Dr. Boris Heifets, MD, PhD, is a board certified anesthesiologist who specializes in providing anesthesia for neurological surgery. He has practiced at Stanford since 2010.
After completing residency training at Stanford, Dr. Heifets completed fellowship training in neuroanesthesiology, also at Stanford. In addition to treating patients, Dr. Heifets also spends a significant amount of time in the lab, where he is investigating the ways in which psychiatric therapies change the function of neural circuits and synapses in the brain.
Dr. Heifets has a special interest in neural stimulation-based treatments for psychiatric and neurological disorders.
Assistant Professor - Med Center Line, Anesthesiology, Perioperative and Pain Medicine
Honors & Awards
K08 Mentored Clinical Scientist Research Career Development Award, National Institute of Mental Health (2017-2021)
Mentored Research Training Grant - Basic Science, Foundation for Anesthesia Education and Research (2013-2015)
Oustanding Contributions to Anesthesia Research, Department of Anesthesiology, Pain & Perioperative Medicine (2013)
Internal Grant Program Award, Department of Anesthesiology, Pain & Perioperative Medicine (2012)
Fellowship:Stanford University Anesthesiology Residency (2016) CA
Medical Education:Albert Einstein College of Medicine Office of the Registrar (2009) NY
Board Certification: Anesthesia, American Board of Anesthesiology (2014)
Residency:Stanford University School of Medicine (2013) CA
Internship:Memorial Sloan-Kettering Cancer Center (2010) NY
Fellowship, Stanford Hospital & Clinics, Research (2013)
PhD, Albert Einstein College of Medicine, Neuroscience (2009)
BS, Yale University, Psychobiology/Neuroscience (1999)
Current Research and Scholarly Interests
Harnessing synaptic plasticity to treat neuropsychiatric disease
Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism.
The American journal of psychiatry
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 DOI 10.1176/appi.ajp.2018.18020138
View details for PubMedID 30153752
5-HT release in nucleus accumbens rescues social deficits in mouse autism model.
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 DOI 10.1038/s41586-018-0416-4
View details for PubMedID 30089910
Fluid management concepts for severe neurological illness: an overview.
Current opinion in anaesthesiology
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 DOI 10.1097/ACO.0000000000000629
View details for PubMedID 30015638
Native System and Cultured Cell Electrophysiology for Investigating Anesthetic Mechanisms.
Methods in enzymology
2018; 602: 301–38
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 DOI 10.1016/bs.mie.2018.01.012
View details for PubMedID 29588037
Rabies screen reveals GPe control of cocaine-triggered plasticity.
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 DOI 10.1038/nature23888
View details for PubMedID 28902833
Case Report of an Awake Craniotomy in a Patient With Eisenmenger Syndrome.
A & A case reports
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
LIPPINCOTT WILLIAMS & WILKINS. 2016
View details for Web of Science ID 000403582200157
MDMA as a Probe and Treatment for Social Behaviors.
2016; 166 (2): 269–72
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 DOI 10.1016/j.cell.2016.06.045
View details for PubMedID 27419864
Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens.
2014; 345 (6196): 535-542
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
LIPPINCOTT WILLIAMS & WILKINS. 2014: S144
View details for Web of Science ID 000209827600126
IMPROVING DEEP BRAIN STIMULATION THROUGH TARGETED SYNAPTIC MODIFICATION
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.) 2013
Endocannabinoid Signaling and Long-Term Synaptic Plasticity
ANNUAL REVIEW OF PHYSIOLOGY
2009; 71: 283-306
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
2008; 105 (29): 10250-10255
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
2007; 54 (5): 801-812
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
2002; 82 (4): 828-838
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
2002; 37 (2): 103-113
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
2002; 8 (4): BR105-12
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 2000; 284 (17): 2190-2190
Anticonvulsant efficacy of N-methyl-D-aspartate antagonists against convulsions induced by cocaine
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
1999; 289 (2): 703-711
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