Response prevention: once confrontation has been achieved best ropinirole 1mg medications osteoarthritis pain, patients are asked to refrain from performing rituals buy ropinirole 2mg low price treatment kitty colds. In thought stopping the patient (or initially the therapist) applies a stimulus which counteracts or interrupts the obsessional preoccupation purchase discount ropinirole online symptoms 9 weeks pregnant. Common techniques include shouting “stop” or applying an aversive stimulus such as a sting on the wrist with an elastic band. Eventually, shouting or stinging can be replaced by less dramatic act, such as clenching a fist, at which point thought stopping can be performed unnoticed, in public settings. Behavioural therapy is as effective as pharmacotherapy, and neuroimaging studies show the same changes in cerebral metabolism with successful behaviour therapy as with successful pharmacotherapy (Swartz et al, 1996). However, both are ineffective in 25% of OCD patients. Behavioural therapy has an advantage over pharmacotherapy as the beneficial effects last longer after therapy has ceased. However, behaviour therapy can be difficult to apply if the patient does not have overt rituals (that is, if the symptoms include mental rituals and obsessional slowness). This approach is unacceptable to some patients and ineffective in others. Pharmacological therapy 70% of treatment naïve OCD patients will improve at least moderately with the use of SSRIs (Rasmussen et al, 1993), but most will have residual symptoms and impairments. All SSRIs appear to be effective (Katzman et al, 2014). Treatment of OCD with SSRIs requires larger than the usual antidepressant dose to be sustained for up to 12 weeks for full effect (Kellner, 2010). When response is unsatisfactory, augmentation of an SSRI with an antipsychotic is recommended (Kellner, 2010), in particular, haloperidol, risperidone and aripiprazole. Clomipramine is an older medication, a tricyclic antidepressant (which has a strong serotonin reuptake inhibition action) was the first pharmacological agent to be effective in the management of OCD. Use has declined in favour of the SSRIs, because the newer medications have less side-effects and are less dangerous in overdose. Current opinion is that clomipramine has no therapeutic advantage over the SSRIs, but it retains a role as a second-line agent, applied when the response to SSRIs has been unsatisfactory (Katzman et al, 2014). The relapse rate is very high (24-89%; Abramowitz et al, 2009). Neurosurgery At least 10% of OCD cases are resistant to conventional therapy (Moon et al, 2017). Cingulotomy, disconnecting the outflow of from the orbitofrontal cortex, has been reported to be effective, sustained and safe. Deep brain stimulation (DBS) offers a clinical response of 60% (Bais et el, 2014). It has been found a cost-effective treatment in Korea and the UK (Moon et al, 2017). Electroconvulsive therapy (ECT) ECT has been used in severe cases, especially when complicated by depressive disorder. HOARDING DISORDER Hoarding, the acquisition of, and inability to discard, worthless items even after they appear (to others) to have no value, has long been considered a feature of a range of mental disorders, but most often, OCD (occurring in 18-42% of OCD patients). However, DSM-5 (2013) described hoarding as a distinct disorder. DSM-5 Hoarding disorder – diagnostic criteria in brief A. Difficulty discarding possessions regardless of their actual value B. Perceived need to save the items, distress associated with discarding C. Causes distress, impaired occupational and social functioning It is suggested, “intolerance of uncertainty” (Wheaton et al, 2016) and “decreased cognitive flexibility” (Carbonella and Timpano, 2016) may be contributing factors. The media frequently report on two types of hoarders: 1) those who clutter the outside of their houses with what appears to neighbours to be unsightly rubbish, and 2) those who hoard animals. Both forms may damage real-estate values and the public health. Hoarding inside the home may leave people with almost no living space. Hoarding, with material extending outside the house. The animal welfare organization found 300 cats being kept in a residential house, 70 decomposing corpses, and surfaces covered in inches of animal waste. Animal hoarders generally have good will toward animals. As the hoarding progresses, however, these individuals are unable to care for their animals adequately, but are unable to give them up. Not all hoarding is a result of OCD, and not all hoarding reaches the extremes which makes it “newsworthy”. Hoarding is frequently associated with other psychopathology, and it is unlikely that punishment is the appropriate remedy. These ten watches, various dials, rings, notebooks (unused) and keys (to unknown locks) were among the belongings carried in a bag by an itinerant man with chronic schizophrenia. The collecting of such items may not satisfy the definition of hoarding, as they may have monetary value (although, none of watches were in working order). And further, these watches may have had delusional value to the owner. Not shown in this picture is that the bag was stuffed full of old newspaper clippings and other “rubbish”. This may qualify as “hoarding”, but was the result of a delusion. A well dressed young man with schizophrenia carried his faeces in a backpack. It was recommended by Morarji Desai (Prime Minister of India, 1977-9). However, the practice is followed by devotees in a number of countries. The author has met 2 patients who have had a strong desire (to which they yielded) to drink their own urine. In neither case was the individual psychotic and in neither case was the thought ego- alien. BODY DYSMORPHIC DISORDER DSM-5 diagnostic criteria A. Preoccupation with perceived defects in physical appearance, not apparent to others B.
Symptoms of distorted reality purchase cheap ropinirole on line medications for bipolar, including visual hallucinations and distortion to time are the desired effects of those taking “hallucinogens” such as LSD purchase discount ropinirole on line treatment croup. Drug induced psychotic disorders are not sought after discount 0.25 mg ropinirole with mastercard schedule 8 medicines, but are common with amphetamine use. They feature delusions and auditory hallucinations and may persist for days after the drug has been ceased. This means that the body adjusts to the effect of the substance and greater quantities are needed to produce the same effect. When this adjustment has occurred, the body may “need” the substance to function roughly normally, and withdrawal symptoms (sweating, trembling, body pain) may occur when the drug is not taken. Withdrawal states, particularly with alcohol, may include disorientation (being unaware of the time and place), inability to concentrate and understand what is happening in the environment, and hallucinations (particularly seeing spiders, snakes and other scary creatures). Physical damage to body and brain results from the toxic effect of the substances and/or nutritional neglect. Using alcohol as an example, the toxic effects lead to liver failure and the nutritional neglect (vitamin B deficiency) leads to irreversible brain failure (dementia). In addition, substance abuse leads to mood and sexual problems, destruction of the family, loss of employment and income, and legal problems. The police become involved because of violence or driving offences during the intoxication phase, or due to theft, prostitution or drug dealing, as the user needs to raise money to support the habit. Categorical and Dimensional Systems The current diagnostic systems are descriptive and categorical (they place conditions/disorders into categories/boxes which are distinct from normality). This is suitable for schizophrenia (hallucinations, delusions and thought slippage are distinct from normal). However, some disorders such as generalized anxiety disorders have features which are continuous with normality (we all have some anxiety from time to time, and some have it continuously, but not at the level sufficient to make a diagnosis). Thus, a case can be made that some mental features should be graded dimensionally – that is, along a spectrum (for example, we would all sit somewhere along the anxiety dimension/spectrum). When published, DSM5 retained the previous categorical system. However, an Alternative DSM5 Model for Personality Disorders - a proposed research model of personality was also presented – with a view to moving further in this direction in the future. The suggested dimensions include, Identity, Self-direction, Empathy and Intimacy. Last modified: November, 2015 12 Strong criticisms of the DSM5 has been expressed (Frances, 2013). The problematic DSM-5 personality disorder proposal: options for plan B. Journal of the American Medical Association 2005; 293:2526-2528. A phenomenological investigation of overvalued ideas and delusions in clinical and subclinical anorexia nervosa. Last modified: November, 2015 1 CHAPTER 4 DELUSIONS AND DELUSIONAL DISORDER Delusions are false beliefs that continue to be believed in spite of evidence to the contrary (these beliefs are not held by the general public, or any sub-group of the community). A particular mental symptom may occur in different mental disorders. Delusions may occur in schizophrenia, bipolar disorder (manic or depressed phases), major depressive disorder, substance abuse and major neurocognitive disorders. In these disorders, delusions are accompanied by other signs and symptoms. Delusional disorder is an exception, as in this disorder, delusions are the only symptoms present. A study in anorexia nervosa (Steinglass et al, 2007) found that the fear of weight gain reached delusional proportions in 20% of cases. Body dysmorphic disorder involves preoccupation with “one or more perceived defects in physical appearance”, which are non-existent or mild. In DSM5 this condition is listed under Obsessive- Compulsive and Related Disorders – and when the belief is held with delusional intensity the qualification “without insight” is added – it is not listed under Delusional disorders. Mental Disorder Comment Delusional Disorder Delusions only. Schizophrenia Delusions may take many forms – including persecutory and bizarre. Are accompanied by at least some other symptoms such as hallucinations, problems with logical thought or self-neglect. Bipolar Disorder (mania) Delusions associated with undue confidence, elation and overactivity, rapid speech. Often grandiose plans to make a fortune or establish world peace. Organic Mental Disorder Variable presentations depending on the pathology. Found in most Lewy body disease cases (Gaig et al, 2011). Anorexia nervosa AN patients may have fears of weight gain which reach delusional proportions (Steinglass et al, 2007). A diagnosis is only possible after consideration of the complete clinical picture. Categories of delusions Delusions can be categorized in various ways. The following are not mutually exclusive categories; for example, a delusion may be both bizarre and systematized. Bizarre delusions are absurd and factually not possible. They may involve newly discovered gods or supernatural/space creatures. Grandiose delusions are beliefs that the individual has exceptional beauty, intelligence or influence. Persecutory (or paranoid) delusions include that the individual is being harassed, threatened, watched or bugged. They often involve spies, bikies, God, Satan or neighbours. Delusions of reference are the belief that the everyday actions of others are premeditated and made with special reference to the patient. Commonly patients complain about being talked about on television or the radio. Patients may believe that music played or words spoken on television have been specifically chosen to identify or annoy them. People crossing the street or coughing may be interpreted as making purposeful actions, performed to indicate something to, or about, the patient. Nihilistic delusions are the belief that part of the individual or the external world does not exist, or that the individual is dead (Cotard syndrome, see later). Financially comfortable individuals may believe they are destitute, in spite of bank statements to the contrary. Patients who believe they have no head or are dead, are unable to explain how that could be possible, but still hold the belief.
For most of these disor- ders buy 0.25mg ropinirole medications you can give your cat, however buy cheapest ropinirole treatment of uti, whether they occur in autism more fre- quently than expected by chance is unclear 1 mg ropinirole free shipping medicine cabinets with lights. TS has the EPIDEMIOLOGY AND GENETIC strongest association; its population prevalence is 1/10,000, MECHANISMS and up to 25% of individuals with TS meet diagnostic crite- ria for autism or PDD (24)(discussed in more detail below). Prevalence Overall, it has been estimated that approximately 5% of The estimated prevalence of autism has increased since the autistic individuals have an associated medical condition mid-1980s from 3 to 5 cases per 10,000 to a current esti- that may play an etiologic role in the development of the mate of 6 to 10 per 10,000 (2,18). Chapter 41: The Molecular and Cellular Genetics of Autism 551 Environmental Determinants the differential gender distribution across IQs suggests ge- netic heterogeneity. The rapidly diminishing relative risk Investigators have repeatedly postulated that in utero events from first- to second- to third-degree relatives, combined might predispose a fetus to the development of autism. Early with the 4:1 MZ:DZ concordance ratio, indicates that twin studies, for example, suggested that obstetric complica- autism is likely to be due to multiple genes interacting in tions differentiated autistic twins from nonautistic co-twins variable combinations in additive, multiplicative, epistatic, (25). Subsequent examination of these and other data, how- or as yet unknown fashions (35). Estimates of the number ever, has shown that the obstetric complications are typically of genes involved have ranged from at least three (36)to quite minor, the association between autism and complica- more than 15 (37). Furthermore, other disorders composed tions is weak (26), and that the causality may be in- of isolated components of the autism phenotype (e. Similarly, some studies have reported genetics of autism will be complicated as well. The weight of evidence, GENETIC INVESTIGATIONS OF AUTISM however, either fails to support such associations or suggests that they account for only a small minority of autism cases Early genetic investigations of autism were hampered by a (29,30). Thus, although perinatal factors are reasonably in- number of constraints, including small sample sizes, incon- ferred in rare instances (e. The they appear to have either a negligible effect or a minor development of standardized diagnostic criteria and ad- effect of undetermined significance. Multicenter col- Estimates of the frequency of chromosomal abnormalities laborations can now gather large, consistently characterized in autism vary widely. Early studies reported rates as high samples, genome-wide screens are practical, sequence data as 20% (31), though recent surveys have reported lower are available for focused genetic investigations, and chromo- frequencies ranging from 3% to 8% (32–34; Wassink et somal studies are more exact and informative. These rates may increase, tions of autism, which are summarized below. Up to 10% of unexplained cases of MR, for example, have been found to be associated with cytoge- Genome-Wide and Focused Linkage and netic abnormalities detectable only by recently developed Association Studies subtelomeric probes, and similar abnormalities may be Four genome-wide linkage studies of autism have been pub- found in autism as well. All these studies have examined abnormalities currently associated with autism include the families containing at least two affected siblings [affected fragile X mutation, other sex chromosome abnormalities, sibling pair (ASP)families] and are summarized in Table and abnormalities of 15q11-q13 (the Prader-Willi/An- 41. The strongest single finding to emerge from these gelman syndrome (PW/AS)region). The CLSA (39)reported a maximum multipoint posed on a strong genetic predisposition. The heritability LOD score (MLS), calculated using the program GENE- for autism of 90% exceeds that of other common psychiatric HUNTER (41)and based on a likelihood that allowed ex- disorders such as schizophrenia, bipolar disorder, or alcohol- plicitly for heterogeneity (42). The mode of heritability, like other psychiatric disor- ported an MLS (37), but the underlying likelihood was ders, appears to be complex. Autism pedigrees have not been parameterized in terms of a multiplicative model allowing reported that demonstrate mendelian segregation (unless for dominance variance, and calculated using ASPEX (43, the broader autism phenotype is included—see below), and 44). The International Molecular Genetic Study of Autism 552 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 41. GENOME-WIDE LINKAGE STUDIES OF AUTISM Sample Characteristics Findings Research Group Sample Markers Chrom Markers cM MLS Comments IMGSAC (38) 87 ASPs 354 7q D7S530 134. Consortium (IMGSAC)also used ASPEX to calculated the (proband and both parents), and are summarized in Table MLS, but under an additive model that assumed no domi- 41. The Paris Autism Research Interna- tional Sibpair Study (PARISS)used a related MLS, maxi- Chromosome 7 mized over the 'possible triangle' (45), using MAPMAKER/SIBS (40). While all these statistical ap- The most replicated evidence for linkage is to chromosome proaches are related to one another (Huang and Vieland, 7q (Fig. The IMGSAC, examining 87 ASPs, reported in press), they may involve estimation of somewhat different a LOD of 2. A recent appropriate use of these data in aggregate, therefore, is not second-stage analysis of 125 ASPs by this same group re- to directly compare numerical results, but rather to look for ported, in poster format, a multipoint MLS near D7S2533 regions that have either very strong support for linkage (140. The CLSA, examining 75 ASPs, within individual studies or that have recurrent support reported an MLS of 2. The samples This group also found high rates of recombination through- for these focused studies include both ASP families and trios out 7q and evidence of linkage disequilibrium at D7S1824 553 554 Neuropsychopharmacology: The Fifth Generation of Progress 22 Marker cM 21 2 5 D7S2204 91. Inversion breakpoint (54) ovals indicate regions with evidence 31. Translocation breakpoint (54) for linkage or association in autism, D7S500 140. No other candidate genes Chromosome 15q11-Q13 tested thus far have found consistent support. Because of numerous reports of cytogenetic abnormalities (discussed below), chromosome 15q11-q13 has been inten- sively examined in linkage and association studies. None of the currently published genome-wide screens, which all CHROMOSOMAL ABNORMALITIES included tightly spaced 15q11-q13 markers, identified link- age to the region. The Duke/USC group screened fourteen Studies of cytogenetic abnormalities can complement mo- 15q11-q13 markers in their families and reported a maxi- lecular approaches by identifying genes whose effects are mum MLS of 1. Another group has either too small to be detected by linkage or are obscured reported highly significant linkage disequilibrium with the by epigenetic phenomena. The X chromosome and chromo- marker GABRB3 155CA-2, a dinucleotide repeat polymor- some 15q11-q13, for example, have both received scrutiny phism that was not typed in any of the genome-wide screens because they are frequent sites, relative to other regions, of (Buxbaum et al. This result was obtained when cytogenetic abnormalities in individuals with autism. Addi- the data were pooled with a number of other focused studies tionally, linked regions in complex disorders are typically that included this marker. This can be done either by cloning the chromosomal break Candidate Gene Studies points and identifying disrupted genes, or by overlaying Genes tested as candidates for involvement in autism in- deleted regions across individuals in order to delineate a clude genes involved in neurotransmission (i. This section, therefore, focuses on abnormal- positive results have occasionally been reported, replication ities in specific regions: 7q, 15q11-q13, the sex chromo- has been limited. Chapter 41: The Molecular and Cellular Genetics of Autism 555 Chromosome 7 Cytogenetic Chromosome 15q11-Q13 Abnormalities Chromosome 15q11-13 is the most frequent site of autoso- A number of chromosome 7 cytogenetic abnormalities in mal abnormalities in autism. In a recent chromosomal sur- close proximity to the 7q linkage findings have been identi- vey, 6 (2. In one family, netic studies had a gross abnormality of chromosome 15 a paracentric inversion, inv(7)(q22q31. These abnormalities most com- brothers, a sister, and their mother (47).
In any patient with evidence of m al- nourishm ent purchase generic ropinirole line illness and treatment, nutritional therapy should be instituted regardless of DECISIONS FOR NUTRITION IN PATIENTS whether the patient will be likely to eat order 2 mg ropinirole overnight delivery doctor of medicine. If a well-nourished patient W ITH ACUTE RENAL FAILURE can resum e a norm al diet within 5 days purchase ropinirole 0.25mg mastercard medicine you can overdose on, no specific nutritional sup- port is necessary. The degree of accom panying catabolism is also a factor. For patients with underlying diseases associated with excess Decisions dependent on protein catabolism , nutritional support should be initiated early. Patients ability to resume oral diet (within 5 days? M odern nutritional strategies should be aimed at 1. W hat patient with acute renal failure needs nutritional support? At what degree of impairment in renal function should the nutritional regimen 24 hours after trauma or surgery) nutritional support should be be adapted for renal failure? In a patient with multiple organ dysfunction, which organ determines the type of utilized, could increase oxygen requirements, and aggravate tissue nutritional support? Is enteral or parenteral nutrition the most appropriate method for providing The nutritional regim en should be adapted for renal failure when nutritional support? The m ultiple m etabolic alterations char- acteristic of ARF occur when kidney function is below 30% of norm al. Thus, when creatinine clearance falls below 50 to 30 m L per m inute/1. N utrition in patients with acute renal failure (ARF): decision m ak- W ith the exception of severe hepatic failure and massively deranged ing. N ot every patient with ARF requires nutritional support. It is amino acid metabolism (hyperammonemia) or protein synthesis (deple- im portant to identify those who will benefit and to define the opti- tion of coagulation factors) renal failure is the major determinant of the m al tim e to initiate therapy. The decision to initiate nutritional support is influenced by the Enteral feeding is preferred for all patients, including those with ARF. Nutrition and M etabolism in Acute Renal Failure 18. FIGURE 18-29 Patient classification: substrate requirem ents. Ideally, a nutritional program should be designed for each individual acute renal failure (ARF) patient. In clinical practice, it has proved useful to distinguish three groups of patients based on the extent of protein catabo- lism associated with the underlying disease and resulting levels of dietary requirem ents. G roup I includes patients without excess catabolism and a UN A of less than 6 g of nitrogen above nitrogen intake per day. ARF is usually caused by nephrotoxins (am inogly- cosides, contrast m edia, m ism atched blood transfusion). In m ost cases, these patients are fed orally and the prognosis for recovery of renal function and survival is excellent. G roup II consists of patients with m oderate hypercatabolism and a UN A exceeding nitrogen intake 6 to 12 g of nitrogen per day. Affected patients frequently suffer from com plicating infections, peritonitis, or m oderate injury in association with ARF. Tube feed- ing or intravenous nutritional support is generally required, and dialysis or hem ofiltration often becom es necessary to lim it waste product accum ulation. G roup III are patients who develop ARF in association with severe traum a, burns, or overwhelm ing infection. UN A is m arkedly elevated (m ore than 12 g of nitrogen above nitrogen intake). Treatm ent strategies are usually com plex and include parenteral nutri- tion, hem odialysis or continuous hem ofiltration plus blood pressure and ventilatory sup- port. To reduce catabolism and avoid protein depletion nutrient requirem ents are high and dialysis is used to m aintain fluid balance and blood urea nitrogen below 100 m g/dL. M ortality in this group of patients exceeds 60% to 80% , but it is not the loss of renal function that accounts for the poor prognosis. It is superim posed hypercatabolism and the severity of the underlying illness. The gastrointestinal tract should be used whenever possible because enteral nutrients m ay help to m aintain gastrointestinal function and the m ucosal barrier and thus prevent translocation of bacteria and system ic infection. Even sm all am ounts of enteral diets exert a protective effect on the intestinal m ucosa. Recent anim al experim ents suggest that enteral feeds m ay exert additional advantages in acute renal failure (ARF) patients: in glycerol-induced ARF in rats enteral feeding im proved renal perfusion, A, and preserved renal function, B. For patients with ARF who are unable to eat because of cerebral im pairm ent, anorexia, or nausea, enteral nutrition should be provided through sm all, soft feeding tubes with the tip positioned in the stom - ach or jejunum. Feeding solutions can be adm inistered by pum p interm ittently or con- tinuously. If given continuously, the stom ach should be aspirated every 2 to 4 hours until adequate gastric em ptying and intestinal peristalsis are established. To avoid diarrhea, the am ount and concentration of the solution should be increased gradually over several days until nutritional requirem ents are m et. Undesired, but potentially treatable side effects include nausea, vom iting, abdom inal distension and cram ping and diarrhea. The protein content is lower and is confined to high- m ulas designed for subjects with norm al renal function that can quality proteins (in part as oligopeptides and free am ino acids), the also be given to patients with acute renal failure (ARF). M ost form ulations contain Unfortunately, the fixed com position of nutrients, including pro- recom m ended allowances of vitam ins and m inerals. The diets can be supplemented with addi- therapy of patients with chronic renal failure (CRF) can be used. Recently, ready-to- The preparations listed here m ay have advantages also for patients use liquid diets have also become available for renal failure patients. Standard solutions are available with am ino acids, glucose, and lipids plus added vitam ins, trace elem ents, and electrolytes contained in a single bag (“total adm ixture” solutions, “all-in-one” solutions). The stability of fat em ulsions in such m ixtures should be tested. If hyperglycem ia is present, insulin can be added to the solution or adm inistered separately. To ensure m axim al nutrient utilization and avoid m etabolic derangem ents as m ineral im balance, hyperglycem ia or blood urea nitrogen rise, the infusion should be started at a slow rate (providing about 50% of requirem ents) and gradually increased over several days. O ptim ally, the solution should be infused continuously over 24 hours to avoid m arked derangem ents in substrate concentrations in the presence of im paired utilization for several nutritional substrates in patients with acute renal failure. EAA, N EAA— essential and nonessential am ino acids; TPN — total parenteral nutrition. Nutrition and M etabolism in Acute Renal Failure 18.
Such abnormalities could no significant differences in caudate volume between treat- be owing to aberrations in prenatal programmed cell death ment-naive pediatric OCDpatients and age- and sex-case or postnatal reductions or delays in myelination (84) discount ropinirole 0.5 mg amex medications diabetic neuropathy. Localized reductions in putamen volume cent investigation has suggested abnormalities of postnatal associated with OCDsymptom severity but not illness dura- myelination in pediatric OCDpatients (91 discount ropinirole online symptoms after embryo transfer,92) generic ropinirole 0.25 mg with mastercard medicine man 1992. Reduced putamen vol- umes have been reported in Tourette syndrome (99), a con- Striatum dition frequently associated with OCDsymptoms. Putami- Despite the striatum being posited as a primary site of pa- nal lesions associated with OCDalso have been reported in thology in OCD(30), structural neuroimaging studies of isolated case reports (100,101) and pediatric OCDpatients the caudate nucleus in adult OCDpatients have revealed have antibodies directed at the putamen at rates significantly contradictory findings. Scarone and colleagues (93) re- greater than in healthy pediatric comparison subjects (102). Four MRI studies have reported no significant differ- OCDor tics associated with group A hemolytic strepto- ences in caudate size between OCDpatients and controls coccal (GABHS) infections and pediatric patients with (79,82,94,95). Investigation of the other components of the Sydenham chorea and associated OCDand tic behaviors basal ganglia, including the putamen and globus pallidus, compared to healthy children. These conditions are now has not demonstrated volumetric differences between adult referred to as pediatric autoimmune neuropsychiatric disor- OCDpatients and controls (84,94,96,97). These studies ders associated with streptococcal infection (PANDAS) were potentially confounded by several factors including (103,104) and may represent discrete subtypes of OCD illness chronicity, past treatments, heterogeneity of OCD, and tic disorders. Increased basal ganglia volumes may be and differences in imaging methodology used. Structural consistent with hypothesized antibody-mediated inflamma- imaging studies in children may prove especially instructive tion of the basal ganglia in poststreptococcal or OCDor because they allow for examination of neurodevelopmental tic disorders (103,104). Giedd and colleagues (24,26), how- factors and repeated studies for longitudinal assessment. Allen and associates (104) OCDpatients is consistent with reductions in striatal vol- observed plasmapheresis to be dramatically effective in ume (information on striatal volumes was not provided). PANDAS patients in reducing OCD and tic symptom se- FIGURE 113. Measurement of putamen in the axial plane using a manual tracing technique (left). Fron- tostriatal measurement in treatment-naive children with ob- sessive-compulsive disorder. Sequential magnetic resonance imaging of basal ganglia volumes in a male adolescent undergo- ingplasma exchangefor infection-relatedobsessive-com- pulsive disorder. Reprinted from Giedd JN, Rapoport JL, Leonard HL,et al. Casestudy: acute basalganglia enlarge- ment and obsessive-compulsive symptoms in an adoles- cent boy. J Am Acad Child Adolesc Psychiatry 1996;3S(7): 913–915. In fact, Giedd and colleagues (25) conducted serial cal volumes have not been found to differ between adult MRI scans and observed a striking relationship among basal OCDpatients and controls (84,85,105). Jenike and associ- ganglia volume, OCDsymptom severity, and treatment ates (84) did observe increased opercular volumes in OCD with plasmapheresis in an adolescent with autoimmune patients. Grachev and co-workers (105) reanalyzed the 10 OCD(PANDAS) (Fig. Recently, Peterson and col- adult female OCDpatients and matched controls studied leagues (27) reported that higher antistreptolysin O anti- by Jenike and associates (84) using a sophisticated topo- body titers were associated with larger basal ganglia volumes graphic parcellation method (106) and found an increase in OCDpatients with chronic or recurrent streptococcal in six right frontal and four left parcellation units in OCD infections. This finding was not specific to OCD; however, patients. Anterior cingulate, orbitofrontal, and opercular as higher antibody titers were also associated with enlarged cortical volumes did not differ significantly between OCD basal ganglia volumes in attention deficit hyperactivity dis- patients and controls. Grachev and associates (105) also order (ADHD) patients with chronic or recurrent strepto- noted a significant correlation between increased volume of coccal infections (Fig. In fact, Peterson right inferior frontal pars triangularis and right midfrontal and colleagues (27) found robust associations between diag- cortical volumes and poor cognitive performance on non- nosis of ADHD and titers of antistreptolysin O and antide- verbal immediate recall testing. More recent investigation oxyribonuclease B titers, whereas no such association was (107) found localized reduced bilateral orbital frontal vol- seen between antibody titers and a diagnosis of OCDor umes in OCDpatients versus healthy comparison subjects. We also do not know the impact of Superior frontal gyrus and anterior cingulate volumes did chronic or recurrent strepto- not differ between OCDpatients and controls. Further leagues (87) reported no significant differences between study is clearly warranted. It also illustrates how function, neurobehavioral response inhibition, with no ab- brain imaging is exploiting advances in developmental normalities in working memory (delayed response) or pre- neurobiology with important implications for neurodiag- paratory set (Fig. Monkey studies and human clini- nostic assessment and treatment development. A neurode- cal studies suggest that ventral prefrontal cortex plays a velopmental perspective is equally critical as illustrated in critical role in mediating the suppression of context inappro- the following. Subsequent investi- Morphometric MRI measurement of the prefrontal cortex gation demonstrated increased corpus callosal area in treat- has also yielded conflicting findings. Total prefrontal corti- ment-naive pediatric OCDpatients compared to controls, Chapter 113: Imaging and Neurocircuitry of OCD 1627 FIGURE 113. Association of titers, diagnoses, and basal gan- glia volumes. The interaction of antistreptolysin 0 titers with at- tention-deficit/hyperactivity disorder and obsessive-compulsive disorder diagnoses are presented graphically. Basal ganglia vol- umes are adjusted for the effects of all independent variables in the multivariate analysis of covariance (Table 113. These volume residuals are plotted against the raw antistreptolysin 0 values for each of the relevant diagnostic groups. Titers are plotted in dark circles for the noted diagnostic group and in lighter diamonds for all other subjects. Reprinted from Peterson BS, Leckman JF, Tucker D, et al. Preliminary find- ings of antistreptococcal antibody titers and basal ganglia vol- umes in tic, obsessive-compulsive, and attention deficit/hyperac- tivity disorders. In support of this hypoth- The corpus callosum connects the cerebral hemispheres so esis, MacMaster and colleagues (92) reported increased sig- that the genu connects ventral prefrontal cortex and the nal intensity localized to the genu region of the corpus callo- striatum, whereas the splenium connects temporal lobe re- sum in pediatric OCDpatients compared to controls. Increased genu area in pediatric OCDpatients could be Rosenberg and associates (91) also noted that the age- related to excess myelin sheath thickness (92). An alternative related increase in corpus callosal area in healthy children explanation is abnormal pruning or reduction of neural ele- and adolescents was absent in OCDpatients (Fig. This may be less likely Controls achieved comparable corpus callosal areas to their because neuronal apoptosis occurs very early in development age-matched OCDcounterparts between 16 and 18 years of (121), whereas myelinization takes place during the peak age, which is consistent with prior findings of no significant periods of onset of pediatric OCD(122). Postnatal reduction or delay in creased ventral prefrontal cortical volumes in anterior cingu- myelination in OCDhas been hypothesized to be involved late cortex in 21 treatment-naive pediatric OCDpatients 1628 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 113. ANTIBODY AND DIAGNOSIS ASSOCIATIONS WITH BASAL GANGLIA VOLUMES Type 3 Type 3 Independent Basal Sum of Independent Basal Sm of Variable Ganglia Squares Fa Pb Varible Ganglia Squares Fa Pb Age Caudate R 185 622.
Nevertheless buy 2 mg ropinirole with visa symptoms jaw cancer, these studies clearly demonstrate that mRNA is found in striatonigral neurons that contain dynor- cannabinoid self-administration is not confined to humans order 2 mg ropinirole visa symptoms gluten intolerance. The presence of CB1 receptors in sensory (42) and auto- Cannabinoid Receptors nomic peripheral fibers (43 buy 1 mg ropinirole with amex medications not to take after gastric bypass,44) has been reported. CB1 re- It is now widely recognized that most of the neurobehavioral ceptors seem to be mostly restricted to spinal interneurons, and peripheral actions of marijuana and THC result from rather than at the axonal level (45), thus possibly accounting activation of selective receptors, two of which, named CB1 for spinal mechanisms of pain control ascribed to psycho- and CB2, have been cloned and characterized (33,34). However, indirect evidence also exists development of transgenic mice lacking the genes encoding for the presence of CB1 receptors in peripheral sensory affer- for either of these two receptors, the CB1 and CB2-receptor ents (46), a finding thus supporting the concept that canna- knockout mice (35–37), have provided conclusive evidence binoids may also exert analgesia at the peripheral level. The that the effects of THC on motor behavior, body tempera- presence of CB1 receptors in parasympathetic and sympa- ture, cardiovascular function, and nociception, on the one thetic fibers, on the other hand, may be at the basis of hand, and on some immunologic responses, on the other the vascular and smooth muscle–relaxing activity of THC hand, are mediated by CB1 and CB2 receptors, respectively. There is no evidence for the pres- malian tissues and have been found not only in the central ence of CB2 receptors in the central nervous system, except and peripheral nervous systems, but also in both male and for their expression in microglia. Clearly, given that CB2 female reproductive organs, immune cells, the gastrointesti- receptors seem to be mostly confined to cells of the immune nal tract, the liver, and the heart (38). In the central nervous system (34), it would not be surprising to find these proteins system, CB1 receptors are most abundant in the hippocam- only in those central nervous system cells deputed to im- pus (i. Lower density of CB1 receptors is present Studies have revealed that activation of the subunits of G /i in discrete nuclei of other brain regions such as the hypo- Go proteins, with subsequent inhibition of adenylate cyclase thalamus, brainstem, thalamus, and limbic forebrain, thus through both CB1 and CB2 receptors (47), blockade of volt- possibly accounting for THC activity on body temperature, age-activated calcium (Ca2 ) channels of the N- and P/Q- appetite, supraspinal mechanisms of pain perception, sen- type through CB1 receptors (48), and activation of inwardly sory perception, and mood or reward. CB1 receptors are rectifying potassium channels through CB1 receptors (49), associated with nerve fibers and axon terminals, but not may not be the sole intracellular signaling messages deliv- in the neuronal soma. This pattern is consistent with the ered by psychoactive cannabinoids. There is now evidence presynaptic inhibitory effects of cannabinoids on neuro- for the coupling of CB1, but not CB2 receptors, to Gs pro- transmitter release in the brain (see ref. CB1- teins, with consequent activation of adenylyl cyclase. It is expressing cells in mouse forebrain can be divided into dis- not clear yet whether this effect may explain the biphasic tinct neuronal subpopulations. Most of the cells that highly nature of cannabinoid effects on behavior in several tests. In the hippocampus, amygdala, and entorhinal cortex THC and synthetic and endogenous cannabinoids can area, CB1 mRNA is present at low but significant levels either stimulate (50) or inhibit (51) NO formation. The in many non-GABAergic cells that can be considered as former effect results in inhibition of dopamine release from projecting principal neurons. These data are in good agree- invertebrate ganglia, whereas the inhibition of NO release ment with the observation that cannabinoids act on princi- in granule cerebellar cells seems to result from inhibition pal glutamatergic circuits as well as modulate local GABAer- of voltage-activated Ca2 channels. In any case, modulation gic inhibitory circuits by inhibiting glutamate and GABA of NO levels may result in changes in cyclic guanosine Chapter 106: Marijuana 1523 monophosphate intracellular concentrations. Finally, pro- sients in HL60 cells through these receptors. Interestingly, tein phosphorylation catalyzed by mitogen-activated pro- in this study, AEA was shown to be a very weak and partial tein kinase is coupled to both CB1- and CB2-receptor stimu- agonist at CB2 receptors. This intracellular effect, together with agonist at CB2 receptors, AEA, and much more so its meta- inhibition of the cyclic adenosine monophosphate bolically stable analogues (R)-methanandamide and 2′-flu- (cAMP)–dependent protein kinase A, is at the basis of can- oro-2-methyl-arachidonoyl-ethanolamide, act as relatively nabinoid action on the expression of several genes such as potent (Ki between 12 and 100 nM) and selective CB1- krox-24 in HL60 cells (52) or the prolactin receptor and receptor agonists, and thus can be considered useful phar- the high-affinity receptors trk for the nerve growth factor in macologic tools for studies on the bioactivity of endocan- human breast cancer cells (53). Likewise, bly in part because of the rapid metabolism of this com- CB1-induced activation of focal adhesion kinase in hippo- pound both in vitro and in vivo (59), and because AEA is campal slices, an effect suggested to lead to modulation by a partial agonist in some functional assays of CB activity 1 cannabinoids of synaptic plasticity and learning, results (60). In the brain, AEA was shown to exert inhibitory ac- from inhibition of adenylate cyclase and protein kinase A. These ef- Endogenous Ligands (Endocannabinoids) fects probably result from the capability of AEA to induce, by activation of CB1 receptors, modulation of neurotrans- Since the mid-1990s, several fatty acid derivatives have been mitter (e. This neuromodula- substances, however, can displace high-affinity cannabinoid tory action may also underlie AEA regulation of hormone ligands from selective binding sites in membrane prepara- release at the level of the hypothalamus-pituitary-adrenal tions containing the CB1 or the CB2 receptor. Anandamide axis, as well as the antinociceptive effects of the compound (arachidonoylethanolamide, AEA), the amide of arachi- through both spinal and supraspinal mechanisms (63). The other prominent endoge- lated through the regulation of either their biosynthesis or nous ligand is a glycerol ester, 2-arachidonoyl glycerol inactivation. It is commonly accepted that the AEA and 2- (2-AG) (55). These compounds share the ability to bind to AG are not stored as such in cells, but rather are synthesized and to activate CB1 and (particularly in the case of 2-AG) 2 and are directly released by cells 'on demand,' after Ca CB2 receptors. Therefore, they induce a series of pharmaco- influx into the cell (such as that occurring in neurons on logic effects in vitro and in vivo that are, to some extent, depolarization or in mast cells after IgE-mediated activa- similar to those exerted by THC. Other fatty acid deriva- tion) and the hydrolysis of phospholipid precursors (40). The molecular mode of action nolamines (NAPEs) (64). This reaction is catalyzed by a of these latter compounds is still a subject for investigation. Several mechanisms for 1 tionship can be best appreciated with a successful conforma- the inactivation of endocannabinoids have been identified tional model (57), in which AEA may assume a low-energy in neuronal and blood cells. A membrane-bound intracellu- conformation resulting in the superimposition of its n-pen- lar hydrolase catalyzes AEA hydrolysis after its diffusion into tyl chain, carbonyl amide group and ethanolamine hydroxyl neuronal cells and leukocytes (64). A mechanism for the group, respectively, with the n-pentyl chain, the phenolic facilitated diffusion of AEA into cells according to its con- hydroxyl group and the C-9 hydroxyl group in 9-nor-9 - centration gradient across the plasma membrane has been OH-hexahydrocannabinol, a potent THC analogue. Struc- partially characterized as a saturable, temperature-sensitive, ture-activity relationship studies for the interaction with selective and sodium-independent 'carrier' (64). This 'car- CB2 receptors have not been performed yet, the sole excep- rier,' probably a protein, may be used for both the reuptake tion being the article by Sugiura et al. The major enzyme moieties necessary to 2-AG analogues to induce Ca2 tran- responsible for AEA hydrolysis is the fatty acid amide hy- 1524 Neuropsychopharmacology: The Fifth Generation of Progress drolase (FAAH), cloned so far in four different mammalian analgesia while leading to the release of AEA in microdialy- species (65). Moreover, the Because the biosynthetic precursors for AEA and 2-AG, injection of formalin into the paw induced a nociceptive by being products of membrane phospholipid remodeling, response concomitantly to the release of AEA from the peri- are likely to occur in most animal tissues, the two endocan- aqueductal gray and thereby established an correlation be- nabinoids are probably to be found, at least in minute tween supraspinal nociception and endocannabinoid re- amounts, as ubiquitous metabolites. In fact, an earlier investigation had suggested that an compounds to work as endogenous agonists of CB1 and endocannabinoid tone may down-modulate pain percep- CB2 receptors, their tissue concentrations need to be in- tion through CB1 receptors in another region of the brain- creased up to at least 50 to 100 nM after cell stimulation stem, the rostral ventromedial medulla, through the same (e. Furthermore, the inactivation of endocan- shown that blockade of the action or expression of spinal nabinoids may be subject to regulation. In agreement with CB receptors by SR141716A or a CB -receptor antisense 1 1 possible regulation of endocannabinoid levels under physio- oligonucleotide, respectively, leads to hyperalgesia (76), a logic and pathologic conditions, the amounts of AEA or 2- finding thus suggesting the existence of an endocannabinoid AG have been found to vary during brain development, to tone down-modulating nociceptive response also at the be higher in some of the brain regions with the highest spinal level. The same group gained evidence for the pres- density of CB1 receptors, such as the basal ganglia and the ence of CB receptors in peripheral sensory afferents in the 1 hippocampus (66), to decrease and increase in the striatum skin, and for their involvement in the control of inflamma- and limbic forebrain, respectively, of rats after chronic treat- tory pain (77). It may well be that an endocannabinoid and ment with THC (67), to be inversely correlated with spon- CB1/CB2 receptors mediate tone controlling pain at the taneous activity in the globus pallidus of reserpine-treated peripheral level, because local administration of the antago- rats (68), to vary during pregnancy in mouse uterus, levels nist for each receptor subtype leads to hyperalgesia and ex- of these agents being maximal when the uterus is least recep- ogenous AEA blocks the painful response of mice to forma- tive to embryo implantation (69), and to be enhanced dur- lin injection. Several studies, taken together with that by ing septic or hemorrhagic shock in rat macrophages and Meng et al. Indeed, several possible regulative mecha- endocannabinoids tonically modulate inflammatory pain nisms have been reported for both the biosynthesis and inac- perception, they may do so at sites different from those of tivation of AEA and 2-AG in isolated, intact cells. There has been considerable interest in determining what role, if any, opioids play in cannabinoid-induced antinoci- PHYSIOLOGIC ROLE OF ENDOGENOUS ception. In one study, marijuana produced significant dose- SYSTEM dependent antinociception (increased finger withdrawal latency) and behavioral effects.
Neuronal glutamate release is known to increase through glial pyruvate dehydrogenase discount ropinirole 0.25 mg without prescription treatment plantar fasciitis. To test this prediction cheap ropinirole 2mg on line symptoms 16 dpo, 13C MRS was used to measure the rates of neuronal glucose oxidation and the glutamate/ glutamine cycle in the rat cerebral cortex at three levels of cortical electrical activity: isoelectric EEG induced by high- dose pentobarbital anesthesia buy 0.5 mg ropinirole overnight delivery medicine used during the civil war, and at two milder levels of anesthesia (26). During isoelectric conditions, under which minimal glutamate release takes place, almost no glutamine synthesis was measured, consistent with the conclusion that the 13C MRS measurement of glutamine synthesis primarily reflects the glutamate/glutamine cycle. Above isoelectricity, the rates of the glutamate/glutamine cycle and neuronal glucose oxidation both increased with higher electrical activ- ity. The relationship measured in this study between the rate of the glutamate/glutamine cycle and neuronal glucose oxidation is described below (see Determination of the In Vivo Coupling Between the Rate of the Glutamate/Gluta- FIGURE 25. In vivo 13C NMR time course of the human occipi- mine Neurotransmitter Cycle and Neuronal Glucose Oxi- tal/parietal lobe: the time course from one subject of the concen- trations of [4-13C] glutamate and [4-13C]glutamine during a dation). At time 0 on the plot an intravenous infusion of [1-13C] glucose was started. The model is shown to provide an 13C MRS Measurements of the Rate of 13 excellent fit to the data. The rise of [4- C] glutamine is clearly seen to lag the labeling of [4-13C] glutamate, consistent with neu- the Glutamate/Glutamine Cycle in Human ronal glutamate being the main precursor for glutamine synthesis Cerebral Cortex via the glutamate/GABA/glutamine cycle. Determination In 1994 we first demonstrated that in vivo C NMRmay of the rate of the glutamate-glutamine cycle in the human brain be used to measure the rate of glutamine labeling (12,18) by in vivo 13C NMR. Proc Natl Acad Sci USA 1999;96:8235–8240, from [1-13C] glucose in human occipital/parietal cortex. However, the rate of the glutamate/glutamine cycle was not uniquely determined in the initial experiments due to the (mean SD, n 6). In agreement with studies in rat inability to distinguish the glutamate/glutamine cycle from cortex, the glutamate/glutamine cycle is a major metabolic other sources of glutamine labeling. To determine whether flux in the resting human brain with a rate approximately there is a similar high rate of the glutamate/glutamine cycle 80% of the rate of total glucose oxidation. A high rate A time course from the study of Shen and co-workers of the glutamate/glutamine cycle was measured using a two- (29) showing the rapid labeling of C4-glutamine and C4- compartment model, similar to the model used by Shen glutamate from [1-13C] glucose in a single subject is shown and co-workers (29). A best fit of the metabolic model is plotted tion provided by the higher field strength at 4 T allowed through the data. A lag is clearly shown in the labeling of the additional positions of the C2 and C3 resonances of C4-glutamine relative to C4-glutamate, which is consistent aspartate, glutamate, and glutamine to be incorporated into with the large neuronal glutamate pool being the main pre- the modeling. More recently Gruetter and co-workers (35) cursor for glutamine synthesis. The combination of the met- studied six subjects using localized 13C MRS measurements abolic model validated in the rodent and improved MRS of a 45-mL volume in the occipital lobe. The main differ- sensitivity allowed the rate of the glutamate/glutamine cycle, ences from the rates derived from the Shen et al. The lower exchange rate was due to the assign- and a glucose oxidation rate of 0. The major complications in deter- C3, and C4 glutamate and glutamine resonances. Both ap- mining the rate of the glutamate/glutamine cycle from iso- proaches suffer from needing to deconvolute 13C label en- topic measurements are separating the labeling of glutamine tering these carbon positions from pyruvate dehydrogenase from the glutamate/glutamine cycle from alternate path- from the label entering via pyruvate carboxylase. In the fu- ways of glutamine synthesis and isotopic exchange, and dis- ture these differences should be reconcilable by using label- tinguishing different pathways of neuronal/glial glutamate ing strategies such as [2-13C] glucose, which labels glutamate trafficking. To overcome these obstacles the metabolic mod- and glutamine internal positions only by pyruvate carboxyl- eling of the glutamate/glutamine cycle has been extended ase. If the anaplerotic pathway is due to glutamate oxidation to include ammonia detoxification, alternate pathways of (see Validation of the 13C MRS Glutamate/Glutamine glutamate trafficking, and glutamate oxidation (27). The Cycle Measurement by Correlation with Brain Electrical MRS rate measurement has been validated by several strate- Activity, above) as opposed to ammonia detoxification, the gies including (a) comparison of the rate of glutamine syn- rate of the glutamate/glutamine cycle reported in both stud- thesis measured under different ammonia levels with mea- ies is an underestimate by the calculated rate of anaplerosis. The results of these studies indicate that the glutamate/ Cellular and Molecular Evidence that glutamine cycle is the major pathway of glutamine synthesis Astroglia have a Major Role in the and neuronal/glial glutamate trafficking under normal con- Uptake of Glutamate Released from ditions, with a rate similar to the rate of neuronal glucose Neurons oxidation under conditions of high electrical activity. Mea- The high rate of the glutamate/glutamine cycle indicates surements in awake nonstimulated human cerebral cortex that astroglial uptake of glutamate and GABA plays a key have found that the rate of the glutamate/glutamine cycle role in maintaining the low extracellular levels of these neu- is between 60% and 80% of total glucose oxidative metabo- rotransmitters needed for proper receptor-mediated func- lism (29,35). There is considerable evidence from several lines of Objections have been raised to the MRS measurement of research that support this conclusion. Overstimulation of the glutamate/glutamine cycle for having neglected alternate glutamate receptors can lead to excitotoxicity (76,77). Stud- pathways of glutamate trafficking and the need for compari- ies of glutamatergic synapses have shown them to be closely son with direct measurements of neuronal glutamate release. Glutamate and GABA trans- to assess these pathways and under physiologic conditions porters are sodium dependent and electrogenic and are pres- they were found to account for less than 20% of glutamate ent on both neurons and glia (58,78–80). However, under pathologic conditions such as porters have an affinity, Km,of1to3 M (80), which is seizure the rate of these pathways may be much higher. Immunohistochemical studies have showed that the to total neuronal/glial glutamate trafficking. However, the glutamate transporters GLT-1 and GLAST (glutamate as- unambiguous in vivo measurement of glutamate oxidation trocytic transporter) are localized primarily in astrocytes (48, will require strategies for eliminating isotopic labeling from 81–83), whereas EAAC1 is found on neurons (51). Although direct measurement of bulk neu- sense oligonucleotides directed against the astrocytic gluta- ronal release of glutamate for comparison with 13CMRS mate transporters GLT-1 or GLAST in vivo results in ele- is presently not possible, advances in molecular and cellular vated ECF glutamate in vivo and excitotoxicity (84,85). The methods for studying glutamate transport indicate that neu- majority of glutamate uptake after its release appears to be rotransmission is the major, if not exclusive, pathway of either postsynaptic or astroglial (86,87), although an elec- glutamate release from glutamatergic neurons and the vast 25: Glutamate and GABA Neurotransmitter Cycles 327 majority of this flux is taken up by astroglia in the cerebral cortex. Correlation of the MRS glutamate/glutamine cycle with indirect measures of neuronal glutamate release such as microdialysis and nerve terminal labeling would be highly desirable, as would further studies better defining the rele- vant pool sizes and enzyme distribution in glia and gluta- matergic neurons, particularly in regions other than the ce- rebral cortex. DETERMINATION OF THE IN VIVO COUPLING BETWEEN THE RATE OF THE GLUTAMATE/GLUTAMINE NEUROTRANSMITTER CYCLE AND NEURONAL GLUCOSE OXIDATION This section presents evidence from MRS and other studies for a model of the coupling between the glutamate/gluta- FIGURE 25. An approximately 1:1 correlation between the mine cycle and glial glucose uptake and subsequent neu- rate of oxidative glucose consumption and the rate of the gluta- mate glutamine cycle. The rate of neuronal glucose oxidation ronal oxidation. The model is based on work in cellular (CMRglc(ox)) and the glutamate/glutamine cycle (Vcycle) was mea- systems primarily by Magistretti and co-workers (90) and sured by 13C MRS at 7 T in the rat somatosensory cortex at differ- recent findings, using 13C MRS in rat cortex, that the gluta- ent levels of cortical activity induced by anesthesia. Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc the rate of total glucose oxidation in the awake nonstimu- Natl Acad Sci USA 1998;95:316–321, with permission. Several comprehen- sive reviews of the evidence from molecular and cellular studies supporting glial localization of glucose uptake re- lated to functional neuroenergetics have been published by neuronal glucose oxidation both increased with increasing Magistretti and co-workers (52,89) and are not duplicated electrical activity. The focus of this section is on the evidence from in an approximately 1:1 relationship between the increase in vivo studies that support the model and key tests that remain the rates of the glutamate/glutamine cycle and neuronal to be performed. Under the highest cortical activity studied, the glutamate/glutamine cycle rate Determination by 13C MRS of the was approximately 80% of the rate of neuronal glucose oxi- dation.