Faculty Bibliography

BACKGROUND:Problem solving therapy (PST) and "Engage," a reward-exposure" based therapy, are important treatment options for late-life depression, given modest efficacy of antidepressants in this disorder. Abnormal function of the reward and default mode networks has been observed during depressive episodes. This study examined whether resting state functional connectivity (rsFC) of reward and DMN circuitries is associated with treatment outcomes. METHODS:Thirty-two older adults with major depression (mean age = 72.7) were randomized to 9-weeks of either PST or "Engage." We assessed rsFC at baseline and week 6. We placed seeds in three a priori regions of interest: subgenual anterior cingulate cortex (sgACC), dorsal anterior cingulate cortex (dACC), and nucleus accumbens (NAcc). Outcome measures included the Hamilton Depression Rating Scale (HAMD) and the Behavioral Activation for Depression Scale (BADS). RESULTS:In both PST and "Engage," higher rsFC between the sgACC and middle temporal gyrus at baseline was associated with greater improvement in depression severity (HAMD). Preliminary findings suggested that in "Engage" treated participants, lower rsFC between the dACC and dorsomedial prefrontal cortex at baseline was associated with HAMD improvement. Finally, in Engage only, increased rsFC from baseline to week 6 between NAcc and Superior Parietal Cortex was associated with increased BADS scores. CONCLUSION/CONCLUSIONS:The results suggest that patients who present with higher rsFC between the sgACC and a structure within the DMN may benefit from behavioral psychotherapies for late life depression. "Engage" may lead to increased rsFC within the reward system reflecting a reconditioning of the reward systems by reward exposure.

We report on the ongoing R21 project "Social Reward Learning in Schizophrenia". Impairments in social cognition are a hallmark of schizophrenia. However, little work has been done on social reward learning deficits in schizophrenia. The overall goal of the project is to assess social reward learning in schizophrenia. A probabilistic reward learning (PRL) task is being used in the MRI scanner to evaluate reward learning to negative and positive social feedback. Monetary reward learning is used as a comparison to assess specificity. Behavioral outcomes and brain areas, included those involved in reward, are assessed in patients with schizophrenia or schizoaffective disorder and controls. It is also critical to determine whether decreased expected value (EV) of social stimuli and/or reward prediction error (RPE) learning underlie social reward learning deficits to inform potential treatment pathways. Our central hypothesis is that the pattern of social learning deficits is an extension of a more general reward learning impairment in schizophrenia and that social reward learning deficits critically contribute to deficits in social motivation and pleasure. We hypothesize that people with schizophrenia will show impaired behavioral social reward learning compared to controls, as well as decreased ventromedial prefrontal cortex (vmPFC) EV signaling at time of choice and decreased striatal RPE signaling at time of outcome, with potentially greater impairment to positive than negative feedback. The grant is in its second year. It is hoped that this innovative approach may lead to novel and more targeted treatment approaches for social cognitive impairments, using cognitive remediation and/or brain stimulation.

Major depressive disorder with psychotic features (psychotic depression) is a severe disorder. Compared with other psychotic disorders such as schizophrenia, relatively few studies on the neurobiology of psychotic depression have been pursued. Neuroimaging studies investigating psychotic depression have provided evidence for distributed structural brain abnormalities implicating the insular cortex and limbic system. We examined structural brain networks in participants (N = 245) using magnetic resonance imaging. This sample included healthy controls (n = 159) and the largest cross-sectional sample of patients with remitted psychotic depression (n = 86) collected to date. All patients participated in the Study of Pharmacotherapy of Psychotic Depression II randomized controlled trial. We used a novel, whole-brain, data-driven parcellation technique-non-negative matrix factorization-and applied it to cortical thickness data to derive structural covariance networks. We compared patients with remitted psychotic depression to healthy controls and found that patients had significantly thinner cortex in five structural covariance networks (insular-limbic, occipito-temporal, temporal, parahippocampal-limbic, and inferior fronto-temporal), confirming our hypothesis that affected brain networks would incorporate cortico-limbic regions. We also found that cross-sectional depression and severity scores at the time of scanning were associated with the insular-limbic network. Furthermore, the insular-limbic network predicted future severity scores that were collected at the time of recurrence of psychotic depression or sustained remission. Overall, decreased cortical thickness was found in five structural brain networks in patients with remitted psychotic depression and brain-behavior relationships were observed, particularly between the insular-limbic network and illness severity.

Importance/UNASSIGNED:Prescriptions for antipsychotic medications continue to increase across many brain disorders, including off-label use in children and elderly individuals. Concerning animal and uncontrolled human data suggest antipsychotics are associated with change in brain structure, but to our knowledge, there are no controlled human studies that have yet addressed this question. Objective/UNASSIGNED:To assess the effects of antipsychotics on brain structure in humans. Design, Setting, and Participants/UNASSIGNED:Prespecified secondary analysis of a double-blind, randomized, placebo-controlled trial over a 36-week period at 5 academic centers. All participants, aged 18 to 85 years, were recruited from the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). All participants had major depressive disorder with psychotic features (psychotic depression) and were prescribed olanzapine and sertraline for a period of 12 to 20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then were randomized to continue receiving this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Data were analyzed between October 2018 and February 2019. Interventions/UNASSIGNED:Those who consented to the imaging study completed a magnetic resonance imaging (MRI) scan at the time of randomization and a second MRI scan at the end of the 36-week period or at time of relapse. Main Outcomes and Measures/UNASSIGNED:The primary outcome measure was cortical thickness in gray matter and the secondary outcome measure was microstructural integrity of white matter. Results/UNASSIGNED:Eighty-eight participants (age range, 18-85 years) completed a baseline scan; 75 completed a follow-up scan, of which 72 (32 men and 40 women) were useable for final analyses. There was a significant treatment-group by time interaction in cortical thickness (left, t = 3.3; P = .001; right, t = 3.6; P < .001) but not surface area. No significant interaction was found for fractional anisotropy, but one for mean diffusivity of the white matter skeleton was present (t = -2.6, P = .01). When the analysis was restricted to those who sustained remission, exposure to olanzapine compared with placebo was associated with significant decreases in cortical thickness in the left hemisphere (β [SE], 0.04 [0.009]; t34.4 = 4.7; P <.001), and the right hemisphere (β [SE], 0.03 [0.009]; t35.1 = 3.6; P <.001). Post hoc analyses showed that those who relapsed receiving placebo experienced decreases in cortical thickness compared with those who sustained remission. Conclusions and Relevance/UNASSIGNED:In this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure. This information is important for prescribing in psychiatric conditions where alternatives are present. However, adverse effects of relapse on brain structure support antipsychotic treatment during active illness. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01427608.

Background: The association between schizophrenia and violence is an important issue in psychiatry. The impact of several factors (social cognition, neurocognition, alexithymia, emotion regulation capacity, and the therapeutic milieu) on aggression in schizophrenia creates an opportunity for the development and evaluation of novel treatments for aggression. Previous studies show that cognitive remediation training (CRT) and social cognitive training (SCT) help to decrease hostility. The parent study examined whether cognitive training leads to improvements in cognition emotion regulation capacity, and impulse control in participants with a history of impulsive aggression. The current study examined the effectiveness of CRT alone versus a combination of CRT and SCT in terms of emotion recognition and cognitive improvement.
Method(s): The study recruited participants with schizophrenia or schizoaffective disorder with a past year history of at least one or more violent acts or a significant lifetime history of aggression as indicated by a score of 5 or more on the Life History of Aggression (LHA) interview from two inpatient sites (Manhattan Psychiatric Center and New York Hospital, Westchester Division). Participants were randomized to two groups of 36 one-hour sessions. Participants in the control group had 24 sessions of CRT (BrainHQ) and 12 sessions of Encyclopedia readings. Participants in the treatment group had 24 sessions of CRT (BrainHQ) and 12 sessions of computerized SCT (MindReading). To assess neurocognition, mentalizing, and facial affect recognition abilities, participants were administered the MATRICS Consensus Cognitive Battery (MCCB), Reading the Mind in the Eyes Task (Eyes Task), and the Emotion Recognition-40 (ER-40) respectively. Negative emotionality was captured using the Positive and Negative Affect Schedule (PANAS).
Result(s): The study data included 49 completers and 5 intent-to-treat samples, with 24 and 25 per group, respectively (CRT+ SCT and CRT alone). Results indicated no significant differences between groups at baseline. Significant overall improvements were observed in the ER-40 for all subjects across time (Mean Time 1 = 25.06 (SD = 25.023), Time 2 Mean = 30.86 (SD = 6.849), p < 0.001), the Mind in the Eyes Test - Revised (Time 1 Mean = 19.70 (SD = 7.407), Time 2 Mean = 26.15 (SD = 7.830), p < 0.001), and the PANAS Negative affect Score (Time 1 Mean = 29.40 (SD = 11.836), Time 2 Mean = 18.47 (SD = 2.688), p < 0.001). Both cognitive groups showed improvements from baseline on the composite cognition score of the MCCB composite (F (1,47)=74.51, p<0.001, eta2 =0.61) with a slight edge to the combined CRT+SCT group (F (1,47)=3.61, p=0.064, eta2 =0.07). The Mind in the Eyes Test showed a significant improvement between groups (p = 0.025) with the CRT + SCT group showing greater improvement at endpoint. There were no other significant differences between groups.
Discussion(s): CRT with and without SCT improved both cognitive functions and emotion recognition as well as aspects of emotion regulation in patients with significant histories of impulsive aggression. While social cognition training only added a small increment in emotion recognition, possibly facilitating better emotion regulation control and impulsivity, more direct measures of aggression and impulsivity need to be interrogated to assess the effect on aggressive behaviors

Functional connectivity (FC) maps from brain fMRI data can be derived with dual regression, a proposed alternative to traditional seed-based FC (SFC) methods that detect temporal correlation between a predefined region (seed) and other regions in the brain. As with SFC, incorporating nuisance regressors (NR) into the dual regression must be done carefully, to prevent potential bias and insensitivity of FC estimates. Here, we explore the potentially untoward effects on dual regression that may occur when NR correlate highly with the signal of interest, using both synthetic and real fMRI data to elucidate mechanisms responsible for loss of accuracy in FC maps. Our tests suggest significantly improved accuracy in FC maps derived with dual regression when highly correlated temporal NR were omitted. Single-map dual regression, a simplified form of dual regression that uses neither spatial nor temporal NR, offers a viable alternative whose FC maps may be more easily interpreted, and in some cases be more accurate than those derived with standard dual regression.

BACKGROUND:White matter hyperintensities (WMH) represent ischemic white matter damage in late-life depression (LLD) and are associated with cognitive control dysfunction. Understanding the impact of WMH on the structural connectivity of gray matter and the cognitive control correlates of WMH-related structural dysconnectivity can provide insight into the pathophysiology of LLD. METHODS:We compared WMH burden and performance on clinical measures of cognitive control in patients with LLD (N = 44) and a control group of non-depressed older adults (N = 59). We used the Network Modification (NeMo) Tool to investigate the impact of WMH on structural dysconnectivity in specific gray matter regions, and how such connectivity was related to cognitive control functions. RESULTS:Compared to the control group, LLD participants had greater WMH burden, poorer performance on Trail Making Test (TMT) A & B, and greater self-reported dysexecutive behavior on the Frosntal Systems Behavior Scale-Executive Function subscale (FrSBe-EF). Within the LLD group, disrupted connectivity in the left supramarginal gyrus, paracentral lobule, thalamus, and pallidum was associated with psychomotor slowing (TMT-A). Altered connectivity in the left supramarginal gyrus, paracentral lobule, precentral gyrus, postcentral gyrus, thalamus, and pallidum was associated with poor attentional set-shifting (TMT-B). A follow-up analysis that isolated set-shifting ability (TMT-B/A ratio) confirmed the association with dysconnectivity in the bilateral paracentral lobule, right thalamus, left precentral gyrus, postcentral gyrus, and pallidum; additionally, it revealed associations with dysconnectivity in the right posterior cingulate, and left anterior cingulate, middle frontal cortex, and putamen. CONCLUSIONS:In LLD, WMH are associated with region-specific disruptions in cortical and subcortical gray matter areas involved in attentional aspects of cognitive control systems and sensorimotor processing, which in turn are associated with slower processing speed, and reduced attentional set-shifting. CLINICAL TRIALS REGISTRATION/BACKGROUND:https://clinicaltrials.gov/ct2/show/NCT01728194.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Changes in cerebral white matter organization have been documented in acute phases of recovery from traumatic brain injury (TBI). However, little is known about reorganization processes in more chronic stages of recovery. The current study identified changes in white matter organization in chronic cases of TBI, and determined the relationship between structural changes and cognitive functioning. METHODS:15 adults with moderate to severe TBI and eight healthy controls completed neuropsychological testing and diffusion tensor imaging (DTI) scanning. Participants returned 3 years from the initial session to complete identical neuropsychological tests and scans. RESULTS:Adults with TBI were found to have significantly reduced fractional anisotropy (FA), a metric of white matter organization, compared to healthy participants at baseline and also at 3-year follow-up. Within the sample of adults with TBI, increases in FA were observed over time. Importantly, increases in FA in the TBI sample were also correlated with improvements in cognitive performance. CONCLUSIONS:This study provides evidence of a dynamic process of white matter change occurring beyond the initial phases of recovery after moderate to severe TBI. The observed relationship between structural reorganization and changes in cognitive performance has implications for rehabilitation potential in more chronic phases of recovery.

BACKGROUND:Transcranial direct current stimulation (tDCS) is a potentially novel treatment for antipsychotic-resistant auditory verbal hallucinations (AVH) in schizophrenia. Nevertheless, results have been mixed across studies. METHODS:89 schizophrenia/schizoaffective subjects (active: 47; Sham: 42) were randomized to five days of twice-daily 20-min active tDCS vs. sham treatments across two recruitment sites. AVH severity was assessed using the Auditory Hallucination Rating Scale (AHRS) total score. To assess target engagement, MRI was obtained in a sub sample. RESULTS:We observed a statistically significant, moderate effect-size change in AHRS total score across one-week and one-month favoring active treatment following covariation for baseline symptoms and antipsychotic dose (p = 0.036; d = 0.48). Greatest change was observed on the AHRS loudness item (p = 0.003; d = 0.69). In exploratory analyses, greatest effects on AHRS were observed in patients with lower cognitive symptoms (d = 0.61). In target engagement analysis, suprathreshold mean field-strength (>0.2 V/m) was seen within language-sensitive regions. However, off-target field-strength, which correlated significantly with less robust clinical response, was observed in anterior regions. CONCLUSIONS:This is the largest study of tDCS for persistent AVH conducted to date. We replicate previous reports of significant therapeutic benefit, but only if medication dosage is considered, with patients receiving lowest medication dosage showing greatest effect. Response was also greatest in patients with lowest levels of cognitive symptoms. Overall, these findings support continued development of tDCS for persistent AVH, but also suggest that response may be influenced by specific patient and treatment characteristics. CLINICALTRIALS.GOV: NCT01898299.

BACKGROUND:Negative self-referential thinking is a common symptom of depression associated with poor treatment response. In late-life depression, white matter abnormalities may contribute to negative self-referential thoughts following antidepressant treatment. We investigated the association of fractional anisotropy (FA) in select regions of the negative valence system (NVS) with residual negative self-referential thoughts following treatment with escitalopram for late-life depression. METHODS:The participants were older adults with major depression and psychiatrically normal controls. Depressed participants received 12 weeks of treatment with escitalopram. To assess self-referential thinking, participants completed a Trait Adjective Task at baseline and at week 12. Baseline MRI scans included a diffusion imaging sequence for FA analyses. RESULTS:Participants with late-life depression differed from controls on all performance measures of the Trait Adjective Task at baseline and at 12 weeks. Depressed participants endorsed fewer negative personality traits and more positive personality traits at week 12 compared to baseline. Lower FA in the dorsal anterior cingulate and in the uncinate fasciculus in depressed participants was correlated with residual negative self-referential thinking (e.g., more endorsed negative adjectives, fewer rejected negative adjectives) at treatment end. LIMITATIONS/CONCLUSIONS:The sample size is modest so the findings are preliminary. FA analyses were restricted to predetermined regions. CONCLUSIONS:Negative self-referential thinking improved in depressed older adults following 12 weeks of treatment with escitalopram. Baseline FA in select white matter regions of the NVS was associated with residual negative self-referential thinking. These findings may help identify treatment targets for residual negative self-referential thoughts.