The effect of sequential lesioning in the basal forebrain on cerebral cortical glucose metabolism in rats. An animal positron emission tomography study

We studied the effect of the cortical projection from the basal forebrain on the cerebral cortical metabolism using positron emission tomography (PET) with [¹⁸F] fluorodeoxyglucose. Unilateral damage of the nucleus basalis magnocellularis (NBM) did not cause a permanent reduction of cortical metabolism: recovery was observed 4 weeks after the operation. Destruction of the contralateral side after recovery from unilateral damage produced persistent bilateral suppression of glucose metabolism, with partial recovery. We speculate that recovery from the unilateral NBM lesions is partly ascribable to the cholinergic projection from the contralateral NBM, and partly due to non-cholinergic systems, and conclude that bilateral damage might be responsible for persistent cortical glucose metabolism suppression.     

Docosahexaenoic acid (DHA) improves the age-related impairment of the coupling mechanism between neuronal activation and functional cerebral blood flow response: a PET study in conscious monkeys

The regional cerebral blood flow (rCBF) response to vibrotactile stimulation was compared in conscious young (5.9+/-1.8 years old) and aged (18.0+/-3.3 years old) monkeys using [15O]H(2)O and high-resolution positron emission tomography (PET). In addition, the effects of docosahexaenoic acid (DAH), an n-3 polyunsaturated fatty acid (PUFA), on the rCBF response to stimulation were evaluated in aged monkeys. Soybean milk (SBM) or DHA-containing SBM (DHA/SBM) was supplied to aged monkeys for 1 and 4 weeks. Under control conditions, vibrotactile stimulation elicited an increase in the rCBF response in the contralateral somatosensory cortices of both young and aged monkeys, but the degree of increase in the rCBF response was significantly lower in aged monkeys (116% of corresponding 'rest' condition) than that in young animals (141%). The regional cerebral metabolic rate of glucose (rCMRglc) response to the stimulation, an index of neuronal activation, was not significantly different between young and aged monkeys as measured by [18F]-2-fluoro-2-deoxy-D-glucose (FDG). Supply of DHA/SBM at a dose of 150 mg/kg/day as DHA for 1 week resulted in a significant increase in rCBF response to stimulation (127%) in aged monkeys, and 4-week supply of DHA induced further facilitation of the rCBF response (133%). In contrast, the reduced rCBF response in the aged monkeys was not affected by SBM alone for either 1 or 4 weeks. The neuronal activation itself elicited by the stimulation, as measured by [18F]FDG, was not affected by SBM or DHA/SBM. These results suggested the involvement of DHA in the coupling mechanism between the neuronal activation and rCBF response, possibly by modulation of cholinergic neuronal transmission.     

Serotonin, cerebral blood flow, and cerebral metabolic rate in geriatric major depression and normal aging

While there is substantial evidence for abnormalities in serotonin (5-HT) neurotransmission in major depressive disorder (MDD), almost all of the findings derive from studies of young adults. Moreover, relatively little research has assessed brain 5-HT transmission in vivo. Neuroendocrine studies do not permit evaluation of a range of brain regions, but only the limited circuitry associated with hormone release. Data from autopsy studies are limited by the difficulties of assessment of the acute clinical picture before death, and by post-mortem artifacts. In vivo neuroimaging techniques overcome many of the methodological limitations of both these approaches. There is a large body of imaging data indicating regional cerebral blood flow (rCBF) and cerebral metabolic rate (rCMR) decrements both with aging and in patients with MDD. While the physiological bases for these phenomena are largely unknown, changes in brain 5-HT function may be involved. Neuroanatomical studies have revealed an intricate network of 5-HT-containing neurons within the cerebral microvasculature, with physiological evidence for serotonergic control of both rCBF and rCMR. Acute pharmacological challenges are available to probe brain 5-HT function. Such paradigms, using neuroendocrine responses as endpoints, have been of some utility in predicting outcome with antidepressant treatment. The role of 5-HT dysregulation in geriatric MDD takes on more importance given concerns regarding putative reduced efficacy of serotonin-specific reuptake inhibitors (SSRIs) in this population. If this is due to diminished responsivity of 5-HT systems, then the ability to identify antidepressant nonresponders via 5-HT challenge in combination with neuroimaging measures may have important clinical utility.     

Interregional correlations of resting cerebral glucose metabolism in old and young women

A correlational analysis of normalized (regional to whole-brain) regional cerebral metabolic rates for glucose obtained in the 'resting' state (eyes covered, ears plugged) using [18F]fluorodeoxyglucose, demonstrated differences between old and young women in patterns of functional associations. Fifteen healthy young (age less than 40 years) and 17 healthy old women (age greater than 64 years) were scanned with a Scanditronix PC1024-7B tomograph. The brain was divided into 65 regions of interest. The old women had fewer and less positive correlations between pairs of metabolic ratios in the frontal and parietal cortices. The results suggest an age-related reduction in frontal and parietal functional interactions in the 'resting' state that is consistent with a prior correlation analysis using a low resolution ECAT II scanner on young and old men. Reduced functional interactions may reflect age-related cognitive changes.     

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.     

Age-related changes in muscarinic cholinergic receptors in the living brain: a PET study using N-[C]methyl-4-piperidyl benzilate combined with cerebral blood flow measurement in conscious monkeys

The effects of changes in regional cerebral blood flow (rCBF) with aging on muscarinic cholinergic receptor binding were evaluated with [¹⁵O]H₂O and N-[¹¹C]methyl-4-piperidyl benzilate (4-MPB) in the living brains of young (5.9±1.8 years old) and aged (19.0±3.3 years old) monkeys (Macaca mulatta) in the conscious state using high-resolution positron emission tomography (PET). For quantitative analysis of receptor binding in vivo with [¹¹C]4-MPB, metabolite-corrected arterial plasma radioactivity curves were obtained as an input function into the brain, and graphical Patlak plot analysis was applied. In addition, two-compartment model analysis using the radioactivity curve in the cerebellum as an input function (reference analysis) was also applied to determine the distribution volume (DV=K₁/k₂′) for [¹¹C]4-MPB. With metabolite-corrected arterial input, Patlak plot analysis of [¹¹C]4-MPB indicated a regionally specific decrease in muscarinic cholinergic receptor binding in vivo in the frontal and temporal cortices as well as the striatum in aged compared with young animals, showing no correlation with the degree of reduced rCBF. In contrast, on the reference analysis with cerebellar input of [¹¹C]4-MPB, all regions assayed except the pons showed a significant age-related decrease of DV, and the degree of reduction of DV was correlated with that of rCBF. These results demonstrated the usefulness of kinetic analysis of [¹¹C]4-MPB with metabolite-corrected arterial input, not with reference region’s input, as an indicator of the aging process of cortical muscarinic cholinergic receptors in vivo measured by PET with less blood flow dependency.     

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.     

Age-related impairment of coupling mechanism between neuronal activation and functional cerebral blood flow response was restored by cholinesterase inhibition: PET study with microdialysis in the awake monkey brain

The effects of three cholinesterase inhibitors (physostigmine, E2020, and Tacrine), all of which are to be cognitive enhancers, on the functional regional cerebral blood flow (rCBF) response were studied in young (5.9+/-1.8 years old) and aged (18.0+/-3.3 years old) monkeys under awake conditions using high-resolution positron emission tomography (PET). Under control condition, vibrotactile stimulation elicited increases in the rCBF response in the contralateral somatosensory cortices of both young and aged monkeys, but the degree of increase in rCBF response was significantly lower in aged (115.8%) than that in young monkeys (139.9%). Regional cerebral metabolic rate of glucose (rCMRglc) response to the stimulation, measured using [18F]-2-fluoro-2-deoxy-Dphysostigmine) were consistent with the data obtained by microdialysis. In contrast, the cognitive enhancers did not alter rCBF response to stimulation in young monkeys. The present results demonstrated that the functional change in rCBF response to the stimulation was induced during the aging process by impairment of the coupling mechanism between the neuronal activation and rCBF response. Furthermore, the observation that cognitive enhancers partly restored the functional rCBF response suggested that the coupling mechanism might be regulated via cholinergic neuronal transmission.     

Cerebral oxygen metabolism and cerebral blood flow in man during light sleep (stage 2)

We measured cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) during light sleep (stage 2) in 8 young healthy volunteers using the Kety-Schmidt technique with 133Xe as the inert gas. Measurements were performed during wakefulness and light sleep as verified by standard polysomnography. Unlike our previous study in man showing a highly significant 25% decrease in CMRO2 during deep sleep (stage 3-4) we found a modest but statistically significant decrease of 5% in CMRO2 during stage 2 sleep. Deep and light sleep are both characterized by an almost complete lack of mental activity. They differ in respect of arousal threshold as a stronger stimulus is required to awaken a subject from deep sleep as compared to light sleep. Our results suggest that during non-rapid eye movement sleep cerebral metabolism and thereby cerebral synaptic activity is correlated to cerebral readiness rather than to mental activity.     

Acute effect of glucose on cerebral blood flow,blood oxygenation,and oxidative metabolism

While it is known that specific nuclei of the brain, for example hypothalamus, contain glucose‐sensing neurons thus their activity is affected by blood glucose level, the effect of glucose modulation on whole‐brain metabolism is not completely understood. Several recent reports have elucidated the long‐term impact of caloric restriction on the brain, showing that animals under caloric restriction had enhanced rate of tricarboxylic acid cycle (TCA) cycle flux accompanied by extended life span. However, acute effect of postprandial blood glucose increase has not been addressed in detail, partly due to a scarcity and complexity of measurement techniques. In this study, using a recently developed noninvasive MR technique, we measured dynamic changes in global cerebral metabolic rate of O₂ (CMRO₂) following a 50 g glucose ingestion (N = 10). A time dependent decrease in CMRO₂ was observed, which was accompanied by a reduction in oxygen extraction fraction (OEF) with unaltered cerebral blood flow (CBF). At 40 min post‐ingestion, the amount of CMRO₂ reduction was 7.8 ± 1.6%. A control study without glucose ingestion was performed (N = 10), which revealed no changes in CMRO₂, CBF, or OEF, suggesting that the observations in the glucose study was not due to subject drowsiness or fatigue after staying inside the scanner. These findings suggest that ingestion of glucose may alter the rate of cerebral metabolism of oxygen in an acute setting. Hum Brain Mapp 36:707–716, 2015. © 2014 Wiley Periodicals, Inc .     

Local blood flow and glucose consumption in the rat brain during sustained bicuculline-induced seizures

The present study addresses the problem of whether brain structures which have been shown to develop neuronal cell damage in recurrent or prolonged epileptic seizures have higher metabolic rates and/or less pronounced increases in blood flow rates than others during sustained seizures. To that end, local cerebral blood flow (CBF) and glucose utilization (CMRgl) were measured autoradiographically in ventilated rats, in which seizures of 20, 60, or 120 min duration were induced by i.v. bicuculline.
After 20 and 60 min of seizure activity, local CBF increased 2- to 4-fold in most of the 21 structures analysed. However, there was a marked heterogeneity with CBF values varying between 150% (caudoputamen) and 500% (globus pallidus) of control. After 120 min, CBF in several structures, notably cortical and limbic regions, fell in spite of unchanged blood pressure and continued seizure activity.
Changes in local CMR_gl were equally heterogenous, and correlated poorly with blood flow rates. Some structures (the cerebral cortices and 3 limbic areas) showed a sustained 2-4 fold increase in CMR_gl. In these, metabolic rate and blood flow wereinititially matched but CBF subsequently fell to yield a pattern of relative hypoperfusion. Other structures showed no, or only modrate, increases in CMR_gl. In spite of this, CBF increased markedly to yield a pattern of relative hyperemia. It is concluded that bicucullineinduced seizures represent a condition in which structures, observed to be prone to develop cell damage, show grossly enhanced metabolic rate and develop relative underperfusion. Furthermore, the results suggest that structures with a large increase of the metabolic rate during seizures, develop a striking mismatch between local metabolic rate and blood flow.     

Caffeine-induced cerebral blood flow changes in schizophrenia

Summary Cerebral blood flow (CBF) measurements and mental status examinations were performed before and 30 min after oral administration of 250 mg of caffeine or a placebo given under double-blind conditions, in two groups of patients with schizophrenia. Caffeine produced significant CBF reductions but no changes in the patient's clinical condition.     

Comparative analysis of regional brain blood flow and glucose metabolism in focal cerebrovascular disease measured by dynamic positron emission tomography of fluorine-18-labelled tracers

Summary Regional cerebral blood flow (rCBF) and glucose metabolism (rCMRglc) were measured in 44 patients with various kinds of focal vascular brain lesions, using multislice positron emission tomography (PET). Haemodynamic data were obtained by a recently developed, non-invasive clearance method utilizing (¹⁸F)-methyl fluoride as a diffusible, gaseous indicator. Shortly after completion of each flow study, rCMRglc was dynamically determined by standard procedures using 2(¹⁸F)-fluorodeoxyglucose. While blood flow and glucose consumption in the structurally damaged area were often uncoupled during the acute phase, metabolism-to-flow ratios were markedly less scattered at later stages of cerebrovascular disease. Individual maximum-likelihood cluster analysis of brain regions revealed remarkable similarity between deactivation patterns of rCBF and rCMRglc, with Tanimoto coefficients averaging 0.56. This similarity was inversely related to the residual rCMRglc of the lesion. These findings are in line with results obtained by PET of other tracers, suggesting that the pair of methods provides valuable and somewhat complementary information on brain function and mechanisms of cerebral vascular disease.     

Effects of 6-month at-home transcranial direct current stimulation on cognition and cerebral glucose metabolism in Alzheimer's disease

BackgroundAlthough single or multiple sessions of transcranial direct current stimulation (tDCS) on the prefrontal cortex over a few weeks improved cognition in patients with Alzheimer's disease (AD), effects of repeated tDCS over longer period and underlying neural correlates remain to be elucidated.ObjectiveThis study investigated changes in cognitive performances and regional cerebral metabolic rate for glucose (rCMRglc) after administration of prefrontal tDCS over 6 months in early AD patients.MethodsPatients with early AD were randomized to receive either active (n = 11) or sham tDCS (n = 7) over the dorsolateral prefrontal cortex (DLPFC) at home every day for 6 months (anode F3/cathode F4, 2 mA for 30 min). All patients underwent neuropsychological tests and brain ¹⁸F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) scans at baseline and 6-month follow-up. Changes in cognitive performances and rCMRglc were compared between the two groups.ResultsCompared to sham tDCS, active tDCS improved global cognition measured with Mini-Mental State Examination (p for interaction = 0.02) and language function assessed by Boston Naming Test (p for interaction = 0.04), but not delayed recall performance. In addition, active tDCS prevented decreases in executive function at a marginal level (p for interaction < 0.10). rCMRglc in the left middle/inferior temporal gyrus was preserved in the active group, but decreased in the sham group (p for interaction < 0.001).ConclusionsDaily tDCS over the DLPFC for 6 months may improve or stabilize cognition and rCMRglc in AD patients, suggesting the therapeutic potential of repeated at-home tDCS.     

年龄、性别、糖尿病史对脑葡萄糖标准化摄取最大值和标准化代谢率的影响

目的 研究年龄、性别、糖尿病史对脑葡萄糖代谢标准化摄取最大值(SUVmax)及标准化代谢率(SCMR)的影响. 方法 选取自2006年5月至2010年11月在南京军区南京总医院核医学科行PET-CT脑代谢体检的健康志愿者79例,采用感兴趣区法分别测量双侧大脑、小脑各13个感兴趣区(左右侧a1、a2、m1、m2、m3、m4、m5、m6、in、cs、p1、p2、ce)的SUVmax值,通过计算左侧感兴趣区SUVmax值/右侧相应感兴趣区SUVmax值得到SCMR值.对受检者进行分层分析,分为男性组(45例)和女性组(34例),＜40岁组(33例)、40～49岁组(21例)和≥50岁(25例),糖尿病组(26例)和非糖尿病组(53例),探讨不同年龄段、不同性别、有无糖尿病史对SUVmax值和SCMR值的影响. 结果 受检者左右侧间各相应感兴趣区的SUVmax值比较差异均无统计学意义(P＞0.05),左右侧半球中各感兴趣区间SUVmax值比较差异有统计学意义(左侧:F=14.280,P=0.000;右侧:F=14.680,P=0.000).女性左右侧m1感兴趣区的SUVmax值明显低于男性,差异有统计学意义(P＜0.05).不同年龄组间左右侧各感兴趣区的SUVmax值比较差异均有统计学意义(P＜0.05).糖尿病组左侧a1、右侧a1、左侧a2、右侧a2、右侧m2、左侧m3、左侧m4、右侧m4、左侧p1、右侧p1、左侧p2、右侧p2、左侧cs、右侧cs、左侧in、右侧in、左侧ce、右侧ce共18个感兴趣区的SUVmax值低于非糖尿病组,差异有统计学意义(P<0.05).但经标准化处理后,不同性别、不同年龄段、有无糖尿病组间各感兴趣区的SCMR值比较差异均无统计学意义(P＞0.05). 结论 SUVmax值受年龄、性别、糖尿病史等因素的影响,而应用SCMR值可以消除上述因素的影响,为不同研究或不同个体之间的比较提供一个可靠的研究指标.     

Dual role of cerebral blood flow in regional brain temperature control in the healthy newborn infant

Small shifts in brain temperature after hypoxia–ischaemia affect cell viability. The main determinants of brain temperature are cerebral metabolism, which contributes to local heat production, and brain perfusion, which removes heat. However, few studies have addressed the effect of cerebral metabolism and perfusion on regional brain temperature in human neonates because of the lack of non-invasive cot-side monitors. This study aimed (i) to determine non-invasive monitoring tools of cerebral metabolism and perfusion by combining near-infrared spectroscopy and echocardiography, and (ii) to investigate the dependence of brain temperature on cerebral metabolism and perfusion in unsedated newborn infants.Thirty-two healthy newborn infants were recruited. They were studied with cerebral near-infrared spectroscopy, echocardiography, and a zero-heat flux tissue thermometer. A surrogate of cerebral blood flow (CBF) was measured using superior vena cava flow adjusted for cerebral volume (rSVC flow). The tissue oxygenation index, fractional oxygen extraction (FOE), and the cerebral metabolic rate of oxygen relative to rSVC flow (CMRO₂ index) were also estimated.A greater rSVC flow was positively associated with higher brain temperatures, particularly for superficial structures. The CMRO₂ index and rSVC flow were positively coupled. However, brain temperature was independent of FOE and the CMRO₂ index. A cooler ambient temperature was associated with a greater temperature gradient between the scalp surface and the body core.Cerebral oxygen metabolism and perfusion were monitored in newborn infants without using tracers. In these healthy newborn infants, cerebral perfusion and ambient temperature were significant independent variables of brain temperature. CBF has primarily been associated with heat removal from the brain. However, our results suggest that CBF is likely to deliver heat specifically to the superficial brain. Further studies are required to assess the effect of cerebral metabolism and perfusion on regional brain temperature in low-cardiac output conditions, fever, and with therapeutic hypothermia.     

Resistance of brain glucose metabolism to thiopental-induced CNS depression in newborn piglets

The transition from mild sedation to deep anaesthesia is marked by the phenomenon of burst suppression (BS). FDG-PET studies show that the cerebral metabolic rate for glucose (CMRglc) declines dramatically with onset of BS in the adult brain. Global CMRglc increases substantially in the post-natal period and achieves its maximum in preadolescence. However, the impact of post-natal brain development on the vulnerability of CMRglc to the onset of BS has not been documented.     

Global reduction in cerebral blood flow and metabolism elicited from intrinsic neurons of fastigial nucleus

We sought to determine whether the global increase in regional cerebral blood flow (rCBF) produced by electrical stimulation of the rostral cerebellar fastigial nucleus (FN) is a consequence of excitation of intrinsic neurons of the FN or of axons of fibers passing through or projecting into it. Studies were conducted in rats anesthetized with chloralose, paralyzed and ventilated. rCBF was measured with [¹⁴C]iodoantipyrine as tracer and regional cerebral glucose utilization (rCGU) by [¹⁴C]2-deoxyglucose in homogenates of 11 brain regions. Neuronal perikarya in FN were excited chemically by local microinjection of the glutamate analogue kainic acid (KA) (5 nmol in 100 nl). KA elicited a transient and significant fall of arterial pressure and heart rate, the fastigial depressor response (FDR). Associated was a significant and symmetrical reduction in rCBF, to 44% of control in all regions except medulla. The response was site- and agent-specific and unrelated to the hypotension. KA also significantly and proportionally reduced, to 52% of control, rCGU in the same 10 areas of brain. In all regions the magnitudes of the reductions in rCBF and rCGU elicited by KA were linearly related. Intrinsic neurons of FN were chronically destroyed by local microinjection of the excitotoxin ibotenic acid (IBO) (10 μg/μl in 0.4 μl). Destruction of intrinsic FN neurons had no effect on resting rCBF nor on the global cerebrovascular vasodilation elicited by electrical stimulation of the FN. We conclude that: (a) excitation of intrinsic neurons of FN elicits a widespread reduction of cerebral metabolism and, secondarily, blood flow; (b) FN neurons do not exert a long-term tonic influence on brain blood flow nor metabolism; (c) the global increase in rCBF elicited by electrical stimulation of the FN is a consequence of excitation of axons projecting into or through the nucleus.     

增龄性脑血管相关改变对阿尔茨海默病模型小鼠SAMP8认知能力的影响

目的 探讨脑血流量、血脑屏障(BBB)通透性、脑葡萄糖跨膜转运蛋白表达情况随年龄增大对阿尔茨海默病(AD)模型小鼠SAMP8认知能力的影响. 方法 选择SAMP8小鼠及正常同源抗快速老化小鼠R1(SAMR1)各10只进行观察.采用Morris水迷宫测定小鼠的学习记忆能力,激光多普勒仪测定脑血流量,荧光分光光度计法测定BBB通透性,Western blotting测定葡萄糖转运蛋白(GLUT)1和3的表达. 结果 与SAMR1相比,SAMP8的认知能力早在4月龄时即已出现明显损伤,表现为思维僵化、学习过程减慢.随着年龄增大,SAMP8脑血流明显下降,BBB渗漏更为严重,皮层和海马的GLUT1和GLUT3表达也有不同程度地改变.脑血流、BBB完整性、GLUT1和GLUT3表达受年龄和品系影响明显,并与认知能力高度相关. 结论 衰老及缺血引起的血管损伤、能量供给不足是造成AD神经元功能异常及导致认知障碍的主要原因.