Longitudinal Interplay Between Alcohol Use, Mood, and Functioning in Bipolar Spectrum Disorders.

Importance: Alcohol use disorder (AUD) is present in nearly half of individuals with bipolar disorder (BD) and is associated with markedly worsening outcomes. Yet, the concurrent treatment of BD and AUD remains neglected in both research and clinical care; characterizing their dynamic interplay is crucial in improving outcomes. Objective: To characterize the longitudinal alcohol use patterns in BD and examine the temporal associations among alcohol use, mood, anxiety, and functioning over time. Design, Setting, and Participants: This cohort study selected participants and analyzed data from the Prechter Longitudinal Study of Bipolar Disorder (PLS-BD), an ongoing cohort study that recruits through psychiatric clinics, mental health centers, and community outreach events across Michigan and collects repeated phenotypic data. Participants selected for the present study were those with a diagnosis of BD type I (BDI) or type II (BDII) who had been in the study for at least 5 years. Data used were extracted from February 2006 to April 2022, and follow-up ranged from 5 to 16 years. Main Outcomes and Measures: Alcohol use was measured using the Alcohol Use Disorders Identification Test. Depression, mania or hypomania, anxiety, and functioning were measured using the 9-Item Patient Health Questionnaire, the Altman Self-Rating Mania Scale, the 7-item Generalized Anxiety Disorder assessment scale, and the Life Functioning Questionnaire, respectively. Results: A total of 584 individuals (386 females (66.1%); mean [SD] age, 40 [13.6] years) were included. These participants had a BDI (445 [76.2%]) or BDII (139 [23.8%]) diagnosis, with or without a lifetime diagnosis of AUD, and a median (IQR) follow-up of 9 (0-16) years. More problematic alcohol use was associated with worse depressive (ß = 0.04; 95% credibility interval [CrI], 0.01-0.07) and manic or hypomanic symptoms (ß = 0.04; 95% CrI, 0.01-0.07) as well as lower workplace functioning (ß = 0.03; 95% CrI, 0.00-0.06) over the next 6 months, but increased depressive and manic or hypomanic symptoms were not associated with greater subsequent alcohol use. These latter 2 associations were more pronounced in BDII than BDI (mania or hypomania: ß = 0.16 [95% CrI, 0.02-0.30]; workplace functioning: ß = 0.26 [95% CrI, 0.06-0.45]). Alcohol use was not associated with anxiety over time. Conclusions and Relevance: This study found that alcohol use, regardless of diagnostic status, was associated with mood instability and poorer work functioning in BD, but increased mood symptoms were not associated with subsequent alcohol use. Given its prevalence and repercussions, dimensional and longitudinal assessment and management of alcohol use are necessary and should be integrated into research and standard treatment of BD.

Lateral Prefrontal Stimulation of Active Cortex With Theta Burst Transcranial Magnetic Stimulation Affects Subsequent Engagement of the Frontoparietal Network.

BACKGROUND: A critical unanswered question about therapeutic transcranial magnetic stimulation is what patients should do during treatment to optimize its effectiveness. Here, we address this lack of knowledge in healthy participants, testing the hypotheses that stimulating the left dorsolateral prefrontal cortex (dlPFC) while participants perform a working memory task will provide stronger effects on subsequent activation, perfusion, connectivity, and performance than stimulating resting dlPFC. METHODS: After a baseline functional magnetic resonance imaging session to localize dlPFC activation and the associated frontoparietal network (FPN) engaged by an n-back task, healthy participants (N = 40, 67.5% female) underwent 3 counterbalanced sessions, separated by several weeks, during which they received intermittent theta burst stimulation (iTBS) followed by magnetic resonance imaging scans as follows: 1) iTBS to the dlPFC while resting passively (passive), 2) iTBS to the dlPFC while performing the n-back task (active), and 3) iTBS to a vertex site, while not engaged in the n-back task and resting passively (control). RESULTS: We found no difference in n-back performance between the 3 conditions. However, FPN activation was reduced while performing the n-back task in the active condition relative to the passive and control conditions. There was no differential activity in the FPN on comparing passive with control conditions, i.e., there was no effect of the site of stimulation. We found no effects of state or site of stimulation on perfusion or connectivity with the dlPFC. CONCLUSIONS: In this study, the state of the brain while receiving iTBS affected FPN activation, possibly reflecting greater efficiency of FPN network activation when participants were stimulated while engaging the FPN.

Aberrant Effective Connectivity During Eye Gaze Processing Is Linked to Social Functioning and Symptoms in Schizophrenia.

BACKGROUND: Patients with schizophrenia show abnormal gaze processing, which is associated with social dysfunction. These abnormalities are related to aberrant connectivity among brain regions that are associated with visual processing, social cognition, and cognitive control. In this study, we investigated 1) how effective connectivity during gaze processing is disrupted in schizophrenia and 2) how this may contribute to social dysfunction and clinical symptoms. METHODS: Thirty-nine patients with schizophrenia/schizoaffective disorder (SZ) and 33 healthy control participants completed an eye gaze processing task during functional magnetic resonance imaging. Participants viewed faces with different gaze angles and performed explicit and implicit gaze processing. Four brain regions-the secondary visual cortex, posterior superior temporal sulcus, inferior parietal lobule, and posterior medial frontal cortex-were identified as nodes for dynamic causal modeling analysis. RESULTS: Both the SZ and healthy control groups showed similar model structures for general gaze processing. Explicit gaze discrimination led to changes in effective connectivity, including stronger excitatory, bottom-up connections from the secondary visual cortex to the posterior superior temporal sulcus and inferior parietal lobule and inhibitory, top-down connections from the posterior medial frontal cortex to the secondary visual cortex. Group differences in top-down modulation from the posterior medial frontal cortex to the posterior superior temporal sulcus and inferior parietal lobule were noted, such that these inhibitory connections were attenuated in the healthy control group but further strengthened in the SZ group. Connectivity was associated with social dysfunction and symptom severity. CONCLUSIONS: The SZ group showed notably stronger top-down inhibition during explicit gaze discrimination, which was associated with more social dysfunction but less severe symptoms among patients. These findings help pinpoint neural mechanisms of aberrant gaze processing and may serve as future targets for interventions that combine neuromodulation with social cognitive training.

Neurobehavioral indices of gaze perception are associated with social cognition across schizophrenia patients and healthy controls.

BACKGROUND: Gaze perception is a basic building block of social cognition, which is impaired in schizophrenia (SZ) and contributes to functional outcomes. Few studies, however, have investigated neural underpinnings of gaze perception and their relation to social cognition. We address this gap. METHOD: We recruited 77 SZ patients and 71 healthy controls, who completed various social-cognition tasks. During functional magnetic resonance imaging, participants (62 SZ, 54 controls) completed a gaze-perception task, where they judged whether faces with varying gaze angles were self-directed or averted; as a control condition, participants identified stimulus gender. Activation estimates were extracted based on (a) task versus baseline, (b) gaze-perception versus gender-identification, (c) parametric modulation by perception of stimuli as self-directed versus averted, and (d) parametric modulation by stimulus gaze angle. We used latent variable analysis to test associations among diagnostic group, brain activation, gaze perception, and social cognition. RESULTS: Preferential activation to gaze perception was observed throughout dorsomedial prefrontal cortex, superior temporal sulcus, and insula. Activation was modulated by stimulus gaze angle and perception of stimuli as self-directed versus averted. More precise gaze perception and higher task-related activation were associated with better social cognition. Patients with SZ showed hyperactivation within left pre-/postcentral gyrus, which was associated with more precise gaze perception and fewer symptoms and thus may be a compensatory mechanism. CONCLUSIONS: Neural and behavioral indices of gaze perception were related to social cognition, across patients and controls. This suggests gaze perception is an important perceptual building block for more complex social cognition. Results are discussed in the context of dimensional psychopathology and clinical heterogeneity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Structural connectivity of an interoception network in schizophrenia.

Interoception refers to the processing, integration, and interpretation of bodily signals by the brain. Interoception is key to not only basic survival, but also motivational and affective functioning. There is emerging evidence suggesting altered interoception in schizophrenia, but few studies have explored potential neural underpinnings. The current study aims to investigate the anatomical connectivity of a previously identified interoception network in individuals with schizophrenia, and the relationship between network structural connectivity and both emotional functioning and clinical symptoms. Thirty-five participants with schizophrenia (SZ) and 36 healthy control participants (HC) underwent diffusion tensor imaging (DTI) and performed tasks measuring emotional functioning. Probabilistic tractography was used to identify white matter tracts connecting key hubs in an interoception network. Microstructural integrity of these tracts was compared across groups and correlated with measures of emotional functioning and symptom severity. Compared with HC, SZ exhibited altered structural connectivity in the interoception network. In HC, the structural connectivity of the network was significantly correlated with emotion recognition, supporting a link between the interoception network and emotional functioning. However, this correlation was much weaker in SZ. These findings suggest that altered interoception may have implications for illness mechanisms of schizophrenia, especially in relation to emotional deficits.

Reductions in regional theta power and fronto-parietal theta-gamma phase-amplitude coupling during gaze processing in bipolar disorder.

Impaired social cognition is common in bipolar disorder (BD) and predicts poor functional outcomes. A critical determinant of social cognition is the ability to discriminate others' gaze direction, and its alteration may contribute to functional impairment in BD. However, the neural mechanisms underlying gaze processing in BD are unclear. Because neural oscillations are crucial neurobiological mechanisms supporting cognition, we aimed to understand their role in gaze processing in BD. Using electroencephalography (EEG) data recorded during a gaze discrimination task for 38 BD and 34 controls (HC), we examined: theta and gamma power over bilateral posterior and midline anterior locations associated with early face processing and higher-level cognitive processing, and theta-gamma phase-amplitude coupling (PAC) between locations. Compared to HC, BD showed reduced midline-anterior and left-posterior theta power, and diminished bottom-up/top-down theta-gamma PAC between anterior/posterior sites. Reduced theta power and theta-gamma PAC related to slower response times. These findings suggest that altered theta oscillations and anterior-posterior cross-frequency coupling between areas associated with higher-level cognition and early face processing may underlie impaired gaze processing in BD. This is a crucial step towards translational research that may inform novel social cognitive interventions (e.g., neuromodulation to target specific oscillatory dynamics) to improve functioning in BD.

Reduced theta-band neural oscillatory activity during affective cognitive control in bipolar I disorder.

Individuals with bipolar I disorder (BD) have difficulty inhibiting context-inappropriate responses. However, neural mechanisms of impaired cognitive control over impulsive behaviors, especially in response to emotion, are unclear. Theta-band neural oscillatory activity over midfrontal areas is thought to reflect cognitive control. The current study examined behavioral performance and theta-band activity during inhibition to affective stimuli in BD, relative to healthy control participants (HC). Sixty-seven participants with BD and 48 HC completed a Go/No-Go task with emotional face stimuli during electroencephalography (EEG) recording. Behavior was measured with reaction time, discriminability (d') and response bias (ß). Time-frequency decomposition of EEG data was used to extract event-related theta-band (4-7 Hz) neural oscillatory power and inter-trial phase consistency (ITPC) over midline fronto-central areas. Behavior and theta-band activity were compared between groups, while covarying for age. Participants with BD exhibited slower response execution times on correct Go trials and reduced behavioral discrimination of emotional versus neutral faces, compared to HC. Theta-band power and ITPC were reduced in BD relative to HC. Theta-band power was higher on No-Go trials than Go trials. The magnitude of differences in theta-band activity between Go/No-Go trial types did not differ between groups. Increased theta-band power was associated with faster response execution times, greater discrimination of differing facial expressions, and stronger tendency to respond both across the full sample and within the BD group. Attenuated midline fronto-central theta-band activity may contribute to reduced cognitive control and maladaptive behavioral responding to emotional cues in individuals with BD.

Mathematical modeling of risk-taking in bipolar disorder: Evidence of reduced behavioral consistency, with altered loss aversion specific to those with history of substance use disorder.

Bipolar disorder (BD) is associated with excessive pleasure-seeking risk-taking behaviors that often characterize its clinical presentation. However, the mechanisms of risk-taking behavior are not well-understood in BD. Recent data suggest prior substance use disorder (SUD) in BD may represent certain trait-level vulnerabilities for risky behavior. This study examined the mechanisms of risk-taking and the role of SUD in BD via mathematical modeling of behavior on the Balloon Analogue Risk Task (BART). Three groups-18 euthymic BD with prior SUD (BD+), 15 euthymic BD without prior SUD (BD-), and 33 healthy comparisons (HC)-completed the BART. We modeled behavior using 4 competing hierarchical Bayesian models, and model comparison results favored the Exponential-Weight Mean-Variance (EWMV) model, which encompasses and delineates five cognitive components of risk-taking: prior belief, learning rate, risk preference, loss aversion, and behavioral consistency. Both BD groups, regardless of SUD history, showed lower behavioral consistency than HC. BD+ exhibited more pessimistic prior beliefs (relative to BD- and HC) and reduced loss aversion (relative to HC) during risk-taking on the BART. Traditional measures of risk-taking on the BART (adjusted pumps, total points, total pops) detected no group differences. These findings suggest that reduced behavioral consistency is a crucial feature of risky decision-making in BD and that SUD history in BD may signal additional trait vulnerabilities for risky behavior even when mood symptoms and substance use are in remission. This study also underscores the value of using mathematical modeling to understand behavior in research on complex disorders like BD.

Continuous Theta Burst Stimulation to the Secondary Visual Cortex at 80% Active Motor Threshold Does Not Impair Central Vision in Humans During a Simple Detection Task.

Continuous theta burst stimulation (cTBS) is a powerful form of repetitive transcranial magnetic stimulation capable of suppressing cortical excitability for up to 50 min. A growing number of studies have applied cTBS to the visual cortex in human subjects to investigate the neural dynamics of visual processing, but few have specifically examined its effects on central vision, which has crucial implications for safety and inference on downstream cognitive effects. The present study assessed the safety of offline, neuronavigated cTBS to V2 by examining its effects on central vision performance. In this single-blind, randomized sham-controlled, crossover study, 17 healthy adults received cTBS (at 80% active motor threshold) and sham to V2 1-2 weeks apart. Their central vision (≤8°) was tested at 1-min (T1) and again at 50-min (T50) post-stimulation. Effects of condition (cTBS vs. sham) and time (T1 vs. T50) on accuracy and reaction time were examined using Bayes factor. Bayes factor results suggested that cTBS did not impair stimulus detection over the entire central visual field nor subfields at T1 or T50. Our results offer the first explicit evidence supporting that cTBS applied to V2 does not create blind spots in the central visual field in humans during a simple detection task. Any subtler changes to vision and downstream visual perception should be investigated in future studies.

Aberrant activation of the mentalizing brain system during eye gaze discrimination in bipolar disorder.

Bipolar disorder (BD) is associated with a range of social cognitive deficits. This study investigated the functioning of the mentalizing brain system in BD probed by an eye gaze perception task during fMRI. Compared with healthy controls (n = 21), BD participants (n = 14) showed reduced preferential activation for self-directed gaze discrimination in the medial prefrontal cortex (mPFC) and temporo-parietal junction (TPJ), which was associated with poorer cognition/social cognition. Aberrant functions of the mentalizing system should be further investigated as marker of social dysfunction and treatment targets.

Neural Oscillatory Abnormalities During Gaze Processing in Schizophrenia: Evidence of Reduced Theta Phase Consistency and Inter-areal Theta-Gamma Coupling.

BACKGROUND: Abnormal gaze discrimination in schizophrenia (SZ) is associated with impairment in social functioning, but the neural mechanisms remain unclear. Evidence suggests that local neural oscillations and inter-areal communication through neural synchronization are critical physiological mechanisms supporting basic and complex cognitive processes. The roles of these mechanisms in abnormal gaze processing in SZ have not been investigated. The present study examined local neural oscillations and connectivity between anterior and bilateral posterior brain areas during gaze processing. METHODS: During electroencephalography recording, 28 participants with SZ and 34 healthy control participants completed a gaze discrimination task. Time-frequency decomposition of electroencephalography data was used to examine neural oscillatory power and intertrial phase consistency at bilateral posterior and midline anterior scalp sites. In addition, connectivity between these anterior and posterior sites, in terms of cross-frequency coupling between theta phase and gamma amplitude, was examined using the Kullback-Leibler Modulation Index. RESULTS: Participants with SZ showed reduced total power of theta-band activity relative to healthy control participants at all sites examined. This group difference could be accounted for by reduced intertrial phase consistency of theta activity in SZ participants, which was related to reduced gaze discrimination accuracy in SZ. In addition, SZ participants exhibited reduced Kullback-Leibler indexing, both feedforward and feedback connectivity, between the posterior and anterior sites. CONCLUSIONS: These findings suggest that abnormal theta phase consistency and dysconnection between posterior face processing and anterior areas may underlie gaze processing deficits in SZ.

Disrupted Eye Gaze Perception as a Biobehavioral Marker of Social Dysfunction: An RDoC Investigation.

Social dysfunction is an intractable problem in a wide spectrum of psychiatric illnesses, undermining patients' capacities for employment, independent living, and maintaining meaningful relationships. Identifying common markers of social impairment across disorders and understanding their mechanisms are prerequisites to developing targeted neurobiological treatments that can be applied productively across diagnoses and illness stages to improve functional outcome. This project focuses on eye gaze perception, the ability to accurately and efficiently discriminate others' gaze direction, as a potential biomarker of social functioning that cuts across psychiatric diagnoses. This premise builds on both the monkey and human literatures showing gaze perception as a basic building block supporting higher-level social communication and social development, and reports of abnormal gaze perception in multiple psychiatric conditions accompanied by prominent social dysfunction (e.g., psychosis-spectrum disorders, autism-spectrum disorders, social phobia). A large sample (n = 225) of adolescent and young adult (age 14-30) psychiatric patients (regardless of diagnosis) with various degrees of impaired social functioning, and demographically-matched healthy controls (n = 75) will be recruited for this study. Participant's psychiatric phenotypes, cognition, social cognition, and community functioning will be dimensionally characterized. Eye gaze perception will be assessed using a psychophysical task, and two metrics (precision, self-referential bias) that respectively tap into gaze perception disturbances at the visual perceptual and interpretation levels, independent of general deficits, will be derived using hierarchical Bayesian modeling. A subset of the participants (150 psychiatric patients, 75 controls) will additionally undergo multimodal fMRI to determine the functional and structural brain network features of altered gaze perception. The specific aims of this project are three-fold: (1) Determine the generality of gaze perception disturbances in psychiatric patients with prominent social dysfunction; (2) Map behavioral indices of gaze perception disturbances to dimensions of psychiatric phenotypes and core functional domains; and (3) Identify the neural correlates of altered gaze perception in psychiatric patients with social dysfunction. Successfully completing these specific aims will identify the specific basic deficits, clinical profile, and underlying neural circuits associated with social dysfunction that can be used to guide targeted, personalized treatments, thus advancing NIMH's Strategic Objective 1 (describe neural circuits associated with mental illnesses and map the connectomes for mental illnesses) and Objective 3 (develop new treatments based on discoveries in neuroscience and behavioral science).

Deconstructing eye contact perception: Measuring perceptual precision and self-referential tendency using an online psychophysical eye contact detection task.

Eye contact perception-the ability to accurately and efficiently discriminate others' gaze directions-is critical to understanding others and functioning in a complex social world. Previous research shows that it is affected in multiple neuropsychiatric disorders accompanied by social dysfunction, and understanding the cognitive processes giving rise to eye contact perception would help advance mechanistic investigations of psychopathology. This study aims to validate an online, psychophysical eye contact detection task through which two constituent cognitive components of eye contact perception (perceptual precision and self-referential tendency) can be derived. Data collected from a large online sample showed excellent test-retest reliability for self-referential tendency and moderate reliability for perceptual precision. Convergence validity was supported by correlations with social cognitive measures tapping into different aspects of understanding others. Hierarchical regression analyses revealed that perceptual precision and self-referential tendency explained unique variance in social cognition, suggesting that they measure unique aspects of related constructs. Overall, this study provided support for the reliability and validity of the eye contact perception metrics derived using the online Eye Contact Detection Task. The value of the task for future psychopathology research was discussed.