Faculty Bibliography

The aim of this study was to characterize dysfunctional cerebral activation in patients with schizophrenia while they performed a response inhibition task. To achieve this, performance on the task and functional magnetic resonance imaging (fMRI) were compared between healthy control subjects (HC) and patients with schizophrenia (SZ). We focused on the default mode network (DMN), as there is strong evidence in the literature that lack of DMN suppression in schizophrenia is associated with cognitive impairment including poor response inhibition. fMRI was used to measure blood-oxygen-level-dependent activation in 84 subjects (44 SZ and 40 HC) while they performed a Go NoGo task. The subjects were also evaluated for psychiatric symptoms and immediate visual memory. SZ performed more poorly than HC on the task; they had a higher number of commission errors. On the fMRI, the patients consistently evidenced higher activation than the controls in several areas of the default mode network (DMN) including the precuneus, rostral anterior cingulate, parahippocampus and insula. The higher brain activation in the patients with schizophrenia indicates a failure to deactivate the DMN while they perform the response inhibition task. These findings point to the importance of DMN dysfunction as an underlying cause of impairment in response inhibition in schizophrenia. DMN disruptions play an essential role in the cognitive impairment present in schizophrenia.

The aim of this study was to characterize dysfunctional cerebral activation in patients with schizophrenia while they performed a response inhibition task. To achieve this, performance on the task and functional magnetic resonance imaging (fMRI) were compared between healthy control subjects (HC) and patients with schizophrenia (SZ). We focused on the default mode network (DMN), as there is strong evidence in the literature that lack of DMN suppression in schizophrenia is associated with cognitive impairment including poor response inhibition. fMRI was used to measure blood-oxygen-level-dependent activation in 84 subjects (44 SZ and 40 HC) while they performed a Go NoGo task. The subjects were also evaluated for psychiatric symptoms and immediate visual memory. SZ performed more poorly than HC on the task; they had a higher number of commission errors. On the fMRI, the patients consistently evidenced higher activation than the controls in several areas of the default mode network (DMN) including the precuneus, rostral anterior cingulate, parahippocampus and insula. The higher brain activation in the patients with schizophrenia indicates a failure to deactivate the DMN while they perform the response inhibition task. These findings point to the importance of DMN dysfunction as an underlying cause of impairment in response inhibition in schizophrenia. DMN disruptions play an essential role in the cognitive impairment present in schizophrenia.

This study aimed to evaluate the dose-dependent brain temperature effects of transcranial photobiomodulation (t-PBM). Thirty adult subjects with major depressive disorder were randomized to three t-PBM sessions with different doses (low: 50 mW/cm², medium: 300 mW/cm², high: 850 mW/cm²) and a sham treatment. The low and medium doses were administered in continuous wave mode, while the high dose was administered in pulsed wave mode. A 3T MRI scanner was used to perform proton magnetic resonance spectroscopy (¹H-MRS). A voxel with a volume of 30 × 30 × 15 mm³ was placed on the left prefrontal region. Brain temperature (°C) was derived by analyzing ¹H-MRS spectrum chemical shift differences between the water (~ 4.7 ppm) and N-acetyl aspartate (NAA) (~ 2.01 ppm) peaks. After quality control of the data, the following group numbers were available for both pre- and post-temperature estimations: sham (n = 10), low (n = 11), medium (n = 10), and high (n = 8). We did not detect significant temperature differences for any t-PBM-active or sham groups post-irradiation (p-value range = 0.105 and 0.781). We also tested for potential differences in the pre-post variability of brain temperature in each group. As for t-PBM active groups, the lowest fluctuation (variance) was observed for the medium dose (σ² = 0.29), followed by the low dose (σ² = 0.47), and the highest fluctuation was for the high dose (σ² = 0.67). t-PBM sham condition showed the overall lowest fluctuation (σ² = 0.11). Our ¹H-MRS thermometry results showed no significant brain temperature elevations during t-PBM administration.

BACKGROUND:The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. METHODS:Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. RESULTS:Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. CONCLUSIONS:Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

Deficits in cognitive control contribute to behavioral impairments across neuropsychiatric disorders. Cognitive control is captured as a construct in the Research Domain Construct (RDoC) matrix and incorporate subdomains of goal selection, response selection, and performance monitoring. Relevant tasks for these subdomains include the "AX" version of the continuous performance task (goal selection) and the Go/NoGo and Stop-Signal reaction time tasks (response selection). Underlying mechanisms for these domains have been investigated intensively using fMRI and event-related potential (ERP) approaches, which provide candidate biomarkers for translational research. In RDoC, impulsive behaviors are provisionally assigned to the cognitive control/response selection construct, but other factors may also contribute. Impulsivity has gained increased importance over recent years due to its link to aggression and suicidality, which is mediated especially through the constructs of urgency and frustrative nonreward. These constructs, in turn, may be captured through scales such as the Urgency, (Lack of) Premeditation, (Lack of) Perseverance, and Sensation Seeking (UPPS-P) impulsivity scale and the Point Subtraction Aggression Paradigm (PSAP), respectively. At present, no validated biomarkers exist for either urgency or aggressivity. Potential directions for the development of predictive biomarkers for both targets are discussed.

INTRODUCTION/UNASSIGNED:Suicidal ideation and behavior (SIB) are serious problems in people with schizophrenia spectrum disorders (SSD). Nevertheless, relatively little is known about the circuitry underlying SIB in SSD. Recently, we showed that elevated emotional impulsivity (urgency) was associated with SIB in SSD. Here we examined brain activity in people with SSD and elevated SIB. METHODS/UNASSIGNED:We tested 16 people with SSD who had low SIB and 14 people with high SIB on a task in which emotion regulation in response to affective pictures was implicitly manipulated using spoken sentences. Thus, there were neutral pictures preceded by neutral statements (NeutNeut condition), as well as negative pictures preceded by either negative (NegNeg) or neutral (NeutNeg) statements. After each picture, participants rated how unpleasant each picture was for them. The latter two conditions were compared to the NeutNeut condition. We compared the emotion-regulated condition (NeutNeg) to the unregulated condition (NeutNeut). Statistics were threshold using threshold free cluster enhancement (TFCE). RESULTS/UNASSIGNED:People in the low SIB group showed higher activation in this contrast in medial frontal gyrus, right rostral anterior cingulate, bilateral superior frontal gyrus/DLPFC, and right middle cingulate gyrus, as well as right superior temporal gyrus. DISCUSSION/UNASSIGNED:This study provides clues to the neural basis of SIB in SSD as well as underlying mechanisms.

Schizophrenia is increasingly recognized as a disorder with altered integration between large-scale functional networks and cortical-subcortical pathways. This spatial long-distance information communication must be associated with white matter (WM) fiber bundles. With accumulating evidence that WM functional signals reflect the intrinsic neural activities, how the deep callosal organization modulates cortical functional activities through WM remains unclear in schizophrenia. Using a data-driven method, we identified nine WM and gray matter (GM) functional networks, and then parcellated corpus callosum into distinct sub-regions. Combining functional connectivity and fiber tracking analysis, we estimated the structural and functional connectivity changes of callosal-WM-cortical circuits in schizophrenia. We observed higher structural and functional connectivity between corpus callosum, WM and GM functional networks involving visual network (visual processing), executive control network (executive controls), ventral attention network (processing of salience), and limbic network (emotion processing) in schizophrenia compared to healthy controls. We also found nine abnormal pathways of callosal-WM-cortical circuits involving the above networks and default mode network (self-related thought). These results highlight the role of connectivity deficits in callosal-WM-cortical circuits may play in understanding the delusions, hallucinations and cognitive impairment of schizophrenia.

The effect of antipsychotic medication on resting state functional connectivity in major depressive disorder (MDD) is currently unknown. To address this gap, we examined patients with MDD with psychotic features (MDDPsy) participating in the Study of the Pharmacotherapy of Psychotic Depression II. All participants were treated with sertraline plus olanzapine and were subsequently randomized to continue sertraline plus olanzapine or be switched to sertraline plus placebo. Participants completed an MRI at randomization and at study endpoint (study completion at Week 36, relapse, or early termination). The primary outcome was change in functional connectivity measured within and between specified networks and the rest of the brain. The secondary outcome was change in network topology measured by graph metrics. Eighty-eight participants completed a baseline scan; 73 completed a follow-up scan, of which 58 were usable for analyses. There was a significant treatment X time interaction for functional connectivity between the secondary visual network and rest of the brain (t = -3.684; p = 0.0004; pFDR = 0.0111). There was no significant treatment X time interaction for graph metrics. Overall, functional connectivity between the secondary visual network and the rest of the brain did not change in participants who stayed on olanzapine but decreased in those switched to placebo. There were no differences in changes in network topology measures when patients stayed on olanzapine or switched to placebo. This suggests that olanzapine may stabilize functional connectivity, particularly between the secondary visual network and the rest of the brain.

BACKGROUND:Schizophrenia is associated with an elevated risk for impulsive aggression for which there are few psychosocial treatment options. Neurocognitive and social cognitive deficits have been associated with aggression with social cognitive deficits seemingly a more proximal contributor. The current study examined the effects of combining cognitive and social cognition treatment on impulsive aggression among inpatients with chronic schizophrenia and schizoaffective disorder and a history of aggression compared to cognitive remediation treatment alone. METHODS:The two-center study randomized 130 participants to receive 36 sessions of either a combination of cognitive remediation and social cognition treatment or cognitive remediation plus a computer-based control. Participants had at least one aggressive incident within the past year or a Life History of Aggression (LHA) score of 5 or more. Participants completed measures of neurocognition, social cognition, symptom severity, and aggression at baseline and endpoint. RESULTS:Study participants were mostly male (84.5 %), had a mean age 34.9 years, and 11.5 years of education. Both Cognitive Remediation Training (CRT) plus Social Cognition Training (SCT) and CRT plus control groups were associated with significant reductions in aggression measures with no group differences except on a block of the Taylor Aggression Paradigm (TAP), a behavioral task of aggression which favored the CRT plus SCT group. Both groups showed significant improvements in neurocognition and social cognition measures with CRT plus SCT being associated with greater improvements. CONCLUSION/CONCLUSIONS:CRT proved to be an effective non-pharmacological treatment in reducing impulsive aggression in schizophrenia inpatient participants with a history of aggressive episodes. The addition of social cognitive training did not enhance this anti-aggression treatment effect but did augment the CRT effect on cognitive functions, on emotion recognition and on mentalizing capacity of our participants.