Biological Psychiatry - Articles in Press

Cocaine-Insensitive Dopamine Transporters with Intact Substrate Transport Produced by Self-Administration - Corrected Proof

Mark J. Ferris, Yolanda Mateo, David C.S. Roberts, Sara R. Jones — 2010-09-01

Background:: Psychomotor stimulant drugs such as cocaine and amphetamine activate brain dopamine (DA) neurotransmission and support self-administration in humans and laboratory animals. Cocaine amplifies DA signaling by blocking the DA transporter (DAT), and this has been described as the most important mechanism underlying cocaine's reinforcing effects. Amphetamine has the added mechanism of reverse transport of intracellular DA through the DAT.Methods:: We used cocaine and amphetamine self-administration under a fixed-ratio 1 schedule followed by microdialysis in freely moving rats to measure extracellular DA levels and fast scan cyclic voltammetry in brain slices to measure subsecond DA release and uptake parameters.Results:: Following a high dose (1.5 mg/kg intravenous) cocaine self-administration paradigm (40 injections/day × 5 days), the DAT was markedly less sensitive to cocaine, as measured by microdialysis and voltammetry in the nucleus accumbens core. In contrast, the DAT substrate amphetamine retained the same efficacy at the DAT in cocaine self-administering animals, and amphetamine did not mimic cocaine's effect on the DAT when self-administered. A single session of cocaine self-administration caused a significant decrease in the ability of cocaine to inhibit the DAT, a finding that may provide a neurochemical basis for rapid tolerance. The effects of cocaine returned to normal within a few weeks following cessation of self-administration.Conclusions:: Here, we, for the first time, demonstrate an in vivo, pharmacologically induced alteration in the sensitivity of the DAT to cocaine that is specific to cocaine, spares DAT and substrate/releaser interactions, and is independent of maximal rate of DA uptake (Vmax).

Blockade of Nicotine Reward and Reinstatement by Activation of Alpha-Type Peroxisome Proliferator-Activated Receptors - Corrected Proof

2010-09-01

Background:: Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine.Methods:: We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats.Results:: The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-αagonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886).Conclusions:: These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.

Reduced Gray Matter Volume of Pars Opercularis Is Associated with Impaired Social Communication in High-Functioning Autism Spectrum Disorders - Corrected Proof

2010-09-01

Background:: Recent literature suggests that the inferior frontal gyrus, especially its posterior portion, has an important role in imitation and social reciprocity and in the pathophysiology of their disturbance in autism spectrum disorders (ASD). However, the structural abnormality of this region has not fully been clarified in subjects with ASD.Methods:: Here we obtained magnetic resonance images from 13 right-handed men with high-functioning ASD (Asperger disorder [n = 10] or autism [n = 3]) and from 11 age-, parental socioeconomic background-, and intelligence quotient-matched right-handed typical men. A reliable manual tracing methodology was employed to measure the gray matter volume of the pars opercularis, corresponding to Brodmann area 44, and the pars triangularis, corresponding to Brodmann area 45.Results:: A significant gray matter volume reduction of both the pars opercularis and triangularis was found bilaterally in the subjects with ASD compared with the typical control subjects. The effect size seemed to be larger for pars opercularis (1.25) than for pars triangularis (.90). The reduced volume of right as well as total pars opercularis showed a significant association with the increased severity of social communication problems in the ASD group.Conclusions:: The current findings support an important role of pars opercularis, a center of the mirror neuron system, in the pathophysiology of ASD.

Analyzing Schizophrenia by DNA Microarrays - Corrected Proof

Szatmár Horváth, Zoltán Janka, Károly Mirnics — 2010-09-01

To understand the pathological processes of schizophrenia, we must embrace the analysis of the diseased human brain: we will never be able to recapitulate the pathology of uniquely human disorders in an animal model. Based on the outcome of the transcriptome profiling experiments performed to date, it appears that schizophrenia is associated with a global gene expression disturbance across many cortical regions. In addition, transcriptome changes are present in multiple cell types, including specific subclasses of principal neurons, interneurons, and oligodendrocytes. Furthermore, transcripts related to synaptic transmission, energy metabolism, and inhibitory neurotransmission are routinely found underexpressed in the postmortem brain tissue of subjects with schizophrenia. To put these transcriptome data in biological context, we must make our data publicly available and report our findings in a proper, expanded Minimum Information About a Microarray Experiment format. Cell-type specific expression profiling and sequencing-based transcript assessments should be expanded, with particular attention to understanding splice-variant changes in various mental disorders. Deciphering the pathophysiology of mental disorders depends on integrating data from across many research fields and techniques. Leads from postmortem transcriptome profiling will be essential to generate model animals, perform tissue culture experiments, and develop or evaluate novel drugs to treat this devastating disorder.

Fronto-Temporal Spontaneous Resting State Functional Connectivity in Pediatric Bipolar Disorder - Corrected Proof

2010-08-27

Background:: The recent upsurge in interest about pediatric bipolar disorder (BD) has spurred the need for greater understanding of its neurobiology. Structural and functional magnetic resonance imaging studies have implicated fronto-temporal dysfunction in pediatric BD. However, recent data suggest that task-dependent neural changes account for a small fraction of the brain's energy consumption. We now report the first use of task-independent spontaneous resting state functional connectivity (RSFC) to study the neural underpinnings of pediatric BD.Methods:: We acquired task-independent RSFC blood oxygen level-dependent functional magnetic resonance imaging scans while participants were at rest and also a high-resolution anatomical image (both at three Tesla) in BD and control youths (n = 15 of each). We focused, on the basis of prior research, on the left dorsolateral prefrontal cortex (DLPFC), amygdala, and accumbens. Image processing and group-level analyses followed that of prior work.Results:: Our primary analysis showed that pediatric BD participants had significantly greater negative RSFC between the left DLPFC and the right superior temporal gyrus versus control subjects. Secondary analyses using partial correlation showed that BD and control youths had opposite phase relationships between spontaneous RSFC fluctuations in the left DLPFC and right superior temporal gyrus.Conclusions:: Our data indicate that pediatric BD is characterized by altered task-independent functional connectivity in a fronto-temporal circuit that is also implicated in working memory and learning. Further study is warranted to determine the effects of age, gender, development, and treatment on this circuit in pediatric BD.

Genome-Wide Association Scan of Trait Depression - Corrected Proof

2010-08-27

Background:: Independent of temporal circumstances, some individuals have greater susceptibility to depressive affects, such as feelings of guilt, sadness, hopelessness, and loneliness. Identifying the genetic variants that contribute to these individual differences can point to biological pathways etiologically involved in psychiatric disorders.Methods:: Genome-wide association scans for the depression scale of the Revised NEO Personality Inventory in community-based samples from a genetically homogeneous area of Sardinia, Italy (n = 3972) and from the Baltimore Longitudinal Study of Aging in the United States (n = 839).Results:: Meta-analytic results for genotyped or imputed single nucleotide polymorphisms indicate that the strongest association signals for trait depression were found in RORA (rs12912233; p = 6 × 10−7), a gene involved in circadian rhythm. A plausible biological association was also found with single nucleotide polymorphisms within GRM8 (rs17864092; p = 5 × 10−6), a metabotropic receptor for glutamate, a major excitatory neurotransmitter in the central nervous system.Conclusions:: These findings suggest shared genetic basis underlying the continuum from personality traits to psychopathology.

Magnetic Resonance Spectroscopy Studies of Glutamate-Related Abnormalities in Mood Disorders - Corrected Proof

Cagri Yüksel, Dost Öngür — 2010-08-23

In mood disorders, there is growing evidence for glutamatergic abnormalities derived from peripheral measures of glutamatergic metabolites in patients, postmortem studies on glutamate-related markers, and animal studies on the mechanism of action of available treatments. Magnetic resonance spectroscopy (MRS) has the potential to corroborate and extend these findings with the advantage of in vivo assessment of glutamate-related metabolites in different disease states, in response to treatment, and in relation with functional imaging data. In this article, we first review the biological significance of glutamate, glutamine, and Glx (composed mainly of glutamate and glutamine). Next, we review the MRS literature in mood disorders, examining these glutamate-related metabolites. Here, we find a highly consistent pattern of Glx-level reductions in major depressive disorder and elevations in bipolar disorder. In addition, studies of depression, regardless of diagnosis, provide suggestive evidence for reduced glutamine/glutamate ratio and in mania for elevated glutamine/glutamate ratio. These patterns suggest that the glutamate-related metabolite pool (not all of it necessarily relevant to neurotransmission) is constricted in major depressive disorder and expanded in bipolar disorder. Depressive and manic episodes may be characterized by modulation of the glutamine/glutamate ratio in opposite directions, possibly suggesting reduced versus elevated glutamate conversion to glutamine by glial cells, respectively. We discuss the implications of these results for the pathophysiology of mood disorders and suggest future directions for MRS studies.

Basic Abnormalities in Visual Processing Affect Face Processing at an Early Age in Autism Spectrum Disorder - Corrected Proof

2010-08-23

Background:: A detailed visual processing style has been noted in autism spectrum disorder (ASD); this contributes to problems in face processing and has been directly related to abnormal processing of spatial frequencies (SFs). Little is known about the early development of face processing in ASD and the relation with abnormal SF processing. We investigated whether young ASD children show abnormalities in low spatial frequency (LSF, global) and high spatial frequency (HSF, detailed) processing and explored whether these are crucially involved in the early development of face processing.Methods:: Three- to 4-year-old children with ASD (n = 22) were compared with developmentally delayed children without ASD (n = 17). Spatial frequency processing was studied by recording visual evoked potentials from visual brain areas while children passively viewed gratings (HSF/LSF). In addition, children watched face stimuli with different expressions, filtered to include only HSF or LSF.Results:: Enhanced activity in visual brain areas was found in response to HSF versus LSF information in children with ASD, in contrast to control subjects. Furthermore, facial-expression processing was also primarily driven by detail in ASD.Conclusions:: Enhanced visual processing of detailed (HSF) information is present early in ASD and occurs for neutral (gratings), as well as for socially relevant stimuli (facial expressions). These data indicate that there is a general abnormality in visual SF processing in early ASD and are in agreement with suggestions that a fast LSF subcortical face processing route might be affected in ASD. This could suggest that abnormal visual processing is causative in the development of social problems in ASD.

Early Life Stress Combined with Serotonin 3A Receptor and Brain-Derived Neurotrophic Factor Valine 66 to Methionine Genotypes Impacts Emotional Brain and Arousal Correlates of Risk for Depression - Corrected Proof

2010-08-23

Background:: Depression will be the second largest burden of disease by 2020. Developing new tools for identifying risk and ultimately prevention of depression relies on elucidating the integrative relationships between susceptibility markers from gene-stress interactions and how they impact emotional brain and arousal systems. They have largely been studied in isolation.Methods:: We examined how genetic (brain-derived neurotrophic factor [BDNF] valine 66 to methionine [Val66Met] and serotonin receptor gene 3A [HTR3A]) and early life stress susceptibility factors interact in predicting electroencephalogram (EEG) asymmetry, emotion-elicited heart rate, and self-reported negativity bias, each correlates of risk for depression. Caucasian volunteers (n = 363) were derived from the Brain Resource International Database, via the Brain Research And Integrative Neuroscience Network.Results:: Individuals with both BDNF methionine and HTR3A CC risk genotypes and early life stressors demonstrated a profile of elevated emotion-elicited heart rate and right frontal hyper-activation with right parietotemporal hypoactivation in EEG asymmetry. Elevations in heart rate were a moderator of negativity bias.Conclusions:: The findings provide new evidence that these gene-stress susceptibility factors contribute to a brain-arousal profile indicative of risk for depression. They are a step toward identifying biological markers for detecting risk before overt symptoms. It would be valuable for future studies to examine comorbidity and specificity issues; for instance, whether these gene-stress factors contribute in different ways to the partially distinct EEG asymmetry profiles found with anxiety.

Atypical Default Network Connectivity in Youth with Attention-Deficit/Hyperactivity Disorder - Corrected Proof

2010-08-23

Background:: Attention-deficit/hyperactivity disorder (ADHD) is a major public health concern. It has been suggested that the brain's default network may provide a crucial avenue for understanding the neurobiology of attention deficit/hyperactivity disorder. Evaluations of the default network have increased over recent years with the applied technique of resting-state functional connectivity magnetic resonance imaging (rs-fcMRI). These investigations have established that spontaneous activity in this network is highly correlated at rest in young adult populations. This coherence seems to be reduced in adults with ADHD. This is an intriguing finding, as coherence in spontaneous activity within the default network strengthens with age. Thus, the pathophysiology of ADHD might include delayed or disrupted maturation of the default network. If so, it is important to determine whether an altered developmental picture can be detected using rs-fcMRI in children with ADHD.Methods:: This study used the typical developmental context provided previously by Fair et al. (2008) to examine coherence of brain activity within the default network using rs-fcMRI in children with (n = 23) and without attention deficit/hyperactivity disorder (n = 23).Results:: We found that functional connections previously shown as developmentally dynamic in the default network were atypical in children with attention deficit/hyperactivity disorder—consistent with perturbation or failure of the maturational processes.Conclusions:: These findings are consistent with the hypothesis that atypical consolidation of this network over development plays a role in attention deficit/hyperactivity disorder.

Effects of an Alpha 7-Nicotinic Agonist on Default Network Activity in Schizophrenia - Corrected Proof

2010-08-23

Background:: 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at α7 nicotinic acetylcholine receptors that has been evaluated clinically for treatment of schizophrenia. This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia.Methods:: Placebo and two doses of DMXB-A were administered in a random, double-blind crossover design during a Phase 2 study of DMXB-A. Functional magnetic resonance imaging was performed on 16 nonsmoking patients with schizophrenia while they performed a simple eye movement task. Independent component analysis was used to identify the default network component. Default network changes were evaluated in the context of a polymorphism in CHRNA7, the α7-nicotinic acetylcholine receptor subunit gene, which was previously found to be associated with schizophrenia.Results:: Compared with placebo, both 150 and 75 mg twice daily DMXB-A altered default network activity, including a reduction in posterior cingulate, inferior parietal cortex, and medial frontal gyrus activity and an increase in precuneus activity. The most robust difference, posterior cingulate activity reduction, was affected by CHRNA7 genotype.Conclusions:: The observed DMXB-A-related changes are consistent with improved default network function in schizophrenia. Pharmacogenetic analysis indicates mediation of the effect through the α7-nicotinic receptor. These results further implicate nicotinic cholinergic dysfunction in the disease and suggest that default network activity may be a useful indicator of biological effects of novel therapeutic agents.

A Shift to Randomness of Brain Oscillations in People with Autism - Corrected Proof

2010-08-23

Background:: Resting-state functional magnetic resonance imaging (fMRI) enables investigation of the intrinsic functional organization of the brain. Fractal parameters such as the Hurst exponent, H, describe the complexity of endogenous low-frequency fMRI time series on a continuum from random (H = .5) to ordered (H = 1). Shifts in fractal scaling of physiological time series have been associated with neurological and cardiac conditions.Methods:: Resting-state fMRI time series were recorded in 30 male adults with an autism spectrum condition (ASC) and 33 age- and IQ-matched male volunteers. The Hurst exponent was estimated in the wavelet domain and between-group differences were investigated at global and voxel level and in regions known to be involved in autism.Results:: Complex fractal scaling of fMRI time series was found in both groups but globally there was a significant shift to randomness in the ASC (mean H = .758, SD = .045) compared with neurotypical volunteers (mean H = .788, SD = .047). Between-group differences in H, which was always reduced in the ASC group, were seen in most regions previously reported to be involved in autism, including cortical midline structures, medial temporal structures, lateral temporal and parietal structures, insula, amygdala, basal ganglia, thalamus, and inferior frontal gyrus. Severity of autistic symptoms was negatively correlated with H in retrosplenial and right anterior insular cortex.Conclusions:: Autism is associated with a small but significant shift to randomness of endogenous brain oscillations. Complexity measures may provide physiological indicators for autism as they have done for other medical conditions.

Is Disturbed Intracortical Excitability a Stable Trait of Chronic Insomnia? A Study Using Transcranial Magnetic Stimulation Before and After Multimodal Sleep Therapy - Corrected Proof

2010-08-23

Background:: Chronic insomnia is a poorly understood disorder. Risk factors for developing chronic insomnia are largely unknown, yet disturbances in brain indexes of arousal seem to accompany the disorder. We here investigate whether insomnia patients and control participants differ with respect to brain responses to direct stimulation, i.e., cortical excitability. Transcranial magnetic stimulation (TMS) offers a method to directly investigate the excitability level of the human cerebral cortex in psychiatric and neurological disease.Methods:: We investigated cortical excitability in 16 insomnia patients and 14 carefully matched control participants using absolute and relative amplitudes of motor evoked potentials in response to single- and paired-pulse stimulation using TMS.Results:: Nonmedicated insomnia patients showed, first, an exaggerated absolute response to both suprathreshold single- and paired-pulse stimulation compared with control participants and second, a reduced relative response to paired-pulse stimulation at long interpulse intervals (i.e., a reduced intracortical facilitation). The abnormal excitability persisted despite sleep therapy that effectively improved sleep quality as well as behavioral and neuroimaging indexes of brain function.Conclusions:: The results suggest that a subtly disturbed intracortical excitability characterizes patients with chronic insomnia: a relatively reduced intracortical facilitation in the context of a globally increased absolute excitability. The findings do not resemble TMS findings after sleep deprivation or in sleep apnea and thus seem specific to insomnia. They may offer diagnostic value and implications for assessment of risk to develop this common and disabling disorder.

Prefrontal Cortex and Impulsive Decision Making - Corrected Proof

Soyoun Kim, Daeyeol Lee — 2010-08-23

Impulsivity refers to a set of heterogeneous behaviors that are tuned suboptimally along certain temporal dimensions. Impulsive intertemporal choice refers to the tendency to forego a large but delayed reward and to seek an inferior but more immediate reward, whereas impulsive motor responses also result when the subjects fail to suppress inappropriate automatic behaviors. In addition, impulsive actions can be produced when too much emphasis is placed on speed rather than accuracy in a wide range of behaviors, including perceptual decision making. Despite this heterogeneous nature, the prefrontal cortex and its connected areas, such as the basal ganglia, play an important role in gating impulsive actions in a variety of behavioral tasks. Here, we describe key features of computations necessary for optimal decision making and how their failures can lead to impulsive behaviors. We also review the recent findings from neuroimaging and single-neuron recording studies on the neural mechanisms related to impulsive behaviors. Converging approaches in economics, psychology, and neuroscience provide a unique vista for better understanding the nature of behavioral impairments associated with impulsivity.

Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans - Corrected Proof

2010-08-19

Background:: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Cav1.2, with a bipolar disorder and depression diagnosis.Methods:: The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects).Results:: In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10−4, 2.1 × 10−4; pcorrected = .03, .04) and were consistent across two large datasets.Conclusions:: Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.

Inflammation-Induced Anhedonia: Endotoxin Reduces Ventral Striatum Responses to Reward - Corrected Proof

2010-08-18

Background: Although inflammatory activity is known to play a role in depression, no work has examined whether experimentally induced systemic inflammation alters neural activity that is associated with anhedonia, a key diagnostic symptom of depression. To investigate this, we examined the effect of an experimental inflammatory challenge on the neural correlates of anhedonia—namely, reduced ventral striatum (VS) activity to reward cues. We also examined whether this altered neural activity related to inflammatory-induced increases in depressed mood.Methods: Participants (n = 39) were randomly assigned to receive either placebo or low-dose endotoxin, which increases proinflammatory cytokine levels in a safe manner. Cytokine levels were repeatedly assessed through hourly blood draws; self-reported and observer-rated depressed mood were assessed regularly as well. Two hours after drug administration, neural activity was recorded as participants completed a task in which they anticipated monetary rewards.Results: Results demonstrated that subjects exposed to endotoxin, compared with placebo, showed greater increases in self-reported and observer-rated depressed mood over time, as well as significant reductions in VS activity to monetary reward cues. Moreover, the relationship between exposure to inflammatory challenge and increases in observer-rated depressed mood was mediated by between-group differences in VS activity to anticipated reward.Conclusions: The data reported here show, for the first time, that inflammation alters reward-related neural responding in humans and that these reward-related neural responses mediate the effects of inflammation on depressed mood. As such, these findings have implications for understanding risk of depression in persons with underlying inflammation.

The Role of the Corpus Callosum in Transcranial Magnetic Stimulation Induced Interhemispheric Signal Propagation - Corrected Proof

2010-08-13

Background: The corpus callosum, the main interhemispheric connection in the brain, may serve to preserve functional asymmetry between homologous cortical regions.Methods: To test this hypothesis, 30 healthy adult subjects underwent combined transcranial magnetic stimulation (TMS)–electroencephalography procedures. Nineteen of these subjects also completed diffusion tensor imaging and tractography procedures. We examined the relationship between microstructural integrity of subdivisions of the corpus callosum with TMS-induced interhemispheric signal propagation.Results: We found a significant inverse relationship between microstructural integrity of callosal motor fibers with TMS-induced interhemispheric signal propagation from left to right motor cortex. We also found a significant inverse relationship between microstructural integrity of genu fibers of the corpus callosum and TMS-induced interhemispheric signal propagation from left to right dorsolateral prefrontal cortex (DLPFC). We then demonstrated neuroanatomic specificity of these relationships.Conclusions: Taken together, our findings suggest that TMS-induced interhemispheric signal propagation is transcallosally mediated and neuroanatomically specific and support a role for the corpus callosum in preservation of functional asymmetry between homologous cortical regions. Delineation of the relationship between corpus callosum microstructure and interhemispheric signal propagation in neuropsychiatric disorders, such as schizophrenia, may reveal novel mechanisms of pathophysiology.

Reduced Medial Prefrontal Cortex Volume in Adults Reporting Childhood Emotional Maltreatment - Corrected Proof

2010-08-09

Background: Childhood emotional maltreatment (CEM) has been associated with a profound and enduring negative impact on behavioral and emotional functioning. Animal models have shown that adverse rearing conditions, such as maternal separation, can induce a cascade of long-term structural alterations in the brain, particularly in the hippocampus, amygdala, and prefrontal cortex. However, in humans, the neurobiological correlates of CEM are unknown.Methods: Using high-resolution T1-weighted 3T magnetic resonance imaging, anatomical scans and a whole-brain optimized voxel-based morphometry approach, we examined whether healthy control subjects and unmedicated patients with depression and/or anxiety disorders reporting CEM before age 16 (n = 84; age: mean = 38.7) displayed structural brain changes compared with control subjects and patients who reported no childhood abuse (n = 97; age: mean = 36.6).Results: We found that self-reported CEM is associated with a significant reduction in predominantly left dorsal medial prefrontal cortex volume, even in the absence of physical or sexual abuse during childhood. In addition, reduced medial prefrontal cortex in individuals reporting CEM is present in males and females, independent of concomitant psychopathology.Conclusions: In this study, we show that CEM is associated with profound reductions of medial prefrontal cortex volume, suggesting that sustained inhibition of growth or structural damage can occur after exposure to CEM. Given the important role of the medial prefrontal cortex in the regulation of emotional behavior, our finding might provide an important link in understanding the increased emotional sensitivity in individuals reporting CEM.

A Meta-Analysis of Cytokines in Alzheimer's Disease - Corrected Proof

2010-08-09

Background: Studies suggest that inflammation is involved in the neurodegenerative cascade leading to Alzheimer's disease (AD) pathology and symptoms. This study sought to quantitatively summarize the clinical cytokine data.Methods: Original English language peer-reviewed studies measuring cytokine concentrations in AD and healthy control subjects were included. Mean (±standard deviation) cytokine concentrations for AD and control subjects were extracted.Results: Forty studies measuring peripheral blood cytokine concentrations and 14 measuring cerebrospinal fluid (CSF) cytokine concentrations were included. In peripheral blood, there were significantly higher concentrations (weighted mean difference [95% confidence interval]) of interleukin (IL)-6 (2.86 [1.68, 4.04] pg/mL, p < .00001, N[AD/control subjects] = 985/680, 14 studies), tumor necrosis factor (TNF)-α (3.25 [.76, 5.74] pg/mL, p = .01, N = 680/447, 14 studies), IL-1β (.55 [.32, .78] pg/mL, p < .00001, N = 574/370, 10 studies), transforming growth factor (TGF)-β (67.23 [28.62, 105.83] pg/mL, p = .0006, N = 190/158, 5 studies), IL-12 (7.60 [5.58, 9.62] pg/mL, p < .00001, N = 148/106, 5 studies), and IL-18 (15.82 [1.98, 29.66] pg/mL, p = .03, N = 131/94, 4 studies) but not of IL-4, IL-8, IL-10, interferon-γ, or C-reactive protein in AD subjects compared with control subjects. There were significantly higher concentrations of TGF-β (7.81 [2.27, 13.35] pg/mL, p =.006, N = 113/114, 5 studies) but not IL-6, TNF-α, and IL-1β in the CSF of AD subjects compared with control subjects.Conclusions: These results strengthen the clinical evidence that AD is accompanied by an inflammatory response, particularly higher peripheral concentrations of IL-6, TNF-α, IL-1β, TGF-β, IL-12 and IL-18 and higher CSF concentrations of TGF-β.

Aerobic Exercise Attenuates Reinstatement of Cocaine-Seeking Behavior and Associated Neuroadaptations in the Prefrontal Cortex - Corrected Proof

2010-08-09

Background: Exercise has recently been suggested as an attractive alternative to pharmacotherapy for treating drug addiction. The goal of this study was to determine, using an animal model, whether aerobic exercise may block reinstatement of cocaine-seeking and its underlying neurobiology (i.e., neuronal signaling in the prefrontal cortex).Methods: Following acquisition and 10 days of 24-hour access to cocaine (1.5 mg/kg/infusion) or saline under a discrete trial procedure (four infusions/hr), rats began a 14-day abstinence period. During this period, rats were either given access to a running-wheel for 2-hours each day or placed in similar boxes with the wheel locked. Cocaine-seeking was assessed following the 14th day of abstinence using a within-session extinction/cue-induced reinstatement procedure. Neuronal activity was assessed by examining phosphorylated levels of extracellular signal-regulated kinase (pERK) using Western blot analysis.Results: Wheel running reduced cocaine-seeking during both extinction and reinstatement. Cocaine-seeking was positively associated with pERK levels in the prefrontal cortex. Although pERK levels were not different among saline controls, in the cocaine group, pERK levels were significantly decreased by exercise.Conclusions: Aerobic exercise may reduce relapse vulnerability by preventing the increase in cocaine-seeking and associated neuroadaptations in the prefrontal cortex that develop over an abstinence period.

Genetic Associations of Brain Structural Networks in Schizophrenia: A Preliminary Study - Corrected Proof

2010-08-06

Background: Schizophrenia is a complex genetic disorder, with multiple putative risk genes and many reports of reduced cortical gray matter. Identifying the genetic loci contributing to these structural alterations in schizophrenia (and likely also to normal structural gray matter patterns) could aid understanding of schizophrenia's pathophysiology. We used structural parameters as potential intermediate illness markers to investigate genomic factors derived from single nucleotide polymorphism (SNP) arrays.Method: We used research quality structural magnetic resonance imaging (sMRI) scans from European American subjects including 33 healthy control subjects and 18 schizophrenia patients. All subjects were genotyped for 367 SNPs. Linked sMRI and genetic (SNP) components were extracted to reveal relationships between brain structure and SNPs, using parallel independent component analysis, a novel multivariate approach that operates effectively in small sample sizes.Results: We identified an sMRI component that significantly correlated with a genetic component (r = −.536, p < .00005); components also distinguished groups. In the sMRI component, schizophrenia gray matter deficits were in brain regions consistently implicated in previous reports, including frontal and temporal lobes and thalamus (p < .01). These deficits were related to SNPs from 16 genes, several previously associated with schizophrenia risk and/or involved in normal central nervous system development, including AKT, PI3K, SLC6A4, DRD2, CHRM2, and ADORA2A.Conclusions: Despite the small sample size, this novel analysis method identified an sMRI component including brain areas previously reported to be abnormal in schizophrenia and an associated genetic component containing several putative schizophrenia risk genes. Thus, we identified multiple genes potentially underlying specific structural brain abnormalities in schizophrenia.

A cis-Phase Interaction Study of Genetic Variants Within the MAOA Gene in Major Depressive Disorder - Corrected Proof

2010-08-06

Background: The genetic basis of major depressive disorder (MDD) has been explored extensively, but the mode of transmission of the disease has yet to be established. To better understand the mechanism by which the monoamine oxidase A (MAOA) gene may play a role in developing MDD, the present work examined the cis-phase interaction between genetic variants within the MAOA gene for the pathogenesis of MDD.Methods: A variable number tandem repeat (VNTR) and 19 single nucleotide polymorphisms (SNPs) within the gene were genotyped in 512 unrelated patients with MDD and 567 unrelated control subjects among a Chinese population. Quantitative real-time polymerase chain reaction analysis was applied to test the effect of genetic variants on expression of the MAOA gene in MDD.Results: Neither the VNTR polymorphism nor seven informative SNPs showed allelic association with MDD, but the cis-acting interactions between the VNTR polymorphism and four individual SNPs were strongly associated with MDD risk, of which the VNTR-rs1465107 combination showed the strongest association (p = .000011). Quantitative real-time polymerase chain reaction analysis showed that overall relative quantity of MAOA messenger RNA was significantly higher in patients with MDD than in control subjects (fold change = 5.28, p = 1.7 × 10−7) and that in the male subjects carrying the VNTR-L, rs1465107-A, rs6323-G, rs2072743-A, or rs1137070-T alleles, expression of MAOA messenger RNA was significantly higher in the patient group than in the control group.Conclusions: The cis-phase interaction between the VNTR polymorphism and functional SNPs may contribute to the etiology of MDD.

Clinically Relevant Doses of Methylphenidate Significantly Occupy Norepinephrine Transporters in Humans In Vivo - Corrected Proof

2010-08-06

Background: Attention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate, the most common treatment for attention deficit hyperactivity disorder, is unclear. In vitro, the affinity of methylphenidate for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylphenidate in vivo in humans.Methods: We used (S,S)-[11C] methylreboxetine ([11C]MRB) to determine the effective dose 50 (ED50) of methylphenidate for NET. In a within-subject design, healthy subjects (n = 11) received oral, single-blind placebo and 2.5, 10, and 40 mg of methylphenidate 75 min before [11C]MRB injection. Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable (BPND) in the thalamus and other NET-rich regions.Results: BPND was reduced by methylphenidate in a dose-dependent manner in thalamus and other NET-rich regions. The global ED50 was estimated to be .14 mg/kg; therefore, the average clinical maintenance dose of methylphenidate (.35–.55 mg/kg) produces 70% to 80% occupancy of NET.Conclusions: For the first time in humans, we demonstrate that oral methylphenidate significantly occupies NET at clinically relevant doses. The ED50 is lower than that for DAT (.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in attention-deficit/hyperactivity disorder.

Stereological Approaches to Identifying Neuropathology in Psychosis - Corrected Proof

Karl-Anton Dorph-Petersen, David A. Lewis — 2010-08-02

The challenges involved in identifying the neuropathological substrates of the clinical syndrome recognized as schizophrenia are well known. Stereological sampling provides a means to obtain accurate and precise quantitative estimates of components of neural circuits and thus offers promise of an enhanced capacity to detect subtle alterations in brain structure associated with schizophrenia. In this review, we 1) consider the importance and rationale for robust quantitative measures of brain abnormalities in postmortem studies of schizophrenia; 2) provide a brief overview of stereological methods for obtaining such measures; 3) discuss the methodological details that should be reported to document the robustness of a stereological study; 4) given the constraints of postmortem human studies, suggest how to approach the limitations of less robust designs; and 5) present an overview of methodologically sound stereological estimates from postmortem studies of schizophrenia.

Changed Relative to What? Housekeeping Genes and Normalization Strategies in Human Brain Gene Expression Studies - Corrected Proof

Elizabeth M. Tunbridge, Sharon L. Eastwood, Paul J. Harrison — 2010-08-02

Many studies in biological psychiatry compare the abundance of individual messenger RNAs between cases and control subjects or, more recently, between genotype groups. Most utilize some form of normalization procedure, usually expressing the transcript(s) of interest relative to that of a housekeeping gene or genes (also called reference genes), to overcome various sources of experimental error. Indeed, normalization is such a standard procedure that its purpose, principles, and limitations are sometimes overlooked, and some papers lack sufficient information as to its implementation. Here, we review the rationales for normalization and argue that in well-conducted psychiatric gene expression studies using human brain tissue, it is reducing intersubject variability rather than experimental error that is the major benefit of normalization. We also review the conceptual and empirical basis for the category of housekeeping genes—i.e., genes with a ubiquitous and invariant expression. We conclude that the evidence is against any such simple categorization and that a more pragmatic, less dogmatic, approach to the selection and implementation of reference genes is required, which takes into account the particular issues that pertain to human brain tissue studies. This pragmatism extends to the issue of whether normalization should be to one or multiple reference genes. We end by making several recommendations toward a more flexible, transparent, and comprehensive approach to data presentation and analysis. We illustrate the review with examples from studies of schizophrenia and mood disorder.

Psychiatric Brain Banking: Three Perspectives on Current Trends and Future Directions - Corrected Proof

2010-08-02

Postmortem human brain tissue is critical for advancing neurobiological studies of psychiatric illness, particularly for identifying brain-specific transcripts and isoforms. State-of-the-art methods and recommendations for maintaining psychiatric brain banks are discussed in three disparate collections, the National Institute of Mental Health Brain Tissue Collection, the Harvard Brain Tissue Resource Center, and the Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank. While the National Institute of Mental Health Brain Tissue Collection obtains donations from medical examiners and focuses on clinical diagnosis, toxicology, and building life span control cohorts, the Harvard Brain Tissue Resource Center is designed as a repository to collect large-volume, high-quality brain tissue from community-based donors across a nationwide network, placing emphasis on the accessibility of tissue and related data to research groups worldwide. The Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank has shown that prospective recruitment is a successful approach to tissue donation, placing particular emphasis on clinical diagnosis through antemortem contact with donors, as well as stereological tissue sampling methods for neuroanatomical studies and frozen tissue sampling approaches that enable multiple assessments (e.g., RNA, DNA, protein, enzyme activity, binding) of the same tissue block. Promising scientific approaches for elucidating the molecular and cellular pathways in brain that may contribute to schizophrenia are briefly discussed. Despite different perspectives from three established brain collections, there is consensus that varied networking strategies, rigorous tissue and clinical characterization, sample and data accessibility, and overall adaptability are integral to the success of psychiatric brain banking.

Striatal and Extrastriatal Dopamine D2/D3 Receptors in Schizophrenia Evaluated With [18F]fallypride Positron Emission Tomography - Corrected Proof

2010-08-02

Background: Alterations in dopamine D2/D3 receptor binding have been reported in schizophrenia, and a meta-analysis of imaging studies has shown a modest elevation in striatum. Newer radioligands now allow the assessment of these receptors in extrastriatal regions. We used positron emission tomography with [18F]fallypride to evaluate D2/D3 receptors in both striatal and extrastriatal regions in schizophrenia.Methods: Twenty-one patients with schizophrenia and 22 matched healthy control subjects were scanned with an ECAT EXACT HR+ camera. Two-tissue compartment modeling and the reference tissue method gave binding potentials relative to nondisplaceable uptake, total plasma concentration, and free plasma concentration. These were compared between groups in five striatal and eight extrastriatal regions. Several regional volumes were lower in the patient group, and positron emission tomography data were corrected for partial volume effects.Results: Binding potential values differed in three regions between groups. Values for binding potential relative to nondisplaceable uptake from two-tissue compartment modeling in patients and control subjects, respectively, were 28.7 ± 6.8 and 25.3 ± 4.3 in postcommissural caudate, 2.9 ± .7 and 2.6 ± .4 in thalamus, and 1.8 ± .5 and 2.1 ± .7 in uncus. Loss of D2/D3 receptors with age was found in striatal and extrastriatal regions and was greater in neocortex.Conclusions: Our study found selective alterations in D2/D3 receptors in striatal and extrastriatal regions, consistent with some but not all previously published reports. As previously shown for the striatum, a more sensitive imaging approach for studying the role of dopamine in the pathophysiology of schizophrenia might be assessment of neurotransmitter levels rather than D2/D3 receptor levels in extrastriatal regions.

Use of Eye Movement Monitoring to Examine Item and Relational Memory in Schizophrenia - Corrected Proof

2010-08-02

Background: Patients with schizophrenia may be impaired at remembering interitem and item-context relationships (relational memory), even when memory for items is intact. Here, we applied the novel approach of using eye movements to assess integrity of item and relational memory in schizophrenia. This method does not rely on introspection and may be more readily translated to animal models than traditional behavioral methods.Methods: Sixteen healthy control subjects and 16 patients were administered a scene memory task while eye movements were monitored. During testing, participants indicated whether the scenes were unchanged, contained a new item (item manipulation), had a change in item location (relational manipulation), or were new. It was predicted that memory would be disproportionately impaired when relational changes were made.Results: Results confirmed that tasks were equally difficult and showed that patients were impaired identifying all scene types. These behavioral impairments were associated with more severe disorganization and negative symptoms. Eye movement results were more specific. Both groups looked disproportionately at critical regions of repeated versus novel scenes—an effect of scene repetition. However, in contrast with predictions, patients showed equivalent eye-movement-based memory impairment whether changes were relational or item-based.Conclusions: This is the first experiment to demonstrate that eye movements can be used to investigate item and relational memory in schizophrenia. The eye movement procedure was well tolerated and was more specific than behavioral measures with respect to memory impairment. Results suggest that eye movements may be of use in clinical trials and translational studies employing animal models.

Nicotine Withdrawal Increases Threat-Induced Anxiety but Not Fear: Neuroadaptation in Human Addiction - Corrected Proof

Joanne M. Hogle, Jesse T. Kaye, John J. Curtin — 2010-08-02

Background: Stress response neuroadaptation has been repeatedly implicated in animal addiction models for many drugs, including nicotine. Programmatic laboratory research that examines the stress response of nicotine-deprived humans is necessary to confirm that stress neuroadaptations observed in animal models generalize to humans.Methods: Two experiments tested the prediction that nicotine deprivation selectively increases startle response associated with anxiety during unpredictable threat but not fear during imminent, predictable threat. Dependent smokers (n = 117) were randomly assigned to 24-hour nicotine-deprived or nondeprived groups and participated in one of two experiments wherein electric shock was administered either unpredictably (noncontingent shock; Experiment 1) or predictably (cue-contingent shock; Experiment 2).Results: Nicotine deprivation increased overall startle response in Experiment 1, which involved unpredictable administration of shock. Age of first cigarette and years of daily smoking were significant moderators of this deprivation effect. Self-reported withdrawal symptoms also predicted startle response during unpredictable shock. In contrast, nicotine deprivation did not alter overall or fear-potentiated startle in Experiment 2, which involved predictable administration of shock.Conclusions: These results provide evidence that startle response during unpredictable threat may be a biomarker of stress neuroadaptations among smokers in nicotine withdrawal. Contrast of results across unpredictable versus predictable shock experiments provides preliminary evidence that these stress neuroadaptations manifest selectively as anxiety during unpredictable threat rather than in every stressful context. Individual differences in unpredictable threat startle response associated with withdrawal symptoms, age of first cigarette, and years daily smoking link this laboratory biomarker to clinically relevant indexes of addiction risk and relapse.

Sex Differences in Striatal Dopamine Release in Young Adults After Oral Alcohol Challenge: A Positron Emission Tomography Imaging Study With [11C]Raclopride - Corrected Proof

2010-08-02

Background: We used a positron emission tomography paradigm with the D2/3 radiotracer [11C]raclopride and an alcohol challenge to examine the magnitude of alcohol-induced dopamine release and compare it between young men and women.Methods: Twenty-one nonalcohol-dependent young social drinkers completed two positron emission tomography scans on separate days following ingestion of a juice mix containing either ethanol (.75 mg/kg body water) or trace ethanol only. The extent of dopamine released after alcohol was estimated by the percentage difference in [11C]raclopride binding potential (ΔBPND) between days.Results: Alcohol administration significantly displaced [11C]raclopride in all striatal subregions, indicating dopamine release, with the largest effect observed in the ventral striatum. Linear mixed model analysis across all striatal subregions of regional ΔBPND with region of interest as repeated measure showed a highly significant effect of sex (p < .001). Ventrostriatal dopamine release in men, but not in women, showed a significant positive correlation to alcohol-induced measures of subjective activation. Furthermore, we found a significant negative correlation between the frequency of maximum alcohol consumption per 24 hours and ventrostriatal ΔBPND (r = .739, p = .009) in men.Conclusions: This study provides definitive evidence that oral alcohol induces dopamine release in nonalcoholic human subjects and shows sex differences in the magnitude of this effect. The ability of alcohol to stimulate dopamine release may contribute to its rewarding effects and, thereby, to its abuse liability in humans. Our report further suggests several biological mechanisms that may mediate the difference in vulnerability for alcoholism between men and women.

Alpha Phase Locking Predicts Residual Working Memory Performance in Schizophrenia - Corrected Proof

2010-08-02

Background: Working memory (WM) deficits are a core feature of schizophrenia. Recent electrophysiological evidence indicates that the brain systems for visual encoding are especially impaired. However, patients still achieve performance levels clearly above chance, which indicates the existence of residual mechanisms supporting WM encoding. The present study presents evidence that alpha phase locking of the electroencephalogram is a marker for such residual cognitive mechanisms.Methods: Alpha phase locking during encoding into WM was compared between 17 patients with early-onset schizophrenia (EOS) and 17 healthy control subjects. Results of phase locking were correlated with accuracy. A median split based on alpha phase locking in patients was used to compare accuracy between control subjects and patients with high and low alpha phase locking.Results: Alpha phase locking increased with WM memory load in both EOS and control subjects, although alpha phase locking was generally reduced in EOS. Furthermore, for EOS, a positive correlation between alpha phase locking and performance was obtained. Additionally, patients exhibiting high phase locking did not differ in performance from control subjects.Conclusions: These results provide the first evidence for a relationship between alpha phase locking and visual WM encoding. This neural mechanism seems to be preserved in some patients with schizophrenia and then allows them to attain normal performance levels.

Common Variants in Major Histocompatibility Complex Region and TCF4 Gene Are Significantly Associated with Schizophrenia in Han Chinese - Corrected Proof

2010-08-02

Background: Schizophrenia is a complex major psychiatric disorder affecting ∼1% of the world population. Recently, in a genome-wide association study and a follow-up in Caucasians, Stefansson et al. examined 7662 schizophrenic cases and 29053 normal control subjects and reported seven common single nucleotide polymorphisms (SNPs) that were significantly (>10−8) associated with schizophrenia.Methods: To investigate whether these risk SNPs were significantly associated in Han Chinese, we analyzed the seven SNPs in 2496 schizophrenia patients and 5184 normal control subjects. Because only three of the seven SNPs were polymorphic in Han Chinese, we genotyped two additional common SNPs from the same risk regions.Results: Three SNPs, rs6932590 (p = .00096), rs3131296 (p = 1.29 × 10−6), and rs3130375 (p = 1.76 × 10−5), mapping to the major histocompatibility complex region and one SNP rs2958182 (p = 3.64 × 10−6) located in the TCF4 gene were significant in our sample set. A meta-analysis using published genome-wide association study results also supported our findings.Conclusions: Our results confirm that common risk factors in the major histocompatibility complex region and TCF4 gene are associated with schizophrenia in Han Chinese, but our results fail to show an association with SNP rs12807809 in the NRGN gene.

Drug Addiction Endophenotypes: Impulsive Versus Sensation-Seeking Personality Traits - Corrected Proof

2010-08-02

Background:: Genetic factors have been implicated in the development of substance abuse disorders, but the role of pre-existing vulnerability in addiction is still poorly understood. Personality traits of impulsivity and sensation-seeking are highly prevalent in chronic drug users and have been linked with an increased risk for substance abuse. However, it has not been clear whether these personality traits are a cause or an effect of stimulant drug dependence.Method:: We compared self-reported levels of impulsivity and sensation-seeking between 30 sibling pairs of stimulant-dependent individuals and their biological brothers/sisters who did not have a significant drug-taking history and 30 unrelated, nondrug-taking control volunteers.Results:: Siblings of chronic stimulant users reported significantly higher levels of trait-impulsivity than control volunteers but did not differ from control volunteers with regard to sensation-seeking traits. Stimulant-dependent individuals reported significantly higher levels of impulsivity and sensation-seeking compared with both their siblings and control volunteers.Conclusions:: These data indicate that impulsivity is a behavioral endophenotype mediating risk for stimulant dependence that may be exacerbated by chronic drug exposure, whereas abnormal sensation-seeking is more likely to be an effect of stimulant drug abuse.

Smoking and Schizophrenia Independently and Additively Reduce White Matter Integrity Between Striatum and Frontal Cortex - Corrected Proof

Xiaochu Zhang, Elliot A. Stein, L. Elliot Hong — 2010-08-02

Background: Although schizophrenia patients are at high risk for tobacco use, the neurobiological basis of this comorbid association is not clear. White matter abnormalities have been described independently in schizophrenia and smoking cohorts. We sought to determine whether smoking and schizophrenia are associated with similar white matter abnormalities that could be biomarkers for the high risk of smoking in schizophrenia.Methods: Whole brain white matter integrity (fractional anisotropy) was measured in 46 schizophrenia patients (32 smokers and 14 nonsmokers) and 69 healthy age-matched control subjects (48 smokers and 21 nonsmokers).Results: Schizophrenia and smoking status were independently and additively associated with reduced fractional anisotropy in left anterior thalamic radiation/anterior limb of the internal capsule, and significant fractional anisotropy decreases were identified in the bilateral uncinate fasciculus/inferior fronto-occipital fasciculus in schizophrenia and the left prefrontal area in smoking status separately.Conclusions: Common and distinct patterns of impaired white matter are associated with schizophrenia and smoking. Particularly, the anatomic congruence of an additive white matter abnormality in the anterior thalamic radiation/anterior limb of the internal capsule suggests that this abnormal fiber connectivity between frontal cortex and striatum/thalamus may be a biomarker for the increased comorbid smoking in schizophrenia patients.

How Psychological Symptoms Relate to Different Motivations for Gambling: An Online Study of Internet Gamblers - Corrected Proof

2010-07-26

Background: Gambling can be motivated by both its hedonic value and by attempts to cope with dysphoric or stressful states. Thus, motivations constitute important mechanisms linking mood fluctuations and gambling. However, little is known about how different kinds of affective disturbance, such as mood elevation and dysphoria, motivate gambling behavior.Methods: To estimate relationships between different mood experiences and gambling motivations, we recruited 4125 Internet gamblers via hyperlinks placed on gambling Web sites. Mean (SD) age of respondents was 35.5 (11.8) years, with 79.1% (3263) being male and 68.8% (2838) UK residents. We collected ratings for 11 gambling motivations. We used principal components analysis, followed by hierarchical linear regression, to model the relationships between motivation factor scores and gambling behavior, depressive symptoms, hypomanic experiences, deliberate self-harm, and alcohol and substance misuse.Results: Gambling to regulate mood, gambling for monetary goals, and gambling for enjoyment were enhanced in individuals at heightened risk of problematic gambling, with mood regulation and enjoyment factors being enhanced in female compared with male problem gamblers. Lowered mood reduced the enjoyment motivation, whereas previous mood elevation enhanced it. Gambling problems alongside previous hypomanic experiences or current dysphoria enhanced gambling to regulate emotional states.Conclusions: Recent theorizing argues that mood disorders and pathologic gambling may share aspects of pathophysiology. Different forms of emotional disturbance, such as mood elevation and dysphoric states, which confer heightened risk for bipolar disorder and depression, are associated with divergent motivations that might represent distinct pathways into gambling behavior.

Glycine Transporter-1 Blockade Leads to Persistently Reduced Relapse-like Alcohol Drinking in Rats - Corrected Proof

2010-07-26

Background: Residual dysfunction of multiple neurotransmitter systems due to chronic alcohol use is likely responsible for the occurrence of compulsive alcohol seeking during abstinence and relapse behavior. There is increasing evidence that glycine, which activates both glycine and N-methyl-D-aspartate receptors, contributes to excessive alcohol consumption. We therefore hypothesized that the blockade of glycine transporter 1 might interfere with compulsive alcohol consumption and relapse behavior.Methods: We used our animal model of alcoholism—long-term alcohol consumption with repeated deprivation phases in rats—to study the effects of a selective blocker of glycine transporter 1 Org25935. The abstinence-promoting drug acamprosate was used as a reference compound. Subsequently, we examined alterations in dorsal striatal gene expression caused by chronic ethanol (EtOH) consumption, focusing on glycinergic and glutamatergic signaling-related genes. Gene expression profiles of Org25935-treated EtOH-drinking rats were compared with vehicle-treated EtOH-drinking versus age-matched EtOH-naive rats.Results: We found that repeated treatment with Org25935 reduced compulsive relapse-like drinking without the development of tolerance. Importantly, these antirelapse properties were maintained for at least 6 weeks in a treatment-free period. This persistent effect was paralleled by a reversal of altered expression levels of a set of glycinergic and glutamatergic signaling-related genes to the levels found in EtOH-naive control rats.Conclusions: This study shows that treatment of rats with Org25935 leads to a reduction of compulsive alcohol consumption and relapse-like drinking behavior—an effect that persists into treatment-free periods. This long-term antirelapse effect might result from a restoration of normal glycinergic and glutamatergic signaling function.

Microarray Analysis of Hippocampal CA1 Neurons Implicates Early Endosomal Dysfunction During Alzheimer's Disease Progression - Corrected Proof

2010-07-26

Background: Endocytic dysfunction and neurotrophin signaling deficits may underlie the selective vulnerability of hippocampal neurons during the progression of Alzheimer's disease (AD), although there is little direct in vivo and biochemical evidence to support this hypothesis.Methods: Microarray analysis of hippocampal CA1 pyramidal neurons acquired via laser capture microdissection was performed using postmortem brain tissue. Validation was achieved using real-time quantitative polymerase chain reaction and immunoblot analysis. Mechanistic studies were performed using human fibroblasts subjected to overexpression with viral vectors or knockdown via small interference RNA.Results: Expression levels of genes regulating early endosomes (rab5) and late endosomes (rab7) are selectively upregulated in homogeneous populations of CA1 neurons from individuals with mild cognitive impairment and AD. The levels of these genes are selectively increased as antemortem measures of cognition decline during AD progression. Hippocampal quantitative polymerase chain reaction and immunoblot analyses confirmed increased levels of these transcripts and their respective protein products. Elevation of select rab GTPases regulating endocytosis paralleled the downregulation of genes encoding the neurotrophin receptors TrkB and TrkC. Overexpression of rab5 in cells suppressed TrkB expression, whereas knockdown of TrkB expression did not alter rab5 levels, suggesting that TrkB downregulation is a consequence of endosomal dysfunction associated with elevated rab5 levels in early AD.Conclusions: These data support the hypothesis that neuronal endosomal dysfunction is associated with preclinical AD. Increased endocytic pathway activity, driven by elevated rab GTPase expression, may result in long-term deficits in hippocampal neurotrophic signaling and represent a key pathogenic mechanism underlying AD progression.

Eye-Movement Behavior Reveals Relational Memory Impairment in Schizophrenia - Corrected Proof

2010-07-26

Background: Previous studies have demonstrated impaired relational memory in schizophrenia. We studied eye-movement behavior as an indirect measure of relational memory, together with forced-choice recognition as an explicit measure.Methods: Thirty-five patients with schizophrenia and 35 healthy participants were trained to associate a face with a background scene. During testing, scenes were presented as a cue and then overlaid with three previously studied faces. Participants were asked to recall the matching face, and both eye movements and forced-choice recognition were recorded. During Non-Match trials, no faces matched the scene. During Match trials, one of the faces had previously been paired with the scene.Results: On Non-Match trials, when no relational memory trace was present, both groups viewed the three faces equally. In contrast, on Match trials, control participants quickly (within 500 msec) and consistently (70%–75% of test trial viewing) showed preferential viewing of the matching face. Viewing of the matching face was significantly delayed and reduced in schizophrenia participants. Forced-choice recognition of the matching face was also impaired in the patient group. An analysis of all correct Match trials revealed that preferential viewing was significantly reduced and delayed in participants with schizophrenia.Conclusions: This study provides novel evidence for a specific relational memory impairment in schizophrenia. Patients showed deficits in their forced-choice recognition responses, as well as abnormal eye-movement patterns during memory recall, even on trials when behavioral responses were accurate. We propose that eye movements provide a promising new avenue for studying relational memory in schizophrenia.

Altered Relationship Between Hippocampal Glutamate Levels and Striatal Dopamine Function in Subjects at Ultra High Risk of Psychosis - Corrected Proof

2010-07-20

Background: Animal models of psychosis propose that striatal hyperdopaminergia is driven by abnormalities in hippocampal glutamatergic neurotransmission, but this has never been tested in humans.Methods: Sixteen individuals with an at-risk mental state for psychosis (ARMS) and 12 control subjects underwent proton magnetic resonance spectroscopy to estimate hippocampal glutamate and [18F]DOPA positron emission tomography to index striatal dopamine function. The relationship between hippocampal glutamate and striatal dopamine, as well as their relationship with prodromal symptoms, was determined using linear regression.Results: In ARMS subjects, but not controls, there was a significant negative relationship between hippocampal glutamate levels and striatal [18F]DOPA uptake (p = .03). Within the ARMS sample, striatal [18F]DOPA uptake was correlated with severity of abnormal beliefs (p = .03), there was a trend for hippocampal glutamate levels to be correlated with disordered speech (p = .06) and a trend for the interaction between hippocampal glutamate and [18F]DOPA uptake to predict later transition to psychosis (p = .07).Conclusions: The relationship between hippocampal glutamate and striatal dopamine systems is altered in people at high risk of psychosis, and the degree to which it is changed may be related to the risk of transition to psychosis. Pharmacologic modulation of the glutamate system before the onset of psychosis might ameliorate this risk.

A Novel, Multiple Symptom Model of Obsessive-Compulsive-Like Behaviors in Animals - Corrected Proof

Susan L. Andersen, Emily A. Greene-Colozzi, Kai C. Sonntag — 2010-07-12

Background: Current animal models of obsessive-compulsive disorder (OCD) typically involve acute, drug-induced symptom provocation or a genetic association with stereotypies or anxiety. None of these current models demonstrate multiple OCD-like behaviors.Methods: Neonatal rats were treated with the tricyclic antidepressant clomipramine or vehicle between days 9 and 16 twice daily and behaviorally tested in adulthood.Results: Clomipramine exposure in immature rats produced significant behavioral and biochemical changes that include enhanced anxiety (elevated plus maze and marble burying), behavioral inflexibility (perseveration in the spontaneous alternation task and impaired reversal learning), working memory impairment (e.g., win-shift paradigm), hoarding, and corticostriatal dysfunction. Dopamine D2 receptors were elevated in the striatum, whereas serotonin 2C, but not serotonin 1A, receptors were elevated in the orbital frontal cortex.Conclusions: This is the first demonstration of multiple symptoms consistent with an OCD-like profile in animals. Moreover, these behaviors are accompanied by biochemical changes in brain regions previously identified as relevant to OCD. This novel model of OCD demonstrates that drug exposure during a sensitive period can program disease-like systems permanently, which could have implications for current and future therapeutic strategies for this and other psychiatric disorders.

The Potential Role of Major Histocompatibility Complex Class I in Schizophrenia - Corrected Proof

Adam E. Handel, Sreeram V. Ramagopalan — 2010-07-12

Schizophrenia is a psychiatric disorder characterized by the disruption of thought processes and psychosis. One leading theory is that the symptoms of schizophrenia result from a disruption to synaptic function and intracerebral connectivity (). Until recently the main candidate genes involved in schizophrenia strongly supported this hypothesis, and indeed, many have been shown to play a strong role in synaptogenesis (). Pathologic work published recently in Biological Psychiatry by Castillo and colleagues () has suggested a key functional role for presynaptic machinery in schizophrenia.

Reply to: The Potential Role of Major Histocompatibility Complex Class I in Schizophrenia - Corrected Proof

Paula G. Ulery-Reynolds — 2010-07-12

We appreciate the attention our article “Deficits in Syntaxin 1 Phosphorylation in Schizophrenia Prefrontal Cortex” has elicited and the interesting hypothesis Handel and Ramagopalan put forth regarding a potential role for the immune system in the etiology of schizophrenia. Although the literature is rich in examples of important immune–nervous system interplays, the possibility of this contributing to a complex disease like schizophrenia is certainly worthy of pursuit. Handel and Ramagopalan base their hypothesis on the vast evidence of synaptic dysfunction in schizophrenia () and the fact that recent genomewide association studies () have found a susceptibility locus for schizophrenia within the short arm of chromosome 6 (chromosome 6p), which contains several MHC Class I genes. MHC Class I proteins have been found presynaptically in rodent brain () and recently in the brain of nonhuman primates (); further, a key component of MHC Class I receptors, CD3zeta, has been found on postsynaptic dendritic membranes (). Thus, as the authors point out, the location of these molecules is compatible with a possible trans-synaptic regulation of synaptic activity, perhaps similar to that exerted by the neuregulin 1-ErbB4 interaction, or the neurexin-neuroligin interaction, both of which have been implicated in schizophrenia (). Of special interest to us, however, is the fact that two of the genomewide studies cited by Handel and Ramagopalan () detected a susceptibility locus on chromosome 6p (6p21.3 and 6p22.1 respectively) that is immediately adjacent to the gene encoding the regulatory subunit of casein kinase 2 (ck2β gene located on 6p21.3). This is particularly gripping, in light of our recent findings implicating ck2 and its presynaptic substrate syntaxin 1 (stx 1) in schizophrenia (). Perhaps the deficit in ck2 that we () and others () have observed in schizophrenia brain, and which we believe leads to the deficit in stx 1 phosphorylation we observe in the same samples (), stems from subtle genetic variants encompassing the ck2β gene that result in decreased expression and/or stability of the protein. Ck2 is a tetramer composed of two catalytic α subunits and two regulatory β subunits, all of which are critical for the proper function of the enzyme, which has been implicated in numerous aspects of brain function (). Together, the proximity of the ck2β gene to the schizophrenia susceptibility locus, the deficit in ck2 and ck2-mediated stx 1 phosphorylation found in schizophrenia brain, and the importance of ck2 in brain activity, suggest its candidacy as a risk gene for schizophrenia. We therefore believe that in addition to looking further at the possible contribution of immune system proteins to the synaptic dysfunction purported to play a key role in schizophrenia, we should also look at a possible genetic association between ck2 (in particular, its regulatory subunit) and schizophrenia.

Adjunctive Intranasal Oxytocin Reduces Symptoms in Schizophrenia Patients - Corrected Proof

2010-07-08

Background: Both human and animal studies suggest oxytocin may have antipsychotic properties. Therefore, we conducted a clinical trial to directly test this notion.Methods: Nineteen schizophrenia patients with residual symptoms despite being on a stable dose of at least one antipsychotic were enrolled in a randomized, double-blind, crossover study. They received 3 weeks of daily intranasal oxytocin (titrated to 40 IU twice a day) and placebo adjunctive to their antipsychotics. Order of intranasal treatment was randomly assigned and there was a 1-week washout between treatments.Results: Analysis of the 15 subjects who completed all the study visits revealed that oxytocin significantly reduced scores on the Positive and Negative Symptom Scale (p < .001) and Clinical Global Impression-Improvement Scale (p < .001) compared with placebo at the 3-week end point. No benefit was seen at the early time points. Oxytocin was well tolerated and produced no adverse effects based upon patient reports or laboratory analysis.Conclusions: The results support the hypothesis that oxytocin has antipsychotic properties and is well tolerated. Higher doses and longer duration of treatment may produce larger benefits and should be evaluated in future studies.

Progression of Cerebral Amyloid Load Is Associated with the Apolipoprotein E ε4 Genotype in Alzheimer's Disease - Corrected Proof

2010-07-02

Background: Pittsburgh Compound B ([11C] PiB) is a specific positron emission tomography (PET) marker of cerebral amyloid deposits. Only few data have been published on in vivo longitudinal changes of amyloid load in Alzheimer's disease (AD) patients, with conflicting results. Therefore, little is known about the factors that influence these changes.Methods: A group of 24 patients with probable AD diagnosed by combining established clinical criteria with an AD-typical pattern in [18F] fluoro-deoxy-glucose PET underwent [11C] PiB-PET examinations at baseline and after 24 months. The difference of amyloid load between the two examinations and the association with clinical and neurobiological variables was examined with a regions-of-interest approach and voxel-based analyses.Results: Cerebral [11C] PiB uptake ratio increased significantly by an annual rate of 3.92%. Although the increase occurred in all parts of the neocortex, no increase was detected in the archipallium. The increase was gene-dose-dependent (analysis of variance p = .012) to the number of apolipoprotein E ε4 alleles. Progression of dementia symptoms was correlated to the [11C] PiB increase in numerous regions associated with cognition.Conclusions: The results of this study indicate that a significant increase of amyloid deposition occurs in patients with AD during a relatively short interval of its clinical course. The rate of amyloid aggregation rate is closely associated with the apolipoprotein E genotype, which might be important for the evaluation of antiamyloid drug treatment effects. The present study further emphasizes the value of amyloid-plaque imaging as a marker of disease progression and as a potential surrogate marker to be used in antiamyloid drug trials.

Elevated Gamma-Aminobutyric Acid Levels in Chronic Schizophrenia - Corrected Proof

Dost Öngür, Andrew P. Prescot, Julie McCarthy, Bruce M. Cohen, Perry F. Renshaw — 2010-07-02

Background: Despite widely replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy control subjects in the anterior cingulate cortex and parieto-occipital cortex.Methods: Twenty-one schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy control subjects (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7-mL voxels and analyzed using LCModel.Results: We found elevations in GABA/creatine in the schizophrenia group compared with control subjects [F(1,65) = 4.149, p = .046] in both brain areas (15.5% elevation in anterior cingulate cortex, 11.9% in parieto-occipital cortex). We also found a positive correlation between GABA/creatine and glutamate/creatine, which was not accounted for by % GM or brain region.Conclusions: We found elevated GABA/creatinine in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia.

Emergence of Dormant Conditioned Incentive Approach by Conditioned Withdrawal in Nicotine Addiction - Corrected Proof

Daniel Scott, Noboru Hiroi — 2010-07-02

Background: Nicotine is one of the determinants for the development of persistent smoking, and this maladaptive behavior is characterized by many symptoms, including withdrawal and nicotine seeking. The process by which withdrawal affects nicotine seeking is poorly understood.Method: The impact of a withdrawal-associated cue on nicotine (.2 mg/kg)-conditioned place preference was assessed in male C57BL/6J mice (n = 8–17/group). To establish a cue selectively associated with withdrawal distinct from those associated with nicotine, a tone was paired with withdrawal in their home cages; mice were chronically exposed to nicotine (200 μg/mL for 15 days) from drinking water in their home cages and received the nicotinic acetylcholine receptor antagonist mecamylamine (2.5 mg/kg) to precipitate withdrawal in the presence of a tone. The effect of the withdrawal-associated tone on nicotine-conditioned place preference was then evaluated in the place-conditioning apparatus after a delay, when nicotine-conditioned place preference spontaneously disappeared.Results: A cue associated with precipitated withdrawal reactivated the dormant effect of nicotine-associated cues on conditioned place preference. This effect occurred during continuous exposure to nicotine but not during abstinence.Conclusions: A conditioned withdrawal cue could directly amplify the incentive properties of cues associated with nicotine. This observation extends the contemporary incentive account of the role of withdrawal in addiction to cue–cue interaction.

Attentional Bias, Emotion Recognition, and Emotion Regulation in Anorexia: State or Trait? - Corrected Proof

Amy Harrison, Kate Tchanturia, Janet Treasure — 2010-06-30

Background: Anorexia nervosa (AN) is associated with difficulties in emotion recognition and regulation and with attentional biases to social affective stimuli. This study aimed to examine these factors in a group of women following long-term recovery from AN.Methods: The Reading the Mind in the Eyes task, Difficulties in Emotion Regulation Scale, and a computerized pictorial Stroop task (angry and neutral faces) were administered to 175 women: 50 with acute AN, 35 recovered from AN, and 90 healthy control subjects (HCs).Results: The recovered group had a significantly higher social and angry-threat attentional bias than HCs, with medium effect sizes, and significantly lower scores on the emotion recognition measure than HCs, with a medium effect size. On the other hand, the recovered group did not significantly differ from the HC group in terms of emotion regulation.Conclusions: Attentional biases to social affective pictorial stimuli and difficulties with emotion recognition appear to be traits associated with a lifetime history of AN, whereas emotion regulation difficulties appear to remit when the individual successfully recovers from the illness.

Brain Mu-Opioid Receptor Binding Predicts Treatment Outcome in Cocaine-Abusing Outpatients - Corrected Proof

2010-06-28

Background: Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown.Methods: We determined whether regional brain mOR binding before treatment correlates with outcome and compared it with standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine abstinence reinforcement, whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography with [11C]-carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment; and 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology.Results: Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sublobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use.Conclusions: Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction.

T-Type Calcium Channel Antagonism Decreases Motivation for Nicotine and Blocks Nicotine- and Cue-Induced Reinstatement for a Response Previously Reinforced with Nicotine - Corrected Proof

2010-06-28

Background: Recent evidence suggests an involvement of T-type calcium channels in the effects of drugs of abuse.Methods: We examined the influence of the novel, potent, and selective T-type calcium channel antagonist [2-(4-Cyclopropylphenyl)-N-((1R)-1-{5-[2,2,2-trifluoroethyl]oxo}pyridine-2-yl)ethyl]acetamide] (TTA-A2) (.3, 1, or 3 mg/kg) on motivation for nicotine, as measured by nicotine self-administration on a progressive ratio (PR) schedule, and nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine delivery (n = 11 or 12 Long Evans rats/group). Furthermore, we examined the specificity of the TTA-A2 effects by characterizing its influence on PR responding for food (in the absence or presence of nicotine-potentiated responding), food- versus nicotine-induced cue-potentiated reinstatement for a response previously reinforced by food administration (n = 11 or 12 Wistar Hannover rats/group), and its ability to induce a conditioned place aversion.Results: TTA-A2 dose-dependently decreased self-administration of nicotine on a PR schedule and the ability of both nicotine and a cue paired with nicotine to reinstate responding. The effects were specific for nicotine's incentive motivational properties, as TTA-A2 did not influence responding for food on a PR schedule but did attenuate the ability of nicotine to potentiate responding for food. Likewise, TTA-A2 did not alter food-induced cue-potentiated reinstatement for a response previously reinforced by food but did decrease nicotine-induced cue-potentiated reinstatement. Finally, TTA-A2 did not produce an aversive state, as indicated by a lack of ability to induce conditioned place aversion.Conclusions: These data suggest that T-type calcium channel antagonists have potential for alleviating nicotine addiction by selectively decreasing the incentive motivational properties of nicotine.

De Novo Truncating Mutation in Kinesin 17 Associated with Schizophrenia - Corrected Proof

2010-06-21

Background: Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ.Methods: As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish.Results: Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect.Conclusions: Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder.