Task-based default mode network connectivity predicts cognitive impairment and negative symptoms in first-episode schizophrenia.

Individuals diagnosed with schizophrenia (SZ) demonstrate difficulty distinguishing between internally and externally generated stimuli. These aberrations in "source monitoring" have been theorized as contributing to symptoms of the disorder, including hallucinations and delusions. Altered connectivity within the default mode network (DMN) of the brain has been proposed as a mechanism through which discrimination between self-generated and externally generated events is disrupted. Source monitoring abnormalities in SZ have additionally been linked to impairments in selective attention and inhibitory processing, which are reliably observed via the N100 component of the event-related brain potential elicited during an auditory paired-stimulus paradigm. Given overlapping constructs associated with DMN connectivity and N100 in SZ, the present investigation evaluated relationships between these measures of disorder-related dysfunction and sought to clarify the nature of task-based DMN function in SZ. DMN connectivity and N100 measures were assessed using EEG recorded from SZ during their first episode of illness (N = 52) and demographically matched healthy comparison participants (N = 25). SZ demonstrated less evoked theta-band connectivity within DMN following presentation of pairs of identical auditory stimuli than HC. Greater DMN connectivity among SZ was associated with better performance on measures of sustained attention (p = .03) and working memory (p = .09), as well as lower severity of negative symptoms, though it was not predictive of N100 measures. Together, present findings provide EEG evidence of lower task-based connectivity among first-episode SZ, reflecting disruptions of DMN functions that support cognitive processes. Attentional processes captured by N100 appear to be supported by different neural mechanisms.

Oscillatory Coupling Between Neural and Cardiac Rhythms.

Oscillations serve a critical role in organizing biological systems. In the brain, oscillatory coupling is a fundamental mechanism of communication. The possibility that neural oscillations interact directly with slower physiological rhythms (e.g., heart rate, respiration) is largely unexplored and may have important implications for psychological functioning. Oscillations in heart rate, an aspect of heart rate variability (HRV), show remarkably robust associations with psychological health. Mather and Thayer proposed coupling between high-frequency HRV (HF-HRV) and neural oscillations as a mechanism that partially accounts for such relationships. We tested this hypothesis by measuring phase-amplitude coupling between HF-HRV and neural oscillations in 37 healthy adults at rest. Robust coupling was detected in all frequency bands. Granger causality analyses indicated stronger heart-to-brain than brain-to-heart effects in all frequency bands except gamma. These findings suggest that cardiac rhythms play a causal role in modulating neural oscillations, which may have important implications for mental health.

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

Prison or treatment? Gender, racial, and ethnic inequities in mental health care utilization and criminal justice history among incarcerated persons with borderline and antisocial personality disorders.

OBJECTIVE: Borderline and antisocial personality disorders are characterized by pervasive psychosocial impairment, disproportionate criminal justice involvement, and high mental health care utilization. Although some evidence suggests that systemic bias may contribute to demographic inequities in criminal justice and mental health care among persons experiencing these mental health conditions, no research to date has explicitly examined such differences. HYPOTHESES: Women and White persons would be more likely to endorse internalizing symptoms and have a more extensive history of mental health service utilization, whereas men, persons from minoritized racial groups, and persons identifying as Hispanic/Latino would be more likely to endorse externalizing symptoms and have more extensive histories of involvement with the criminal justice system. METHOD: This study examined gender, racial, and ethnic differences in symptom presentation, criminal justice history, and mental health care utilization in a sample of 314 adults with comorbid borderline and antisocial personality disorders enrolled in prison-based substance use treatment programs in the United States. RESULTS: Results suggested that men with these personality disorders were more likely to have early extensive criminal justice involvement, whereas women and White people had more extensive mental health treatment histories. Women were also more likely to endorse a range of internalizing symptoms, and White and non-Hispanic participants were more likely to endorse a history of reckless behavior. Notably, however, many associations-particularly, racial differences in symptom presentation and mental health utilization history and gender differences in symptom presentation-did not persist after we controlled for preincarceration employment and educational attainment. CONCLUSION: Results highlight a range of gender, racial, and ethnic inequities in criminal justice involvement and mental health utilization among this high-risk high-need population. Findings attest to the likely impact of societal, structural, and systemic factors on trajectories of persons affected by this comorbidity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Theories of psychopathology: Potential to promote clinical science, empowerment, and justice.

This invited commentary evaluates eight target articles that offer ambitious theoretical frameworks intended to advance psychopathology research. We discuss their consideration of the perspectives and priorities of treatment-seekers, including respect for and promotion of individuals' agency and self-determination; their positioning of individuals within dynamic social systems and their consideration of interventions beyond the individual level; their assumptions and proposals about the relationship between psychological and biological concepts and phenomena, relative to the reductionism that has been dominant but unsuccessful in the psychopathology literature in recent decades; and their implications for clinical care and for individual and community health. Despite some overlapping features, the articles cover very different ground and offer different challenges to the status quo, which has seen strikingly slow progress for decades. None of the proposed theories is comprehensive, but each has unique appeals; each has limitations, and each warrants consideration and development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits.

Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia (SCZ), yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in SCZ. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in SCZ, calling into question accounts of exclusively focal functional disturbances.

Structural Covariance Reveals Alterations in Control and Salience Network Integrity in Chronic Schizophrenia.

Schizophrenia (SCZ) is recognized as a disorder of distributed brain dysconnectivity. While progress has been made delineating large-scale functional networks in SCZ, little is known about alterations in grey matter integrity of these networks. We used a multivariate approach to identify the structural covariance of the salience, default, motor, visual, fronto-parietal control, and dorsal attention networks. We derived individual scores reflecting covariance in each structural image for a given network. Seed-based multivariate analyses were conducted on structural images in a discovery (n = 90) and replication (n = 74) sample of SCZ patients and healthy controls. We first validated patterns across all networks, consistent with well-established functional connectivity reports. Next, across two SCZ samples, we found reliable and robust reductions in structural integrity of the fronto-parietal control and salience networks, but not default, dorsal attention, motor and sensory networks. Well-powered exploratory analyses failed to identify relationships with symptoms. These findings provide evidence of selective structural decline in associative networks in SCZ. Such decline may be linked with recently identified functional disturbances in associative networks, providing more sensitive multi-modal network-level probes in SCZ. Absence of symptom effects suggests that identified disturbances may underlie a trait-type marker in SCZ.

Effects of reward on spatial working memory in schizophrenia.

Reward processing and cognition are disrupted in schizophrenia (SCZ), yet how these processes interface is unknown. In SCZ, deficits in reward representation may affect motivated, goal-directed behaviors. To test this, we examined the effects of monetary reward on spatial working memory (WM) performance in patients with SCZ. To capture complimentary effects, we tested biophysically grounded computational models of neuropharmacologic manipulations onto a canonical fronto-parietal association cortical microcircuit capable of WM computations. Patients with SCZ (n = 33) and healthy control subjects (HCS; n = 32) performed a spatial WM task with 2 reward manipulations: reward cues presented prior to each trial, or contextually prior to a block of trials. WM performance was compared with cortical circuit models of WM subjected to feed-forward glutamatergic excitation, feed-forward GABAergic inhibition, or recurrent modulation strengthening local connections. Results demonstrated that both groups improved WM performance to reward cues presented prior to each trial (HCS d = -0.62; SCZ d = -1.0), with percent improvement correlating with baseline WM performance (r = .472, p < .001). However, rewards presented contextually before a block of trials did not improve WM performance in patients with SCZ (d = 0.01). Modeling simulations achieved improved WM precision through strengthened local connections via neuromodulation, or feed-forward inhibition. Taken together, this work demonstrates that patients with SCZ can improve WM performance to short-term, but not longer-term rewards-thus, motivated behaviors may be limited by strength of reward representation. A potential mechanism for transiently improved WM performance may be strengthening of local fronto-parietal microcircuit connections via neuromodulation or feed-forward inhibitory drive. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Impact of a medical home model on costs and utilization among comorbid HIV-positive Medicaid patients.

OBJECTIVES: The Pennsylvania Chronic Care Initiative (CCI) was a statewide patient-centered medical home (PCMH) initiative implemented from 2008 to 2011. This study examined whether the CCI affected utilization and costs for HIV-positive Medicaid patients with both medical and behavioral health comorbidities. STUDY DESIGN: Nonrandomized comparison of 302 HIV-positive Medicaid patients treated in 137 CCI practices and 2577 HIV-positive Medicaid patients treated elsewhere. METHODS: All patients had chronic medical conditions (diabetes, chronic obstructive pulmonary disease, asthma, or congestive heart failure) and a psychiatric and/or substance use disorder. Analyses used Medicaid claims data to examine changes in total per patient costs per month from 1 year prior to 1 year following an index episode. Propensity score weighting was used to adjust for potential sample differences. Secondary outcomes included costs and utilization of emergency department, inpatient, and outpatient/pharmacy services. RESULTS: We identified an average total cost savings of $214.10 per patient per month (P = .002) for the CCI group relative to the non-CCI group. This was a function of decreased inpatient medical (-$415.69; P = .007) and outpatient substance abuse treatment (-$4.86; P = .001) costs, but increased non-HIV pharmacy costs ($158.43; P = .001). Utilization for the CCI group, relative to the non-CCI group, was correspondingly decreased for inpatient medical services (odds ratio [OR], 0.619; P = .002) and inpatient services overall (OR, 0.404; P = .001), but that group had greater numbers of outpatient medical service claims when they occurred (11.7%; P = .003) and increased non-HIV pharmacy claims (9.7%; P = .001). CONCLUSIONS: There was increased outpatient service utilization, yet relative cost savings, for HIV-positive Medicaid patients with medical and behavioral health comorbidities who were treated in PCMHs.

A self-report version of the Ways of Responding: Reliability and validity in a clinical sample.

OBJECTIVE: The Ways of Responding (WOR) instrument measures compensatory skills, a central construct in some theories of the mechanism of cognitive therapy for depression. However, the instrument is time-consuming and expensive to use in community settings, because it requires trained independent judges to rate subjects' open-ended written responses to depressogenic scenarios. The present study evaluated the reliability and validity of a self-report version of the WOR (WOR-SR) in a community mental health sample with depressive symptoms (N = 467). METHOD: Subjects completed the WOR-SR, a modified version of the original WOR, and other measures of depressive symptoms, dysfunctional cognitions, functioning, quality of life, and interpersonal problems at multiple time points. RESULTS: An exploratory factor analysis confirmed the two-factor structure of the WOR-SR. The positive and negative subscales both demonstrated excellent internal consistency (Cronbach's alphas = .91) and moderate convergent validity with other measures. CONCLUSION: The WOR-SR is a reliable and valid measure of compensatory skills in patients receiving treatment for depression at community mental health centers.

The Measurement of Cognitive Schemas: Validation of the Psychological Distance Scaling Task in a Community Mental Health Sample.

OBJECTIVE: The purpose of this study was to examine the validity of the Psychological Distance Scaling Task (PDST), a measure of cognitive schema organization, in a community mental health setting. We also compared validity among African Americans and Caucasians. METHOD: In order to accommodate participants with low education levels, 26 out of 80 PDST word stimuli were replaced with similar words at a lower reading level. A sample of 466 (42% African American; 50% Caucasian; 8% other) community patients with major depressive disorder completed the PDST and a variety of depressive symptom measures. RESULTS: The modified PDST demonstrated acceptable validity within all subscales. Validity coefficients resembled those reported in prior studies and were similar within minority and non-minority subsamples. CONCLUSIONS: The modified PDST appears to be a valid measure of schema organization in a low-income, racially diverse population seeking treatment for depression at community clinics.

Mechanisms of change in cognitive therapy for major depressive disorder in the community mental health setting.

OBJECTIVE: This study examined the relation of change in theory-relevant cognitive variables to depressive symptom change over the course of cognitive therapy, as well as the specificity of change mechanisms to cognitive therapy as compared with dynamic therapy. METHOD: There were 237 adult outpatients who were randomized to either cognitive (n = 119) or dynamic (n = 118) therapy for major depressive disorder in a community mental health setting. Assessments of compensatory skills (Ways of Responding Community Version and Self-Report Version), dysfunctional attitudes (Dysfunctional Attitudes Scale), and depressogenic schemas (Psychological Distance Scaling Task) were obtained at baseline and months 1, 2, and 5 following baseline. Primary outcome was measured using the Hamilton Rating Scale for Depression. RESULTS: Across both therapy conditions, change in all 3 cognitive domains was associated with concurrent change in depressive symptoms. After controlling for other cognitive variables, increased interconnectedness of the positive achievement-related schema was significantly associated with concurrent symptom change in cognitive (rp = .26, p < .001) but not dynamic therapy (rp = .08, p = .29). Increases in positive compensatory skills were associated with subsequent change in depressive symptoms in cognitive therapy (rp = -.36, p = .003), but not in dynamic therapy (rp = .11, p = .386). CONCLUSIONS: Results provide support for the compensatory skills model of cognitive therapy (CT) within a community mental health setting. Additional research is necessary to understand other possible mechanisms of change in CT in the community setting. (PsycINFO Database Record

Methods for Incorporating Patient Preferences for Treatments of Depression in Community Mental Health Settings.

We developed three methods (rating, ranking, and discrete choice) for identifying patients' preferred depression treatments based on their prioritization of specific treatment attributes (e.g., medication side effects, psychotherapy characteristics) at treatment intake. Community mental health patients with depressive symptoms participated in separate studies of predictive validity (N = 193) and short-term (1-week) stability (N = 40). Patients who received non-preferred initial treatments (based on the choice method) switched treatments significantly more often than those who received preferred initial treatments. Receiving a non-preferred treatment at any point (based on rating and choice methods) was a significant predictor of longer treatment duration. All three methods demonstrated good short-term stability.

Schizophrenia is associated with a pattern of spatial working memory deficits consistent with cortical disinhibition.

Schizophrenia is associated with severe cognitive deficits, including impaired working memory (WM). A neural mechanism that may contribute to WM impairment is the disruption in excitation-inhibition (E/I) balance in cortical microcircuits. It remains unknown, however, how these alterations map onto quantifiable behavioral deficits in patients. Based on predictions from a validated microcircuit model of spatial WM, we hypothesized two key behavioral consequences: i) increased variability of WM traces over time, reducing performance precision; and ii) decreased ability to filter out distractors that overlap with WM representations. To test model predictions, we studied N=27 schizophrenia patients and N=28 matched healthy comparison subjects (HCS) who performed a spatial WM task designed to test the computational model. Specifically, we manipulated delay duration and distractor distance presented during the delay. Subjects used a high-sensitivity joystick to indicate the remembered location, yielding a continuous response measure. Results largely followed model predictions, whereby patients exhibited increased variance and less WM precision as the delay period increased relative to HCS. Schizophrenia patients also exhibited increased WM distractibility, with reports biased toward distractors at specific spatial locations, as predicted by the model. Finally, the magnitude of the WM drift and distractibility were significantly correlated, indicating a possibly shared underlying mechanism. Effects are consistent with elevated E/I ratio in schizophrenia, establishing a framework for translating neural circuit computational model of cognition to human experiments, explicitly testing mechanistic behavioral hypotheses of cellular-level neural deficits in patients.

Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk.

IMPORTANCE: Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness. OBJECTIVES: To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012. MAIN OUTCOMES AND MEASURES: Whole-brain thalamic functional connectivity maps were generated using individuals' anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging. RESULTS: Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t(173) = 3.77, P < .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t(173) = 2.85, P < .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P < 3.6 × 10(-8), Spearman ρ = 0.27, P < 4.75 × 10(-5), 2-tailed). CONCLUSIONS AND RELEVANCE: Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness.