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

Evidence that Ca²⁺-activated K⁺ (K_Ca) channels play a role in cell volume changes and K⁺ homeostasis led to a prediction that astrocytes would have K_Ca channels near blood vessels in order to maintain K⁺ homeostasis. Consistent with this thinking the present study demonstrates that rSlo K_Ca channels are in glial cells of the adult rat central nervous system (CNS) and highly localized to specializations of astrocytes associated with the brain vasculature. Using confocal and thin-section electron microscopic immunolabeling methods the distribution of rSlo was examined in adult rat brain. Strong rSlo immunolabeling was present around the vasculature of most brain regions. Examination of dye-filled hippocampal astrocytes revealed rSlo immunolabeling polarized in astrocytic endfeet. Ultrastructural analysis confirmed that the rSlo staining was concentrated in astrocytic endfeet ensheathing capillaries as well as abutting the pia mater. Immunostaining within the endfeet was predominantly distributed at the plasma membrane directly adjacent to either the vascular basal lamina or the pial surface. The distribution of the aquaporin-4 (AQP-4) water channel was also examined using dye-filled hippocampal astrocytes. In confirmation of earlier reports, intense AQP-4 immunolabeling was generally observed at the perimeter of blood vessels, and coincided with perivascular endfeet and rSlo labeling. We propose that rSlo K_Ca channels, with their sensitivity to membrane depolarization and intracellular calcium, play a role in the K⁺ modulation of cerebral blood flow. Additional knowledge of the molecular and cellular machinery present at perivascular endfeet may provide insight into the structural and functional molecular elements responsible for the neuronal activity-dependent regulation of cerebral blood flow.     

Cerebral autoregulation in the microvasculature measured with near-infrared spectroscopy

Cerebral autoregulation (CA) is the mechanism that allows the brain to maintain a stable blood flow despite changes in blood pressure. Dynamic CA can be quantified based on continuous measurements of systemic mean arterial pressure (MAP) and global cerebral blood flow. Here, we show that dynamic CA can be quantified also from local measurements that are sensitive to the microvasculature. We used near-infrared spectroscopy (NIRS) to measure temporal changes in oxy- and deoxy-hemoglobin concentrations in the prefrontal cortex of 11 human subjects. A novel hemodynamic model translates those changes into changes of cerebral blood volume and blood flow. The interplay between them is described by transfer function analysis, specifically by a high-pass filter whose cutoff frequency describes the autoregulation efficiency. We have used pneumatic thigh cuffs to induce MAP perturbation by a fast release during rest and during hyperventilation, which is known to enhance autoregulation. Based on our model, we found that the autoregulation cutoff frequency increased during hyperventilation in comparison to normal breathing in 10 out of 11 subjects, indicating a greater autoregulation efficiency. We have shown that autoregulation can reliably be measured noninvasively in the microvasculature, opening up the possibility of localized CA monitoring with NIRS.     

Intracerebral hemodynamics probed by near infrared spectroscopy in the transition between wakefulness and sleep

Previous imaging studies have shown that cerebral metabolism is gradually reduced at the beginning of sleep. Few studies have examined the sleep state transition periods from wakefulness to sleep and sleep to wakefulness. The current study used the Near Infrared Spectroscopy (NIRS) technique to describe the intracerebral hemodynamics at the frontal pole in the circumscribed period between wakefulness and sleep. Nine healthy young adults were studied during afternoon naps. Optical probes were placed on the forehead and EEG electrodes on the scalp. At sleep onset oxygenated hemoglobin (oxy-Hb) was reduced (P<0.01) and deoxygenated hemoglobin (deoxy-Hb) showed a near significant reduction (P<0.063). At sleep offset there were increases in oxy-Hb (P<0.005) and deoxy-Hb (P<0.05). In 18 of 26 transitions to sleep there was a coordinated fall in both NIRS parameters, we call the Switch Point, that lasted a mean of 3.6 s. In 32 of 36 transitions to wakefulness there was an analogous Switch Point that lasted a mean of 3.4 s. Before and after the Switch Point, changes were small and the relationship between oxy-Hb and deoxy-Hb was a combination of parallel and reciprocal fluctuations. A synchronized, parallel and short-lived change in oxy-Hb and deoxy-Hb is a discrete event in the transition period between wakefulness and sleep. The concentration of these light absorbing molecules is abruptly set to a new level at sleep-wake transitions and probably reflects the different perfusion demands of these states.     

Effect of Valproate on Cerebral Metabolism and Blood Flow: An 18F-2-Deoxyglusose and 15O Water Positron Emission Tomography Study

Summary: We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF), measured with ¹⁸F-2–deoxyglucose (^I8FDG) and ¹⁵O water positron emission tomography (PET), in 10 normal volunteers. Mean VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (±16.5) for 4 weeks. VPA reduced global CMRGlc by 9.4% (9.60 2 0.76 vs. 8.59 ± 1.02 mg Glc/min/100 g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas). VPA diminished global CBF by 14.9% (56.55 ± 6.70 vs. 47.48 ± 4.42 ml/min/100 g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas). No significant correlation was noted between VPA level and either global CMRGlc or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine (CBZ) and phenytoin but less than that of phenobarbital, Valium, or combination therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the thalamus, an effect that may be associated with VPA's mechanism of action against generalized seizures.     

Sequential PET studies in neuro-behcet's syndrome

Summary A case of neuro-Behcet's syndrome is presented with sequential positron emission tomography (PET) studies. Regional cerebral blood flow (rCBF) and oxygen consumption (rCMRO₂) were decreased in the brain lesion; however, on follow-up studies 3 months after steroid therapy rCBF and rCMRO₂ had increased in the lesion, which demonstrated the reversibility of this disease. Such monitored improvement may accurately reflect the early stage of the disease and its response to steroid therapy.     

Effect of Seizures on Cerebral Blood Flow Measured with 15–H2O and Positron Emission Tomography

Summary: To study quantitative alterations in regional cerebral blood flow (rCBF) accompanying seizures, and to assess the utility of ictal activation PET scanning as a noninvasive clinical tool for localization of epileptogenic foci, we used pentylenetetrazole (F'TZ) to induce seizures during ¹⁵O-water positron emission tomography (PET) CBF measurement in 15 patients with uncontrolled complex partial seizures (CPS) who had been referred for surgical evaluation. Continuous EEG monitoring was performed during the PET scans. After baseline scans were obtained, each patient was injected with 150–300 mg PTZ. Two patients had generalized tonic-clonic seizures (GTCs). CBF increases were asymmetrical. Two patients (in 1 the seizure occurred spontaneously, without PTZ injection) who had CPS had bitemporal 70–80% increases in CBF. Thalamic CBF increased during both CPS and GTCS. Five patients had an increase in focal EEG in-terictal abnormality, accompanied by focal flow decreases in 3. PTZ injection not accompanied by clinical seizures did not increase CBF. Partial seizures may be associated with bilateral increases in CBF, and subcortical gray regions are involved in ictal activation.     

Time course of tetrahydrocannabinol-induced changes in regional cerebral blood flow measured with positron emission tomography

While several studies are available on the immediate effects of marijuana and its active ingredient tetrahydrocannabinol (THC) on regional cerebral blood flow (rCBF), we examined the effects of intravenous infusion of THC on rCBF and behavior over a 120-min. period using positron emission tomography. Indices of rCBF, intoxication and physiology were measured at baseline and 30, 60, 90 and 120 min. after a 20-min. intravenous infusion of 0.15 or 0.25 mg/min. of THC, or placebo given to 47 subjects. The rCBF remained increased up to 120 min. after the high-dose THC infusion. Significant increases were seen in global perfusion and in the frontal, insular and anterior cingulate regions. Changes were greater in the right hemisphere. After the high dose, cerebellar flow was increased at both 30 and 60 min. The anterioposterior ratio of cortical rCBF increased in both hemispheres, and remained significantly greater than in the placebo condition until 120 min. in the right hemisphere. Intoxication peaked at 30 min. and remained elevated at 120 min. THC had significant effects on global CBF and rCBF, and feeling intoxicated accounted for changes in rCBF better than plasma level of THC.     

Evaluation of cerebral circulation and oxygen metabolism in infants using near-infrared light

Bedside monitoring of cerebral circulation or oxygen metabolism in infants to appropriately manage circulation and establish the oxygen dose, aiming at improving the neurological prognosis, is needed in general clinical practice. Near-infrared spectroscopy is used for measurements of neonatal cerebral Hb oxygen saturation, cerebral blood volume, cerebral blood flow and cerebral metabolic rate of oxygen. Near-infrared time-resolved spectroscopy is particularly useful for bedside evaluation of cerebral circulation and oxygen metabolism because of its simple measurement procedure. Combined evaluation of cerebral blood volume and cerebral Hb oxygen saturation is expected to contribute to treatment centering on the brain in neonatal medical care.     

Changes in cerebral blood flow after acetazolamide: an experimental study comparing near-infrared spectroscopy and SPECT

Background and purpose:  It is important to find a reliable and bedside method, which can estimate the cerebral blood flow (CBF) of patients in clinical settings. Estimation of CBF by calculating a blood flow index (BFI) using continuous wave near-infrared spectroscopy (CW-NIRS) and indocyanine green (ICG) as an iv tracer has been proposed to be a feasible and promising method. To validate if the BFI method can detect relative changes in CBF we compared data with the established method ¹³³Xenon single photon emission computer tomography (¹³³Xe-SPECT).
Methods:  Ten healthy subjects were investigated before and after a bolus of acetazolamide. NIRS data were obtained using a multi source detector separation configuration in order to assess a corrected BFI (BFI_corr) value, which attempts to eliminate contamination of skin blood flow.
Results:  Data obtained showed no significant correlation between CBF changes measured by ¹³³Xe-SPECT and BFI_corr (0.133, P  =   0.732). After acetazolamide, a 49% increase in CBF was detected using the ¹³³Xe-SPECT method, whereas no changes in any ICG variables were observed after acetazolamide.
Conclusion:  The study shows that it is not possible to obtain reliable BFI data, which reflect changes in CBF after acetazolamide infusion, using the CW-NIRS and ICG method.     

Cerebral blood volume in the sleep measured by near-infrared spectroscopy

Abstract We investigated the relationship between hemodynamic changes in the cortex measured by near-infrared spectroscopy (NIRS) and the polysomnographic changes during sleep. Four healthy male volunteers participated in the study. Near-infrared spectroscopy measuring and polysomnographic recordings were done simultaneously during sleep. In many case, oxy-hemoglobin (oxy-Hb) decreased and deoxy-hemoglobin (deoxy-Hb) increased during the transition from wakefulness to sleep, and oxy-Hb increased toward deep sleep. Oxy-Hb and deoxy-Hb had larger fluctuations during REM sleep than those during non-REM sleep. During REM sleep, oxy-Hb often showed a lower level and deoxy-Hb showed a higher level than those during the preceding and following non-REM sleep.     

Serotonin modulation of cerebral blood flow measured with positron emission tomography (PET) in humans

To develop a method to measure the dynamic response of the serotonin system in vivo, the effects of intravenously administered citalopram (the most selective of the serotonin reuptake inhibitors) or clomipramine on cerebral blood flow (CBF) were evaluated. CBF was measured with positron emission tomography (PET) in 27 normal subjects scanned under baseline conditions and, on the same day, after an intravenous (IV) infusion of placebo, citalopram, or clomipramine using a randomized, double-blind design. The main effects of the drugs on blood flow occurred in the thalamus, hypothalamus, and cingulate cortex. Compared to placebo, clomipramine reduced blood flow in the mediodorsal and ventral lateral nuclei of the thalamus, whereas citalopram reduced blood flow in the pulvinar nucleus and the hypothalamus. Compared to clomipramine, citalopram decreased blood flow in the cingulate cortex. The findings support previous reports showing acute central effects of citalopram and clomipramine on regional serotonergic functions measured by PET. Acute side effects may, however, require that care is taken in the selection of experimental designs for future PET studies using IV administration of these antidepressants.     

Cerebral hemodynamics and oxygenation after serial CSF drainage in infants with PHVD

The aim of our study was to assess consecutive changes in cerebral oxygenation and hemodynamics after serial cerebrospinal fluid (CSF) drainage from a subcutaneous ventricular catheter reservoir (SVCR) in infants with PHVD. Infants with PHVD were studied during CSF drainage from a SVCR on the day of SVCR placement, half a week and one week after SVCR placement. Changes in cHbD and CBV were assessed using near infrared spectrophotometry. Time averaged peak flow velocity (TAPFV), end diastolic flow velocity (EDFV), peak systolic flow velocity (PSFV) and pulsatility index (PI) were measured before (baseline) and after CSF drainage using Doppler ultrasound. Longitudinal data analysis was performed using linear mixed models. Seven patients (GA 26.7–40.4 weeks, BW 800–4575 g) were studied. CSF drainage resulted in a statistically significant increase in CBV during each measurement. The change in CBV was maximal on the day of SVCR placement. A significant increase in cHbD and EDFV, and decrease in PI was observed after CSF drainage only on the day of SVCR placement. Baseline values of all Doppler variables improved consecutively after serial CSF removal in the first week after SVCR placement. Frequent CSF drainage results in consecutive improvement of cerebral perfusion and oxygenation in infants with PHVD.     

The hemodynamics of cognitive control: the level of concentration of oxygenated hemoglobin in the superior prefrontal cortex varies as a function of performance in a modified Stroop task

The purpose of this study was to establish the relationship between the hemodynamic response of prefrontal cortex (PFC) and individual differences in cognitive control, as measured by a color-word interference task. Twenty-five healthy volunteers were observed through functional near infrared spectroscopy (fNIRS) while performing a modified Stroop paradigm. Mean concentration levels of oxygenated hemoglobin (oxy-Hb) were correlated with behavioral performance in the conflict task. Those with shorter reaction times had higher levels of oxy-Hb concentration in superior dorsolateral PFC. Our results are the first to show a positive correlation between behavioral performance and oxy-Hb levels in superior dorsolateral PFC in a cognitive conflict task. These results suggest that the availability of oxygen in the superior PFC, possibly linked to an increase in metabolism, may be related to attention level and effectiveness of cognitive control.     

Scopolamine abolishes cerebral blood flow response to somatosensory stimulation in anesthetized cats: PET study

The effect of the cholinergic blocker, scopolamine on the cerebral blood flow (CBF) response to vibrotactile stimulation of a fore paw was studied using high-resolution positron emission tomography and H₂¹⁵O in 5 pentobarbital-anesthetized cats. Before scopolamine injection, the CBF response to the stimulation was found in the contralateral somatosensory cortex (mean ratio (contralateral/ipsilateral) control: stimulated1.02 ± 0.02: 1.17 ± 0.05; P < 0.01). After intravenous injection of scopolamine (0.35 mg/kg), the CBF response was abolished. However, the cerebral metabolic rate of glucose (CMRGlu) response to the same stimulation was unchanged after scopolamine injection in the same cats. We concluded that scopolamine abolishes the CBF response but not neuronal response to stimulation. We suggest that cholinergic mechanisms may play an important role for mediating CBF coupling to neuronal activity during physiological stimulation.     

Complex Partial Seizures: Cerebral Structure and Cerebral Function

We studied the relationships between cerebral structure and function in 10 patients with complex partial seizures who had major cerebral lesions, including porencephalic cysts, tuberose sclerosis, agenesis of the corpus callosum, and cerebral hemiatrophy. Evaluation included computed tomography (CT) and magnetic resonance imaging (MRI) scanning, EEG, and positron emission tomography (PET) using [18F]-2-deoxyglucose. Surface EEG usually showed widespread, bilateral epileptiform discharges even if pathology was clearly restricted to one hemisphere. In several cases, interictal PET hypometabolism was more widespread than structural changes seen on CT and MRI, extending to involve the ipsilateral temporal lobe in patients with extratemporal lesions. This study shows that patterns of metabolic and electrophysiologic dysfunction may not be predicted by structural lesions in patients with partial seizure disorders.     

Age-related changes in cerebral blood flow and glucose metabolism in conscious rhesus monkeys

Regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose (rCMRglc) were measured in aged and young monkeys by positron emission tomography (PET). Our purpose was to examine whether the age-related changes observed in the human brain also occur in the monkey brain. Studies were performed on six aged and six young-adult male rhesus monkeys (Macaca mulatta). rCBF and the rCMRglc were serially measured using PET with [(15)O]H(2)O and 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG), respectively. In order to minimize the bias induced by anesthesia, the PET emission scans were performed in the conscious state. ROIs were taken for the cerebellum, hippocampus with adjacent cortex, striatum, occipital cortex, temporal cortex, frontal cortex and cingulate. Group differences and correlations between rCBF and rCMRglc in each group were determined. Aged monkeys had significantly lower rCBF in the cerebellum, hippocampus with the adjacent cortex, striatum, occipital cortex, temporal cortex, frontal cortex, and significantly lower rCMRglc in the cerebellum, hippocampus with the adjacent cortex, striatum, occipital cortex, temporal cortex, frontal cortex and cingulate, compared to young monkeys. There were significant correlations between rCBF and rCMRglc in both the aged and young groups, but no significant difference was found in relationship between the two groups. Age-related changes were observed not only in rCMRglc, but also in rCBF in aged monkeys, while the coupling between rCBF and rCMRglc was maintained even in aged monkeys. These results demonstrated the potential of aged monkeys to serve as an aged human model using PET.     

Prefrontal brain function in children with anorexia nervosa: A near-infrared spectroscopy study

To investigate the prefrontal hemodynamic response during a cognitive task in childhood anorexia nervosa (AN), we measured regional cerebral blood volume changes in terms of changes in hemoglobin concentrations [Hb], using near-infrared spectroscopy (NIRS). Sixteen females with AN (mean age 14.2 years old) and 12 age-matched healthy female control subjects (mean age 14.3 years old) participated in this study. Waveform patterns for [Hb] during the word fluency task differed between the two groups, although their task performances showed no significant difference. In the control group, the [total-Hb] and [oxy-Hb] immediately increased and the [deoxy-Hb] immediately decreased after the beginning of the task and gradually reached the baseline level after the end of the task. The patients with AN were consistently characterized by an unchanged or less fluctuating response pattern of [total-Hb], [oxy-Hb] and [deoxy-Hb] during the task and rest periods. In the AN group, subjects with higher Eating Attitudes Test (EAT-26) scores showed higher [oxy-Hb] during the task. On the other hand, in the control group, subjects with higher EAT-26 scores showed lower [oxy-Hb] during the task. The grand waveforms of each [Hb] during a motor activation task, which was applied as a control task, did not differ significantly between two groups. The different prefrontal hemodynamic responses might indicate that AN subjects might apply fewer brain circuits or fewer neurons per circuit during cognitive tasks and might use different brain circuits in relation to their preoccupation with eating behaviors.     

Cerebral blood flow in spinocerebellar degenerations: a single photon emission tomography study in 28 patients

We used single photon emission tomography to study regional cerebral perfusion in patients with different forms of spinocerebellar degeneration: 6 patients with Friedreich’s ataxia (FA), 6 with early-onset cerebellar ataxia with retained tendon reflexes (EOCA), 5 with autosomal dominant cerebellar ataxia type 1 (ADCA I) and 11 with idiopathic late-onset cerebellar ataxia (ILOCA). The results were related to clinical and magnetic resonance imaging (MRI) findings. Cerebellar hypoperfusion was constant in ADCA I and frequent in patients with other spinocerebellar degenerations. Brain stem hypoperfusion was constant in ADCA I, frequent in ILOCA patients with pontocerebellar atrophy and absent in FA and EOCA. FA and EOCA often showed a reduction in the parietotemporal cortex blood flow, which was not related to cortical atrophy. ILOCA patients had an asymmetric pattern in the temporal areas with decreased blood flow in the right side only. Caudate hypoperfusion was found in ADCA I patients. Cerebral atrophy did not account for changes in regional blood flow, which probably indicate early involvement of cerebral structures. Received: 26 August 1997 Received in revised form: 22 January 1998 Accepted: 27 January 1998     

血管性认知功能障碍脑血流灌注的临床研究

目的 探讨血管性认知功能障碍（vascular cognitive impairment,VCI）脑血流灌注的早期表现,分析局部脑血流量（regional cerebral blood flow,rCBF）的减低与认知受损领域的关系。方法 将入组患者按照认知受损程度分为：认知正常组、非痴呆血管性认知功能障碍（vascular cognitive impairment not dementia,VCIND）组及血管性痴呆（vascular dementia,VaD）组。分析比较三组患者不同区域rCBF的差异,及各区域rCBF与蒙特利尔认知评分（Montreal Cognitive Assessment,MoCA）相关性;分析比较血流灌注显像与形态学显像的差异;分析rCBF与各认知受损领域的关系。结果 三组患者左侧颞叶、左丘脑、左侧海马局部脑血流量差异有显著性（F=8.232、6.237、6.136;P=0.002、0.006、0.000）。左侧颞叶、丘脑及海马rCBF与MoCA评分具有相关性（P=0.011、0.023、0.029）且为正性相关（r=0.421、0.355、0.323）。SPECT检查下出现rCBF减低的平均区域数多于头部磁共振检查下出现梗死灶的平均区域数,但二者差异无显著性。左侧顶叶rCBF与计算力相关,且呈正相关性（Beta=0.445,P=0.020）;右侧海马、右侧颞叶与时间地点定向力相关,且为正相关（Beta=0.626、0.740;P=0.035、0.023）。结论 SPECT检查下显示rCBF的变化为VCI是以颞叶、海马、丘脑低血流代谢为主要表现提供了病理生理学依据。SPECT检查下显示rCBF的变化有早于脑组织结构检查下形态结构变化的趋势。     

Glucose metabolism in the caudate nuclei of patients with eating disorders,measured by PET

Summary Regional cerebral glucose metabolism was measured with¹⁸F-2-fluoro-2-deoxyglucose and positron emission tomography in nine patients with bulimia nervosa and in seven patients with anorexia nervosa. Relative caudate glucose metabolism (caudate glucose metabolism divided by global cerebral glucose metabolism) was significantly higher in anorexia nervosa than in bulimia nervosa, suggesting that caudate hyperactivity is characteristic of the anorexic state. Whether increased caudate function is a consequence of anorexic behaviour or whether it is directly involved in the pathogenesis of anorexia nervosa is an issue still to be clarified.