Faculty Bibliography

Glioma growth can cause pervasive changes in the functional connectivity (FC) of brain networks, which has been associated with re-organization of brain functions and development of functional deficits in patients. Mechanisms underlying functional re-organization in brain networks are not understood and efforts to utilize functional imaging for surgical planning, or as a biomarker of functional outcomes are confounded by the heterogeneity in available human data. Here we apply multiple imaging modalities in a well-controlled murine model of glioma with extensive validation using human data to explore mechanisms of FC disruption due to glioma growth. We find gliomas cause both local and distal changes in FC. FC changes in networks proximal to the tumor occur secondary to hemodynamic alterations but surprisingly, remote FC changes are independent of hemodynamic mechanisms. Our data strongly implicate hemodynamic alterations as the main driver of local changes in measurements of FC in patients with glioma.

The basal ganglia, thalamus, and cerebral cortex form an interconnected network implicated in many neurological and psychiatric illnesses. A better understanding of cortico-subcortical circuits in individuals will aid in development of personalized treatments. Using precision functional mapping-individual-specific analysis of highly sampled human participants-we investigated individual-specific functional connectivity between subcortical structures and cortical functional networks. This approach revealed distinct subcortical zones of network specificity and multi-network integration. Integration zones were systematic, with convergence of cingulo-opercular control and somatomotor networks in the ventral intermediate thalamus (motor integration zones), dorsal attention and visual networks in the pulvinar, and default mode and multiple control networks in the caudate nucleus. The motor integration zones were present in every individual and correspond to consistently successful sites of deep brain stimulation (DBS; essential tremor). Individually variable subcortical zones correspond to DBS sites with less consistent treatment effects, highlighting the importance of PFM for neurosurgery, neurology, and psychiatry.

BACKGROUND:We reanalyzed a multisite 26-week randomized double-blind placebo-controlled clinical trial of 600 mg twice-a-day Gabapentin Enacarbil Extended-Release (GE-XR), a gabapentin prodrug, designed to evaluate safety and efficacy for treating alcohol use disorder. In the original analysis (n = 338), published in 2019, GE-XR did not differ from placebo. Our aim is to advance precision medicine by identifying likely responders to GE-XR from the trial data and to determine for likely responders if GE-XR is causally superior to placebo. METHODS:The primary outcome measure in the reanalysis is the reduction from baseline of the number of heavy drinking days (ΔHDD). Baseline features including measures of alcohol use, anxiety, depression, mood states, sleep, and impulsivity were used in a random forest (RF) model to predict ΔHDD to treatment with GE-XR based on those assigned to GE-XR. The resulting RF model was used to obtain predicted outcomes for those randomized to GE-XR and counterfactually to those randomized to placebo. Likely responders to GE-XR were defined as those predicted to have a reduction of 14 days or more. Tests of causal superiority of GE-XR to placebo were obtained for likely responders and for the whole sample. RESULTS:For likely responders, GE-XR was causally superior to placebo (p < 0.0033), while for the whole sample, there was no difference. Likely responders exhibited improved outcomes for the related outcomes of percent HDD and drinks per week. Compared with unlikely responders, at baseline likely responders had higher HDDs; lower levels of anxiety, depression, and general mood disturbances; and higher levels of cognitive and motor impulsivity. CONCLUSIONS:There are substantial causal benefits of treatment with GE-XR for a subset of patients predicted to be likely responders. The likely responder statistical paradigm is a promising approach for analyzing randomized clinical trials to advance personalized treatment.

BACKGROUND:Relatively little is known about the prognostic value of comorbid mental disorders in alcohol use disorder (AUD) treatment for older adults (OA). AIMS/OBJECTIVE:This article aimed to investigate 1) the impact of current unipolar mood and anxiety disorders in AUD treatment success in OA, 2) the timing of this putative comorbidity impact over six months, and 3) the role of treatment length in comorbidity effects. METHODS:We analyzed baseline and one-, three-, and six-month follow-up data from the international multicenter RCT "ELDERLY-Study" (baseline n = 693, median age: 64.0 years) using mixed effects regression models. In adults aged 60+ with DSM-5 AUD "ELDERLY" compared outpatient motivational enhancement therapy (MET, four sessions) with outpatient MET plus community reinforcement approach for seniors (MET & CRA-S; up to 12 sessions). Aiming for abstinence or minimal alcohol use (AU), both conditions included CBT-elements. We assessed AU with Form 90, and mental disorders with the Mini International Neuropsychiatric Interview (M.I.N.I.). RESULTS:Mood-related disorders were associated with more drinks per day at baseline and greater reductions in drinks per day at one and six months (main effect mood disorder: Coef. 2.1, 95% CI 0.6-3.6; one month interaction effect: Coef. -1.9, 95% CI -3.3- -0.5; six months interaction effect: Coef. -2.1, 95% CI -3.5 - -0.6). These results were replicated within MET & CRA-S but not within MET. CONCLUSION/CONCLUSIONS:Comorbid mental disorders had modest effects on short-term outpatient treatment outcomes. OA with AUD and unipolar mood-related disorders may profit from short interventions based on motivational interviewing and CBT-elements. ClinicalTrials.gov:NCT02084173.

BACKGROUND:As the USA grapples with an opioid epidemic, medical emergency departments (EDs) have become a critical setting for intervening with opioid-dependent patients. Brief interventions designed to bridge the gap from acute ED care to longer-term treatment have shown limited efficacy for this population. Strength-based case management (SBCM) has shown strong effects on treatment linkage among patients with substance use disorders in other healthcare settings. This study aimed to investigate whether SBCM is an effective model for linking opioid-dependent ED patients with addiction treatment and pharmacotherapy. Here, we describe the implementation and challenges of adapting SBCM for the ED (SBCM-ED). Study rationale, design, and baseline characteristics are also described. METHODS:This study compared the effects of SBCM-ED to screening, assessment, and referral alone (SAR) on treatment linkage, substance use, and functioning. We recruited participants from a public hospital in NYC. Working alliance between case managers and participants and the feasibility of SBCM implementation were evaluated. Baseline data from the randomized sample were analyzed for group equivalency. Outcomes analyses are forthcoming. RESULTS:Three hundred adult participants meeting DSM-IV criteria for opioid dependence were randomly assigned to either SBCM, in which they received a maximum of six case management sessions within 90 days of enrollment, or SAR, in which they received a comprehensive referral list and pamphlet outlining drug use consequences. No significant differences were found between groups at baseline on demographic or substance use characteristics. All SAR participants and 92.6% of SBCM-ED participants initiated their assigned intervention. Over half of SBCM-ED first sessions occurred in the ED on the day of enrollment. Case managers developed a strong working alliance with SBCM-ED participants after just one session. CONCLUSION/CONCLUSIONS:Interventions that exceed SBIRT were accepted by an opioid-dependent patient population seen in an urban medical ED. At the time of study funding, this trial was one of the first to focus specifically on this population in this challenging setting. The successful implementation of SBCM demonstrates its adaptability to the ED and may serve as a potential model for EDs seeking to adopt an intervention that overcomes the barrier between the ED encounter and more intensive treatment. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT02586896 . Registered on 27 October 2015.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Nitrous oxide has long been used recreationally for its ability to induce euphoria and other deliriant effects. In modern times, it remains a popular, legal, and widely available option for those seeking altered states. Though substance-induced psychotic symptoms have been mentioned in the literature, the potential long-term negative neuropsychiatric effects related to its use have not been well established. METHODS AND RESULTS/RESULTS:This is a patient case report of a young man (N = 1) who initially presented with acute neurological symptoms requiring hospitalization due to heavy nitrous oxide inhalant use, and went on to present with symptoms concerning for a primary psychotic illness over multiple inpatient admissions. He provided both verbal and written consent to share his story for this case report. DISCUSSION AND CONCLUSIONS/CONCLUSIONS:It is important to consider nitrous oxide use as a possible contributing factor to the development of primary psychotic illness. SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:deficiency. Here, we present a patient with risk factors for psychotic illness developing psychotic illness following extensive nitrous oxide use. This report offers a unique perspective of longitudinal follow-up (often not provided with reports on this topic), and illustrates the importance of healthcare providers inquiring about nitrous oxide abuse in patients presenting with early psychotic symptoms. (Am J Addict 2020;00:00-00).

BACKGROUND:Higher levels of anxiety, negative affect, and impaired emotion regulation are associated with alcohol use disorder (AUD) and contribute to relapse and worse treatment outcomes. Prazosin, while typically used to treat post-traumatic stress disorder (PTSD) and other anxiety disorders, has shown promise for treating AUD. In order to better understand these underlying neural processes in individuals with AUD, our aims in this study were to measure brain activation during an anticipatory anxiety task before treatment to determine whether observed patterns supported previous work. We then aimed to measure the effects of prazosin on patients with AUD and explore whether greater baseline anticipatory anxiety (as measured by subjective and neural measures) predicts better treatment outcomes. METHODS:Thirty-four individuals seeking treatment for AUD participated in a six-week placebo-controlled study of prazosin and underwent an anticipatory anxiety task during fMRI scans at baseline and three weeks. Alcohol use over six weeks was measured. RESULTS:Greater levels of subjective anxiety and deactivation in posterior cingulate cortex (PCC) and ventromedial prefrontal cortex (vmPFC) were observed during high-threat stimuli compared to low-threat stimuli. Compared to placebo, prazosin reduced subjective anxiety to high-threat stimuli but there were no observed significant effects of prazosin on brain activation during the task. However, AUD patients with greater vmPFC deactivation during high threat relative to low threat and patients with low baseline anticipatory anxiety during the task had worse clinical outcomes on prazosin. CONCLUSIONS:Deactivation in PCC and vmPFC to high-threat stimuli replicated previous work and shows promise for further study as a marker for AUD. Although prazosin did not affect brain activation in the regions of interest during the anticipatory anxiety task, subjective levels of anxiety and brain activation in vmPFC predicted treatment outcomes in individuals with AUD undergoing treatment with prazosin, highlighting individuals more likely to benefit from prazosin than others.

BACKGROUND/UNASSIGNED:A recently published randomized controlled trial compared single-dose psilocybin with single-dose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric distress. Results suggested that psilocybin-assisted psychotherapy facilitated improvements in psychiatric and existential distress, quality of life, and spiritual well-being up to seven weeks prior to the crossover. At the 6.5-month follow-up, after the crossover, 60-80% of participants continued to meet criteria for clinically significant antidepressant or anxiolytic responses. METHODS/UNASSIGNED:The present study is a long-term within-subjects follow-up analysis of self-reported symptomatology involving a subset of participants that completed the parent trial. All 16 participants who were still alive were contacted, and 15 participants agreed to participate at an average of 3.2 and 4.5 years following psilocybin administration. RESULTS/UNASSIGNED:Reductions in anxiety, depression, hopelessness, demoralization, and death anxiety were sustained at the first and second follow-ups. Within-group effect sizes were large. At the second (4.5 year) follow-up approximately 60-80% of participants met criteria for clinically significant antidepressant or anxiolytic responses. Participants overwhelmingly (71-100%) attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually significant experiences of their lives. CONCLUSION/UNASSIGNED:These findings suggest that psilocybin-assisted psychotherapy holds promise in promoting long-term relief from cancer-related psychiatric distress. Limited conclusions, however, can be drawn regarding the efficacy of this therapy due to the crossover design of the parent study. Nonetheless, the present study adds to the emerging literature base suggesting that psilocybin-facilitated therapy may enhance the psychological, emotional, and spiritual well-being of patients with life-threatening cancer.

Importance/UNASSIGNED:Opioid addiction is a major public health problem. Despite availability of evidence-based treatments, relapse and dropout are common outcomes. Efforts aimed at identifying reuse risk and gaining more precise understanding of the mechanisms conferring reuse vulnerability are needed. Objective/UNASSIGNED:To use tools from computational psychiatry and decision neuroscience to identify changes in decision-making processes preceding opioid reuse. Design, Setting, and Participants/UNASSIGNED:A cohort of individuals with opioid use disorder were studied longitudinally at a community-based treatment setting for up to 7 months (1-15 sessions per person). At each session, patients completed a risky decision-making task amenable to computational modeling and standard clinical assessments. Time-lagged mixed-effects logistic regression analyses were used to assess the likelihood of opioid use between sessions (t to t + 1; within the subsequent 1-4 weeks) from data acquired at the current session (t). A cohort of control participants completed similar procedures (1-5 sessions per person), serving both as a baseline comparison group and an independent sample in which to assess measurement test-retest reliability. Data were analyzed between January 1, 2018, and September 5, 2019. Main Outcomes and Measures/UNASSIGNED:Two individual model-based behavioral markers were derived from the task completed at each session, capturing a participant's current tolerance of known risks and ambiguity (partially unknown risks). Current anxiety, craving, withdrawal, and nonadherence were assessed via interview and clinic records. Opioid use was ascertained from random urine toxicology tests and self-reports. Results/UNASSIGNED:Seventy patients (mean [SE] age, 44.7 [1.3] years; 12 women and 58 men [82.9% male]) and 55 control participants (mean [SE] age, 42.4 [1.5] years; 13 women and 42 men [76.4% male]) were included. Of the 552 sessions completed with patients (mean [SE], 7.89 [0.59] sessions per person), 252 (45.7%) directly preceded opioid use events (mean [SE], 3.60 [0.44] sessions per person). From the task parameters, only ambiguity tolerance was significantly associated with increased odds of prospective opioid use (adjusted odds ratio, 1.37 [95% CI, 1.07-1.76]), indicating patients were more tolerant specifically of ambiguous risks prior to these use events. The association of ambiguity tolerance with prospective use was independent of established clinical factors (adjusted odds ratio, 1.29 [95% CI, 1.01-1.65]; P = .04), such that a model combining these factors explained more variance in reuse risk. No significant differences in ambiguity tolerance were observed between patients and control participants, who completed 197 sessions (mean [SE], 3.58 [0.21] sessions per person); however, patients were more tolerant of known risks (B = 0.56 [95% CI, 0.05-1.07]). Conclusions and Relevance/UNASSIGNED:Computational approaches can provide mechanistic insights about the cognitive factors underlying opioid reuse vulnerability and may hold promise for clinical use.