Reductions in synaptic marker SV2A in early-course Schizophrenia.

Excess synaptic pruning during neurodevelopment has emerged as one of the leading hypotheses on the causal mechanism for schizophrenia. It proposes that excess synaptic elimination occurs during development before the formal onset of illness. Accordingly, synaptic deficits may be observable at all stages of illnesses, including in the early phases. The availability of [11C]UCB-J, the first-in-human in vivo synaptic marker, represents an opportunity for testing this hypothesis with a relatively high level of precision. The first two published [11C]UCB-J schizophrenia studies have documented significant, widespread reductions in binding in chronic patients. The present study tested the hypothesis that reductions are present in early-course patients. 18 subjects completed [11C]UCB-J PET scans, (nine with schizophrenia, average duration of illness of 3.36 years, and nine demographically-matched healthy individuals). We compared binding levels, quantified as non-displaceable specific binding (BPND), in a set of a priori-specified brain regions of interest (ROIs). Eight ROIs (left and right hippocampus, right superior temporal and Heschl's gyrus, left and right putamen, and right caudal and rostral middle frontal gyrus) showed large reductions meeting Bonferroni corrected significant levels, p < 0.0036. Exploratory, atlas-wide analyses confirmed widespread reductions in schizophrenia. We also observed significant positive correlations between binding levels and cognitive performance and a negative correlation with the severity of delusions. These results largely replicate findings from chronic patients, indicating that extensive [11C]UCB-J binding deficits are reliable and reproducible. Moreover, these results add to the growing evidence that excess synaptic pruning is a major disease mechanism for schizophrenia.

State Cannabis Legalization and Psychosis-Related Health Care Utilization.

Importance: Psychosis is a hypothesized consequence of cannabis use. Legalization of cannabis could therefore be associated with an increase in rates of health care utilization for psychosis. Objective: To evaluate the association of state medical and recreational cannabis laws and commercialization with rates of psychosis-related health care utilization. Design, Setting, and Participants: Retrospective cohort design using state-level panel fixed effects to model within-state changes in monthly rates of psychosis-related health care claims as a function of state cannabis policy level, adjusting for time-varying state-level characteristics and state, year, and month fixed effects. Commercial and Medicare Advantage claims data for beneficiaries aged 16 years and older in all 50 US states and the District of Columbia, 2003 to 2017 were used. Data were analyzed from April 2021 to October 2022. Exposure: State cannabis legalization policies were measured for each state and month based on law type (medical or recreational) and degree of commercialization (presence or absence of retail outlets). Main Outcomes and Measures: Outcomes were rates of psychosis-related diagnoses and prescribed antipsychotics. Results: This study included 63 680 589 beneficiaries followed for 2 015 189 706 person-months. Women accounted for 51.8% of follow-up time with the majority of person-months recorded for those aged 65 years and older (77.3%) and among White beneficiaries (64.6%). Results from fully-adjusted models showed that, compared with no legalization policy, states with legalization policies experienced no statistically significant increase in rates of psychosis-related diagnoses (medical, no retail outlets: rate ratio [RR], 1.13; 95% CI, 0.97-1.36; medical, retail outlets: RR, 1.24; 95% CI, 0.96-1.61; recreational, no retail outlets: RR, 1.38; 95% CI, 0.93-2.04; recreational, retail outlets: RR, 1.39; 95% CI, 0.98-1.97) or prescribed antipsychotics (medical, no retail outlets RR, 1.00; 95% CI, 0.88-1.13; medical, retail outlets: RR, 1.01; 95% CI, 0.87-1.19; recreational, no retail outlets: RR, 1.13; 95% CI, 0.84-1.51; recreational, retail outlets: RR, 1.14; 95% CI, 0.89-1.45). In exploratory secondary analyses, rates of psychosis-related diagnoses increased significantly among men, people aged 55 to 64 years, and Asian beneficiaries in states with recreational policies compared with no policy. Conclusions and Relevance: In this retrospective cohort study of commercial and Medicare Advantage claims data, state medical and recreational cannabis policies were not associated with a statistically significant increase in rates of psychosis-related health outcomes. As states continue to introduce new cannabis policies, continued evaluation of psychosis as a potential consequence of state cannabis legalization may be informative.

Profiles in conspiracism: Associations with two psychiatric syndromes, religiosity and pandemic-related health behaviors.

Introduction: Conspiratorial beliefs are often maladaptive for individuals and dangerous for societies. Other prevalent belief systems such as (normative) religious belief and (pathological) delusional belief show parallels to conspiratorial beliefs, which may also be linked to excessive social media exposure. We conducted an online survey to characterize heterogeneous profiles of conspiracy-mindedness, with respect to these other phenomena. Methods: Eight hundred and thirty six American adults from online panels completed validated questionnaires including the Conspiracy Mindedness Questionnaire (CMQ), Centrality of Religion Scale (CRS), Peters Delusion Inventory (PDI; 21-item version), and Facebook Addiction Scale (FAS). Additionally, they completed 4 questions addressing categorical belief in the origin of SARS-CoV-2, and pandemic-related health behaviors. Total scores on each questionnaire were Z-transformed and entered into K-means cluster analysis. Cluster membership was used in post-hoc analyses to compare pandemic-related items. Results: An optimal solution included 3 clusters with above-mean (high) CMQ and 3 below-mean (low) CMQ scores. The 3 high-CMQ clusters included: (1) high-religion, low-social media addiction; (2) high religion, social media addiction and delusion; (3) low religion and delusion. High-CMQ clusters 1 and 2 each had rates of zoonotic and malevolent viral origin beliefs that were relatively lower and higher than the grand sample rates, respectively. Significant differences in intended pandemic health-related behaviors among the high-CMQ clusters (compared to the rest of the sample) included Cluster 1-high on Precautions and low on Vaccination; Cluster 2-high on Testing. Respondents who endorsed SARS-CoV-2 origin beliefs (across clusters) that were least plausible and most malevolent were least inclined to engage in pandemic health behaviors. Conclusions: Distinct subpopulations of persons with high conspiracy-mindedness exist, which are highly heterogeneous in their other coexisting beliefs and behaviors. Some of these may be pathological, such as delusional belief and social media addiction-like behavior, and they have varied associations with pandemic-related belief and behavior. These results, while cross-sectional, suggest that the psychological origins and consequences of conspiratorial beliefs may not be unitary. Instead, conspiratorial belief may be a common expression of diverse psychological and social/experiential factors, and in turn exert varied influence on decisions and overt behavior.

Schizophrenia and bipolar disorder are associated with opposite brain reward anticipation-associated response.

Blunted and exaggerated neuronal response to rewards are hypothesized to be core features of schizophrenia spectrum disorders (SZ) and bipolar disorder (BD), respectively. Nonetheless, direct tests of this hypothesis, in which response between SZ and BD is compared in the same study, are lacking. Here we examined the functional correlates of reward processing during the Incentivized Control Engagement Task (ICE-T) using 3T fMRI. Reward-associated activation was examined in 49 healthy controls (HCs), 52 recent-onset individuals with SZ, and 22 recent-onset individuals with Type I BD using anterior cingulate (ACC), anterior insula, and ventral striatal regions of interest. Significant group X reward condition (neutral vs. reward) interactions were observed during reward anticipation in the dorsal ACC (F(2,120) = 4.21, P = 0.017) and right insula (F(2,120) = 4.77, P = 0.010). The ACC interaction was driven by relatively higher activation in the BD group vs. HCs (P = 0.007) and vs. individuals with SZ (P = 0.010). The insula interaction was driven by reduced activation in the SZ group relative to HCs (P = 0.018) and vs. people with BD (P = 0.008). A composite of reward anticipation-associated response across all associated ROIs also differed significantly by diagnosis (F(1,120) = 5.59, P = 0.02), BD > HC > SZ. No effects of group or group X reward interactions were observed during reward feedback. These results suggest that people with SZ and BD have opposite patterns of activation associated with reward anticipation but not reward receipt. Implications of these findings in regard to Research Domain Criteria-based classification of illness and the neurobiology of reward in psychosis are discussed.

Transcranial Magnetic Stimulation: A Clinical Primer for Nonexperts.

Transcranial magnetic stimulation (TMS) is a safe and effective therapeutic modality for a rapidly expanding range of neuropsychiatric indications. Among psychiatric conditions, it is presently approved by the US Food and Drug Administration for treatment-resistant unipolar major depressive disorder and obsessive-compulsive disorder, 2 highly prevalent conditions with a considerable public health impact. There is also mounting evidence for its clinical utility in numerous other neuropsychiatric conditions. Nonetheless, many mental health providers, as well as primary care and other providers, remain unfamiliar with its clinical use. In this primer, we seek to describe in nontechnical terms how the magnetic field is applied to the brain, the unmet needs that may be remediated with TMS, the present state of evidence for clinical effectiveness, particularly in major depressive disorder, the safety profile of TMS, what patients experience during TMS, and some recent developments that serve to advance the use of this still novel intervention. TMS is poised to assume an important place in the armamentarium of interventions to better serve our patients, especially those with serious, chronic conditions with high rates of resistance to more conventional treatments. Consequently, it is essential that mental health providers gain as adequate a working knowledge of device-based interventions such as TMS as they currently have of psychopharmacological and psychosocial interventions. Among other potential benefits, this information should aid the process of obtaining informed consent from patients who are candidates for these treatments.

A Clinical Program to Implement Repetitive Transcranial Magnetic Stimulation for Depression in the Department of Veterans Affairs.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain. The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The annual suicide rate of veterans has been higher than the national average; treating depression with rTMS would likely decrease suicide risk. MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief. METHODS: A pilot program was created to supply rTMS devices to 35 different sites in the VA nationwide in order to treat treatment-resistant depression. CONCLUSIONS: At time of analysis more than 950 veterans have started the program and 412 have finished. Nationwide, we have seen the depression scores decline, indicating an improvement in well-being. In addition, there is high patient satisfaction. Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response which might be lost on a smaller subset of cases.

Reduced in vivo visual cortex GABA in schizophrenia, a replication in a recent onset sample.

The GABA deficit hypothesis remains one of the most compelling explanations for the information processing impairments in schizophrenia. However, much of the supportive evidence has been derived from post-mortem studies, whereas in vivo studies have largely yielded inconsistent results. We undertook this single voxel proton magnetic resonance (MRS) GABA study to test in a sample of recent onset patients the replicability of our prior finding of reduced early visual cortex GABA in schizophrenia. We also examined the possibility that antipsychotics could represent a significant confound by studying a small subsample of antipsychotic naïve subjects. 23 adults with recent onset schizophrenia and a demographically matched sample of 31 healthy control subjects underwent MRS using a MEGA PRESS sequence on a 3T MR scanner to measure GABA concentration in early visual cortex. To control for in-scanner head movement confounding the results, we quantified the amount of head movement during GABA scans to identify and exclude from analysis scans with excessive movement. Patients demonstrated significantly reduced GABA levels compared to control subjects, p = 0.029. GABA levels did not differ significantly between patients who were antipsychotic naïve (n = 7) and patients treated with antipsychotics. This replication in a recent onset sample suggest that diminished GABA in the visual cortex is a reliable finding, present in early phase of illness and not confounded by illness chronicity.

Impaired prefrontal functional connectivity associated with working memory task performance and disorganization despite intact activations in schizophrenia.

Working memory (WM) deficits are key features of schizophrenia and are associated with significant functional impairment. The precise mechanisms of WM and their relationship between WM deficits with other clinical symptoms of schizophrenia remain unclear. Contemporary models propose that WM requires synchronous activity across brain regions within a distributed network, including lateral prefrontal cortex (PFC) and task-relevant posterior sensory cortical regions. This suggests that WM deficits in patients may be due to PFC functional connectivity (FC) impairments rather than activation impairments per se. We tested this hypothesis by measuring the magnitude of FC between lateral PFC and visual cortex and univariate activations within these regions during visual WM. We found decreased FC in patients compared to healthy subjects in the context of similar levels of univariate activity. Furthermore, this decreased FC was associated with task performance and clinical symptomatology in patients. The magnitude of FC, particularly during the delay period, was positively correlated with WM task accuracy, while FC during cue was inversely correlated with severity of disorganization. Taken together, these results suggest that impairment in lateral PFC FC is a key aspect of information processing impairment in patients with schizophrenia, and may be a sensitive index of altered neurophysiology.

Subthalamic Nucleus Activation Occurs Early during Stopping and Is Associated with Trait Impulsivity.

The subthalamic nucleus (STN) is thought to be a central regulator of behavioral inhibition, which is thought to be a major determinant of impulsivity. Thus, it would be reasonable to hypothesize that STN function is related to impulsivity. However, it has been difficult to test this hypothesis because of the challenges in noninvasively and accurately measuring this structure's signal in humans. We utilized a novel approach for STN signal localization that entails identifying this structure directly on fMRI images for each individual participant in native space. Using this approach, we measured STN responses during the stop signal task in a sample of healthy adult participants. We confirmed that the STN exhibited selective activation during "Stop" trials. Furthermore, the magnitude of STN activation during successful Stop trials inversely correlated with individual differences in trait impulsivity as measured by a personality inventory. Time course analysis revealed that early STN activation differentiated successful from unsuccessful Stop trials, and individual differences in the magnitude of STN activation inversely correlated with stop signal RT, an estimate of time required to stop. These results are consistent with the STN playing a central role in inhibition and related behavioral proclivities, with implications for both normal range function and clinical syndromes of inhibitory dyscontrol. Moreover, the methods utilized in this study for measuring STN fMRI signal in humans may be gainfully applied in future studies to further our understanding of the role of the STN in regulating behavior and neuropsychiatric conditions.

Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition.

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits.

Dorsolateral Prefrontal Cortex GABA Concentration in Humans Predicts Working Memory Load Processing Capacity.

The discovery of neural mechanisms of working memory (WM) would significantly enhance our understanding of complex human behaviors and guide treatment development for WM-related impairments found in neuropsychiatric conditions and aging. Although the dorsolateral prefrontal cortex (DLPFC) has long been considered critical for WM, we still know little about the neural elements and pathways within the DLPFC that support WM in humans. In this study, we tested whether an individual's DLPFC gamma-aminobutryic acid (GABA) content predicts individual differences in WM task performance using a novel behavioral approach. Twenty-three healthy adults completed a task that measured the unique contribution of major WM components (memory load, maintenance, and distraction resistance) to performance. This was done to address the possibility that components have differing GABA dependencies and the failure to parse WM into components would lead to missing true associations with GABA. The subjects then had their DLPFC GABA content measured by single-voxel proton magnetic spectroscopy. We found that individuals with lower DLPFC GABA showed greater performance degradation with higher load, accounting for 31% of variance, p(corrected) = 0.015. This relationship was component, neurochemical, and brain region specific. DLPFC GABA content did not predict performance sensitivity to other components tested; DLPFC glutamate + glutamine and visual cortical GABA content did not predict load sensitivity. These results confirm the involvement of DLPFC GABA in WM load processing in humans and implicate factors controlling DLPFC GABA content in the neural mechanisms of WM and its impairments. SIGNIFICANCE STATEMENT: This study demonstrated for the first time that the amount of gamma-aminobutryic acid (GABA), the major inhibitory neurotransmitter of the brain, in an individual's prefrontal cortex predicts working memory (WM) task performance. Given that WM is required for many of the most characteristic cognitive and behavioral capabilities in humans, this finding could have a significant impact on our understanding of the neural basis of complex human behavior. Furthermore, this finding suggests that efforts to preserve or increase brain GABA levels could be fruitful in remediating WM-related deficits associated with neuropsychiatric conditions.

A case of butane hash oil (marijuana wax)-induced psychosis.

BACKGROUND: Marijuana is one of the most widely used controlled substances in the United States. Despite extensive research on smoked marijuana, little is known regarding the potential psychotropic effects of marijuana "wax," a high-potency form of marijuana that is gaining in popularity. CASE: The authors present a case of "Mr. B," a 34-year-old veteran who presented with profound psychosis in the setting of recent initiation of heavy, daily marijuana wax use. He exhibited incoherent speech and odd behaviors and appeared to be in a dream-like state with perseverating thoughts about his combat experience. His condition persisted despite treatment with risperidone 4 mg twice a day (BID), but improved dramatically on day 8 of hospitalization with the return of baseline mental function. Following discharge, Mr. B discontinued all marijuana use and did not exhibit the return of any psychotic symptoms. DISCUSSION: This study highlights the need for future research regarding the potential medical and psychiatric effects of new, high-potency forms of marijuana. Could cannabis have a dose-dependent impact on psychosis? What other potential psychiatric effects could emerge heretofore unseen in lower potency formulations? Given the recent legalization of marijuana, these questions merit timely exploration.

The impact of acute bouts of exercise on circulating cardiac natriuretic peptide and left ventricular function in untrained healthy young subjects.

BACKGROUND: To examine the impact of a single bout of exercise on cardiac function and the blood level of brain natriuretic peptide (BNP) in healthy subjects. METHODS: Thirty untrained, healthy young (aged between 20 and 29 years) volunteers (15 men and 15 women) were prospectively recruited. The plasma N-terminal pro-B-type BNP (NT-proBNP) level was checked, cardiac function was assessed using echocardiography in baseline conditions, and the values were compared with those obtained after treadmill exercise according to the Bruce protocol. RESULTS: Left ventricular (LV) ejection fraction decreased after exercise in men, but not in women. Parameters of LV diastolic function were likely to change unfavorably in both sexes after exercise. NT-proBNP levels were significantly elevated by exercise in both sexes (from 22.1±18.3 to 24.7±20.2 pg/mL, P=0.006 in men; from 41.1±21.5 to 46.5±24.9 pg/mL, P<0.001 in women). Changes in NT-proBNP levels were significantly associated with those in E wave velocity, E wave deceleration time, E/e' and E/propagation velocity (Vp) in men (P<0.05 for each) even after controlling for the effects of blood pressure and heart rate. In women, there were no significant associations between changes in parameters of LV diastolic function and those in NT-proBNP levels. CONCLUSIONS: LV systolic and diastolic functions may deteriorate, and proBNP levels could be elevated even by a single bout of treadmill exercise in untrained young subjects. Dynamic change in LV diastolic function is a major stimulus to NT-proBNP release following exercise in men but not in women.

Sustained Modafinil Treatment Effects on Control-Related Gamma Oscillatory Power in Schizophrenia.

Control-related cognitive processes such as rule selection and maintenance are associated with cortical oscillations in the gamma range, and modulated by catecholamine neurotransmission. Control-related gamma power is impaired in schizophrenia, and an understudied treatment target. It remains unknown whether pro-catecholamine pharmacological agents augment control-related gamma oscillations in schizophrenia. We tested the effects of 4-week fixed-dose daily adjunctive modafinil (MOD) 200 mg, in a randomized double-blind, placebo-controlled, parallel-groups design. Twenty-seven stable schizophrenia patients performed a cognitive control task during EEG, at baseline and after 4 weeks of treatment. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4-80 Hz oscillations. The modafinil group (n=14), relative to placebo group (n=13), exhibited enhanced oscillatory power associated with high-control rule selection in the gamma range after treatment, with additional effects during rule maintenance in gamma and sub-gamma ranges. MOD-treated patients who exhibited improved task performance with treatment also showed greater treatment-related delay period gamma compared with MOD-treated patients without improved performance. This is the first evidence in schizophrenia of augmentation of cognition-related gamma oscillations by an FDA-approved agent with therapeutic potential. Gamma oscillations represent a novel treatment target in this disorder, and modulation of catecholamine signaling may represent a viable strategy at this target.

Frontal Motor Cortex Activity During Reactive Control Is Associated With Past Suicidal Behavior in Recent-Onset Schizophrenia.

BACKGROUND: Suicide is prevalent in schizophrenia (SZ), yet the neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in SZ, including those that support reactive control, and PFC changes are observed in postmortem studies of heterogeneous suicide victims. AIMS: We tested whether history of suicide attempt is associated with altered frontal motor cortex activity during reactive control processes. METHOD: We evaluated 17 patients with recent onset of DSM-IV-TR-defined SZ using the Columbia Suicide Severity Rating Scale and functional magnetic resonance imaging during Stroop task performance. Group-level regression models relating past suicidal behavior to frontal activation controlled for depression, psychosis, and impulsivity. RESULTS: Past suicidal behavior was associated with relatively higher activation in the left-hemisphere supplementary motor area (SMA), pre-SMA, premotor cortex, and dorsolateral PFC, all ipsilateral to the active primary motor cortex. CONCLUSION: This study provides unique evidence that suicidal behavior in patients with recent-onset SZ directly relates to frontal motor cortex activity during reactive control, in a pattern reciprocal to the relationship with proactive control found previously. Further work should address how frontal-based control functions change with risk over time, and their potential utility as a biomarker for interventions to mitigate suicide risk in SZ.

Control-related frontal-striatal function is associated with past suicidal ideation and behavior in patients with recent-onset psychotic major mood disorders.

OBJECTIVE: Suicide is highly-prevalent in major mood disorders, yet it remains unclear how suicidal ideation and suicidal behavior relate to brain functions, especially those that support control processes. We evaluated how prefrontal cortex (PFC) activity during goal-representation (an important component of cognitive control) relates to past suicidal ideation and behavior in patients with psychotic major mood disorders. METHOD: 30 patients with recent-onset of either DSM-IV-TR-defined bipolar disorder type I (n=21) or major depressive disorder (n=9) with psychotic features, but neither in a major mood episode nor acutely psychotic at study, were evaluated for past suicidal ideation and behavior (Columbia Suicide Severity Rating Scale) and functional MRI during cognitive control task performance. Group-level regression models of brain activation accounted for current depression, psychosis and trait impulsivity. RESULTS: Intensity of past suicidal ideation was associated with higher control-related activation in right-hemisphere regions including the ventrolateral PFC (VLPFC) and orbitofrontal cortex, rostral insula, and dorsal striatum. Among those with past suicidal ideation (n=16), past suicidal behavior (n=8) was associated with higher control-related activation in right-hemisphere regions including VLPFC, rostrolateral PFC, and frontal operculum/rostral insula; and relatively lower activity in midline parietal regions, including cuneus and precuneus. LIMITATIONS: The sample size of subjects with past suicidal behavior was modest, and all subjects were taking psychotropic medication. CONCLUSIONS: This study provides unique evidence that in early-course psychotic major mood disorders, suicidal ideation and behavior histories directly relate to PFC-based circuit function in support of cognitive control.

Conflict-related anterior cingulate functional connectivity is associated with past suicidal ideation and behavior in recent-onset schizophrenia.

Suicide is highly prevalent in schizophrenia (SZ), yet it remains unclear how suicide risk factors such as past suicidal ideation or behavior relate to brain function. Circuits modulated by the prefrontal cortex (PFC) are altered in SZ, including in dorsal anterior cingulate cortex (dACC) during conflict-monitoring (an important component of cognitive control), and dACC changes are observed in post-mortem studies of heterogeneous suicide victims. We tested whether conflict-related dACC functional connectivity is associated with past suicidal ideation and behavior in SZ. 32 patients with recent-onset of DSM-IV-TR-defined SZ were evaluated with the Columbia Suicide Severity Rating Scale and functional MRI during cognitive control (AX-CPT) task performance. Group-level regression models relating past history of suicidal ideation or behavior to dACC-seeded functional connectivity during conflict-monitoring controlled for severity of depression, psychosis and impulsivity. Past suicidal ideation was associated with relatively higher functional connectivity of the dACC with the precuneus during conflict-monitoring. Intensity of worst-point past suicidal ideation was associated with relatively higher dACC functional connectivity in medial parietal lobe and striato-thalamic nuclei. In contrast, among those with past suicidal ideation (n = 17), past suicidal behavior was associated with lower conflict-related dACC connectivity with multiple lateral and medial PFC regions, parietal and temporal cortical regions. This study provides unique evidence that recent-onset schizophrenia patients with past suicidal ideation or behavior show altered dACC-based circuit function during conflict-monitoring. Suicidal ideation and suicidal behavior have divergent patterns of associated dACC functional connectivity, suggesting a differing pattern of conflict-related brain dysfunction with these two distinct features of suicide phenomenology.

A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia.

IMPORTANCE: Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter. OBJECTIVE: To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner. MAIN OUTCOMES AND MEASURES: Behavioral performance was measured by trial accuracy, reaction time, and d'-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain. RESULTS: Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group. CONCLUSIONS AND RELEVANCE: These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.