Damla Senturk

Oxytocin-Augmented Social Cognitive Skills Training in Schizophrenia

Impairments in social cognition are common in schizophrenia and predict poor functional outcome. The purpose of this proof-of-concept randomized, parallel group clinical trial was to assess whether intranasal oxytocin (OT), given before social cognitive training, enhances learning of social cognitive skills. Twenty seven male outpatients with schizophrenia participated in a 6-week (12 session) training on social cognitive skills. Training focused on three domains: facial affect recognition, social perception, and empathy. Subjects were randomly assigned (double blind) to receive either intranasal OTor placebo 30 min before each session. Participants did not receive OT between sessions or on the day of assessments. We evaluated scores on social-cognition measures, as well as clinical symptoms and neurocognition, at baseline, 1 week following the final training session, and 1 month later. Our prespecified primary outcome measure was a social-cognition composite score comprised of five individual measures. There were main effects of time (indicating improvement across the combined-treatment groups) on the social-cognition composite score at both 1 week and 1 month following completion of training. Subjects receiving OT demonstrated significantly greater improvements in empathic accuracy than those receiving placebo at both posttreatment and 1 month follow up. There were no OT-related effects for the other social cognitive tests, clinical symptoms, or neurocognition. This study provides initial support for the idea that OT enhances the effectiveness of training when administered shortly before social cognitive training sessions. The effects were most pronounced on empathic accuracy, a high-level social cognitive process that is not easily improved in current social cognitive remediation programs.

Caregiver-Mediated Intervention for Low-Resourced Preschoolers With Autism: An RCT

OBJECTIVES: To compare 2 short-term, community caregiver training interventions for preschool-aged children with Autism Spectrum Disorder who had low resources. Low resource was defined by the US Department of Housing and Urban Development low-income index or 1 “indicator,” (eg, Medicaid eligibility). Child outcomes focused on joint engagement, joint attention, and play. METHODS: Participants included 112 families of a child who had Autism Spectrum Disorder who met criteria for being low-resourced and who were randomly assigned to 1 of 2 3-month interventions, group caregiver education or individualized caregiver-mediated intervention (CMM). Children were assessed for social communication skills pre- and post-treatment, and followed up at 3 months. RESULTS: All children improved in joint engagement and initiating joint attention, with significantly greater improvement by the CMM group. Outcomes on play skills were mixed, with improvement of symbolic play for the CMM group and no change in functional play skills. Joint engagement maintained over time for the CMM group, and initiating joint attention maintained for both groups over time. CONCLUSIONS: This study is among the first randomized trials comparing 2 active interventions with a large sample of low-resourced families. Results suggest improvements in core autism deficits of joint engagement, joint attention, and symbolic play with relatively brief, caregiver-mediated interventions, but additional support is necessary to maintain and generalize these gains over time.

Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms

Introduction 22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins. Methods High-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10–25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed. Results Relative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS. Conclusion Differential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population.

Social cognition in 22q11.2 microdeletion syndrome: Relevance to psychosis?

22q11.2 deletion syndrome (22qDS) represents one of the largest known genetic risk factors for schizophrenia. Approximately 30% of individuals with 22qDS develop psychotic illness in adolescence or young adulthood. Given that deficits in social cognition are increasingly viewed as a central aspect of idiopathic schizophrenia, we sought to investigate abilities in this domain as a predictor of psychotic symptoms in 22qDS participants. We assessed multiple domains of social and non-social cognition in 22qDS youth to: 1) characterize performance across these domains in 22qDS, and identify whether 22qDS participants fail to show expected patterns of age-related improvements on these tasks; and 2) determine whether social cognition better predicts positive and negative symptoms than does non-social cognition. Task domains assessed were: emotion recognition and differentiation, Theory of Mind (ToM), verbal knowledge, visuospatial skills, working memory, and processing speed. Positive and negative symptoms were measured using scores obtained from the Structured Interview for Prodromal Symptoms (SIPS). 22qDS participants (N=31, mean age: 15.9) showed the largest impairment, relative to healthy controls (N=31, mean age: 15.6), on measures of ToM and processing speed. In contrast to controls, 22qDS participants did not show age-related improvements on measures of working memory and verbal knowledge. Notably, ToM performance was the best predictor of positive symptoms in 22qDS, accounting for 39% of the variance in symptom severity. Processing speed emerged as the best predictor of negative symptoms, accounting for 37% of the variance in symptoms. Given that ToM was a robust predictor of positive symptoms in our sample, these findings suggest that social cognition may be a valuable intermediate trait for predicting the development of psychosis.

Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome.

22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk.

Early developmental trajectories associated with ASD in infants with tuberous sclerosis complex

Objective: We performed a longitudinal cohort study of infants with tuberous sclerosis complex (TSC), with the overarching goal of defining early clinical, behavioral, and biological markers of autism spectrum disorder (ASD) in this high-risk population. Methods: Infants with TSC and typically developing controls were recruited as early as 3 months of age and followed longitudinally until 36 months of age. Data gathered at each time point included detailed seizure history, developmental testing using the Mullen Scales of Early Learning, and social-communication assessments using the Autism Observation Scale for Infants. At 18 to 36 months, a diagnostic evaluation for ASD was performed using the Autism Diagnostic Observation Schedule. Results: Infants with TSC demonstrated delays confined to nonverbal abilities, particularly in the visual domain, which then generalized to more global delays by age 9 months. Twenty-two of 40 infants with TSC were diagnosed with ASD. Both 12-month cognitive ability and developmental trajectories over the second and third years of life differentiated the groups. By 12 months of age, the ASD group demonstrated significantly greater cognitive delays and a significant decline in nonverbal IQ from 12 to 36 months. Conclusions: This prospective study characterizes early developmental markers of ASD in infants with TSC. The early delay in visual reception and fine motor ability in the TSC group as a whole, coupled with the decline in nonverbal ability in infants diagnosed with ASD, suggests a domain-specific pathway to ASD that can inform more targeted interventions for these high-risk infants.

Perinatal vs Genetic Programming of Serotonin States Associated with Anxiety

Large numbers of women undergo antidepressant treatment during pregnancy; however, long-term consequences for their offspring remain largely unknown. Rodents exposed to serotonin transporter (SERT)-inhibiting antidepressants during development show changes in adult emotion-like behavior. These changes have been equated with behavioral alterations arising from genetic reductions in SERT. Both models are highly relevant to humans yet they vary in their time frames of SERT disruption. We find that anxiety-related behavior and, importantly, underlying serotonin neurotransmission diverge between the two models. In mice, constitutive loss of SERT causes life-long increases in anxiety-related behavior and hyperserotonemia. Conversely, early exposure to the antidepressant escitalopram (ESC; Lexapro) results in decreased anxiety-related behavior beginning in adolescence, which is associated with adult serotonin system hypofunction in the ventral hippocampus. Adult behavioral changes resulting from early fluoxetine (Prozac) exposure were different from those of ESC and, although somewhat similar to SERT deficiency, were not associated with changes in hippocampal serotonin transmission in late adulthood. These findings reveal dissimilarities in adult behavior and neurotransmission arising from developmental exposure to different widely prescribed antidepressants that are not recapitulated by genetic SERT insufficiency. Moreover, they support a pivotal role for serotonergic modulation of anxiety-related behavior.

Efficacy of structured approach therapy in reducing PTSD in returning veterans: A randomized clinical trial.

The U.S. military deployed in support to Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) show high rates of posttraumatic stress disorder (PTSD) and relationship, partner, and parenting distress. Given the pervasive effect of combat-related PTSD on returning veterans and its effect on their loved ones, the investigators have developed a couples-based treatment, structured approach therapy (SAT), to reduce PTSD while simultaneously decreasing relationship and partner distress. This study presents treatment outcome data measuring PTSD and relationship outcomes from a randomized clinical trial (RCT) comparing SAT, a manualized 12-session novel couples-based PTSD treatment, to a manualized 12-session couples-based educational intervention (PTSD Family Education [PFE]). Data were collected from 57 returning veterans meeting Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision; DSM-IV-TR) criteria for PTSD and their cohabiting partners; data collection was scheduled for pretreatment, posttreatment, and 3-month follow-up. Findings from an intent-to-treat analysis revealed that veterans receiving SAT showed significantly greater reductions in self-rated (PTSD Checklist; p < .0006) and Clinician-Administered PTSD Scale (CAPS)-rated PTSD (p < .0001) through the 3-month follow-up compared with veterans receiving PFE; 15 of 29 (52%) veterans receiving SAT and 2 of 28 (7%) receiving PFE no longer met DSM-IV-TR criteria for PTSD. Furthermore, SAT was associated with significant improvements in veteran relationship adjustment, attachment avoidance, and state anxiety. Partners showed significant reductions in attachment anxiety. This couples-based treatment for combat-related PTSD appears to have a strong therapeutic effect on combat-related PTSD in recently returned veterans.

Sex- and SERT-mediated differences in stimulated serotonin revealed by fast microdialysis.

In vivo microdialysis is widely used to investigate how neurotransmitter levels in the brain respond to biologically relevant challenges. Here, we combined recent improvements in the temporal resolution of online sampling and analysis for serotonin with a brief high-K(+) stimulus paradigm to study the dynamics of evoked release. We observed stimulated serotonin overflow with high-K(+) pulses as short as 1 min when determined with 2-min dialysate sampling in ventral striatum. Stimulated serotonin levels in female mice during the high estrogen period of the estrous cycle were similar to serotonin levels in male mice. By contrast, stimulated serotonin overflow during the low estrogen period in female mice was increased to levels similar to those in male mice with local serotonin transporter (SERT) inhibition. Stimulated serotonin levels in mice with constitutive loss of SERT were considerably higher yet, pointing to neuroadaptive potentiation of serotonin release. When combined with brief K(+) stimulation, fast microdialysis reveals dynamic changes in extracellular serotonin levels associated with normal hormonal cycles and pharmacologic vs genetic loss of SERT function.

Peak alpha frequency is a neural marker of cognitive function across the autism spectrum

Cognitive function varies substantially and serves as a key predictor of outcome and response to intervention in autism spectrum disorder (ASD), yet we know little about the neurobiological mechanisms that underlie cognitive function in children with ASD. The dynamics of neuronal oscillations in the alpha range (6–12 Hz) are associated with cognition in typical development. Peak alpha frequency is also highly sensitive to developmental changes in neural networks, which underlie cognitive function, and therefore, it holds promise as a developmentally sensitive neural marker of cognitive function in ASD. Here, we measured peak alpha band frequency under a task‐free condition in a heterogeneous sample of children with ASD (N = 59) and age‐matched typically developing (TD) children (N = 38). At a group level, peak alpha frequency was decreased in ASD compared to TD children. Moreover, within the ASD group, peak alpha frequency correlated strongly with non‐verbal cognition. As peak alpha frequency reflects the integrity of neural networks, our results suggest that deviations in network development may underlie cognitive function in individuals with ASD. By shedding light on the neurobiological correlates of cognitive function in ASD, our findings lay the groundwork for considering peak alpha frequency as a useful biomarker of cognitive function within this population which, in turn, will facilitate investigations of early markers of cognitive impairment and predictors of outcome in high risk infants.