Local Metabolic Rates For Glucose Research Articles

Clinical significance of MRI/18F-FDG PET fusion imaging of the spinal cord in patients with cervical compressive myelopathy

Purpose 18F-FDG PET is used to investigate the metabolic activity of neural tissue. MRI is used to visualize morphological changes, but the relationship between intramedullary signal changes and clinical outcome remains controversial. The present study was designed to evaluate the use of 3-D MRI/18F-FDG PET fusion imaging for defining intramedullary signal changes on MRI scans and local glucose metabolic rate measured on 18F-FDG PET scans in relation to clinical outcome and prognosis.MethodsWe studied 24 patients undergoing decompressive surgery for cervical compressive myelopathy. All patients underwent 3-D MRI and 18F-FDG PET before surgery. Quantitative analysis of intramedullary signal changes on MRI scans included calculation of the signal intensity ratio (SIR) as the ratio between the increased lesional signal intensity and the signal intensity at the level of the C7/T1 disc. Using an Advantage workstation, the same slices of cervical 3-D MRI and 18F-FDG PET images were fused. On the fused images, the maximal count of the lesion was adopted as the standardized uptake value (SUVmax). In a similar manner to SIR, the SUV ratio (SUVR) was also calculated. Neurological assessment was conducted using the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy.ResultsThe SIR on T1-weighted (T1-W) images, but not SIR on T2-W images, was significantly correlated with preoperative JOA score and postoperative neurological improvement. Lesion SUVmax was significantly correlated with SIR on T1-W images, but not with SIR on T2-W images, and also with postoperative neurological outcome. The SUVR correlated better than SIR on T1-W images and lesion SUVmax with neurological improvement. Longer symptom duration was correlated negatively with SIR on T1-W images, positively with SIR on T2-W images, and negatively with SUVmax.ConclusionOur results suggest that low-intensity signal on T1-W images, but not on T2-W images, is correlated with a poor postoperative neurological outcome. SUVmax of lesions showing increased signal intensity and SUVR measured on fusion MRI/PET scans are more sensitive parameters for predicting clinical outcome than signal intensity on the MRI scan.

Effects of behavioral therapy or pharmacotherapy on brain glucose metabolism in subjects with obsessive–compulsive disorder as assessed by brain FDG PET

This prospective study investigated the effect of pharmacotherapy (PT) and cognitive behavioral therapy (CBT) on cerebral glucose metabolism in adults with obsessive–compulsive disorder (OCD). Dynamic positron emission tomography (PET) of the brain with F-18-fluorodeoxyglucose (FDG) was performed before and after treatment in 16 subjects diagnosed for OCD for at least 2 years (PT: n = 7). Pre-to-post-treatment change of scaled local metabolic rate of glucose (SLMRGlc) was assessed separately in therapy responders and non-responders. Correlation was tested between SLMRGlc change and change of OCD, depression, or anxiety symptoms. SLMRGlc increased in the right caudate after successful therapy. The increase tended to correlate with the improvement of OCD symptom severity. The finding of increased local caudate activity after successful therapy is in contrast to most previous studies. Possible explanations include effects of therapy on concomitant depression symptoms and/or the large proportion of early-onset OCD in the present sample.

A method based on Monte Carlo simulations and voxelized anatomical atlases to evaluate and correct uncertainties on radiotracer accumulation quantitation in beta microprobe studies in the rat brain

The β-microprobe is a simple and versatile technique complementary to small animal positron emission tomography (PET). It relies on local measurements of the concentration of positron-labeled molecules. So far, it has been successfully used in anesthetized rats for pharmacokinetics experiments and for the study of brain energetic metabolism. However, the ability of the technique to provide accurate quantitative measurements using 18F, 11C and 15O tracers is likely to suffer from the contribution of 511 keV gamma rays background to the signal and from the contribution of positrons from brain loci surrounding the locus of interest. The aim of the present paper is to provide a method of evaluating several parameters, which are supposed to affect the quantification of recordings performed in vivo with this methodology. We have developed realistic voxelized phantoms of the rat whole body and brain, and used them as input geometries for Monte Carlo simulations of previous β-microprobe reports. In the context of realistic experiments (binding of 11C-Raclopride to D2 dopaminergic receptors in the striatum; local glucose metabolic rate measurement with 18F-FDG and H2O15 blood flow measurements in the somatosensory cortex), we have calculated the detection efficiencies and corresponding contribution of 511 keV gammas from peripheral organs accumulation. We confirmed that the 511 keV gammas background does not impair quantification. To evaluate the contribution of positrons from adjacent structures, we have developed β-Assistant, a program based on a rat brain voxelized atlas and matrices of local detection efficiencies calculated by Monte Carlo simulations for several probe geometries. This program was used to calculate the ‘apparent sensitivity’ of the probe for each brain structure included in the detection volume. For a given localization of a probe within the brain, this allows us to quantify the different sources of beta signal. Finally, since stereotaxic accuracy is crucial for quantification in most microprobe studies, the influence of stereotaxic positioning error was studied for several realistic experiments in favorable and unfavorable experimental situations (binding of 11C-Raclopride to D2 dopaminergic receptors in the striatum; binding of 18F-MPPF to 5HT1A receptors in the dorsal raphe nucleus).

Accurate determination of metabolic rates from dynamic positron emission tomography data with very-low temporal resolution.

The graphical approach is widely used for the pixelwise determination of local metabolic rate of glucose from dynamic positron emission tomography (PET) data. In its conventional implementation, measured integrals over time frames are used to approximate instantaneous tracer concentrations at midframe times ("midframe approach"). This is justified in case of high temporal resolution of the PET measurement; that is, if scan protocols with a large number of short frames are used. This requires fast data handling and large amounts of memory. Cardiac gating and three-dimensional (3D) acquisition of dynamic studies is hardly possible with this approach. Therefore, a new variant of the graphical method is proposed which can be used with a very low number of rather long frames. An operational equation of the graphical method was derived which uses measured time integrals only and, thus, avoids the systematic errors of the midframe approximation. This "integral approach" was evaluated in computer simulations based on experimental data. The integral approach enables the use of protocols with 3 frames only without compromising accuracy of the derived metabolic rates whereas the midframe approach leads to bias of about 10% to 20% for these protocols. Furthermore, test-retest stability can significantly be improved when using the integral approach. The integral approach to the graphical evaluation of dynamic PET data yields accurate and precise results using scan protocols with down to only 3 frames. This can be relevant to gating and/or 3D acquisition of dynamic studies. The integral approach is applied most naturally whenever the input function is derived from the dynamic PET data.

Increased hippocampal CA3 vulnerability to low-level kainic acid following lateral fluid percussion injury.

This study was designed to determine whether a secondary increase in neuronal activity induced by a low dose of kainic acid (KA), a glutamate analogue, exacerbates the anatomical damage in hippocampal regions following a mild lateral fluid percussion (LFP) brain injury. KA (9 mg/kg) was injected intraperitoneally in LFP-injured rats (n = 16) 1 h post-trauma. The neuronal loss in the CA3, CA4, and hilar regions at 7 days was quantified by two-dimensional cell counts. Hippocampal activation 15 min following KA injection was assessed by measuring local glucose metabolic rates (lCMR(glc)). Following LFP + KA, the ipsilateral side exhibited a 62.7%, 75.7%, and 52.1% decrease in the number of CA3, CA4 and hilar neurons, respectively, compared to naive rats (n = 3). These CA3 and CA4 neuronal counts were also significantly decreased compared to LFP + saline (n = 5) and sham + KA (n = 9) groups. The median Racine Score, used to rate the severity of behavioral seizures, was 4 in LFP + KA and 2 in sham + KA groups (p < 0.015), suggesting a reduction in seizure threshold following injury. lCMRglc in CA3 following LFP + KA was 121.8 +/- 2.0 (mean +/- SE) ipsilaterally and 71.5 +/- 5.4 contralaterally (p < 0.0012). No changes were found in the BBB permeability as measured by [(14)C]aminoisobutyric acid in CA3, CA4, and hilar regions. We conclude that the presence of low-level KA 1 h after LFP dramatically increases the extent of hippocampal activation and induces a striking loss of ipsilateral CA3 and CA4 pyramidal neurons. Neuronal excitation during a time of cellular vulnerability may trigger or amplify the cycle of secondary damage in functionally impaired, but potentially viable, tissue.

Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture.

The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables-factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy. The ischemic penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke. Gene expression: Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration. NEUROPROTECTION: A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32 degrees C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg--a therapy that reduces infarct volume in this ischemia model by 60% to 65%, markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours. The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.

A critical maturational period of reduced brain vulnerability to injury. A study of cerebral glucose metabolism in cats

We have developed a feline cerebral hemispherectomy model as an analog to the surgical procedure used in pediatric intractable epilepsy. Previous work with this model has shown a remarkable plasticity associated with an early period of brain development, which we have defined using morphological, cerebral metabolic and behavioral methods. However, the important functional-metabolic bracketing of this period has not yet been performed. We have conducted the present study to answer questions raised by our previous findings using [ 14C] 2-deoxy- d-glucose autoradiography but only including animals lesioned at day 10 postnatally (P10) or in adulthood. The questions were; (a) is there any age better than P10 for an optimal metabolic outcome?, and (b) can we determine a cutoff point for the beneficial effects of the young age-at-lesion? Twenty-one adult cats were studied. Seven cats served as intact controls, five received a left hemineodecortication at P30, three at P60, three at P90 and three at P120, respectively. Histological analysis indicated that the extent of the lesion was similar between the age groups. Local glucose metabolic rates (LCMR glc) were measured in 50 structures bilaterally and used to calculate overall LCMR glc for seven grouped sites within the cerebral cortex, thalamus, basal ganglia, mesencephalic tegmentum (and tectum), limbic system and cerebellum. Results indicated a widespread bilateral depression of LCMR glc in all age-at-lesion groups. The depression in overall LCMR glc across all structures measured in each hemisphere was significant ( P<0.05) for the P120 group relative to intacts for both ipsilateral (left) and contralateral (right) sides of the brain. The ipsilateral thalamus was the region most effected by the injury, with significant losses for all age-at-lesion groups. In addition, while there were widespread depressions for all lesion groups, these losses were significant for the P120 group in five groups of structures ipsilaterally (thalamus, basal ganglia, tectum, limbic system, cerebellum) and in three contralaterally (thalamus, tectum, cerebellum). In contrast, significant depressions for the earlier age-at-lesion groups (P30, P60, P90) were found only in the ipsilateral thalamus and bilaterally in the tectum. These results, together with our previous results for the P10 group, indicate a relative sparing of LCMR glc after hemineodecortication during the first 60 days of life, with gradually decreasing plasticity thereafter, such that there is some residual sparing at 90 days of age, and afterwards an almost complete loss of metabolic plasticity, with lesions at P120 producing a dismal outcome. These results complement earlier morphological and behavioral studies and support the concept of a ‘Critical Maturational Period’ of reduced vulnerability to developmental injury.

Sleep deprivation as a model experimental antidepressant treatment: findings from functional brain imaging.

This paper reviews the functional brain imaging studies in depressed patients treated with sleep deprivation. Sleep deprivation is an excellent experimental model of antidepressant treatments which offer new opportunities to understand the basic neural mechanisms. Its antidepressant effects are efficacious and rapid; sleep deprivation is easy to administer, inexpensive, and relatively safe; it can be studied in patients, normal controls, and animals; and it may lead to new treatments and new paradigms for antidepressant therapies. Seven published papers, coming from five different research centers, using either positron emission tomography (PET) with 18fluorodeoxyglucose (FDG) or single photon emission computerized tomography (SPECT) with Technetium-99-bexamethyl propyleneamine oxime (HMPAO) have relatively consistent findings. First, before sleep deprivation, responders have significantly elevated metabolism compared with non-responders, and usually the normal controls, in the orbital medial prefrontal cortex, and especially in the ventral portions of the anterior cingulate cortex. Secondly, after sleep deprivation, these hyperactive areas normalize in the responders. The magnitude of the clinical improvement was significantly correlated with decreased local glucose metabolic rate or cerebral blood flow in three studies. The results are consistent with some but not all functional brain imaging studies of antidepressant medications in depressed patients. Finally, a SPECT study using a radioactively labeled D2 receptor antagonist suggests that the antidepressant benefits of sleep deprivation are correlated with endogenous release of dopamine.

Naloxone alters the local metabolic rate for glucose in discrete brain regions associated with opiate withdrawal

The current 2-deoxy- d-[1- 14C]glucose investigation was performed to test the hypothesis that endogenous opioids influence basal synaptic activity within discrete brain regions. To examine this hypothesis, the effects of naloxone (1.0 mg/kg s.c.) on local cerebral metabolic rate for glucose (LCMR glu) in 84 brain regions were compared to saline controls. The specificity of naloxone's effects for opioid receptors was assessed by the coadministration of the opiate agonist morphine in a separate group. In naloxone-treated rats, there was a significant decrease in LCMR glu in the locus coeruleus (LC) and an increase in the central nucleus of the amygdala (CAMY), supporting a tonic influence of endogenous opioids on these regions. These metabolic changes were reversed by coadministered morphine, indicating that naloxone's metabolic actions are specific for opioid receptors. Based on the role of the LC and CAMY in opiate withdrawal, the present results suggest a subthreshold naloxone precipitated withdrawal from endogenous opioids. Although morphine administered alone significantly reduced LCMR glu in 16 brain regions, these did not include the LC or the CAMY. These results identify brain regions in which synaptic activity is under tonic modulation by endogenous opioids.

In vivo metabolism of childhood posterior fossa tumors and primitive neuroectodermal tumors before and after treatment.

Despite an increasing interest in the clinical application of positron emission tomography (PET) in tumors of the adult patient as a diagnostic and prognostic tool, only a few studies have been concerned with the usefulness of PET with [18F]2-deoxy-2-fluoro-D-glucose (FDG) in childhood tumors. Fifteen children and young adults (0.5-26.0 years of age) with histologically confirmed brain tumors were studied with PET and FDG. Seven children with medulloblastoma (n = 5) or primitive neuroectodermal tumor (PNET) (n = 2) underwent repeated PET studies during their therapy. The other eight children with medulloblastoma (n = 5) or astrocytoma (n = 3) were studied only once before initiation of treatment. A close clinical follow-up was performed in every case. Comparison of local glucose metabolic rates obtained in the various tumor lesions revealed that the mean rates found in medulloblastomas (mean glucose metabolic rate, 42.8 +/- 14.03 mumol/100 g/min) were twice as high as the rates measured in either PNET (17.3 +/- 4.5 mumol/100g/min) or infratentorial gliomas (21.8 +/- 4.2 mumol/100g/min). The high metabolism of medulloblastomas enabled the observer to identify the tumor more easily and to clearly separate it from the surrounding unaffected brain tissue. In the seven patients with follow-up PET studies during therapy, decreasing or increasing ratios of tumor-to-white matter metabolic rate were not only commensurate with neuroradiologically defined tumor reduction or growth, but also corresponded to the duration of initial clinical improvement. These preliminary results suggest that PET with FDG may be a useful tool to evaluate metabolic activity of pediatric brain tumors over time and to assess response to treatment.

Evidence of multiple memory systems in the human brain. A [18F]FDG PET metabolic study.

Patients with global amnesia of different aetiologies (n = 11), and patients with probable Alzheimer's disease of recent onset and mild to moderate severity (n = 18) underwent extensive neuropsychological examination, which included the evaluation of multiple components of memory, and a measurement of regional cerebral glucose metabolism with [18F]fluoro-deoxyglucose ([18F]FDG) and PET. In the neuropsychological tests, both global amnesia and Alzheimer's disease patients had impaired episodic long-term memory, while deficits of short-term, semantic and implicit memory were present only in Alzheimer's disease. When local metabolic rates for glucose were compared with values from age- and education-matched normal controls, a common pattern of bilateral hypometabolism was present in the hippocampus, cingulate and frontal basal cortex of both global amnesia and Alzheimer's disease patients. On the other hand, significant hypometabolism was found in the thalamus in only global amnesia, and in the frontal, parietal and temporal associative cortex in only Alzheimer's disease. The results of a multivariate regression analysis of test scores with metabolic data indicated that different clusters of cerebral areas were associated with each of the main components of memory function. These data are in agreement with 'neural network' models of the neural basis of cognition, according to which complex functions are subserved by multiple interconnected cortical and subcortical structures.

Residual effects of tracer in sequential double label deoxyglucose studies

The validity of sequential double label deoxyglucose (DG) determinations of local metabolic rate for glucose (IMR glc) was examined by quantifying the degree of trapping of residual first DG tracer during the second experimental period. One sciatic nerve was repetitively stimulated for 25 min, beginning either at the time of the DG injection or 25 min later. IMR glc in the ipsilateral dorsal horn of the lumbar spinal cord was found to be 105% and 56%, respectively, greater than that of the contralateral unstimulated side. Attempts to lower the body burden of radioactive DG by exchange blood transfusion failed to reduce this delayed effect. These data indicate that residual effects of the first tracer could obscure possible differences in IMR glc between two sequential experimental states.

Correlations of regional postmortem enzyme activities with premortem local glucose metabolic rates in alzheimer's disease

Correlations were sought between local cerebral metabolic rates (LCMRs) for glucose in various regions of the cortex, determined in premortem PET scans, with the regional activities of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), beta-glucuronidase (Gluc, a probable index of reactive gliosis), and phosphate-activated glutaminase (PAG, a possible indice of the large pyramidal neurons) measured on postmortem tissue. Significant negative correlations between LCMRs and Gluc activities were found in 6 PET-scanned cases of Alzheimer disease (AD), and positive correlations of LCMRs with PAG were found in 5. By contrast, a positive correlation with ChAT and AChE was found in only 1. The results are consistent with the metabolic deficits in AD being primarily a reflection of local neuronal loss and gliosis. Similar data on two cases of Huntington's disease showed no significant correlations, while 1 patient with Parkinson dementia showed a significant (negative) correlation only with Gluc.

Deoxyglucose kinetics in a rat brain tumor.

Accurate quantitation of local glucose metabolic rates (LMRglc) of abnormal tissues such as brain tumors with the 2-deoxyglucose (DG) method requires knowledge of the tissue rate constants and lumped constant. The deoxyglucose rate constants were measured in an experimental intracerebral glioma in 24 awake rats with a dual tracer [(3H)-DG and (14C)-DG] method. Tissue time points were obtained at 2, 5, 10, 18, 30, 60, 90, and 180 min after injection by decapitation and liquid scintillation counting. Blood samples were obtained at 1 min intervals initially and at longer intervals later. The rate constants were estimated with parameter estimation. LMRglc was calculated from the rate constants, assuming a lumped constant of 0.5. K1 for normal cerebrum was found to be 0.258 ml/g/min, and k2-k4 were 0.406, 0.075, and 0.0103 min-1; LMRglc = 65.1 mumol/100 g/min. The corresponding values for the glioma were 0.108, 0.126, 0.040, and 0.0019 with LMRglc = 41.7. The considerably lower k4 in the glioma was reflected in persistent higher activity in the glioma at longer times. Thus, tissue activity alone cannot be used to assess relative glucose metabolic rates in abnormal tissues such as gliomas, particularly at late times after injection.

Human task-specific somatosensory activation.

We used positron emission tomography to study normal patterns of local cortical metabolic activation induced by somatosensory stimuli. Palpation and sorting of mah-jongg tiles by textured design increased local glucose metabolic rate (lCMRgl), by 18% on average, in contralateral somatosensory cortex. A graphesthesia task gave a similar result. In contrast, vigorous vibrotactile stimulation of fingers, face, or knee did not produce a consistent focus of activation. Our results indicate that lCMRgl activation is best achieved by somatosensory tasks requiring an active perceptual effort.

L8FLOURODEOXYGLUCOSE PET SCANNING IN HPRT DEFICIENCY: 150

The Lesch-Nyhan syndrome (LNS) results from the virtually complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT); partial deficiency of HPRT results in gout. The metabolic mechanisms for neurologic dysfunction in the more severe HPRT deficiency states remain unclear. Previous attempts to assess therapy for LNS also have been limited due to the lack of non-invasive measures of metabolic and neurochemical function in the CNS. In an effort to develop such measures, we have examined the local glucose metabolic rate (LGMR) using the positron emitter 18Flourodeoxyglucose (FDG) with positron emission tomography (PET) scanning in 10 normal subjects and in four HPRT deficient individuals. One subject had partial HPRT deficiency with gout and no clinical neurologic disease. Two subjects had no detectable RBC HPRT and age-related, progressive neurologic dysfunction. The fourth subject had the classical LNS. LGMR in the basal ganglia was normal in the first subject without neurologic disease and reduced in the regions of the basal ganglia in both partially deficient subjects with neurologic disease. LGMR was severely reduced in the basal ganglia of the subject with LNS. From these initial studies we conclude that the severity of neurologic dysfunction appears to be proportional to the degree of HPRT deficiency and that PET scanning of the basal ganglia with 18FDG may provide a sensitive non-invasive measure of metabolic derangement resulting from HPRT deficiency. This study suggests for the first time a characteristic abnormality in CNS metabolism unique to HPRT deficiency with neurologic dysfunction.

Regional comparisons of brain glucose influx

The regional influx of glucose across the blood-brain barrier and regional blood flow were studied simultaneously in conscious and restrained rats using the single pass bolus injection of [ 14C]butanol and [ 3H] d-glucose method. Glucose extraction by the cerebellum was about twice that of other brain regions. Thus, despite the lower cerebellar blood flow, the influx of glucose into the cerebellum was equivalent to that of the cerebral cortex and higher than that of the hippocampus over a wide range of plasma glucose concentrations. Because the local metabolic rate for glucose is higher in the cerebral cortex than in the cerebellum, the equal influx of glucose in these two regions means a relative oversupply of glucose to the cerebellum. In vivo analysis of blood to brain glucose transport kinetics showed similar plasma glucose concentrations at half-maximal transport ( K t ) in all brain regions that were studied. The values for K t ranged between 4.4 and 5.1 mM. Maximal transport capability (T max), on the other hand, was similar in the cerebral cortex and cerebellum but significantly lower in the hippocampus ( P < 0.05). The higher ratio of glucose influx to glucose utilization in the cerebellum may explain the clinical and experimental findings of relative resistance of the cerebellum to hypoglycemia while the lower T max in the hippocampus may be the mechanism underlying its selective vulnerability during pathophysiologic conditions associated with marked increments in brain oxidative metabolism, such as status epilepticus.

The effect of antidepressant drugs on regional cerebral glucose utilization in the rat

The 2-deoxyglucose (2-DG) technique is a potentially powerful method for assessing the effect of centrally acting drugs on local neuronal function in the brain. Since little is established on the effect of antidepressant drugs on local functional activity throughout the brain, we have employed this technique to study the effects of desmethylimipramine (DMI), a tricyclic antidepressant, and phenelzine, a monoamine oxidase inhibitor used clinically as an antidepressant, on local glucose utilization. The drugs were administered either as an acute dose, or repeatedely for 7 days, or chronically for 28 days. The local metabolic rate of glucose was determined in 30 regions of rat brain. Acute DMI increased glucose utilization in 11 regions whereas, in contrast,chronic DMI decreased glucose utilization in 7 regions of rat brain. Many of the areas affected are those of the telencephalon and diencephalon that receive prominent noradrenergic innervation. This is consistent with the notion that acute DMI treatment leads to enhanced and chronic DMI treatment leads to reduced noradrenergic functioning in the CNS. In contrast to these effects with DMI, phenelzine had little effect on glucose utilization either after acute of chronic dosing.