Faculty Bibliography

Aims: ED-based SBIRT for alcohol and drug use has the potential to impact public health greatly. Time and resource constraints limit implementation. Targeted intervention may be more efficient and practical. We hypothesized that we could use chief complaints to identify patients at highest risk of positive drug or alcohol use assessments. Methods: Using baseline data from NIDA CTN0047: SMARTED, free text chief complaints of 14,972 subjects from six sites were coded using a tested algorithm (Thompson, 2006). Multiple team members manually reviewed and further collapsed the chief complaint categorization to ensure agreement. We excluded subjects having missing data or complaints related to substance use and chief complaints stated by <15 subjects. Positive screens were defined as AUDIT-C > 4 for men and >3 for women (alcohol) and DAST > 2 (drugs). We ranked-ordered the chief complaints by their sensitivity and positive predictive value to (1) minimize the number of chief complaints and (2) assess the fewest number of ED patients. Our goal was to identify 75% of ED patients having positive assessments using these strategies. Results: The screening assessments were positive in 5805/14,561 (39.9%) for alcohol and 2454/14,494 (16.9%) for drugs. We collapsed the free-text chief complaints into 50 usable categories. To identify 75% of all ED patients having positive assessments using the first strategy would require including 19 chief complaints for alcohol screening and 20 chief complaints for drug screening. Adapting the second strategy, we would need to screen at least 71% and 68% of all ED patients for alcohol and drugs respectively to identify 75% of those having positive assessments. Conclusions: Based on this large, multicenter study, chief complaints provide little assistance in targeting SBIRT for alcohol or drug use in the ED

Individuals with alcohol use disorders (AUDs) have deficits in cognitive control, but how they change with treatment is unclear. Seven patients with AUD and anxiety from an open-label trial of disulfiram plus lorazepam performed a multisensory Stroop task during fMRI (both pre and post initiation of treatment), and were compared to nine healthy controls (HCs) (n = 16; Albuquerque, NM; years 2009-2012). Evoked BOLD signal and resting state functional connectivity were compared (HC vs. AUD; Scan 1 vs. Scan 2). AUD demonstrated hyperactivity and altered connectivity in the cognitive control network compared to HC, but treatment did not normalize function.

RATIONALE: It is well established that the rewarding effects of alcohol are modulated by the mesolimbic dopaminergic system. Olanzapine, a D2 dopamine antagonist, has been shown to reduce alcohol craving and consumption. OBJECTIVE: To clarify whether olanzapine has clinical utility in the treatment of alcohol dependence, a 12-week, double-blind, and randomized clinical trial was conducted. METHODS: One hundred twenty-nine treatment-seeking alcohol-dependent adults were randomly assigned to 12 weeks of olanzapine (5 vs. 2.5 mg) or placebo. Outcomes examined were average drinks per drinking day (DDD), proportion of drinking days (PDD) to total days in treatment, alcohol craving, and impaired control over alcohol use. Mixed models were used to examine medication effects during the course of treatment on specified outcomes. RESULTS: All of the analyses indicated a main effect for time, such that there were reductions in alcohol use and craving and an increase in control over alcohol use across treatment conditions. Dose-response analyses indicated that, in comparison to placebo, participants in the 5 mg group experienced reduced craving for alcohol and participants in the 2.5 mg group decreased in PDD and increased in their control over alcohol use. Better control over alcohol use remained significant 6 months post-treatment for the 2.5 mg group. Subjective experiences of the medication suggest that 2.5 and 5 mg were equally well tolerated. CONCLUSIONS: Results provide some support for the notion that dosage is an important consideration in relation to effectiveness; however, the cost-benefit balance does not support the clinical utility of olanzapine in treating alcohol dependence.

Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. TRIAL REGISTRATION: NCT02061293.

BACKGROUND:Functional imaging and lesion studies have associated willed behavior with the anterior cingulate cortex (ACC). Abulia is a syndrome characterized by apathy and deficiency of motivated behavior. Abulia is most frequently associated with ACC damage, but also occurs following damage to subcortical nuclei (striatum, globus pallidus, thalamic nuclei). We present resting state functional connectivity MRI (fcMRI) data from an individual who suffered a stroke leading to abulia. We hypothesized that, although structural imaging revealed no damage to the patient's ACC, fcMRI would uncover aberrant function in this region and in the relevant cortical networks. METHODS:Resting state correlations in the patient's gray matter were compared to those of age-matched controls. Using a novel method to identify abnormal patterns of functional connectivity in single subjects, we identified areas and networks with aberrant connectivity. RESULTS:Networks associated with memory (default mode network) and executive function (cingulo-opercular network) were abnormal. The patient's anterior cingulate was among the areas showing aberrant functional connectivity. In a rescan 3 years later, deficits remained stable and fcMRI findings were replicated. CONCLUSIONS:These findings suggest that the aberrant functional connectivity mapping approach described may be useful for linking stroke symptoms to disrupted network connectivity.

Subject motion degrades the quality of task functional magnetic resonance imaging (fMRI) data. Here, we test two classes of methods to counteract the effects of motion in task fMRI data: (1) a variety of motion regressions and (2) motion censoring ("motion scrubbing"). In motion regression, various regressors based on realignment estimates were included as nuisance regressors in general linear model (GLM) estimation. In motion censoring, volumes in which head motion exceeded a threshold were withheld from GLM estimation. The effects of each method were explored in several task fMRI data sets and compared using indicators of data quality and signal-to-noise ratio. Motion censoring decreased variance in parameter estimates within- and across-subjects, reduced residual error in GLM estimation, and increased the magnitude of statistical effects. Motion censoring performed better than all forms of motion regression and also performed well across a variety of parameter spaces, in GLMs with assumed or unassumed response shapes. We conclude that motion censoring improves the quality of task fMRI data and can be a valuable processing step in studies involving populations with even mild amounts of head movement.

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α-synuclein (aSyn) expression is implicated in neurodegenerative processes, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In animal models of these diseases, axon pathology often precedes cell death, raising the question of whether aSyn has compartment-specific toxic effects that could require early and/or independent therapeutic intervention. The relevance of axonal pathology to degeneration can only be addressed through longitudinal, in vivo monitoring of different neuronal compartments. With current imaging methods, dopaminergic neurons do not readily lend themselves to such a task in any vertebrate system. We therefore expressed human wild-type aSyn in zebrafish peripheral sensory neurons, which project elaborate superficial axons that can be continuously imaged in vivo. Axonal outgrowth was normal in these neurons but, by 2 days post-fertilization (dpf), many aSyn-expressing axons became dystrophic, with focal varicosities or diffuse beading. Approximately 20% of aSyn-expressing cells died by 3 dpf. Time-lapse imaging revealed that focal axonal swelling, but not overt fragmentation, usually preceded cell death. Co-expressing aSyn with a mitochondrial reporter revealed deficits in mitochondrial transport and morphology even when axons appeared overtly normal. The axon-protective protein Wallerian degeneration slow (WldS) delayed axon degeneration but not cell death caused by aSyn. By contrast, the transcriptional coactivator PGC-1α, which has roles in the regulation of mitochondrial biogenesis and reactive-oxygen-species detoxification, abrogated aSyn toxicity in both the axon and the cell body. The rapid onset of axonal pathology in this system, and the relatively moderate degree of cell death, provide a new model for the study of aSyn toxicity and protection. Moreover, the accessibility of peripheral sensory axons will allow effects of aSyn to be studied in different neuronal compartments and might have utility in screening for novel disease-modifying compounds.