Gregory Lee Sahlem

All Publications

• A Preliminary Investigation Of Repetitive Transcranial Magnetic Stimulation Applied To The Left Dorsolateral Prefrontal Cortex In Treatment Seeking Participants With Cannabis Use Disorder. medRxiv : the preprint server for health sciences Sahlem, G. L., Kim, B., Baker, N. L., Wong, B. L., Caruso, M. A., Campbell, L. A., Kaloani, I., Sherman, B. J., Ford, T. J., Musleh, A. H., Kim, J. P., Williams, N. R., Manett, A. J., Kratter, I. H., Short, E. B., Killeen, T. K., George, M. S., McRae-Clark, A. L. 2023

  Abstract

  Background: Cannabis use disorder (CUD) is a common and consequential disorder. When applied to the dorsolateral prefrontal cortex (DLPFC), repetitive transcranial magnetic stimulation (rTMS) reduces craving across substance use disorders and may have a therapeutic clinical effect when applied in serial sessions. The present study sought to preliminarily determine whether serial sessions of rTMS applied to the DLPFC had a therapeutic effect in CUD.Methods: This study was a two-site, phase-2, double-blind, randomized-controlled-trial. Seventy-two treatment-seeking participants (37.5% Women, mean age 30.2±9.9SD) with ≥moderate-CUD were randomized to active or sham rTMS (Beam-F3, 10Hz, 20-total-sessions, with cannabis cues) while undergoing a three-session motivational enhancement therapy intervention. The primary outcome was the change in craving between pre- and post- treatment (Marijuana Craving Questionnaire Short-Form-MCQ-SF). Secondary outcomes included the number of weeks of abstinence and the number of days-per-week of cannabis use during 4-weeks of follow-up.Results: There were no significant differences in craving between conditions. Participants who received active rTMS reported numerically, but not significantly, more weeks of abstinence in the follow-up period than those who received sham rTMS (15.5%-Active; 9.3%-Sham; rate ratio = 1.66 [95% CI: 0.84, 3.28]; p =0.14). Participants who received active rTMS reported fewer days-per-week of cannabis use over the final two-weeks of the follow-up period (Active vs. Sham: -0.72; Z=-2.33, p =0.02).Conclusions: This trial suggests rTMS is safe and feasible in individuals with CUD and may have a therapeutic effect on frequency of cannabis use, though further study is needed with additional rTMS-sessions and a longer follow-up period.Highlights: This phase-2 RCT tested the efficacy of prefrontal rTMS for cannabis use disorderThe study paradigm was safe and feasible, and participants tolerated rTMS wellThe active-group had numerically more weeks of abstinence during follow-upThe active-group had fewer days-per-week of cannabis use during follow-upMore rTMS and a longer follow-up may result in a larger effect in future studies.

  View details for DOI 10.1101/2023.07.10.23292461

  View details for PubMedID 37503294

• Sex Differences in Cortical Thickness in Cannabis Use Disorder Martin, E., Thorn, K., Sahlem, G., McRae-Clark, A., Benitez, A. ELSEVIER SCIENCE INC. 2022: S106-S107

  View details for Web of Science ID 000789022200260

• Varenicline as a treatment for cannabis use disorder: A placebo-controlled pilot trial. Drug and alcohol dependence McRae-Clark, A. L., Gray, K. M., Baker, N. L., Sherman, B. J., Squeglia, L., Sahlem, G. L., Wagner, A., Tomko, R. 2021; 229 (Pt B): 109111

  Abstract

  BACKGROUND: An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial.METHODS: Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n=35) or placebo (n=37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day.RESULTS: Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR=3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9ng/mg (95% CI: -0.4,4.3); Delta=3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals.CONCLUSIONS: Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted.

  View details for DOI 10.1016/j.drugalcdep.2021.109111

  View details for PubMedID 34655945

• TMS and CBT-I for comorbid depression and insomnia. Exploring feasibility and tolerability of transcranial magnetic stimulation (TMS) and cognitive behavioral therapy for insomnia (CBT-I) for comorbid major depressive disorder and insomnia during the COVID-19 pandemic. Brain stimulation Norred, M. A., Haselden, L., Sahlem, G. L., Wilkerson, A. K., Short, E. B., McTeague, L. M., George, M. S. 2021

  View details for DOI 10.1016/j.brs.2021.09.007

  View details for PubMedID 34563744

• Sleep and substance use disorder treatment: A preliminary study of subjective and objective assessment of sleep during an intensive outpatient program. The American journal on addictions Wilkerson, A. K., Simmons, R. O., Sahlem, G. L., Taylor, D. J., Smith, J. P., Book, S. W., McRae-Clark, A. L. 2021

  Abstract

  BACKGROUND AND OBJECTIVES: Characteristics of sleep concerns and their relationship to mental health in heterogeneous substance use disorder (SUD) treatment settings are not well understood. The purpose of this preliminary study was to assess sleep using subjective and objective measures at two time points during SUD treatment and compare sleep changes to changes in mental health measures.METHODS: Treatment-seeking participants completed an assessment battery at the beginning of treatment (Time 1, N=30) and again upon treatment completion (Time 2, approximately 4 weeks later, N=22). The majority of participants were White (80%), male (63%), and presenting for alcohol use disorder (60.0%), though almost half reported polysubstance abuse (43%). Comorbidity was common (53%). Sleep and mental health questionnaires with 1 week of actigraphy and sleep diaries were completed at both time points.RESULTS: Most participants met the criteria for a sleep disorder and mean scores on questionnaires showed poor sleep quality, insomnia symptoms, and frequent nightmares, with sleep quality and insomnia improving over time but remaining clinically significant. Nightmares did not improve. Actigraphy indicated poor sleep at both time points. Improvement in insomnia was related to improvement in measures of mental health while changes in actigraphy variables were not related to these measures.DISCUSSION AND CONCLUSIONS: Multiple types of sleep disturbance are prevalent in this population, with nightmares persisting throughout treatment and insomnia symptoms showing a relationship with mental health symptoms.SCIENTIFIC SIGNIFICANCE: This was the first study to longitudinally assess mental health with subjective and objective measures of sleep across multiple types of SUDs in a community SUD treatment setting.

  View details for DOI 10.1111/ajad.13194

  View details for PubMedID 34164864

• NMDA-Receptor Agonist Reveals LTP-like Properties of 10-Hz rTMS in the Human Motor Cortex. Brain stimulation Brown, J. C., Yuan, S., DeVries, W. H., Armstrong, N. M., Korte, J. E., Sahlem, G. L., Carpenter, L. L., George, M. S. 2021

  View details for DOI 10.1016/j.brs.2021.03.016

  View details for PubMedID 33794339

• A two-site, open-label, non-randomized trial comparing Focal Electrically-Administered Seizure Therapy (FEAST) and right unilateral ultrabrief pulse electroconvulsive therapy (RUL-UBP ECT). Brain stimulation Sahlem, G. L., McCall, W. V., Short, E. B., Rosenquist, P. B., Fox, J. B., Youssef, N. A., Manett, A. J., Kerns, S. E., Dancy, M. M., McCloud, L., George, M. S., Sackeim, H. A. 2020; 13 (5): 1416-1425

  Abstract

  Focal Electrically-Administered Seizure Therapy (FEAST) is a form of electroconvulsive therapy (ECT) that spatially focuses the electrical stimulus to initiate seizure activity in right prefrontal cortex. Two open-label non-comparative studies suggested that FEAST has reduced cognitive side effects when compared to historical data from other forms of ECT. In two different ECT clinics, we compared the efficacy and cognitive side effects of FEAST and Right Unilateral Ultrabrief Pulse (RUL-UBP) ECT.Using a non-randomized, open-label design, 39 depressed adults were recruited after referral for ECT. Twenty patients received FEAST (14 women; age 45.2 ± 12.7), and 19 received RUL-UBP ECT (16 women; age 43.2 ± 16.4). Key cognitive outcome measures were the postictal time to reorientation and the Columbia University Autobiographical Memory Interview: Short-Form (CUAMI-SF). Antidepressant effects were assessed using the Hamilton Rating Scale for Depression (HRSD24).In the Intent-to-treat sample, a repeated measures mixed model suggested no between group difference in HRSD24 score over time (F1,35 = 0.82, p = 0.37), while the response rate favored FEAST (FEAST: 65%; RUL-UBP ECT: 57.9%), and the remission rate favored RUL-UBP ECT (FEAST: 35%; RUL-UBP ECT: 47.4%). The FEAST group had numeric superiority in average time to reorientation (FEAST: 6.6 ± 5.0 min; RUL-UBP ECT: 8.8 ± 5.8 min; Cohens d = 0.41), and CUAMI-SF consistency score (FEAST: 69.2 ± 14.2%; RUL-UBP ECT: 63.9 ± 9.9%; Cohens d = 0.43); findings that failed to meet statistical significance.FEAST exerts similar efficacy relative to an optimal form of conventional ECT and may have milder cognitive side effects. A blinded, randomized, non-inferiority trial is needed.

  View details for DOI 10.1016/j.brs.2020.07.015

  View details for PubMedID 32735987

• Treatment of Adults with Autism and Major Depressive Disorder Using Transcranial Magnetic Stimulation: An Open Label Pilot Study. Autism research : official journal of the International Society for Autism Research Gwynette, M. F., Lowe, D. W., Henneberry, E. A., Sahlem, G. L., Wiley, M. G., Alsarraf, H., Russo, S. B., Joseph, J. E., Summers, P. M., Lohnes, L., George, M. S. 2020; 13 (3): 346-351

  Abstract

  Patients with autism spectrum disorder (ASD) are at high risk for comorbid major depressive disorder (MDD), which can severely impair functioning and quality of life. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique, which is Food and Drug Administration (FDA) cleared for the treatment of MDD in adults. Despite demonstrated efficacy in the treatment of depression, there are limited data on the use of rTMS in patients with ASD and comorbid MDD. We hypothesized that a standard rTMS protocol for MDD would reduce depressive symptoms for adults with ASD and MDD. Secondarily, we investigated whether this treatment would also reduce core ASD symptoms. Participants of 18-65 years old with ASD and MDD without any medication changes in the last month were eligible for this open-label trial. Participants underwent 25 sessions of rTMS (figure-of-eight coil, 100-120% resting motor threshold, 10 Hz, 3,000 pulses per session) applied to the left dorsolateral prefrontal cortex. Thirteen participants enrolled in the study, with two withdrawing due to tolerability, and one excluded from analysis. Overall, side effects were mild and rTMS was well tolerated. The Hamilton rating scale for depression (HAM-D17 ) improved 13.5 points (IQR 5-15), and 40% of participants achieved remission (HAM-D17  ≤ 7) after rTMS treatment. Informant clinical scales of core symptoms of autism also suggested improvement with rTMS, though no change was observed by the participants themselves. Thus, this open-label trial suggests that high-frequency rTMS is well tolerated by adults with autism and MDD, with improvement in depressive symptoms and possible effects on core autism symptoms. Autism Res 2020, 13: 346-351. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: This study evaluated the safety and effects of repetitive transcranial magnetic stimulation (rTMS) on depression and autism symptoms in individuals with both major depressive disorder and autism spectrum disorder. rTMS was well tolerated by the participants, depression improved with treatment, and family members' assessment of autism symptoms improved as well. This study supports the need for further work to evaluate rTMS in individuals who have both autism and depression.

  View details for DOI 10.1002/aur.2266

  View details for PubMedID 31944611

• NMDA receptor partial agonist, d-cycloserine, enhances 10 Hz rTMS-induced motor plasticity, suggesting long-term potentiation (LTP) as underlying mechanism. Brain stimulation Brown, J. C., DeVries, W. H., Korte, J. E., Sahlem, G. L., Bonilha, L., Short, E. B., George, M. S. 2020; 13 (3): 530-532

  View details for DOI 10.1016/j.brs.2020.01.005

  View details for PubMedID 32289670

  View details for PubMedCentralID PMC7224691

• A case series exploring the effect of twenty sessions of repetitive transcranial magnetic stimulation (rTMS) on cannabis use and craving. Brain stimulation Sahlem, G. L., Caruso, M. A., Short, E. B., Fox, J. B., Sherman, B. J., Manett, A. J., Malcolm, R. J., George, M. S., McRae-Clark, A. L. 2019; 13 (1): 265-266

  View details for DOI 10.1016/j.brs.2019.09.014

  View details for PubMedID 31619347

  View details for PubMedCentralID PMC7263465

• 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

• Transcranial electrical and magnetic stimulation (tES and TMS) for addiction medicine: A consensus paper on the present state of the science and the road ahead. Neuroscience and biobehavioral reviews Ekhtiari, H., Tavakoli, H., Addolorato, G., Baeken, C., Bonci, A., Campanella, S., Castelo-Branco, L., Challet-Bouju, G., Clark, V. P., Claus, E., Dannon, P. N., Del Felice, A., den Uyl, T., Diana, M., di Giannantonio, M., Fedota, J. R., Fitzgerald, P., Gallimberti, L., Grall-Bronnec, M., Herremans, S. C., Herrmann, M. J., Jamil, A., Khedr, E., Kouimtsidis, C., Kozak, K., Krupitsky, E., Lamm, C., Lechner, W. V., Madeo, G., Malmir, N., Martinotti, G., McDonald, W. M., Montemitro, C., Nakamura-Palacios, E. M., Nasehi, M., Noël, X., Nosratabadi, M., Paulus, M., Pettorruso, M., Pradhan, B., Praharaj, S. K., Rafferty, H., Sahlem, G., Salmeron, B. J., Sauvaget, A., Schluter, R. S., Sergiou, C., Shahbabaie, A., Sheffer, C., Spagnolo, P. A., Steele, V. R., Yuan, T. F., van Dongen, J. D., Van Waes, V., Venkatasubramanian, G., Verdejo-García, A., Verveer, I., Welsh, J. W., Wesley, M. J., Witkiewitz, K., Yavari, F., Zarrindast, M. R., Zawertailo, L., Zhang, X., Cha, Y. H., George, T. P., Frohlich, F., Goudriaan, A. E., Fecteau, S., Daughters, S. B., Stein, E. A., Fregni, F., Nitsche, M. A., Zangen, A., Bikson, M., Hanlon, C. A. 2019; 104: 118-140

  Abstract

  There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data - emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.

  View details for DOI 10.1016/j.neubiorev.2019.06.007

  View details for PubMedID 31271802

• Tolerability and feasibility of accelerated repetitive transcranial stimulation for reduction of nicotine craving. Brain stimulation Friedrich, D., Li, X., Hartwell, K. J., Short, E. B., Sahlem, G. L., George, M. S. 2019; 12 (5): 1315-1316

  View details for DOI 10.1016/j.brs.2019.06.023

  View details for PubMedID 31253502

  View details for PubMedCentralID PMC7263463

• Repetitive transcranial magnetic stimulation (rTMS) administration to heavy cannabis users. The American journal of drug and alcohol abuse Sahlem, G. L., Baker, N. L., George, M. S., Malcolm, R. J., McRae-Clark, A. L. 2018; 44 (1): 47-55

  Abstract

  Cannabis use disorder (CUD) is a common condition with few treatments. Several studies in other substance use disorders have found that applying repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) decreases cue-elicited craving and possibly decreases use. To date, there have been no studies attempting to use rTMS in CUD.This study was conducted to determine if rTMS could be feasibly delivered to a group of non-treatment seeking CUD participants. Secondarily, the study aimed to estimate the effect of rTMS on craving.In a double-blind, sham-controlled, crossover design, a single session of active or sham rTMS (Left DLPFC, 10 Hz, 110% rMT, 4000 pulses) was delivered during a validated cannabis cue paradigm. Participants crossed over to complete the other condition one week later. The feasibility and tolerability were measured by the rate of retention, and the percentage of participants able to tolerate full dose rTMS, respectively. Craving was measured using the Marijuana Craving Questionnaire (MCQ).Eighteen non-treatment seeking CUD participants were recruited from the community; 16 (three women) completed the trial (89% retained for the three study visits). All of the treatment completers tolerated rTMS at full dose without adverse effects. There was not a significant reduction in the total MCQ when participants received active rTMS as compared to sham rTMS.rTMS can be safely and feasibly delivered to CUD participants, and treatment is well tolerated. A single session of rTMS applied to the DLPFC may not reduce cue-elicited craving in heavy cannabis users.

  View details for DOI 10.1080/00952990.2017.1355920

  View details for PubMedID 28806104

  View details for PubMedCentralID PMC5962012

• Impact of cannabis legalization on treatment and research priorities for cannabis use disorder. International review of psychiatry (Abingdon, England) Sahlem, G. L., Tomko, R. L., Sherman, B. J., Gray, K. M., McRae-Clark, A. L. 2018; 30 (3): 216-225

  Abstract

  An increasing proportion of the world has legalized cannabis for medicinal or recreational use. The legalization trend appears to be continuing. These changes in the legislative landscape may have important health, treatment, and research implications. This review discusses public health outcomes that may be impacted by increases in cannabis availability and use. It additionally considers potential research and treatment priorities in the face of widespread cannabis legalization.

  View details for DOI 10.1080/09540261.2018.1465398

  View details for PubMedID 29956576

  View details for PubMedCentralID PMC6322658

• Neurogenic Pulmonary Edema Complicating ECT. The journal of ECT Fryml, L., Fox, J., Manett, A. J., Sahlem, G., Short, E. B. 2018; 34 (2): 78

  View details for DOI 10.1097/YCT.0000000000000471

  View details for PubMedID 29166318

• Biological correlates of self-reported new and continued abstinence in cannabis cessation treatment clinical trials. Drug and alcohol dependence Baker, N. L., Gray, K. M., Sherman, B. J., Morella, K., Sahlem, G. L., Wagner, A. M., McRae-Clark, A. L. 2018; 187: 270-277

  Abstract

  The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence.Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials.Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component.Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement.

  View details for DOI 10.1016/j.drugalcdep.2018.03.017

  View details for PubMedID 29698894

  View details for PubMedCentralID PMC5959795

• The role of rTMS for patients with severe PTSD and depression. Evidence-based mental health Fryml, L. D., Sahlem, G., Fox, J., Short, E. B. 2018; 21 (1): 39-40

  View details for DOI 10.1136/eb-2017-102819

  View details for PubMedID 29305359

• Transcranial magnetic stimulation of the dorsal lateral prefrontal cortex inhibits medial orbitofrontal activity in smokers. The American journal on addictions Li, X., Sahlem, G. L., Badran, B. W., McTeague, L. M., Hanlon, C. A., Hartwell, K. J., Henderson, S., George, M. S. 2017; 26 (8): 788-794

  Abstract

  Several studies have shown that repetitive transcranial magnetic stimulation (rTMS), applied to the dorsolateral prefrontal cortex (DLPFC), can reduce cue-elicited craving in smokers. Currently, the mechanism of this effect is unknown. We used functional magnetic resonance imaging (fMRI) to explore the effect of a single treatment of rTMS on cortical and sub-cortical neural activity in non-treatment seeking nicotine-dependent participants.We conducted a randomized, counterbalanced, crossover trial in which participants attended two experimental visits separated by at least 1 week. On the first visit, participants received either active, or sham rTMS (10 Hz, 5 s-on, 10 s-off, 100% motor threshold, 3,000 pulses) over the left DLPFC, and on the second visit they received the opposite condition (active or sham). Cue craving fMRI scans were completed before and after each rTMS session.A total of 11 non-treatment seeking nicotine-dependent cigarette smokers were enrolled in the study [six female, average age 39.7 ± 13.2, average cigarettes per day 17.3 ± 5.9]. Active rTMS decreased activity in the contralateral medial orbitofrontal cortex (mOFC) and ipsilateral nucleus accumbens (NAc) compared to sham rTMS.This preliminary data suggests that one session of rTMS applied to the DLPFC decreases brain activity in the NAc and mOFC in smokers.rTMS may exert its anti-craving effect by decreasing activity in the NAc and mOFC in smokers. Despite a small sample size, these findings warrant future rTMS/fMRI studies in addictions. (Am J Addict 2017;26:788-794).

  View details for DOI 10.1111/ajad.12621

  View details for PubMedID 28898485

  View details for PubMedCentralID PMC5699931

• Simultaneous aerobic exercise and rTMS: Feasibility of combining therapeutic modalities to treat depression. Brain stimulation Ross, R. E., VanDerwerker, C. J., Newton, J. H., George, M. S., Short, E. B., Sahlem, G. L., Manett, A. J., Fox, J. B., Gregory, C. M. 2017; 11 (1): 245-246

  View details for DOI 10.1016/j.brs.2017.10.019

  View details for PubMedID 29126945

  View details for PubMedCentralID PMC5801690

• Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex reduces resting-state insula activity and modulates functional connectivity of the orbitofrontal cortex in cigarette smokers. Drug and alcohol dependence Li, X., Du, L., Sahlem, G. L., Badran, B. W., Henderson, S., George, M. S. 2017; 174: 98-105

  Abstract

  Previous studies reported that repetitive transcranial magnetic stimulation (rTMS) can reduce cue-elicited craving and decrease cigarette consumption in smokers. The mechanism of this effect however, remains unclear. We used resting-state functional magnetic resonance imaging (rsfMRI) to test the effect of rTMS in non-treatment seeking smokers.We used a single blinded, sham-controlled, randomized counterbalanced crossover design where participants underwent two visits separated by at least 1 week. Participants received active rTMS over the left dorsolateral prefrontal cortex (DLPFC) during one of their visits, and sham rTMS during their other visit. They had two rsFMRI scans before and after each rTMS session. We used the same rTMS stimulation parameters as in a previous study (10Hz, 5s-on, 10s-off, 100% resting motor threshold, 3000 pulses).Ten non-treatment-seeking, nicotine-dependent, cigarette smokers (6 women, an average age of 39.72 and an average cigarette per day of 17.30) finished the study. rsFMRI results demonstrate that as compared to a single session of sham rTMS, a single session of active rTMS inhibits brain activity in the right insula and thalamus in fractional amplitude of low frequency fluctuation (fALFF). For intrinsic brain connectivity comparisons, active TMS resulted in significantly decreased connectivity from the site of rTMS to the left orbitomedial prefrontal cortex.This data suggests that one session of rTMS can reduce activity in the right insula and right thalamus as measured by fALFF. The data also demonstrates that rTMS can reduce rsFC between the left DLPFC and the medial orbitofrontal cortex.

  View details for DOI 10.1016/j.drugalcdep.2017.02.002

  View details for PubMedID 28319755

  View details for PubMedCentralID PMC5400684

• The Role of Amantadine Withdrawal in 3 Cases of Treatment-Refractory Altered Mental Status. Journal of psychiatric practice Fryml, L. D., Williams, K. R., Pelic, C. G., Fox, J., Sahlem, G., Robert, S., Revuelta, G. J., Short, E. B. 2017; 23 (3): 191-199

  Abstract

  Amantadine, which was originally developed as an antiviral medication, functions as a dopamine agonist in the central nervous system and consequently is utilized in the treatment of Parkinson disease, drug-induced extrapyramidal reactions, and neuroleptic malignant syndrome. For reasons that are not entirely understood, abrupt changes in amantadine dosage can produce a severe withdrawal syndrome. Existing medical literature describes case reports of amantadine withdrawal leading to delirium, which at times has progressed to neuroleptic malignant syndrome. Amantadine withdrawal may be under-recognized by mental health clinicians, which has the potential to lead to protracted hospital courses and suboptimal outcomes. The goal of this case series is to highlight the role of amantadine withdrawal in the cases of 3 medically complex patients with altered mental status. In the first case, the cognitive side effects of electroconvulsive therapy masked acute amantadine withdrawal in a 64-year-old man with Parkinson disease. In the second case, a 75-year-old depressed patient developed a catatonic delirium when amantadine was discontinued. Finally, a refractory case of neuroleptic malignant syndrome in a 57-year-old patient with schizoaffective disorder rapidly resolved with the reintroduction of outpatient amantadine. These cases highlight several learning objectives regarding amantadine withdrawal syndrome: First, it may be concealed by co-occurring causes of delirium in medically complex patients. Second, its symptoms are likely to be related to a cortical and limbic dopamine shortage, which may be reversed with electroconvulsive therapy or reintroduction of amantadine. Third, its clinical presentation may occur on a spectrum and may include features suggestive of delirium, catatonia, or neuroleptic malignant syndrome.

  View details for DOI 10.1097/PRA.0000000000000237

  View details for PubMedID 28492457

• 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

  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 Web of Science ID 000398035900004

  View details for PubMedCentralID PMC5133197

• Neuroversion: using electroconvulsive therapy as a bridge to deep brain stimulation implantation NEUROCASE Williams, N. R., Sahlem, G., Pannu, J., Takacs, I., Short, B., Revuelta, G., George, M. S. 2017; 23 (1): 26-30

  Abstract

  Parkinson's disease (PD) is a movement disorder with significant neuropsychiatric comorbidities. Electroconvulsive therapy (ECT) is effective in treating these neuropsychiatric symptoms; however, clinicians are reluctant to use ECT in patients with deep brain stimulation (DBS) implantations for fear of damaging the device, as well as potential cognitive side effects. Right unilateral ultra-brief pulse (RUL UBP) ECT has a more favorable cognitive side-effect profile yet has never been reported in PD patients with DBS implants. We present a case series of three patients with a history of PD that all presented with psychiatric decompensation immediately prior to planned DBS surgery. All three patients had DBS electrode(s) in place at the time and an acute course of ECT was utilized in a novel method to "bridge" these individuals to neurosurgery. The patients all experienced symptom resolution (psychosis and/or depression and/or anxiety) without apparent cognitive side effects. This case series not only illustrates that right unilateral ultra-brief pulse can be utilized in patients with DBS electrodes but also illustrates that this intervention can be utilized as a neuromodulatory "bridge", where nonoperative surgical candidates with unstable psychiatric symptoms can be converted to operative candidates in a manner similar to electrical cardioversion.

  View details for DOI 10.1080/13554794.2016.1276605

  View details for Web of Science ID 000399644200005

  View details for PubMedID 28376692

• 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

• Expanded Safety and Efficacy Data for a New Method of Performing Electroconvulsive Therapy: Focal Electrically Administered Seizure Therapy. The journal of ECT Sahlem, G. L., Short, E. B., Kerns, S., Snipes, J., DeVries, W., Fox, J. B., Burns, C., Schmidt, M., Nahas, Z. H., George, M. S., Sackeim, H. A. 2016; 32 (3): 197-203

  Abstract

  Electroconvulsive therapy (ECT) is the most rapid and effective antidepressant treatment but with concerns about cognitive adverse effects. A new form of ECT, focal electrically administered seizure therapy (FEAST), was designed to increase the focality of stimulation and better match stimulus parameters with neurophysiology. We recently reported on the safety and feasibility of FEAST in a cohort (n = 17) of depressed patients. We now report on the safety, feasibility, preliminary efficacy, and cognitive effects of FEAST in a new cohort.Open-label FEAST was administered to 20 depressed adults (6 men; 3 with bipolar disorder; age 49.1 ± 10.6 years). Clinical and cognitive assessments were obtained at baseline and end of course. Time to orientation recovery was assessed at each treatment. Nonresponders switched to conventional ECT.Participants tolerated the treatment well with no dropouts. Five patients (25%) transitioned from FEAST to conventional ECT due to inadequate response. After FEAST (mean, 9.3 ± 3.5 sessions; range, 4-14), there was a 58.1% ± 36.0% improvement in Hamilton Rating Scale for Depression scores compared with that in the baseline (P < 0.0001); 13 (65%) of 20 patients met response criteria, and 11 (55%) of 20 met remission criteria. Patients achieved reorientation (4 of 5 items) in 4.4 ± 3.0 minutes (median, 4.5 minutes), timed from eyes opening. There was no deterioration in neuropsychological measures.These findings provide further support for the safety and efficacy of FEAST. The remission and response rates were in the range found using conventional ECT, and the time to reorientation may be quicker. However, without a randomized comparison group, conclusions are tentative.

  View details for DOI 10.1097/YCT.0000000000000328

  View details for PubMedID 27379790

  View details for PubMedCentralID PMC5058644

• 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

• Reward circuit DBS improves Parkinson's gait along with severe depression and OCD NEUROCASE Williams, N. R., Hopkins, T. R., Short, E. B., Sahlem, G. L., Snipes, J., Revuelta, G. J., George, M. S., Takacs, I. 2016; 22 (2): 201-204

  Abstract

  A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD-related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry.

  View details for DOI 10.1080/13554794.2015.1112019

  View details for Web of Science ID 000369770400011

  View details for PubMedID 26644268

• Oscillating Square Wave Transcranial Direct Current Stimulation (tDCS) Delivered During Slow Wave Sleep Does Not Improve Declarative Memory More Than Sham: A Randomized Sham Controlled Crossover Study BRAIN STIMULATION Sahlem, G. L., Badran, B. W., Halford, J. J., Williams, N. R., Korte, J. E., Leslie, K., Strachan, M., Breedlove, J. L., Runion, J., Bachman, D. L., Uhde, T. W., Borckardt, J. J., George, M. S. 2015; 8 (3): 528-534

  Abstract

  A 2006 trial in healthy medical students found that anodal slow oscillating tDCS delivered bi-frontally during slow wave sleep had an enhancing effect in declarative, but not procedural memory. Although there have been supporting animal studies, and similar findings in pathological groups, this study has not been replicated, or refuted, in the intervening years. We therefore tested these earlier results for replication using similar methods with the exception of current waveform (square in our study, nearly sinusoidal in the original).Our objective was to test the findings of a 2006 trial suggesting bi-frontal anodal tDCS during slow wave sleep enhances declarative memory.Twelve students (mean age 25, 9 women) free of medical problems underwent two testing conditions (active, sham) in a randomized counterbalanced fashion. Active stimulation consisted of oscillating square wave tDCS delivered during early Non-Rapid Eye Movement (NREM) sleep. The sham condition consisted of setting-up the tDCS device and electrodes, but not turning it on during sleep. tDCS was delivered bi-frontally with anodes placed at F3/F4, and cathodes placed at mastoids. Current density was 0.517 mA/cm(2), and oscillated between zero and maximal current at a frequency of 0.75 Hz. Stimulation occurred during five-five minute blocks with 1-min inter-block intervals (25 min total stimulation). The primary outcomes were both declarative memory consolidation measured by a paired word association test (PWA), and non-declarative memory, measured by a non-dominant finger-tapping test (FTT). We also recorded and analyzed sleep EEG.There was no difference in the number of paired word associations remembered before compared to after sleep [(active = 3.1 ± 3.0 SD more associations) (sham = 3.8 ± 3.1 SD more associations)]. Finger tapping improved, (non-significantly) following active stimulation [(3.6 ± 2.7 SD correctly typed sequences) compared to sham stimulation (2.3 ± 2.2 SD correctly typed sequences)].In this study, we failed to find improvements in declarative or performance memory and could not replicate an earlier study using nearly identical settings. Specifically we failed to find a beneficial effect on either overnight declarative or non-declarative memory consolidation via square-wave oscillating tDCS intervention applied bi-frontally during early NREM sleep. It is unclear if the morphology of the tDCS pulse is critical in any memory related improvements.

  View details for DOI 10.1016/j.brs.2015.01.414

  View details for Web of Science ID 000355772300013

  View details for PubMedID 25795621

  View details for PubMedCentralID PMC4598642

• Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study JOURNAL OF PSYCHIATRIC RESEARCH Sahlem, G. L., Kalivas, B., Fox, J. B., Lamb, K., Roper, A., Williams, E. N., Williams, N. R., Korte, J. E., Zuschlag, Z. D., El Sabbagh, S., Guille, C., Barth, K. S., Uhde, T. W., George, M. S., Short, E. B. 2014; 59: 101-107

  Abstract

  Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N = 10, Mean age = 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33-36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day five (p = .002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean of 7.2 ± 5.5 SD on day five (p = .01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed.

  View details for DOI 10.1016/j.jpsychires.2014.08.015

  View details for Web of Science ID 000344205700014

  View details for PubMedID 25231629

  View details for PubMedCentralID PMC4252537

• Safe management of a bipolar depressed patient with prefrontal repetitive transcranial magnetic stimulation (rTMS) Over 7 years and >2 million stimuli. Brain stimulation Li, X., Fryml, L., Rodriguez, J. J., Taylor, J., Borckardt, J. J., Short, B., Sahlem, G., Roberts, D., George, M. S. 2014; 7 (6): 919-21

  View details for DOI 10.1016/j.brs.2014.09.005

  View details for PubMedID 25440291