessed directly in these anaesthetized patients. In another study using PET, patients who were temporarily hemiparetic because of vasospasm after subarachnoid haemorrhage had CBF values of 15–26 ml/100 g/min measured in the affected brain region (Powers et al., 1985). Finally, in a controlled experiment in awake baboons, Jones and colleagues defined a threshold of 23 ml/100 g/min for the onset of hemiparesis when the middle cerebral artery was ligated (Jones et al., 1981).
The ischaemic threshold values we report in this study are higher than those reported in the literature, and may be higher for two reasons. First, CBF values in the PET study and the baboon study included measurements from the subcortical white matter, which is known to have lower average blood flow values than the grey matter (Powers et al., 1985). In addition, our measure of brain function was sustained attention, which we have reported previously as being more sensitive to early ischaemia than other neurological deficits, including motor, language and sensory function (Lazar et al., 1996). A large distributed network of brain regions may exist for sustained attention (Pardo et al., 1991; Marshall et al., 1997) and may therefore require higher average CBF values over a broader region for this system to function. Of note, among the 12 patients in our study whose motor function was affected during the test occlusion, CBF fell to an average of 23 ml/100 g/min.
Disruption of higher cerebral function during hemispheric hypoperfusion may be presumed to be related to three interdependent haemodynamic factors: the volume of hypoperfusion, the duration of hypoperfusion and the absolute level of CBF (Hossmann et al., 1994; Heiss et al., 1998). The better the collateralization across the circle of Willis or over the cortical convexity, the smaller the volume of critical hypoperfusion will be and the less likely that the effects of ischaemia will be manifested (Fisher, 1997). The presence or absence of pre-existing collaterals in our patients may have determined how well they tolerated the carotid occlusion. With regard to cell pathophysiology at various CBF levels, cellular protein synthesis is inhibited at CBF of 35–55 ml/100 g/min (Mies et al., 1991), metabolism changes to anaerobic glycolysis at CBF at 20–35 ml/100 g/min (Hossmann, 1994), glucose metabolism overall declines at CBF 20–25 ml/100 g/min (Siesjo, 1992) and cellular ion homeostasis fails below 10–12 ml/100 g/min (Harris et al., 1981). In human stroke, a CBF below 10 ml/100 g/min is thought to exist at the `ischaemic core' of an infarct, and the elusive `ischaemic penumbra' in brain regions adjacent to the infarction has been variously defined to include CBF values from 11 to 35 ml/100 g/min (Fisher, 1997; Hossmann, 1994; Kaufman et al., 1999). The changes in sustained attention we observed occurred with CBF in the range of 25–40 ml/100 g/min, at levels that might be seen in an ischaemic penumbra. If neuronal dysfunction is reversible in the penumbra, similar reversible mechanisms might be operating at the same levels of CBF in the setting of test occlusions.
The mechanism of recovery we report in the D–R group is not known. Critical flow thresholds depend on the duration of hypoperfusion. At low levels of perfusion, time appears to work against the preservation of cellular function (Jacewicz et al., 1990; Zivin, 1998). Our observation of the reversibility of brain dysfunction at 30–40 ml/100 g/min, however, suggests that in milder hypoperfusion the passage of time may favour the restoration of neuronal function. Because of the predetermined time limitation of the test occlusion, it was not possible to know whether some patients whose CBF dropped below 30 ml/100 g/min would have recovered if the test occlusion had continued for a longer time. Recovery in our patients in the D–R group generally occurred 5–10 min after the deterioration was seen.
One explanation for functional recovery is a delayed haemodynamic response. In this scenario, recovery of brain function would be accompanied by a restoration of blood flow either by establishment of collaterals or by autoregulatory vasodilation of cerebral arterioles. The rise in MCA flow velocity over 3–6 min that we observed by TCD in several patients suggests that there may be a time course of several minutes over which collaterals are established. If the mechanism of recovery is a `haemodynamic rescue,' however, an increase in CBF should be observed as recovery occurs. We documented such an increase in two of the nine patients in the D–R group. In three others, including the patient shown in Fig. 3, recovery occurred even when the hemispheric CBF remained low. The two-detector 133Xe-CBF technique averages cortical blood flow over a relatively large region and it is possible that focal CBF increases in smaller regions could have been missed by our measurements. However, there should be no systematic errors in measuring cortical CBF by this method (Young et al., 1990), which has a test–retest accuracy of 8–10%. If recovery is occurring in the setting of no increase in CBF, `metabolic rescue' during low perfusion could be postulated to be occurring, via an increase in oxygen extraction fraction (Derdeyn et al., 1999a) or a switch to anaerobic metabolism (Marrif and Juurlink, 1999). The recovery of sustained attention at CBF 25–40 ml/100 g/min occurred above the animal model threshold for failing glucose metabolism but within the range of the onset of anaerobic metabolism. Although anaerobic metabolism has not been demonstrated as a long-term compensatory mechanism in human PET studies (Derdeyn et al., 1999b), there is preclinical evidence that neural tissue and glial cells can generate ATP anaerobically and metabolize lactate in response to hypoxia–ischaemia (Nagatomo et al., 1995; Schurr and Rigor, 1998).
On the basis of our study, the following working model for the physiological mechanisms to preserve brain function might be proposed (Fig. 4). As cerebral perfusion pressure falls, CBF may be maintained haemodynamically by autoregulatory vasodilation of cortical arterioles and recruitment of collateral vascular channels. If the CBF falls into the 30–40 ml/100 g/min range before the haemodynamic mechanisms are fully established, brain function may be compromised, but then can recover as CBF returns. The `haemodynamic rescue' would be reflected by a decrease and return of CBF, an increase in cerebral blood volume and the emergence of collateral blood flow. Once haemodynamic compensatory mechanisms are maximized, a further drop in cerebral perfusion pressure will result in a decrease in CBF. As CBF falls to the range of 30–40 ml/100 g/min once more, brain function may again deteriorate. Recovery of function at this point may be accomplished by metabolic adjustments, such as an increase in oxygen extraction fraction (Baron et al., 1981; Powers, 1991; Grubb et al., 1998), a switch to anaerobic metabolism (Schurr and Rigor, 1998) or some other alteration in neuronal metabolism (Vannucci et al., 1998). In this model the preservation, deterioration or recovery of neurological function is determined by the time course of the haemodynamic and metabolic rescue mechanisms that emerge during hemispheric hypoperfusion.
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Although the carotid test occlusion may not replicate precisely the conditions of pathological arterial occlusion in clinical stroke, our preliminary data suggest that compensatory mechanisms related to functional recovery may occur during or even be induced by moderate cerebral hypoperfusion. Quantification of CBF levels that correlate with deterioration versus recovery of higher cerebral function may be useful clinically as we learn more about tissue reperfusion requirements in treating stroke. Whereas the data we report are direct observations and the proposed explanations of the underlying mechanisms are based on evidence from animal and tissue culture experiments, it may be that with higher resolution imaging techniques applied in real-time haemodynamic situations, knowledge from preclinical science can be translated to the clinical arena to explain more fully deterioration and recovery of human brain function during acute hypoperfusion.
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Acknowledgements |
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This work was supported by NINDS grant K02 NS02144, RO1 NS27713 and by the Doris and Stanley Tananbaum Foundation.
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Received October 2, 2000. Revised November 27, 2000. Accepted January 29, 2001.
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