Biological Psychiatry - Articles in Press

Stress in the Adult Rat Exacerbates Muscle Pain Induced by Early-Life Stress - Corrected Proof

Pedro Alvarez, Paul G. Green, Jon D. Levine — 2013-05-23

Background: Early-life stress and exposure to stressful stimuli play a major role in the development of chronic widespread pain in adults. However, how they interact in chronic pain syndromes remains unclear.Methods: Dams and neonatal litters were submitted to a restriction of nesting material (neonatal limited bedding [NLB]) for 1 week. As adults, these rats were exposed to a painless sound stress protocol. The involvement of sympathoadrenal catecholamines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) in nociception was evaluated through behavioral and enzyme-linked immunosorbent assays, surgical interventions, and intrathecal antisense treatments.Results: Adult NLB rats exhibited mild muscle hyperalgesia, which was markedly aggravated by sound stress (peaking 15 days after exposure). Adrenal medullectomy did not modify hyperalgesia in NLB rats but prevented its aggravation by sound stress. Sustained administration of epinephrine to NLB rats mimicked sound stress effect. Intrathecal treatment with antisense directed to IL-6 receptor subunit gp130 (gp130), but not to tumor necrosis factor receptor type 1 (TNFR1), inhibited hyperalgesia in NLB rats. However, antisense against either gp130 or TNFR1 inhibited sound stress-induced enhancement of hyperalgesia. Compared with control rats, NLB rats exhibit increased plasma levels of IL-6 but decreased levels of TNFα, whereas sound stress increases IL-6 plasma levels in control rats but not in NLB rats.Conclusions: Early-life stress induces a persistent elevation of IL-6, hyperalgesia, and susceptibility to chronic muscle pain, which is unveiled by exposure to stress in adults. This probably depends on an interaction between adrenal catecholamines and proinflammatory cytokines acting at muscle nociceptor level.

ELK1 Transcription Factor Linked to Dysregulated Striatal Mu Opioid Receptor Signaling Network and OPRM1 Polymorphism in Human Heroin Abusers - Corrected Proof

2013-05-22

Background: Abuse of heroin and prescription opiate medications has grown to disturbing levels. Opioids mediate their effects through mu opioid receptors (MOR), but minimal information exists regarding MOR-related striatal signaling relevant to the human condition. The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders.Methods: We examined molecular mechanisms related to MOR in postmortem human brain striatal specimens from a homogenous European Caucasian population of heroin abusers and control subjects and in an animal model of heroin self-administration. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history.Results: A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed ~20% of downregulated genes in human heroin abusers are ELK1 targets. Using chromatin immune precipitation, we confirmed decreased ELK1 promoter occupancy of the target gene Use1.Conclusions: ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1.

Proteomic Similarities Between Heterozygous Reeler Mice and Schizophrenia - Corrected Proof

2013-05-20

To the Editor: Reelin is a neural extracellular glycoprotein that participates in the control of pivotal processes during neurodevelopment, such as neuronal migration and positioning as well as postnatally such as growth of dendrites and axons, synaptogenesis, and neurotransmission . Associations between Reelin single nucleotide polymorphisms with working memory dysfunction and more severe positive and negative symptoms in schizophrenia including sensorimotor gating deficits have been demonstrated in Biological Psychiatry. Moreover, reduced Reelin messenger RNA levels of have been observed in six brain regions and in interstitial neurons from schizophrenia patients. Reelin downregulation has also been associated with a reduced number of cerebellar Purkinje neurons in psychosis .

Impaired Anatomical Connectivity and Related Executive Functions: Differentiating Vulnerability and Disease Marker in Bipolar Disorder - Corrected Proof

2013-05-20

Background: Bipolar 1 disorder (BD1) has been associated with impaired set shifting, increased risk taking, and impaired integrity of frontolimbic white matter. However, it remains unknown to what extent these findings are related to each other and whether these abnormalities represent risk factors or consequences of the illness. Methods: We addressed the first question by comparing 19 patients with BD1 and 19 healthy control subjects (sample 1) with diffusion tensor imaging, the Intra-Extra Dimensional Set Shift Task, and the Cambridge Gambling Task. The second question we approached by applying the same protocol to 22 healthy first-degree relatives of patients with BD1 and 22 persons without a family history of mental disorders (sample 2).Results: In comparison with their control groups, BD1 patients and healthy first-degree relatives of patients with BD1 showed significantly reduced fractional anisotropy (FA) in the right anterior limb of the internal capsule and right uncinate fasciculus. White matter integrity in corpus callosum was reduced in BD1 patients only. In addition, reduced FA in anterior limb of the internal capsule correlated significantly with an increased number of errors during set shifting and increased risk taking and reduced FA in uncinate fasciculus correlated significantly with increased risk taking.Conclusions: Similar white matter alterations in BD1 patients and healthy relatives of BD1 patients are associated with comparable behavioral abnormalities. Further, results indicate that altered frontolimbic and frontothalamic connectivity and corresponding behavioral abnormalities might be a trait and vulnerability marker of BD1, whereas interhemispheric connectivity appears to be a disease marker.

Meta-Analysis of Oxidative Stress in Schizophrenia - Corrected Proof

Joshua Flatow, Peter Buckley, Brian J. Miller — 2013-05-17

Background: Schizophrenia is associated with impaired antioxidant defense, including abnormal serum, plasma, and red blood cell (RBC) oxidative stress parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment after an acute exacerbation of psychosis.Methods: We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information, and the reference lists of identified studies.Results: Forty-four studies met the inclusion criteria. Total antioxidant status seemed to be a state marker, because levels were significantly decreased in cross-sectional studies of serum and plasma in first-episode psychosis (FEP) and significantly increased in longitudinal studies of antipsychotic treatment for acute exacerbations of psychosis (p < .01 for each). The RBC catalase and plasma nitrite seemed to be state-related markers, because levels in cross-sectional studies were significantly decreased in FEP (p < .01) and significantly increased in stable outpatients (p = .01). In contrast, RBC superoxide dismutase seemed to be a trait marker for schizophrenia, because levels in cross-sectional studies were significantly decreased in acutely relapsed inpatients, FEP, and stable outpatients (p < .01 for each).Conclusions: Oxidative stress abnormalities in FEP suggest an effect that might be independent of antipsychotic medications. Although some parameters (total antioxidant status, RBC catalase, and plasma nitrite) might be state markers for acute exacerbations of psychosis, others (RBC superoxide dismutase) might be trait markers; however, more longitudinal studies are needed. Our findings suggest that oxidative stress might serve as a potential biomarker in the etiopathophysiology and clinical course of schizophrenia.

5-Lipoxygenase Activating Protein Reduction Ameliorates Cognitive Deficit, Synaptic Dysfunction, and Neuropathology in a Mouse Model of Alzheimer’s Disease - Corrected Proof

2013-05-17

Background: 5-lipoxygenase activating protein (FLAP) is abundantly present in the central nervous system. Although its function has been extensively interrogated in the context of peripheral inflammation, novel roles for this protein are emerging in the central nervous system. The objective of our study was to investigate the functional role that FLAP plays in a mouse model of Alzheimer’s disease (AD) with plaques and tangles (i.e., 3xTg mice).Methods: By implementing a genetic knockout of FLAP and pharmacologic inhibition with a FLAP inhibitor (MK-591), we evaluated the effect on the AD-like neuropathology, cognition, and synaptic plasticity in the 3xTg mice.Results: We show that reduction of FLAP leads to amelioration of cognition and memory along with the rescuing of synaptic dysfunction at an early age before the development of overt neuropathology. Genetic knockout and pharmacologic inhibition of FLAP also yielded an improvement in AD pathology through a reduction in Aβ via the γ-secretase pathway and a decrease in tau phosphorylation through the cdk5 pathway.Conclusions: Our studies identify a novel functional role for FLAP in regulating memory and synaptic plasticity. They establish this protein at the crossroad of multiple pathways that ultimately contribute to the development of the entire AD-like phenotype, making it a viable therapeutic target with disease-modifying capacity for the treatment of this disease.

Role of Prefrontal Cortex Glucocorticoid Receptors in Stress and Emotion - Corrected Proof

2013-05-16

Background: Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation.Methods: We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field.Results: The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyperlocomotion in the open field, but did not affect stress sensitization or helplessness behavior.Conclusions: The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation.

Immunotherapy in Alzheimer’s Disease: Do We Have All the Pieces of the Puzzle? - Corrected Proof

Marie Sarazin, Guillaume Dorothée, Leonardo Cruz de Souza, Pierre Aucouturier — 2013-05-16

Results of Phase III studies involving a large number of Alzheimer’s disease (AD) patients treated by passive immunotherapy with humanized anti-amyloid β monoclonal antibodies have recently been released. These approaches failed to show a significant clinical benefit in patients with mild to moderate AD. The most considered explanation is that the patients have been treated too late. Whereas targeting patients at asymptomatic stages of the disease is a critical step in the goal of improving the efficacy of such antibody-based strategies, several other important factors should be considered in the development and clinical evaluation of anti-amyloid β immunotherapies, including the as yet poorly understood relationship of AD with the immune system and the importance of cerebral amyloid angiopathy. Better understanding the role of immune responses in AD and their impact on immunotherapy appears essential in the design of alternative or combinatorial immunotherapy approaches in AD, which may imply effectors other than antibodies and even additional antigenic targets.

Brain Serotonin 1A Receptor Binding as a Predictor of Treatment Outcome in Major Depressive Disorder - Corrected Proof

2013-05-13

Background: We previously reported higher serotonin 1A receptor (5-HT1A) binding in subjects with major depressive disorder (MDD) during a major depressive episode using positron emission tomography imaging with [11C]WAY-100635. 5-HT1A receptor binding is also associated with treatment outcome after nonstandardized antidepressant treatment. We examined whether pretreatment 5-HT1A binding is associated with treatment outcome following standardized escitalopram treatment in MDD. We also compared 5-HT1A binding between all MDD subjects in this cohort and a sample of healthy control subjects.Methods: Twenty-four MDD subjects in a current major depressive episode and 51 previously studied healthy control subjects underwent positron emission tomography scanning with [11C]WAY-100635, acquiring a metabolite-corrected arterial input function and free-fraction measurement to estimate 5-HT1A binding potential (BPF = Bmax/KD, where Bmax = available receptors and KD = dissociation constant). Major depressive disorder subjects then received 8 weeks of treatment with escitalopram; remission was defined as a posttreatment 24-item Hamilton Depression Rating Scale <10 and ≥50% reduction in Hamilton Depression Rating Scale.Results: Remitters to escitalopram had 33% higher baseline 5-HT1A binding in the raphe nuclei than nonremitters (p = .047). Across 12 cortical and subcortical regions, 5-HT1A binding did not differ between remitters and nonremitters (p = .86). Serotonin 1A receptor binding was higher in MDD than control subjects across all regions (p = .0003). Remitters did not differ from nonremitters in several relevant clinical measures.Conclusions: Elevated 5-HT1A binding in raphe nuclei is associated with subsequent remission with the selective serotonin reuptake inhibitor escitalopram; this is consistent with data from a separate cohort receiving naturalistic antidepressant treatment. We confirmed our previous findings of higher 5-HT1A binding in current MDD compared with control subjects.

Prefrontal Cortical Dysfunction After Overexpression of Histone Deacetylase 1 - Corrected Proof

2013-05-09

Background: Postmortem brain studies have shown that HDAC1—a lysine deacetylase with broad activity against histones and nonhistone proteins—is frequently expressed at increased levels in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia and related disease. However, it remains unclear whether upregulated expression of Hdac1 in the PFC could affect cognition and behavior.Methods: Using adeno-associated virus, an Hdac1 transgene was expressed in young adult mouse PFC, followed by behavioral assays for working and long-term memory, repetitive activity, and response to novelty. Prefrontal cortex transcriptomes were profiled by microarray. Antipsychotic drug effects were explored in mice treated for 21 days with haloperidol or clozapine.Results: Hdac1 overexpression in PFC neurons and astrocytes resulted in robust impairments in working memory, increased repetitive behaviors, and abnormal locomotor response profiles in novel environments. Long-term memory remained intact. Over 300 transcripts showed subtle but significant changes in Hdac1-overexpressing PFC. Major histocompatibility complex class II (MHC II)-related transcripts, including HLA-DQA1/H2-Aa, HLA-DQB1/H2-Ab1, and HLA-DRB1/H2-Eb1, located in the chromosome 6p21.3-22.1 schizophrenia and bipolar disorder risk locus, were among the subset of genes with a more robust (>1.5-fold) downregulation in expression. Hdac1 levels declined during the course of normal PFC development. Antipsychotic drug treatment, including the atypical clozapine, did not affect Hdac1 levels in PFC but induced expression of multiple MHC II transcripts.Conclusions: Excessive HDAC1 activity, due to developmental defects or other factors, is associated with behavioral alterations and dysregulated expression of MHC II and other gene transcripts in the PFC.

A Test of the Cognitive Self-Medication Hypothesis of Tobacco Smoking in Schizophrenia - Corrected Proof

2013-05-08

Background: Heavier tobacco smoking among people with schizophrenia (SCZ) has been suggested to reflect self-medication of cognitive deficits. The idea that cognitive-enhancing effects of nicotine are a primary motivator of tobacco consumption in SCZ and that abstinence would deprive SCZ of such beneficial effects might explain hesitation among providers to pursue smoking cessation in SCZ. This study tested predictions of the cognitive self-medication hypothesis.Methods: In three counterbalanced sessions, 17 SCZ and 17 healthy control subjects (HCS), all smokers, were tested under ad libitum smoking or 3.5 hours after abstaining and receiving a nicotine (14 mg/24 hours) or placebo patch.Results: Attention task performance was improved by transdermal nicotine relative to placebo, with intermediate performance by ad libitum smoking. These effects were of similar size in SCZ and HCS and did not reflect remediation of functions disproportionately impaired in SCZ. Although more SCZ reported that the need to concentrate influenced their smoking, this was not reflected by the actual behavior of these patients. Self-reported ability to concentrate changed with nicotine status in HCS but not SCZ, suggesting insensitivity of SCZ to nicotine-derived performance benefits. Nicotine plasma concentrations after ad libitum smoking were not associated with performance benefits but instead with the propensity to experience nicotine withdrawal upon abstinence. This association was seen selectively in SCZ, suggesting a possible reason for heavier smoking.Conclusions: These findings suggest that subjective or objective attentional benefits are unlikely the primary driving force of tobacco consumption in SCZ and should not discourage providers from supporting quit attempts.

Lower Amygdala Volume in Men Is Associated with Childhood Aggression, Early Psychopathic Traits, and Future Violence - Corrected Proof

Dustin A. Pardini, Kirk Erickson, Rolf Loeber, Adrian Raine — 2013-05-06

Background: Reduced amygdala volume has been implicated in the development of severe and persistent aggression and the development of psychopathic personality. With longitudinal data, the current study examined whether male subjects with lower amygdala volume have a history of aggression and psychopathic features dating back to childhood and are at increased risk for engaging in future aggression/violence.Methods: Participants were selected from a longitudinal study of 503 male subjects initially recruited when they were in the first grade in 1986–1987. At age 26, a subsample of 56 men with varying histories of violence was recruited for a neuroimaging substudy. Automated segmentation was used to index individual differences in amygdala volume. Analyses examined the association between amygdala volume and levels of aggression and psychopathic features of participants measured in childhood and adolescence. Analyses also examined whether amygdala volume was associated with violence and psychopathic traits assessed at a 3-year follow-up.Results: Men with lower amygdala volume exhibited higher levels of aggression and psychopathic features from childhood to adulthood. Lower amygdala volume was also associated with aggression, violence, and psychopathic traits at a 3-year follow-up, even after controlling for earlier levels of these features. All effects remained after accounting for several potential confounds.Conclusions: This represents the first prospective study to demonstrate that men with lower amygdala volume have a longstanding history of aggression and psychopathic features and are at increased risk for committing future violence. Studies should further examine whether specific amygdala abnormalities might be a useful biomarker for severe and persistent aggression.

Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism - Corrected Proof

2013-04-26

Background: Gestation is a critical window for neurodevelopmental vulnerability. This study examined whether the presence of trophoblast inclusions (TIs) in the placenta could serve as a predictor for children at elevated risk for autism spectrum disorder (ASD).Methods: Placentas were obtained from 117 births in the MARBLES (Markers of Autism Risk in Babies—Learning Early Signs) cohort of families who have one or more previous biological children with ASD, placing their newborn at elevated risk for neurodevelopmental compromise. Control samples were obtained from 100 uncomplicated term pregnancies of multiparous women with one or more typically developing biological children. Frequency of TIs was compared across the two groups.Results: Placentas from at-risk pregnancies had an eightfold increased odds of having two or more TIs compared with control samples (odds ratio: 8.0, 95% confidence interval: 3.6–18.0). The presence of≥2 TIs yielded a sensitivity of 41% and a specificity of 92% for predicting ASD risk status, whereas≥4 TIs yielded a sensitivity of 19%, a specificity of 99.9%, and a positive likelihood ratio of 242 and conservatively predicted an infant with a 74% probability of being at risk for ASD.Conclusions: Our findings suggest that the placentas from women whose fetuses are at elevated risk for autism are markedly different from control placentas. These differences are manifested histologically as TIs. Their identification has the possibility of identifying newborns at risk for ASD who might benefit from targeted early interventions aimed at preventing or ameliorating behavioral symptoms and optimizing developmental outcomes.

Disruption of Anterior Insula Modulation of Large-Scale Brain Networks in Schizophrenia - Corrected Proof

2013-04-26

Background: Systems level modeling of functional magnetic resonance imaging data has demonstrated dysfunction of several large-scale brain networks in schizophrenia. Anomalies across multiple functional networks associated with schizophrenia could be due to diffuse pathology across multiple networks or, alternatively, dysfunction at converging control(s) common to these networks. The right anterior insula has been shown to modulate activity in the central executive and default mode networks in healthy individuals. We tested the hypothesis that right anterior insula modulation of central executive and default mode networks is disrupted in schizophrenia and associated with cognitive deficits.Methods: In 44 patients with schizophrenia and 44 healthy control subjects, we used seed-based resting state functional connectivity functional magnetic resonance imaging analysis to examine connectivity between right insular subregions and central executive/default mode network regions. We also performed two directed connectivity analyses of resting state data: Granger analysis and confirmatory structural equation modeling. Between-group differences in path coefficients were used to evaluate anterior insula modulation of central executive and default mode networks. Cognitive performance was assessed with the rapid visual information processing task, a test of sustained attention.Results: With multiple connectivity techniques, we found compelling, corroborative evidence of disruption of right anterior insula modulation of central executive and default mode networks in patients with schizophrenia. The strength of right anterior insula modulation of these networks predicted cognitive performance.Conclusions: Individuals with schizophrenia have impaired right anterior insula modulation of large-scale brain networks. The right anterior insula might be an emergent pathophysiological gateway in schizophrenia.

Deep Brain Stimulation Targeted at the Nucleus Accumbens Decreases the Potential for Pathologic Network Communication - Corrected Proof

2013-04-26

Deep brain stimulation (DBS) entails electrode implantation and high-frequency electrical stimulation of a specific brain target. DBS targeted at the nucleus accumbens (NAc) is a promising treatment option for otherwise treatment-refractory obsessive-compulsive disorder (OCD) . Recently, our group demonstrated that NAc DBS in OCD not only results in local activity changes but also in reduction of pathological overconnectivity throughout the frontostriatal network . This reduction in overconnectivity correlates with symptom improvements, empirically supporting the hypothesis that DBS overwrites pathologic network activity . The goal of our current endeavor was to determine mechanistically how DBS could modulate connectivity within the frontostriatal network.

Hair Cortisol as a Biomarker of Traumatization in Healthy Individuals and Posttraumatic Stress Disorder Patients - Corrected Proof

2013-04-25

Background: Previous evidence on endocrine correlates of posttraumatic stress disorder (PTSD) has been rather inconsistent. The analysis of cortisol in hair is a recent methodological development that may increase the quality of long-term cortisol assessments in such research. Here, we use this method to closely assess hair cortisol relationships with trauma-related characteristics and PTSD symptom patterns.Methods: Hair cortisol concentrations (HCC), diurnal salivary cortisol, and relevant psychometric data were assessed in matched groups of 28 PTSD patients and 27 traumatized and 32 nontraumatized healthy control subjects. Cortisol levels were quantified by liquid chromatography tandem mass spectrometry.Results: Posttraumatic stress disorder patients and traumatized control subjects exhibited 59% and 51% lower HCC than nontraumatized control subjects, respectively. Hair cortisol concentrations were found to be negatively related to the severity of intrusion symptoms, the number of different lifetime traumatic events, the frequency of traumatization, and the time interval since traumatization. The overall pattern of HCC associations was not reflected in short-term salivary cortisol findings.Conclusions: Our results indicate that trauma exposure per se, either in the absence or presence of PTSD, is a crucial correlate of long-term basal cortisol levels. Particularly, the experience of multiple events with a longer time since traumatization and an increased severity of intrusion symptoms may be related to hypocortisolism. The fact that HCC findings were not consistently seen in salivary cortisol data underscores the importance of the method of cortisol assessment and highlights the utility of hair cortisol analyses for future biological psychiatry research.

The One-Two Punch of Alcoholism: Role of Central Amygdala Dynorphins/Kappa-Opioid Receptors - Corrected Proof

2013-04-23

Background: The dynorphin (DYN)/kappa-opioid receptor (KOR) system undergoes neuroadaptations following chronic alcohol exposure that promote excessive operant self-administration and negative affective-like states; however, the exact mechanisms are unknown. The present studies tested the hypothesis that an upregulated DYN/KOR system mediates excessive alcohol self-administration that occurs during withdrawal in alcohol-dependent rats by assessing DYN A peptide expression and KOR function, in combination with site-specific pharmacologic manipulations.Methods: Male Wistar rats were trained to self-administer alcohol using operant behavioral strategies and subjected to intermittent alcohol vapor or air exposure. Changes in self-administration were assessed by pharmacologic challenges during acute withdrawal. In addition, 22-kHz ultrasonic vocalizations were utilized to measure negative affective-like states. Immunohistochemical techniques assessed DYN A peptide expression and [35S]GTPγS coupling assays were performed to assess KOR function.Results: Alcohol-dependent rats displayed increased alcohol self-administration, negative affective-like behavior, DYN A-like immunoreactivity, and KOR signaling in the amygdala compared with nondependent control rats. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats, whereas a mu-opioid receptor/delta-opioid receptor antagonist cocktail selectively reduced self-administration in nondependent rats. A mu-opioid receptor antagonist/partial KOR agonist attenuated self-administration in both cohorts.Conclusions: Increased DYN A and increased KOR signaling could set the stage for a one-two punch during withdrawal that drives excessive alcohol consumption in alcohol dependence. Importantly, intracentral nucleus of the amygdala pharmacologic challenges functionally confirmed a DYN/KOR system involvement in the escalated alcohol self-administration. Together, the DYN/KOR system is heavily dysregulated in alcohol dependence and contributes to the excessive alcohol consumption during withdrawal.

Follow-up of a Major Psychosis Linkage Site in 13q13-q14 Reveals Significant Association in Both Case-Control and Family Samples - Corrected Proof

2013-04-22

Background: We previously reported a genome-wide significant linkage for major psychosis in chromosome 13q13-q14.Methods: An association analysis was conducted in 247 unrelated DSM-IV schizophrenia (SZ) patients and 250 unrelated control subjects from the Eastern Quebec population genotyped with 2150 single nucleotide polymorphisms in 13q13-q14. We also used the kindred sample where linkage was detected (125 SZ, 120 bipolar disorder [BD] and 36 schizoaffective disorder patients vs. 467 unaffected adult relatives) for replication.Results: An association of the T allele of rs1156026 found in the case-control sample (odds ratio [OR] = 1.81, p = 4×10−6, false discovery rate = .01) was replicated in the kindred sample (OR = 1.54, p = .01), strengthening the overall association evidence (p = 8×10−7). The effect size increased in the subset of unrelated patients with a family history (OR = 2.28) and in the 15 families where SZ was predominant (OR = 2.03). In the kindred sample, onset of either SZ or BD was, on average, 5 years earlier for T/T compared with C/C homozygotes, leading to stronger association in patients with onset before 26 years of age (SZ: OR = 2.40, p = 1.3×10−4; SZ, BD, and schizoaffective disorder combined: OR = 1.87, p = 8×10−5).Conclusions: Case-control and family-based association provided evidence of a locus at 13q13-q14 related to SZ. The proximity of the associated single nucleotide polymorphism with the linkage signal and the extension of the associated phenotype to major psychosis with younger age of onset indicate congruence between the linkage and association signals. The rs1156026 association is novel and factors explaining its nondetection in previous studies are discussed.

Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau - Corrected Proof

2013-04-22

Background: The microtubule-associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer’s disease. One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau’s toxic accretion.Methods: Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the heat shock protein 70 (Hsp70) family in the brain, heat shock cognate 70 protein (Hsc70). The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures, and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured.Results: Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, overexpression of heat shock protein 40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wild-type mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in tau transgenic brain slices.Conclusions: Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in Alzheimer’s disease and other tauopathies.

Anomalous Gray Matter Structural Networks in Major Depressive Disorder - Corrected Proof

2013-04-22

Background: Major depressive disorder (MDD) is characterized by abnormalities in structure, function, and connectivity in several brain regions. Few studies have examined how these regions are organized in the brain or investigated network-level structural aberrations that might be associated with depression.Methods: We used graph analysis to examine the gray matter structural networks of individuals diagnosed with MDD (n = 93) and a demographically similar healthy comparison group (n = 151) with no history of psychopathology. The efficiency of structural networks for processing information was determined by quantifying local interconnectivity (clustering) and global integration (path length). We also compared the groups on the contributions of high-degree nodes (i.e., hubs) and regional network measures, including degree (number of connections in a node) and betweenness (fraction of short path connections in a node).Results: Depressed participants had significantly decreased clustering in their brain networks across a range of network densities. Compared with control subjects, depressed participants had fewer hubs primarily in medial frontal and medial temporal areas, had higher degree in the left supramarginal gyrus and right gyrus rectus, and had higher betweenness in the right amygdala and left medial orbitofrontal gyrus.Conclusions: Networks of depressed individuals are characterized by a less efficient organization involving decreased regional connectivity compared with control subjects. Regional connections in the amygdala and medial prefrontal cortex may play a role in maintaining or adapting to depressive pathology. This is the first report of anomalous large-scale gray matter structural networks in MDD and provides new insights concerning the neurobiological mechanisms associated with this disorder.

Fetal Glucocorticoid Exposure Is Associated with Preadolescent Brain Development - Corrected Proof

Elysia Poggi Davis, Curt A. Sandman, Claudia Buss, Deborah A. Wing, Kevin Head — 2013-04-22

Background: Glucocorticoids play a critical role in normative regulation of fetal brain development. Exposure to excessive levels may have detrimental consequences and disrupt maturational processes. This may especially be true when synthetic glucocorticoids are administered during the fetal period, as they are to women in preterm labor. This study investigated the consequences for brain development and affective problems of fetal exposure to synthetic glucocorticoids.Methods: Brain development and affective problems were evaluated in 54 children (56% female), aged 6 to 10, who were full term at birth. Children were recruited into two groups: those with and without fetal exposure to synthetic glucocorticoids. Structural magnetic resonance imaging scans were acquired and cortical thickness was determined. Child affective problems were assessed using the Child Behavior Checklist.Results: Children in the fetal glucocorticoid exposure group showed significant and bilateral cortical thinning. The largest group differences were in the rostral anterior cingulate cortex (rACC). More than 30% of the rACC was thinner among children with fetal glucocorticoid exposure. Furthermore, children with more affective problems had a thinner left rACC.Conclusions: Fetal exposure to synthetic glucocorticoids has neurologic consequences that persist for at least 6 to 10 years. Children with fetal glucocorticoid exposure had a thinner cortex primarily in the rACC. Our data indicating that the rACC is associated with affective problems in conjunction with evidence that this region is involved in affective disorders raise the possibility that glucocorticoid-associated neurologic changes increase vulnerability to mental health problems.

Cell Number and Neuropil Alterations in Subregions of the Anterior Hippocampus in a Female Monkey Model of Depression - Corrected Proof

Stephanie L. Willard, David R. Riddle, M. Elizabeth Forbes, Carol A. Shively — 2013-04-22

Background: The anterior hippocampus is associated with emotional functioning and hippocampal volume is reduced in depression. More women are clinically depressed than men, yet the depressed female brain is little studied. We reported reduced anterior hippocampal volume in behaviorally depressed adult female cynomolgus macaques; the mechanisms contributing to that reduction are unknown. The present study represents the first systematic morphological investigation of the entire hippocampus in depressed female primates.Methods: Cellular determinants of hippocampal size were examined in subregions of anterior and posterior hippocampus in antidepressant-naïve, adult female monkeys characterized for behavioral depression and matched on variables that influence hippocampal size (n = 8 depressed, 8 nondepressed). Unbiased stereology was used to estimate neuronal and glial numbers, neuronal soma size, and regional and layer volumes.Results: Neuropil and cell layer volumes were reduced in cornu ammonis (CA)1 and dentate gyrus (DG) of the anterior but not the posterior hippocampus of depressed compared with nondepressed monkeys. Glial numbers were 30% lower in anterior CA1 and DG of depressed monkeys, with no differences observed in the posterior hippocampus. Granule neuron number tended toward a reduction in anterior DG; pyramidal neuron number was unchanged in any region. Size of pyramidal neurons and glial densities tended to be reduced throughout the whole hippocampus of depressed monkeys, whereas neuronal densities were unchanged.Conclusions: The reduced size of the anterior hippocampus in depressed female monkeys appears to arise from alterations in numbers of glia and extent of neuropil, but not numbers of neurons, in CA1 and DG.

Not All Inflammatory Biomarkers Are Elevated in Bipolar Disorder: Evidence for Procalcitonin - Corrected Proof

2013-04-19

The pathogenesis of bipolar disorder (BD) is still unknown, although a growing body of evidence suggests that a pro-inflammatory state may play a significant role . Increased circulating levels of inflammatory biomarkers have been consistently reported in BD, especially during mood episodes (i.e., mania or depression) . It has been proposed that this pro-inflammatory state would be acting as a major “toxic player,” contributing to increased rates of coronary artery disease and diabetes mellitus, explaining at least in part the reduction in life expectancy in these patients .

The Role of Memory-related Gene WWC1 (KIBRA) in Lifetime Posttraumatic Stress Disorder: Evidence from Two Independent Samples from African Conflict Regions - Corrected Proof

2013-04-15

Background: Posttraumatic stress disorder (PTSD) results from the formation of a strong memory for the sensory-perceptual and affective representations of traumatic experiences, which is detached from the corresponding autobiographical context information. Because WWC1, the gene encoding protein KIBRA, is associated with long-term memory performance, we hypothesized that common WWC1 alleles influence the risk for a lifetime diagnosis of PTSD.Methods: Traumatic load and diagnosis of current and lifetime PTSD were assessed in two independent African samples of survivors from conflict zones who had faced severe trauma (n = 392, Rwanda, and n = 399, Northern Uganda, respectively). Array-based single nucleotide polymorphism (SNP) genotyping was performed. The influence of WWC1 tagging SNPs and traumatic load on lifetime PTSD was estimated by means of logistic regression models with correction for multiple comparisons in the Rwandan sample. Replication analysis was performed in the independent Ugandan sample.Results: An association of two neighboring SNPs in almost complete linkage disequilibrium, rs10038727 and rs4576167, with lifetime PTSD was discovered in the Rwandan sample. Although each traumatic event added to the probability of lifetime PTSD in a dose-dependent manner in both genotype groups, carriers of the minor allele of both SNPs displayed a diminished risk (p = .007, odds ratio = .29 [95% confidence interval = .15–.54]). This effect was confirmed in the independent Ugandan sample.Conclusions: This study reveals an association between two WWC1 SNPs and the likelihood of PTSD development, indicating that this memory-related gene might be involved in processes that occur in response to traumatic stress and influence the strengthening of fear memories.

A Selective Insular Perfusion Deficit Contributes to Compromised Salience Network Connectivity in Recovering Alcoholic Men - Corrected Proof

2013-04-15

Background: Alcoholism can disrupt neural synchrony between nodes of intrinsic functional networks that are maximally active when resting relative to engaging in a task, the default mode network (DMN) pattern. Untested, however, are whether the DMN in alcoholics can rebound normally from the relatively depressed task state to the active resting state and whether local perfusion deficits could disrupt network synchrony when switching from conditions of rest to task to rest, thereby indicating a physiological mechanism of neural network adaptation capability.Methods: Whole-brain, three-dimensional pulsed-continuous arterial spin labeling provided measurements of regional cerebral blood flow (CBF) in 12 alcoholics and 12 control subjects under three conditions: pretask rest, spatial working-memory task, and posttask rest.Results: With practice, alcoholics and control subjects achieved similar task accuracy and reaction times. Both groups exhibited a high-low-high pattern of perfusion levels in DMN regions during the rest-task-rest runs and the opposite pattern in posterior and cerebellar regions known to be associated with spatial working memory. Alcoholics showed selective differences from control subjects in the rest-task-rest CBF pattern in the anterior precuneus and CBF level in the insula, a hub of the salience network. Connectivity analysis identified activation synchrony from an insula seed to salience nodes (parietal, medial frontal, anterior cingulate cortices) in control subjects only.Conclusions: We propose that attenuated insular CBF is a mechanism underlying compromised connectivity among salience network nodes. This local perfusion deficit in alcoholics has the potential to impair ability to switch from cognitive states of interoceptive cravings to cognitive control for curbing internal urges.

Impulsivity is Associated with Uric Acid: Evidence from Humans and Mice - Corrected Proof

2013-04-12

Background: The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice.Methods: Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid.Results: In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice.Conclusions: Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention.

Myelin and Axon Abnormalities in Schizophrenia Measured with Magnetic Resonance Imaging Techniques - Corrected Proof

Fei Du, Alissa J. Cooper, Thida Thida, Ann K. Shinn, Bruce M. Cohen, Dost Öngür — 2013-04-09

Background: In schizophrenia (SZ), disturbances in integration of activity among brain regions seem to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging has provided compelling evidence for WM abnormalities in SZ. However, diffusion tensor imaging alone cannot currently pinpoint the biological basis of these abnormalities.Methods: In this study, we combined a myelin-specific and an axon-specific magnetic resonance imaging approach to examine potentially distinct abnormalities of WM components in SZ. Magnetization transfer ratio (MTR) provides information on myelin content, whereas diffusion tensor spectroscopy provides information on metabolite diffusion within axons. We collected data from a 1×3×3 cm voxel within the right prefrontal cortex WM at 4 Tesla and studied 23 patients with SZ and 22 age- and sex-matched healthy control participants.Results: The MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-acetylaspartate (NAA) was significantly elevated, suggesting intra-axonal abnormalities. Greater abnormality of both MTR and the apparent diffusion coefficient of NAA correlated with more adverse outcomes in the patient group.Conclusions: The results suggest that WM abnormalities in SZ include both abnormal myelination and abnormal NAA diffusion within axons. These processes might be associated with abnormal signal transduction and abnormal information processing in SZ.

White Matter Alterations at 33-Year Follow-Up in Adults with Childhood Attention-Deficit/Hyperactivity Disorder - Corrected Proof

2013-04-08

Background: Attention-deficit/hyperactivity disorder (ADHD) is increasingly conceived as reflecting altered functional and structural brain connectivity. The latter can be addressed with diffusion tensor imaging (DTI). We examined fractional anisotropy (FA), a DTI index related to white matter structural properties, in adult male subjects diagnosed with ADHD in childhood (probands) and matched control subjects without childhood ADHD. Additionally, we contrasted FA among probands with and without current ADHD in adulthood and control subjects.Methods: Participants were from an original cohort of 207 boys and 178 male control subjects. At 33-year follow-up, analyzable DTI scans were obtained in 51 probands (41.3±2.8 yrs) and 66 control subjects (41.2±3.1 yrs). Voxel-based FA was computed with tract-based spatial statistics, controlling for multiple comparisons.Results: Probands with childhood ADHD exhibited significantly lower FA than control subjects without childhood ADHD in the right superior and posterior corona radiata, right superior longitudinal fasciculus, and in a left cluster including the posterior thalamic radiation, the retrolenticular part of the internal capsule, and the sagittal stratum (p<.05, corrected). Fractional anisotropy was significantly decreased relative to control subjects in several tracts in both probands with current and remitted ADHD, who did not differ significantly from each other. Fractional anisotropy was not significantly increased in probands in any region.Conclusions: Decreased FA in adults with childhood ADHD regardless of current ADHD might be an enduring trait of ADHD. White matter tracts with decreased FA connect regions involved in high-level as well as sensorimotor functions, suggesting that both types of processes are involved in the pathophysiology of ADHD.

Rapid Effects of Deep Brain Stimulation for Treatment-Resistant Major Depression - Corrected Proof

2013-04-05

Background: Treatment-resistant major depressive disorder is a prevalent and debilitating condition. Deep brain stimulation to different targets has been proposed as a putative treatment.Methods: In this pilot study, we assessed safety and efficacy of deep brain stimulation to the supero-lateral branch of the medial forebrain bundle in seven patients with highly refractory depression. Primary outcome criterion was severity of treatment-resistant major depressive disorder as assessed with the Montgomery-Åsberg Depression Rating Scale. General psychopathologic parameters, social functioning, and tolerance were assessed with standardized scales, the Global Assessment of Functioning scale, quality of life (Short-Form Health Survey Questionnaire), and neuropsychological tests.Results: All patients showed strikingly similar intraoperative effects of increased appetitive motivation. Six patients attained the response criterion; response was rapid—mean Montgomery-Åsberg Depression Rating Scale of the whole sample was reduced by>50% at day 7 after onset of stimulation. At last observation (12–33 weeks), six patients were responders; among them, four were classified as remitters. Social functioning (Global Assessment of Functioning) improved in the sample as a whole from serious to mild impairment. Mean stimulation current was 2.86 mA; all side effects (strabismus at higher stimulation current, one small intracranial bleeding during surgery, infection at the implanted pulse generator site) could be resolved at short term.Conclusions: These preliminary findings suggest that bilateral stimulation of the supero-lateral branch of the medial forebrain bundle may significantly reduce symptoms in treatment-resistant major depressive disorder. Onset of antidepressant efficacy was rapid (days), and a higher proportion of the population responded at lower stimulation intensities than observed in previous studies.

Cortisol Levels and Risk for Psychosis: Initial Findings from the North American Prodrome Longitudinal Study - Corrected Proof

2013-04-04

Background: Studies of biomarkers of hypothalamic-pituitary-adrenal activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy control subjects and individuals who met clinical high-risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be 1) elevated in the CHR group relative to control subjects, 2) positively correlated with symptom severity, and 3) most elevated in CHR patients who transition to psychotic level severity.Methods: Baseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study. The present CHR sample included 256 individuals meeting the Scale for Prodromal Symptoms criteria and 141 control subjects, all of whom underwent baseline assessment and measurement of salivary cortisol.Results: Consistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and analysis of covariance revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared with healthy control subjects and CHR subjects who remitted.Conclusions: The present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of hypothalamic-pituitary-adrenal activity in prediction of conversion to psychosis and its relation with other biomarkers of risk should receive attention in future research.

Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression - Corrected Proof

2013-04-04

Background: Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression.Methods: We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared.Results: Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects.Conclusions: Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.

How Might Circadian Rhythms Control Mood? Let Me Count the Ways..... - Corrected Proof

Colleen A. McClung — 2013-04-03

Mood disorders are serious diseases that affect a large portion of the population. There have been many hypotheses put forth over the years to explain the development of major depression, bipolar disorder, and other mood disorders. These hypotheses include disruptions in monoamine transmission, hypothalamus-pituitary-adrenal axis function, immune function, neurogenesis, mitochondrial dysfunction, and neuropeptide signaling (to name a few). Nearly all people suffering from mood disorders have significant disruptions in circadian rhythms and the sleep/wake cycle. In fact, altered sleep patterns are one of the major diagnostic criteria for these disorders. Moreover, environmental disruptions to circadian rhythms, including shift work, travel across time zones, and irregular social schedules, tend to precipitate or exacerbate mood-related episodes. Recent studies have found that molecular clocks are found throughout the brain and body where they participate in the regulation of most physiological processes, including those thought to be involved in mood regulation. This review will summarize recent data that implicate the circadian system as a vital regulator of a variety of systems that are thought to play a role in the development of mood disorders.

Developmental Disruption of Gamma-Aminobutyric Acid Function in the Medial Prefrontal Cortex by Noncontingent Cocaine Exposure During Early Adolescence - Corrected Proof

Daryn K. Cass, Daniel R. Thomases, Adriana Caballero, Kuei Y. Tseng — 2013-04-03

Background: Drug experimentation during adolescence is associated with increased risk of drug addiction relative to any other age group. To further understand the neurobiology underlying such liability, we investigate how early adolescent cocaine experience impacts medial prefrontal cortex (mPFC) network function in adulthood.Methods: A noncontingent administration paradigm was used to assess the impact of early adolescent cocaine treatment (rats; postnatal days [PD] 35–40) on the overall inhibitory regulation of mPFC activity in adulthood (PD 65–75) by means of histochemical and in vivo electrophysiological measures combined with pharmacologic manipulations.Results: Cocaine exposure during early adolescence yields a distinctive hypermetabolic prefrontal cortex state that was not observed in adult-treated rats (PD 75–80). Local field potential recordings revealed that early adolescent cocaine exposure is associated with an attenuation of mPFC gamma-aminobutyric acid (GABA)ergic inhibition evoked by ventral hippocampal stimulation at beta and gamma frequencies that endures throughout adulthood. Such cocaine-induced mPFC disinhibition was not observed in adult-exposed animals. Furthermore, the normal developmental upregulation of parvalbumin immunoreactivity observed in the mPFC from PD 35 to PD 65 is lacking following early adolescent cocaine treatment.Conclusions: Our data indicate that repeated cocaine exposure during early adolescence can elicit a state of mPFC disinhibition resulting from a functional impairment of the local prefrontal GABAergic network that endures through adulthood. A lack of acquisition of prefrontal GABAergic function during adolescence could trigger long-term deficits in the mPFC that may increase the susceptibility for the onset of substance abuse and related psychiatric disorders.

Neural Correlates of Rapid Antidepressant Response to Ketamine in Treatment-Resistant Unipolar Depression: A Preliminary Positron Emission Tomography Study - Corrected Proof

2013-04-01

Background: Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown.Methods: In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response.Results: Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex.Conclusions: Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine’s rapid antidepressant effects.

Shared and Distinct Intrinsic Functional Network Centrality in Autism and Attention-Deficit/Hyperactivity Disorder - Corrected Proof

2013-04-01

Background: Individuals with autism spectrum disorders (ASD) often exhibit symptoms of attention-deficit/hyperactivity disorder (ADHD). Across both disorders, observations of distributed functional abnormalities suggest aberrant large-scale brain network connectivity. Yet, common and distinct network correlates of ASD and ADHD remain unidentified. Here, we aimed to examine patterns of dysconnection in school-age children with ASD and ADHD and typically developing children who completed a resting state functional magnetic resonance imaging scan.Methods: We measured voxelwise network centrality, functional connectivity metrics indexing local (degree centrality [DC]) and global (eigenvector centrality) functional relationships across the entire brain connectome, in resting state functional magnetic resonance imaging data from 56 children with ASD, 45 children with ADHD, and 50 typically developing children. A one-way analysis of covariance, with group as fixed factor (whole-brain corrected), was followed by post hoc pairwise comparisons.Results: Cortical and subcortical areas exhibited centrality abnormalities, some common to both ADHD and ASD, such as in precuneus. Others were disorder-specific and included ADHD-related increases in DC in right striatum/pallidum, in contrast with ASD-related increases in bilateral temporolimbic areas. Secondary analyses differentiating children with ASD into those with or without ADHD-like comorbidity (ASD+ and ASD−, respectively) revealed that the ASD+ group shared ADHD-specific abnormalities in basal ganglia. By contrast, centrality increases in temporolimbic areas characterized children with ASD regardless of ADHD-like comorbidity. At the cluster level, eigenvector centrality group patterns were similar to DC.Conclusions: ADHD and ASD are neurodevelopmental disorders with distinct and overlapping clinical presentations. This work provides evidence for both shared and distinct underlying mechanisms at the large-scale network level.

Cognitive Impairment and Dentate Gyrus Synaptic Dysfunction in Experimental Parkinsonism - Corrected Proof

2013-04-01

Background: Parkinson’s disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway and the emergence of rigidity, tremor, and bradykinesia. Accumulating evidence indicates that PD is also accompanied by nonmotor symptoms including cognitive deficits, often manifested as impaired visuospatial memory.Methods: We studied cognitive performance and synaptic plasticity in a mouse model of PD, characterized by partial lesion of the dopaminergic and noradrenergic inputs to striatum and hippocampus. Sham– and 6-hydroxydopamine–lesioned mice were subjected to the novel object recognition test, and long-term potentiation was examined in the dentate gyrus and CA1 regions of the hippocampus.Results: Bilateral 6-hydroxydopamine lesion reduced long-term but not short-term novel object recognition and decreased long-term potentiation specifically in the dentate gyrus. These abnormalities did not depend on the loss of noradrenaline but were abolished by the antiparkinsonian drug, L-DOPA, or by SKF81297, a dopamine D1-type receptor agonist. In contrast, activation of dopamine D2-type receptors did not modify the effects produced by the lesion. Blockade of the extracellular signal-regulated kinases prevented the ability of SKF81297 to rescue novel object recognition and long-term potentiation.Conclusions: These findings show that partial dopamine depletion leads to impairment of long-term recognition memory accompanied by abnormal synaptic plasticity in the dentate gyrus. They also demonstrate that activation of dopamine D1 receptors corrects these deficits, through a mechanism that requires intact extracellular signal-regulated kinases signaling.

Ventral Striatum Binding of a Dopamine D2/3 Receptor Agonist But Not Antagonist Predicts Normal Body Mass Index - Corrected Proof

2013-04-01

Background: Positron emission tomography research has shown that dopamine D2/3 receptor (D2/3R) availability is negatively correlated with body mass index (BMI) in obese but not in healthy subjects. However, previous positron emission tomography studies have not looked specifically at the ventral striatum (VS), which plays an important role in motivation and feeding. Furthermore, these studies have only used antagonist radiotracers. Normal-weight rats given free access to high-fat diets demonstrate behavioral sensitization to D2/3R agonists but not to antagonists. Sensitization is associated with increased D2/3R affinity, which affects binding of agonists but not antagonists.Methods: We examined the association between BMI within the nonobese range (18.6–27.8) and D2/3R availability in the VS with the use of the agonist radiotracer [11C]-(+)-PHNO (n = 26) and the antagonist [11C]-raclopride (n = 35) in healthy humans.Results: In the VS, we found a positive correlation between BMI and [11C]-(+)-PHNO binding but no relationship with [11C]-raclopride binding. Secondary analyses revealed no relationship between BMI and binding in the dorsal striatum with either radiotracer.Conclusions: We propose that in nonobese individuals, higher BMI may be associated with increased D2R affinity in the VS. This increased affinity may potentiate the incentive salience of food cues and counteract the effects of satiety cues, thereby increasing feeding.

Enhancing Putative Mirror Neuron Activity with Magnetic Stimulation: A Single-Case Functional Neuroimaging Study - Corrected Proof

2013-03-25

Mirror neuron-driven embodied simulation, based on the neural exploitation hypothesis has been proposed as a physiological basis of social cognitive abilities in humans . Experimental evidence points to a relationship between social cognition and putative mirror neuron activity in neuropsychiatric disorders like schizophrenia and autism . Experiments to explore strategies to modulate mirror neuron activity (MNA) are rare . We are unaware of any previous report that applied targeted brain stimulation to improve functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) activation during action observation paradigms, an indirect method of measuring MNA. Transcranial magnetic stimulation (TMS) is a safe, noninvasive method of administering targeted brain stimulation to enhance focal brain activity. In this letter, we describe the first report of a single session of high-frequency repetitive TMS (HF-rTMS) delivered at the left inferior frontal gyrus (IFG) enhancing putative MNA as ascertained by functional magnetic resonance imaging (MRI).

Geographic Variation in the Prevalence of Attention-Deficit/Hyperactivity Disorder: The Sunny Perspective - Corrected Proof

Martijn Arns, Kristiaan B. van der Heijden, L. Eugene Arnold, J. Leon Kenemans — 2013-03-25

Background: Attention-deficit/hyperactivity disorder (ADHD) is the most common psychiatric disorder of childhood, with average worldwide prevalence of 5.3%, varying by region.Methods: We assessed the relationship between the prevalence of ADHD and solar intensity (SI) (kilowatt hours/square meters/day) on the basis of multinational and cross-state studies. Prevalence data for the U.S. were based on self-report of professional diagnoses; prevalence data for the other countries were based on diagnostic assessment. The SI data were obtained from national institutes.Results: In three datasets (across 49 U.S. states for 2003 and 2007, and across 9 non-U.S. countries) a relationship between SI and the prevalence of ADHD was found, explaining 34%–57% of the variance in ADHD prevalence, with high SI having an apparent preventative effect. Controlling for low birth weight, infant mortality, average income (socioeconomic status), latitude, and other relevant factors did not change these findings. Furthermore, these findings were specific to ADHD, not found for the prevalence of autism spectrum disorders or major depressive disorder.Conclusions: In this study we found a lower prevalence of ADHD in areas with high SI for both U.S. and non-U.S. data. This association has not been reported before in the literature. The preventative effect of high SI might be related to an improvement of circadian clock disturbances, which have recently been associated with ADHD. These findings likely apply to a substantial subgroup of ADHD patients and have major implications in our understanding of the etiology and possibly prevention of ADHD by medical professionals, schools, parents, and manufacturers of mobile devices.

Behavioral Consequences of Aberrant Alpha Lateralization in Attention-Deficit/Hyperactivity Disorder - Corrected Proof

2013-03-18

Background: Attention-deficit/hyperactivity disorder (ADHD) is characterized by problems in directing and sustaining attention. Recent findings suggest that alpha oscillations (8–12 Hz) are crucially involved in gating information between brain regions when allocating attention. The current study investigates whether aberrant modulation of alpha oscillations contributes to attention problems in ADHD patients.Methods: Magnetoencephalographic signals were recorded in adults with ADHD (n = 17) and healthy control subjects (n = 18) while they performed a visuospatial attention task. Cues directed attention to the left or right visual hemifield with an 80% validity with respect to the upcoming target.Results: Unlike the control group, subjects with ADHD showed a higher accuracy for invalidly cued right targets compared with invalidly cued left targets (p = .04). This coincided with an inability of the ADHD subjects to sustain the posterior hemispheric alpha lateralization in the period before the target for the left cue condition (p = .011). Furthermore, the control group showed a strong correlation between the degree of alpha lateralization and the magnitude of the cueing effect assessed in terms of accuracy (rs = .71, p = .001) and reaction times (rs =−.81, p<.001). These correlations were absent in the ADHD group.Conclusions: Our results demonstrate that subjects with ADHD have a failure in sustaining hemispheric alpha lateralization when cued to the left, resulting in an attentional bias to the right visual hemifield. These findings suggest that aberrant modulations of alpha oscillations reflect attention problems in ADHD and might be related to the neurophysiological substrate of the disorder.

Frontal Lobe γ-Aminobutyric Acid Levels During Adolescence: Associations with Impulsivity and Response Inhibition - Corrected Proof

2013-03-18

Background: The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels.Methods: Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents (n=30) and emerging adults (n = 20).Results: ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males.Conclusions: These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety.

Down-Regulation of Amygdala and Insula Functional Circuits by Varenicline and Nicotine in Abstinent Cigarette Smokers - Corrected Proof

2013-03-18

Background: Although the amygdala and insula are regarded as critical neural substrates perpetuating cigarette smoking, little is known about their circuit-level interactions with interconnected regions during nicotine withdrawal or following pharmacotherapy administration. To elucidate neurocircuitry associated with early smoking abstinence, we examined the impact of varenicline and nicotine, two modestly efficacious pharmacologic cessation aids, on amygdala- and insula-centered circuits using resting-state functional connectivity (rsFC).Methods: In a functional magnetic resonance imaging study employing a two-drug, placebo-controlled design, 24 overnight-abstinent smokers and 20 nonsmokers underwent ∼17 days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. We examined the impact of varenicline and nicotine (both alone and in combination) on amygdala- and insula-centered rsFC using seed-based assessments.Results: Beginning with a functionally defined amygdala seed, we observed that rsFC strength in an amygdala-insula circuit was down-regulated by varenicline and nicotine in abstinent smokers. Using this identified insula region as a new seed, both drugs similarly decreased rsFC between the insula and constituents of the canonical default-mode network (posterior cingulate cortex, ventromedial/dorsomedial prefrontal cortex, parahippocampus). Drug-induced rsFC modulations were critically linked with nicotine withdrawal, as similar effects were not detected in nonsmokers.Conclusions: These results suggest that nicotine withdrawal is associated with elevated amygdala-insula and insula–default-mode network interactions. As these potentiated interactions were down-regulated by two pharmacotherapies, this effect may be a characteristic shared by pharmacologic agents promoting smoking cessation. Decreased rsFC in these circuits may contribute to amelioration of subjective withdrawal symptoms.

Enhanced Avoidance Habits in Obsessive-Compulsive Disorder - Corrected Proof

2013-03-18

Background: Obsessive-compulsive disorder (OCD) is a psychiatric condition that typically manifests in compulsive urges to perform irrational or excessive avoidance behaviors. A recent account has suggested that compulsivity in OCD might arise from excessive stimulus-response habit formation, rendering behavior insensitive to goal value. We tested if OCD patients have a bias toward habits using a novel shock avoidance task. To explore how habits, as a putative model of compulsivity, might relate to obsessions and anxiety, we recorded measures of contingency knowledge, explicit fear, and physiological arousal.Methods: Twenty-five OCD patients and 25 control subjects completed a shock avoidance task designed to induce habits through overtraining, which were identified using goal-devaluation. The relationship between habitual behavior, erroneous cognitions, and physiological arousal was assessed using behavior, questionnaires, subjective report, and skin conductance responses.Results: A devaluation sensitivity test revealed that both groups could inhibit unnecessary behavioral responses before overtraining. Following overtraining, OCD patients showed greater avoidance habits than control subjects. Groups did not differ in conditioned arousal (skin conductance responses) at any stage. Additionally, groups did not differ in contingency knowledge or explicit ratings of shock expectancy following the habit test. Habit responses were associated with a subjective urge to respond.Conclusions: These data indicate that OCD patients have a tendency to develop excessive avoidance habits, providing support for a habit account of OCD. Future research is needed to fully characterize the causal role of physiological arousal and explicit fear in habit formation in OCD.

Epilepsy in Simplex Autism Pedigrees Is Much Lower Than the Rate in Multiplex Autism Pedigrees - Corrected Proof

2013-03-18

Epilepsy occurs in 5% to 40% of individuals with autism, whereas the prevalence in the general population is about .7% . The variability of rates in autism have been attributed to the heterogeneity of samples with respect to age, sex, intellectual disability (ID), comorbidity, subtype of pervasive developmental disorder, or causes. Another hypothesis is that prevalence rate of epilepsy in autism depends on the genetic background of autism and may therefore differ between simplex or multiplex forms. Indeed, the 12.8% rate of epilepsy in Autism Genetic Research Exchange multiplex autism pedigrees is high . The current study aimed to assess the prevalence of epilepsy in the Simons Simplex Collection (SSC) and whether ID and female sex are risk factors of epilepsy in simplex autism.

Worldwide Population Variation and Haplotype Analysis at the Serotonin Transporter Gene SLC6A4 and Implications for Association Studies - Corrected Proof

2013-03-18

Background: Variation at the serotonin transporter gene, SLC6A4, has been associated with a variety of neuropsychiatric disorders and could be involved in other health-related phenotypes.Methods: To determine the extent of variation at SLC6A4, we genotyped 23 markers on approximately 2500 individuals from 47 global populations, including the promoter variable number tandem repeat (VNTR) and 2 single nucleotide polymorphisms (SNPs) immediately flanking its variable region (rs25531 and rs25532), the intron 2 VNTR, and 19 additional SNPs.Results: We observed several rare alleles at the promoter VNTR (some novel) and population-specific distributions of the reported functional SNPs rs25531, rs25532, and rs6355, as well as two alleles at the intron 2 VNTR. Alleles of interest at the VNTRs occurred on specific haplotype backgrounds. The repeat-number variants at the promoter VNTR and the intron 2 VNTR, as well as the putative functional SNPs, showed ethnic variation in frequencies. The more common alleles at the VNTR polymorphisms show wide geographic distributions, whereas rare alleles at both show more restricted distributions. The derived alleles at the two functional SNPs in the promoter VNTR show restricted distributions and occur primarily on different repeat number alleles.Conclusions: Our findings illustrate significant variation worldwide at SLC6A4 and that the functionally implicated alleles at the SNPs rs25531, rs25532, and rs6355 occur on limited haplotypes and vary significantly in global distribution. Association studies at SLC6A4 cannot a priori extrapolate across populations and should account for the multiple polymorphisms with possible functional variation across this locus, rather than focusing solely on one or two polymorphisms as commonly seen.

Effects of Intranasal Oxytocin on the Neural Basis of Face Processing in Autism Spectrum Disorder - Corrected Proof

2013-03-18

Background: Autism spectrum disorder (ASD) is associated with altered face processing and decreased activity in brain regions involved in face processing. The neuropeptide oxytocin has been shown to promote face processing and modulate brain activity in healthy adults. The present study examined the effects of oxytocin on the neural basis of face processing in adults with Asperger syndrome (AS).Methods: A group of 14 individuals with AS and a group of 14 neurotypical control participants performed a face-matching and a house-matching task during functional magnetic resonance imaging. The effects of a single dose of 24 IU intranasally administered oxytocin were tested in a randomized, placebo-controlled, within-subject, cross-over design.Results: Under placebo, the AS group showed decreased activity in the right amygdala, fusiform gyrus, and inferior occipital gyrus compared with the control group during face processing. After oxytocin treatment, right amygdala activity to facial stimuli increased in the AS group.Conclusions: These findings indicate that oxytocin increases the saliency of social stimuli and in ASD and suggest that oxytocin might promote face processing and eye contact in individuals with ASD as prerequisites for neurotypical social interaction.

Altered Activation in Fronto-Striatal Circuits During Sequential Processing of Conflict in Unmedicated Adults with Obsessive-Compulsive Disorder - Corrected Proof

2013-03-14

Background: The aim of this study was to examine the functioning of fronto-striatal brain circuits that support self-regulatory capacities including conflict resolution and sequential processing in unmedicated adults with obsessive-compulsive disorder (OCD).Methods: We compared functional magnetic resonance imaging blood oxygen level–dependent response in 22 adults with OCD with 22 healthy, age-matched control subjects during performance of a Simon Spatial Incompatibility task. We used general linear modeling to compare groups in their patterns of brain activation during correct responses to conflict-laden stimuli and explore the effects of trial sequence on group differences.Results: Behavioral performance on the Simon task did not differ between groups. In response to conflict-laden stimuli, OCD participants activated fronto-striatal regions significantly more than control subjects, specifically a right hemisphere cluster encompassing the putamen, insula, and inferior frontal gyrus. Their activation of this cluster was driven not by conflict on a current trial but by their response to the alternation of stimulus congruence (incongruent or congruent) across trial sequences (i.e., current and preceding trials) and was most accentuated in participants with more severe symptoms in the doubt/checking dimension. Functional connectivity from the putamen to other fronto-striatal regions was also greater in the OCD compared with control participants.Conclusions: When engaging the self-regulatory control necessary to resolve conflict and process alternating stimuli, OCD participants displayed excessive activation in a fronto-striatal circuit that differs from the orbitofrontal cortex–anterior cingulate cortex–caudate circuit typically implicated in OCD. Dysfunction in this circuit was associated with processing changes in the stimulus context. We speculate that this dysfunction might be related to the cognitive inflexibility typical of persons with OCD.

Patterns of Neural Connectivity During an Attention Bias Task Moderates Associations Between Early Childhood Temperament and Internalizing Symptoms in Young Adulthood - Corrected Proof

2013-03-14

Background: Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area might clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood.Methods: Children were assessed for BI at multiple age points from infancy through age seven. On the basis of a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (n = 44). Participants completed an event-related functional magnetic resonance imaging attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews.Results: The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms.Conclusions: Behavioral inhibition during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology.

Neural Antecedents of Emotional Disorders: A Functional Magnetic Resonance Imaging Study of Subsyndromal Emotional Symptoms in Adolescent Girls - Corrected Proof

2013-03-11

Background: Emotional symptoms (ES) emerge forme fruste in adolescence, before manifesting as fully fledged emotional disorders. Studies indicate that subsyndromal ES precede the onset of emotional disorders. We hypothesized that adolescents showing subsyndromal ES will show perturbations in the emotion regulatory frontolimbic network (FLN) during emotion processing.Methods: Fifty-eight female adolescents underwent functional magnetic resonance imaging while viewing an image-based emotion-processing task. Within this sample, 33 (56.9%) displayed emotional symptoms and 25 (43.1%) did not. Clinical measures, including assessments of mood and anxiety, were administered and participants were allocated to one of two groups based on the presence (ES+) or absence (ES−) of subsyndromal ES. Group comparisons were used to identify differential patterns of neural engagement and their relationship to clinical variables.Results: Groups displayed emotion-specific differences in FLN activity with increased frontal activity in ES+ girls during positive emotion processing and decreased frontal and limbic activity during negative emotion processing. Trait anxiety was the strongest clinical predictor of group membership (ES+ versus ES−) and displayed a significant negative correlation with hippocampal neural activity during negative emotion processing. In addition, between the groups, the hippocampus displayed a pattern of reverse coupling with the amygdala and insula that was also significantly correlated with trait anxiety.Conclusions: There is divergence in the pattern of FLN neural processing in adolescent female subjects determined by emotional symptoms. Future research is needed to corroborate these findings and to underline their implications longitudinally.

Focal Adhesion Dynamics Are Altered in Schizophrenia - Corrected Proof

2013-03-07

Background: Evidence from genetic association studies implicate genes involved in neural migration associated with schizophrenia risk. Neural stem/progenitor cell cultures (neurosphere-derived cells) from olfactory mucosa of schizophrenia patients have significantly dysregulated expression of genes in focal adhesion kinase (FAK) signaling, a key pathway regulating cell adhesion and migration. The aim of this study was to investigate whether olfactory neurosphere-derived cells from schizophrenia patients have altered cell adhesion, cell motility, and focal adhesion dynamics.Methods: Olfactory neurosphere-derived cells from nine male schizophrenia patients and nine male healthy control subjects were used. Cells were assayed for cell adhesion and cell motility and analyzed for integrins and FAK proteins. Focal adhesions were counted and measured in fixed cells, and time-lapse imaging was used to assess cell motility and focal adhesion dynamics.Results: Patient-derived cells were less adhesive and more motile than cells derived from healthy control subjects, and their motility was reduced to control cell levels by integrin-blocking antibodies and by inhibition of FAK. Vinculin-stained focal adhesion complexes were significantly smaller and fewer in patient cells. Time-lapse imaging of cells expressing FAK tagged with green fluorescent protein revealed that the disassembly of focal adhesions was significantly faster in patient cells.Conclusions: The evidence for altered motility and focal adhesion dynamics in patient-derived cells is consistent with dysregulated gene expression in the FAK signaling pathway in these cells. Alterations in cell adhesion dynamics and cell motility could bias the trajectory of brain development in schizophrenia.