Ashley K. Smith

Effect of Catechol O-Methyltransferase Val158Met Polymorphism on the P50 Gating Endophenotype in Schizophrenia

BACKGROUND Studies have implicated prefrontal dopamine in cortical information filtering. Deficit in stimulus filtering, an endophenotype of schizophrenia, can be demonstrated using the auditory P50 paired-click gating paradigm. The role of prefrontal dopamine on P50 gating was investigated, using catechol-O-methyltransferase (COMT) valine (val)(158)methionine (met) polymorphism as a predictor of prefrontal dopamine activity. METHODS Twenty-five comparison and 42 schizophrenia subjects underwent P50 gating measurement and COMT genotyping. RESULTS In the combined sample, COMT polymorphism accounted for a unique 10% of gating variance (p = .02), after variance due to diagnosis, smoking status, and antipsychotic use was removed. Valine homozygous individuals exhibited the greatest gating deficit. CONCLUSIONS Valine homozygous individuals are more likely to have gating deficits, supporting COMT as a genetic determinant of the P50 endophenotype, as well as a role for prefrontal dopamine in auditory filtering.

Neuropsychological and sensory gating deficits related to remote alcohol abuse history in schizophrenia.

Recent evidence suggests that changes in brain structure associated with alcohol abuse are compounded in individuals dually diagnosed with alcohol abuse and schizophrenia. To investigate the separate, and possibly interacting, effects of these diagnoses, an event-related brain potential (ERP) measure of auditory information processing (P50 sensory gating paradigm) and neuropsychological measures were administered to healthy control participants with either (1a) no history of alcohol abuse/dependence, or (1b) a remote history of alcohol abuse/dependence, and patients with schizophrenia with either (2a) no history of alcohol abuse/dependence, or (2b) a remote history of alcohol abuse/dependence. Schizophrenia was associated with impaired P50 sensory gating and poorer performance across neuropsychological scores compared to measurements in healthy control participants. Those with a positive alcohol history had impaired gating ratios in contrast to those with a negative alcohol history. There were additive effects of schizophrenia diagnosis and alcohol history for P50 sensory gating and for neuropsychological scores: attention, working memory, and behavioral inhibition. For executive attention and general memory there was an interaction, suggesting that the combination of schizophrenia and history of alcohol abuse results in greater impairment than that predicted by the presence of either diagnosis alone.

Physical Activity Level and Medial Temporal Health in Youth at Ultra High-Risk for Psychosis

A growing body of evidence suggests that moderate to vigorous activity levels can affect quality of life, cognition, and brain structure in patients diagnosed with schizophrenia. However, physical activity has not been systematically studied during the period immediately preceding the onset of psychosis. Given reports of exercise-based neurogenesis in schizophrenia, understanding naturalistic physical activity levels in the prodrome may provide valuable information for early intervention efforts. The present study examined 29 ultra high-risk (UHR) and 27 matched controls to determine relationships between physical activity level, brain structure (hippocampus and parahippocampal gyrus), and symptoms. Participants were assessed with actigraphy for a 5-day period, MRI, and structured clinical interviews. UHR participants showed a greater percentage of time in sedentary behavior while healthy controls spent more time engaged in light to vigorous activity. There was a strong trend to suggest the UHR group showed less total physical activity. The UHR group exhibited smaller medial temporal volumes when compared with healthy controls. Total level of physical activity in the UHR group was moderately correlated with parahippocampal gyri bilaterally (right: r = .44, left: r = .55) and with occupational functioning (r = -.36; of negative symptom domain), but not positive symptomatology. Results suggest that inactivity is associated with medial temporal lobe health. Future studies are needed to determine if symptoms are driving inactivity, which in turn may be affecting the health of the parahippocampal structure and progression of illness. Although causality cannot be determined from the present design, these findings hold important implications for etiological conceptions and suggest promise for an experimental trial.

Lateralized abnormalities in auditory M50 sensory gating and cortical thickness of the superior temporal gyrus in post-traumatic stress disorder: Preliminary results

Auditory sensory gating deficits have been reported in subjects with post-traumatic stress disorder (PTSD), but the hemispheric and neuronal origins of this deficit are not well understood. The objectives of this study were to: (1) investigate auditory sensory gating of the 50-ms response (M50) in patients diagnosed with PTSD by utilizing magnetoencephalography (MEG); (2) explore the relationship between M50 sensory gating and cortical thickness of the superior temporal gyrus (STG) measured with structural magnetic resonance imaging (MRI); and (3) examine the association between PTSD symptomatology and bilateral sensory gating. Seven participants with combat-related PTSD and eleven controls underwent the paired-click sensory gating paradigm. MEG localized M50 neuronal generators to the STG in both groups. The PTSD group displayed impaired M50 gating in the right hemisphere. Thinner right STG cortical thickness was associated with worse right sensory gating in the PTSD group. The right S1 M50 source strength and gating ratio were correlated with PTSD symptomatology. These findings suggest that the structural integrity of right hemisphere STG cortices play an important role in auditory sensory gating deficits in PTSD.

Schizophrenia diagnosis and anterior hippocampal volume make separate contributions to sensory gating

Impaired P50 gating is thought to reflect a core deficit in schizophrenia, but the relevant neural network is not well understood. The present study used EEG and MEG to assess sensory gating and volumetric MRI to measure hippocampal volume to investigate relationships between them in 22 normal controls and 22 patients with schizophrenia. In the schizophrenia group, anterior but not posterior hippocampal volume was smaller, and both the P50 and M50 gating ratios were larger (worse) than in controls. Independent of group, left-hemisphere M50 gating ratio correlated negatively with left anterior hippocampal volume, and right-hemisphere M50 gating ratio correlated negatively with right anterior hippocampal volume. Schizophrenia diagnosis predicted M50 gating independent of hippocampal volume. These results are consistent with the finding that hippocampus is a critical part of a fronto-temporal circuit involved in auditory gating.

The role of attention-deficit/hyperactivity disorder in the association between verbal ability and conduct disorder

Although there is clear evidence that low verbal ability is a risk factor for conduct disorder (CD), some researchers have questioned whether this association is due to the common comorbidity between attention-deficit/hyperactivity disorder (ADHD) and CD. The present study examined the association among verbal ability, ADHD, and CD in a genetically informative sample in order to examine the role of genes and/or environmental influences shared in common with ADHD on the covariation between verbal ability and CD. Participants were 2744 adolescents from the Center for Antisocial Drug Dependence (CADD), and included 360 monozygotic (MZ) female twin pairs, 221 dizygotic (DZ) female twin pairs, 297 MZ male twin pairs, 220 DZ male twin pairs, and 274 opposite-sex DZ twin pairs. The Diagnostic Interview Schedule for Children (DISC-IV) was used to assess lifetime symptoms of ADHD and CD. Verbal ability was assessed via the Vocabulary subtest of the Wechsler Adult Intelligence Scale III (WAIS-III) for individuals over the age of 16 and the Vocabulary subtest of the Wechsler Intelligence Scale for Children III (WISC-III) for individuals under the age of 16. There was a small but significant negative covariance between verbal ability and CD and between verbal ability and ADHD. Results also suggest that the covariation between verbal ability and CD is due to influences shared in common with ADHD.

Hypothalamic–pituitary–adrenal axis dysfunction in non-clinical psychosis

While studies have examined psychosocial stress in non-clinical psychosis (NCP), it is unclear if the elevated cortisol seen in schizophrenia also occurs in this group. Cortisol was sampled in High- and Low-NCP groups, and findings of elevated resting cortisol in the former suggest that hypothalamic-pituitary-adrenal-axis dysfunction underlies a psychosis continuum.

The Etiology of Observed Negative Emotionality from 14 to 24 Months

We examined the magnitude of genetic and environmental influences on observed negative emotionality at age 14, 20, and 24 months. Participants were 403 same-sex twin pairs recruited from the Longitudinal Twin Study whose emotional responses to four different situations were coded by independent raters. Negative emotionality showed significant consistency across settings, and there was evidence of a latent underlying negative emotionality construct. Heritability decreased, and the magnitude of shared environmental influences increased, for the latent negative emotionality construct from age 14 to 24 months. There were significant correlations between negative emotionality assessed at age 14, 20, and 24 months, and results suggested common genetic and shared environmental influences affecting negative emotionality across age, and that age-specific influences are limited to non-shared environmental influences, which include measurement error.

Emotion recognition and social/role dysfunction in non-clinical psychosis

As researchers continue to understand non-clinical psychosis (NCP-brief psychotic-like experiences occurring in 5-7% of the general population; van Os et al., 2009), it is becoming evident that functioning deficits and facial emotion recognition (FER) impairment characterize this phenomenon. However, the extent to which these domains are related remains unclear. Social/role functioning and FER were assessed in 65 adolescents/young adults exhibiting low and high-NCP. Results indicate that FER and social/role functioning deficits were present in the High-NCP group, and that the domains were associated in this group alone. Taken together, findings suggest that a core emotive deficit is tied to broader social/role dysfunction in NCP.

BDNF Val66Met and spontaneous dyskinesias in non-clinical psychosis

BACKGROUND Evidence indicating that symptoms of non-clinical psychosis (NCP) occur in 6-8% of the general population suggests that psychosis may occur across a continuum. Although a number of studies have examined environmental contributors, to date there have been few investigations of biological/genetic factors in this integral population. A recent study observed spontaneous dyskinetic movements (reflecting an innervated striatal system) in individuals reporting NCP. The present investigation is designed to replicate this finding and determine if brain-derived neurotrophic factor (BDNF) (implicated in striatal dopamine function) is associated with dyskinesias. METHOD A total of 68 young-adult participants reporting High and Low-NCP were assessed for dyskinetic movements using a sensitive instrumental measure of force variability. Saliva from the participants was genotyped for val66met (rs6265), a common functional polymorphism of the BDNF gene (the Met allele is associated with lower activity-dependent release of BDNF). RESULTS Participants in the High-NCP group showed significantly elevated levels of force variability. Met allele carriers exhibited significantly higher levels of force variability when compared with the Val homozygotes. Logistic regression indicated that the odds of membership in the High-NCP group were significantly higher given the presence of dyskinesias (OR=2.32; CI: 1.25-4.28). CONCLUSION Findings of elevated force variability suggest that individuals with NCP exhibit subtle signs of striatal vulnerability, reflected more dramatically as jerking and hyperkinetic movements in patients with formal psychosis. The results are consistent with a larger literature implicating BDNF as a critical factor underlying abnormal movements, and suggest that specific candidate genes underlie putative markers across a psychosis continuum.