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These studies have largely demonstrated that be- geneous conductivity of the brain purchase vytorin 20mg free shipping, Cerri et al order vytorin. Very matter purchase vytorin 20 mg without a prescription, and cerebrospinal fluid, and a conductivity versus basic questions remain largely unexplored. These include gray level interpolation function derived from tissue con- how best to position the coil (functional behavioral versus ductivity data in the literature to obtain a three-dimensional probabilistic), how to adjust the intensity for nonmotor conductivity map. They then divided the brain into discrete areas of cortex, and whether to account for differences in resistive cells (quasistatic approximation) and used a super- depth into the brain (e. Additionally, a true computer to determine the current distribution that would understanding of TMS effects on the brain are still lacking, be induced in the three-dimensional resistive network by 408 Neuropsychopharmacology: The Fifth Generation of Progress an external magnetic field pulse However, such methods of finding the solution space of A is called singular value are not generally available and are still an approximation. A means of imaging the induced electric field is what is Singular value decomposition explicitly constructs or- really needed. APPENDIX II Principal Component Analysis And Singular ValueDecomposition REFERENCES 1. In: George Principal Component Analysis MS, Belmaker RH, eds. Transcranial magnetic stimulation (TMS) Principal component analysis is a mathematical device that in neuropsychiatry. Washington, DC: American Psychiatric Press, 2000:115–140. Transcranial magnetic stimulation in fMRI data to reduce its dimensionality. Washington, DC: American Psychiatric Press, to a specific statistical model, entails few assumptions, and 2000. By orthogonalizing the covariance matrix, PCA stimulation: applications in neuropsychiatry. These vectors are the linear combina- ulation of the human motor cortex. A theoretical comparison of variance in the observed data. In terms of functional of electric and magnetic stimulation of the brain. Ann Biomed connectivity, a principal component represents a spatially Eng 1991;19:317–328. A theoretical calculation distributed brain system, comprising a subset of brain re- of the electric field induced in the cortex during magnetic stimu- gion, within which many temporal intercorrelations exist. Because any one principal component is orthogonal to the 7. In: remaining principal components, these systems are func- George MS, Belmaker RH, eds. Transcranial magnetic stimulation tionally unconnected from each other, even though any sin- in neuropsychiatry. Washington, DC: American Psychiatric Press, 2000:13–44. Mapping transcra- perform PCA, a mathematical technique called singular nial magnetic stimulation (TMS) fields in vivo with MRI. Risk and safety of repetitive transcranial mag- netic stimulation: report and suggested guidelines from the Inter- Singular ValueDecomposition national Workshop in the Safety of Repetitive Transcranial Mag- netic Stimulation, June 5–7, 1996. Electroencephalogr Clin Given a set of M linear algebraic equations relating a set of Neurophysiol 1998;108:1–16. Implications of kindling and quenching for the possible frequency dependence of rTMS. Responses ⋅⋅⋅ ⋅⋅⋅ to rapid-rate transcranial magnetic stimulation of the human motor cortex. Crossed reduction of motor cortex excitability by 1 Hz transcranial mag- or, in matrix form, netic stimulation. Frequency dependence of antidepressant response to left prefrontal repetitive transcranial where the as and bs are known. If N M, there are as magnetic stimulation (rTMS) as a function of baseline cerebral many equations as unknowns, and there is a good chance glucose metabolism. Safety concerns of transcranial of finding a unique solution set of xjs. Trans- If M N or M N but the equations are not all linearly cranial magnetic stimulation in neuropsychiatry. Washington, DC: independent, then there are effectively fewer equations than American Psychiatric Press, 2000:141–162. In this case, either there is no solution, or else 15. Optimum stimulus param- there is more than one solution vector x. In the latter event, eters for lateralized suppression of speech with magnetic brain stimulation. Noninvasive functional brain mapping by to any linear combination of (typically) N-M vectors (which change-distribution analysis of averaged PET images of H 15O 2 are said to be in the nullspace of the matrix A). Latent variable models: an introduction to factor, path strategies for time-course data sets in functional MRI of the and structural analysis. Functional and effective connectivity in neuroimag- Psychiatry 1997;41:108S- 374(abst). Structural equation modeling initial studies combining conventional functional imaging (PET, and its application to network analysis in functional brain imag- SPECT, fMRI) with transcranial magnetic stimulation (TMS) ing. Simultaneously recorded trains of ac- prefrontal stimulation decreases relative perfusion locally in a tion potentials: analysis and functional interpretation. Proceedings of the IEEE Trans Biomed Eng 1989;36:4–14. International Society of Magnetic Resonance in Medicine 2000;8: 25. New York: John Wiley Electroencephalogr Clin Neurol 1990;75:350–357. Functional interactions cortex on the MRI with transcranial magnetic stimulation and among neurons in inferior temporal cortex of the awake macaque. EEG patterns during ping of motor cortex: comparing echoplanar BOLD fMRI and cognitive tasks. Methodology and analysis of complex behav- transcranial magnetic stimulation. Co-planar stereotaxic atlas of the human human brain during cognition: a new method of reveals dynamic brain: 3-dimensional proportional system: an approach to cerebral patterns of correlation. Three-dimensional multi- ances during a bimanual visuomotor task. Methods and analysis modal image guidance for neurosurgery.
The atypical chotic medication for at least 90 days best buy vytorin. At the end of the antipsychotics appear preferable for the management of psy 6-week placebo-substitution period vytorin 30mg overnight delivery, disruptive behaviors se chosis in DLB (73) buy generic vytorin online. Also, several studies suggest that com vere enough to warrant reinstitution of antipsychotic medi pensating for the profound cholinergic deficit of DLB with cation had developed in only one patient. Of the remaining cholinesterase inhibitor therapy improves psychotic and eight patients, five actually were less agitated, two were un other noncognitive behavioral problems in this disorder (26, changed, and only one was rated as more agitated than when 74,75). This small study supports the wisdom of periodic dis continuation of long-term antipsychotic medication to Other Pharmacologic Approaches to the evaluate the need for maintenance. In a larger study per- Management of Agitated Behaviors in formed in 36 community nursing home patients (mean age, Alzheimer Disease 82 years) who met criteria for probable or possible AD, Despite their somewhat disappointing therapeutic effect patients were randomly assigned to either continuation of size, the consensus is that antipsychotic drugs should be antipsychotic medication or withdrawal from antipsychotic prescribed for clear and troublesome delusions and halluci medication and substitution of placebo (68). However, the rationale for prescribing antipsy patients withdrawn from antipsychotic medication, 20 chotic drugs as the drug class of choice for AD patients (91%) were able to complete the 4-week, double-blinded with disruptive agitation in the absence of clear psychotic withdrawal. In only two cases did the nursing home staff symptoms is less compelling. In such patients, attempts to request that the patients be withdrawn from the study be- demonstrate efficacy for other types of psychotropic drugs cause of emergencies involving unacceptable levels of agita are both reasonable and important. No significant difference in the incidence of emergent base derived from well-designed clinical trials of psycho- physically aggressive behavior was found between patients tropic drugs other than the antipsychotics for the manage withdrawn from antipsychotic medication and those main ment of disruptive behaviors in AD is even less robust than tained on antipsychotic medication. Half of the patients that for the antipsychotic drugs. The following review, withdrawn from antipsychotic medication remained off the therefore, relies heavily on anecdotal reports and non–pla drugs for an extended period of time after the end of the cebo-controlled studies when data from interpretable pla study, even after the blind had been broken. These two cebo-controlled studies are not available. Benzodiazepines The use of benzodiazepines in patients with AD and other dementing disorders has been reviewed (76). In a group Dementia with LewyBodies: Implications of 'emotionally disturbed' elderly patients (mean age, 81 for Psychopharmacology years), Sanders (77) evaluated the efficacy of oxazepam in It is increasingly clear that a subgroup of patients meeting comparison with placebo in an 8-week treatment trial. Oxa formal criteria for probable AD (69) are more accurately zepam was superior to placebo, particularly for reduction classified diagnostically as having DLB (46). Interpretation of this study is ham- 1260 Neuropsychopharmacology: The Fifth Generation of Progress pered by the vagueness of the diagnoses and the likelihood chotropic medications, principally antipsychotic drugs. Coccaro et of 16 patients were rated as much or very much improved al. Levy (83) antihistamine diphenhydramine in elderly institutionalized used buspirone to treat 20 patients with AD and behavioral patients. The mean age of these subjects was 75 years, most disturbances rated as at least moderately troublesome on met criteria for AD, and target signs and symptoms included the BEHAVE-AD in a single-blinded dose-escalation study. Ratings of target signs and symptoms im subjects were given placebo for 1 week and then progres proved during an 8-week period in all treatment groups. A dose–response improvement in anxiety rating groups did not emerge, a trend for greater improvement occurred. The lack of a placebo group in this study compli In these studies of buspirone, adverse effects were unusual. The group in which serotoninergic activity and aggressive behaviors in nonde the drug was discontinued showed greater improvements mented persons (84) provide the rationale for studies ad- in memory than did the group that continued to take benzo dressing the behavioral efficacy of drugs that enhance central diazepine, and no differences between the groups were serotoninergic neurotransmission in AD patients with agi found in measures of depression, anxiety, irritability, or tated behaviors. This study suggests that at least a subgroup of patients subjects selected for the presence of psychosis or disruptive maintained for an extended time on short-acting benzodi agitation were first treated openly with the cholinesterase azepines may benefit from a trial of drug discontinuation. Sertraline had diazepines have been associated with falls in geriatric psychi a modest positive effect on agitated behaviors (but not psy atric inpatients (80). Taken together, these studies of benzo chosis) in comparison with placebo. Two multisite Scandi diazepines in behaviorally disturbed patients with dementia navian studies have evaluated SSRIs in demented patients suggest that the use of benzodiazepines is best limited to with a variety of predominantly nonpsychotic behavioral short-term treatment of acute anxiety and agitation, and disturbances. These patients were not reported to have met that benzodiazepines are a poor choice for long-term man diagnostic criteria for depression. In demented patients with agement of disruptive agitation in AD. Buspirone Improvement was limited to demented patients with AD. Buspirone is a partial 5-hydroxytryptamine subtype 1A (5- No significant effects of citalopram were noted in patients HT )-receptor agonist with antianxiety activity and a rela with vascular dementia. Cognitive function was unaffected 1A tively benign adverse effect profile. Two uncontrolled stud by either citalopram or placebo, and citalopram was well tolerated by the elderly subjects in this study. In another ies of buspirone in dementia patients with agitated behavior study of demented patients with AD or vascular dementia have been reported. A modest but statistically significant anxiety, fear/panic, mood level, and restlessness. The differ overall reduction of agitated behaviors was noted, as was a ences between fluvoxamine and placebo, however, failed substantial variability in response, with 4 of the 10 patients to reach statistical significance. Although more studies are demonstrating marked declines in disruptive behaviors. In needed to evaluate the possible roles of the SSRIs for disrup a similar study, Hermann and Eryavec (82) prescribed tive agitation, results to date do not support their use as buspirone to a group of elderly nursing home residents with first-line agents for this indication. All subjects had demonstrated severe behavioral Other Serotoninergic Drugs disturbances, including agitation and aggression, and all had Trazodone is a sedating antidepressant with serotoninergic failed to improve with previous trials of other types of psy agonist activity. Simpson and Foster (88) treated four de- Chapter 88: Alzheimer Disease: Treatment of Noncognitive Behavioral Abnormalities 1261 mented patients who manifested disruptive behaviors with superiority of carbamazepine compared with placebo was trazodone after antipsychotic drug treatment had proved attributable primarily to a greater decrease in agitation and ineffective. In this anecdotal report, trazodone in doses of aggression in the carbamazepine group. Pinner and Rich (89) treated seven demonstrated antimanic activity. Again, all subjects had failed to improve with tated behaviors with doses of valproate ranging from 500 antipsychotic drug therapy. Three of the seven patients mg twice daily to 500 mg three times daily; treatment lasted demonstrated an apparent marked decrease in aggressive for 1 to 3 months. Substantial behavioral improvement was behavior following 4 to 6 weeks of trazodone at doses rang noted in two of the four patients, and adverse effects did ing from 200 to 350 mg/d. A recently reported multisite study of the anti study comparing haloperidol, trazodone, behavioral man convulsant valproate sodium has been less encouraging (97). In a double-blinded, placebo-controlled crossover turely. Although at the end of the study agitation was re study, Lawlor et al. Methodologically, this study a small but significant behavioral improvement in compari was designed to address 'mania-like' symptoms in persons son with placebo, whereas buspirone had no apparent ef with AD, and the higher doses of valproate typically pre- fect. Lower doses of valproate may have beneficial therapeutic effects with a more tolerable adverse effect pro- Anticonvulsant Drugs file. Because the hyperactive and aggressive behaviors encoun tered in the manic phase of bipolar disorder at least superfi Cholinergic Enhancement cially can resemble agitated behaviors in AD and other de mentias, the anticonvulsant drugs effective in the treatment That drugs that enhance cholinergic neurotransmission in of mania may benefit behaviorally disturbed patients with the central nervous system decrease agitation and psychotic dementia.
Antimicrobial resistance associ- among brothel-based sex workers in Tel-Aviv area 30 mg vytorin free shipping, Israel: high preva- ated with the treatment of bacterial vaginosis vytorin 20 mg free shipping. Te efects of intravagi- comes of pharyngeal Neisseria gonorrhoeae and Chlamydia trachomatis nal clindamycin and metronidazole therapy on vaginal mobiluncus infections in men who have sex with men: a 13-year retrospective cohort morphotypes in patients with bacterial vaginosis safe 30mg vytorin. A review of evidence supporting the American Academy 334. Te efcacy of retreatment with of Pediatrics recommendation for prescribing cephalosporin antibiotics the same medication for early treatment failure of bacterial vaginosis. Suppressive antibacterial therapy with single-dose intramuscular ceftriaxone. Boric acid addition to suppressive rial vaginosis in the United States, 2001–2004: associations with antimicrobial therapy for recurrent bacterial vaginosis. Sex Transm Dis symptoms, sexual behaviors, and reproductive health. Diagnostic vaginal health for Kenyan women at risk for acquisition of human criteria and microbial and epidemiologic associations. Am J Med immunodefciency virus type 1: results of a randomized trial. Reduced incidence stain for the diagnosis of bacterial vaginosis. Obstet Gynecol 1996;88(4 of preterm delivery with metronidazole and erythromycin in women Pt 1):573–6. Efect of metronidazole in patients detection of vaginal bacteria associated with bacterial vaginosis. J Clin with preterm birth in preceding pregnancy and bacterial vaginosis: Microbiol 2007;45:3270–6. A randomized trial of metronidazole in 1994;171:345–7. Clinical and cervical cytokine transmitted diseases. Efectiveness of rial vaginosis during pregnancy: a randomized trial. Obstet Gynecol two tinidazole regimens in treatment of bacterial vaginosis: a random- 2003;102:527–34. Efcacy of clindamycin vaginal and intermediate fora in pregnancy and efect of oral clindamycin. Am J Obstet Gynecol 1995;172(2 Pt probiotic Lactobacillus crispatus CTV-05 is decreased by sexual activity 1):525–9. Lactobacillus-containing vaginal tablets in the treatment of symptom- 344. Preterm labour—is bacterial atic bacterial vaginosis. Prevalence of rectal vent preterm delivery in pregnant women with asymptomatic Trichomonas vaginalis and Mycoplasma genitalium in male patients bacterial vaginosis. National Institute of Child Health and Human at the San Francisco STD clinic, 2005–2006. Sex Transm Dis Development Network of Maternal-Fetal Medicine Units. Prevalence of metronidazole- preterm birth in women with an increased recurrence risk: a ran- resistant Trichomonas vaginalis in a gynecology clinic. J Reprod Med domised placebo-controlled double-blind trial. Impact of met- with resistance to metronidazole and tinidazole. Antimicrob Agents ronidazole therapy on preterm birth in women with bacterial vaginosis Chemother 2006;50:4209–10. An incremental dosing protocol J Obstet Gynaecol 1997;104:1391–7. Management of Trichomonas Obstet Gynecol 2003;101:516–22. Bacterial vaginosis is associated J Obstet Gynecol 2008;198:370–7. Failure of metronidazole to a controlled trial of topical clindamycin cream. Am J Obstet Gynecol prevent preterm delivery among pregnant women with asymptomatic 1994;170:1048–59. Treatment of treatment for bacterial vaginosis: efects on preterm delivery and low Trichomonas in pregnancy and adverse outcomes of pregnancy: a suba- birth weight. Trichomonas vaginalis history, and response to treatment of Trichomonas vaginalis infection infection and human immunodefciency virus acquisition in African among adolescent women. Infuence of HIV-1 Trichomonas vaginalis infection among reproductive-age women in the coinfection on efective management of abnormal vaginal discharge. Trichomonas vaginalis is vaginalis organisms on a liquid-based papanicolaou smear. Am J Obstet associated with pelvic infammatory disease in women infected with Gynecol 2003;188:354–6. Use of an adaptation of a com-Use of an adaptation of a com- 373. Infection with mercially available PCR assay aimed at diagnosis of chlamydia and Trichomonas vaginalis increases the risk of HIV-1 acquisition. J Infect gonorrhea to detect Trichomonas vaginalis in urogenital specimens. Comparison between the Gen- Trichomonas vaginalis among HIV-positive and HIV-negative women. Probe transcription-mediated amplifcation Trichomonas vaginalis Clin Infect Dis 2008;46:994–9. Trichomonas vaginalis treatment using a Roche LightCycler instrument with female self-obtained reduces vaginal HIV-1 shedding. Rapid antigen testing com- virus type 1 in antiretroviral-experienced women. J Infect Dis pares favorably with transcription-mediated amplifcation assay for the 2003;187:375–84. Trichomonas vaginalis transcription-mediated amplifcation to wet 378. Incidence and predictors of mount microscopy, culture, and polymerase chain reaction for diag- reinfection with Trichomonas vaginalis in HIV-infected women. Comparing ceftriaxone plus versus 7-day dose of metronidazole for the treatment of Trichomonas azithromycin or doxycycline for pelvic infammatory disease: a random- vaginalis among HIV-infected women. Treatment of vaginitis caused defciency virus 1 infection on microbial origins of pelvic infammatory by Candida glabrata: use of topical boric acid and fucytosine. Am J disease and on efcacy of ambulatory oral therapy.
Comparison of the rates of neuronal glucose oxidation mea- sured in these studies with conventional arteriovenous (AV) difference and PET measurements of total glucose con- sumption found that the majority (between 70% and 90%) of total glucose oxidation in the rat and human brain is associated with the large glutamate pool generic 30mg vytorin visa, believed to reflect glutamatergic neurons generic vytorin 20 mg without prescription, measured by MRS 30 mg vytorin. In two recent 13C MRS studies of resting awake human occipital parietal FIGURE 25. The figure shows a 50- cortex, in which other pathways of glucose metabolism were minute accumulation 13C MRS spectrum obtained at 4 T approxi- directly measured, a similar range of between 60% (35) and mately 60 minutes after the start of a 1-13C glucose infusion. The 80% (29) of total glucose oxidation was calculated for the spectrum was obtained from a 72-mL volume centered on the midline in the occipital/parietal lobe. The large percentage of cortical syn- sion of regions of the bottom trace. Labeled resonances include apses that are glutamatergic and the high electrical activity the C2, C3, and C4 positions of glutamate, glutamine, aspartate, of glutamatergic pyramidal cells (4,45) may explain why and -aminobutyric acid (GABA) and the C3 position of lactate. As described in the text (see In Vivo 13C MRS Measurements of such a large fraction of total glucose oxidation is associated the Pathways of Glucose Oxidation: Findings and Validation), the with glutamatergic neurons. Local- ized in vivo 13C-NMR of glutamate metabolism in the human other neuron types, particularly GABAergic, the assignment brain: initial resultsat 4 tesla. DevNeurosci 1999;20:380–388, with of the fraction of glucose oxidation occurring in gluta- permission. In the future, the fraction of glutamate in glia may be measured more accurately through dynamic 13C MRS measurements of glutamate and glutamine labeling during the infusion of label is then transferred to the tricarboxylic acid cycle (TCA) labeled acetate that is incorporated into the brain selectively by the actions of pyruvate dehydrogenase (PDH) and citrate in the glia (28,38,39). When the label reaches C4- -ketoglutarate it is transferred to the large neuronal glutamate pool by the high MRS Measurements of the Rate Glucose activity exchange reactions of the amino acid transaminases Oxidation in GABAergic Neurons and mitochondrial/cytosolic transporters. The large gluta- mate pool was first identified in 14C tracer studies (40). GABA is the major inhibitory neurotransmitter and may Based on kinetic and immunohistochemical staining stud- represent over 30% of the synapses in the cerebral cortex (4, ies, it is believed to correspond to the glutamate pool of 46,47). GABA is synthesized from glutamate in GABAergic glutamatergic neurons (18,41,42). Due to the rate of these neurons by the enzyme glutamic acid decarboxylase (GAD). Almost all of the brain GABA pool tion of 13C label into the trapping glutamate pool, and the is localized to GABAergic neurons under normal condi- kinetic curves analyzed by metabolic modeling to calculate tions. The labeling of the GABA pool from [1-13C] glucose the rate of the neuronal TCA cycle (18). The trapping pool provides a minimum estimate of the rate of glucose oxida- assumption is not essential to determine the rate of the tion in the GABAergic neuron. The estimate is a minimum TCA cycle because subsequent labeling in the C3 position because label may bypass GABA and continue from -keto- of glutamate can be measured to allow calculation of the glutarate/glutamate into the TCA cycle directly. Because glucose is the primary MRS analysis of cerebral cortex from extracts of rats infused fuel for neuronal oxidation, the measurements of the TCA with [1-13C] glucose has been used to measure the time cycle may be converted to measurements of glucose oxida- course of labeling in the GABA and glutamate pools (24, tion using known stoichiometries (17,18). Isotopic labeling of C4-glutamine by the glutamate/glutamine cycle from a [1-13C] glucose precursor. Infused [1-13C] glucose labels neuronal C3-pyruvate. This label is then incorpo- rated via the combined action of pyruvate dehydrogenase and the TCA cycle into -ketoglutarate, which is in rapid exchange with glutamate due to the action of several transaminases. The large glutamate pool in the neuron acts as a label trap with [4-13C]-glutamate accumulating at the rate of the neuronal TCA cycle. Released [4-13C] glutamate from the nerve terminal is taken up by glial transport and the 13C label is transferred to [4-13C] glutamine through the action of glutamine synthetase at the rate of the glutamate/glutamine cycle. Interpretation of glutamine labeling is complicated by 13C label entering by the astrocyte pyruvate dehydrogenase reaction. MRS studies using 15N ammonia, [2-13C] glucose, and [2-13C] acetate, as well as comparison with traditional measurementsof theuptake ofnet glutamineprecursors, haveshown thatthe majorityof labeling in glutamine from [1-13C] glucose is from the glutamate/glutamine cycle (27,36–39). Under conditions of -chloralose anesthesia studies of human cerebral cortex (13,29,35), the rate of the rate of glucose oxidation in GABAergic neurons was GABA synthesis, and by inference glucose oxidation in the estimated to be between 10% and 20% of total neuronal GABAergic pool, was estimated to be on the order of 10% glucose oxidation. This value is similar to previous estimates of total glucose oxidation, although no rates were given. In obtained using isotopic methods and by inhibiting the de- the future, with the higher sensitivity available using inverse gradative enzyme GABA transaminase (24). It should be MRS methods in combination with the development of noted that determination of the rate of GABA synthesis ultrahigh field magnets for human studies, measurements from isotopic methods depends on the assumption that the of the rate of glucose oxidation in GABAergic neurons glutamate precursor pool for GABA is severalfold lower in should be possible in humans. A long-term controversy in brain metabolism studies has been the rate of glucose oxidation in glial cells. Early esti- IN VIVO MRS MEASUREMENTS OF THE mates range from 10% to over 50% of glucose oxidation RATE OF THE GLUTAMATE/GLUTAMINE (49). MRS may be used to measure the rate of glial glucose CYCLE: FINDINGS AND VALIDATION oxidation based on the localization of the enzyme glutamine synthetase in the glia (50). This localization allows the rate The function of the glutamate/glutamine cycle is to prevent of the glial TCA cycle to be calculated from the labeling of depletion of the nerve terminal glutamate pool by synaptic glutamine from glial glutamate. Glial cells have a high capacity for transporting glu- findings were by Van den Berg and co-workers (40), who, tamate from the synaptic cleft in order to maintain a low using 14C isotopic labeling strategies, assigned a rate to glial ECF (extracellular fluid) concentration of glutamate (50, pyruvate dehydrogenase, which they referred to as the small 51). In vivo and in vitro studies indicate that glutamate glutamate pool, of 15% to 25% of total pyruvate dehydro- released by the neuron is taken up by the glia and converted genase (neuronal glial) activity. The pyruvate dehydro- to glutamine by glutamine synthetase (53,54), an enzyme genase rate is equal to the rate of complete glucose oxidation found exclusively in glia (52). Glutamine is transported by the TCA cycle plus the rate of net glial anaplerosis. These from the glia into the ECF where it is taken up by neurons measurements were performed using extract analysis of and converted back to glutamate through the action of whole brains. Two recent 13C MRS measurements of hu- phosphate-activated glutaminase (PAG) (55). Based on ex- mans have measured glial pyruvate dehydrogenase as ac- tensive data from isotopic labeling studies, immunohisto- counting for between 8% (29) and 15% (35) of total pyru- chemical staining of cortical cells for specific enzymes, iso- vate dehydrogenase activity in the occipital parietal lobe. A lated cell, and tissue fractionation studies, it has been limitation of these studies is that they did not measure the proposed that glutamate (as well as GABA) taken up by the rate of the glial TCA cycle, only the pyruvate dehydrogenase glia from the synaptic cleft may be returned to the neuron in step, and therefore the total oxidative energy produced in the form of glutamine (40,56–58). The generally accepted model of the glutamate/glutamine neurotransmitter cycle is the glia was not calculated. Supporting the concept that of glucose oxidation is associated with the large glutamate glutamate neurotransmitter flux is a small fraction of total pool, reflecting primarily glutamatergic neurons. The re- glucose metabolism are findings in isolated cells and nonac- mainder is primarily distributed between GABAergic neu- tivated brain slices of a low rate of label incorporation from rons and glia. The development of new labeling strategies [1-13C] glucose (61). The concept of a metabolically inac- such as [2-13C] acetate and higher sensitivity MRS measure- tive neurotransmitter pool was brought into question in ments should allow the contributions of these cell types to 1995, when, using 13C nuclear magnetic resonance (NMR), be more accurately determined. Within the error of the we measured a high rate of glutamine labeling from [1-13C] MRS measurements, and the contribution of glutamate glucose in the occipital/parietal lobe of human subjects (12). At the time of the initial 13C NMRstudy, the available for other cell types such as dopaminergic and sero- rate of the glutamate/glutamine cycle could not be calcu- toninergic nerve terminals. An objection that has been raised lated due to the lack of a model for distinguishing isotopic to these findings is the possibility that small highly metaboli- labeling from this cycle from other sources of glutamine cally active pools may be missed by the MRS method.