Bio

Bio

Dr. Bentzley received his bachelors in physics from The College of New Jersey. Upon graduating he spent a year conducting plasma physics research in a joint project between Princeton University and NASA. Brandon then turned his interests to neuroscience and began his training in the Medical Scientist Training Program (MD/PhD) at the Medical University of South Carolina (MUSC). At MUSC Brandon completed his dissertation research with Gary Aston-Jones, PhD, studying the behavioral economics and neuroeconomics of substance use disorders. Simultaneously, he conducted clinical research on buprenorphine maintenance therapy, focusing on how patient perspectives influence treatment. Dr. Bentzley is now a psychiatrist and Clinical Assistant Professor in the Department of Psychiatry & Behavioral Sciences at Stanford University School of Medicine. His current research interests focus on the role of dopamine in economic decisions and developing neurostimulation-based treatments for severe depression and suicidality.

Clinical Focus

  • Substance use disorders
  • Psychiatry
  • Treatment resistant depression
  • Suicidality

Academic Appointments

  • Clinical Assistant Professor, Psychiatry and Behavioral Sciences

Professional Education

  • Residency: Stanford University Adult Psychiatry Residency (2020) CA
  • Medical Education: Medical University of South Carolina Registrar (2016) SC

Contact

  • Stanford Dept of Psychiatry and Behavioral Sciences 401 Quarry Rd MC 5718 Stanford, CA 94305
    • Tel: (650) 721-4420
    Fax: (650) 320-9443

Teaching

2020-21 Courses

Publications

All Publications

  • Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. The American journal of psychiatry Cole, E. J., Stimpson, K. H., Bentzley, B. S., Gulser, M. n., Cherian, K. n., Tischler, C. n., Nejad, R. n., Pankow, H. n., Choi, E. n., Aaron, H. n., Espil, F. M., Pannu, J. n., Xiao, X. n., Duvio, D. n., Solvason, H. B., Hawkins, J. n., Guerra, A. n., Jo, B. n., Raj, K. S., Phillips, A. L., Barmak, F. n., Bishop, J. H., Coetzee, J. P., DeBattista, C. n., Keller, J. n., Schatzberg, A. F., Sudheimer, K. D., Williams, N. R. 2020: appiajp201919070720

    Abstract

    New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression.Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects.SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

    View details for DOI 10.1176/appi.ajp.2019.19070720

    View details for PubMedID 32252538

  • Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential. Addiction biology Bentzley, B. S., Aston-Jones, G. 2016

    Abstract

    Preclinical evidence indicates that inactivation of subthalamic nucleus (STN) may be effective for treating cocaine addiction, and therapies that target STN, e.g. deep brain stimulation, are available indicating that this may have clinical promise. Here, we assessed the therapeutic potential of STN inactivation using a translationally relevant economic approach that quantitatively describes drug-taking behavior, and tested these results with drug-seeking tasks. Economic demand for cocaine was assessed in rats (n?=?11) using a within-session threshold procedure in which cocaine price (responses/mg cocaine) was sequentially increased throughout the session. Cocaine demand was assessed in this manner immediately after bilateral microinfusions into STN of either vehicle (artificial cerebrospinal fluid) or the GABAA receptor agonist muscimol. A separate group of animals (n?=?8) was tested for changes in cocaine seeking either during extinction or in response to cocaine-associated cues. Muscimol-induced inhibition of STN significantly attenuated cocaine consumption at high prices, drug seeking during extinction and cued reinstatement of cocaine seeking. In contrast, STN inhibition did not reduce cocaine consumption at low prices or locomotor activity. Thus, STN inactivation reduced economic demand for cocaine and multiple measures of drug seeking during extinction. In view of the association between economic demand and addiction severity in both rat and human, these results indicate that STN inactivation has substantial clinical potential for treatment of cocaine addiction.

    View details for DOI 10.1111/adb.12380

    View details for PubMedID 26935125

  • Patient Perspectives Associated with Intended Duration of Buprenorphine Maintenance Therapy JOURNAL OF SUBSTANCE ABUSE TREATMENT Bentzley, B. S., Barth, K. S., Back, S. E., Aronson, G., Book, S. W. 2015; 56: 48-53

    Abstract

    Patients with opioid use disorders frequently discontinue opioid maintenance therapy (OMT) prematurely, reducing retention and possibly limiting the efficacy of OMT. The current study is a cross-sectional survey of patients (N=69) enrolled in buprenorphine maintenance therapy (BMT). We examined patient demographics, BMT characteristics (e.g., dose, time in BMT), and patient perspectives regarding intended duration of BMT. In addition, patients' reasons for continuing or discontinuing BMT were investigated. Results revealed that the majority (82%) of participants reported wanting to continue BMT for at least 12months. Age at first drug use, time in BMT, concern about pain, and concern about relapse were all positively associated with intended duration of BMT. The following were negatively associated with intended duration of BMT: recent discussion with a treatment provider about BMT discontinuation, prior attempt to discontinue BMT, concern about withdrawal symptoms, experiencing pleasurable effects from taking buprenorphine, and perceived conflicts of BMT with life, work, or school obligations. The most common reasons for wanting to continue BMT included concerns about withdrawal symptoms, relapse, and pain. Although preliminary, the findings highlight key issues with regard to patients' perspectives of BMT. The results of this study provide information that may be useful in improving OMT programs and treatment outcomes.

    View details for DOI 10.1016/j.jsat.2015.04.002

    View details for Web of Science ID 000359179000007

    View details for PubMedID 25899872

  • Discontinuation of Buprenorphine Maintenance Therapy: Perspectives and Outcomes JOURNAL OF SUBSTANCE ABUSE TREATMENT Bentzley, B. S., Barth, K. S., Back, S. E., Book, S. W. 2015; 52: 48-57

    Abstract

    Buprenorphine maintenance therapy (BMT) is increasingly the preferred opioid maintenance agent due to its reduced toxicity and availability in an office-based setting in the United States. Although BMT has been shown to be highly efficacious, it is often discontinued soon after initiation. No current systematic review has yet investigated providers' or patients' reasons for BMT discontinuation or the outcomes that follow. Hence, provider and patient perspectives associated with BMT discontinuation after a period of stable buprenorphine maintenance and the resultant outcomes were systematically reviewed with specific emphasis on pre-buprenorphine-taper parameters predictive of relapse following BMT discontinuation. Few identified studies address provider or patient perspectives associated with buprenorphine discontinuation. Within the studies reviewed providers with residency training in BMT were more likely to favor long term BMT instead of detoxification, and providers were likely to consider BMT discontinuation in the face of medication misuse. Patients often desired to remain on BMT because of fear of relapse to illicit opioid use if they were to discontinue BMT. The majority of patients who discontinued BMT did so involuntarily, often due to failure to follow strict program requirements, and 1 month following discontinuation, rates of relapse to illicit opioid use exceeded 50% in every study reviewed. Only lower buprenorphine maintenance dose, which may be a marker for attenuated addiction severity, predicted better outcomes across studies. Relaxed BMT program requirements and frequent counsel on the high probability of relapse if BMT is discontinued may improve retention in treatment and prevent the relapse to illicit opioid use that is likely to follow BMT discontinuation.

    View details for DOI 10.1016/j.jsat.2014.12.011

    View details for Web of Science ID 000352674800007

    View details for PubMedID 25601365

  • Orexin-1 receptor signaling increases motivation for cocaine-associated cues EUROPEAN JOURNAL OF NEUROSCIENCE Bentzley, B. S., Aston-Jones, G. 2015; 41 (9): 1149-1156

    Abstract

    The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at orexin-1 receptors (OX1Rs), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light + tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then investigated whether cocaine demand was linked to the cued reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high-demand animals, i.e. animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not that of cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.

    View details for DOI 10.1111/ejn.12866

    View details for Web of Science ID 000354186400005

    View details for PubMedID 25754681

  • Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bentzley, B. S., Jhou, T. C., Aston-Jones, G. 2014; 111 (32): 11822-11827

    Abstract

    Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaine-seeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments.

    View details for DOI 10.1073/pnas.1406324111

    View details for Web of Science ID 000340097900059

    View details for PubMedID 25071176

  • The behavioral economics of drug self-administration: A review and new analytical approach for within-session procedures PSYCHOPHARMACOLOGY Bentzley, B. S., Fender, K. M., Aston-Jones, G. 2013; 226 (1): 113-125

    Abstract

    Behavioral-economic demand curve analysis offers several useful measures of drug self-administration. Although generation of demand curves previously required multiple days, recent within-session procedures allow curve construction from a single 110-min cocaine self-administration session, making behavioral-economic analyses available to a broad range of self-administration experiments. However, a mathematical approach of curve fitting has not been reported for the within-session threshold procedure.We review demand curve analysis in drug self-administration experiments and provide a quantitative method for fitting curves to single-session data that incorporates relative stability of brain drug concentration.Sprague-Dawley rats were trained to self-administer cocaine, and then tested with the threshold procedure in which the cocaine dose was sequentially decreased on a fixed ratio-1 schedule. Price points (responses/mg cocaine) outside of relatively stable brain cocaine concentrations were removed before curves were fit. Curve-fit accuracy was determined by the degree of correlation between graphical and calculated parameters for cocaine consumption at low price (Q(0)) and the price at which maximal responding occurred (P(max)).Removing price points that occurred at relatively unstable brain cocaine concentrations generated precise estimates of Q(0) and resulted in P (max) values with significantly closer agreement with graphical P(max) than conventional methods.The exponential demand equation can be fit to single-session data using the threshold procedure for cocaine self-administration. Removing data points that occur during relatively unstable brain cocaine concentrations resulted in more accurate estimates of demand curve slope than graphical methods, permitting a more comprehensive analysis of drug self-administration via a behavioral-economic framework.

    View details for DOI 10.1007/s00213-012-2899-2

    View details for Web of Science ID 000314848000012

    View details for PubMedID 23086021

  • Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System. The international journal of neuropsychopharmacology Freeman, L. R., Bentzley, B. S., James, M. H., Aston-Jones, G. 2020

    Abstract

    BACKGROUND: The prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared to male rats.METHODS: Here, we describe a novel within-session behavioral-economic paradigm that allows for the simultaneous measurement of the intake at null cost (Q0) and normalized demand elasticity (alpha) of 3 types of palatable food (low fat, high fat and chocolate sucrose pellets) via demand curve analysis. In light of evidence that the orexin (hypocretin) system is critically involved in reward and feeding behaviors, we next examined the role of orexin function in sex differences of economic demand for palatable foods.RESULTS: The novel within-session behavioral-economic approach revealed that female rats have higher intake (demand) than males for all palatable foods at low cost (normalized to body weight) but no difference in intake at higher prices, indicating sex-dependent differences in the hedonic, but not motivational, aspects of palatable food. Immediately following behavioral-economic testing, in female rats we observed more orexin-expressing neurons and cFos expression (measure of recent neural activation) in these neurons compared to male rats. Moreover, the orexin-1 receptor antagonist SB334867 reduced both low and high-cost intake for palatable food in both male and female rats.CONCLUSIONS: These findings provide evidence of higher demand at low prices for palatable food in females and indicate that these behavioral differences may be associated with sexual dimorphism in orexin system function.

    View details for DOI 10.1093/ijnp/pyaa040

    View details for PubMedID 32496559

  • Transcranial Magnetic Stimulation Parameter Space: Wide Open for Exploration. Biological psychiatry Bentzley, B. S., Williams, N. R. 2020; 87 (5): 384?85

    View details for DOI 10.1016/j.biopsych.2019.11.012

    View details for PubMedID 32029073

  • The Role of Dopamine in Reward-Related Behavior: Shining New Light on an Old Debate. Journal of neurophysiology Wang, A. R., Groome, A. M., Taniguchi, L. n., Eshel, N. n., Bentzley, B. S. 2020

    Abstract

    The role dopamine plays in reward-related behaviors has been debated for decades. Heymann et al. (Heymann G, Jo YS, Reichard KL, McFarland N, Chavkin C, Palmiter RD, Soden ME, Zweifel LS. Neuron 105(5): 909-920, 2020) identify subpopulations of dopamine-producing neurons that separately mediate reward association and motivation. Their results help demonstrate that dopamine signaling may partake in both reinforcement learning and incentive salience functions, instantiated by neuropeptide-defined subpopulations of the VTA with different projection targets.

    View details for DOI 10.1152/jn.00323.2020

    View details for PubMedID 32639896

  • On the early life origins of vulnerability to opioid addiction. Molecular psychiatry Levis, S. C., Bentzley, B. S., Molet, J., Bolton, J. L., Perrone, C. R., Baram, T. Z., Mahler, S. V. 2019

    Abstract

    The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function, and cause opioid addiction vulnerability, is unknown. We simulated ELA in female rats and this led to a striking opioid addiction-like phenotype. This was characterized by resistance to extinction, increased relapse-like behavior, and, as in addicted humans, major increases in opioid economic demand. By contrast, seeking of a less salient natural reward was unaffected by ELA, whereas demand for highly palatable treats was augmented. These discoveries provide novel insights into the origins and nature of reward circuit malfunction that may set the stage for addiction.

    View details for DOI 10.1038/s41380-019-0628-5

    View details for PubMedID 31822817

  • Supporting the Use of Medications for Addiction Treatment in US Drug Courts: Opportunities for Health Professionals. Journal of addiction medicine Morris, N. P., Bentzley, B. S. 2019

    Abstract

    : Drug courts are specialty courts that offer treatment services as alternatives to incarceration for defendants struggling with problems related to substance use. These courts have become major access points in the United States for the treatment of substance use disorders, but drug court participants often have limited access to medications for addiction treatment (MAT). A growing chorus of advocates and organizations have called for expanding access to MAT in drug courts, and health professionals may wonder how to join in these efforts. This article reviews practical ways in which individual health professionals might support access to MAT in drug courts, including working with drug courts, fighting public stigma against MAT, contributing to research on MAT in drug courts, and expanding addiction training among clinicians.

    View details for DOI 10.1097/ADM.0000000000000583

    View details for PubMedID 31688147

  • Insomnia severity during early abstinence is related to substance use treatment completion in adults enrolled in an intensive outpatient program JOURNAL OF SUBSTANCE ABUSE TREATMENT Wilkerson, A. K., Sahlem, G. L., Bentzley, B. S., Lord, J., Smith, J. P., Simmons, R. O., Uhde, T. W., Book, S. W. 2019; 104: 97?103

    Abstract

    Insomnia and other types of sleep disturbance are highly prevalent during withdrawal across many different types of substance use disorders (SUDs). It is largely unknown how sleep impacts SUD treatment outcomes, including treatment completion.A retrospective chart review was conducted to obtain information about sleep disturbance and treatment completion in individuals beginning an intensive outpatient (IOP) SUD treatment program. Demographic data were collected along with number of sessions completed, treatment completion, comorbid psychiatric diagnosis, pertinent lab results, and scores on three self-reported measures of sleep: the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS).Pertinent information was available for 110 individuals. The majority had clinically significant scores on the ISI and PSQI but not the ESS. ISI, but not PSQI or ESS, was associated with treatment completion, such that those with more insomnia were less likely to complete treatment.The high prevalence of insomnia symptoms and poor sleep quality coupled with the relationship between insomnia severity and treatment completion may indicate that more severe symptoms of insomnia are a risk factor for treatment completion and subsequent relapse across many substance types. Applying evidence-based insomnia interventions in SUD treatment programs may have meaningful implications for outcomes.

    View details for DOI 10.1016/j.jsat.2019.06.003

    View details for Web of Science ID 000480372000012

    View details for PubMedID 31370990

  • The impact of cocaine and heroin drug history on motivation and cue sensitivity in a rat model of polydrug abuse. Psychopharmacology Crummy, E. A., Donckels, E. A., Baskin, B. M., Bentzley, B. S., Ferguson, S. M. 2019

    Abstract

    RATIONALE: Comorbid use of heroin and cocaine is highly prevalent among drug users and can greatly increase addiction risk. Nonetheless, little is known regarding how a multi-drug history impacts motivation and cue responsivity to individual drugs.OBJECTIVE: We used behavioral-economic procedures to examine motivation to maintain drug consumption and tests of drug-seeking to drug-associated cues to assess sensitivity to heroin and cocaine-associated cues in rats that had a self-administration history of heroin, cocaine, or both drugs.RESULTS: Unexpectedly, we found that groups with a polydrug history of heroin and cocaine did not have higher levels of motivation or cue-induced reinstatement of drug-seeking for either cocaine or heroin compared to single drug groups. Nonetheless, we did find drug-specific differences in both economic price and cue sensitivity. Specifically, demand elasticity was lower for cocaine compared to heroin in animals with a single drug history, but not with polydrug groups. In addition, cocaine demand was predictive of the degree of cue-induced reinstatement of drug-seeking for cocaine following extinction, whereas heroin demand was predictive of the degree of reactivity to a heroin-associated cue. Furthermore, although cue reactivity following the initial self-administration phase did not differ across cues and drug history, reactivity to both heroin and cocaine cues was greater during subsequent heroin use compared to cocaine use, and this enhanced reactivity to heroin cues persisted during forced abstinence.CONCLUSIONS: These results indicate that there is a greater motivation to maintain cocaine consumption, but higher sensitivity to drug-associated cues with a history of heroin use, suggesting that cocaine and heroin may drive continued drug use through different behavioral processes.

    View details for DOI 10.1007/s00213-019-05349-2

    View details for PubMedID 31463541

  • Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine's Antidepressant Effect JAMA PSYCHIATRY Heifets, B. D., Williams, N. R., Bentzley, B. S., Schatzberg, A. F. 2019; 76 (6): 657?58

    View details for DOI 10.1001/jamapsychiatry.2019.0766

    View details for Web of Science ID 000474836500016

  • Attenuation of Anti-Suicidal Effects of Ketamine by Opioid Receptor Antagonism Williams, N., Heifets, B., Bentzley, B., Blasey, C., Sudheimer, K., Lyons, D., Schatzberg, A. ELSEVIER SCIENCE INC. 2019: S113

    View details for DOI 10.1016/j.biopsych.2019.03.284

    View details for Web of Science ID 000472661000271

  • Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine's Antidepressant Effect. JAMA psychiatry Heifets, B. D., Williams, N. R., Bentzley, B. S., Schatzberg, A. F. 2019

    View details for PubMedID 31042274

  • Requiring Buprenorphine Waivers for Psychiatry Residents ACADEMIC PSYCHIATRY Morris, N. P., Bentzley, B. S. 2019; 43 (1): 131?34

    View details for DOI 10.1007/s40596-018-1005-4

    View details for Web of Science ID 000459533100025

  • The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand. Addiction biology Pantazis, C. B., James, M. H., Bentzley, B. S., Aston-Jones, G. n. 2019: e12795

    Abstract

    Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as after a 2-week period of abstinence, to relate the number of LH orexin cells to economic demand for cocaine. We also knocked down LH orexin expression with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. We found that animals with greater baseline motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a 2-week abstinence from cocaine, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence, indicating that orexin expression is a persistent marker for demand. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual motivation for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.

    View details for DOI 10.1111/adb.12795

    View details for PubMedID 31297913

  • Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Molecular psychiatry Williams, N. R., Heifets, B. D., Bentzley, B. S., Blasey, C. n., Sudheimer, K. D., Hawkins, J. n., Lyons, D. M., Schatzberg, A. F. 2019

    Abstract

    We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine's antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery-Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p?

    View details for DOI 10.1038/s41380-019-0503-4

    View details for PubMedID 31467392

  • Requiring Buprenorphine Waivers for Psychiatry Residents. Academic psychiatry : the journal of the American Association of Directors of Psychiatric Residency Training and the Association for Academic Psychiatry Morris, N. P., Bentzley, B. S. 2018

    View details for PubMedID 30414072

  • High-Dose Spaced Theta-Burst Transcranial Magnetic Stimulation as a Rapid-Acting Anti- Depressant in Highly Refractory Depression Williams, N., Sudheimer, K., Bentzley, B., Pannu, J., Stimpson, K., Duvio, D., Cherian, K., Hawkins, J., Scherrer, K., Vyssoki, B., DeSouza, D., Raj, K., Keller, J., Schatzberg, A. ELSEVIER SCIENCE INC. 2018: S191

    View details for Web of Science ID 000432466300476

  • High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain : a journal of neurology Williams, N. R., Sudheimer, K. D., Bentzley, B. S., Pannu, J. n., Stimpson, K. H., Duvio, D. n., Cherian, K. n., Hawkins, J. n., Scherrer, K. H., Vyssoki, B. n., DeSouza, D. n., Raj, K. S., Keller, J. n., Schatzberg, A. F. 2018

    View details for PubMedID 29415152

  • Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease ACTA NEUROLOGICA SCANDINAVICA Williams, N. R., Bentzley, B. S., Sahlem, G. L., Pannu, J., Korte, J. E., Revuelta, G., Short, E. B., George, M. S. 2017; 135 (4): 407-411

    View details for DOI 10.1111/ane.12614

    View details for Web of Science ID 000398035900004

  • It takes time to tune ANNALS OF TRANSLATIONAL MEDICINE Bentzley, B. S., Pannu, J., Badran, B. W., Halpern, C. H., Williams, N. R. 2017; 5 (7): 171

    View details for PubMedID 28480207

    View details for PubMedCentralID PMC5401673

  • It Takes Time to Tune Annals of Translational Medicine Bentzley, B. S., Pannu, J., Badran, B. W., Halpern, C. H., Williams, N. R. 2017; In Press
  • A Novel Communication Value Task Demonstrates Evidence of Response Bias in Cases with Presbyacusis. Scientific reports Eckert, M. A., Vaden, K. I., Teubner-Rhodes, S. n., Bentzley, B. S. 2017; 7 (1): 16512

    Abstract

    Decision-making about the expected value of an experience or behavior can explain hearing health behaviors in older adults with hearing loss. Forty-four middle-aged to older adults (68.45?±?7.73 years) performed a task in which they were asked to decide whether information from a surgeon or an administrative assistant would be important to their health in hypothetical communication scenarios across visual signal-to-noise ratios (SNR). Participants also could choose to view the briefly presented sentences multiple times. The number of these effortful attempts to read the stimuli served as a measure of demand for information to make a health importance decision. Participants with poorer high frequency hearing more frequently decided that information was important to their health compared to participants with better high frequency hearing. This appeared to reflect a response bias because participants with high frequency hearing loss demonstrated shorter response latencies when they rated the sentences as important to their health. However, elevated high frequency hearing thresholds did not predict demand for information to make a health importance decision. The results highlight the utility of a performance-based measure to characterize effort and expected value from performing tasks in older adults with hearing loss.

    View details for PubMedID 29184188

    View details for PubMedCentralID PMC5705661

  • Optimization of epidural cortical stimulation for treatment-resistant depression. Brain stimulation Williams, N. R., Bentzley, B. S., Hopkins, T. n., Pannu, J. n., Sahlem, G. L., Takacs, I. n., George, M. S., Nahas, Z. n., Short, E. B. 2017

    View details for PubMedID 28918944

  • Five Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression BRAIN STIMULATION Williams, N. R., Short, E. B., Hopkins, T., Bentzle, B. S., Sahlem, G. L., Pannu, J., Schmidt, M., Borckardt, J. J., Korte, J. E., George, M. S., Takacs, I., Nahas, Z. 2016; 9 (6): 897-904

    Abstract

    Epidural prefrontal cortical stimulation (EpCS) represents a novel therapeutic approach with many unique benefits that can be used for treatment-resistant depression (TRD).To examine the long-term safety and efficacy of EpCS of the frontopolar cortex (FPC) and dorsolateral prefrontal cortex (DLPFC) for treatment of TRD.Adults (N?=?5) who were 21-80 years old with severe TRD [failure to respond to adequate courses of at least 4 antidepressant medications, psychotherapy and ?20 on the Hamilton Rating Scale for Depression (HRSD24)] were recruited. Participants were implanted with bilateral EpCS over the FPC and DLPFC and received constant, chronic stimulation throughout the five years with Medtronic IPGs. They were followed for 5 years (2/1/2008-10/14/2013). Efficacy of EpCS was assessed with the HRSD24 in an open-label design as the primary outcome measure at five years.All 5 patients continued to tolerate the therapy. The mean improvements from pre-implant baseline on the HRSD24 were [7 months] 54.9% (±37.7), [1 year] 41.2% (±36.6), [2 years] 53.8% (±21.7), and [5 years] 45% (±47). Three of 5 (60%) subjects continued to be in remission at 5 years. There were 5 serious adverse events: 1 electrode 'paddle' infection and 4 device malfunctions, all resulting in suicidal ideation and/or hospitalization.These results suggest that chronic bilateral EpCS over the FPC and DLPFC is a promising and potentially durable new technology for treating TRD, both acutely and over 5 years.

    View details for DOI 10.1016/j.brs.2016.06.054

    View details for Web of Science ID 000387197500013

    View details for PubMedID 27443912

  • Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior PSYCHOPHARMACOLOGY Kawa, A. B., Bentzley, B. S., Robinson, T. E. 2016; 233 (19-20): 3587-3602

    Abstract

    Contemporary animal models of cocaine addiction focus on increasing the amount of drug consumption to produce addiction-like behavior. However, another critical factor is the temporal pattern of consumption, which in humans is characterized by intermittency, both within and between bouts of use.To model this, we combined prolonged access to cocaine (?70 days in total) with an intermittent access (IntA) self-administration procedure and used behavioral economic indicators to quantify changes in motivation for cocaine.IntA produced escalation of intake, a progressive increase in cocaine demand (incentive-sensitization), and robust drug- and cue-induced reinstatement of drug-seeking behavior. We also asked whether rats that vary in their propensity to attribute incentive salience to reward cues (sign-trackers [STs] vs. goal-trackers [GTs]) vary in the development of addiction-like behavior. Although STs were more motivated to take cocaine after limited drug experience, after IntA, STs and GTs no longer differed on any measure of addiction-like behavior.Exposure to large quantities of cocaine is not necessary for escalation of intake, incentive-sensitization, or other addiction-like behaviors (IntA results in far less total cocaine consumption than 'long access' procedures). Also, the ST phenotype may increase susceptibility to addiction, not because STs are inherently susceptible to incentive-sensitization (perhaps all individuals are at risk), but because this phenotype promotes continued drug use, subjecting them to incentive-sensitization. Thus, the pharmacokinetics associated with the IntA procedure are especially effective in producing a number of addiction-like behaviors and may be valuable for studying associated neuroadaptations and for assessing individual variation in vulnerability.

    View details for DOI 10.1007/s00213-016-4393-8

    View details for Web of Science ID 000383672500009

    View details for PubMedID 27481050

  • Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease. Acta neurologica Scandinavica Williams, N. R., Bentzley, B. S., Sahlem, G. L., Pannu, J., Korte, J. E., Revuelta, G., Short, E. B., George, M. S. 2016

    Abstract

    Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinson's disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra-brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD.This open-label pilot study included 6 patients who were assessed in the motoric, cognitive, and neuropsychiatric domains prior to and after RUL UBP ECT. Primary endpoints were changes in total score on the HAM-D-17 and GDS-30 rating scales.Patients were found to improve in motoric and psychiatric domains following RUL UBP ECT without cognitive side effects, both immediately following ECT and at 1-month follow-up.This study demonstrates that RUL UBP ECT is safe, feasible, and potentially efficacious in treating multiple domains of PD, including motor and mood, without clear cognitive side effects.

    View details for DOI 10.1111/ane.12614

    View details for PubMedID 27241213

    View details for PubMedCentralID PMC5133197

  • Stimulating Across the Frontostriatal Circuitry to Treat Parkinson's Disease Williams, N. R., Short, E., Bentzley, B., Pannu, J., Sahlem, G., Hanlon, C., Korte, J., Revuelta, G., George, M. ELSEVIER SCIENCE INC. 2016: 402S?403S

    View details for Web of Science ID 000432440805134

  • Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand. Biological psychiatry Cox, B. M., Bentzley, B. S., Regen-Tuero, H. n., See, R. E., Reichel, C. M., Aston-Jones, G. n. 2016

    Abstract

    Evidence indicates that oxytocin, an endogenous peptide well known for its role in social behaviors, childbirth, and lactation, is a promising addiction pharmacotherapy. We employed a within-session behavioral-economic (BE) procedure in rats to examine oxytocin as a pharmacotherapy for methamphetamine (meth) addiction. The BE paradigm was modeled after BE procedures used to assess motivation for drugs in humans with addiction. The same BE variables assessed across species have been shown to predict later relapse behavior. Thus, the translational potential of preclinical BE studies is particularly strong.We tested the effects of systemic and microinfused oxytocin on demand for self-administered intravenous meth and reinstatement of extinguished meth seeking in male and female rats using a BE paradigm. Correlations between meth demand and meth seeking were assessed.Female rats showed greater demand (i.e., motivation) for meth compared with male rats. In both male and female rats, meth demand predicted reinstatement of meth seeking, and systemic oxytocin decreased demand for meth and attenuated reinstatement to meth seeking. Oxytocin was most effective at decreasing meth demand and seeking in rats with the strongest motivation for drug. Finally, these effects of systemic oxytocin were mediated by actions in the nucleus accumbens.Oxytocin decreases meth demand and seeking in both sexes, and these effects depend on oxytocin signaling in the nucleus accumbens. Overall, these data indicate that development of oxytocin-based therapies may be a promising treatment approach for meth addiction in humans.

    View details for DOI 10.1016/j.biopsych.2016.11.011

    View details for PubMedID 28110822

  • Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. Addiction biology Porter-Stransky, K. A., Bentzley, B. S., Aston-Jones, G. 2015

    Abstract

    Orexin-1 receptors (Ox1Rs) have been implicated in the motivation for drugs of abuse. Here, we utilized a within-session behavioral-economics threshold procedure to screen for individual differences in economic demand for the ultra-short-acting opioid remifentanil and to test whether antagonism of Ox1Rs reduces remifentanil demand. The behavioral-economics procedure revealed robust individual differences in free consumption of remifentanil (Q0 parameter; hedonic set point). Rats with low baseline Q0 (low takers) displayed high demand elasticity (? parameter; reduced responding as drug price increased indicating low motivation for drug), whereas subjects with a higher Q0 (high takers) exhibit low demand elasticity (low ?) by continuing to self-administer remifentanil despite increased cost (reflecting higher motivation for drug). In a punished responding paradigm utilizing footshock, subjects that were classified as high takers at baseline withstood twice as much shock as low takers to continue self-administering remifentanil. Interestingly, Ox1R antagonism with SB-334867 reduced Q0 and increased ? in low takers but not in high takers. Similarly, the Ox1R antagonist attenuated cue-induced, but not drug-induced, reinstatement of remifentanil seeking in low takers but had no significant effect on reinstatement of drug seeking in high takers. Together, these data reveal a novel role of orexins in demand for remifentanil: Ox1Rs modulate demand in low takers but not in individuals that exhibit addictive-like behaviors (high takers). Finally, the behavioral assays in this study can serve as a novel laboratory model for studying individual differences in opioid use disorders.

    View details for DOI 10.1111/adb.12323

    View details for PubMedID 26598295

  • Delay Discounting for Sucrose in Alcohol-Preferring and Nonpreferring Rats Using a Sipper Tube Within-Sessions Task ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Perkel, J. K., Bentzley, B. S., Andrzejewski, M. E., Martinetti, M. P. 2015; 39 (2): 232-238

    Abstract

    Delay discounting (DD) is a measure of impulsivity that quantifies preference for a small reward delivered immediately over a large reward delivered after a delay. It has been hypothesized that impulsivity is an endophenotype associated with increased risk for development of alcohol use disorders (AUDs); however, a causal role of impulsivity is difficult to determine with human studies. We tested this hypothesis by assessing the degree of DD present in alcohol-naïve rats selectively bred for either high- or low-alcohol preference.A novel adaptation of a within-sessions DD procedure was used to compare impulsivity differences between male alcohol-preferring (P) and nonpreferring (NP) rat lines (n = 6 per line) using a 5% sucrose reward. Animals chose between 2 options: 2-second sipper tube access delivered immediately (small reward) or 8-second access after a variable delay (large reward). Each 50-minute session consisted of 5 blocks of ten 60-second trials. Within each session, the delay to the large reward increased in each block of trials. Delays were gradually increased over 3 sets to attain a final delay set of 3, 8, 15, 18, and 25 seconds.Prior to starting delays, there were no significant differences between lines in sucrose consumption or percent choice for the large reward, and both lines exhibited a clear preference for the large reward. After delays were initiated, choice for the large reward decreased as the delay to its presentation increased. Although discounting of the large, delayed reward was observed for both lines, the degree of discounting, or "impulsivity," was greater for P rats compared with NP rats.P rats are more impulsive for sucrose rewards before exposure to alcohol compared with NP rats. Thus, individuals genetically predisposed toward developing AUDs may be more likely to engage in impulsive decision making prior to alcohol exposure.

    View details for DOI 10.1111/acer.12632

    View details for Web of Science ID 000350100900004

    View details for PubMedID 25684046

  • Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders: what makes a good homeostat? ANNALS REPORTS, VOL 1334 Frank, E., Benabou, M., Bentzley, B., Bianchi, M., Goldstein, T., Konopka, G., Maywood, E., Pritchett, D., Sheaves, B., Thomas, J. 2014; 1334: 1-25

    Abstract

    All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well-being. This is no less true for psychiatric well-being than for physical well-being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well-being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis.

    View details for DOI 10.1111/nyas.12600

    View details for Web of Science ID 000350025200001

    View details for PubMedID 25532787

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