Boris Heifets

All Publications

• An immune signature of postoperative cognitive decline: A prospective cohort study. International journal of surgery (London, England) Verdonk, F., Cambriel, A., Hedou, J., Ganio, E., Bellan, G., Gaudilliere, D., Einhaus, J., Sabayev, M., Stelzer, I. A., Feyaerts, D., Bonham, A. T., Ando, K., Choisy, B., Drover, D., Heifets, B., Chretien, F., Aghaeepour, N., Angst, M. S., Molliex, S., Sharshar, T., Gaillard, R., Gaudilliere, B. 2024

  Abstract

  Postoperative cognitive decline (POCD) is the predominant complication affecting patients over 60 years old following major surgery, yet its prediction and prevention remain challenging. Understanding the biological processes underlying the pathogenesis of POCD is essential for identifying mechanistic biomarkers to advance diagnostics and therapeutics. This study aimed to provide a comprehensive analysis of immune cell trajectories differentiating patients with and without POCD and to derive a predictive score enabling the identification of high-risk patients during the preoperative period.Twenty-six patients aged 60 years old and older undergoing elective major orthopedic surgery were enrolled in a prospective longitudinal study, and the occurrence of POCD was assessed seven days after surgery. Serial samples collected before surgery, and one, seven, and 90 days after surgery were analyzed using a combined single-cell mass cytometry and plasma proteomic approach. Unsupervised clustering of the high-dimensional mass cytometry data was employed to characterize time-dependent trajectories of all major innate and adaptive immune cell frequencies and signaling responses. Sparse machine learning coupled with data-driven feature selection was applied to the pre-surgery immunological dataset to classify patients at risk for POCD.The analysis identified cell-type and signaling-specific immune trajectories differentiating patients with and without POCD. The most prominent trajectory features revealed early exacerbation of JAK/STAT and dampening of inhibitory κB and nuclear factor-κB immune signaling responses in patients with POCD. Further analyses integrating immunological and clinical data collected before surgery identified a preoperative predictive model comprising one plasma protein and ten immune cell features that classified patients at risk for POCD with excellent accuracy (AUC=0.80, P=2.21e-02 U-test).Immune system-wide monitoring of patients over 60 years old undergoing surgery unveiled a peripheral immune signature of POCD. A predictive model built on immunological data collected before surgery demonstrated greater accuracy in predicting POCD compared to known clinical preoperative risk factors, offering a concise list of biomarker candidates to personalize perioperative management.

  View details for DOI 10.1097/JS9.0000000000002118

  View details for PubMedID 39411891

• Opioids Diminish the Placebo Antidepressant Response: A Post Hoc Analysis of a Randomized Controlled Ketamine Trial. medRxiv : the preprint server for health sciences Lii, T. R., Flohr, J. R., Okada, R. L., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2024

  Abstract

  The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses.This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment.The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity.This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies.Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

  View details for DOI 10.1101/2024.09.24.24314243

  View details for PubMedID 39399033

  View details for PubMedCentralID PMC11469457

• Ketamine, the First Associative Anesthetic? Some Considerations on Classifying Psychedelics, Entactogens, and Dissociatives. The American journal of psychiatry Denomme, N., Heifets, B. D. 2024; 181 (9): 784-786

  View details for DOI 10.1176/appi.ajp.20240644

  View details for PubMedID 39217435

• Prevalence and characteristics of preoperative patients with depression. British journal of anaesthesia Hietamies, T. M., Smith, A. E., Lii, T. R., Muzzall, E., Flohr, J., Okada, R. L., Andriella, Z. G., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Heifets, B. D. 2024

  Abstract

  Within the perioperative period, depression-related diagnoses are associated with postoperative complications. We developed a perioperative depression screening programme to assess disease prevalence and feasibility for intervention.Adult patients in multiple surgical departments at a single academic centre were screened for depression via the electronic health record patient portal or preoperative anaesthesia clinic before surgery, using the Patient Health Questionnaire (PHQ)-2 and -8. We utilised a broad method, screening all patients, and a focused method, only screening patients with a history of depression. Logistic regression was used to identify characteristics associated with clinically significant depression (PHQ-8 ≥10). Symptomatic patients were administered a brief psychoeducational intervention and referred for mental health services.A total of 3735 patients were identified by the broad and focused screens, of whom 2940 (79%) returned PHQ-2 data and were included in analysis. The broad screen (N=1216) found 46 (4%) patients who reported symptoms of moderate or greater severity. The focused screen (N=1724) found 242 (14%) patients with symptoms of moderate or greater severity and over all higher rates of depression across the symptom severity scale. Using the total screened pool, logistic regression identified a history of depression as the strongest associated patient characteristic variable but this did not capture most cases. Finally, we found that 66% of patients who were contacted about mental health services accepted referrals or sought outside care.At least 4% of preoperative patients have clinically significant symptoms of depression, most of whom do not have a chart history of depression.

  View details for DOI 10.1016/j.bja.2024.04.017

  View details for PubMedID 38782617

• Neural Circuit Delineation of (±)-3,4-methylenedioxymethamphetamine (MDMA)-evoked Sociability and Fear Memory Deficits Casey, A., Rijsketic, D., Zhao, W., Palmer, A., Salgado, J., Llorach, P., Wall, N., Pomrenze, M., Malenka, R., Heifets, B. ELSEVIER SCIENCE INC. 2024: S254

  View details for Web of Science ID 001282811900602

• Anesthesia as a Control for Blinding in Psychedelic Therapy Hietamies, T., Casey, A., Zhao, W., Rijsketic, D., Deverett, B., Restagar, Z., Heifets, B. ELSEVIER SCIENCE INC. 2024: S199

  View details for Web of Science ID 001282811900467

• Clinical Outcomes and Biomarkers From a Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients Heifets, B., Lii, T., Smith, A., Flohr, J., Nyongesa, C., Cianfichi, L., Hack, L., Schatzberg, A. ELSEVIER SCIENCE INC. 2024: S47

  View details for Web of Science ID 001282811900110

• Opioid Use Diminishes Placebo Antidepressant Response Independently of Pain in a Ketamine Depression Trial: A Post Hoc Analysis Lii, T., Smith, A., Flohr, J., Okada, R., Nyongesa, C., Cianfichi, L., Hack, L., Schatzberg, A., Heifets, B. ELSEVIER SCIENCE INC. 2024: S184-S185

  View details for Web of Science ID 001282811900431

• Comparing the Antisuicidal and Antidepressant Effects of Intravenous Ketamine in Major Depressive Episodes With Suicidal Ideation Bandeira, I. D., Tucciarone, J., Kratter, I. H., Heifets, B. D., Pankow, H., Chang, M., Hawkins, J., Schatzberg, A. F. ELSEVIER SCIENCE INC. 2024: S211

  View details for Web of Science ID 001282811900497

• DREAMING UNDER ANESTHESIA OCCURS DURING PRE-EMERGENCE STATE Ishii, T., Kawai, M., Heifets, B., Chow, H. OXFORD UNIV PRESS INC. 2024

  View details for Web of Science ID 001262172001456

• MDMA enhances empathy-like behaviors in mice via 5-HT release in the nucleus accumbens. Science advances Rein, B., Raymond, K., Boustani, C., Tuy, S., Zhang, J., St Laurent, R., Pomrenze, M. B., Boroon, P., Heifets, B., Smith, M., Malenka, R. C. 2024; 10 (17): eadl6554

  Abstract

  MDMA (3,4-methylenedioxymethamphetamine) is a psychoactive drug with powerful prosocial effects. While MDMA is sometimes termed an "empathogen," empirical studies have struggled to clearly demonstrate these effects or pinpoint underlying mechanisms. Here, we paired the social transfer of pain and analgesia-behavioral tests modeling empathy in mice-with region-specific neuropharmacology, optogenetics, and transgenic manipulations to explore MDMA's action as an empathogen. We report that MDMA, given intraperitoneally or infused directly into the nucleus accumbens (NAc), robustly enhances the social transfer of pain and analgesia. Optogenetic stimulation of 5-HT release in the NAc recapitulates the effects of MDMA, implicating 5-HT signaling as a core mechanism. Last, we demonstrate that systemic MDMA or optogenetic stimulation of NAc 5-HT inputs restores deficits in empathy-like behaviors in the Shank3-deficient mouse model of autism. These findings demonstrate enhancement of empathy-related behaviors by MDMA and implicate 5-HT signaling in the NAc as a core mechanism mediating MDMA's empathogenic effects.

  View details for DOI 10.1126/sciadv.adl6554

  View details for PubMedID 38657057

• Reduction in Trauma-Related Symptoms After Anesthetic-Induced Intra-Operative Dreaming. The American journal of psychiatry Hack, L. M., Sikka, P., Zhou, K., Kawai, M., Chow, H. S., Heifets, B. 2024: appiajp20230698

  View details for DOI 10.1176/appi.ajp.20230698

  View details for PubMedID 38476046

• Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice. bioRxiv : the preprint server for biology Pomrenze, M. B., Vaillancourt, S., Llorach, P., Rijsketic, D. R., Casey, A. B., Gregory, N., Salgado, J. S., Malenka, R. C., Heifets, B. D. 2024

  Abstract

  Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone blocks a direct effect of ketamine at ORs, or whether normal functioning of the OR system is required to realize the full antidepressant effects of treatment. In mice, the effect of ketamine on locomotion, but not analgesia or the forced swim test, was sensitive to naltrexone and was therefore used as a behavioral readout to localize the effect of naltrexone in the brain. We performed whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, and identified the central amygdala (CeA) as the area with greatest difference in cFos intensity. CeA neurons expressing both μOR (MOR) and PKCμ were strongly activated by naltrexone but not ketamine, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that MORs expressed in CeA neurons gate behavioral effects of ketamine but are not direct targets of ketamine.

  View details for DOI 10.1101/2024.03.03.583196

  View details for PubMedID 38496451

  View details for PubMedCentralID PMC10942405

• Expectancy effects in psychedelic trials. Biological psychiatry. Cognitive neuroscience and neuroimaging Szigeti, B., Heifets, B. 2024

  Abstract

  Clinical trials of psychedelic compounds like psilocybin, LSD and DMT have forced a reconsideration of how non-drug factors, like participant expectations, are measured and controlled in mental health research. As doses of these profoundly psychoactive substances increase, so does the difficulty in concealing the treatment condition in the classic double-blind, placebo-controlled trial design. As widespread public enthusiasm for the promise of psychedelic therapy grows, so do questions regarding whether, and how much, trial results are biased by positive expectancy. First, we review the key concepts related to expectancy and its measurement. Then, we review expectancy effects reported in both micro- and macrodose psychedelic trials from the modern era. Finally, we consider expectancy as a discrete physiological process that can be independent of, or even interact with, the drug effect. Expectancy effects can be harnessed to improve treatment outcomes, and can also be actively managed in controlled studies to enhance the rigor and generalizability of future psychedelic trials.

  View details for DOI 10.1016/j.bpsc.2024.02.004

  View details for PubMedID 38387698

• REPETITIVE CONTENT AND CLINICAL REPRODUCIBILITY OF ANESATHESIA DREAMS REPORTED IN BREAST CANCER SURGICAL PATIENTS Shull, M., Strowd, S., Sikka, P., Heifets, B., Chow, H. ELSEVIER. 2024: 40

  View details for Web of Science ID 001295366700108

• Brain-Wide Activity Mapping Reveals a Required Role for the Dorsal Endopiriform Nucleus in MDMA-Evoked Prosocial Behavior Heifets, B. SPRINGERNATURE. 2023: 42-43

  View details for Web of Science ID 001184093500104

• Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nature mental health Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2023; 1 (11): 876-886

  Abstract

  Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. We present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988). Forty adult patients with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during usual anesthesia. All participants, investigators, and direct patient care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (-5.82, 95% CI -13.3 to 1.64, p=0.13). 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias.

  View details for DOI 10.1038/s44220-023-00140-x

  View details for PubMedID 38188539

  View details for PubMedCentralID PMC10769130

• Ketamine's acute effects on negative brain states are mediated through distinct altered states of consciousness in humans. Nature communications Hack, L. M., Zhang, X., Heifets, B. D., Suppes, T., van Roessel, P. J., Yesavage, J. A., Gray, N. J., Hilton, R., Bertrand, C., Rodriguez, C. I., Deisseroth, K., Knutson, B., Williams, L. M. 2023; 14 (1): 6631

  Abstract

  Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain's affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.

  View details for DOI 10.1038/s41467-023-42141-5

  View details for PubMedID 37857620

  View details for PubMedCentralID 5126726

• An orexigenic subnetwork within the human hippocampus. Nature Barbosa, D. A., Gattas, S., Salgado, J. S., Kuijper, F. M., Wang, A. R., Huang, Y., Kakusa, B., Leuze, C., Luczak, A., Rapp, P., Malenka, R. C., Hermes, D., Miller, K. J., Heifets, B. D., Bohon, C., McNab, J. A., Halpern, C. H. 2023

  Abstract

  Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

  View details for DOI 10.1038/s41586-023-06459-w

  View details for PubMedID 37648849

  View details for PubMedCentralID 6468104

• An orexigenic subnetwork within the human hippocampus NATURE Barbosa, D. N., Gattas, S., Salgado, J. S., Kuijper, F., Wang, A. R., Huang, Y., Kakusa, B., Leuze, C., Luczak, A., Rapp, P., Malenka, R. C., Hermes, D., Miller, K. J., Heifets, B. D., Bohon, C., Mcnab, J. A., Halpern, C. H. 2023

  View details for DOI 10.1038/s41586-023-06459

  View details for Web of Science ID 001064862900002

• Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Heifets, B. D., Olson, D. E. 2023

  Abstract

  Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration-factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity-outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.

  View details for DOI 10.1038/s41386-023-01666-5

  View details for PubMedID 37488282

  View details for PubMedCentralID 3573678

• UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Rijsketic, D. R., Casey, A. B., Barbosa, D. A., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M. B., Halpern, C. H., Williams, L. M., Malenka, R. C., Heifets, B. D. 2023

  Abstract

  The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos+ cell density measurements. Psilocybin increased c-Fos expression in subregions of the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while it decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum in a predominantly context-independent manner. To gauge feasibility of future mechanistic studies on ensembles activated by psilocybin, we confirmed activity- and Cre-dependent genetic labeling in a subset of these neurons using TRAP2+/-;Ai14+ mice. Network analyses treating each psilocybin-sensitive cluster as a node indicated that psilocybin disrupted co-activity between highly correlated regions, reduced brain modularity, and dramatically attenuated intermodular co-activity. Overall, our results indicate that main effects of context and psilocybin were robust, widespread, and reorganized network architecture, whereas context×psilocybin interactions were surprisingly sparse.

  View details for DOI 10.1038/s41386-023-01613-4

  View details for PubMedID 37248402

  View details for PubMedCentralID 7007572

• The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis. Journal of affective disorders Hietamies, T. M., McInnes, L. A., Klise, A. J., Worley, M. J., Qian, J. J., Williams, L. M., Heifets, B. D., Levine, S. P. 2023

  Abstract

  Ketamine intravenous therapy (KIT) appears effective for treating depression in controlled trials testing a short series of infusions. A rapidly proliferating number of clinics offer KIT for depression and anxiety, using protocols without a strong evidence basis. Controlled comparison of mood and anxiety from real-world KIT clinics, and the stability of outcomes, is lacking.We performed a retrospective controlled analysis on patients treated with KIT in ten community clinics across the US, between 08/2017-03/2020. Depression and anxiety symptoms were evaluated using the Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS) and the Generalized Anxiety Disorder 7-item (GAD-7) scales, respectively. Comparison data sets from patients who did not undergo KIT were obtained from previously published real-world studies.Of 2758 patients treated, 714 and 836 met criteria for analysis of KIT induction and maintenance outcomes, respectively. Patients exhibited significant and concordant reduction in both anxiety and depression symptoms after induction (Cohen's d = 1.14 and d = 0.9, respectively). Compared to two external datasets of KIT-naive depressed patients or patients starting standard antidepressant therapy, KIT patients experienced a significantly greater reduction in depression symptoms at eight weeks (Cohen's d = -1.03 and d = -0.62 respectively). Furthermore, we identified a subpopulation of late-responders. During maintenance, up to a year post-induction, increases in symptoms were minimal.Due to the retrospective nature of the analyses, interpreting this dataset is limited by incomplete patient information and sample attrition.KIT treatment elicited robust symptomatic relief that remained stable up to one year of follow-up.

  View details for DOI 10.1016/j.jad.2023.04.141

  View details for PubMedID 37201900

• Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients. medRxiv : the preprint server for health sciences Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2023

  Abstract

  BACKGROUND: Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials.METHODS: In a triple-masked, randomized, placebo-controlled trial, 40 adult patients with major depressive disorder were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during anesthesia for routine surgery. The primary outcome was depression severity measured by the Montgomery-Asberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. The secondary outcome was the proportion of participants with clinical response (≥50% reduction in MADRS scores) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received.RESULTS: Mean MADRS scores did not differ between groups at screening or pre-infusion baseline. The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13). Clinical response rates were similar between groups (60% versus 50% on day 1) and comparable to previous studies of ketamine in depressed populations. Secondary and exploratory outcomes found no evidence of benefit for ketamine. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions.CONCLUSION: A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias. ( ClinicalTrials.gov number, NCT03861988 ).

  View details for DOI 10.1101/2023.04.28.23289210

  View details for PubMedID 37205558

• Brain-Wide Activity Mapping Reveals a Required Role for the Dorsal Endopiriform Nucleus in MDMA-Evoked Prosocial Behavior Heifets, B., Rijsketic, D., Salgado, J., Wall, N., Ramirez-Ovalle, G., Llorach, P., Lopez, R., Casey, A., Hietamies, T., Rastegar, Z., Barbosa, D., Beier, K., Malenka, R. ELSEVIER SCIENCE INC. 2023: S57-S58

  View details for Web of Science ID 000993018500139

• Ketamine's Acute Effects on Negative Brain States are Mediated Through Distinct Altered States in Humans Zhang, X., Hack, L., Heifets, B., Suppes, T., Van Roessel, P., Yesavage, J., Gray, N., Hilton, R., Rodriguez, C., Deisseroth, K., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2023: S312

  View details for Web of Science ID 000993018500757

• Acute Effects of MDMA on Negative Affective Brain Circuit Function: A Randomized Controlled Mechanistic Trial Hack, L., Zhang, X., Heifets, B., Suppes, T., van Roessel, P., Yesavage, J., Gray, N., Hilton, R., Rodriguez, C., Deisseroth, K., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2023: S88

  View details for Web of Science ID 000993018500209

• Acute Effects of MDMA on Intrinsic Functional Connectomes Associated With Altered States of Consciousness and Defensiveness Zhang, X., Hack, L., Heifets, B., Suppes, T., van Roessel, P., Yesavage, J., Gray, N., Hilton, R., Rodriguez, C., Deisseroth, K., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2023: S87-S88

  View details for Web of Science ID 000993018500208

• UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. bioRxiv : the preprint server for biology Rijsketic, D. R., Casey, A. B., Barbosa, D. A., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M., Halpern, C. H., Williams, L. M., Malenka, R. C., Heifets, B. D. 2023

  Abstract

  The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos + cell density measurements. Psilocybin increased c-Fos expression in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus and decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum. Main effects of context and psilocybin-treatment were robust, widespread, and spatially distinct, whereas interactions were surprisingly sparse.

  View details for DOI 10.1101/2023.02.19.528997

  View details for PubMedID 36865251

  View details for PubMedCentralID PMC9980055

• A Protocol for Reducing Intensive Care Utilization After Craniotomy: A 3-Year Assessment. Neurosurgery Ruiz Colón, G. D., Ohkuma, R., Pendharkar, A. V., Heifets, B. D., Li, G., Lu, A., Gephart, M. H., Ratliff, J. K. 2023

  Abstract

  Craniotomy patients have traditionally received intensive care unit (ICU) care postoperatively. Our institution developed the "Non-Intensive CarE" (NICE) protocol to identify craniotomy patients who did not require postoperative ICU care.To determine the longitudinal impact of the NICE protocol on postoperative length of stay (LOS), ICU utilization, readmissions, and complications.In this retrospective cohort study, our institution's electronic medical record was queried to identify craniotomies before protocol deployment (May 2014-May 2018) and after deployment (May 2018-December 2021). The primary end points were average postoperative LOS and ICU utilization; secondary end points included readmissions, reoperation, and postoperative complications rate. End points were compared between pre- and postintervention cohorts.Four thousand eight hundred thirty-seven craniotomies were performed from May 2014 to December 2021 (2302 preprotocol and 2535 postprotocol). Twenty-one percent of postprotocol craniotomies were enrolled in the NICE protocol. After protocol deployment, the overall postoperative LOS decreased from 4.0 to 3.5 days (P = .0031), which was driven by deceased postoperative LOS among protocol patients (average 2.4 days). ICU utilization decreased from 57% of patients to 42% (P < .0001), generating ∼$760 000 in savings. Return to the ICU and complications decreased after protocol deployment. 5.8% of protocol patients had a readmission within 30 days; none could have been prevented through ICU stay.The NICE protocol is an effective, sustainable method to increase ICU bed availability and decrease costs without changing outcomes. To our knowledge, this study features the largest series of patients enrolling in an ICU utilization reduction protocol. Careful patient selection is a requirement for the success of this approach.

  View details for DOI 10.1227/neu.0000000000002337

  View details for PubMedID 36639854

• Cervical sympathectomy to treat cerebral vasospasm: a scoping review. Regional anesthesia and pain medicine Bombardieri, A. M., Heifets, B. D., Treggiari, M., Albers, G. W., Steinberg, G. K., Heit, J. J. 2022

  Abstract

  Delayed cerebral ischemia (DCI) is the second-leading cause of death and disability in patients with aneurysmal subarachnoid hemorrhage (aSAH), and is associated with cerebral arterial vasospasm (CAV). Current treatments for CAV are expensive, invasive, and have limited efficacy. Cervical sympathetic block (CSB) is an underappreciated, but potentially highly effective therapy for CAV.To provide a comprehensive review of the preclinical and human literature pertinent to CSB in the context of CAV.This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. We conducted a literature search using Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science until February 2022, to identify abstracts, conference proceedings, and full-text papers pertinent to cervical sympathectomy and CAV in animal/adult patients.We included six human and six experimental studies. Human studies were mostly prospective observational, except one retrospective and one randomized clinical trial, and used various imaging modalities to measure changes in arterial diameter after the block. Studies that used digital subtraction angiography showed an improvement in cerebral perfusion without change in vessel diameter. Transcranial Doppler studies found an approximately 15% statistically significant decrease in velocities consistent with arterial vasodilatation. Overall, the results suggest an increase in cerebral arterial diameter and neurological improvement in patients receiving a CSB. Animal studies demonstrate that sympathetic system ablation vasodilates cerebral vasculature and decreases the incidence of symptomatic vasospasm.This scoping review suggests that CSB may be a viable option for treatment and prevention of CAV/DCI in patients with aSAH, although the included studies were heterogeneous, mostly observational, and with a small sample size. Further research is needed to standardize the technique and prove its effectiveness to treat patients suffering of CAV/DCI after aSAH.

  View details for DOI 10.1136/rapm-2022-103999

  View details for PubMedID 36424089

• Intraoperative Anesthetic Probes of Brain Health: Ketamine as a Canary in the Coal Mine? Anesthesia and analgesia Reese, M., Heifets, B. D., Berger, M. 2022; 135 (4): 679-682

  View details for DOI 10.1213/ANE.0000000000005965

  View details for PubMedID 36108180

• Modulation of 5-HT release by dynorphin mediates social deficits during opioid withdrawal. Neuron Pomrenze, M. B., Cardozo Pinto, D. F., Neumann, P. A., Llorach, P., Tucciarone, J. M., Morishita, W., Eshel, N., Heifets, B. D., Malenka, R. C. 2022

  Abstract

  Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid withdrawal in mice require activation of kappa opioid receptors (KORs) in the nucleus accumbens (NAc) medial shell. Blockade of release from dynorphin (Pdyn)-expressing dorsal raphe neurons (DRPdyn), but not from NAcPdyn neurons, prevents these deficits in prosocial behaviors. Conversely, optogenetic activation of DRPdyn neurons reproduced NAc KOR-dependent decreases in sociability. Deletion of KORs from serotonin (5-HT) neurons, but not from NAc neurons or dopamine (DA) neurons, prevented sociability deficits during withdrawal. Finally, measurements with the genetically encoded GRAB5-HT sensor revealed that during withdrawal KORs block the NAc 5-HT release that normally occurs during social interactions. These results define a neuromodulatory mechanism that is engaged during protracted opioid withdrawal to induce maladaptive deficits in prosocial behaviors, which in humans contribute to relapse.

  View details for DOI 10.1016/j.neuron.2022.09.024

  View details for PubMedID 36202097

• Anesthetic-Induced Intraoperative Dream Associated With Remission of a Psychiatric Disorder: A Case Report. A&A practice Chow, H. S., Hack, L. M., Kawai, M., Heifets, B. D. 2022; 16 (8): e01613

  Abstract

  Trauma is associated with debilitating acute and posttraumatic stress disorders, which have limited treatment options. We report on a patient undergoing surgical hand repair after a recent knife attack who experienced vivid dreaming and subsequent remission of acute stress disorder. After local anesthesia with propofol sedation she recalled a dream wherein she relived the attack, sought medical care, completed surgery, and returned home with a healed hand. While intraoperative dreaming is common, this case details potential associations between anesthetic state, dreaming, intraoperative electroencephalography, and remission of a psychiatric disorder. Our experience suggests a novel intervention for stress disorders.

  View details for DOI 10.1213/XAA.0000000000001613

  View details for PubMedID 35952341

• Deconstructing Ketamine-Induced Changes in Cortisol and Dissociative and Affective States in a Controlled Mechanistic Study Hack, L. M., Zhang, X., Brawer, J., Gray, N., Heifets, B., Suppes, T., van Roessel, P., Rodriguez, C., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2022: S178-S179

  View details for Web of Science ID 000789022200436

• An immune signature of postoperative cognitive dysfunction (POCD) Verdonk, F., Tsai, A. S., Hedou, J., Heifets, B. D., Gaudilliere, D., Bellan, G., Sharshar, T., Gaillard, R., Molliex, S., Feyaerts, D., Stelzer, I., Ganio, E. A., Sato, M., Bonham, A., Ando, K., Aghaeepour, N., Angst, M. S., Gaudilliere, B. LIPPINCOTT WILLIAMS & WILKINS. 2022: 577-578

  View details for Web of Science ID 000840283000229

• Acute Ketamine Modulates Cognitive Control Network Activity During Cognitive Inhibition: Evidence From a Mechanistic Trial Zhang, X., Hack, L., Brawer, J., Gray, N., Heifets, B., Suppes, T., van Roessel, P., Rodriguez, C., Knutson, B., Williams, L. ELSEVIER SCIENCE INC. 2022: S225

  View details for Web of Science ID 000789022200552

• Great Expectations: recommendations for improving the methodological rigor of psychedelic clinical trials. Psychopharmacology Aday, J. S., Heifets, B. D., Pratscher, S. D., Bradley, E., Rosen, R., Woolley, J. D. 2022

  Abstract

  RATIONALE: Psychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research.OBJECTIVE: In this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research.RESULTS: Although some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants' expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies are discussed in the context of study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy.CONCLUSION: Incorporating therecommended design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increases the ability to discern treatment-specific effects of psychedelic therapy.

  View details for DOI 10.1007/s00213-022-06123-7

  View details for PubMedID 35359159

• A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. Journal of affective disorders McInnes, L. A., Qian, J. J., Gargeya, R. S., DeBattista, C., Heifets, B. D. 1800

  Abstract

  BACKGROUND: Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices.METHODS: We retrospectively analyzed 9016 depression patients who received KIT between 2016 and 2020 at one of 178 community practices across the United States. Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). The induction phase of KIT was defined to be a series of 4-8 infusions administered over 7 to 28 days.RESULTS: Among the 537 patients who underwent induction and had sufficient data, 53.6% of patients showed a response (≥50% reduction in PHQ-9 score) at 14-31 days post-induction and 28.9% remitted (PHQ-9 score drop to <5). The effect size was d=1.5. Among patients with baseline suicidal ideation (SI), 73.0% exhibited a reduction in SI. A subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI. The response rate was uniform across 4 levels of baseline depression severity. However, more severe illness was weakly correlated with a greater drop in scores while remission status was weakly inversely correlated with depression severity. Kaplan-Meier analyses showed that a patient who responds to KIT induction has approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions.CONCLUSION: KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened.

  View details for DOI 10.1016/j.jad.2021.12.097

  View details for PubMedID 35027209

• Local accumbens invivo imaging during deep brain stimulation reveals a strategy-dependent amelioration of hedonic feeding. Proceedings of the National Academy of Sciences of the United States of America Wu, H., Kakusa, B., Neuner, S., Christoffel, D. J., Heifets, B. D., Malenka, R. C., Halpern, C. H. 1800; 119 (1)

  Abstract

  Impulsive overeating is a common, disabling feature of eating disorders. Both continuous deep brain stimulation (DBS) and responsive DBS, which limits current delivery to pathological brain states, have emerged as potential therapies. We used invivo fiber photometry in wild-type, Drd1-cre, and A2a-cre mice to 1) assay subtype-specific medium spiny neuron (MSN) activity of the nucleus accumbens (NAc) during hedonic feeding of high-fat food, and 2) examine DBS strategy-specific effects on NAc activity. D1, but not D2, NAc GCaMP activity increased immediately prior to high-fat food approach. Responsive DBS triggered a GCaMP surge throughout the stimulation period and durably reduced high-fat intake. However, with continuous DBS, this surge decayed, and high-fat intake reemerged. Our results argue for a stimulation strategy-dependent modulation of D1 MSNs with a more sustained decrease in consumption with responsive DBS. This study illustrates the important role invivo imaging can play in understanding effects of such novel therapies.

  View details for DOI 10.1073/pnas.2109269118

  View details for PubMedID 34921100

• Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Walsh, J. J., Llorach, P., Cardozo Pinto, D. F., Wenderski, W., Christoffel, D. J., Salgado, J. S., Heifets, B. D., Crabtree, G. R., Malenka, R. C. 2021

  Abstract

  Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.

  View details for DOI 10.1038/s41386-021-01091-6

  View details for PubMedID 34239048

• Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin. Proceedings of the National Academy of Sciences of the United States of America Christoffel, D. J., Walsh, J. J., Hoerbelt, P., Heifets, B. D., Llorach, P., Lopez, R. C., Ramakrishnan, C., Deisseroth, K., Malenka, R. C. 2021; 118 (24)

  Abstract

  The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or medial prefrontal cortex (mPFC) inputs. In contrast, 5-HT reduced EPSCs generated by inputs from all areas except the mPFC. Release of endogenous DA and 5-HT by methamphetamine (METH) and (±)3,4-methylenedioxymethamphetamine (MDMA), respectively, recapitulated these input-specific synaptic effects. Optogenetic inhibition of PVT inputs enhanced cocaine-conditioned place preference, whereas mPFC input inhibition reduced the enhancement of sociability elicited by MDMA. These findings suggest that the distinct, input-specific filtering of excitatory inputs in the NAc by DA and 5-HT contribute to their discrete behavioral effects.

  View details for DOI 10.1073/pnas.2106648118

  View details for PubMedID 34103400

• Unraveling the opioid actions of S-ketamine and R-ketamine: comment on Bonaventura et al. Molecular psychiatry Heifets, B. D., Bentzley, B. S., Williams, N., Schatzberg, A. F. 2021

  View details for DOI 10.1038/s41380-021-01167-1

  View details for PubMedID 34006965

• Brain wide mapping of neuronal activity evoked by MDMA, a rapid-acting therapy for post-traumatic stress disorder Ryskamp, D., Llorach, P., Schlozman, S., Rastegar, Z., Salgado, J. S., Hietamies, T., Barbosa, D. A., Pinto, D., Neuman, P., Hell, M., Beier, K., Malenka, R. C., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2021: 583-584

  View details for Web of Science ID 000752526600251

• Brain-wide unbiased mapping of neuronal activity pinpoints ketamine's interaction with the opioid system in mice Ryskamp, D., Hietamies, T., Schlozman, S., Llorach, P., Salgado, J. S., Barbosa, D. A., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2021: 582

  View details for Web of Science ID 000752526600250

• Antidepressant Effect of Intraoperative Ketamine in Patients with Major Depression Undergoing Surgery: An Open-Label Pilot Study Lii, T., Okada, R., Pfaff, K., Thordstein, R., Cianfichi, L., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2021: 876

  View details for Web of Science ID 000752526600375

• Morphine Tolerance and Reward is Regulated by Aldehyde Dehydrogenase-2 in Mice Zambelli, V., Salgado, J. S., Heifets, B. D., Tawfik, V., Gross, E. R. LIPPINCOTT WILLIAMS & WILKINS. 2021: 626-627

  View details for Web of Science ID 000752526600272

• Input-specific modulation of murine nucleus accumbens differentially regulates hedonic feeding. Nature communications Christoffel, D. J., Walsh, J. J., Heifets, B. D., Hoerbelt, P., Neuner, S., Sun, G., Ravikumar, V. K., Wu, H., Halpern, C. H., Malenka, R. C. 2021; 12 (1): 2135

  Abstract

  Hedonic feeding is driven by the "pleasure" derived from consuming palatable food and occurs in the absence of metabolic need. It plays a critical role in the excessive feeding that underlies obesity. Compared to other pathological motivated behaviors, little is known about the neural circuit mechanisms mediating excessive hedonic feeding. Here, we show that modulation of prefrontal cortex (PFC) and anterior paraventricular thalamus (aPVT) excitatory inputs to the nucleus accumbens (NAc), a key node of reward circuitry, has opposing effects on high fat intake in mice. Prolonged high fat intake leads to input- and cell type-specific changes in synaptic strength. Modifying synaptic strength via plasticity protocols, either in an input-specific optogenetic or non-specific electrical manner, causes sustained changes in high fat intake. These results demonstrate that input-specific NAc circuit adaptations occur with repeated exposure to a potent natural reward and suggest that neuromodulatory interventions may be therapeutically useful for individuals with pathologic hedonic feeding.

  View details for DOI 10.1038/s41467-021-22430-7

  View details for PubMedID 33837200

• 5-HT modulation of a medial septal circuit tunes social memory stability. Nature Wu, X., Morishita, W., Beier, K. T., Heifets, B. D., Malenka, R. C. 2021

  Abstract

  Social memory-the ability to recognize and remember familiar conspecifics-is critical for the survival of an animal in its social group1,2. The dorsal CA2 (dCA2)3-5 and ventral CA1 (vCA1)6 subregions of the hippocampus, and their projection targets6,7, have important roles in social memory. However, the relevant extrahippocampal input regions remain poorly defined. Here we identify the medial septum (MS) as a dCA2 input region that is critical for social memory and reveal that modulation of the MS by serotonin (5-HT) bidirectionally controls social memory formation, thereby affecting memory stability. Novel social interactions increase activity in dCA2-projecting MS neurons and induce plasticity at glutamatergic synapses from MS neurons onto dCA2 pyramidal neurons. The activity of dCA2-projecting MS cells is enhanced by the neuromodulator 5-HT acting on 5-HT1B receptors. Moreover, optogenetic manipulation of median raphe 5-HT terminals in the MS bidirectionally regulates social memory stability. This work expands our understanding of the neural mechanisms by which social interactions lead to social memory and provides evidence that 5-HT has a critical role in promoting not only prosocial behaviours8,9, but also social memory, by influencing distinct target structures.

  View details for DOI 10.1038/s41586-021-03956-8

  View details for PubMedID 34616037

• Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine. The Journal of neuroscience : the official journal of the Society for Neuroscience De Gregorio, D., Aguilar-Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., Gobbi, G. 2020

  Abstract

  A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.

  View details for DOI 10.1523/JNEUROSCI.1659-20.2020

  View details for PubMedID 33257322

• Piercing the Ketamine Cloud ANESTHESIOLOGY Heifets, B. D. 2020; 133 (5): 970–72

  View details for DOI 10.1097/ALN.0000000000003562

  View details for Web of Science ID 000578753200006

  View details for PubMedID 32946552

• Brain-wide unbiased mapping of neuronal activity pinpoints ketamine's interaction with the opioid system in mice Ryskamp, D., Salgado, J., Barbosa, D. A., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2020: 415

  View details for Web of Science ID 000619264500195

• Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning. Neuron Steinberg, E. E., Gore, F. n., Heifets, B. D., Taylor, M. D., Norville, Z. C., Beier, K. T., Földy, C. n., Lerner, T. N., Luo, L. n., Deisseroth, K. n., Malenka, R. C. 2020

  Abstract

  The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice. CeA→SNL neural responses to appetitive and aversive stimuli were modulated by expectation and magnitude consistent with a population-level salience signal, which was required for Pavlovian conditioned reward-seeking and defensive behaviors. CeA→SNL terminal activation elicited reinforcement when linked to voluntary actions but failed to support Pavlovian associations that rely on incentive value signals. Consistent with a disinhibitory mechanism, CeA inputs preferentially target SNL GABA neurons, and CeA→SNL and SNL dopamine neurons respond similarly to salient stimuli. Collectively, our results suggest that amygdala-nigra interactions represent a previously unappreciated mechanism for influencing emotional behaviors.

  View details for DOI 10.1016/j.neuron.2020.03.016

  View details for PubMedID 32294466

• Better living through chemistry: MDMA's prosocial mechanism as a starting point for improved therapeutics. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Heifets, B. D., Malenka, R. C. 2020

  View details for DOI 10.1038/s41386-020-00803-8

  View details for PubMedID 32792684

• A newly developed anesthetic based on a unique chemical core. Proceedings of the National Academy of Sciences of the United States of America Cayla, N. S., Dagne, B. A., Wu, Y., Lu, Y., Rodriguez, L., Davies, D. L., Gross, E. R., Heifets, B. D., Davies, M. F., MacIver, M. B., Bertaccini, E. J. 2019

  Abstract

  Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that is highly selective for the slow type of gamma-aminobutyric acid type A receptor (GABAAR) could have potent anesthetic efficacy with limited cardiovascular effects. Through in silico screening using our GABAAR model, we identified a class of lead compounds that are N-arylpyrrole derivatives. Electrophysiological analyses using both an in vitro expression system and intact rodent hippocampal brain slice recordings demonstrate a GABAAR-mediated mechanism. In vivo experiments also demonstrate overt anesthetic activity in both tadpoles and rats with a potency slightly greater than that of propofol. Unlike the clinically approved GABAergic anesthetic etomidate, the chemical structure of our N-arylpyrrole derivative is devoid of the chemical moieties producing adrenal suppression. Our class of compounds also shows minimal to no suppression of blood pressure, in marked contrast to the hemodynamic effects of propofol. These compounds are derived from chemical structures not previously associated with anesthesia and demonstrate that selective targeting of GABAAR-slow subtypes may eliminate the hemodynamic side effects associated with conventional IV anesthetics.

  View details for DOI 10.1073/pnas.1822076116

  View details for PubMedID 31308218

• Disruptive Psychopharmacology. JAMA psychiatry Heifets, B. D., Malenka, R. C. 2019

  View details for DOI 10.1001/jamapsychiatry.2019.1145

  View details for PubMedID 31241740

• 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

• Rigorous Translational Models Are Key to Studying Ketamine's Antidepressant Mechanism: Response to Wang and Kaplin AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (5): 412

  View details for DOI 10.1176/appi.ajp.2019.19010044r

  View details for Web of Science ID 000466364500015

• Rigorous Translational Models Are Key to Studying Ketamine's Antidepressant Mechanism: Response to Wang and Kaplin. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (5): 412

  View details for PubMedID 31039633

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for DOI 10.1176/appi.ajp.2018.18091061r

  View details for Web of Science ID 000462846900011

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for PubMedID 30818989

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for PubMedID 30818991

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for DOI 10.1176/appi.ajp.2018.18111231r

  View details for Web of Science ID 000462846900013

• Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Science translational medicine Heifets, B. D., Salgado, J. S., Taylor, M. D., Hoerbelt, P. n., Cardozo Pinto, D. F., Steinberg, E. E., Walsh, J. J., Sze, J. Y., Malenka, R. C. 2019; 11 (522)

  Abstract

  The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region-specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA's prosocial effect. MDMA's acute rewarding properties, in contrast, require dopaminergic signaling. MDMA's prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA's prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.

  View details for DOI 10.1126/scitranslmed.aaw6435

  View details for PubMedID 31826983

• 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 < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

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

  View details for PubMedID 31467392

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. AMER PSYCHIATRIC PUBLISHING, INC. 2018: 1205–15

  View details for DOI 10.1176/appi.ajp.2018.18020138

  View details for Web of Science ID 000451749000012

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. The American journal of psychiatry Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. 2018: appiajp201818020138

  Abstract

  OBJECTIVE: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.METHOD: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.RESULTS: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.CONCLUSIONS: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

  View details for PubMedID 30153752

• 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature Walsh, J. J., Christoffel, D. J., Heifets, B. D., Ben-Dor, G. A., Selimbeyoglu, A., Hung, L. W., Deisseroth, K., Malenka, R. C. 2018

  Abstract

  Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

  View details for PubMedID 30089910

• Case Report of an Awake Craniotomy in a Patient With Eisenmenger Syndrome. A&A practice Heifets, B. D., Crawford, E., Jackson, E., Brodt, J., Jaffe, R. A., Burbridge, M. A. 2018; 10 (9): 219-222

  Abstract

  We present a detailed report of an awake craniotomy for recurrent third ventricular colloid cyst in a patient with severe pulmonary arterial hypertension in the setting of Eisenmenger syndrome, performed 6 weeks after we managed the same patient for a more conservative procedure. This patient has a high risk of perioperative mortality and may be particularly susceptible to perioperative hemodynamic changes or fluid shifts. The risks of general anesthesia induction and emergence must be balanced against the risks inherent in an awake craniotomy on a per case basis.

  View details for DOI 10.1213/XAA.0000000000000664

  View details for PubMedID 29708913

  View details for PubMedCentralID PMC6309536

• KETAMINE'S ANTIDEPRESSANT EFFECT IS BLOCKED BY A MU-OPIOID RECEPTOR ANTAGONIST IN HUMANS AND MICE Heifets, B. D., Williams, N., Sudheimer, K., Pankow, H., Blasey, C., Lyons, D., Schatzberg, A. F. LIPPINCOTT WILLIAMS & WILKINS. 2018: 343

  View details for Web of Science ID 000460106500197

• Fluid management concepts for severe neurological illness: an overview. Current opinion in anaesthesiology Heifets, B. D., Tanaka, P. n., Burbridge, M. A. 2018

  Abstract

  The acute care of a patient with severe neurological injury is organized around one relatively straightforward goal: avoid brain ischemia. A coherent strategy for fluid management in these patients has been particularly elusive, and a well considered fluid management strategy is essential for patients with critical neurological illness.In this review, several gaps in our collective knowledge are summarized, including a rigorous definition of volume status that can be practically measured; an understanding of how electrolyte derangements interact with therapy; a measurable endpoint against which we can titrate our patients' fluid balance; and agreement on the composition of fluid we should give in various clinical contexts.As the possibility grows closer that we can monitor the physiological parameters with direct relevance for neurological outcomes and the various complications associated with neurocritical illness, we may finally move away from static therapy recommendations, and toward individualized, precise therapy. Although we believe therapy should ultimately be individualized rather than standardized, it is clear that the monitoring tools and analytical methods used ought to be standardized to facilitate appropriately powered, prospective clinical outcome trials.

  View details for PubMedID 30015638

• Native System and Cultured Cell Electrophysiology for Investigating Anesthetic Mechanisms. Methods in enzymology Hoerbelt, P. n., Heifets, B. D. 2018; 602: 301–38

  Abstract

  Anesthetic agents interact with a variety of ion channels and membrane-bound receptors, often at agent-specific binding sites of a single protein. These molecular-level interactions are ultimately responsible for producing the clinically anesthetized state. Between these two scales of effect, anesthetic agents can be studied in terms of how they impact the physiology of neuronal circuits, individual neurons, and cells expressing individual receptor types. The acutely dissected hippocampal slice is one of the most extensively studied and characterized preparations of intact neural tissue and serves as a highly useful experimental model system to test hypotheses of anesthetic mechanisms. Specific agent-receptor interactions and their effect on excitable membranes can further be defined with molecular precision in cell-based expression systems. We highlight several approaches in these respective systems that we have used and that also have been used by many investigators worldwide. We emphasize economy and quality control, to allow an experimenter to carry out these types of studies in a rigorous and efficient manner.

  View details for PubMedID 29588037

• Rabies screen reveals GPe control of cocaine-triggered plasticity. Nature Beier, K. T., Kim, C. K., Hoerbelt, P. n., Hung, L. W., Heifets, B. D., DeLoach, K. E., Mosca, T. J., Neuner, S. n., Deisseroth, K. n., Luo, L. n., Malenka, R. C. 2017

  Abstract

  Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.

  View details for PubMedID 28902833

• Case Report of an Awake Craniotomy in a Patient With Eisenmenger Syndrome. A & A case reports Heifets, B. D., Crawford, E. n., Jackson, E. n., Brodt, J. n., Jaffe, R. A., Burbridge, M. A. 2017

  Abstract

  We present a detailed report of an awake craniotomy for recurrent third ventricular colloid cyst in a patient with severe pulmonary arterial hypertension in the setting of Eisenmenger syndrome, performed 6 weeks after we managed the same patient for a more conservative procedure. This patient has a high risk of perioperative mortality and may be particularly susceptible to perioperative hemodynamic changes or fluid shifts. The risks of general anesthesia induction and emergence must be balanced against the risks inherent in an awake craniotomy on a per case basis.

  View details for DOI 10.1213/XAA.0000000000000664

  View details for PubMedID 29135526

• BEYOND KETAMINE FOR PSYCHIATRIC DISEASE: UNRAVELING THE MURINE NEURAL MECHANISMS OF THE EMPATHOGEN MDMA, A NOVEL, RAPID-ONSET SINGLE-SHOT CLINICAL THERAPY FOR POST-TRAUMATIC STRESS DISORDER Heifets, B. D., Taylor, M., Hung, L. W., Malenka, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000403582200157

• MDMA as a Probe and Treatment for Social Behaviors. Cell Heifets, B. D., Malenka, R. C. 2016; 166 (2): 269–72

  Abstract

  MDMA, better known as the recreational drug "ecstasy," is well known for stimulating a feeling of closeness and empathy in its users. We advocate that exploring its mechanism of action could lead to new treatments for psychiatric conditions characterized by impairments in social behavior.

  View details for PubMedID 27419864

• Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science Schwartz, N., Temkin, P., Jurado, S., Lim, B. K., Heifets, B. D., Polepalli, J. S., Malenka, R. C. 2014; 345 (6196): 535-542

  Abstract

  Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1-triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons. These results demonstrate a previously unknown pathological adaption in a key node of motivational neural circuitry that is required for one of the major sequela of chronic pain states and syndromes.

  View details for DOI 10.1126/science.1253994

  View details for PubMedID 25082697

• HIPPOCAMPAL GABAERGIC FIELD POTENTIALS: A NOVEL HIGH THROUGHPUT SCREEN FOR GENERAL ANESTHETICS IN RAT Nie, J., Sharma, B., Maclver, B., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2014: S144

  View details for Web of Science ID 000209827600126

• IMPROVING DEEP BRAIN STIMULATION THROUGH TARGETED SYNAPTIC MODIFICATION Heifets, B. D., Deisseroth, K., Malenka, R., MacIver, B. LIPPINCOTT WILLIAMS & WILKINS. 2013: 159

  View details for Web of Science ID 000330441700136

• Acute Cardiovascular Toxicity of Low-Dose Intrathecal Ziconotide. Pain medicine (Malden, Mass.) Heifets, B. D., Smith, S. M., Leong, M. S. 2013

  View details for PubMedID 23855951

• Endocannabinoid Signaling and Long-Term Synaptic Plasticity ANNUAL REVIEW OF PHYSIOLOGY Heifets, B. D., Castillo, P. E. 2009; 71: 283-306

  Abstract

  Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the central nervous system. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g., cannabis) and endogenous cannabinoids affect behavior. Because behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long-term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, although remarkably similar at various synapses, are controlled by an array of regulatory influences that we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity.

  View details for DOI 10.1146/annurev.physiol.010908.163149

  View details for Web of Science ID 000264489600014

  View details for PubMedID 19575681

• Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Heifets, B. D., Chevaleyre, V., Castillo, P. E. 2008; 105 (29): 10250-10255

  Abstract

  Retrograde signaling by endocannabinoids (eCBs) mediates a widely expressed form of long-term depression at excitatory and inhibitory synapses (eCB-LTD), involving a reduction in neurotransmitter release. In the hippocampus, eCB-LTD occurs at interneuron (IN)-pyramidal cell (PC) synapses (I-LTD), and its induction requires a presynaptic reduction of cAMP/PKA signaling resulting from minutes of type 1 cannabinoid receptor (CB1R) activation. Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CB1R-containing GABAergic terminals are passive targets of eCBs or whether they actively contribute to induction. Here, we show that the minutes-long induction period for I-LTD may serve as a window to integrate associated spontaneous activity in the same IN receiving the retrograde eCB signal. Indeed, reducing spontaneous IN firing blocked I-LTD, which could be rescued with extra stimulation of inhibitory afferents. Moreover, cell pair recordings showed that a single IN expressed LTD onto a PC only if it was active during eCB signaling. Several methods of disrupting presynaptic Ca(2+) dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca(2+) at the nerve terminal. Finally, inhibiting the Ca(2+)-activated phosphatase, calcineurin, fully blocked I-LTD, but blocking another phosphatase did not. Our findings support a model where both CB1R signaling and IN activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD.

  View details for DOI 10.1073/pnas.0711880105

  View details for Web of Science ID 000257913200072

  View details for PubMedID 18632563

• Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1 alpha NEURON Chevaleyre, V., Heifets, B. D., Kaeser, P. S., Sudhof, T. C., Purpura, D. P., Castillo, P. E. 2007; 54 (5): 801-812

  Abstract

  Endocannabinoids (eCBs) have emerged as key activity-dependent signals that, by activating presynaptic cannabinoid receptors (i.e., CB1) coupled to G(i/o) protein, can mediate short-term and long-term synaptic depression (LTD). While the presynaptic mechanisms underlying eCB-dependent short-term depression have been identified, the molecular events linking CB1 receptors to LTD are unknown. Here we show in the hippocampus that long-term, but not short-term, eCB-dependent depression of inhibitory transmission requires presynaptic cAMP/PKA signaling. We further identify the active zone protein RIM1alpha as a key mediator of both CB1 receptor effects on the release machinery and eCB-dependent LTD in the hippocampus. Moreover, we show that eCB-dependent LTD in the amygdala and hippocampus shares major mechanistic features. These findings reveal the signaling pathway by which CB1 receptors mediate long-term effects of eCBs in two crucial brain structures. Furthermore, our results highlight a conserved mechanism of presynaptic plasticity in the brain.

  View details for DOI 10.1016/j.neuron.2007.05.020

  View details for Web of Science ID 000247329900012

  View details for PubMedID 17553427

• Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures JOURNAL OF NEUROCHEMISTRY Gold, S. J., Heifets, B. D., Pudiak, C. M., Potts, B. W., Nestler, E. J. 2002; 82 (4): 828-838

  Abstract

  G protein-coupled receptor (GPCR) signaling cascades may be key substrates for the antidepressant effects of chronic electroconvulsive seizures (ECS). To better understand changes in these signaling pathways, alterations in levels of mRNA's encoding regulators of G protein signaling (RGS) protein subtypes-2, -4, -7, -8 and -10 were evaluated in rat brain using northern blotting and in situ hybridization. In prefrontal cortex, RGS2 mRNA levels were increased several-fold 2 h following an acute ECS. Increases in RGS8 mRNA were of lesser magnitude (30%), and no changes were evident for the other RGS subtypes. At 24 h following a chronic ECS regimen, RGS4, -7, and -10 mRNA levels were reduced by 20-30%; only RGS10 was significantly reduced 24 h after acute ECS. Levels of RGS2 mRNA were unchanged 24 h following either acute or chronic ECS. In hippocampus, RGS2 mRNA levels were markedly increased 2 h following acute ECS. More modest increases were seen for RGS4 mRNA expression, whereas levels of the other RGS subtypes were unaltered. At 24 h following chronic ECS, RGS7, -8 and -10 mRNA levels were decreased in the granule cell layer, and RGS7 and -8 mRNA levels were decreased in the pyramidal cell layers. Only RGS8 and -10 mRNA levels were significantly reduced in hippocampus 24 h following an acute ECS. Paralleling neocortex, RGS2 mRNA content was unchanged in hippocampus 24 h following either acute or chronic ECS. In ventromedial hypothalamus, RGS4 mRNA content was increased 24 h following chronic ECS, whereas RGS7 mRNA levels were only increased 24 h following an acute ECS. The increased RGS4 mRNA levels in hypothalamus were significant by 2 h following an acute ECS. These studies demonstrate subtype-, time-, and region-specific regulation of RGS proteins by ECS, adaptations that may contribute to the antidepressant effects of this treatment.

  View details for Web of Science ID 000177369300011

  View details for PubMedID 12358788

• The effect of scopolamine in older rabbits tested in the 750 ms delay eyeblink classical conditioning procedure INTEGRATIVE PHYSIOLOGICAL AND BEHAVIORAL SCIENCE Woodruff-Pak, D. S., Green, J. T., Pak, J. T., Heifets, B., Pak, M. H. 2002; 37 (2): 103-113

  Abstract

  We investigated the effect of several doses of scopolamine in older rabbits that were trained for 20 days in the 750 ms delay eyeblink classical conditioning procedure. Our aim was to determine if the scopolamine-injected older rabbit would be a useful model for testing drugs for cognition enhancement in Alzheimer's disease (AD). A total of 39 rabbits with a mean age of 31 months received classical eyeblink conditioning with daily injections of 0.25, 0.75, or 1.5 mg/kg scopolamine hydrobromide or sterile saline vehicle. Doses of 0.75 and 1.5 mg/kg scopolamine significantly impaired acquisition, whereas acquisition was not significantly impaired with 0.25 mg/kg scopolamine. Results exhibit parallels in performance on delay eyeblink classical conditioning between scopolamine-treated older rabbits and human patients diagnosed with AD.

  View details for Web of Science ID 000177491000002

  View details for PubMedID 12186305

• Nefiracetam ameliorates associative learning impairment in the scopolamine-injected older rabbit. Medical science monitor Pak, J., Green, J., Heifets, B., Pak, M., Woodruff-Pak, D. 2002; 8 (4): BR105-12

  Abstract

  The cognition-enhancing drug, nefiracetam, is in Phase III clinical trials to treat memory impairment in Alzheimer's disease (AD). Nefiracetam ameliorates acquisition of delay eyeblink classical conditioning in older rabbits, a form of associative learning with striking behavioral and neurobiological similarities in rabbits and humans. In both species, delay eyeblink conditioning engages the septo-hippocampal cholinergic system and is disrupted when the cholinergic system is antagonized. Delay eyeblink classical conditioning is impaired in normal aging and severely disrupted in AD.To test further the efficacy of nefiracetam in an animal model that mimics some of the neurobiological and behavioral effects present in AD, we tested 56 older rabbits assigned to 7 treatment groups in the 750 ms delay eyeblink conditioning procedure. Older rabbits were injected with 1.5 mg/kg scopolamine to simulate disruption of the cholinergic system in AD. Three doses of nefiracetam (5, 10, or 15 mg/kg) were also injected in older rabbits receiving 1.5 mg/kg scopolamine. Control groups were treated with 1.5 mg/kg scopolamine + vehicle, vehicle alone, or explicitly unpaired presentations of conditioning stimuli and vehicle or 1.5 mg/kg scopolamine + 15 mg/kg nefiracetam.Rabbits injected with 1.5 mg/kg scopolamine alone were impaired, but a dose of 15 mg/kg nefiracetam reversed significantly the behavioral impairment.Nefiracetam had ameliorating effects on a task impaired in AD in an animal model of AD: older rabbits with cholinergic system antagonism.

  View details for PubMedID 11951055

• Chemical analysis of ecstasy pills JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Baggott, M., Heifets, B., Jones, R. T., Mendelson, J., Sferios, E., Zehnder, J. 2000; 284 (17): 2190-2190

  View details for Web of Science ID 000090052600026

  View details for PubMedID 11056589

• Anticonvulsant efficacy of N-methyl-D-aspartate antagonists against convulsions induced by cocaine JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Witkin, J. M., Gasior, M., Heifets, B., Tortella, F. C. 1999; 289 (2): 703-711

  Abstract

  Convulsions associated with cocaine abuse can be life threatening and resistant to standard emergency treatment. Cocaine (75 mg/kg, i. p.) produced clonic convulsions in approximately 90% of male, Swiss-Webster mice. A variety of clinically used antiepileptic agents did not significantly protect against cocaine convulsions (e. g., diazepam and phenobarbital). Anticonvulsants in clinical practice that did significantly protect against convulsion did so only at doses with significant sedative/ataxic effects (e.g., clonazepam and valproic acid). In contrast, functional N-methyl-D-aspartate (NMDA) antagonists all produced dose-dependent and significant protection against the convulsant effects of cocaine. Anticonvulsant efficacy was achieved by blockade of both competitive and noncompetitive modulatory sites on the NMDA receptor complex. Thus, competitive antagonists, ion-channel blockers, polyamine antagonists, and functional blockers of the strychnine-insensitive glycine modulatory site all prevented cocaine seizures. The role of NMDA receptors in the control of cocaine-induced convulsions was further strengthened by the positive correlation between the potencies of noncompetititve antagonists or competitive antagonists to block convulsions and their respective affinities for their specific binding sites on the NMDA receptor complex. Although some NMDA blockers produced profound behavioral side effects at efficacious doses (e.g., noncompetitive antagonists), others (e.g., some low-affinity channel blockers, some competitive antagonists, and glycine antagonists) demonstrated significant and favorable separation between their anticonvulsant and side effect profiles. The present results provide the most extensive evidence to date identifying NMDA receptor blockade as a potential strategy for the discovery of agents for clinical use in averting toxic sequelae from cocaine overdose. Given the literature suggesting a role for these drugs in other areas of drug abuse treatments, NMDA receptor antagonists sit in a unique position as potential therapeutic candidates.

  View details for Web of Science ID 000079857100013

  View details for PubMedID 10215643