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During the past 20 years the survival after out-of-hospital cardiac arrest (OHCA) has almost quadrupled from 4% in 2001 to 14% in 2020. There has been a huge focus on layman education in cardiopulmonary resuscitation and use of automated external defibrillators (AED), implementation of healthcare staff at 1-1-2 dispatch centers, early recognition of OHCA, establishment of a national AED register with publicly available AEDs, and dispatch of volunteer responders in case of nearby OHCA. This review describes implemented initiatives with the purpose of improving survival from OHCA in Denmark.

Introduction: Approximately 25% of all deliveries in Denmark are medically induced, typically characterized by more intense uterine contractions. The aim of this paper is to investigate the differences in the administration of epidural analgesia and pain experience between spontaneous and medically induced labor in nulliparous and multiparous women., Methods: This is a prospective case-controlled study of 100 participating women in labor. The primary outcome was the timing of administration of epidural analgesia, by delivery progression and frequency. Pain scores were indicated by the McGill Pain Questionnaire and the duration of pain was also notified., Results: In nulliparous and multiparous women, medically induced labor was associated with earlier administration of epidural analgesia in relation to the onset of labor pain, compared to women with a spontaneous onset of labor (10.4 vs 26.10 hours, p=0.0). There was a trend, however not statistical, in the use of epidural analgesia in relation to delivery progression, assessed as dilation of the cervix (3 cm vs 4.5 cm, p=0.07) and towards higher frequency for medically induced labor (51.5% vs 32.8%, p=0.07). In nulliparous women, a reduced period of labor pain was shown in medically induced deliveries compared to spontaneous deliveries (9.30 vs 19.00 hours, p=0.03). However, no significant differences in experienced pain were shown (Score: 28.70 vs 29.60, p=0.194)., Conclusions: Epidural analgesia was administered earlier, and duration of experienced pain was shorter in medically induced labor, in comparison to spontaneous deliveries. However, the experienced pain was not different, possibly explained by a more intense labor process., Competing Interests: Authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2018 Jacobsen L. K.)

Enzyme-linked and electrochemiluminescence immunoassays were developed for quantification of amino (N-) terminal fragments of the skeletal muscle protein titin (N-ter titin) and qualified for use in detection of urinary N-ter titin excretion. Urine from normal subjects contained a small but measurable level of N-ter titin (1.0 ± 0.4 ng/ml). A 365-fold increase (365.4 ± 65.0, P = 0.0001) in urinary N-ter titin excretion was seen in Duchene muscular dystrophy (DMD) patients. Urinary N-ter titin was also evaluated in dystrophin deficient rodent models. Mdx mice exhibited low urinary N-ter titin levels at 2 weeks of age followed by a robust and sustained elevation starting at 3 weeks of age, coincident with the development of systemic skeletal muscle damage in this model; fold elevation could not be determined because urinary N-ter titin was not detected in age-matched wild type mice. Levels of serum creatine kinase and serum skeletal muscle troponin I (TnI) were also low at 2 weeks, elevated at later time points and were significantly correlated with urinary N-ter titin excretion in mdx mice. Corticosteroid treatment of mdx mice resulted in improved exercise performance and lowering of both urinary N-ter titin and serum skeletal muscle TnI concentrations. Low urinary N-ter titin levels were detected in wild type rats (3.0 ± 0.6 ng/ml), while Dmd mdx rats exhibited a 556-fold increase (1652.5 ± 405.7 ng/ml, P = 0.002) (both at 5 months of age). These results suggest that urinary N-ter titin is present at low basal concentrations in normal urine and increases dramatically coincident with muscle damage produced by dystrophin deficiency. Urinary N-ter titin has potential as a facile, non-invasive and translational biomarker for DMD., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [(11)C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V(ND)) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated., Methods: For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [(11)C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n=1 and 30 mg, n=5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (V(T)). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and V(ND). The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [(11)C]GR103545 in vivo K(D) was also estimated., Results: Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that V(T) was reduced in all regions; thus no suitable reference region is available for the radiotracer. V(ND) was estimated reliably from the occupancy plot of naltrexone blocking (V(ND)=3.4±0.9 mL/cm(3)). The IC50 of PF-04455242 was calculated as 55 ng/mL. [(11)C]GR103545 in vivo K(D) value was estimated as 0.069 nmol/L., Conclusions: [(11)C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In both children and adults there is large variability in reading skill, with approximately 5-10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher-order cognition, is associated with reading and reading-related skills, at the level of both brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill., (© 2012 Blackwell Publishing Ltd.)

Pharmacokinetic-pharmacodynamic (PK-PD) modeling greatly enables quantitative implementation of the "learn and confirm" paradigm across different stages of drug discovery and development. This work describes the successful prospective application of this concept in the discovery and early development of a novel κ-opioid receptor (KOR) antagonist, PF-04455242, where PK-PD understanding from preclinical biomarker responses enabled successful prediction of the clinical response in a proof of mechanism study. Preclinical data obtained in rats included time course measures of the KOR antagonist (PF-04455242), a KOR agonist (spiradoline), and a KOR-mediated biomarker response (prolactin secretion) in plasma. Clinical data included time course measures of PF-04455242 and prolactin in 24 healthy volunteers following a spiradoline challenge and single oral doses of PF-04455242 (18 and 30 mg). In both species, PF-04455242 successfully reversed spiradoline-induced prolactin response. A competitive antagonism model was developed and implemented within NONMEM to describe the effect of PF-04455242 on spiradoline-induced prolactin elevation in rats and humans. The PK-PD model-based estimate of K(i) for PF-04455242 in rats was 414 ng/mL. Accounting for species differences in unbound fraction, in vitro K(i) and brain penetration provided a predicted human K(i) of 44.4 ng/mL. This prediction was in good agreement with that estimated via the application of the proposed PK-PD model to the clinical data (i.e., 39.2 ng/mL). These results illustrate the utility of the proposed PK-PD model in supporting the quantitative translation of preclinical studies into an accurate clinical expectation. As such, the proposed PK-PD model is useful for supporting the design, selection, and early development of novel KOR antagonists.

Background: Exposure to nicotine in tobacco smoke during development has been linked to subsequent deficits in attention and memory. The present study tested for evidence that genetic variation may contribute to individual differences in vulnerability to the effects of developmental exposure to tobacco smoke on memory and medial temporal lobe function in adolescents., Methods: Verbal and visuospatial memory were assessed and functional magnetic resonance imaging (fMRI) data were acquired in 101 adolescents systematically characterized for prenatal and adolescent exposure to tobacco smoke, while they performed an encoding and recognition memory task. The impact of allelic variation at loci within CLSTN2 (encoding synaptic protein calsyntenin 2) and KIBRA, shown previously to modulate early and delayed recall of words, on the dependent measures was examined., Results: KIBRA genotype did not exert significant main or interacting effects with prenatal or adolescent exposure to tobacco smoke on verbal or visuospatial memory. Previous observations of a beneficial effect of the CLSTN2 C allele on verbal recall were replicated. Adolescent exposure to tobacco smoke reversed this beneficial effect and was associated with increased activation of parahippocampal gyrus during early and delayed recognition in CLTSN2 C allele carriers. While the CLSTN2 C allele conferred enhanced functional connectivity between brain regions subserving accurate verbal recognition, adolescent exposure to tobacco smoke reversed this effect., Conclusions: These findings extend previous work demonstrating that calsyntenins play an essential role in learning and indicate that this role is modulated both by CLSTN2 genotype and, during adolescent development, by exposure to tobacco smoke.

Prenatal exposure to maternal smoking has been linked to cognitive and auditory processing deficits in offspring. Preclinical studies have demonstrated that exposure to nicotine disrupts neurodevelopment during gestation and adolescence, possibly by disrupting the trophic effects of acetylcholine. Given recent clinical and preclinical work suggesting that neurocircuits that support auditory processing may be particularly vulnerable to developmental disruption by nicotine, we examined white matter microstructure in 67 adolescent smokers and nonsmokers with and without prenatal exposure to maternal smoking. The groups did not differ in age, educational attainment, IQ, years of parent education, or symptoms of inattention. Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired, and auditory attention was assessed, in all subjects. Both prenatal exposure and adolescent exposure to tobacco smoke was associated with increased fractional anisotropy (FA) in anterior cortical white matter. Adolescent smoking was also associated with increased FA of regions of the internal capsule that contain auditory thalamocortical and corticofugal fibers. FA of the posterior limb of the left internal capsule was positively correlated with reaction time during performance of an auditory attention task in smokers but not in nonsmokers. Development of anterior cortical and internal capsule fibers may be particularly vulnerable to disruption in cholinergic signaling induced by nicotine in tobacco smoke. Nicotine-induced disruption of the development of auditory corticofugal fibers may interfere with the ability of these fibers to modulate ascending auditory signals, leading to greater noise and reduced efficiency of neurocircuitry that supports auditory processing.

Prenatal exposure to active maternal tobacco smoking elevates risk of cognitive and auditory processing deficits, and of smoking in offspring. Recent preclinical work has demonstrated a sex-specific pattern of reduction in cortical cholinergic markers following prenatal, adolescent, or combined prenatal and adolescent exposure to nicotine, the primary psychoactive component of tobacco smoke. Given the importance of cortical cholinergic neurotransmission to attentional function, we examined auditory and visual selective and divided attention in 181 male and female adolescent smokers and nonsmokers with and without prenatal exposure to maternal smoking. Groups did not differ in age, educational attainment, symptoms of inattention, or years of parent education. A subset of 63 subjects also underwent functional magnetic resonance imaging while performing an auditory and visual selective and divided attention task. Among females, exposure to tobacco smoke during prenatal or adolescent development was associated with reductions in auditory and visual attention performance accuracy that were greatest in female smokers with prenatal exposure (combined exposure). Among males, combined exposure was associated with marked deficits in auditory attention, suggesting greater vulnerability of neurocircuitry supporting auditory attention to insult stemming from developmental exposure to tobacco smoke in males. Activation of brain regions that support auditory attention was greater in adolescents with prenatal or adolescent exposure to tobacco smoke relative to adolescents with neither prenatal nor adolescent exposure to tobacco smoke. These findings extend earlier preclinical work and suggest that, in humans, prenatal and adolescent exposure to nicotine exerts gender-specific deleterious effects on auditory and visual attention, with concomitant alterations in the efficiency of neurocircuitry supporting auditory attention.

Rationale: Efficient function of neurocircuitry that supports working memory occurs within a narrow range of dopamine neurotransmission. Work in rodents has shown that exposure to nicotine during adolescence leads to nicotine withdrawal emergent alterations in cortical and subcortical dopamine neurotransmission., Objectives: To test for evidence that the efficiency of neurocircuitry supporting working memory is altered during acute smoking abstinence in adolescent daily tobacco smokers., Materials and Methods: Fifty-five adolescent daily tobacco smokers were compared with 38 nonsmokers using functional magnetic resonance imaging while subjects performed a verbal working memory task. Smokers were studied during smoking and after 24 h of abstinence from tobacco use., Results: Performance of a task with high working memory load in the context of smoking abstinence was associated with greater activation of components of the verbal working memory neurocircuit, including left ventrolateral prefrontal cortex and left inferior parietal lobe, among smokers relative to nonsmokers. During smoking abstinence, smokers failed to exhibit increases in functional connectivity between components of the working memory neurocircuit with increasing working memory load observed in nonsmoking adolescents and in prior studies of adults., Conclusions: Smoking abstinence in adolescent smokers is associated with reductions in the efficiency of working memory neurocircuitry and alterations in the functional coordination between components of the working memory neurocircuit. These alterations may stem from effects of nicotine exposure on catecholaminergic systems during adolescent development.

Objective: In animals, nicotine, the primary psychoactive constituent of tobacco smoke, reduces neurogenesis and increases cell loss in both hippocampus and cortex. Accordingly, tobacco smoking has been linked to reduced performance on cognitive paradigms requiring attention and working memory in humans. However, few prior studies have tested for evidence of structural brain alterations in human tobacco smokers. In this study, proton magnetic resonance spectroscopy was used to assess the effects of chronic smoking on neuronal integrity of the hippocampus and anterior cingulate cortex (ACC)., Methods: Absolute concentrations of N-acetylaspartate, total choline (tCho), and total creatine were measured in the left hippocampus and ACC in 13 chronic tobacco smokers and 13 nonsmokers matched for age, sex, and education., Results: The N-acetylaspartate concentration was significantly reduced in smokers relative to nonsmokers in the left hippocampus but not in the ACC. There were no group differences in the tCho and total creatine concentrations in either voxel. However, ACC tCho concentration was positively correlated with magnitude of lifetime exposure to tobacco smoke (pack-years)., Conclusion: The results are consistent with prior observations of hippocampal neuronal damage in rodents receiving nicotine and working memory deficits in human tobacco smokers. The positive relationship between tCho and lifetime tobacco exposure suggests that a component of tobacco smoke, presumably nicotine, may increase cortical membrane turnover or modify cell density. Together, these results add to growing evidence that nicotine exerts neurotoxic effects in human brain, although an a priori nature of the findings cannot be ruled out.

Background: Cannabis remains the most widely used illicit substance by adolescents and is typically consumed by this population in the context of ongoing tobacco use. Human studies have shown that both cannabis and tobacco exert effects on cognitive function; however, little is known about possible interacting effects of these drugs on brain function and cognition during adolescent development., Methods: Verbal learning and memory were assessed in 20 adolescent users of tobacco and cannabis and 25 adolescent tobacco users with minimal history of cannabis use. Functional magnetic resonance imaging was used to examine brain function and functional connectivity while a subset of these subjects performed a verbal working memory task., Results: Delayed recall of verbal stimuli deteriorated during nicotine withdrawal among cannabis users but not among comparison subjects. During high verbal working memory load, nicotine withdrawal selectively increased task-related activation of posterior cortical regions and was associated with disruption of frontoparietal connectivity in adolescent cannabis users relative to comparison subjects., Conclusions: These observations suggest that cannabis use during adolescent development may disrupt neurocircuitry supporting verbal memory formation and that deficits associated with disruption of these neurocircuits are unmasked during nicotine withdrawal.

Rationale: In both animals and humans, nicotine produces behavioral effects that vary across individuals. Studies examining the role of genetic variability in modulating individual response to nicotine in humans have increased, with recent work showing that genetic variation at the dopamine D2 receptor (DRD2) predicts response to pharmacotherapy for tobacco dependence., Objectives: To determine whether a polymorphism of the DRD2 gene, C957T, that alters DRD2 binding availability in humans modifies the effects of nicotine on verbal working memory performance and on processing efficiency of brain regions that support verbal working memory., Materials and Methods: Working memory and brain function were assessed in 36 adult subjects (15,957T allele carriers and 21,957C homozygotes), each of whom was studied twice, once after placement of a placebo patch and once after placement of a nicotine patch. Brain function was assessed using functional magnetic resonance imaging while the subjects performed a verbal working memory task., Results: During performance of a task with high verbal working memory load, nicotine administration worsened performance accuracy and reduced the processing efficiency of brain regions that support phonological rehearsal during verbal working memory in carriers of the 957T allele., Conclusions: These findings are consistent with the notion that genetic variation in DRD2 contributes to individual variation in a range of behavioral and brain responses to nicotine in humans.

Growing evidence from animal studies indicates brain-damaging properties of nicotine exposure. Investigations in humans found a wide range of functional cerebral effects of nicotine and cigarette smoking, but studies focusing on brain damage are sparse. In 22 smokers and 23 never-smokers possible differences of the cerebral structures were investigated using magnetic resonance imaging and voxel-based morphometry. Significantly smaller grey matter volume and lower grey matter density (P = 0.05, corrected) were observed in the frontal regions (anterior cingulate, prefrontal and orbitofrontal cortex), the occipital lobe and the temporal lobe including parahippocampal gyrus, in smokers than in never-smokers. Group differences of either grey matter volume or grey matter density were also found in the thalamus, cerebellum and substantia nigra, among other regions. Smokers did not show greater volumes than never-smokers in any cerebral region. Magnitude of lifetime exposure to tobacco smoke (pack-years) was inversely correlated with volume of frontal and temporal lobes and cerebellum (P = 0.001, uncorrected). The data indicate structural deficits of several cortical and subcortical regions in smokers relative to never-smokers. The topographic profile of the group differences show some similarities to brain networks known to mediate drug reinforcement, attention and working memory processing. The present findings may explain in part the frequently reported cognitive dysfunctions in chronic cigarette consumers.

Active maternal smoking during pregnancy elevates the risk of cognitive deficits and tobacco smoking among offspring. Preclinical work has shown that combined prenatal and adolescent exposure to nicotine produces more pronounced hippocampal changes and greater deficits in cholinergic activity upon nicotine withdrawal than does prenatal or adolescent exposure to nicotine alone. Few prior studies have examined the potential modifying effects of gestational exposure to active maternal smoking on cognitive or brain functional response to tobacco smoking or nicotine withdrawal in adolescents. We examined visuospatial and verbal memory in 35 adolescent tobacco smokers with prenatal exposure to active maternal smoking and 26 adolescent tobacco smokers with no prenatal exposure to maternal smoking who were similar in age, educational attainment, general intelligence, and baseline plasma cotinine. Subjects were studied during ad libitum smoking and after 24 h of abstinence from smoking. A subset of subjects from each group also underwent functional magnetic resonance imaging while performing a visuospatial encoding and recognition task. Adolescent tobacco smokers with prenatal exposure experienced greater nicotine withdrawal-related deficits in immediate and delayed visuospatial memory relative to adolescent smokers with no prenatal exposure. Among adolescent smokers with prenatal exposure, nicotine withdrawal was associated with increased activation of left parahippocampal gyrus during early recognition testing of visuospatial stimuli and increased activation of bilateral hippocampus during delayed recognition testing of visuospatial stimuli. These findings extend prior preclinical work and suggest that, in human adolescent tobacco smokers, prenatal exposure to active maternal smoking is associated with alterations in medial temporal lobe function and concomitant deficits in visuospatial memory.

Unlabelled: A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the 3' untranslated region of the gene (SLC6A3) coding for the dopamine transporter (DAT). This polymorphism has 2 common alleles, designated as 10-repeat (*10R) and 9-repeat (*9R), that have been linked with several human clinical phenotypes. Previous investigations of the effects of the SLC6A3 polymorphism on DAT availability in smaller samples of humans have yielded divergent results., Methods: We assessed genotype at the SLC6A3 promoter VNTR polymorphism in 96 healthy European Americans (age range, 18-88 y) who also underwent SPECT with (123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) for measurement of striatal DAT protein availability. A ratio of specific to nondisplaceable brain uptake (i.e., V(3)'' = [striatal -occipital]/occipital), a measure proportional to the binding potential, was derived. For this analysis, 9-9 homozygotes and 9-10 heterozygotes were grouped as SLC6A3 *9R carriers and contrasted with SLC6A3 *10R homozygotes., Results: The SLC6A3 *9R carriers had significantly higher striatal DAT availability (V(3)'') than did the SLC6A3 *10R homozygotes, controlling for age (F(1,93) = 6.25, P = 0.014, analysis of covariance). The *9R carriers (n = 41, 49.8 +/- 19.5 y) had a mean increase in striatal DAT availability of 8.9% relative to the *10R homozygotes (n = 53, 49.9 +/- 19.2 y). Striatal subregion analysis revealed that the effect of DAT genotype was significant for both the caudate and the putamen., Conclusion: These results support the interpretation of higher DAT levels in association with the *9R allele in European Americans and may relate to previously observed associations between DAT genotype and neuropsychiatric diseases.

Background: In adult animals and humans, nicotine can produce short-term cognitive enhancement and, in some cases, neuroprotection. Recent work in animals, however, suggests that exposure to nicotine during adolescence might be neurotoxic. We tested for evidence of acute and chronic effects of tobacco smoking on cognition in adolescents who smoked tobacco daily and were compared with adolescent nonsmokers., Methods: Verbal working memory, verbal learning and memory, selective, divided, sustained attention, mood, symptoms of nicotine withdrawal, and tobacco craving were examined in 41 adolescent daily smokers and 32 nonsmokers who were similar in age, gender, and education. Analyses were controlled for general intelligence, reading achievement, parental educational attainment, baseline affective symptoms, and lifetime exposure to alcohol and cannabis., Results: In adolescent smokers, cessation of tobacco use increased tobacco craving, symptoms of nicotine withdrawal, and depressed mood. Adolescent smokers were found to have impairments in accuracy of working memory performance irrespective of recency of smoking. Performance decrements were more severe with earlier age of onset of smoking. Adolescent smokers experienced further disruption of working memory and verbal memory during smoking cessation. As a group, male smokers initiated smoking at an earlier age than female smokers and were significantly more impaired during tests of selective and divided attention than female smokers and nonsmokers., Conclusions: Adolescent daily tobacco smokers experience acute impairments of verbal memory and working memory after smoking cessation, along with chronic decrements in cognitive performance that are consistent with preclinical evidence that neurotoxic effects of nicotine are more severe when exposure to nicotine occurs at earlier periods in development.

Cannabis is the most common illicit substance used by adolescents. This paper reports results of a pilot study using fMRI and a working memory task to compare brain function of adolescent cannabis users to that of two control groups, one matched for tobacco use and the other for nonsmokers.

Rationale: 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a potent and selective serotonin neurotoxin whose use is growing among adolescents. Although cognitive deficits among adult MDMA users are well documented, little is known of the cognitive and brain functional sequelae of MDMA use during adolescence., Objective: We tested for evidence of cognitive deficits and changes in brain function in a pilot sample of adolescent MDMA users, who were compared with adolescent non-users of MDMA., Methods: Selective and divided attention and verbal working memory were examined in six adolescent MDMA users and six non-users of MDMA who were similar in age, gender, IQ, and other substance use. Brain function was assessed during performance of the working memory task using functional magnetic resonance imaging (fMRI)., Results: MDMA users had significantly prolonged reaction times during tests of selective and divided attention, and failed to deactivate the left hippocampus normally during high verbal working memory load., Conclusions: MDMA use in adolescence may be associated with cognitive impairments and dysfunction of inhibitory circuits within the hippocampus. Further work is urgently needed to delineate the developmental impact and long-term functional and clinical significance of MDMA use during adolescence.

Background: Nicotine in tobacco smoke can improve functioning in multiple cognitive domains. High rates of smoking among schizophrenic patients may reflect an effort to remediate cognitive dysfunction. Our primary aim was to determine whether nicotine improves cognitive function by facilitating activation of brain regions mediating task performance or by facilitating functional connectivity., Methods: Thirteen smokers with schizophrenia and 13 smokers with no mental illness were withdrawn from tobacco and underwent functional magnetic resonance imaging (fMRI) scanning twice, once after placement of a placebo patch and once after placement of a nicotine patch. During scanning, subjects performed an n-back task with two levels of working memory load and of selective attention load., Results: During the most difficult (dichotic 2-back) task condition, nicotine improved performance of schizophrenic subjects and worsened performance of control subjects. Nicotine also enhanced activation of a network of regions, including anterior cingulate cortex and bilateral thalamus, and modulated thalamocortical functional connectivity to a greater degree in schizophrenic than in control subjects during dichotic 2-back task performance., Conclusions: In tasks that tax working memory and selective attention, nicotine may improve performance in schizophrenia patients by enhancing activation of and functional connectivity between brain regions that mediate task performance.

Objective: A functional polymorphism has been described in the promoter region of the gene (SLC6A4) coding for the serotonin transporter protein (SERT). This polymorphism has two common alleles, designated as long and short. Each allele has been linked with a number of human clinical phenotypes, including neuropsychiatric diseases associated with dysregulation of serotonin transmission. In vitro studies of nonneural cells have suggested that the long allele may have higher transcriptional activity than the short allele. However, the relevance of these findings for SERT levels in the brain remains unclear., Method: The authors assessed genotypes at the SLC6A4 promoter polymorphism in 96 healthy European American subjects who underwent single photon emission computed tomography scanning with [123I]2beta-carbomethoxy-3beta-(4-iodophenyl) tropane ([123I]beta-CIT) for measurement of central SERT availability. A ratio of specific to nondisplaceable brain uptake (i.e., V3"=[brainstem-diencephalon-occipital]/occipital), a measure proportional to the binding potential (Bmax/KD), was derived., Results: The results showed that the main effect of genotype was significant. Post hoc Tukey pairwise comparisons revealed that the short-short homozygotes had significantly greater SERT availability than the long-short heterozygotes. There was a nonsignificant tendency for the long-long homozygotes to have greater SERT availability than the heterozygotes, but no difference was observed between the long-long homozygotes and the short-short homozygotes. The effect of age was significant in the analysis of covariance model., Conclusions: These results do not suggest higher central SERT levels in association with the long allele in European American subjects but point to a more complex relationship between SLC6A4 genotype and protein availability.

Functional magnetic resonance imaging (fMRI) is increasingly being applied in the study of brain effects of nicotine. In addition, because tobacco smoking is common, many subjects studied with fMRI for other reasons may have appreciable levels of nicotine in plasma and brain during scanning. However, there is concern that the vascular effects of nicotine may alter the coupling between blood oxygen level dependent (BOLD) signal and neuronal activity. The objective of this study was to test for evidence of alteration of BOLD signal response of occipital cortex, a region with a relatively low concentration of neuronal nicotine receptors, to photic stimulation during intravenous infusion of nicotine. Nine nicotine dependent healthy smokers were withdrawn from nicotine under controlled conditions and then scanned while receiving photic stimulation and successive intravenous infusions of saline and nicotine. No evidence for an effect of nicotine on BOLD signal response to photic stimulation was detected at the doses studied. This observation suggests that nicotine does not alter the coupling between BOLD signal and neuronal activity in the visual cortex.

Objective: Alcohol use disorders and other substance use disorders are extremely common among patients with posttraumatic stress disorder (PTSD). This article reviews studies pertaining to the epidemiology, clinical phenomenology, and pathophysiology of comorbid PTSD and substance use disorders., Method: Studies were identified by means of computerized and manual searches. The review of research on the pathophysiology of PTSD and substance use disorders was focused on studies of the hypothalamic-pituitary-adrenal axis and the noradrenergic system., Results: High rates of comorbidity suggest that PTSD and substance use disorders are functionally related to one another. Most published data support a pathway whereby PTSD precedes substance abuse or dependence. Substances are initially used to modify PTSD symptoms. With the development of dependence, physiologic arousal resulting from substance withdrawal may exacerbate PTSD symptoms, thereby contributing to a relapse of substance use. Preclinical work has led to the proposal that in PTSD, corticotropin-releasing hormone and noradrenergic systems may interact such that the stress response is progressively augmented. Patients may use sedatives, hypnotics, or alcohol in an effort to interrupt this progressive augmentation., Conclusions: Vigorous control of withdrawal and PTSD-related arousal symptoms should be sought during detoxification of patients with comorbid PTSD and substance use disorders. Inclusion of patients with comorbid PTSD and substance use disorders in neurobiologic research and in clinical trials will be critical for development of effective treatments for this severely symptomatic patient population.

Objective: Although childhood-onset schizophrenia is relatively rare, a sizable group of children with severe emotional disturbances have transient psychotic symptoms that fall outside of current syndrome boundaries. The relationship of this group of children to those with childhood-onset schizophrenia and other childhood psychiatric disorders is unclear. In this study, the authors compared smooth pursuit eye tracking, a biological trait marker associated with schizophrenia, of children and adolescents with psychotic disorder not otherwise specified to that of children with childhood-onset schizophrenia and healthy comparison subjects., Method: By means of infrared oculography, smooth pursuit eye movements during a 17 degrees /second visual pursuit task were quantitatively and qualitatively compared in 55 young adolescents (29 with childhood-onset schizophrenia and 26 with psychotic disorder not otherwise specified) and their respective independent healthy comparison groups (a total of 38 healthy subjects)., Results: Subjects with childhood-onset schizophrenia had qualitatively poorer eye tracking, higher root mean square error, lower gain, and a greater frequency of catch-up saccades than healthy children. Subjects with psychotic disorder not otherwise specified also had qualitatively poorer eye tracking, higher root mean square error, and lower gain than healthy children, but saccade frequency did not differ significantly., Conclusions: Children with childhood-onset schizophrenia exhibit a pattern of eye-tracking dysfunction similar to that reported for adult patients. Similar abnormalities were seen in the subjects with psychotic disorder not otherwise specified except that they did not exhibit a greater frequency of catch-up saccades. Prospective longitudinal neurobiological and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders. Also, family studies are planned to establish whether eye-tracking dysfunction represents a trait- or state-related phenomenon in subjects with psychotic disorder not otherwise specified.

Objective: Deficits in dopaminergic function may contribute to hypertrophy of striatal structures associated with typical neuroleptic treatment. In light of a body of research that has associated chronic cocaine use with extrapyramidal symptoms and striatal dopaminergic depletion, the authors looked for evidence of striatal dysmorphology in patients with chronic cocaine dependence., Method: Caudate, putamen, and total brain volumes were quantified by means of magnetic resonance imaging in 25 cocaine-dependent and 20 healthy subjects., Results: Normalized caudate and putamen volumes were 3.40% and 9.18% larger, respectively, in the cocaine-dependent subjects., Conclusions: These observations suggest that deficits in dopaminergic function associated with cocaine dependence may contribute to striatal hypertrophy.

Preclinical and clinical studies have shown that cocaine increases plasma adrenocorticotropin hormone (ACTH) and cortisol. Chronic elevation of plasma cortisol exerts direct toxic effects upon hippocampal neurons and exacerbates hippocampal damage resulting from ischemia and seizures. The authors tested for evidence of hippocampal damage in patients with chronic cocaine dependence. Medial temporal lobe and total brain volumes were quantified using magnetic resonance imaging (MRI) in 27 patients with cocaine dependence and 16 healthy subjects. Basal and ovine corticotropin releasing hormone (oCRH) stimulated ACTH and cortisol levels were also examined in a subset of 8 healthy and 9 cocaine dependent subjects after 21 days of abstinence. No evidence for decreased hippocampal or total brain volume in cocaine dependence was observed. Similarly, basal and oCRH stimulated ACTH and cortisol levels in cocaine dependent patients did not differ from those in healthy subjects.

Objective: This study evaluated neurologic functioning in adolescents with schizophrenia with onset of psychosis before age 13., Method: The authors administered a structured neurologic examination to 21 adolescents with early-onset schizophrenia and 27 healthy age- and sex-matched comparison subjects., Results: The adolescents with schizophrenia had a high frequency of neurologic abnormalities. Neurologic signs decreased with age in the healthy comparison subjects but not in the subjects with schizophrenia., Conclusions: The adolescents with schizophrenia had a high burden of neurologic impairment and a pattern of abnormalities similar to that of adults with schizophrenia. The persistence of neurologic signs in the adolescents with schizophrenia, which faded with age in the healthy comparison adolescents, supports earlier evidence of a delay in or failure of normal brain development during adolescence.

Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:749-753, 2000. Published 2000 Wiley-Liss, Inc.

Objective: Evidence of a relationship between genotype and binding availability was assessed for the dopamine and serotonin transporter genes., Method: The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT., Results: Subjects homozygous for the 10-repeat allele at the SLC6A3 locus demonstrated significantly lower dopamine transporter binding than carriers of the nine-repeat allele. There was no effect of SLC6A4 genotype upon serotonin transporter binding., Conclusions: These findings suggest that genetic variation at the SLC6A3 3' VNTR polymorphism may modify dopamine transporter function.

Objective: Although childhood-onset schizophrenia is rare, children with brief psychotic symptoms and prominent emotional disturbances commonly present diagnostic and treatment problems. Quantitative anatomic brain magnetic resonance images (MRIs) of a subgroup of children with psychotic disorder not otherwise specified were compared with those of children with childhood-onset schizophrenia and healthy comparison subjects., Method: Anatomic MRIs were obtained for 71 patients (44 with childhood-onset schizophrenia and 27 with psychotic disorder not otherwise specified) and 106 healthy volunteers. Most patients had been treated with neuroleptics. Volumetric measurements for the cerebrum, anterior frontal region, lateral ventricles, corpus callosum, caudate, putamen, globus pallidus, and midsagittal thalamic area were obtained., Results: Patients had a smaller total cerebral volume than healthy comparison subjects. Analysis of covariance for total cerebral volume and age found that lateral ventricles were larger in both patient groups than in healthy comparison subjects and that schizophrenia patients had a smaller midsagittal thalamic area than both subjects with psychotic disorder not otherwise specified and healthy comparison subjects., Conclusions: Pediatric patients with psychotic disorder not otherwise specified showed a pattern of brain volumes similar to those found in childhood-onset schizophrenia. Neither group showed a decrease in volumes of temporal lobe structures. Prospective longitudinal magnetic resonance imaging and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders.

Objective: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence., Method: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography., Results: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups., Conclusions: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.

Objective: Children with transient psychotic symptoms and serious emotional disturbances who do not meet current criteria for schizophrenia or other presently recognized diagnostic categories commonly present diagnostic and treatment problems. Clarifying the connections between children with narrowly defined schizophrenia and children with a more broadly defined phenotype (i.e., Psychotic Disorder Not Otherwise Specified, PD-NOS) has implications for understanding the pathophysiology of schizophrenia. In this study, the neuropsychological test performance of a subgroup of children with atypical psychosis was compared with that of patients with childhood-onset schizophrenia (COS)., Method: Cognitive function was assessed with neuropsychological test battery regimens in 51 neuroleptic-nonresponsive patients within the first 270 at NIMH testing (24 PD-NOS, 27 COS) were included in this analysis. Seventeen (39%) of 44 COS subjects were unavailable for this study as their IQ tested <70. The PD-NOS patients were younger than the COS patients at the time of testing (12.0+/-2.8 vs 14.4+/-1.8years, respectively, p<0.004). The test levels of these groups were compared with each other., Results: The neuropsychological test results for the PD-NOS and COS patients were 1-2standard deviations below normative data across a broad array of cognitive functions. There were no overall differences in the test levels for the six summary scales (F=2.82, df=1, 36, p=0.10) or in the profile shape (F=1.70, df=5, 180, p=0.14) between the PD-NOS and COS groups. For the COS patients, there was a significant difference between their mean full-scale WISC IQ (84.7+/-16.2) and their average standard scores for both the spelling (97.7+/-16.1, n=23, t=4.0, p=0.001) and reading decoding subtests (97.7+/-13.7, n=23, t=3.7, p=0.001) of the Kaufman Test of Educational Achievement., Conclusions: Treatment-refractory PD-NOS and COS patients share a similar pattern of generalized cognitive deficits, including deficits in attention, learning and abstraction which are commonly observed in adult patients with schizophrenia. These data support a hypothesis that at least some of the PD-NOS cases belong within the schizophrenic spectrum, which is of importance for future genetic studies planned for this cohort.

The cost to society of alcohol, tobacco, and illicit drug dependence is enormous. Although the importance of treatment for substance abuse to public health is increasingly acknowledged, pharmacotherapy is generally underutilized. However, the selection of medications for clinical testing is increasingly guided by the rapidly evolving science of addictive drugs and behavior. The benefit of medication for smoking cessation is firmly established, particularly for nicotine replacement and antidepressant therapy. Naltrexone is an important addition to the pharmacopoeia, and acamprosate may soon be approved as well. Although no new medications are approved for cocaine and amphetamine abuse, a variety of candidate treatments have shown promise in ongoing studies. Opiate substitution therapy is highly effective for rehabilitation of heroin addiction, and several alternative forms will soon be available; alternative forms of opiate detoxification have also received attention. Overall, there is increasing recognition that physicians have an obligation to identify and treat all forms of substance dependence, although knowledge of the efficacy of the available treatments is steadily increasing.

Objective: There has been an increasing focus on the ethical issues raised by studies requiring the withdrawal of effective medication in schizophrenic adults. This article examines the risks and benefits of a medication-free period for pediatric patients with treatment-refractory schizophrenia who are participating in an ongoing study., Method: Between April 1993 and March 1998, 31 children and adolescents were admitted with a diagnosis of treatment-resistant, childhood-onset schizophrenia. Parental consent was obtained so that patients could participate in a medication-free research period. Patients were evaluated at screening, at the end of a 4-week washout, at the completion of a 6- to 8-week atypical neuroleptic trial, and at a 2- to 4-year follow-up., Results: At the completion of a 4-week drug-free period, seven patients (23%) were diagnosed with another disorder on the basis of data gained from the drug-free period and their lack of schizophrenic symptoms. Their revised diagnoses were posttraumatic stress disorder (N = 1), an atypical psychosis labeled "multidimensionally impaired" (N = 4), and personality disorder (N = 2). At follow-up, three of these patients remained free of neuroleptic therapy. For eight patients (26%), the washout was curtailed because of rapid and severe deterioration of their schizophrenic symptoms., Conclusions: For children and adolescents with treatment-refractory schizophrenia, a medication-free period can be conducted safely for at least 4 weeks for inpatients. Such trials are useful on clinical grounds and for providing homogeneous patient groups for research. This study also highlights the necessity of having access to hospitalization to observe children and adolescents with psychotic symptoms while medication free.

Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.

Objective: A previous cross-sectional study of brain morphology in childhood-onset schizophrenia indicated sparing of the temporal lobes from processes reducing total cerebral volume in this population. In the present study, subjects with childhood-onset schizophrenia and healthy subjects were rescanned at 2-year follow-up to determine whether this pattern of temporal lobe sparing persists with ongoing illness., Method: Anatomic brain magnetic resonance imaging scans were acquired for 10 adolescent patients with average onset of schizophrenia at 10.4 years (SD = 1.7) and 17 healthy adolescents. Scans were obtained on initial admission and at 2-year follow-up by using identical equipment and measurement methodology., Results: Schizophrenic subjects showed significantly greater decreases than healthy subjects in right temporal lobe, bilateral superior temporal gyrus and posterior superior temporal gyrus, right anterior superior temporal gyrus, and left hippocampal volumes during the follow-up interval. Decline in right posterior superior temporal gyrus was associated with high total scores on the Scale for the Assessment of Positive Symptoms at baseline and at follow-up., Conclusions: Progressive reduction of temporal lobe structures occurs with ongoing illness in childhood-onset schizophrenia.

Clinical, neuroanatomic, neurobehavioral, and functional brain-imaging studies suggest a role for the cerebellum in cognitive functions, including attention. However, the cerebellum has not been systematically studied in attention-deficit hyperactivity disorder (ADHD). We quantified the cerebellar and vermal volumes, and the midsagittal areas of three vermal regions, from MRIs of 46 right-handed boys with ADHD and 47 matched healthy controls. Vermal volume was significantly less in the boys with ADHD. This reduction involved mainly the posterior inferior lobe (lobules VIII to X) but not the posterior superior lobe (lobules VI to VII). These results remained significant even after adjustment for brain volume and IQ. A cerebello-thalamo-prefrontal circuit dysfunction may subserve the motor control, inhibition, and executive function deficits encountered in ADHD.

Objective: Olanzapine, a potent 5-HT2a/2c, dopamine D1D2D4 antagonist with anticholinergic activity, has a profile of known receptor affinity similar to that of clozapine. This pilot study examined the efficacy of olanzapine for treatment-refractory childhood-onset schizophrenia in eight patients who had received 8-week open-label trials. For comparison, data are included from 15 patients who had received 6-week open-label clozapine trials using identical rating instruments (largely by the same raters) in the same treatment setting., Method: Twenty-three children and adolescents with an onset of DSM-III-R schizophrenia by age 12 for whom at least two different typical neuroleptics had been ineffective participated in the two separate studies. Some of the patients were intolerant of clozapine, although it had been effective (n = 4). Patients receiving olanzapine were evaluated over 8 weeks with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Clinical Global Impressions Scale for Improvement., Results: For the eight patients who received olanzapine trials, at week 8 there was a 17% improvement in the BPRS total score, a 27% improvement in the Scale for the Assessment of Negative Symptoms, and a 1% improvement in the Scale for the Assessment of Positive Symptoms, relative to "ideal" admission status on typical neuroleptics. In contrast, the magnitude of the effect sizes for each of the clinical ratings was larger at week 6 of the previous clozapine trial than for an 8-week olanzapine trial, relative to admission status on typical neuroleptics. For the four children who had received both clozapine and olanzapine, BPRS total scores were significantly lower at week 6 of clozapine treatment compared with week 6 of olanzapine treatment (p = .03)., Conclusion: These data provide preliminary evidence for the efficacy of olanzapine for some children and adolescents with treatment-refractory schizophrenia, but they also suggest the need for a more rigorous double-blind comparison of these two atypical antipsychotics.

Objective: An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DMS-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI)., Method: From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine., Results: Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, chi 2 = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed., Conclusions: These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine.

Since its first description almost a century ago schizophrenia with childhood onset, a rare yet devastating disorder, has been diagnosed in children as young as age 5. Recently, the velocardiofacial syndrome, whose underlying cause is interstitial deletions of 22q11.2, was found in 2 of 100 cases of schizophrenics with adult onset [Karayiorgou et al., Proc Natl Acad Sci USA 92: 7612-7616, 1995]. No study has documented the prevalence of velocardiofacial syndrome and the 22q11.2 deletion in a population of schizophrenics with childhood onset. Here we describe the result of such a study in a sample originally selected for a trial of atypical antipsychotic drugs. A separate group of patients was also included in the study; they can best be accounted for as a variant of childhood-onset schizophrenia (COS) and had been provisionally termed "multidimensionally impaired." Fluorescent in situ hybridization screening of 32 COS and 21 multidimensionally impaired patients revealed 1 COS patient with an interstitial deletion spanning at least 2.5 megabases.

The hypothesis of continuity between childhood-onset and adult schizophrenia was tested by comparing the performance of 15 patients with childhood-onset schizophrenia and 52 age-matched controls on 2 reaction time paradigms that have been used to study adult schizophrenia. On simple reaction time to tones with regular and irregular preparatory intervals of 2, 4, and 8 s, patients showed greater effects of the length of the preparatory interval in the regular condition and greater effects of the preparatory interval (girls only) and the preceding preparatory interval in the irregular series. On simple reaction time to random lights and tones, patients were faster on ipsimodal sequences than cross-modal sequences compared with controls. Overall, patients were much slower than controls in both paradigms. The results suggest similar attention dysfunction as is found in adult schizophrenia and thus are consistent with the continuity hypothesis.

Objective: Neuroleptic-treated pediatric patients with childhood-onset schizophrenia (COS) are at risk for developing extrapyramidal side effects and involuntary movement disorders. A preliminary examination of the incidence of withdrawal dyskinesias (WD), tardive dyskinesia (TD), and extrapyramidal side effects in these patients is presented., Method: Thirty-four COS patients (mean age +/- SD, 14.2 +/- 2.1 years) were examined for TD using the Abnormal Involuntary Movements Scale and for extrapyramidal side effects using the Simpson-Angus Neurologic Rating Scale, after a 14- to 28-day drug-free period (n = 33), at week 6 of treatment and 2 to 4 years after completion of the study (n = 14). The mean (+/-SD) number of months of prior neuroleptic exposure for the group was 22.4 (15.0) months., Results: Seventeen (50%) of 34 patients were noted to have either WD or TD at some point during their participation in the studies. The majority of patients experienced WD that were mainly in the orofacial region, transient in nature, and diminished with haloperidol and clozapine. Patients with TD/WD had greater levels of premorbid impairment (p = .02), increased severity of positive symptoms of schizophrenia (p < .01), and a trend toward more months of neuroleptic exposure (p = .10, one-tailed)., Conclusions: A high proportion of COS patients were found to have TD/WD. The majority of these abnormal movements were not severe and generally improved over time. TD/WD in COS appears to be associated with greater premorbid impairment, severity of illness, and duration of neuroleptic exposure. J. Am. Acad.

Objective: To examine the validity of diagnostic criteria for a subgroup of children with atypical psychosis (n = 19), designated here as "multidimensionally impaired." These children are characterized by poor attention and impulse control, psychotic symptoms, and poor affective control., Method: Children and adolescents (n = 19) meeting our criteria for multidimensionally impaired syndrome with onset of psychotic symptoms at or before age 12 years were identified from a total of 150 in-person screenings for very early-onset schizophrenia between 1990 and 1996. We compared the premorbid adjustment, family history, follow-up status, and laboratory measures for a subgroup of these children with those of (1) a rigorously defined group of 29 children with DSM-III-R schizophrenia and (2) 19 children with attention-deficit hyperactivity disorder., Results: Patients with multidimensionally impaired syndrome and patients with very early-onset schizophrenia shared a similar pattern of early transient autistic features, postpsychotic cognitive decline, and an elevated risk of schizophrenic-spectrum disorders among their first-degree relatives. This pattern was not seen in the attention-deficit hyperactivity disorder group. In contrast to very early-onset schizophrenia, the multidimensionally impaired group had significantly poorer scores on the Freedom From Distractibility factor on the WISC-R, a less deviant pattern of autonomic reactivity, and no progression to schizophrenia., Conclusions: The findings support the distinction of the multidimensionally impaired cases as separate from those with other psychiatric disorders, and there is somewhat greater evidence to suggest that this disorder belongs in the schizophrenia spectrum.

Childhood-onset schizophrenia is a rare, clinically severe form of schizophrenia, which is associated with disrupted cognitive, linguistic, and social development well before the appearance of frank psychotic symptoms. This disruption of multiple developmental domains signals the important opportunity these patients present for examining neurodevelopmental and other etiologic hypotheses of schizophrenia. The present research update reviews studies of the phenomenology and neurobiology of childhood-onset schizophrenia conducted since 1994. Findings from these studies indicate that children can be diagnosed with schizophrenia using unmodified DSM-III, -IIIR, and -IV criteria, and that the atypical neuroleptic clozapine is an effective medication for this treatment refractory group. Neuropsychologic and neurobiologic studies generally support continuity with adult-onset schizophrenia, with evidence of more severe premorbid impairment. Longitudinal studies show preliminary evidence of progressive ventricular enlargement and more prolonged deterioration in intellectual function than is seen in the adult-onset disorder. If replicated, these observations, together with the insidious onset of this disorder, would suggest that the pathologic underpinning of childhood-onset schizophrenia is not a single static lesion or event but may be a continuous or multi-event process.

Objective: Studies have suggested that the maldeveloped neural circuitry producing schizophrenic symptoms may include the cerebellum. The authors found further support for this hypothesis by examining cerebellar morphology in severely ill children and adolescents with childhood-onset schizophrenia., Method: Anatomic brain scans were acquired with a 1.5-T magnetic resonance imaging scanner for 24 patients (mean age = 14.1 years, SD = 2.2) with onset of schizophrenia by age 12 (mean age at onset = 10.0 years, SD = 1.9) and 52 healthy children. Volumes of the vermis, inferior posterior lobe, fourth ventricle, and total cerebellum and the midsagittal area of the vermis were measured manually., Results: After adjustment for total cerebral volume, the volume of the vermis and the midsagittal area and volume of the inferior posterior lobe remained significantly smaller in the schizophrenic patients. There was no group difference in total cerebellar or fourth ventricle volume., Conclusions: These findings are consistent with observations of small vermal size in adult schizophrenia and provide further support for abnormal cerebellar function in childhood- and adult-onset schizophrenia.

Decreased frontal cortical glucose metabolism has been demonstrated in adult schizophrenics both at rest and while engaging in tasks that normally increase frontal metabolism, such as the Continuous Performance Test (CPT). The authors tested the hypothesis that adolescents with childhood onset schizophrenia would also demonstrate hypofrontality while performing the CPT. Cerebral glucose metabolism was examined in 16 adolescents (mean age 14.1 +/- 1.7) with onset of schizophrenia by age 12 (mean age at onset 9.9 +/- 1.8) and 26 healthy adolescents selected to be similar in age, sex and handedness using positron emission tomography and 18F-fluorodeoxyglucose. Patients with childhood onset schizophrenia made fewer correct and more incorrect identifications on the CPT. Region of interest analysis revealed no significant group differences in global cerebral glucose metabolism, but increased metabolic rate in supramarginal gyrus (F = 6.74, P < 0.05) and inferior frontal gyrus/insula (F = 7.09, P < 0.05) and decreased metabolic rate in middle frontal gyrus (F = 6.72, P < 0.05) and superior frontal gyrus (t = 2.04, P < 0.05) in schizophrenics. Comparison of effect sizes with an identically designed study of adult schizophrenics did not indicate more severe hypofrontality in childhood onset schizophrenia. Pixel-based analyses indicated a more complex pattern of group differences in cerebral metabolism with bilaterally increased cerebellar metabolic rate in childhood onset schizophrenics. These findings suggest that childhood onset schizophrenia may be associated with a similar, but not more severe, degree of hypofrontality relative to that seen in adult onset schizophrenia.

Background: Consistent abnormalities in peripheral indicators of autonomic activity, ie, skin conductance (SC) and heart rate (HR), have been reported in adult-onset schizophrenia. Herein, we use these markers to test the hypothesis of continuity between childhood-onset schizophrenia and adult-onset schizophrenia., Methods: Skin conductance and HR were recorded from 21 severely ill children and adolescents (mean age, 14.1 years) with childhood-onset (< or = 12 years) schizophrenia (patient group) and from 54 age-matched controls (control group) during a rest period, a series of innocuous tones, reaction time instructions, and a simple warned reaction time task., Results: During rest, patients had higher rates of spontaneous SC responses (SCRs) and HRs than controls, but their SC level was marginally lower and declined more slowly over time. Half of the patients, compared with 4% of the controls, failed to give SC-orienting responses to the first 2 tones. Patients who responded had impaired SCR magnitudes, and their habituation was more erratic than that of controls. The increase in SC level and SCR frequency at the onset of the task period was greatly attenuated in the patients, so that both variables were higher in controls. Patients had smaller SCRs and anticipatory HR responses to the reaction time stimuli. Skin conductance nonresponding was associated with negative and total symptoms, and spontaneous SCR frequency was associated with positive symptoms., Conclusions: The findings show similar abnormalities in autonomic nervous system activity in childhood-onset schizophrenia to those found in adult chronic schizophrenia, thus supporting the hypothesis of continuity of the childhood and adult forms of the illness. Comparisons with data from other childhood disorders suggest that the combination of low-elicited SC activity with high levels of spontaneous SC activity may be specific to schizophrenia.

This study examines cerebrospinal fluid from patients with three neuropsychiatric diseases of childhood for the presence and levels of several cytokines relevant to cell-mediated (type 1) and humoral (type 2) immunity. The patient groups include childhood-onset schizophrenia (n = 22), obsessive-compulsive disorder (OCD) (n = 24), and attention deficit hyperactivity disorder (n = 42). The cytokines examined include IL-2, IFN-gamma, TNF-beta/LT, IL-4, IL-5, IL-10, and TNF-alpha. Patients with OCD had a preponderance of type 1 cytokines. IL-4 was detectable only in samples from patients with schizophrenia. IL-10 was rarely detected and never in patients with OCD. Few patients with schizophrenia had detectable amounts of IFN-gamma in CSFL. We conclude that there is a relative skewing of CSFL profiles toward type 1 cytokines in patients with OCD, whereas in schizophrenia the relative preponderance is toward type 2 mediators. Patients with attention deficit hyperactivity disorder exhibited profiles intermediate between OCD and schizophrenia. We infer that cell-mediated immunity may be involved in the etiopathogenesis of OCD, whereas a relative lack of cell-mediated immunity and involvement of humoral immunity may be present in schizophrenia. These data provide a rationale for immune-based strategies of study and therapeutics in childhood neuropsychiatric disease.

Objective: Anomalous planum temporale asymmetry has been linked to both schizophrenia and dyslexia. The authors examined the planum temporale of adolescents with childhood-onset schizophrenia who had a high rate of prepsychotic language disorders., Method: Planum temporale area and asymmetry were measured in 16 right-handed adolescent patients with schizophrenia who had experienced onset of psychosis by age 12. The same measures were made in 16 healthy adolescents matched for age, sex, and handedness., Results: No differences between the healthy adolescents and those with schizophrenia in planum temporale area or asymmetry were observed. Prepsychotic language disorder predicted abnormal planum temporale asymmetry in the adolescents with schizophrenia., Conclusions: These findings do not support anomalous planum temporale asymmetry as a basis for psychopathology in childhood-onset schizophrenia.