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Loss of sleep spindling and K complexes have also that can uncover the brain mechanisms that underlie these been noted in dementia effective diclofenac 50 mg rheumatoid arthritis vertigo. Sleep apnea has been observed in descriptive changes generic 50 mg diclofenac with amex rheumatoid arthritis statistics. Nocturnal behavioral disruptions effective diclofenac 50mg rheumatoid arthritis memes, or ize changes in information processing during sleep in rela- 'sundowning' are reported commonly in the clinical man- tion to mental disorders. Despite extensive clinical research in this area, the brain function as it transitions throughout the sleep/wake pathophysiology of sundowning, including its relationship cycle. In this manner, the functional neuroanatomic basis with brain mechanisms that control sleep/wake and circa- of the electrophysiologic abnormalities can be determined dian regulation remain unclear. The discovery of the genetic basis of narcolepsy ease and that the sleep changes are secondary manifestations brings the dream of uncovering the genetic basis of sleep of the disorder. If sleep is viewed as generated by core sleep disruption into closer view. The authors thank craps, pains, nightmares, vivid dreams, visual hallucinations, Robert Y. These changes may result from the disease itself, or to complication from treatment with dopaminergic agents (103–105,107). Regularly occurring periods of eye be related to this comorbid disorder (103). Science Sleep architecture abnormalities include increased awak- 1953;118:273–274. Recherches sur les structures nerveuses et les meca- Chapter 134: Sleep Disturbances and Neuropsychiatric Disease 1957 nismes responsables des differentes phases du sommeil physio- 23. Is there a relationship between roimag 1999;91:59–78. The hypocretin flow changes as a function of delta and spindle activity during neuron system: an arousal system in the human brain. Brainstem control of wakefulness and by synchronized sleep visualized by positron emission tomogra- sleep. Regional brain glu- brain: towards a cognitive neuroscience of conscious states. Magnocellular nuclei of the basal forebrain: sub- 30. Functional neuroanatomy of strates of sleep and arousal regulation. Altered brain ioral state control: cellular and molecular mechanisms. Boca Raton, response to verbal learning following sleep deprivation. Sleep-wake circadian rhythms and aging: potential 32. Hum etiologies and relevance to age-related changes in integrated Neurobiol 1982;1:195–204. Narcolepsy in orexin formation: a role for 'noisy' brain states. Neuroscience 1989; knockout mice: molecular genetics of sleep regulation [see com- 31:551–70. Sleep and dynamic stabilization of neural circuitry: over the sleep cycle: a structural and mathematical model. The mesopontine cholinergic system: a dual role in 38. Inhibitory mechanisms related to another mental disorder (nonsubstance/primary): a in the dorsal raphe nucleus and locus ceruleus during sleep. Handbook of behavioral state control: 244–255; discussion 256–259. Effects of episode dura- 1958 Neuropsychopharmacology: The Fifth Generation of Progress tion and other clinical and psychosocial factors in older adults. Acta Psychiatr Scand 1994;89: movement latency: a predictor of recurrence in depression. Nefazodone—a novel anti- of suicidality in schizophrenia. A longitudinal movement test with arecoline in depression. Slow-wave sleep free amino acid drink challenge on normal human sleep electro- deficits and outcome in schizophrenia and schizoaffective disor- encephalogram and mood. Electroenceph Clin Neurophysiol 1977;43: lism during non-rapid eye movement sleep in major depression: 229.

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Al- GENETICS OF TOURETTE SYNDROME though the strongest evidence points to chronic mechanisms that influence the supply of nutrients by the placenta (96 buy discount diclofenac 100mg line vitamin d arthritis pain, TS may be the most clearly inheritable common neuropsy- 97) buy 50 mg diclofenac with mastercard arthritis relief gnc, other risk factors have been proposed including severe chiatric disorder 100 mg diclofenac fast delivery arthritis patients means. First-degree relatives of TS probands ap- nausea and vomiting during the first trimester, severe mater- pear to be 20 to 150 times more likely to develop TS, com- nal stress during pregnancy, exposure to high levels of an- pared with unrelated persons (83). Concordance rates for drogenic steroids, and chronic or acute hypoxic and is- TS among monozygotic twins approach 90%, if the pheno- chemic injury (98–101). Although no specific mechanism typic boundaries include chronic motor or vocal tics, versus is known to connect these early life events and the develop- 10% to 25% concordance for dizygotic twins, across the ment of TS, preclinical studies have shown that various same boundaries (84). The mode of inheritance remains neural insults during the prenatal and perinatal period result elusive, even after more than 15 years of studies. Some segre- in the delayed emergence of pathology within intercon- gation analyses have supported transmission through an in- nected CSPT circuitry and in specific behavioral abnormali- completely penetrant autosomal dominant major locus (85, ties that are also manifested by individuals with TS, such 86), but in other studies, more complex models could not as reductions in sensorimotor gating of the startle reflex be excluded (87). The impact of assortive mating on inheri- (102–106). These early insults may also set the stage for a tance may be particularly strong in TS, based on higher- heightened stress response in adulthood and altered im- than-predicted rates of bilineal transmission (88–90). Approaches using candi- dysfunction, including OCD, schizophrenia, and affective date genes or chromosomal translocations have offered re- disorders, increased life stressors are associated with symp- sults that were exciting but thus far not generally informa- tom exacerbation in TS. Perhaps the most conservative assessment is TS report worsening of tic symptoms during periods of that susceptibility to TS may be determined by a major stress and anxiety (110). A direct assessment of the relation- gene in some families and by multiple genes of small relative ship between stress and tics revealed that anticipation of a effect in others, with a 'dose-effect' of greater susceptibility stressful medical procedure, a lumbar puncture, has been for individuals homozygous versus heterozygous for these shown to produce greater elevations in plasma adrenocorti- genes. Patients with 1690 Neuropsychopharmacology: The Fifth Generation of Progress TS also have been reported to have elevated levels of cere- aspects of OCD and ADHD, this area of investigation has brospinal fluid norepinephrine and corticotropin-releasing become a major public health issue. Importantly, although stress clearly alters CSPT dynamics and increases symptoms of numerous dif- ferent neuropsychiatric disorders, no existing data implicate TREATMENT a specific etiologic relationship between stress and TS. It is well known that group A -hemolytic streptococcal Therapeutic models of TS emphasize the importance of flex- (GABHS) infections can trigger immune-mediated disease ible, integrated biopsychosocial strategies. Flexibility is im- in genetically predisposed persons (112). Acute rheumatic portant because the nature of the disorder and its impact on fever (RF) can occur approximately 3 weeks after an inade- patients and families change dramatically across its course. In addition to inflamma- is often the case that, when families first present for assess- tory lesions involving the heart (rheumatic carditis) and ment of TS, confusion, fear, anger, and embarrassment fill joints (polymigratory arthritis), rheumatic fever can be ac- an 'information void' and are exacerbated by the very pub- companied by CSPT disease responsible for the manifesta- lic outward manifestations of tics, their deceptive 'voli- tion of Sydenham chorea. Patients with Sydenham chorea tional' appearance, and their sometimes socially unaccept- frequently display motor and vocal tics, obsessive-compul- able content. As in Sydenham chorea, antineuronal an- in them a more intense, visceral sense of desperation. Such tibodies have been reported to be elevated in the sera of reactions reverberate throughout the family and affect the patients with TS (68). The familial nature of the illness means that, almost invariably, when a child first manifests symptoms, close rela- It has been proposed that pediatric autoimmune neuropsy- tives (often parents or siblings) are, or were once, also af- chiatric disorder associated with streptococcal infection (PAN- fected; this sets the stage for a range of 'generational' psy- DAS) represents a distinct clinical entity and includes chological consequences for parents, as painful memories Sydenham chorea and some cases of TS and OCD (115). The most compelling evidence that acute exacerbations of TS and OCD can be triggered by GABHS comes from two independent reports that most patients with childhood- Education onset TS or OCD have elevated expression of a stable B- Initially, much of the distress associated with TS can result cell marker (116,117). The D8/17 marker identifies close from a lack of understanding of the illness. Education about to 100% of patients with rheumatic fever (with or without the natural history of TS, emphasizing the involuntary, 'no- Sydenham chorea), but it is present at low levels of expres- fault' nature of certain brain-behavior relationships, is an sion in healthy control populations. Susan Swedo and essential part of the early treatment of this disorder. This her colleagues reported that in children who met PANDAS process can begin in the diagnostic assessment: faced with criteria, GABHS infection was likely to have preceded neu- a set of simple, matter-of-fact questions about tic symptoms, ropsychiatric symptom onset for 44% of the children, many of which are found in printed, standardized scales whereas pharyngitis (no culture obtained) preceded onset such as the Yale Global Tic Severity Scale (118), parents for another 28% of the children. In a minority of cases and patients recognize that other people must have had (31%), neuropsychiatric symptom exacerbations were asso- experiences much like their own. Although these results are intriguing, they are not waxing and waning nature of the illness. An initial clinical compelling with regard to specific immunologic mecha- visit may be precipitated by a recent exacerbation of previ- nisms linking PANDAS and TS. Clearly, independent repli- ously subclinical or tolerable symptoms. Given the cyclic cation and systematic study of this intriguing phenomenon pattern of TS, such periods are often followed by a gradual may provide a basis for the rational design of therapeutic diminution of symptoms, even in the absence of a specific and preventative interventions. One danger of rapidly initiating complete information in this area is underscored by the medication treatment in TS is that a 'false-positive' re- finding that, based solely on the existing minimal data, par- sponse, based on the normal cyclic fluctuation of symptoms, ents are actively seeking for their children invasive treat- will convince patient, family, or physician that a particular ments such as plasmapheresis and intravenous immuno- medication is 'effective. With emerging preliminary findings suggesting the false hope that it creates, can result in unnecessary medi- possible links between streptococcal infections and some cation exposure and side effects and, ultimately, in height- Chapter 117: Tourette Syndrome and Related Tic Disorders 1691 ened frustration when the illness follows its natural course Dopamine Antagonists toward the next phase of exacerbation. Dopamine antagonists, particularly high potency, D2- course and can thereby be a useful basis for interpreting preferential blockers such as haloperidol, fluphenazine, and future medication effects. These critically important: persons with TS can and should be medications may be most useful in patients with severe, expected to live full, productive lives; as many as half of intractable tics, but they also have undesired side effects, these persons will be largely symptom free by the time they causing blunting of cognitive skills, mood, and motivation enter their twenties; and every persons has strengths that (120–121); when discontinued, these high potency D2 must be nurtured and developed and that will ultimately blockers can precipitate withdrawal dyskinesia and signifi- be more significant determinants of life quality and charac- cant worsening of tics (120).

However purchase diclofenac 100 mg with visa arthritis diet oatmeal, under pathologic conditions such as porters have an affinity generic 100mg diclofenac visa arthritis toes, Km buy diclofenac 50 mg osteoarthritis hip diet,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. A similar ratio of the rate of the glutamate/glutamine Relationship Between the Glutamate/ cycle to the rate of neuronal glucose oxidation has been Glutamine Cycle and Neuronal Oxidative reported for measurements of awake nonstimulated human Glucose Consumption cerebral cortex (13,29,35). To determine the relationship between the glutamate/gluta- mine cycle and cerebral cortex neuroenergetics, 13CMRS A Model for the Stoichiometric Coupling was used to measure the rate of neuronal glucose oxidation of the Glutamate/Glutamine Cycle to and the glutamate/glutamine cycle in rat cortex under con- Neuronal Glucose Oxidation ditions of isoelectric EEG induced by high-dose pentobarbi- tal anesthesia, and at two milder levels of anesthesia (26). Under isoelectric conditions, at tretti and co-workers that nonoxidative glial glycolysis is which minimal glutamate release takes place, almost no glu- coupled to glutamate uptake due to the preference of the tamine synthesis was measured, consistent with the conclu- glia to use glycolytic adenosine triphosphate (ATP) to pump sion that the 13C MRS measurement of glutamine synthesis out the cotransported three Na ions (52,90,91). The pyru- primarily reflects the glutamate/glutamine cycle. Above iso- vate and lactate formed by glial glycolysis would then be electricity, the rates of the glutamate/glutamine cycle and transported to the neuron where it is oxidized. Prior to the 328 Neuropsychopharmacology: The Fifth Generation of Progress glia by the Na /K adenosine triphosphatase (ATPase) on the glial end process membrane requires approximately one ATP molecule (91). Synthesis of glutamine from glutamate through glutamine synthetase requires one ATP molecule per glutamine molecule synthesized (53). If the ATP for this process were derived entirely from glycolysis, then a 1:1 stoichiometry is predicted between glial nonoxidative glucose consumption and the glutamate/glutamine neuro- transmitter cycle. Provided that the lactate formed is re- leased to the neurons for oxidation, then this predicted stoi- chiometry is in excellent agreement with the in vivo 13C MRS findings. If the model is correct, it may account for a substantial fraction of total glucose consumption in the awake nonstim- FIGURE 25. A metabolic model coupling the glutamate/gluta- ulated cerebral cortex. Based on the measurements of the mine cycle to oxidative glucose consumption. In this model the two molecules of adenosine triphosphate (ATP) required by the rate of the glutamate/glutamine cycle and total glucose oxi- astrocyte to take up one molecule of glutamate (Glu) and convert dation in human cerebral cortex (13,29), between 60% and it through glutamine synthetase to glutamine (Gln) are provided 80% of total brain glucose oxidation may be accounted for by nonoxidative glycolysis of one molecule of glucose (Glc). The lactate produced by nonoxidative glycolysis is then released from by this mechanism. Glc, glucose; Lac, lactate; Vgln, rate of glutamine synthesis; Vcycle, rate of the glutamate/glutamine cycle. Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad The model (90) has been criticized for not leaving room Sci USA 1998;95:316–321, with permission. Within the error of the measurements, approximately 10% of total glucose oxidation is available for other neuronal systems such as dopaminergic or serotoninergic.

Information schizophrenia: transient 'on line' storage versus executive func- tioning order diclofenac 50 mg on line arthritis diet express. Neuropsychological indica- trasting attentional profiles in schizophrenic and depressed pa- tors of the vulnerability to schizophrenia 50 mg diclofenac with mastercard arthritis in back of knee. Vulnerability to schiz- pathophysiology of schizophrenia order 100 mg diclofenac visa rheumatoid arthritis and zoloft. Span of apprehen- cessing abnormalities as neuropsychological vulnerability indi- sion performance, neuropsychological functioning, and indices cators for schizophrenia. Acta Psychiatr Scand Suppl 1994;384: of psychosis-proneness. Further evidence for a multidimensional person- 136. Glucose metabolic ality disposition to schizophrenia in terms of cognitive inhibi- correlates of continuous performance test performance in adults tion. Information processing dysfunction continuous performance test. Arch Gen Psychiatry 1977;34: in paranoid schizophrenia: a two factor deficit. Effect of antipsychotic medication on Chapter 51: Endophenotypes in the Genetics of Schizophrenia 715 speed of information processing in schizophrenic patients. Am visual channels in the visual backward masking deficits of schizo- J Psychiatry 1982;139:1127–1130. Am J Psychiatry 1985;142: Ment Dis 1966;143:80–91 170–174. Electroencephalogr Clin Neurophysiol performance in unaffected siblings of schizophrenic patients. Electroencephalogr Clin Neurophysiol 1970;29: dysfunction in schizophrenia: studies of visual backward mask- 429–440. Very short-term memory dys- Steinhauer S, Gruzelier JH, eds. Defective short time constant infor- ogy, and information processing (Handbook of schizophrenia, vol mation processing in schizophrenia. On peripheral and central processes in vision: infer- 182. Auditory ences from an information-processing analysis of masking with P300 abnormalities and left posterior superior temporal gyrus patterned stimuli. P300 in schizophrenia: suppression and information processing. Psychol Rev 1976,83: interactions between amplitudes and topography. P300 subcomponent abnor- schizophrenia: new findings using RDC schizophrenic malities in schizophrenia: II. Longitudinal stability and relation- subgroups and manic controls. Arch Gen Psychiatry 1981;38: ship to symptom change. Symptom correlates of vulnerability to logical and P300 abnormalities in schizophrenics and their rela- backward masking in schizophrenia. Backward-masking performance in chronic and non- (ERPs) as indicators of risk for schizophrenia. Information pro- cents at increased risk of schizophrenia. Z Kinder Jugenpsychiatr cessing deficits of schizophrenia patients: relationship to clinical 1996;24:282—292. II: Familial status of auditory evoked potential 169. Genetic influence tasks in adolescents at high genetic risk for schizophrenia. Schi- on auditory information processing in schizophrenia: P300 in zophr Res 1996;21:171–182. Impaired speed of information processing in nonmed- 191. J Clin Psychol 1984;40: tials in schizotypal personality disorder. A comparison of MMPI-identified schizotyp- P300 in schizotypal personality. Altered P300 topogra- mation-processing deficits and clinical symptoms in schizotypal phy in schizophrenia. Early information processing deficit in schizophrenic psychosis differs from first-episode affective psy- schizophrenia: new findings using RDC schizophrenic chosis and controls in P300 amplitude over left temporal lobe. Arch Gen Psychiatry 1981;38: Arch Gen Psychiatry 1998;55:173–180. Backward masking in differs in schizophrenia and manic psychosis.

H. Murak. George Mason University.