Cerebral blood flow changes induced by CO2 in anxiety

Cerebral blood flow (CBF) was measured twice with the 133Xenon inhalation technique, under resting conditions and during 5% CO2 inhalation, in 13 patients with generalized anxiety disorder and a group of normal volunteers of comparable age and sex distribution. CO2 inhalation was associated with similar increases in end-tidal CO2 (PECO2) and CBF. Neither group showed statistically significant increases in state anxiety. However, when subjects (both patients and controls) who became anxious during CO2 inhalation were compared with those who did not, on associated CBF changes, significant differences emerged. The former showed less marked CBF increase as compared to the latter in the absence of any significant differences between the two groups on PECO2 during the second measurement. Changes in state anxiety and CBF showed a statistically significant inverse correlation for the entire group.     

Cerebral blood flow and CO2 reactivity in patients with transient ischemic attack]

To elucidate the changes in cerebral blood flow (CBF) and CO2 reactivity in patients with transient ischemic attack (TIA), 10 patients with TIA and 5 healthy adults (controls) underwent two consecutive CBF measurements (i.e. the first measurement during room air inhalation and the second measurement during 5%CO2 inhalation). Hemispheric mean CBF was determined by each CBF measurement using 133Xenon inhalation method. CO2 reactivity was evaluated by analysing delta CBF (= mean CBF during hypercapnea-mean CBF at rest) and delta CBF/delta PaCO2. The resting mean CBF values in the bilateral hemispheres (i.e. both of the affected and unaffected hemispheres) were significantly lower in TIA patients than controls (p less than 0.05). Inhalation of 5%CO2 significantly increased mean CBF in TIA patients bilaterally, however the mean CBF value during hypercapnea was again significantly lower in TIA patients than controls (p less than 0.05). CO2 reactivity in TIA patients was not significantly different from controls (p greater than 0.05). The result demonstrated that TIA patients have a chronic and global cerebral oligemia with normal CO2 reactivity. The chronic and global cerebral oligemia may develop a transient ischemic neurological symptom by being superimposed with local decrease of CBF.     

Determinants of resting regional cerebral blood flow in normal subjects

Study of brain function via cerebral blood flow and metabolism measurements is believed to be of considerable significance in psychiatry. The present study examined the factors that determined patterns of regional cerebral blood flow (CBF) in 140 physically and mentally healthy, drug-free volunteers under resting conditions. Age, sex, and end-tidal CO2 levels were identified as the most powerful determinants of CBF, in that order. Age-related CBF reduction was found to be most marked in the frontal region. Women had higher CBF than men, and the difference was most obvious in the frontal region. The correlations between CO2 and CBF showed less striking, but significant, regional variations. Hematocrit was found to exert only minimal influence in the control of resting CBF.     

Chronicity and a low anteroposterior gradient of cerebral blood flow in schizophrenia

Regional cerebral blood flow (CBF) was measured with the 133xenon inhalation technique in 27 patients with schizophrenia of less than 5 years' duration and in 27 patients with schizophrenia of more than 12 years' duration, under resting conditions. Similar measurements were also performed in 54 normal control subjects matched for age and sex. Patients with schizophrenia of long duration had lower anteroposterior gradients of CBF than patients with schizophrenia of short duration and matched control subjects. Covarying out age and end-tidal levels of CO2 did not alter the results.     

Cerebral blood flow and cognitive testing correlate in Huntington's disease

Brain atrophy estimated by computed tomographic (CT) scanning and mean hemispheric and regional gray matter cerebral blood flow (CBF) values were measured in patients with mild to moderate Huntington's disease (HD) (N = 16) using the xenon Xe 133 inhalation method and in asymptomatic blood relatives at risk from HD (N = 6) using both the xenon Xe 133 inhalation and the stable xenon CT contrast CBF methods. Results were compared with measurements in two groups of age-matched normal volunteers (N = 48 and N = 42, respectively). Significant brain atrophy in the vicinity of both caudate nuclei was present in patients with HD but not in at-risk individuals. Mean hemispheric xenon Xe 133 CBF values were reduced in patients with HD but seemed to be normal in at-risk individuals. In HD, reductions in CBF were found in both frontotemporal regions. Correlations were found between severity of dementia estimated by reductions of Mini-Mental Status Questionnaire scores and reductions of either mean hemispheric or regional frontotemporal CBF values in HD. The CT estimates of brain atrophy and three-dimensional CBF by stable xenon-contrast measurements were normal in asymptomatic individuals at risk from HD.     

Effect of nimodipine on cerebral blood flow and cerebrovascular reactivity after subarachnoid haemorrhage

The aim of the present study was to investigate the effect of nimodipine on autoregulation of cerebral blood flow (CBF), CO2 reactivity and cerebral oxygen metabolism (CMRO2) in patients with subarachnoid haemorrhage (SAH). Eight patients with severe SAH were studied with repeated CBF and CMRO2 measurements on the first day of the bleeding and after at least 12 h of treatment of nimodipine. An initial resting study, an autoregulation study and a hyperventilation study was performed. CBF was measured using the 133-Xenon intravenous method. CMRO2 was calculated as AVDO2 x CBF. Nimodipine did not significantly change CBF and CMRO2 in the initial resting study. After induced arterial hypotension intact autoregulation was found before as well as after treatment with nimodipine. Beneficial effects of nimodipine were found on CO2 reactivity and CMRO2 during hypotension that may be explained as a positive effect on cerebral ischaemia.     

Cerebral hemodynamics measured with simultaneous PET and near-infrared spectroscopy in humans

Near-infrared spectroscopy (NIRS) enables continuous non-invasive quantification of blood and tissue oxygenation, and may be useful for quantification of cerebral blood volume (CBV) changes. In this study, changes in cerebral oxy- and deoxyhemoglobin were compared to corresponding changes in CBF and CBV as measured by positron emission tomography (PET). Furthermore, the results were compared using a physiological model of cerebral oxygenation. In five healthy volunteers changes in CBF were induced in a randomized order by hyperventilation or inhalation of 6% CO(2). Arterial content of O(2) and CO(2) was measured several times during each scanning. Changes in deoxyhemoglobin (deltaHb), oxyhemoglobin (deltaHbO(2)) and total hemoglobin (deltaHb(tot)) were continuously recorded with NIRS equipment. CBF and CBV was also determined in MRI-coregistered PET-slices in regions determined by the placement of the two optodes, as localized from the transmission scan. The PET-measurements showed an average CBV of 5.5+/-0.74 ml 100 g(-1) in normoventilation, with an increase of 29% during hypercapnia, whereas no significant changes were seen during hyperventilation. CBF was 51+/-10 in normoventilation, increased by 37% during 6% CO(2) and decreased by 25% during hyperventilation. NIRS showed significant increases in oxygenation during hypercapnia, and a trend towards decreases during hyperventilation. Changes in CBV measured with both techniques were significantly correlated to CO(2) levels. However, deltaCBV(NIRS) was much smaller than deltaCBV(PET), and measured NIRS parameters smaller than those predicted from the model. It is concluded that while qualitatively correct, NIRS measurements of CBV should be used with caution when quantitative results are needed.     

Regional cerebral blood flow in stroke: hemispheric effects of cognitive activity

Regional cerebral blood flow (rCBF) was measured with the xenon-133 inhalation technique in 15 patients with unilateral cerebral infarction and 12 matched controls. Measurements were performed during a standard resting baseline condition and during the performance of standardized verbal analogies and spatial line orientation tasks. Resting and activated CBF were lower in patients than in controls, and there were differences in the hemispheric pattern of activated CBF. Control subjects replicated earlier findings of asymmetric increase in CBF for the cognitive tasks, whereas patients showed abnormalities in lateralized CBF changes consistent with side of infarction. These findings underscore the utility of cognitive challenges in the study of rCBF in stroke. This can lead to an experimental paradigm in clinical studies of the relation between behavioral deficits and regional brain dysfunction and may also improve the utility of CBF measurements in clinical settings.     

Right motor neglect associated with dynamic aphasia, loss of drive and amnesia: case report and cerebral blood flow study.

A 30-year-old right-handed man had right motor neglect, amnesia, aphasia and loss of drive following bilateral thalamic and subthalamic infarctions. Serial resting cerebral blood flow (CBF) measurements with either Xenon 133 inhalation or positron emission tomography at 1, 8 and 10 months post-onset showed a widespread and long-lasting low CBF in the cortex. An additional CBF measurement, during motor tasks, showed a marked interhemispheric asymmetry in the pattern of activation: whereas left hand movement resulted in a CBF increase in contralateral superior rolandic and prerolandic areas, no significant regional CBF changes were seen during right hand movement, despite recovery from motor neglect. This loss of CBF increase in cortical motor and premotor areas during voluntary movement of the previously neglected side points to a disruption of cortico-subcortical pathways subserving motor activation. The pathophysiology of aphasia, loss of drive and amnesia as well as their relationships to motor neglect, may also be discussed on the basis of thalamo-cortical disconnections.     

Responses to hypercarbia induced by acetazolamide in panic disorder patients

CO2 inhalation has been reported to induce panic attacks in panic disorder patients. State anxiety, somatic symptoms of anxiety, physiological changes, and cerebral blood flow (CBF) were monitored in panic disorder patients before and after intravenous injections of 1 g of acetazolamide (13 patients) and saline (10 patients), given under double-blind conditions. In spite of significant hypercarbia, as evidenced by increased CBF in the former group, only one subject reported panic and even that attack did not meet DSM-III-R criteria. There was only one significant difference between the drug and placebo groups; the acetazolamide group experienced significantly more dizziness.     

Brain luxury perfusion during cardiopulmonary bypass in humans. A study of the cerebral blood flow response to changes in CO2, O2, and blood pressure

CBF and related parameters were studied in 68 patients before, during, and following cardiopulmonary bypass. CBF was measured using the intraarterial 133Xe injection method. The extracorporeal circuit was nonpulsatile with a bubble oxygenator administering 3-5% CO2 in the main group of hypercapnic patients (n = 59) and no CO2 in a second group of hypocapnic patients. In the hypercapnic patients, marked changes in CBF occurred during bypass. Evidence was found of a brain luxury perfusion that could not be related to the effect of CO2 per se. Mean CBF was 29 ml/100 g/min just before bypass, 49 ml/100 g/min at steady-state hypothermia (27 degrees C), reached a maximum of 73 ml/100 g/min during the rewarming phase (32 degrees C), fell to 56 ml/100 g/min at steady-state normothermic bypass (37 degrees C), and was 48 ml/100 g/min shortly after bypass was stopped. Addition of CO2 evoked systemic vasodilation with low blood pressure and a rebound hyperemia. The hypocapnic group responded more physiologically to the induced changes in hematocrit (Htc) and temperature, CBF being 25, 23, 25, 34, and 35 ml/100 g/min, respectively, during the five corresponding periods. Carbon dioxide was an important regulator of CBF during all phases of cardiac surgery, the responsiveness of CBF being approximately 4% for each 1-mm Hg change of PaCO2. The level of MABP was important for the CO2 response. At low blood pressure states, the CBF responsiveness to changes in PaCO2 was almost abolished. An optimal level of PaCO2 during hypothermic bypass of approximately 25 mm Hg (at actual temperature) is recommended. A normal autoregulatory response of CBF to changes in blood pressure was found during and following bypass. The lower limit of autoregulation was at pressure levels of approximately 50-60 mm Hg. CBF autoregulation was almost abolished at PaCO2 levels of greater than 50 mm Hg. The degree of hemodilution neither affected the CO2 response nor impaired CBF autoregulation, although, as would be expected, it influenced CBF: In 33 women CBF was 55 ml/100 g/min at an Htc of 24%, as compared with 42 ml/100 g/min in 35 men (Htc = 28%). High PaO2 was a vasoconstrictor, the autoregulatory plateau being narrowed. The lower limit of autoregulation was shifted to a higher pressure when PaO2 was low.     

Resting CBF sequential study during recovery from aphasia due to ischemic stroke

Cerebral blood flow (¹³³xenon inhalation method) has been studied in 30 aphasic stroke patients at 15, 30, 60 and 90 days after onset. In total aphasia the CBF values are low and the regional hypoperfused areas are extensive. In Broca's, Wernicke's and nominal aphasias, resting CBF measurements do not provide the clinician with useful additional information and clinical improvement can by no means be attributed to a resting CBF rise during the observation period.     

Effect of labetalol on cerebral blood flow and middle cerebral arterial flow velocity in healthy volunteers.

The effect of labetalol, a combined alpha- and beta-adrenoceptor antagonist, on the cerebral circulation was investigated in 7 normotensive subjects. Cerebral blood flow (CBF) was measured with the intravenous 133Xe method and mean flow velocity (Vmean) in the middle cerebral artery was determined using transcranial Doppler (TCD) ultrasound. Examination was performed before and then 15, 60 and 120 min after 0.75 mg/kg i.v. labetalol. Reactivity to inhalation of 5% CO2 in air was studied before, and again 90 min after labetalol administration. Neither CBF nor Vmean changed following labetalol administration, whereas a marked increase occurred during inhalation of CO2. The median CO2 reactivity was 3.2%/mmHg (range: 1.8-4.0) for CBF and 4.4%/mmHg (1.5-5.6) for Vmean. These results indicate that labetalol, given in moderate but clinically relevant doses, does not affect the cerebral circulation in normotensive subjects. Neither does it affect CO2 reactivity. The uniform results obtained with the two methods suggest TCD as a usable alternative to conventional CBF technique in the assessment of cerebral vasoactivity of various drugs in subjects with a normal cerebral circulation.     

Effects of midazolam on cerebral hemodynamics and cerebral vasomotor responsiveness to carbon dioxide

Although it is known that hypercarbia increases and benzodiazepines decrease cerebral blood flow (CBF), the effects of benzodiazepines on CBF responsiveness to CO2 are not well documented. The influence on CBF and CBF-CO2 sensitivity of placebo or midazolam, which is a new water-soluble benzodiazepine, was measured in eight healthy volunteers using the noninvasive 133Xe inhalation method for CBF determination. Under normocarbia, midazolam decreased CBF from 40.6 +/- 3.2 to 27.0 +/- 5.0 ml 100 g-1 min-1 (means +/- SD). At a later session under hypercarbia, CBF was 58.8 +/- 4.4 ml 100 g-1 min-1 after administration of placebo, and 49.1 +/- 10.2 ml 100 g-1 min-1 after midazolam. The mean of the slopes correlating PaCO2 and CBF was significantly steeper with midazolam (2.5 +/- 1.2 ml 100 g-1 min-1 mm Hg-1) than with placebo (1.5 +/- 0.4 ml 100 g-1 min-1 mm Hg-1). Our results suggest that midazolam may be a safe agent to use in patients with intracranial hypertension, since it decreases CBF and thus cerebral blood volume; however, it should be administered with caution in nonventilated patients with increased intracranial pressure, since its beneficial effects on cerebrovascular tone can be readily counteracted by the increase in arterial CO2 tension induced by this drug.     

Effect of L-threo-3,4-dihydroxyphenylserine on regional cerebral blood flow in patients with Parkinson's disease

Regional cerebral blood flow (rCBF) was measured by the 133Xe inhalation technique in 9 patients with Parkinson's disease and in 1 patient with pure akinesia before and during treatment with L-threo-3,4-dihydroxyphenylserine (DOPS). L-DOPS alone was administered in 4 patients, and combined with L-DOPA or bromocriptine in 6 patients. The mean, hemispheric and regional CBF was unaffected by the chronic administration of L-DOPS. In addition, no significant difference in the mean CBF was observed between the patients who showed marked or moderate improvement in parkinsonian symptoms during the treatment with L-DOPS and those who showed slight improvement or no change, or between the group treated with L-DOPS alone and the group treated in combination with L-DOPS and other drugs. These results indicate that L-DOPS does not increase the CBF in parkinsonian patients, thus the anti-parkinsonian effects of the agent are not mediated by changes in CBF.     

Intelligence in children with moyamoya disease: evaluation after surgical treatments with special reference to changes in cerebral blood flow

The effect of surgical treatment upon the intelligence of 20 children with moyamoya disease was evaluated and related to changes in cerebral blood flow (CBF). The patients were treated by various surgical revascularization procedures, mainly by encephalo-myo-synangiosis. Intelligence was tested using the Wechsler intelligence scale for children (WISC) in 19 children and the Wechsler adult intelligence scale (WAIS) in one child. Measurements of regional CBF were performed by a 133Xe inhalation method. In the preoperative state, the degree of reduction in the intelligence quotient (IQ) correlated well with the age of the patients; the older patients revealed a more marked reduction of IQ, and the patients with lower intelligence scores in general showed a tendency for more marked depression of mean CBF. Postoperatively, most of the patients showed increase in IQ, especially in performance IQ which improved significantly in 10 patients, remained unchanged in 3 and deteriorated in 2. Mean CBF increased by an average of 11.4%, and postoperative changes in mean CBF correlated well with the changes in IQ in most patients. This may show that the postoperative increase in CBF is quite possibly responsible for the changes in IQ.     

Provocation of panic with carbon dioxide inhalation in patients with premenstrual dysphoria

The effects of double breath inhalation of a 35% CO2 mixture in oxygen and placebo air inhalation were compared in 14 women seeking treatment for marked premenstrual dysphoric changes who did not have panic disorder and 12 control women. The first exposure to CO2 inhalation induced a panic attack reaction (severe subjective anxiety with autonomic symptoms) in 9 of 14 women with premenstrual dysphoria but none of the controls. Neither patients nor controls panicked in response to the air inhalation. Control subjects experienced mild anxiety and/or somatic symptoms after CO2 inhalation, but these did not resemble panic attacks and were clearly different from the response of the patient group.     

The reproducibility of the 133Xe inhalation technique in resting studies: task order and sex related effects in healthy young adults

Repeated applications of the 133Xe inhalation technique for measuring regional CBF (rCBF) were made during consecutive resting conditions in a sample of young healthy subjects. Subjects were grouped by order and by sex [nine had resting studies as the initial two measurements in a series of four measurement (six men, three women) and six had these measurements later (two men, four women)]. Three flow parameters were examined: f1 (fast flow) and IS (initial slope) for gray matter CBF, and CBF-15 for mean CBF (gray and white matter over 15-min integration), as well as w1, the percentage of tissue with fast clearing characteristics. With all groups combined, there were no significant differences between the two resting measurements, and high test-retest correlations were obtained for the flow parameters and w1. Analyses by order and sex grouping revealed, for the flow parameters, significant interactions of test-retest difference with order. Repeated initial studies showed reduced CBF from the first to second measurement, whereas resting studies performed later in the series showed no reduction. Interactions for test-retest difference with sex indicated that reduced CBF in serial measures was more pronounced for women. No hemispheric or regional specificity to account for these effects was found. Correction for PaCO2 differences did not alter these results. The results resemble data regarding habituation effects measured for other psychophysiologic measures, and suggest that reduction in CBF for consecutive measurements made on the same day may reflect habituation. This underscores the importance of controlling for effects of habituation on serial measurements of CBF and metabolism.     

Behavioral and cerebrovascular effects of caffeine in patients with anxiety disorders

Caffeine is believed to induce anxiety in normal people and anxiety disorder patients and panic attacks in panic disorder patients. The drug is also known to reduce cerebral blood flow (CBF). Findings suggesting an anxiety-related cerebral vasoconstrictive factor have been reported. We examined the relationship between changes in anxiety and CBF induced by intravenously injecting 250 mg of caffeine (comparable to 2 cups of coffee) in 8 patients with generalized anxiety disorder, 9 patients with panic disorder and 9 normal controls. CBF measurements were also obtained before and after an injection of normal saline in another group of 9 normal volunteers. The anxiety disorder patients did not show any evidence of increase in anxiety and panic after caffeine. Both patients and controls who received caffeine but not normal controls who received saline showed significant CBF decrease. The CBF changes were unrelated to changes in mood, autonomic activity and carbon dioxide levels.     

Regional cerebral blood flow after marijuana smoking.

Regional CBF was measured with the 133Xe inhalation technique before and thrice after smoking marijuana of two strengths and placebo in 20 physically and mentally healthy male volunteers with a previous history of exposure to marijuana. They were drug-free at the time of the study. Blood pressure, pulse rate, end-tidal carbon dioxide, end-tidal carbon monoxide, and forehead skin perfusion were quantified during the CBF measurements. Blood samples were drawn for quantification of plasma levels of delta 9-tetrahydrocannabinol (THC) before and during the 2 h after smoking marijuana or placebo. Drug-induced intoxication and changes in mood were quantified with rating scales. Marijuana smoking was associated with bilateral CBF increase, which was maximal 30 min later. Greater CBF increases were seen in the frontal region and right hemisphere. No significant CBF changes were seen after placebo. Pulse rate and respiration increased significantly after marijuana but not placebo. Both marijuana and placebo smoking were associated with increased end-tidal carbon monoxide. CBF increase in both hemispheres correlated significantly with degree of intoxication, plasma levels of THC, and pulse rate.