Conflict-Related Anterior Cingulate Functional Connectivity Is Associated With Past Suicidal Ideation and Behavior in Recent-Onset Psychotic Major Mood Disorders.

Suicidal ideation and behavior are highly prevalent in psychotic major mood disorders, yet their relationship to brain function remains unclear. Thirty patients with recent-onset of bipolar disorder type I (N=21) or major depressive disorder (N=9) with past psychosis were evaluated for past suicidal ideation/behavior and functional MRI during conflict-monitoring. Suicidal ideation was related to relatively higher dorsal anterior cingulate cortex (dACC)-seeded functional connectivity with dorsal fronto-parietal and inferior temporal-occipital cortex, as well as lower dACC connectivity with bilateral ventrolateral prefrontal cortex (PFC) and adjacent fronto-striatal regions. Past suicidal behavior was associated with lower dACC functional connectivity with dorsolateral PFC and premotor cortex, as well as temporal-parietal cortex.

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.

Modafinil effects on middle-frequency oscillatory power during rule selection in schizophrenia.

Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4-30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4-30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control.