Neural response to threat and reward among young adults at risk for alcohol use disorder.

Alcohol use disorder (AUD) is heritable. Thus, young adults with positive family histories represent an at-risk group relative to those without a family history, and if studied at a time when both groups have similar levels of alcohol use, it provides an opportunity to identify neural processing patterns associated with risk for AUD. Previous studies have shown that diminished response to potential reward is associated with genetic risk for AUD, but it is unclear how threat may modulate this response. We used a modified Monetary Incentive Delay task during fMRI to examine neural correlates of the interaction between threat and reward anticipation in a sample of young adults with (n = 31) and without (n = 44) family histories of harmful alcohol use. We found an interaction (p = 0.048) between cue and group in the right nucleus accumbens where the family history positive group showed less differentiation to the anticipation of gaining $5 and losing $5 relative to gaining $0. The family history-positive group also reported less excitement for trials to gain $5 relative to gaining $0 (p < 0.001). Family history-positive individuals showed less activation in the left insula during both safe and threat blocks compared to family history-negative individuals (p = 0.005), but the groups did not differ as a function of threat (p > 0.70). Young adults with, relative to without, enriched risk for AUD may have diminished reward processing via both neural and behavioural markers to potential rewarding and negative consequences. Neural response to threat may not be a contributing factor to risk at this stage.

Opioid receptor antagonism and neural response to monetary rewards: Pilot studies in light and heavy alcohol users.

Alcohol use disorder (AUD) is a prevalent condition associated with high degree of comorbidity and mortality. Among the few approved pharmacotherapies for AUD, two involve opioid receptor antagonism. Naltrexone and nalmefene are thought to act via opioid receptor blockage to reduce neural response to alcohol and drug-associated cues and consumption, but there have been limited efforts to characterize these effects in humans. In these studies, we sought to test the magnitude of opioid antagonism effects on neural response to monetary rewards in two groups: light drinkers (for the naltrexone study) and heavy drinkers (for the nalmefene study). We conducted double-blind, randomized, crossover pilot studies of reward activation in the brain following acute administration of opioid antagonist and placebo in 11 light and 9 heavy alcohol users. We used a monetary incentive delay task during functional MRI. We found a main effect of cue type on BOLD activation in the nucleus accumbens, demonstrating a neural reward response. The effect of opioid antagonism, relative to placebo, was small and nonsignificant for reward activation in the accumbens for both light and heavy alcohol users. Based on the results of two pilot studies, opioid antagonist medications do not appear to decrease neural activation to monetary rewards in the nucleus accumbens relative to placebo.

NEURAL RESPONSE TO THREAT AND REWARD AMONG YOUNG ADULTS AT RISK FOR ALCOHOL USE DISORDER.

Alcohol use disorder is 50% heritable; those with positive family histories represent an at-risk group within which we can test anticipation of threat and reward prior to development of harmful alcohol use. We examined neural correlates of the interaction between family history, threat anticipation (unpredictable threat), and monetary reward anticipation, in a sample of healthy young adults with (n=31) and without (n=44) family histories of harmful alcohol use. We used a modified Monetary Incentive Delay task with sustained threat of hearing a scream during fMRI. We examined the interaction between family history group, anticipation of threat, and anticipation of reward in the insula, nucleus accumbens, and medial prefrontal cortex. Family history positive individuals showed less activation in the left insula during both safe and threat blocks compared to family history negative individuals (p=0.005), but the groups did not differ as a function of unpredictable threat (p>0.70). We found an interaction (p=0.048) between cue and group in the right nucleus accumbens where the family history positive group showed less differentiation to the anticipation of gaining $5 and losing $5 relative to gaining $0. The family history positive group also reported less excitement for trials to gain $5 relative to gaining $0 (p<0.001). Prior to chronic heavy alcohol use, individuals with, relative to without, enriched risk may have diminished reward processing via both neural and behavioral markers to potential rewarding and negative consequences. Neural response to unpredictable threat may not be a contributing factor to risk at this stage.

Emotion regulation in young adults with family history of harmful alcohol use: A fMRI study.

BACKGROUND: Alcohol use disorder is associated with difficulties in emotion regulation and cognitive reappraisal. Family history of harmful alcohol use increases risk of substance use disorders, but no studies have examined whether family history is associated with altered neural activation during cognitive reappraisal relative to passive viewing of negative images in a sample of young adults without current substance use disorders. METHODS: Participants (N = 75 with positive [n = 31] or negative [n = 44] family histories of harmful alcohol use) completed the emotion regulation task during an MRI scan, and the Emotion Regulation Questionnaire to assess use of emotion regulation and suppression strategies. Whole-brain analyses and amygdala region of interest analyses using linear mixed-effects models assessed family history group and cue effects on neural activation during the task. RESULTS: The groups did not differ on trait reappraisal, suppression, or negative emotion following reappraisal. In general, group effects in whole-brain and amygdala activation during the cognitive reappraisal contrast indicated small effect sizes (2.2% of voxels had d>0.20) that were not significantly different. Participants with positive family histories engaged the right middle and superior frontal gyri to a greater extent than participants with negative family histories during the decrease-negative cue (t = 4.14, p = .001). CONCLUSIONS: For at-risk young adults without current harmful substance use, family history of harmful alcohol use does not appear to be associated with disrupted emotion regulation when instructed to apply cognitive reappraisal. Reappraisal may be a feasible therapeutic target for those who develop a substance use disorder with associated emotion dysregulation.

The Neural Circuitry of Reward During Sustained Threat.

Reward processing is important for understanding behavior in psychopathology. Opportunities to earn money activate the ventral striatum, as shown by the monetary incentive delay (MID) task. Anxiety conditions have been modeled by presenting shocks and startling sounds. To further investigate the co-occurrence of an anxiety condition and a rewarding stimulus, we modified the MID to include a sustained threat of scream. This study investigated neural patterns of the MID task with an uncertain threat of a startling scream. Forty-three young adults completed a functional MRI scan. The task included two conditions (scream and safe) and three cues (gain $5, gain $0, lose $5). Analyses included a whole brain, group analysis using a linear mixed-effects model and a paired t-test. The whole brain analysis revealed a main effect of cue, with increased ventral striatal activation (F2,210 = 58.8, p < 0.001) during cues to gain or lose $5. We observed a main effect of condition during cue presentation, such that bilateral insula and putamen activation was diminished (p < 0.001) in the scream versus the safe condition. A t-test of condition showed increased activation during threat blocks in the insula and putamen. A time course graph revealed that activation in the insula and putamen responded similarly to incentive but had an overall elevation during the scream condition. These results replicated expected activation in reward and in the setting of uncertain threat. Our results show that uncertain threat increases the magnitude of activation in the dorsal striatum.

Clinical Affective Neuroscience.

Affective neuroscience is a promising young field in neuroscience for understanding the basis of many types of psychopathology. It describes the scientific investigation of the neural basis of affect, emotion, and feelings. These phenomena arise from mental processes that are not always directly observable, which complicates discovering their neural basis. Nevertheless, as it has done for other inferred processes, such as memory and language, neuroscience should transform our emotion-based patient formulations and lead to novel, targeted therapeutics for emotional issues. In this Translations article, we aim to provide a brief introduction to affective neuroscience for clinicians, beginning with defining key terms and then reviewing clinical applications.

Assessing Career Outcomes of a Resident Academic Administrator, Clinician Educator Track: A Seven-Year Follow-up.

OBJECTIVE: This study reports the academic outcomes, including scholarly productivity, of the graduates of one residency training track for future clinician educators and academic administrators. Since its implementation in 2008, the Academic Administrator, Clinician Educator (AACE) track at Western Psychiatric Institute and Clinic - UPMC has grown in popularity with reports of participants achieving post-graduate academic success; however, there has been no prior assessment of outcomes. METHODS: In 2015 all graduates of the track were surveyed using an anonymous, web-based survey. Twenty-nine total graduates were surveyed RESULTS: Twenty-four graduates responded to the survey (83% response rate). The graduates are very active in academic psychiatry with 23 (96%) holding an academic appointment with different administrative roles, medical director (50%) and training director (17%) being the most frequent. Participants have also been active in pursuing scholarship with 80% presenting their scholarly projects at local and national conferences and producing post-graduate, peer-reviewed articles (50%). CONCLUSION: This study underscores the benefits of a clinician educator track and suggests areas for future growth.

Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function.

Mammalian target of rapamycin (mTOR) is a key regulator for cell growth through modulating components of the translation machinery. Previously, numerous pharmacological studies using rapamycin suggested that mTOR has an important role in regulating cardiac hypertrophic growth. To further investigate this assumption, we have generated two lines of cardiac specific mTOR transgenic mice, kinase-dead (kd) mTOR and constitutively active (ca) mTOR, using alpha-myosin heavy chain promoter. alpha-Myosin heavy chain (alphaMHC)-mTORkd mice had a near complete inhibition of p70 S6k and 4E-BP1 phosphorylation, whereas alphaMHC-mTORca had a significant increase in p70 S6k and 4E-BP1 phosphorylation. Although the cardiac function of alphaMHC-mTORkd mice was significantly altered, the cardiac morphology of these transgenic mice was normal. The cardiac hypertrophic growth in response to physiological and pathological stimuli was not different in alphaMHC-mTORkd and alphaMHC-mTORca transgenic mice when compared with that of nontransgenic littermates. These findings suggest that the mTOR-mediated signaling pathway is not essential to cardiac hypertrophic growth but is involved in regulating cardiac function. Additional analysis of cardiac responses to fasting-refeeding or acute insulin administration indicated that alphaMHC-mTORkd mice had a largely impaired physiological response to nutrient energy supply and insulin stimulation.