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Introduction It has long been suspected that bedtime hunger can potentially disturb sleep. The neural circuits that control sleep are now known to receive signals of appetite and energy balance via hypocretin/orexin neurons from the lateral hypothalamus. But there remains need to specifically identify how, and under what conditions, appetite mechanisms affect human sleep. This study documents the relationship between bedtime hunger and subsequent sleep efficiency in users of a consumer sleep measurement device. Methods The Zeo headband (sold to the public during 2009–2013) used detected electrical potentials to periodically calculate the most probable stage of sleep or wake. Users uploaded sleep records online and could track nightly conditions — including bedtime hunger — on provided rating scales. De-identified summary data from these nightly records were aggregated into a research registry. We extracted the sleep records with bedtime hunger ratings and analyzed them using multilevel modeling to identify within-person and between-person relationships between bedtime hunger and sleep efficiency. We decomposed bedtime hunger ratings into person-mean hunger and nightly hunger, the difference between each night’s hunger rating and the person’s mean. Results 4,284 nightly sleep records with a bedtime hunger rating were provided by 183 people (age 19–77, 68% male, mean: 23 records/person). Sleep efficiency was not related to person-mean hunger (p=0.26), but was inversely related to nightly hunger that night (p=0.01). The model predicted a within-person difference in sleep efficiency between nights with high, versus low, nightly hunger that varied across the people in the sample (mean [range]: -2.4 [-12.5-1.6] percentage points) and correlated positively with typical sleep efficiency (r=0.73, p=0.00) and negatively with unexplained variability in sleep efficiency (r=-0.47, p=0.00). Conclusion For the people in this dataset, on average, going to bed hungrier than usual predicted reduced sleep efficiency that night. The effect was strongest in people who tend toward low and variable sleep efficiency. This finding strongly suggests that bedtime hunger can indeed disturb sleep, especially in poor sleepers. Further research is needed to determine who is most affected and to understand implications, such as for weight management, eating disorders, food insecurity, or sleep-supporting foods and dietary practices. Support (if any) USDA-NIFA-AFRI and NIH-NCATS

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-l-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-l-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.

Background: In recent years, the impact of various micronutrients on the symptoms of ADHD and ASD has been studied. Our study was aimed at evaluating the association between the level of serum magnesium, zinc and ferritin in children diagnosed with ADHD and/or ASD. Methods: This case-control pilot study consisted of 32 children who met DSM-V criteria for ADHD, 15 children who met DSM-V criteria for ASD and 12 age-matched control children from Electronic Medical Record database. Serum magnesium, zinc and ferritin values were com-pared with ANOVA. Results: Blood ferritin level was found to be significantly lower in affected groups (F=5.9, p=0.0056). A trend towards decreased values of plasma zinc level was also found in affected children (F=2.25, p=0.12); whereas no suggestion of any difference in blood magnesium levels between three groups was significant. Non-parametric analyses were also run and the p value for ferritin 0.08, showed weaker evidence of significance. Conclusions: Results of this study indicated that low level of blood ferritin may be a risk factor for development of ASD and ADHD. Future investigations with larger controlled trials are needed and correlational studies would also be helpful.

Paranoia in methamphetamine (MA) users is not well characterized or understood. To investigate this phenomenon, we created the Methamphetamine Experience Questionnaire (MEQ), and tested its reliability and validity in assessing MA-induced paranoia. We administered the MEQ to 274 MA-dependent subjects. Of the total subjects, 45% (123) first experienced paranoia with MA use; 55% did not. Obtaining or using a weapon while paranoid was common (37% and 11% of subjects with MA-induced paranoia, respectively). Test-retest and inter-rater reliability for MA-induced paranoia showed substantial agreement (kappa = .77, p < .05 and kappa = .80, p < .05, respectively). First episodes of paranoia occurred more often with intravenous use of MA, and subsequent episodes at higher doses. There was modest correlation between paranoia on the MEQ and the Brief Symptom Inventory (BSI) paranoid ideation scale (rho = .27, p < .05). As expected, there was a poor correlation between paranoia on the MEQ and the BSI depression scale (rho = .14, p = .07). The MEQ provides useful information on drug use variables that contribute to paranoia commonly associated with MA use. (Am J Addict 2010;00:1-14).

Background Methamphetamine (MA) abuse causes damage to structures within the human cerebrum, with particular susceptibility to white matter (WM). Abnormalities have been reported in anterior regions with less evidence of changes in posterior regions. Methamphetamine abusers have also shown deficits on attention tests that measure response conflict and cognitive control. Methods We examined cognitive control with a computerized measure of the Stroop selective attention task and indices of WM microstructure obtained from diffusion tensor imaging (DTI) in the callosal genu and splenium of 37 currently abstinent MA abusers and 17 non-substance abusing control subjects. Measurements of fractional anisotropy (FA), apparent diffusion coefficient (ADC) of callosal fibers, and diffusion tensor eigenvalues were obtained in all subjects. Results The MA abusers exhibited greater Stroop reaction time interference (i.e., reduced cognitive control) (p = .04) compared with control subjects. After correcting for multiple comparisons, FA within the genu correlated significantly with measures of cognitive control in the MA abusers (p = .04, Bonferroni corrected) but not in control subjects (p = .26). Group differences in genu but not splenium FA were trend significant (p = .09). Conclusions Methamphetamine abuse seems to alter anterior callosal WM microstructure with less evidence of change within posterior callosal WM microstructure. The DTI indices within the genu but not splenium correlated with measures of cognitive control in chronic MA abusers.

Long-term methamphetamine (MA) abuse is associated with a wide range of deficits on explicit tasks of selective attention. Less is known however about the effects of MA abuse on implicit measures of attention. Accordingly, we used a computerized spatial priming task to assess implicit attentional processes in 54 MA dependent subjects (mean age=37.04+/-8.9 years) and 32 healthy controls without history of any form of substance abuse (mean age=33.63+/-7.05 years). The MA dependent subjects had been drug-abstinent a minimum of 3 weeks with a mean duration of MA use of 13.27+/-7.75 years. The MA dependent subjects did not differ significantly from controls on either inhibitory priming [p=.37] or facilitory priming) [p=.69]. This result comports with our earlier findings of intact object-based priming in MA dependent individuals and suggests that intact priming effects extend across spatial domains. Further, this pattern of sparing suggests that cortical brain systems typically supporting implicit attentional functioning are relatively intact in long-term MA dependent individuals whereas brain systems supporting explicit attentional processes are affected.

Background Methamphetamine abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. Methods By using a computerized measure of selective attention and single-voxel proton magnetic resonance spectroscopy, we examined the relationship between attentional control and brain metabolite levels in the anterior cingulate cortex (ACC) and primary visual cortex (PVC) in 36 currently abstinent methamphetamine abusers and 16 non–substance-using controls. Results The methamphetamine abusers exhibited reduced attentional control (i.e., increased Stroop interference) compared with the controls ( p = .04). Bonferroni-adjusted comparisons revealed that ACC levels of N -acetyl aspartate (NAA)–creatine and phosphocreatine (Cr) were lower and that levels of choline (Cho)–NAA were higher in the methamphetamine abusers compared with the controls, at the adjusted p value of .0125. Levels of NAA-Cr, but not of Cho-NAA, within the ACC correlated with measures of attentional control in the methamphetamine abusers ( r = −.41; p = .01) but not in controls ( r = .22; p = .42). No significant correlations were observed in the PVC (methamphetamine abusers, r = .19; p = .28, controls, r = .38; p = .15). Conclusions Changes in neurochemicals within frontostriatal brain regions including ACC may contribute to deficits in attentional control among chronic methamphetamine abusers.

Background Selective attention comprises multiple, dissociable component processes, including task shifting and selective inhibition. The goal of this study was to test whether task-shifting, selective inhibition, or both processes were impaired in long-term but currently abstinent methamphetamine-dependent individuals. Methods Participants were 34 methamphetamine-dependent subjects and 20 nonsubstance abusing controls who were tested on an alternating-runs switch task with conflict sequences that required subjects to switch tasks on every second trial (AABBAABB). Results Methamphetamine-dependent individuals committed more errors on trials that required inhibition of distracting information compared with controls (methamphetamine = 17%; controls = 13%; p = .02). By contrast, error rates did not differ between the groups on switch trials (methamphetamine = 7%; controls = 6%; p = .68). Conclusions These results indicate that selective inhibition, but not task switching, is selectively compromised by methamphetamine.

Methamphetamine use is on the rise, with an imminent upsurge of abuse and dependence reported across the United States. Currently, preliminary evidence suggests that methamphetamine dependence may cause long-term neural damage in humans, with concomitant deleterious effects on cognitive processes such as memory and attention. This selective review provides an outline and synthesis of studies that assess the neurotoxic mechanisms of methamphetamine, as well as those that evaluate the cognitive sequelae of methamphetamine abuse.

Studies based on animal models report that methamphetamine (MA) abuse diminishes dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo human study, we used proton magnetic resonance spectroscopy (MRS), which yields measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine frontal brain regions possibly affected by methamphetamine dependence (MD). We tested the hypothesis that MD subjects would exhibit abnormally low levels of NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further hypothesized that the primary visual cortex, which receives relatively less DA innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD subjects. Subjects included nine MD men (mean+/-standard deviation (S.D.)=32.5+/-6.4 years) and nine age-matched control men (mean+/-S.D.=32.7+/-6.8 years). The MD subjects were MA-free for 4-13 weeks. Proton MRS metabolites were expressed as ratios of creatine; the absolute values of which did not distinguish controls and MD subjects. With regard to metabolite ratios, the MD men had significantly lower NAA/Cr in the cingulum (mean+/-standard error (S.E.): control=1.46+/-0.03; MD=1.30+/-0.03; Mann-Whitney P=0.01) but not in the visual cortex (mean+/-S.E.: control=1.64+/-0.06; MD=1.69+/-11; Mann-Whitney P=0.52) relative to controls. These results provide evidence for NAA/Cr deficit that is selective to the anterior cingulum, at least with respect to visual cortex, in MD subjects. The neuronal compromise that these changes reflect may contribute to the attentional deficits and dampened reward system in MD.

A Stroop negative priming (NP) task was used to assess immediate selective attention and priming in schizophrenia and schizoaffective disorder. Subject groups were comprised of 12 state hospital inpatients (41.8 ± 7.5 years of age), 11 outpatients (39.8 ± 7.5 years of age), and 16 controls (36.4 ± 11.7 years of age). Compared with the control group and the outpatients, inpatients failed to exhibit NP [F(2,36) = 6.09, p < .01], despite exhibiting equivalent Stroop RT interference (p > .05). Error rates did not differ significantly between the 3 groups. Although medication types and dosages were similar between the 2 patient groups, length of illness was significantly longer in the inpatients (19.8 years) than in the outpatients (12.4 years; p < .05). Positive symptom ratings were also significantly higher in the inpatients. The finding of reduced NP in the state hospital patients appears to be related to severity of symptomatology and chronicity of illness. (JINS, 2002, 8, 794–803.)

a Abstract Chronic methamphetamine abuse is associated with disruption of frontostriatal function involving serotonin and dopamine circuitry. Clinically, methamphetamine-dependent (MD) individuals are highly distractible and have difficulty focussing. Here, we used a computerized single-trial version of the Stroop Test to examine selective attention and priming in MD. Subject groups comprised eight MD men (31.7"7.2 years of age), who had used methamphetamine for 15.75"8.4 years but were currently abstinent for 2-4 months, and 12 controls (35.7q9.7 years of age). Compared with the control group, the MD group exhibited significantly greater interference (P-0.05) despite intact priming. Error rates did not differ between the groups. This preliminary finding of reduced cognitive inhibition in MD individuals is consistent with the distractibility they show clinically. Furthermore, the dissociation between explicit attentional performance and priming effects suggests that some attentional functions are not as affected by long-term methamphetamine use as others. 2002 Elsevier Science Ireland Ltd. All rights reserved.

Using [O-15]-H2O PET Carter et al. (1997) reported that medicated patients with schizophrenia performing computerized single trial Stroop (1935) showed a reduction in the anterior cingulate activation response to the more attention demanding, incongruent Stroop condition. In that study, both patients and controls also showed a direct correlation between anterior cingulate activation and errors committed during incongruent trials of the task. In this study we follow up with an examination of paranoid schizophrenia outpatients and controls with very high resolution positron emission tomography (PET) and the longer half-life tracer [F-18]-fluorinated deoxyglucose (FDG) (Valk et al. 1990). All subjects (10 controls and 9 paranoid schizophrenia patients) were studied with FDG-PET while performing a computerized trial-by-trial version of the Stroop task during the uptake phase of the tracer (Carter et al. 1992). Results: As in previous studies using the single trial Stroop, patients were able to perform the task but made more color-naming errors during incongruent trials than controls. The patients in the present study showed a trend towards increased metabolic activity in the right anterior cingulate cortex. In the patient group, but not in controls, the anterior cingulate glucose metabolic rate correlated positively with the total incongruent trial errors. Conclusion: These results are consistent with the hypothesis that the anterior cingulate plays a performance-monitoring role during human cognition. This study does not rule out a reduction in error sensitivity in this region of the brain in schizophrenia, as other studies have suggested, however the data show that in unmedicated patients with the paranoid subtype this function is preserved to some extent.

The regional cerebral metabolic rates of 19 male medication-withdrawn schizophrenic patients were determined by positron emission tomography (PET) while performing an auditory discrimination task (CPT). Regardless of the accuracy of their CPT performance, the schizophrenic patients had lower metabolic rates in their prefrontal cortex and higher rates in their posterior putamen compared to 41 healthy males. Abnormally low right anterior midprefrontal cortex metabolic rates predicted better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response to neuroleptics. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role in the expression of psychotic symptoms and the mediation of their response to antipsychotics.

The authors used a Stroop negative priming paradigm to examine the effects of antipsychotic medication on selective attentional processes. The performance of 14 patients with schizophrenia who were withdrawn from neuroleptic medication was compared with that of 10 medicated patients and 16 matched controls. Results demonstrated an increase in negative priming to normal levels with neurolepetic therapy. In contrast, within-trial interference and facilitation effects appeared to be less sensitive to medication therapy. The sustainment of inhibitory processes over time may differentiate the inhibitory mechanisms of the medication-withdrawn patients from both the medicated patients and the matched controls. The study of sequential inhibitory processes and their response to neuroleptic treatment could be important methods for understanding the temporal parameters associated with inhibition in schizophrenia.

Sustained attentional deficits have been widely reported in groups of medicated schizophrenic patients, but less is known about sequential attentional processes in patients withdrawn from medication. The attentional performance of 12 medication-withdrawn schizophrenic outpatients was compared with that of 16 matched normal volunteers on a Stroop negative priming task. This task allowed examination of both within-trial and between-trial attentional effects. Compared with the volunteers, the medication-withdrawn schizophrenic patients showed normal within-trial attentional effects as measured by standard Stroop interference and facilitation. Across trials, however, the schizophrenics exhibited reduced negative priming compared with the volunteers and in some cases a complete reversal of sustained inhibitory processes. The findings suggest that a normal inhibitory tag occurred during initial selection in the patient group, but it did not influence a subsequent act of selection as was the case for the normal volunteers. Either inhibition decayed at an abnormally fast rate in the patient group or a separate facilatory tag dominated. In either case, priming effects linked to attentional selection were clearly abnormal in the medication-withdrawn patient group.

This story and history are derived from multiple discussions with Dave Park that began when I was a psychiatrist at Turning Point’s Pathways out of Homelessness and Dave was the case manager for many of my patients; a good number of these patients had a current or past history of methamphetamine dependence. When we both left Turning Point, we continued our discussions and thought it might be worth having something in print including Dave’s first-hand eyewitness perspective of the history of methamphetamine use in California. I gave lists of questions and thoughts to Dave and I would then organize his written responses and integrate our research findings. Methamphetamine abuse first appeared in California in the early 1950’s, primarily among former military personnel who had been exposed to methamphetamine or Benzedrine during World War II. The German and Japanese military supplied troops with these drugs to increase aggressiveness and alertness, and Allied soldiers often encountered the stimulants with captured supplies. US and British troops used captured German methamphetamine in North Africa [Amphetamine at War Web Site]. US Air Force pilots used meth during the long-range bombing missions of World War II [Vermont Department of Health Website, 2013; Methamphetamine at War]. After these users returned to civilian life, some became involved in the early motorcycle clubs and gangs, and by the early 1960’s methamphetamine abuse was widespread within the biker community. At one time access to methamphetamine typically had been through physicians, who prescribed stimulants for allergy problems or for weight loss, or through unscrupulous physicians who wrote prescriptions in exchange for cash or favors. In the early 1960’s, bikers or their associates who were college chemistry majors or friends of chemistry majors began manufacturing methamphetamine, which led to the involvement of the motorcycle clubs in the manufacture and distribution of the drug. Although in the early 1960’s methamphetamine was used and abused mostly within the biker community, physicians increasingly prescribed it for women in the general population as an agent for weight loss. In this early period most illegal methamphetamine was pharmaceutical grade, produced from chemical formulas gleaned from the Merck Manual or from information bought from employees of pharmaceutical companies. Though some sellers (connections or dealers) claimed to be using “original German formulas,” buyers usually dismissed these claims as bragging to justify a higher asking price. Rumors of “original German formulas” persist to this day. In the mid-to-late 1960’s, soldiers began coming home from the

Alzheimer's disease (AD) is characterized by a pathological process with specific predilection for association neocortex and the mesial temporal lobes. Recently developed high-resolution positron emission tomographs (PET) are able to quantitate regional cerebral metabolic rates for glucose (rCMRglc) in these brain regions and map the distribution of the metabolic consequences of Alzheimer pathology. In order to evaluate the relative involvement of mesial and neocortical temporal lobe brain regions in AD, we studied 22 AD patients, 11 of whom were mildly demented and 11 of whom were moderately demented in comparison to 8 age-matched control subjects. We used a PET instrument with 2.6 mm in-plane resolution and quantitated rCMRglc in anterior, middle, and posterior temporal neocortex, visual association cortex, primary visual cortex, and mesial temporal cortex. Although the moderately demented AD patients showed significantly lower metabolic rates than controls in visual association cortex and all temporal lobe regions except right anterior temporal neocortex, the mildly demented patients were different from the controls in only middle temporal neocortex. Considerable variability was found in the relative involvement of mesial temporal lobes and temporal neocortex in the AD patients, however, as shown by greater variance of a ratio of mesial temporal lobe rCMRglc to temporal neocortical rCMRglc (MES/NEO ratio) in the AD patients than the controls. A series of stepwise multiple regressions showed that this ratio was related to patient cognitive symptomatology, with more severely memory-impaired patients showing lower MES/NEO ratios, while patients with visuospatial disturbances showed higher MES/NEO ratios. In addition, the only biological variable that was related to this ratio was patient age, with older patients showing lower MES/NEO ratios. These results indicate that mesial temporal lobe structures are not invariably the earliest nor the most severely metabolically involved brain regions in AD and that the relative involvement of the mesial and neocortical temporal lobe is related to the patient's cognitive symptoms and age.

Fourteen subjects (affected, n = 7; at risk, n = 7) from one well-known kindred with adult onset autosomal dominant olivopontocerebellar atrophy (OPCA), were studied with [ 18 F]-2-fluoro-2-deoxy- d -glucose (FDG) positron emission tomography (PET), magnetic resonance imaging (MRI), cognitive testing and scored neurological examination, and compared with normal controls. The neurological examination, MRI and cognitive tests showed no significant differences between at risk and normal control subjects. Mild cognitive deficits were seen in affected subjects; the degree of cognitive change appeared to relate to the severity of the illness. MRI demonstrated cerebellar and brainstem atrophy in all affected subjects. PET studies showed higher global metabolic rates (mean [SD]) in at risk subjects (10.5 [1.5] mg per min per 100 g) as compared to affected (9.0 [0.8] mg per min per 100 g) and normal control subjects (9.1 [1.5] mg per min per 100 g). Normalized (region/global average) regional metabolic rates were reduced in cerebellar hemispheres and vermis, and in frontal and prefrontal areas of affected subjects in comparison to at risk and normal control subjects. These findings indicate that functional changes in some forms of autosomal dominant hereditary cerebellar ataxia may extend beyond the cerebellum and brainstem to involve other parts of the neuraxis.

In a study using a trial by trial version of the Stroop color naming task, we previously found that unmedicated patients with schizophrenia show a pattern of abnormal performance characterized by increased facilitation (speeding) of color-naming, color-congruent words but normal amounts of interference (slowing) of color-naming, color-incongruent words (Carter et al., 1992). Since a similar finding had recently been reported in patients with Parkinson's disease, we suggested that this findings was consistent with hypotheses about the neurobiological substrates of cognitive impairment that draw upon parallel patterns of cognitive performance in the two illnesses. We now report results from an enlarged group of unmedicated patients with schizophrenia that extend our original finding by allowing us to evaluate the role of illness subtype in abnormal performance on the Stroop task. We found that patients with the undifferentiated subtype of the disorder account for the increased Stroop facilitation effect. Patients with the paranoid subtype show their own pattern of abnormal performance, with normal amounts of facilitation and increased interference. These findings are consistent with the results of other studies which suggest that illness subtype is an important source of variability in studies of cognitive functioning in schizophrenia.

Recent work in our laboratory has demonstrated both global and regional reductions in cerebral glucose metabolism in adult subjects with attention-deficit hyperactivity disorder (ADHD). The purpose of the present study was to examine the effects of an acute dose of stimulant medication on cerebral metabolism in adults with ADHD using positron emission tomography with fluorodeoxyglucose-18 as the tracer. Each subject underwent scanning twice, once off-drug and again after receiving a single oral dose of either dextroamphetamine (0.25 mg/kg) or methylphenidate (0.35 mg/kg). Subjects completed behavioral self-report measures before and after the scan and performed an auditory continuous performance task during the tracer uptake period. Neither drug changed global metabolism. Both drugs increased systolic blood pressure, and dextroamphetamine improved performance on the auditory attention task. Each stimulant produced a differential pattern of increases and decreases in regional metabolism throughout the regions of interest that were sampled. Rather than increasing glucose utilization in specific brain regions with lowered metabolic rates in adults with ADHD, stimulants may act by altering glucose use throughout the brain.

Background Insomnia in patients with bipolar disorder (BD) can cause distress, daytime dysfunction, cognitive impairment, worsening of hypomanic/manic symptoms and increased suicide risk. Physicians often prescribe hypnotics for BD patients with insomnia although no hypnotic has a specific FDA indication for this use. In this study, the patterns of use, efficacy and safety of five nonbenzodiazepine hypnotics (NBZHs) were assessed in a large group of outpatients with BD. Method A chart review was performed for all older adolescents and adult BD outpatients in a private outpatient clinic. Clinical data was collected for any patient who had ever been prescribed a NBZH for insomnia and included successful current use, past unsuccessful treatments, side effects, duration of use, concurrent psychiatric medications, and absence or presence of untoward events often associated with chronic use of hypnotics. Results A significant number of BD patients take NBZHs as needed or on a daily basis. Four NBZHs had adequate success rates; ramelteon was limited in efficacy. Some patients experienced satisfactory results from a NBZH after unsuccessful trials with one or more other NBZHs. About half of the current NBZH users are taking them on a daily long-term basis, and none of these patients have experienced unacceptable untoward events. About three quarters of the chronic NBZH users are taking antimanic medications concurrently, and less than half of the chronic users are taking antidepressants. Limitations The results may not be generalizable to other BD populations. A control group was not included in the design. Chronic users of NBZHs were not asked to discontinue their NBZH in order to confirm indication for long-term use. Conclusions Most NBZHs can be effective and safe agents for selected BD outpatients with episodic or chronic insomnia. Failure to respond to one or more NBZH does not preclude a satisfactory response to a different NBZH. Some BD patients who take maintenance antimanic agents also require NBZH treatment. Overactivation from antidepressant treatment does not contribute to chronic NBZH use in most BD patients.

Thirteen medication-free chronic schizophrenic patients and 11 normal control subjects were administered a trial by trial version of the Stroop Color Naming Task which evaluated separately the processes of interference and facilitation. There was no difference between the groups in the amount of interference to naming the colors of color-incongruent words. However, patients with schizophrenia showed significantly greater speed in naming the colors of color-congruent words when compared with control subjects. Thus, facilitation on the Stroop Task appears to be selectively enhanced in schizophrenia. Similar findings have been recently observed in patients with Parkinson's disease. This result may indicate a selective disruption of an automatic inhibitory process in this patient group and is consistent with the hypothesis that a deficit in mesocortical dopamine projections to the frontal cortex underlies some of the cognitive deficits of chronic schizophrenia.

Plasma catecholamines and their metabolites were sampled in 13 medication-free patients with obsessive-compulsive disorder (OCD) and 29 normal controls. In addition to severe OCD symptoms, the patients had significantly higher anxiety, tension, and resting pulse rates than the controls. Nonetheless, mean plasma concentrations of norepinephrine (NE) and epinephrine (E), the catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA), and the stress-related hormone cortisol did not differ between OCD patients and normal controls. When the patients and control populations were combined and average plasma NE and E levels calculated over 35 min, subjects with a higher mean NE output (greater than 1.1 pm/ml) had higher Profile of Mood States depression scores than subjects with a low NE output (less than 1.1 pm/ml). Altogether, these results indicate that elevated plasma catecholamine measures are not likely to be associated with the pathophysiology of OCD.

The goal of this study was to examine behavioral characteristics of currently drug-abstinent methamphetamine (MA)-dependent subjects (n=39) who experienced psychotic symptoms associated with MA abuse. All participants completed the Wender Utah Rating Scale (WURS), which retrospectively assesses Attention Deficit Hyperactivity Disorder-relevant childhood behaviors. The results suggest the existence of possible behavioral markers reflecting an early cognitive vulnerability to the development of frequent MA-induced psychotic symptoms as well as increased vulnerability associated with a family history of psychiatric illness.

The corpus callosum (CC) has been of interest in schizophrenia research because of its possible role in reduced lateralization and because of its sexually dimorphic characteristics. The literature has been replete with structural brain studies that have yielded equivocal results because of failure to address sex differences, handedness, and overall reductions in total brain volume (TBV) associated with schizophrenia. We performed midsagittal corpus callosum area MRI measurements on 71 chronically ill patients with schizophrenia (52 males, 19 females) and 67 controls (49 males, 18 females) using a semiautomated analytic technique subdividing the corpus callosum into five segments. Consistent with a meta-analysis [J. Neurol., Neurosurg. Psychiatry 58 (1995) 457], reductions in total CC area (after controlling for TBV and age) were found in schizophrenia patients relative to controls. However, our effect size, though not statistically significant, was -0.33 compared to -0.18 for the meta-analysis, indicating greater reductions in total CC area in our group of patients. Statistical significance was achieved only in male patients versus male controls (effect size=-0.50). The effect size remained the same when only right-handers were included in the analysis; thus, handedness did not account for this result. CC size was not related to psychiatric symptoms nor cognitive functioning in this group of patients.

A variety of studies have shown an effect of estrogen on dopamine function and suggest that estrogen may modulate central dopaminergic activity. Positron emission tomography (PET) and the dopamine metabolism tracer, [18F]6-fluoro- l -m-tyrosine (FMT) were used to evaluate dopaminergic function in the frontal cortex and striatum in six aged, but pre-menopausal, female monkeys before and after ovariectomy (OVX). Dynamic PET brain uptake data and metabolite-corrected blood input functions were fit to a three-compartment model for FMT uptake. Prior to OVX, all animals showed preferential accumulation of the tracer bilaterally in the striatum and less but measurable activity in the frontal cortex. Paired comparisons showed that there were no significant differences in FMT uptake (Ki) in either brain region before and after OVX. In addition, FMT uptake did not differ from a group of young adult female monkeys at either time point. These findings may represent a compensatory up-regulation of aromatic L- amino acid decarboxylase (AADC) activity.

OBJECTIVE: This study sought to determine the relationship of estrogen levels with psychiatric symptoms and neuropsychological function in female patients with schizophrenia. METHOD: Psychiatric symptoms were assessed and average estrogen and progesterone levels from four consecutive weekly blood samples were measured in 22 female inpatients with schizophrenia who were also administered a neuropsychological battery. RESULTS: There were strong positive correlations between average estrogen level and cognitive function, especially measures of global cognitive function, verbal and spatial declarative memory, and perceptual-motor speed. Correlations of hormone levels with psychiatric symptoms were nonsignificant. CONCLUSIONS: Higher estrogen levels in female patients with schizophrenia are associated with better cognitive ability. These results may have implications for potential treatment of cognitive dysfunction with adjunctive estrogen in female patients with schizophrenia.

The regional cerebral glucose metabolic rates of clozapine-treated and fluphenazine-treated women with schizophrenia and normal controls were obtained by positron emission tomography (PET) using [18F]-2-fluoro-2-deoxy-D-glucose (FDG) as the tracer. The regional metabolic patterns were compared to each other and to the changes previously observed in men. In women, as in men, both clozapine- and fluphenazine-treatment were associated with lower metabolism in the superior prefrontal cortex and higher metabolism in the medial temporal lobe. In both men and women, clozapine treatment led to a greater lowering of inferior prefrontal cortex activity than fluphenazine, which was statistically significant in the larger male cohort. Fluphenazine led to higher metabolic rates in the lateral temporal lobe than clozapine did, but the differences between the two neuroleptics were not statistically significant in either group. The greatest differences in the female as compared to the male responses to fluphenazine and clozapine were in the cingulate and striatum. As compared to controls, the cingulate metabolic rates of women were reduced by 9.1% and 11.4% on clozapine and fluphenazine, respectively; whereas, men have a statistically nonsignificant reduction of 0.1% with clozapine and a 3.2% increase with fluphenazine. In men, fluphenazine was associated with a much greater elevation in basal ganglia metabolic rates than was clozapine, 23.5 % as compared to 3.75%; whereas, in women, basal ganglia metabolic rates are nearly equally increased by fluphenazine (21.6%) and clozapine (15.1%).

Background: There is currently controversy as to the frequency of Alzheimer's disease (AD) in elderly persons with schizophrenia. Several studies have reported an increased frequency of AD in elderly schizophrenics, whereas others have found no increase. This issue is important because it has been hypothesized that medications used to treat schizophrenia may exacerbate AD histopathology. Methods: We examined autopsy cases from a state psychiatric hospital and a Veterans Affairs medical center. Charts were reviewed on 166 subjects to determine if the history warranted a DSM-IV diagnosis of schizophrenia. All subjects had complete gross and microscopic neuropathologic evaluations, which were reviewed for evidence of Alzheimer's disease. Results: Retrospective chart review identified 51 subjects over the age of 55 who met DSM-IV criteria for schizophrenia (mean age = 71.7 years, SD = 8.6, range 56–95 years). Of these 51, only 1 met neuropathologic criteria for AD, a frequency of 2%. Conclusions: The frequency of subjects meeting neuropathologic criteria for Alzheimer's disease in our sample of schizophrenics was equal to or less than that found in the general population. Because institutionalized populations may contain an excess of elderly schizophrenic patients with severe behavioral pathologies, which may in turn reflect the presence of neurodegenerative processes such as Alzheimer's disease, our results may actually overestimate the frequency of Alzheimer's in the entire schizophrenic population. The frequency of Alzheimer's disease in the elderly with schizophrenia may be less than that in the general population.

Background: The comparison of the effects of 2 classes of neuroleptic drugs on regional brain functional activities may reveal common mechanisms of antipsychotic drug efficacy. Methods: The regional cerebral glucose metabolic rates of patients with schizophrenia who were and were not receiving neuroleptic drugs and normal control subjects were obtained by positron emission tomography using fludeoxyglucose F 18 as the tracer. Results: Compared with normal controls and patients not receiving medication, fluphenazine hydrochloride—and clozapine-treated patients had lower global gray matter absolute metabolic rates throughout the cortex. When normalized regional glucose metabolic rates were examined, both medications lowered rates in the superior prefrontal cortex and increased rates in the limbic cortex. Fluphenazine, but not clozapine, increased metabolic rates in the subcortical and lateral temporal lobes, whereas clozapine, but not fluphenazine, decreased inferior prefrontal cortex activity. Conclusions: These changes are consistent with the idea that neuroleptic drugs lead to "compensation" and "adaptation" rather than "normalization" of the functional activities of brain structures in schizophrenia. The overall similarity of their global and regional metabolic effects suggests that both classes of antipsychotic drugs share some common mechanisms of action. One possibility is that of inducing a shift in the balance of cortical to limbic cortex activity. Differential effects in the inferior prefrontal cortex and the basal ganglia might underlie differences in the therapeutic efficacy and side effect profile of clozapine and fluphenazine.

Regional cerebral glucose metabolic rates (rCMRglc) were compared in 18 unmedicated outpatients with schizophrenia and 11 normal controls using high resolution positron emission tomography (PET) and the tracer [F-18]-2-fluoro-2D-deoxyglucose (FDG). From previous work we expected to see abnormal hippocampal rCMRglc in the patients, but no striatal abnormalities. Trial-by-trial Stroop cognitive task, which has been shown to activate the anterior cingulate, was performed within a day of the PET study. As our patients performed abnormally on the Stroop we tested for a correlation between the anterior cingulate rCMRglc and Stroop performance. We found no whole slice cortical average glucose metabolic abnormalities. As predicted we found abnormally decreased left hippocampal rCMRglc in the patients. No striatal or cingulate rCMRglc abnormalities were noted in patients, but they demonstrated a highly positive correlation between anterior and cingulate rCMRglc and Stroop facilitation. Patients with higher Stroop interference had more prominent hippocampal metabolic decreases. These localized temporal lobe abnormalities could account for some of the patient's positive symptoms and are consistent with recent findings in the literature. © American College of Neuropsychopharmacology

Increasing evidence suggests the presence of a lateralizing attentional deficit in schizophrenia. In the present study, 23 unmedicated patients with schizophrenia (mean age = 32.1 years) and 14 age- and sex-matched normal subjects were studied with the Global/Local Task to provide converging evidence for the presence of a left-hemisphere-associated attentional deficit in schizophrenia. This task is sensitive to the integrity of mechanisms involved in discriminating local and global elements of stimuli. Previous research has linked the discrimination of local targets to left hemispheric processes and the discrimination of global targets to right hemispheric processes. As predicted, patients were impaired in the detection of local level targets, consistent with a left hemispheric deficit. The degree of impairment correlated with the patient's level of auditory hallucinations. These results are consistent with previous studies showing an asymmetrical attentional deficit in schizophrenia and left hemispheric dysfunction. The correlation between this deficit and auditory hallucinations is consistent with a hypothesized relationship between this symptom in schizophrenia and left temporal pathology.

The results of a positron emission tomography study of regional cerebral metabolic rates of glucose are reported for 8 healthy old subjects (mean age, 66 yr; standard deviation [SD], 5) and 9 young subjects (mean age, 27 yr; SD, 4.6) using a high-resolution positron emission tomograph and the glucose metabolic tracer 18F-fluorodeoxyglucose. Older subjects showed significantly lower cerebral metabolic rates than did the young subjects, in anterior, middle, and posterior temporal neocortex and in mesial temporal cortex, with the largest differences occurring in anterior temporal cortex (temporal pole). The current findings may reflect either decreases in regional cerebral metabolic rates for glucose that occur with normal aging, or early indications of cognitive dysfunction that is associated with age-related disorders.

Context The hypothesis of a serotonin (5-hydroxytryptamine [5-HT]) dysfunction in obsessive-compulsive disorder (OCD) stems largely from the clinical efficacy of 5-HT reuptake inhibitors. Serotonergic abnormalities in the unmedicated symptomatic state, however, remain to be fully characterized. Objective To investigate brain regional 5-HT synthesis, as indexed by positron emission tomography and theα-[ 11 C]methyl-L-tryptophan trapping constant (K*), in treatment-free adults meeting criteria for OCD. Design Between-group comparison. Setting Department of Psychiatry and Montreal Neurological Institute, McGill University, and Department of Psychology, McGill University Health Centre, Quebec, Canada. Participants Twenty-one medication-free patients with OCD (15 men with a mean [SD] age of 33.2 [9.3] years and 6 women with a mean [SD] age of 35.8 [7.1] years) and 21 healthy controls matched for age and sex (15 men with a mean [SD] age of 32.9 [10.1] years and 6 women with a mean [SD] age of 36.5.5 [8.6] years). Main Outcome Measure Theα-[ 11 C]methyl-L-tryptophan brain trapping constant K*, which was analyzed with Statistical Parametric Mapping (SPM8) and with proportional normalization (extent threshold of 100 voxels with a peak threshold of P ≤ .005). Results Compared with healthy controls, the patients with OCD exhibited significantly greaterα-[ 11 C]methyl-L-tryptophan trapping in the right hippocampus and left temporal gyrus (Brodmann area 20). In the larger subsample of all men, these same differences were also evident, as well as higher K* values in the caudate nucleus. Individual differences in symptom severity correlated positively with K* values sampled from the caudate and temporal lobe of the patients with OCD, respectively. There were no regions where the patients exhibited abnormally low K* values. Volumetric analyses found no morphometric alterations that would account for the group differences. Conclusion The results support previous reports of greater striatal and temporal lobe activity in patients with OCD than in healthy controls and suggest that these disturbances include a serotonergic component. Previously reported glucose metabolic disturbances in OCD involving the orbitofrontal and cingulate cortices, in comparison, might reflect postsynaptic changes in the serotonergic system.

Positron emission tomography of [18F]-2-fluorodeoxyglucose was used to assess the functional brain activity of normal subjects while performing auditory discrimination (CPT), while receiving an identical set of tones as in CPT, but with the instructions that they were background noise, or while at rest. The present study: (1) confirms earlier findings of an association between the functional activity of the right midprefrontal cortex and the performance of auditory discrimination, (2) localizes this increase in right prefrontal cortex activity to the middle prefrontal gyrus; and (3) provides a framework of specific testable hypotheses for the evaluation of the importance of certain limbic and paralimbic areas in the biological determination of sustained attention to be addressed in future studies. The framework accounts for the now confirmed finding that the middle cingulate has lower metabolic activity in CPT than at rest, and new findings of alterations in temporal lobe processing of tones in response to attention.

The cause of childhood hyperactivity (attention deficit-hyperactivity disorder) is unknown. We investigated the hypothesis that cerebral glucose metabolism might differ between normal adults (controls) and adults with histories of hyperactivity in childhood who continued to have symptoms. Each patient was also the biologic parent of a hyperactive child. None of the adults had ever been treated with stimulant medication. To measure cerebral glucose metabolism, we administered 148 to 185 MBq (4 to 5 mCi) of [18F]fluoro-2-deoxy-D-glucose intravenously to 50 normal adults and 25 hyperactive adults while they performed an auditory-attention task. Images were obtained for 30 minutes with a Scanditronix positron-emission tomograph with a resolution of 5 to 6 mm. Whole-brain and regional rates of glucose metabolism were measured with computer assistance by two trained research assistants, working independently, who were blinded to the subjects' status (control or hyperactive).Global cerebral glucose metabolism was 8.1 percent lower in the adults with hyperactivity than in the normal controls (mean +/- SD, 9.05 +/- 1.20 mg per minute per 100 g vs. 9.85 +/- 1.68 mg per minute per 100 g; P = 0.034). In the adults with hyperactivity, glucose metabolism was significantly reduced, as compared with the values for the controls, in 30 of 60 specific regions of the brain (P less than 0.05). Among the regions of the brain with the greatest reductions in glucose metabolism were the premotor cortex and the superior prefrontal cortex. When the seven women with hyperactivity or the six patients with learning disabilities were omitted from the analysis, the results were similar.Glucose metabolism, both global and regional, was reduced in adults who had been hyperactive since childhood. The largest reductions were in the premotor cortex and the superior prefrontal cortex--areas earlier shown to be involved in the control of attention and motor activity.

• In a recent study, we reported abnormal local cerebral glucose metabolic rates in the orbital frontal cortex of patients with obsessive-compulsive disorder. Eight patients with obsessivecompulsive disorder scanned previously were scanned again during treatment with the tricyclic antidepressant clomipramine hydrochloride. Comparisons of local cerebral glucose metabolic rates for both groups showed a relative decrease in regions of the orbital frontal cortex and the left caudate, and an increase in other areas of the basal ganglia, including the right anterior putamen. When comparing patients who responded well to clomipramine with those who were either poor or partial responders, we found significant decreases only in the left caudate of patients who responded well to the drug. The present study suggests that clomipramine-induced improvement in obsessive-compulsive symptoms is associated with a return of regional brain metabolism to a more normal level in regions of the orbital frontal cortex and the caudate nucleus.

Abnormal patterns of metabolite levels have been detected by magnetic resonance spectroscopy in frontostriatal regions of individuals meeting DSM-IV criteria for methamphetamine dependence, but less is known about the effects of drug abstinence on metabolite levels.To assess the effects of long-term methamphetamine use and drug abstinence on brain metabolite levels.To assess regional specific metabolite levels using magnetic resonance spectroscopy imaging techniques in 2 groups of currently abstinent methamphetamine users: methamphetamine users who recently initiated abstinence and methamphetamine users who had initiated abstinence more than 1 year prior to study.Participants were recruited from outpatient substance abuse treatment centers.Eight methamphetamine users with sustained abstinence (1 year to 5 years) and 16 recently abstinent methamphetamine users (1 month to 6 months) were compared with 13 healthy, non-substance-using controls.Magnetic resonance spectroscopy measures of N-acetylaspartate-creatine and phosphocreatine (NAA/Cr), choline-creatine and phosphocreatine (Cho/Cr), and choline-N-acetylaspartate (Cho/NAA) ratios were obtained in the anterior cingulate cortex as well as in the primary visual cortex, which served as a control region.The absolute values of Cr did not differ between controls and methamphetamine users. Methamphetamine users had abnormally low NAA/Cr levels within the anterior cingulate cortex, regardless of the time spent abstinent (F(2,34) = 12.61; P.001). No NAA/Cr group differences were observed in the primary visual cortex (F(2,33) = 0.29; P = .75). The Cho/NAA values for the anterior cingulate cortex were abnormally high in the methamphetamine users who recently initiated abstinence but followed a normal pattern in the methamphetamine users who had initiated abstinence more than 1 year prior to study (F(2,34) = 7.31; P = .002).The relative choline normalization across periods of abstinence suggests that following cessation of methamphetamine use, adaptive changes occur, which might contribute to some degree of normalization of neuronal structure and function in the anterior cingulum. More research is needed to elucidate the mechanisms underlying these adaptive changes.