Response of regional cerebral blood flow and oxygen metabolism to thalamic stimulation in humans as revealed by positron emission tomography

To clarify functional neural pathways originating from the thalamic nucleus ventralis posterolateralis (VPL) in humans, the responses of regional CBF (rCBF) and regional CMRO2 (rCMRO2) to VPL stimulation were investigated by positron emission tomography in five patients who had undergone chronic implantation of electrodes into the VPL for therapeutic purposes. Measurement of rCBF and rCMRO2 under continuous inhalation of C15O2 and 15O2 by steady-state methods revealed significant increases of rCBF and rCMRO2 in the frontal, postcentral, and thalamic regions. The increases in rCBF and rCMRO2 of the postcentral regions were clearly predominant in the stimulated hemisphere insofar as the stimulation produced moderate paresthesia in restricted areas of the body. These results indicate that the VPL relays peripheral somatosensory information, which has previously been demonstrated to be transmitted to the frontal as well as postcentral regions.     

Changes in human regional cerebral blood flow and cerebral blood volume during visual stimulation measured by positron emission tomography.

The hemodynamic mechanism of increase in cerebral blood flow (CBF) during neural activation has not been elucidated in humans. In the current study, changes in both regional CBF and cerebral blood volume (CBV) during visual stimulation in humans were investigated. Cerebral blood flow and CBV were measured by positron emission tomography using H(2)(15)O and (11)CO, respectively, at rest and during 2-Hz and 8-Hz photic flicker stimulation in each of 10 subjects. Changes in CBF in the primary visual cortex were 16% +/- 16% and 68% +/- 20% for the visual stimulation of 2 Hz and 8 Hz, respectively. The changes in CBV were 10% +/- 13% and 21% +/- 5% for 2-Hz and 8-Hz stimulation, respectively. Significant differences between changes in CBF and CBV were observed for visual stimulation of 8 Hz. The relation between CBF and CBV values during rest and visual stimulation was CBV = 0.88CBF(0.30). This indicates that when the increase in CBF during neural activation is great, that increase is caused primarily by the increase in vascular blood velocity rather than by the increase in CBV. This observation is consistent with reported findings obtained during hypercapnia.     

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.     

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.     

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.     

Brain regions involved in prospective memory as determined by positron emission tomography

Prospective memory (PM) refers to the functions that enables a person to carry out an intended act after a delay. Despite the ubiquity of this behaviour, little is known about the supporting brain structures and the roles that they play. In this study, eight healthy participants performed four different PM tasks, each under three conditions: a baseline, and two conditions involving an intention. In the first of the intention conditions, subjects were asked to make a novel response to a certain class of stimuli whilst performing an attention-demanding task. However, the expected stimuli never actually occurred. In the second intention condition subjects were expecting to see these stimuli as before, and they did occur on approximately 20% of trials. Relative to the baseline condition, increases in regional cerebral blood flow (rCBF) as estimated by oxygen-15 positron emission tomography technique across all four tasks were seen in the frontal pole (Brodmann's area 10) bilaterally, right lateral prefrontal and inferior parietal regions plus the precuneus when subjects were expecting a PM stimulus regardless of whether it actually occurred. Further activation was seen in the thalamus when the PM stimuli occurred and was acted upon, with a corresponding rCBF decrease in right lateral prefrontal cortex. It is argued that the first set of region play a role in the maintenance of an intention, with the second set involved additionally in its realisation.     

Effect of adenosine on human cerebral blood flow as determined by positron emission tomography

The effect of intravenous infusion of adenosine on CBF was studied in seven patients with cerebral arteriovenous malformation. The patients were examined with positron emission tomography with controlled ventilation using [15O] water and [11C] fluoromethane as tracers. Total and regional CBF were determined before and during infusion of adenosine at rates producing a reduction of the MABP by approximately 10-40%. Six patients were normoventilated, and one was hyperventilated. Mean CBF in areas with normal brain tissue was 54 ml/100 g/min before adenosine infusion under normoventilation. Adenosine infusion increased mean CBF with 23-85%. Mean CVR was decreased with 43-65% and exceeded the percentage reduction of MABP in all normoventilated subjects. In the hyperventilated patient, the reduction of CVR was similar to the reduction of MABP, and CBF was unaffected, except for the 30% increase in the thalamus. It is concluded that intravenous administration of adenosine produces marked cerebral vasodilation in normoventilated subjects and that this response can be counteracted by hyperventilation.     

Vibratory stimulation increases and decreases the regional cerebral blood flow and oxidative metabolism: a positron emission tomography (PET) study

The aim of this study was to examine the hypothesis, if the activation of some cerebral structures due to physiological stimulation is accompanied by deactivations of other structures elsewhere in the brain. A vibratory stimulus was applied to the right hand palm of healthy volunteers and the regional cerebral blood flow (rCBF) and regional cerebral oxygen metabolism (rCMRO2) were measured with positron emission tomography (PET). Regional analysis and voxel-by-voxel plots indicated that the stimulation induced increases and decreases of the rCBF were coupled to increases and decreases of the rCMRO2. The increases were localized in the left primary somatosensory area (SI), the left secondary somatosensory area (SII), the left retroinsular field (RI), the left anterior parietal cortex, the left primary motor area (MI), and the left supplementary motor area (SMA). The decreases occurred bilaterally in the superior parietal cortex, in paralimbic association areas, and the left globus pallidus. The increases and decreases of the rCBF and rCMRO2 were balanced in such a way that the mean global CBF and CMRO2 did not change compared with rest. We conclude that the decreases of the cerebral oxidative metabolism indicated regional depressions of synaptic activity.     

Effects of acetazolamide on cerebral blood flow, blood volume, and oxygen metabolism: a positron emission tomography study with healthy volunteers.

To evaluate changes in cerebral hemodynamics and metabolism induced by acetazolamide in healthy subjects, positron emission tomography studies for measurement of cerebral perfusion and oxygen consumption were performed. Sixteen healthy volunteers underwent positron emission tomography studies with 15O-gas and water before and after intravenous administration of acetazolamide. Dynamic positron emission tomography data were acquired after bolus injection of H2[15O] and bolus inhalation of 15O2. Cerebral blood flow, metabolic rate of oxygen, and arterial-to-capillary blood volume images were calculated using the three-weighted integral method. The images of cerebral blood volume were calculated using the bolus inhalation technique of C[15O]. The scans for cerebral blood flow and volume and metabolic rate of oxygen after acetazolamide challenge were performed at 10, 20, and 30 minutes after drug injection. The parametric images obtained under the two conditions at baseline and after acetazolamide administration were compared. The global and regional values for cerebral blood flow and volume and arterial-to-capillary blood volume increased significantly after acetazolamide administration compared with the baseline condition, whereas no difference in metabolic rate of oxygen was observed. Acetazolamide-induced increases in both blood flow and volume in the normal brain occurred as a vasodilatory reaction of functioning vessels. The increase in arterial-to-capillary blood volume made the major contribution to the cerebral blood volume increase, indicating that the raise in cerebral blood flow during the acetazolamide challenge is closely related to arterial-to-capillary vasomotor responsiveness.     

Normal distribution of regional cerebral blood flow measured by dynamic single-photon emission tomography

Regional CBF (rCBF) was measured quantitatively using the inert-gas washout technique with xenon-133 and single-photon emission computed tomography. Tomographic data were reconstructed by filtered back projection, and flow was calculated according to the double-integral method. Ninety-seven subjects ranging in age from 20 to 59 years received a single examination; eight of these received a second examination within 1 h of the first; seven others received a second examination separated from the first by 1-10 days. Transverse-section images were obtained at 2, 6, and 10 cm above and parallel to the canthomeatal line (CML). Cortical gray matter flows were obtained from 12 brain regions in the slice 6 cm above the CML, and cerebellar and inferior cerebral gray matter flows were obtained from 4 regions in the slice 2 cm above the CML. Mean gray matter flow was 72 +/- 12 ml/min/100 g, with highest flows in the parietal lobes and visual cortex. No significant differences in rCBF occurred when a second study followed the first by 30 min to 10 days. Right-sided rCBF was slightly higher than left in all regions except frontal and parietal lobes where there was no difference. Flow was higher in women than in men and declined mildly with age for both sexes (slope = -0.33 ml/min/100 g/year; p less than 0.05).     

Increased prefrontal cerebral blood flow in first-episode schizophrenia following treatment: longitudinal positron emission tomography study

OBJECTIVE: Cognitive deficits, particularly those related to executive function and behavioural control, are a core feature of patients with schizophrenia and implicate disturbances of the prefrontal cortex (PFC). Consistent with this, functional imaging studies have identified abnormalities of PFC activity in chronically affected patients. The objective of the current study was to investigate executive-control related neural activity from first onset of the illness through to symptom stabilization. METHOD: The authors examined eight neuroleptic-na?ve first-episode psychosis (FEP) patients within 3 days of first presentation and eight healthy age- premorbid-IQ, and gender-matched controls (CTL). All FEP patients were later confirmed with a diagnosis of schizophrenia. Subjects underwent H2-15O positron emission tomography (PET) while performing the Stroop interference task that has previously been shown to engage the PFC in healthy samples. In a double-blind paradigm, FEP patients were randomly treated with either haloperidol or risperidone for 8 weeks, after which CTLs and all but one of the FEP patients were re-scanned. RESULTS: Behaviorally, there was no change in task performance from baseline to follow up for either the FEPs or CTLs. However, there were significant changes in functional activation in both groups across the same period. For CTLs, task-performance was associated with greater recruitment of posterior brain regions at follow up compared to baseline, while for FEP this involved greater recruitment frontal regions. Concurrently, FEP also showed significant improvement in positive symptomatology. CONCLUSIONS: These findings suggest that disturbances of the PFC often seen in FEP may be, at least partially, associated with acute symptom expression. However, it is still unclear whether this increase in frontal activity is due to symptom stabilization per se, the effects of medication, a lack of neurophysiological 'learning' with experience/practice, or a combination of these factors. In the context of the CTLs performance, we interpret the patient findings as reflective of greater neurophysiological effort required for task accomplishment relative to the learned, more automated, processing apparent in the CTLs.     

Verbal and spatial working memory in older individuals: A positron emission tomography study

Recent reviews of a substantial number of studies have partially resolved questions concerning the brain regions used by working memory for manipulation and representation. We report a large single experiment in middle-aged to older adults (n = 89), classified by hypertensive status. Our design addresses the question of regions related to manipulation and representation, most particularly comparing spatial and verbal working memory. A control, memory search, and 2-back running memory task were performed with identical stimuli and responses during whole-brain 15O water positron emission tomography (PET) scans. Letter or spatial position instructions created verbal or spatial working memory versions of the tasks. We assessed agreement with the literature using regions of interest that were defined by clusters of activation empirically derived from the literature by Wager and Smith (Wager, T.D. and Smith, E.E., Neuroimaging studies of working memory: a meta-analysis, Cognitive, Affective and Behavioral Neuroscience, 3 (2003) 255-274). Our results largely confirmed conclusions from the review on the organization of working memory into dorsal prefrontal manipulation and ventrolateral prefrontal maintenance areas and representation in dorsal and ventral paths. Specific verbal versus spatial comparisons were also concordant with prior work establishing posterior lateralized representation for different contents by working memory. The similarity of results between this older sample and results derived by others from younger participants is notable.     

Effect of gender on glucose utilization rates in healthy humans: a positron emission tomography study

Positron emission tomography (PET) was used with 18fluorodeoxyglucose to see if gender differences in resting cerebral glucose utilization could be detected. Thirty-two healthy subjects (15 women and 17 men; age range: 21-38 yr) were examined using a high-resolution PET scanner to determine the regional cerebral metabolic rate for glucose (CMRglc) in 65 gray matter regions of interest. Whole brain CMRglc did not differ significantly between the two genders, nor did any of the regional CMRglc values. Only 1 of 65 ratios of regional-to-whole brain CMRglc differed significantly between men and women, which is consistent with chance. These results indicate that there are no differences in resting regional cerebral glucose utilization between young men and women.     

Interdependence of regional and global cerebral blood flow during visual stimulation: an O-15-butanol positron emission tomography study.

The authors investigated the influence of variations in global cerebral blood flow (gCBF) on regional flow changes during visual stimulation. Global flow was varied using different end-expiratory CO2 values (PETCO2) between 20 and 70 mm Hg. Visual stimulation was performed with a red LED-array flashing at 8 Hz. Blood flow was measured with 0-15-butanol, continuous arterial blood sampling, and positron emission tomography (PET). Global flow changes surpassed the published values of O-15-H2O studies, better fitting the results of the inert gas technique (gCBF at 20, 40, and 70 mm Hg PETCO2 +/- SD was 31 +/- 4, 48 +/- 13, and 160 +/- 50 mL 100 g(-1) min(-1), respectively). The relation between PETCO2 and CBF in the current study was best described by an exponential rather than a linear function. At low PETCO2, the activation-induced flow changes are moderately damped, whereas at high PETCO2, they are nearly lost (deltaCBF (+/-SD): 52% +/- 25%, 68% +/- 22%, 16% +/- 25% at PETCO2 = 20, 40, 70 mm Hg, respectively).     

Regional cerebral blood flow and episodic memory in Parkinson's disease: a single photon emission tomography study

In this paper we examined 46 nondemented Parkinson's disease (PD) patients by means of perfusion single photon emission computed tomography (SPECT) and neuropsychological testing. The aim was to detect correlations of regional cerebral blood flow with episodic memory performance, using an operator-independent technique for the analysis of SPECT data. A significant positive correlation was found between prefrontal blood flow and episodic memory performances. However, age was the most important determinant of memory scores. Age also correlated significantly negatively with prefrontal perfusion. Our methodology also allowed detection of an inverse correlation of left medial temporal lobe perfusion with the memory score. This had not been found in previous studies and might indicate compensatory mechanisms in the brain of PD patients. It is concluded that episodic memory in nondemented PD patients is most dependent on the effects of aging and that the aging effects on cerebral perfusion in the PD brain parallel to a large extent the findings in normal controls.     

Changes in human cerebral blood flow and cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography.

Hypercapnia induces cerebral vasodilation and increases cerebral blood flow (CBF), and hypocapnia induces cerebral vasoconstriction and decreases CBF. The relation between changes in CBF and cerebral blood volume (CBV) during hypercapnia and hypocapnia in humans, however, is not clear. Both CBF and CBV were measured at rest and during hypercapnia and hypocapnia in nine healthy subjects by positron emission tomography. The vascular responses to hypercapnia in terms of CBF and CBV were 6.0 +/- 2.6%/mm Hg and 1.8 +/- 1.3%/mm Hg, respectively, and those to hypocapnia were -3.5 +/- 0.6%/mm Hg and -1.3 +/- 1.0%/mm Hg, respectively. The relation between CBF and CBV was CBV = 1.09 CBF0.29. The increase in CBF was greater than that in CBV during hypercapnia, indicating an increase in vascular blood velocity. The degree of decrease in CBF during hypocapnia was greater than that in CBV, indicating a decrease in vascular blood velocity. The relation between changes in CBF and CBV during hypercapnia was similar to that during neural activation; however, the relation during hypocapnia was different from that during neural deactivation observed in crossed cerebellar diaschisis. This suggests that augmentation of CBF and CBV might be governed by a similar microcirculatory mechanism between neural activation and hypercapnia, but diminution of CBF and CBV might be governed by a different mechanism between neural deactivation and hypocapnia.     

Brief report: Attention performance in autism and regional brain metabolic rate assessed by positron emission tomography

The Stallone Foundation and the MacArthur Foundation provided partial support for this research. Andrew Russell, Linda Bott, and Cathy Sammons did the diagnostic interviews.     

Regional cerebral blood flow and metabolism in patients with transient global amnesia: a positron emission tomography study.

In four patients who experienced transient global amnesia (TGA), clinical features and neuroradiological findings including positron emission tomography (PET) were studied within three months of the episodes, and compared with those in seven cases with cerebral transient ischaemic attacks (TIA). None of TGA patients had a previous history or significant risk factors for the cerebrovascular diseases. Their electroencephalogram, brain CT and angiogram for the head and neck were almost normal. PET study showed better preserved cerebral blood flow and oxygen metabolism in each area of the brain in patients with TGA compared with those with TIA in whom focal reductions of flow and metabolism were evident. These observations suggest that TGA is caused by reversible circulatory and/or metabolic disturbance, of which mechanism might be different from that in TIA.     

Relationship between clock drawing test performance and regional cerebral blood flow in Alzheimer's disease: a single photon emission computed tomography study

The clock drawing test (CDT) is a useful tool for screening cognitive impairment. Previous neuropsychological studies have revealed that CDT performance requires several cognitive functions including semantic memory, visuospatial function and executive function. However, the neural substrates involved remain to be elucidated. The aim of the present study was to identify the brain regions responsible for CDT performance in patients with Alzheimer's disease (AD). Twenty-six patients satisfying the National Institute of Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD underwent the CDT and the Mini-Mental State Examination (MMSE), together with a N-isopropyl-p-[123I] iodoamphetamine (IMP) single photon emission computed tomography measurements of the resting regional cerebral blood flow (rCBF). The CDT score correlated significantly with the MMSE score (r=0.582; P < 0.05). Stepwise multiple regression analysis revealed that the MMSE score and the left posterior temporal rCBF were major predictors of CDT score. These findings suggest that the CDT score may reflect the severity of dementia, and that it has a close relationship with the left posterior temporal function. Our findings provide the first functional neuroimaging evidence for the neural substrates involved in CDT performance.