Regional Cerebral Glucose Utilization Research Articles

Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro-functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG). In this chapter, we summarize the results from PET, MRI, and MEG imaging. Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients. Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS. By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients.

Shuttling glucose across brain microvessels, with a little help from GLUT1 and AMP kinase. Focus on “AMP kinase regulation of sugar transport in brain capillary endothelial cells during acute metabolic stress”

The Blood-Brain Barrier: a Gatekeeper of Brain “Individuality” The blood-brain barrier (BBB) maintains the individuality of brain fluid, while allowing it to selectively import nutrients and process toxic products. Its major constituent is a single layer of continuous, nonfenestrated endothelium lining the microvessels, whose unique features account in large part for the integrity of the barrier. The endothelial cell monolayer is the major determinant, but other cells in the central nervous system (e.g., pericytes and astrocytes) contribute to the integrity of the BBB. The interendothelial tight junctions of the BBB are one of its signature elements that greatly restrict paracellular permeability to solutes, fluid, and transmigrating cells. This is markedly distinct from the leakier, discontinuous, and fenestrated endothelium of liver microvessels (sinusoids). For example, the tight junctions of the cerebral endothelium (pial vessels) confer an electrical resistance (1,300 ·cm 2 ) far higher than other endothelia (6). Therefore, communication between blood and the brain interstitial fluid requires individually tailored molecular mechanisms. Transcytosis is the movement of molecules through a cellular barrier. Whereas proteins can traverse through vesicular carrier processes that could carry solutes through fluid phase endocytosis, the brain microvasculature is uniquely poor in plasmalemmal and cytoplasmic caveolae (1). Instead, bidirectional passage of small molecules across the BBB is stringently regulated by numerous transporters and receptors. These typically work in tandem across the luminal and abluminal membranes of the endothelial cell.

Impact of L-DOPA treatment on regional cerebral blood flow and metabolism in the basal ganglia in a rat model of Parkinson's disease.

Large increases in regional cerebral blood flow (rCBF) have been measured in patients with Parkinson's disease (PD) following the administration of L-DOPA, but the underlying mechanisms have remained unknown. In this study, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions were used to compare patterns of rCBF and regional cerebral glucose utilisation (rCGU) in chronically L-DOPA-treated subjects following a final injection of L-DOPA or saline. The same animal model was used to the leakage of a blood-brain barrier (BBB) tracer molecule at 60 min vs. 24h following the last L-DOPA injection of a chronic treatment. All the parameters under investigation were examined with brain autoradiography following intravenous injections of specific radiotracers in awake animals ([14C]-iodoantipyrine for rCBF, [14C]-2-deoxyglucose for rCGU, and [14C]-α-aminoisobutyric acid for BBB leakage). Significant changes in rCBF and rCGU on the side ipsilateral to the 6-OHDA lesion relative to the non-lesioned side were seen at 60 min ("ON") but not 24h ("OFF") following L-DOPA administration. These changes were not seen in sham-operated rats. In the output nuclei of the basal ganglia (the entopeduncular nucleus and the substantia nigra pars reticulata) both rCBF and rCGU were elevated both in acutely L-DOPA-treated rats and chronically L-DOPA-treated rats displaying dyskinesia, but did not change significantly in chronically L-DOPA-treated non-dyskinetic cases. Acutely and chronically L-DOPA-treated rats with dyskinesia exhibited increases in rCBF "ON L-DOPA" also in the motor cortex, the striatum, and the globus pallidus, but the corresponding changes in rCGU did not show the same direction, magnitude, and/or relative group differences. The uptake of a BBB tracer (studied in the striatum and the substantia nigra reticulata in chronically L-DOPA treated rats) was significantly higher ON vs. OFF L-DOPA. The present results are the first to show that the administration of L-DOPA is followed by transient and robust increases in rCBF in the dopamine-denervated basal ganglia. This effect occurs already upon acute L-DOPA treatment and persists upon repeated drug administration in animals that develop dyskinesia. Increases in rCBF ON L-DOPA are not necessarily accompanied by enhanced glucose utilisation in the affected regions, pointing to altered mechanisms of neurovascular coupling. Finally, our results show that increases in rCBF ON L-DOPA may be accompanied by BBB hyperpermeability in the most affected regions.

The effect of solifenacin on cognitive function in stroke patients

but data are lacking on African Americans (AA). This pilot study will 1) determine whether AA with mild AD can be enrolled, randomized, retained and comply with a 6-month aerobic exercise-training; 2) evaluate the effects of aerobic-fitness on neurocognition using ADAS-Cog as the primary outcome measure; 3) secondarily compare changes in regional cerebral glucose utilization between exerciser and control groups; 4) explore the effects of APOE gene polymorphism on standardized aerobic exercise training-induced changes in neurocognition and on biomarkers; and 5) generate data needed to investigate mechanisms by which aerobic-fitness influence neurocognitive processes. Methods: After obtaining informed consent, participants are screened using pre-specified inclusion exclusion criteria, and a qualifying treadmill test to determine ability to exercise safely; followed by dietary stabilization. After randomizing volunteers into exercise intervention (n1⁄437) and control (n1⁄437) groups, baseline neuropsychological, brain imaging, and biomarker evaluations are performed. Following baseline VO2Max test, the intervention group undergoes supervised aerobic exercise-training 3-times/week, while the control group undergoes stretch-exercise 3-times/week. At the completion of 6-month exercise training, all baseline tests are repeated in both the intervention and control groups. Between groups analysis of the differences in neuropsychological, neuroimaging and biomarker outcomes are performed using appropriate multivariate methods.Results: Preliminarily, results from the first cohort baseline data will be presented. Conclusions: This study will form the basis for large scale clinicaltrials needed to establish the efficacy of the prescription of aerobic fitnesstraining for the prevention or attenuation of Alzheimer’s disease.

Acute challenge with d-fenfluramine decreases regional cerebral glucose utilization in Sham, but not in OBX, rats: An autoradiographic study

The olfactory bulbectomized (OBX) rat is an animal model of depression with neurochemical, neuroendocrinological and behavioral features resembling some human depression. d-Fenfluramine is a 5-HT releasing drug, frequently used in the study of the responsivity of the 5-HT system in subjects with psychiatric disorders, including depression. The aim of the study is to assess the influence of the serotonin-releaser, d-fenfluramine, in the OBX rat model of depression, as measured by the change in the regional cerebral glucose utilization rCGU) following d-fenfluramine injection. Male Sprague–Dawley rats (160–180 g) were used. The rats were divided into OBX and Sham groups. Two weeks following the olfactory bulbectomy or the sham surgery, six rats (randomly assigned) from each group received an i.p. injection of d-fenfluramine with a dose of 5 mg/kg or the same volume of saline. Twenty minutes later, the rCGU rates were measured using 2-[ 14C]deoxyglucose autoradiography. The general linear model statistical analysis has shown that the rCGU in the sham-operated rats treated with d-fenfluramine, compared to the sham-operated rats treated with saline, was lower in 14 (36%) out of 39 examined brain regions. There was no significant difference in the rCGU between the OBX rats treated with d-fenfluramine and OBX rats treated with saline. The results suggest the blunted capacity of the 5-HT system in OBX rats to respond to the challenge by the 5-HT releasing compound, d-fenfluramine. This resembles similar findings in clinical studies on depressed patients.

Chronic therapy with citalopram decreases regional cerebral glucose utilization in OBX, and not sham-operated, rats: an autoradiographic study

Chronic treatment with the selective serotonin reuptake inhibitor, citalopram, normalizes several behavioral and neurochemical abnormalities in the olfactory bulbectomized (OBX) rat model of depression. To assess the changes in regional cerebral glucose utilization (rCGU) following chronic treatment with citalopram in OBX and sham-operated rats. Male Sprague Dawley rats (160-190 g) were used. Two weeks following the surgeries, the rats were implanted with osmotic minipumps which delivered 10 mg/kg/day of citalopram (the sham-CTP and OBX-CTP groups) or saline (to the sham-SAL and OBX-SAL groups) for 2 weeks. Following the treatment, the rates of rCGU were determined in 43 brain regions using 2-[(14)C]deoxyglucose (2-[(14)C]DG) autoradiography. The general linear model statistical analysis revealed significantly lower rCGU in the OBX-SAL group compared to the sham-SAL group in the medial prefrontal cortex and the median forebrain bundle. The sham-CTP group had significantly lower rCGU relative to the sham-SAL group in the medial prefrontal cortex. The OBX-CTP group had significantly lower rCGU than the OBX-SAL group in the anterior olfactory nucleus, orbitofrontal cortex, frontal cortex, anterior cingulate cortex, visual cortex, and substantia nigra--pars reticulata. The rCGU in the OBX-CTP group was significantly lower than that in the sham-CTP group in the anterior olfactory nucleus, orbitofrontal cortex, visual cortex, and substantia nigra--pars reticulata. The results imply that chronic citalopram treatment, shown previously to result in behavioral normalization in OBX rats, establishes a new pattern of rCGU, rather than normalizing it to the pattern of the sham-CTP rats.

Biological substrates of schizophrenia.

Schizophrenia is increasingly believed to represent a group of organic disorders which primarily, although not exclusively, affect the central nervous system. Our purpose is to review a representative sample of twentieth-century literature which speaks to the biological substrates of the syndrome. Subjects reviewed include genetic and environmental contributions to the onset of illness, early and recent findings of gross structural anomalies, and apparent histopathological alterations in cerebral cortex, cerebellar vermis, limbic system, and brain stem, as well as problems of cerebral asymmetry. Data from a diverse group of electrophysiological studies reveal several promising correlates of these areas of investigation. Despite the inconsistent nature of the findings to date, several themes have begun to emerge, including patterns of hypofrontal/hyperparietal regional cerebral flow and glucose utilization, left hemispheric dysfunction, and deficits of interhemispheric information processing. The interpretation and significance of these emerging patterns remains unclear and must await more profound insights into the nature of normal and abnormal cerebral function.

Cerebral glucose metabolism in Parkinson's disease with dementia

To assess the regional cerebral glucose utilization and the imaging characteristic of Parkinson's disease with dementia (PDD) with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Questionnaire survey, mini-mental state examination (MMSE), physical examination, and FDG PET on brain at rest state were performed on 20 patients with PDD, 13 males and 7 females, aged (70 +/- 6), and sex- and age-matched 8 patients with non-demented PD, and 30 healthy parsons. Visual inspection and statistical parametric mapping (SPM) were used to investigate the regional cerebral metabolic rate of glucose (rCMRglc) and the distribution of the tracer. The MMSE score of the PDD group was (27.5 +/- 2.4), (10 - 24), significantly lower than those of the non-PDD group [(27.5 +/- 2.4) (22 - 30)] and control group [(27.9 +/- 2.2) (21 - 30)] (F = 60.31, P = 0.000). There were no significant differences in Hoehn-Yahr staging and disease courses between the two PD groups (P > 0.05). Visual inspection showed that there were no significant focal hypometabolic areas in the imaging of the non-demented PD patients, while compared to the controls, the rCMRglc levels of the PDD patients decreased in bilateral superior parietal lobules (BA 7), inferior parietal lobules (BA 40, 39), superior frontal gyri (BA 6), middle frontal gyri (BA 6, 8, 9), middle temporal gyri (BA 21), cuneate lobes (BA 17, 18, 19), cingulate cortices (BA 31), lingual gyri (BA 19) basal ganglia, and thalamus. According to the severity of memory impairment and the onset of hallucination, the subtype of PDD was classified into memory impairment dominant group (MD) and hallucination dominant group (HD). The rCMRglc of MD subgroup decreased significantly in the parietotemporal association cortex, especially in the precuneus lobe. The rCMRglc of the HD subgroup decreased significantly in the occipital cortex. There were no significant differences in MMSE score and Hoehn-Yahr staging between the MD and HD groups (both P > 0.05), while the age of the HD subgroup was significantly lower, and the disease duration of the HD subgroup was significantly longer than those toe MD group (both P < 0.05). (18)F-FDG/PET imaging is helpful to the diagnosis of PDD and may help investigate the potential pathophysiology of PDD.

Neural Response to Catecholamine Depletion in Unmedicated Subjects With Major Depressive Disorder in Remission and Healthy Subjects

The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD). To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD. Randomized, double-blind, placebo-controlled, crossover, single-site experimental trial. Psychiatric outpatient clinic. Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls. Induction of CD by oral administration of alpha-methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose. Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia). Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatal-pallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms. This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. It demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry.

Olfactory bulbectomy reduces cerebral glucose utilization: 2-[ 14C]deoxyglucose autoradiographic study

The olfactory bulbectomized (OBX) rat is an extensively investigated animal model of depression. In the present study the effects of olfactory bulbectomy in drug-naive adult male Sprague–Dawley rats (200–240 g) on global (gCGU) and regional cerebral glucose (rCGU) utilization was evaluated. Two weeks following surgery, the autoradiographic measurement of CGU using [ 14C]-2-deoxyglucose was employed. The levels of CGU in the OBX and sham-operated rats were compared in 40 brain regions. Statistical methods indicate significantly lower levels of global (overall) CGU in the OBX group than in the sham group. Discriminant analysis was done on the z-scores to remove animal to animal variability. The following thirteen regions were identified by the stepwise discriminant analysis of the z-scores as significantly contributing to the differences between the sham and OBX: amygdala, cingulate cortex, caudate putamen at the level of globus pallidus, caudate putamen-lateral part, dorsal subiculum, dorsal thalamus, hypothalamus, median raphe, somatosensory cortex, substantia nigra, ventral hippocampus, ventral tegmental area and the ventral thalamus. The pattern of changes in the rCGU following OBX does not completely correlate with the pattern of connectivity of the olfactory bulbs, however, many regions with direct connection to the olfactory bulbs (e.g., amygdala, hypothalamus, ventral hippocampus, and ventral tegmental area) were found to be important for differentiation. No left to right asymmetries in the rCGU were found. The data suggest that there are very important regional differences in glucose utilization between the OBX and sham operated rats, which points to the need to study antidepressants in an animal model of depression rather than in normal animals.

Evaluation of the effect of training using auditory stimulation on rhythmic movement in Parkinsonian patients—a combined motor and [ 18F]-FDG PET study

Introduction: A programme of rehabilitation using auditory cues has previously been shown to decrease movement variability in the gait of Parkinsonian patients. Objective and methods: We studied the temporal variability of finger-tapping and gait in 9 patients with Parkinson's disease (PD) before and after they undertook a physical rehabilitation programme. Positron Emission Tomography (PET) using 2-deoxy-2[ 18F]fluoro- d-glucose (FDG) was performed in these subjects to look for changes in metabolic brain activity after completion of the rehabilitation program. Results: The reduction of variability was seen not only in gait but also other repetitive movements such as finger tapping. Furthermore, here we show differences in resting regional cerebral glucose utilisation in these patients compared to healthy controls (significant hypometabolism— p<0.001—for the PD group in the right parietal and temporal lobes, left temporal and frontal lobes and a hypermetabolism in the left cerebellum) and specific changes following the improvements in repetitive movement abilities (significant metabolic increment— p<0.001—in the PD group in the right cerebellum and in the right parietal and temporal lobes). Conclusions: Although our study does not allow us to draw firm conclusions, it provides new information on the neural basis of auditory stimulation in PD. Our results extend those from previous studies to show improvement in the temporal variability of two types of rhythmic movements after participation by PD patients in a physical rehabilitation programme, along with changes in glucose uptake in several brain areas involved in sensorimotor processing.

Low-dose cholinesterase inhibitors do not induce delayed effects on cerebral blood flow and metabolism

The acetylcholinesterase (AChE) inhibitors sarin and pyridostigmine bromide (PB) have been proposed as causes of neurobehavioral dysfunction in Persian Gulf War veterans. To test possible delayed effects of these agents, we exposed rats to low (subsymptomatic) levels of sarin (0.5 LD 50 s.c. 3 times weekly) and/or PB (80 mg/L in drinking water) for 3 weeks. Controls received saline s.c. and tap water. At 2, 4 and 16 weeks after exposure, regional cerebral blood flow (rCBF) and glucose utilization (rCGU) were measured in conscious animals with the Iodo- 14C-antipyrine and 14C-2 deoxyglucose methods, respectively. Two weeks after exposure, PB+sarin caused significant rCBF elevations, but no changes in rCGU, in neocortex, with lesser effects on allocortex. Four weeks after exposure, the same general pattern was found with sarin. Only a few changes were found at 16 weeks post-treatment. The predominant effects of sarin or PB+sarin on rCBF at earlier times after treatment are consistent with the well known direct cerebral vascular effect of cholinergic agonists. The lack of changes in rCBF and rCGU observed at 16 weeks after treatment does not support the hypothesis that repeat exposure to low-dose cholinesterase inhibitors can generate permanent alterations in cerebral activity.

18F]FDG mouse brain PET imaging: absolute quantification of regional cerebral glucose utilization as compared with 2-[ 14C]DG autoradiography

The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR glc) in mice with 18FDG PET. To evaluate its use as a gold standard, rCMR glc was also measured simultaneously with the autoradiographic 2-[ 14C]DG method. Serial arterial samples were drawn over 45 min to determine plasma tracer time activities and glucose concentrations. Animals were euthanized at 45 min followed first by brain PET imaging for 15 min and then by brain 2-[ 14C]DG autoradiography. Average 18FDG rCMR glc values in the cerebral cortex were generally lower (by 8.3%), but strongly correlated with those of 2-[ 14C]DG ( r 2=0.95). The present PET imaging technique allows accurate absolute quantification of rCMR glc in mice within the limits of the resolution possible with PET.

Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness

Whereas converging lines of evidence suggest that anesthetic-induced unconsciousness may result from disruption of functional interactions within neural networks involving the thalamus and cerebral cortex, the effects anesthetics have on human thalamocortical connectivity remain unexamined with current neuroimaging techniques. To address this issue we retrospectively analyzed positron emission tomography data from 11 volunteers scanned for regional cerebral glucose utilization (rCMRglu) when awake and again during isoflurane- ( n = 6) or halothane- ( n = 5) induced unconsciousness using statistical parametric mapping (SPM99) and structural equation modeling. A main effect analysis, contrasting awake and unconscious metabolic activity, localized a discrete region of the left va/vl thalamus whose relative rCMRglu activity was significantly suppressed ( P < 0.05, corrected) during the unconscious state. To identify brain regions whose functional connectivity with this region of the thalamus was impaired during the unconscious state, a psychophysiological interaction analysis was performed. This analysis revealed effects predominantly in topographically related areas of the primary motor and supplementary motor association cortices. Structural equation modeling of a neuroanatomical network encompassing these empirically identified regions revealed significant state-related changes in effective connectivity (χ 2diff (6)-15.88; P < 0.05) which primarily involved impairment of thalamocortical and corticocortical projections during the unconscious state. These findings support the hypothesis that a mechanistic component underlying general-anesthetic-induced unconsciousness involves disruption of functional interactions within thalamocortical neural networks.

Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model.

1. Rat bilateral common carotid artery occlusion (BCAO) was used as a chronic cerebral hypoperfusion model. We observed autoradiographically the long-term changes in regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) after 2 days and 1, 4 and 8 weeks of BCAO and in controls. Regions evaluated included the cerebral cortex, white matter and basal ganglia. Pathological changes were also observed with Klüver-Barrera and haematoxylin-eosin staining. 2. After 2 days, rCBF was significantly reduced to 33-58% in the cortex, white matter and amygdala and similar reductions were observed after 1 week. 3. After 4 weeks, rCBF recovered; however, rCBF remained significantly reduced in the occipital cortex, white matter, globus pallidus and substantia nigra. 4. After 2 days, rCGU was mostly maintained but, after 1 week, rCGU was reduced significantly to 40-70% in the cortex, white matter, basal ganglia and thalamus. Four weeks later, these reductions were no longer seen. 5. Rarefaction of the white matter was observed from 1 week. 6. These results showed that the BCAO in rats is an appropriate model for chronic cerebral hypoperfusion and that uncoupling of rCBF and rCGU was observed from 2 days until 4 weeks in the white matter.

Fatigue in anesthesia: implications and strategies for patient and provider safety.

HEALTHCARE delivery takes place 24 h a day, 7 days a week, and is colloquially termed a “24/7” operation. Anesthesia providers are required to deliver critical around-the-clock care to a variety of patients. This parallels the situation in many other domains that provide such services, e.g., transportation, law enforcement, communications, fire fighting, technology, manufacturing, and the military. Even “convenience” industries (e.g., gas stations and grocery stores) now provide uninterrupted access. These continuous operational demands present unique physiologic challenges to the humans who are called on to provide safe operations within these systems. Human physiologic design dictates circadian patterns of alertness and performance and includes a vital need for sleep. Human requirements for sleep and a stable circadian clock can be, and often are, in direct opposition to the societal demand for continuous operations. Recently, patient safety has taken center stage in health care. The Institute of Medicine’s report “To Err Is Human: Building a Safer Health System,” revealed that medical errors contribute to many hospital deaths and serious adverse events. The response to this report was widespread and included the Quality Interagency Coordination Task Force’s response to the President of the United States, “Doing What Counts for Patient Safety: Federal Actions to Reduce Medical Errors and Their Impact.” 2 This report listed more than 100 action items to be undertaken by federal agencies to improve quality and reduce medical errors. One action promised by the Agency for Healthcare Research and Quality was “the development and dissemination of evidence-based, best safety practices to provider organizations.” In addition to the multiple recommendations to improve patient safety, the report from the Agency for Healthcare Research and Quality included a review chapter on sleep, fatigue,# and medical errors.** There is evidence that the issue of fatigue in health care is coming to prominence on a national level. In April 2001, Public Citizen (a consumer and health advocacy group) and a consortium of interested parties petitioned the Occupational Safety and Health Administration to implement new regulations on resident work hours (table 1). The primary intent of the regulations is to provide more humane working conditions, which the petitioners declare will result in a better standard of care for all patients. Also, the Patient and Physician Safety and Protection Act of 2001, which would limit resident physician work hours, was introduced in Congress. Recently, the Accreditation Council on Graduate Medical Education, the accrediting organization for residency training programs in the United States, has approved common program requirements for resident duty and rest hours that will take effect in July 2003.†† This article is accompanied by an Editorial View. Please see: Lydic R: Fact and fantasy about sleep and anesthesiology. ANESTHESIOLOGY 2002; 97:1050–1.

Persistent hypertension does not alter the cerebral blood flow and glucose utilization in young-adult Dahl salt-sensitive rats

The Dahl–Iwai salt-sensitive (DS) rat develops hypertension due to a high-salt diet without any structural alterations of the brain arteries and arterioles. We investigated the effect of persistent hypertension on the regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCGU) in the DS rats. The rats were fed either a high-salt diet (HSD; 8% NaCl, n=5) or a low-salt diet (LSD; 0.3% NaCl, n=6) from 8 to 16 weeks of age, and the HSD group developed hypertension lasting for 1 month. At 16 weeks of age, the rCBF was measured in the sensorimotor and visual cortices using the hydrogen clearance method, and the rCGU was measured in 26 different brain structures using the [ 14C]deoxyglucose method. The mean arterial pressure was significantly higher in the HSD group (168±7 mm Hg) than in the LSD group (139±3 mm Hg) ( P<0.01). The mean rCBF and the rCGU values tended to be lower in the HSD group than in the LSD group; however, there were no statistically significant differences except for the reduced rCGU value in the nucleus accumbens. These results suggest that hypertension itself does not alter either the rCBF or the rCGU in young-adult DS rats. This indicates that the functional/structural changes of the cerebral arteries and arterioles that are associated with hypertension appear to be responsible for altered rCBF and rCGU in other animal models of hypertension.

Regional cerebral glucose utilization in patients with a range of severities of unipolar depression

Background: Patients with unipolar depression are most often reported to have decreased regional cerebral glucose metabolism (rCMRglu) in dorsal prefrontal and anterior cingulate cortices compared with healthy control subjects, often correlating inversely with severity of depression. Methods: We measured rCMRglu with fluorine-18 deoxyglucose positron emission tomography (PET) in 38 medication-free patients with unipolar depression and 37 healthy control subjects performing an auditory continuous performance task to further investigate potential prefrontal and anterior paralimbic rCMRglu abnormalities in patients attending to this task. Results: Compared with control subjects, the subgroup of patients with Hamilton depression scores of 22 or greater demonstrated decreased absolute rCMRglu in right prefrontal cortex and paralimbic/amygdala regions as well as bilaterally in the insula and temporoparietal cortex (right > left); they also exhibited increased normalized metabolic activity bilaterally in the cerebellum, lingula/cuneus, and brain stem. Severity of depression negatively correlated with absolute rCMRglu in almost the entire extent of the right cingulate cortex as well as bilaterally in prefrontal cortex, insula, basal ganglia, and temporoparietal cortex (right > left). Conclusions: Areas of frontal, cingulate, insula, and temporal cortex appear hypometabolic in association with different components of the severity and course of illness in treatment-resistant unipolar depression.

Networks mediating the clinical effects of pallidal brain stimulation for Parkinson's disease: a PET study of resting-state glucose metabolism.

Employing [(18)F]fluorodeoxyglucose (FDG) and PET, we have found previously that stereotaxic ablation of the internal globus pallidus (GPi) for Parkinson's disease causes resting metabolic changes in brain regions remote from the lesion site. In this study we determined whether similar metabolic changes occur in Parkinson's disease patients treated with deep brain stimulation (DBS) of the GPi. We studied seven Parkinson's disease patients with FDG-PET to measure resting regional cerebral glucose utilization on and off GPi stimulation. We used statistical parametric mapping to identify significant changes in regional brain metabolism that occurred with this intervention. We also quantified stimulation-related changes in the expression of a specific abnormal Parkinson's disease-related pattern of metabolic covariation (PDRP) that had been identified in earlier FDG-PET studies. Metabolic changes with DBS were correlated with clinical improvement as measured by changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor ratings off medication. GPi DBS improved UPDRS motor ratings (36%, P < 0.001) and significantly increased regional glucose metabolism in the premotor cortex ipsilateral to stimulation and in the cerebellum bilaterally. GPi DBS also resulted in a significant (P < 0.01) decline in PDRP activity ipsilateral to stimulation, which correlated significantly with clinical improvement in UPDRS motor ratings (P < 0.03). Clinical improvement with GPi DBS is associated with reduced expression of an abnormal Parkinson's disease-related metabolic network involving elements of the cortico-striato-pallido-thalamocortical and the cerebello-cortical motor loops.

Exercise increases metabolic capacity in the motor cortex and striatum, but not in the hippocampus

Acute bouts of exercise have been shown to produce transient increases in regional cerebral glucose utilization, oxygen uptake, and cerebral blood flow in motor cortex, striatum, and hippocampus. The purpose of this study was to determine whether or not chronic exercise will cause long-term metabolic plasticity in brain structures activated during physical activity. The activity of cytochrome oxidase (COX), is coupled to the production of ATP, and reflects long-term plasticity in metabolic capacity. The present study examined whether or not 6 months of voluntary exercise would increase COX activity in the striatum, sensorimotor cortex, and three hippocampal subfields. Five-month-old, female Long–Evans hooded rats were randomly assigned to a control or exercise condition. Exercising rats had running wheels attached to their home cages. After the training period, fresh brains were rapidly frozen and sectioned with a cryostat. COX activity was measured using COX histochemical methods and optical densitometry. Rats in the exercise condition had significantly higher optical density in the hindlimb and forelimb motor cortices (18%, P<0.01) and dorsolateral caudate putamen (17%, P<0.01), but not in the ventrolateral caudate putamen or any subfield of the hippocampus. Although exercise is believed to increase neuronal activity in the hippocampus, motor cortex and striatum, only limb representations in the motor cortex and striatum increase bioenergetic capacity after regular exercise.