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COMMENTARY

Deep Repetitive Transcranial Magnetic Stimulation
for Smoking Cessation: Is Going Deeper Better?
Mera S. Barr and Tony P. George

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n this issue of Biological Psychiatry, Dinur-Klein et al. (1) report
on an impressive proof-of-concept study using a randomized,
double-blind, sham-controlled trial design that demonstrates
10-Hz deep repetitive transcranial magnetic stimulation (TMS)
using H-coil methods administered bilaterally to the dorsolateral
prefrontal cortex (DLPFC) and insular cortex could reduce shortterm biochemically verified cigarette consumption and nicotine
dependence levels and increase short-term and long-term smoking abstinence rates. The lack of observed effects on craving are
not surprising in a clinical trial setting because subjects were at
various stages of cigarette use (no change, reduced, abstinent),
which would have produced significant intersubject variability in
this measure. The effects of 10-Hz repetitive TMS on certain
outcomes (e.g., nicotine dependence) may have been enhanced
through cigarette cue exposure before the stimulation; however,
these effects were underpowered. Nonetheless, this study is a fine
example of a neuroscience-informed, hypothesis-driven addiction
treatment trial that is certain to set the standard for future work in
the field of brain stimulation methods for the treatment of
tobacco dependence.
A decade of research has suggested that superficial brain
stimulation may transiently reduce cravings and consumption in
tobacco-dependent individuals (2). In their timely study, DinurKlein et al. extended previous work and conducted the first
smoking cessation trial employing the H-coil, which has been
shown to target brain regions approximately 5–7 cm deep. This
focal depth with the H-coil is very exciting given its potential to
target the brain reward circuitry that mediates all drugs of
addiction. However, is going deeper better for tobacco treatment
outcomes? The findings from the study by Dinur-Klein et al.
suggest that targeting the insular cortex rather than superficial
brain regions such as the DLPFC may be the key to successful
smoking cessation and possibly better long-term outcomes.
It is unclear if cue exposure reduces nicotine dependence,
reduces level of cravings, or improves abstinence rates. Borrowing
from the posttraumatic stress disorder research conducted by the
same group, this study evaluated if cue exposure—in this case,
observing someone else lighting the subject’s preferred brand of
cigarette—would enhance the effects of repetitive TMS. The
authors suggested that cue exposure before repetitive TMS
activates the neurocircuitry that mediates cue-induced craving
and that repetitive TMS would subsequently disrupt drug-related
memory consolidation. Although this study was underpowered to
evaluate the effects of cue exposure on the outcome measures, it
From the Biobehavioural Addictions and Concurrent Disorders Laboratory,
Schizophrenia Division (MSB, TPG), and Temerty Centre for Therapeutic
Brain Intervention (MSB), Centre for Addiction and Mental Health; and
Department of Psychiatry, Division of Brain and Therapeutics (MSB,
TPG), University of Toronto, Toronto, Canada.
Address correspondence to Tony P. George, M.D., FRCPC, Schizophrenia
Division, Centre for Addiction and Mental Health, 1001 Queen Street
West, Unit 2 Room 118A, Toronto, Ontario M6J 1H4, Canada; E-mail:
tony.george@camh.ca.
Received Aug 5, 2014; revised Aug 6, 2014; accepted Aug 7, 2014.

0006-3223/$36.00
http://dx.doi.org/10.1016/j.biopsych.2014.08.003

raises an interesting question of the possible mechanism through
which repetitive TMS exerts its effects on smoking cessation. Did
repetitive TMS disrupt drug-related memory consolidation? Does
it matter if a smoking cue is observed before 10-Hz deep
repetitive TMS? Although Dinur-Klein et al. offer a host of possible
mechanisms for these effects, it is unlikely that 10-Hz repetitive
TMS disrupts memory consolidation because high-frequency
repetitive TMS has been shown to improve memory (3).
We contend that repetitive TMS effects on synaptic plasticity
alter cortical excitability (Figure 1). There are several lines of
evidence that support our contention. N-methyl-D-aspartate and
gamma-aminobutyric acid (GABA) receptor function contribute to
many forms of neuroplasticity in important ways. Studies of TMS
have elegantly demonstrated that increased frequency is related
to increased GABAB receptor–mediated neurotransmission,
whereas the effects on GABAA activity were related to baseline
level (4). However, all of these studies were conducted in the
motor cortex and not in the DLPFC or insular cortices that were
targeted in the current study. In this regard, neuroimaging studies
have shown that high-frequency repetitive TMS applied to the
left, but not the right, DLPFC increases dopamine in the ipsilateral
anterior cingulate and orbitofrontal cortices (5). The increase of
dopamine with repetitive TMS may be related to its role in
neuroplasticity through the modulation of N-methyl-D-aspartate
receptor–mediated activity (6). Although future studies are
needed to examine the mechanism of repetitive TMS on smoking
cessation, we suggest that the current effects observed in the
study by Dinur-Klein et al. may be mediated through the
concomitant increase of dopamine and GABAB and their modulation of N-methyl-D-aspartate and GABAA receptor activities.
Smoking cessation with repetitive TMS may be related to the
potentiation of prefrontal cortex–mediated cognition. Although
smoking has been associated with both enhanced and reduced
cognition, TMS and neuroimaging studies have demonstrated
reduced GABA levels in the motor and prefrontal cortices of
tobacco-dependent individuals. Reduced GABA levels may underlie the severe cognitive deficits observed with heavier smokers
and account for the high smoking rates among patients with
schizophrenia. Selective prefrontal cortex–mediated cognition
deficits, including working memory and performance on the
Wisconsin Card Sorting Test, have been shown to be related to
smoking cessation failure with pharmacologic treatment (7). In
the current study, could it be possible that smoking cessation was
related to the degree of baseline working memory impairment?
Furthermore, could the response to repetitive TMS be related to
working memory improvement? To help answer these questions,
repetitive TMS has been shown to normalize GABAergic-mediated
gamma (30–50 Hz) oscillations depending on baseline activity
and to improve working memory accuracy among patients with
schizophrenia (3). It is possible that working memory may
represent a neurophysiologic index for predicting smoking
cessation success and an indication that repetitive TMS exerts
its effects through the modulation of neuroplasticity. It appears
that Dinur-Klein et al. missed a golden opportunity to evaluate
the effect of repetitive TMS on working memory and its
BIOL PSYCHIATRY 2014;76:678–680
& 2014 Society of Biological Psychiatry

Remote effects of deep repetitive TMS are less clear. time will tell if this may be a feasible treatment for nicotine and other drug addictions. Also. both direct and remote effects may modulate long-term potentiation and contribute to the observed decrease in cigarettes per day and cotinine-to-creatinine ratio resulting in observed success of smoking cessation in the Dinur-Klein study.Commentary BIOL PSYCHIATRY 2014. this report that going deeper with repetitive TMS may be the key to successful smoking cessation is exciting. the time to lapse to the first cigarette may be prolonged with brain stimulation possibly reducing withdrawal symptoms. NAc. Hadar A. dorsolateral prefrontal cortex. Rosenberg O.g. For example. Dinur-Klein L. NMDAR. Using deep repetitive TMS and other brain stimulation protocols that are known to potentiate neuroplasticity (e.sobp. This model suggests that direct effects of repetitive TMS stimulation of pyramidal neurons produces increases in activity of gamma-aminobutyric acid and dopamine. It may be possible that using a laboratory-based research model with repetitive TMS may provide clinically relevant information on how to optimize brain stimulation as a treatment for smoking cessation. which has been a marker for predicting success of smoking cessation. cognitive enhancement therapies that have been suggested as possible treatments for addiction may be optimized during the withdrawal-induced cognitive deficits. ventral tegmental area. the model developed by Perkins et al. Dannon P. Such increases in these neurotransmitters may act on the N-methyl-D-aspartate receptor resulting in protein kinase A–cyclic adenosine monophosphate–adenylyl cyclase (PKAcAMP-AC) signaling in the modulation of long-term potentiation.76:678–680 679 Figure 1. Food and Drug Administration. Kotler M. they suggest that repetitive TMS could be a new approach to treating nicotine addiction in the future. the findings from this proof-of-concept study must be considered very preliminary. Using these laboratory models is more feasible and less costly to determine an early signal for medication efficacy to be tested later in a clinical smoking cessation trial. MOP#1151145 (to TPG) and a 2013 National Alliance for Research on Schizophrenia and Depression Young Investigator Award (to MSB). Together.. ventral tegmental area and nucleus accumbens). Simplified model of the effects of deep repetitive transcranial magnetic stimulation (TMS) on long-term potentiation for smoking cessation.org/journal . Another validated model developed by McKee (9) evaluates the ability to resist the first cigarette after a quit attempt. www. dopamine. DA. This duration or lapse has been shown to be one of the best predictors of smoking relapse. working memory. executive function). such as varenicline or sustained-release bupropion. DLPFC. nucleus accumbens. Nonetheless.. (8) employs a within-subject crossover study design in which smokers undergo a 7-day abstinence period during which they receive monetary incentives. LTP. brings into question intriguing possibilities on how to optimize brain stimulation for tobacco dependence. We also propose that the modulation of long-term potentiation with deep repetitive TMS may enhance prefrontal cortex–mediated cognition (e. MSB reports no biomedical financial interests or potential conflicts of interest. long-term potentiation.S. These questions need to be carefully evaluated in future trials. GABA. In conclusion. Given that repetitive TMS has been shown to improve working memory (3) and reduce craving (2). Given the more invasive nature of deep repetitive TMS and associated level of tolerability. relationship to smoking cessation. randomized controlled trial. Roth Y. The study by Dinur-Klein et al. gamma-aminobutyric acid. This work was supported by Canadian Institutes of Health Research Operating Grant No. This abstinence period is based on the evidence demonstrating that the first week is predictive of long-term abstinence. Biol Psychiatry 76:742–749. However. Using McKee’s relapse model. it may be possible to determine the optimal dosing of repetitive TMS more effectively through a laboratory model for smoking relapse prevention. N-methyl-D-aspartate receptor. TPG reports having received consulting fees from Novartis and investigator-initiated research funding from Pfizer. Using such validated models creates several opportunities to evaluate the efficacy of other brain stimulation techniques combined with smoking cessation drugs as well as psychosocial education. 1. VTA.. theta-burst stimulation and transcranial direct current stimulation) begs the question of how to employ these techniques most appropriately in the context of current human laboratory research models that evaluate the effects of smoking cessation medications approved by the U. Deep repetitive TMS targeted to the dorsolateral prefrontal cortex and insular cortices produces direct cortical effects at the site of stimulation and remote effects downstream within the brain reward circuitry (e. Zangen A (2014): Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: A prospective.g.g.

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