Jesse T. Kaye

Nicotine Withdrawal Increases Threat-Induced Anxiety but Not Fear: Neuroadaptation in Human Addiction

BACKGROUND Stress response neuroadaptation has been repeatedly implicated in animal addiction models for many drugs, including nicotine. Programmatic laboratory research that examines the stress response of nicotine-deprived humans is necessary to confirm that stress neuroadaptations observed in animal models generalize to humans. METHODS Two experiments tested the prediction that nicotine deprivation selectively increases startle response associated with anxiety during unpredictable threat but not fear during imminent, predictable threat. Dependent smokers (n = 117) were randomly assigned to 24-hour nicotine-deprived or nondeprived groups and participated in one of two experiments wherein electric shock was administered either unpredictably (noncontingent shock; Experiment 1) or predictably (cue-contingent shock; Experiment 2). RESULTS Nicotine deprivation increased overall startle response in Experiment 1, which involved unpredictable administration of shock. Age of first cigarette and years of daily smoking were significant moderators of this deprivation effect. Self-reported withdrawal symptoms also predicted startle response during unpredictable shock. In contrast, nicotine deprivation did not alter overall or fear-potentiated startle in Experiment 2, which involved predictable administration of shock. CONCLUSIONS These results provide evidence that startle response during unpredictable threat may be a biomarker of stress neuroadaptations among smokers in nicotine withdrawal. Contrast of results across unpredictable versus predictable shock experiments provides preliminary evidence that these stress neuroadaptations manifest selectively as anxiety during unpredictable threat rather than in every stressful context. Individual differences in unpredictable threat startle response associated with withdrawal symptoms, age of first cigarette, and years daily smoking link this laboratory biomarker to clinically relevant indexes of addiction risk and relapse.

Acupressure as a Non-Pharmacological Intervention for Traumatic Brain Injury (TBI)

Acupressure is a complementary and alternative medicine (CAM) treatment using fingertips to stimulate acupoints on the skin. Although suggested to improve cognitive function, acupressure has not been previously investigated with a controlled design in traumatic brain injury (TBI) survivors, who could particularly benefit from a non-pharmacological intervention for cognitive impairment. A randomized, placebo-controlled, single-blind design assessed the effects of acupressure (eight treatments over 4 weeks) on cognitive impairment and state of being following TBI, including assessment of event-related potentials (ERPs) during Stroop and auditory oddball tasks. It was hypothesized that active acupressure treatments would confer greater cognitive improvement than placebo treatments, perhaps because of enhanced relaxation response induction and resulting stress reduction. Significant treatment effects were found comparing pre- to post-treatment change between groups. During the Stroop task, the active-treatment group showed greater reduction in both P300 latency (p = 0.010, partial η² = 0.26) and amplitude (p = 0.011, partial η² = 0.26), as well as a reduced Stroop effect on accuracy (p = 0.008, partial η² = 0.21) than did the placebo group. Additionally, the active-treatment group improved more than did the placebo group on the digit span test (p = 0.043, Cohens d = 0.68). Together, these results suggest an enhancement in working memory function associated with active treatments. Because acupressure emphasizes self-care and can be taught to novice individuals, it warrants further study as an adjunct treatment for TBI.

Psychometric properties of startle and corrugator response in NPU, affective picture viewing, and resting state tasks.

The current study provides a comprehensive evaluation of critical psychometric properties of commonly used psychophysiology laboratory tasks/measures within the NIMH RDoC. Participants (N = 128) completed the no-shock, predictable shock, unpredictable shock (NPU) task, affective picture viewing task, and resting state task at two study visits separated by 1 week. We examined potentiation/modulation scores in NPU (predictable or unpredictable shock vs. no-shock) and affective picture viewing tasks (pleasant or unpleasant vs. neutral pictures) for startle and corrugator responses with two commonly used quantification methods. We quantified startle potentiation/modulation scores with raw and standardized responses. We quantified corrugator potentiation/modulation in the time and frequency domains. We quantified general startle reactivity in the resting state task as the mean raw startle response during the task. For these three tasks, two measures, and two quantification methods, we evaluated effect size robustness and stability, internal consistency (i.e., split-half reliability), and 1-week temporal stability. The psychometric properties of startle potentiation in the NPU task were good, but concerns were noted for corrugator potentiation in this task. Some concerns also were noted for the psychometric properties of both startle and corrugator modulation in the affective picture viewing task, in particular, for pleasant picture modulation. Psychometric properties of general startle reactivity in the resting state task were good. Some salient differences in the psychometric properties of the NPU and affective picture viewing tasks were observed within and across quantification methods.

Cannabis Cue Reactivity and Craving Among Never, Infrequent and Heavy Cannabis Users

Substance cue reactivity is theorized as having a significant role in addiction processes, promoting compulsive patterns of drug-seeking and drug-taking behavior. However, research extending this phenomenon to cannabis has been limited. To that end, the goal of the current work was to examine the relationship between cannabis cue reactivity and craving in a sample of 353 participants varying in self-reported cannabis use. Participants completed a visual oddball task whereby neutral, exercise, and cannabis cue images were presented, and a neutral auditory oddball task while event-related brain potentials (ERPs) were recorded. Consistent with past research, greater cannabis use was associated with greater reactivity to cannabis images, as reflected in the P300 component of the ERP, but not to neutral auditory oddball cues. The latter indicates the specificity of cue reactivity differences as a function of substance-related cues and not generalized cue reactivity. Additionally, cannabis cue reactivity was significantly related to self-reported cannabis craving as well as problems associated with cannabis use. Implications for cannabis use and addiction more generally are discussed.

Not just noise: Individual differences in general startle reactivity predict startle response to uncertain and certain threat

General startle reactivity reflects defensive reactivity independent of affective foreground. We examined the relationship between general startle reactivity and startle response to threat in three tasks with distinct manipulations of threat uncertainty. General startle reactivity was a stronger predictor of startle response during threat (vs. no threat) and uncertain (vs. certain threat). These results confirm that including general startle reactivity in our analyses can increase the power and/or precision to test effects of other focal experimental manipulations or grouping variables. Moreover, this suggests that individual differences in defensive reactivity moderate responding to threats of various types in our environment. As such, individual differences in general startle reactivity may index important psychological attributes related to trait affectivity, premorbid vulnerability for psychopathology, and manifest psychopathology.

Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans.

Stress plays a key role in addiction etiology and relapse. Rodent models posit that following repeated periods of alcohol and other drug intoxication, compensatory allostatic changes occur in the central nervous system (CNS) circuits involved in behavioral and emotional response to stressors. We examine a predicted manifestation of this neuroadaptation in recently abstinent alcohol-dependent humans. Participants completed a translational laboratory task that uses startle potentiation to unpredictable (vs. predictable) stressors implicated in the putative CNS mechanisms that mediate this neuroadaptation. Alcohol-dependent participants displayed significantly greater startle potentiation to unpredictable than predictable stressors relative to nonalcoholic controls. The size of this effect covaried with alcohol-related problems and degree of withdrawal syndrome. This supports the rodent model thesis of a sensitized stress response in abstinent alcoholics. However, this effect could also represent premorbid risk or mark more severe and/or comorbid psychopathology. Regardless, pharmacotherapy and psychological interventions may target unpredictable stressor response to reduce stress-induced relapse.

The need for precise answers for the goals of precision medicine in alcohol dependence to succeed

Dear Editor, We read the study by Mann et al. [1] with great interest. Clinical trials of pharmacotherapies for alcohol use disorder have yielded inconsistent or suboptimal outcomes, but it may be that drinker characteristics moderate pharmacotherapy efficacy. To begin to answer the important clinical question of “which medication will work best for which patient,” Mann et al. [1] grouped drinkers by whether they drank for alcohol’s positive and/or negative reinforcing qualities. This yielded: ‘reward drinkers’ (high-reward and low-relief), ‘relief drinkers’ (low-reward and high-relief), ‘all high drinkers’ (high-reward and high-relief) and ‘all low drinkers’ (low-reward and low-relief). The authors sought “to test differential efficacy of naltrexone and acamprosate based on individual differences in neurotransmitter dysfunction” putatively expected across these subgroups. They predicted “individuals with primarily reward drinking tendencies [reward drinkers w/opioidergic dysfunction] would respond better to naltrexone ... whereas individuals with primarily relief drinking tendencies [relief drinkers w/glutamatergic dysfunction] would respond better to acamprosate” [1]. The study takes a novel precision medicine approach within a rigorously designed clinical trial and a mechanistic focus. It offers immediate potential to address longstanding shortcomings in treatment efficacy and efficiency. We were surprised, however, to find that the reported analyses never directly tested the differential efficacy of naltrexone versus acamprosate in any subgroups as proposed. Instead, the authors compared the effects of each drug (vs. placebo) for each of the reward and relief drinkers relative to the effects of the same drug (vs. placebo) for all low drinkers. The key finding was a 2 (naltrexone vs. placebo) × 2 (reward drinkers vs. all low drinkers) interaction, which indicated the differential efficacy of naltrexone vs. placebo was improved in reward drinkers relative to all low drinkers (means displayed in Fig. 1a). This finding in a welldesigned study such as this one is perhaps itself worth publication. Its clinical implications for precision medicine, however, are limited as it only implies clinicians should choose naltrexone over placebo to treat reward drinkers. It does not speak to whether clinicians should choose naltrexone over acamprosate to treat reward drinkers. The results of their analyses thereby fail to address the proposed research question: “which medication will work best for which patients (i.e. precision medicine)” [1]. To rigorously test the differential efficacy of naltrexone vs. acamprosate for reward drinkers, the authors could have tested the 2 (naltrexone vs. acamprosate) × 2 (reward drinkers vs. all low drinkers) interaction (Fig. 1b). Unfortunately, the observed pattern of means provides no evidence that clinicians should choose naltrexone over acamprosate when they treat reward drinkers specifically. It also does not demonstrate any match between selective drug mechanisms and putative subgroup dysfunction that serves as the foundation for this precision medicine study. Although this correspondence focuses only on one recent paper, these analytic concerns and related issues remain rampant in clinical research [2, 3]. As the rigor of research increases through open science practices, such as preregistration of analyses,