Rich-club connectivity and structural connectome organization in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Brain dysconnectivity has been posited as a biological marker of schizophrenia. Emerging schizophrenia connectome research has focused on rich-club organization, a tendency for brain hubs to be highly-interconnected but disproportionately vulnerable to dysconnectivity. However, less is known about rich-club organization in individuals at clinical high-risk for psychosis (CHR-P) and how it compares with abnormalities early in schizophrenia (ESZ). Combining diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI), we examined rich-club and global network organization in CHR-P (n = 41) and ESZ (n = 70) relative to healthy controls (HC; n = 74) after accounting for normal aging. To characterize rich-club regions, we examined rich-club MRI morphometry (thickness, surface area). We also examined connectome metric associations with symptom severity, antipsychotic dosage, and in CHR-P specifically, transition to a full-blown psychotic disorder. ESZ had fewer connections among rich-club regions (ps < .024) relative to HC and CHR-P, with this reduction specific to the rich-club even after accounting for other connections in ESZ relative to HC (ps < .048). There was also cortical thinning of rich-club regions in ESZ (ps < .013). In contrast, there was no strong evidence of global network organization differences among the three groups. Although connectome abnormalities were not present in CHR-P overall, CHR-P converters to psychosis (n = 9) had fewer connections among rich-club regions (ps < .037) and greater modularity (ps < .037) compared to CHR-P non-converters (n = 19). Lastly, symptom severity and antipsychotic dosage were not significantly associated with connectome metrics (ps < .012). Findings suggest that rich-club and connectome organization abnormalities are present early in schizophrenia and in CHR-P individuals who subsequently transition to psychosis.

Mismatch Negativity and Theta Oscillations Evoked by Auditory Deviance in Early Schizophrenia.

BACKGROUND: Amplitude reduction of mismatch negativity (MMN), an event-related potential component indexing NMDA receptor-dependent auditory echoic memory and predictive coding, is widely replicated in schizophrenia. Time-frequency analyses of single-trial electroencephalography epochs suggest that theta oscillation abnormalities underlie MMN deficits in schizophrenia. However, this has received less attention in early schizophrenia (ESZ). METHODS: Patients with ESZ (n = 89), within 5 years of illness onset, and healthy control subjects (n = 105) completed an electroencephalography MMN paradigm (duration-deviant, pitch-deviant, duration + pitch double-deviant). Repeated measures analyses of variance assessed group differences in MMN, theta intertrial phase coherence (ITC), and theta total power from frontocentral electrodes, after normal age adjustment. Group differences were retested after covarying MMN and theta measures. RESULTS: Relative to healthy control subjects, patients with ESZ showed auditory deviance deficits. Patients with ESZ had MMN deficits for duration-deviants (p = .041), pitch-deviants (ps = .007), and double-deviants (ps < .047). Patients with ESZ had reduced theta ITC for standards (ps < .040) and duration-deviants (ps < .030). Furthermore, patients with ESZ had reduced theta power across deviants at central electrodes (p = .013). MMN group deficits were not fully accounted for by theta ITC and power, and neither were theta ITC group deficits fully accounted for by MMN. Group differences in theta total power were no longer significant after covarying for MMN. CONCLUSIONS: Patients with ESZ showed reduced MMN and theta total power for all deviant types. Theta ITC showed a relatively specific reduction for duration-deviants. Although MMN and theta ITC were correlated in ESZ, covarying for one did not fully account for deficits in the other, raising the possibility of their sensitivity to dissociable pathophysiological processes.

Impact of Alcohol Use, Traumatic Stress, and Cigarette Smoking on Cognitive Functioning in Veterans With Co-occurring Alcohol Use Disorder and Posttraumatic Stress Disorder.

INTRODUCTION: Alcohol use disorder (AUD) and PTSD have high rates of co-occurrence in U.S. Military Veterans resulting in incrementally worse functional outcomes relative to having either one of these disorders alone. Cognitive dysfunction can impede one's ability to benefit from standard behavioral AUD and PTSD treatments. Cigarette smoking is also highly prevalent among U.S. Military Veterans, and cognitive dysfunction is associated with chronic cigarette use among individuals with AUD and PTSD independently. However, much less is known about to what extent cigarette smoking further impairs cognitive functioning in individuals with both co-occurring AUD and PTSD. MATERIALS AND METHODS: U.S. Veterans with co-occurring AUD and PTSD (n = 162) completed a comprehensive cognitive assessment covering various domains: working memory, processing speed, mental switching, cognitive inhibition, auditory-verbal learning, auditory-verbal memory, and verbal fluency. To examine the impact of alcohol use, traumatic stress, and cigarette smoking on cognitive function, we conducted a three-way interaction examining the moderated effects of smoking status on the association between alcohol use and PTSD symptoms on a composite domain of global cognition. RESULTS: Smoking status in Veterans with co-occurring AUD and PTSD moderated the relationship between alcohol use and global cognition (P = .042), such that higher levels of alcohol use in the past week were related to worse global cognitive function among Veterans cigarette smokers (P = .015) but not among nonsmokers (P = .833). On follow-up analyses of individual cognitive domains, greater alcohol use in the past week was associated with lower cognitive inhibition in smokers but not nonsmokers, with traumatic stress symptoms moderating this effect (P = .039). Additionally, smoking status moderated the relationship between alcohol use and auditory-verbal learning, such that there was a differential relationship between alcohol use and auditory-verbal learning between smokers and nonsmokers. CONCLUSIONS: Overall, results provide evidence for the compounding impact of alcohol use, traumatic stress, and cigarette smoking on cognitive functioning. Impaired cognitive performance on a global level as well as on individual domains of cognitive inhibition and auditory-verbal learning were evident. Cognitive dysfunction may impede a Veteran's ability to benefit from therapeutic treatment, and these cognitive domains may represent potential targets for cognitive training efforts. Further, study results support smoking cessation initiatives and smoke-free policies enacted at Veterans Affairs healthcare facilities and medical centers.

Alcohol use in emerging adults associated with lower rich-club connectivity and greater connectome network disorganization.

BACKGROUND: Emerging adulthood is a critical neurodevelopmental stage, with alcohol use during this period consistently associated with brain abnormalities and damage in anatomical structure and white matter integrity. However, it is less clear how alcohol use is associated with the brain's structural organization (i.e., white matter connections between anatomical regions). Recent connectome research has focused on rich-club regions, a collection of highly-interconnected hubs that are critical in brain communication and global network organization and disproportionately vulnerable to insults. METHODS: For the first time, we examined alcohol use associations with structural rich-club and connectome organization in emerging adults (N = 66). RESULTS: Greater lifetime drinks and current monthly drinks were significantly associated with lower rich-club organization (rs =-0.38, ps < 0.003) and lower rich-club connectivity (rs <-0.34, ps < 0.007). Additionally, rich-club connectivity was significantly more negatively correlated with alcohol use than connectivity among non-rich-club regions (ps < 0.035). Examining overall structural organization, greater lifetime drinks and current monthly drinks were significantly associated with lower network density (i.e., lower network resilience; rs <-0.36, ps = 0.004). Additionally, greater lifetime drinks and current monthly drinks were significantly associated with higher network segregation (i.e., network's tendency to divide into subnetworks; rs >0.33, ps<0.008). Alcohol use was not significantly associated with network integration (i.e., network's efficiency in combining information across the brain; ps > 0.064). CONCLUSIONS: Results provide novel evidence that alcohol use is associated with decreased rich-club connectivity and structural network disorganization. Given that both are critical in global brain communication, these results highlight the importance of examining alcohol use and brain relationships in emerging adulthood.

Functional connectivity between the ventral anterior cingulate and amygdala during implicit emotional conflict regulation and daily-life emotion dysregulation.

Emotional conflict adaptation involving ventral anterior cingulate cortex (ACC) suppression of the amygdala is thought to be important in emotion regulation, with evidence of impaired implicit emotion regulation in emotional distress disorders. However, it is unclear how this impairment is associated with daily-life emotion dysregulation in emotional distress disorders. In the current study, female participants with an emotional distress disorder (N = 27) were scanned with MRI while completing an implicit emotion conflict regulation task that involved identifying the facial expression of an image while ignoring an overlaid congruent or incongruent affect label. Participants then completed two weeks of ambulatory assessment of daily-life emotion dysregulation. Consistent with previous research on comorbid emotional distress disorders (Etkin and Schatzberg, 2011), there was no behavioral effect of emotional conflict adaptation (p = .701) but a significant effect of congruent adaptation (p = .006), suggesting impairment is specific to implicit emotional conflict regulation. Additionally, there was no neural evidence of emotional conflict adaptation in the ventral ACC and amygdala (ps > .766). Further, in our primary psychophysiological interactions analyses, we examined ventral ACC-amygdala functional connectivity. As hypothesized, increased ventral ACC-amygdala functional connectivity for emotional conflict adaptation was associated with increased daily-life affective instability (p = .022), but not mean daily-life negative affect (p = .372). Overall, results provide behavioral and neural evidence of impaired implicit emotional conflict adaptation in individuals with emotional distress disorders and suggests that this impairment is related to daily-life affective instability in these disorders.