High-frequency repetitive transcranial magnetic stimulation decreases cigarette smoking

High-Frequency rTMS Decreases Cigarette Smoking High-Frequency Repetitive Transcranial
Magnetic Stimulation Decreases Cigarette Smoking
Peter Eichhammer, M.D.; Monika Johann, M.D.;
Alexander Kharraz, M.D.; Harald Binder, M.A.; David Pittrow, M.D.;
Norbert Wodarz, M.D.; and Göran Hajak, M.D.
epetitive transcranial magnetic stimulation (rTMS) R is a new technique that has been found to be
useful as a potential treatment for neuropsychiatricdiseases.1 With regard to the neurobiological mechanismsinvolved, there is compelling evidence that rTMS causes Background: The mesolimbic dopaminergic
changes in neuronal circuits. Such alterations include se- reward system seems to play a crucial role in re- lected local modifications in the dynamic release patterns inforcing effects of nicotine. Recently, acute high-frequency repetitive transcranial magnetic stimu- of biogenic amines and amino acids.2 Using intracerebral lation (rTMS) of frontal brain regions has been microdialysis in rodents, stimulation of dopamine release shown to efficiently modulate the mesostriatal could be demonstrated in the dorsal hippocampus as well and mesolimbic dopaminergic system in both as in the shell of the nucleus accumbens.3 These data pro- animals and humans. For this reason, we investi- vide compelling in vivo evidence that acute high-frequency gated whether high-frequency rTMS would beable to influence nicotine-related behavior by rTMS of frontal brain regions has a modulatory effect on studying rTMS effects on craving and cigarette both the mesolimbic and the mesostriatal dopaminergic systems. Moreover, these findings are fairly compatible Method: Fourteen treatment-seeking smokers
with data showing that high-frequency rTMS of the human were included in a double-blind crossover trial, prefrontal cortex induces dopamine release in the caudate conducted in 2002, comparing single days ofactive versus sham stimulation. Outcome mea- nucleus.4 For this reason, high-frequency rTMS is consid- sures were rTMS effects on number of cigarettes ered to be especially useful in neuropsychiatric disorders smoked during an ad libitum smoking period associated with subcortical dopamine dysfunction.2–4 and effects on craving after a period of acute The primary subjective and physiologic effects of smok- ing are known to result from the central actions of nico- Results: High-frequency (20-Hz) rTMS of left
dorsolateral prefrontal cortex reduced cigarette tine.5,6 In this context, the mesolimbic dopaminergic reward smoking significantly (p < .01) in an active system seems to play a pivotal role in reinforcing effects of stimulation compared with sham stimulation.
nicotine.6,7 Decreased function in brain reward systems dur- Levels of craving did not change significantly.
ing nicotine withdrawal seems to be closely associated with Conclusion: High-frequency rTMS may be
craving, relapse, and continued nicotine consumption.8 For useful for treatment in smoking cessation.
(J Clin Psychiatry 2003;64:951–953) this reason, modulation of dopaminergic neurotransmissionmight serve as a potential target for treating tobacco addic-tion. Additional support for this hypothesis comes fromstudies with bupropion, an atypical antidepressant block- Received Oct. 4, 2002; accepted Feb. 14, 2003. From the Department ing neuronal uptake of dopamine, which has recently been of Psychiatry and Psychotherapy, University of Regensburg, approved as a treatment for smoking cessation.9,10 Considering that high-frequency rTMS has been shown The authors report no financial affiliation or other relationship relevant to the subject matter of this article. to alter dopaminergic neurotransmission in subcortical Corresponding author and reprints: Peter Eichhammer, M.D., structures, we investigated whether 20-Hz rTMS is able to Department of Psychiatry and Psychotherapy, University of RegensburgUniversitaetsstrasse 84, 93053 Regensburg – Germany reduce cigarette smoking and craving.
(e-mail: [email protected]). Fourteen right-handed probands who wished to quit smoking were recruited through advertisement in 2002.
Table 1. Baseline Demographics and Smoking Characteristics
Figure 1. Effect of High-Frequency Repetitive Transcranial
of 14 Treatment-Seeking Probandsa
Magnetic Stimulation on the Number of Cigarettes Smoked
± SD) During an Ad Libitum Smoking Phase of 6
aValues shown as mean ± SD unless otherwise noted.
Abbreviation: FTND = Fagerström Test for Nicotine Dependence.
Subjects were regular cigarette smokers (12 female, 2 male) aged 23 to 55 years. Smoking characteristics (Table 1) were comparable to those reported in other stud-ies investigating therapeutics for nicotine addiction.11 All *Denotes significant difference from sham stimulation (p < .01).
candidates received a structured clinical interview com-bined with a short physical examination and completedseveral questionnaires, including the Fagerström Test administered at baseline and 30 minutes after rTMS treat- of Nicotine Dependence (FTND)11 as well as a drug and ment. Using this scale, the subjective state “desire to health history questionnaire. Standard cut-off thresholds smoke” was assessed, as it has been done earlier in a study were used to eliminate those persons with significant on naltrexone alteration of acute smoking response.13 current or past alcohol, drug, or psychiatric symptoma- “Desire to smoke” ratings have been shown to be sensitive tology.12 Subjects were also excluded for positive urine to assess self-reported levels of craving.14 Number of ciga- toxicology (cocaine, opiates, amphetamines, benzodiaze- rettes smoked was noted during an ad libitum smoking pines). All candidates abstained from smoking 12 hours phase (6-hour period) after rTMS treatment. The subjects before each rTMS session and gave written informed con- were instructed to smoke freely using their own chosen sent to take part in the study, which was approved by the brand of cigarettes. Data were obtained under natural conditions in the subjects’ normal living or working envi-ronment, not under laboratory conditions, since environ- mental and other contextual factors have been shown to Within a crossover design, each subject received 2 decisively influence individual smoking behavior.15 For trials of active and 2 trials of sham stimulation in a ran- this reason, subjects had to keep a daily diary 3 weeks be- domized order on 4 consecutive days. Patients and clinical fore entering the study in order to check compliance and staff were unaware of stimulation condition. On each accurate assessment of numbers of cigarettes smoked.
study day, sessions started in the early afternoon (1 p.m.).
The participants received 20 trains of rTMS at a rate of 20 Hz for 2.5 seconds over 14 minutes (1000 pulses/session; Each subject participated in several trials, so we ex- intertrain interval: 42.5 seconds) by means of a repetitive pected a repeated-measures covariance structure of the magnetic stimulator (Magstim Co., Whitland, Dyfed, data. Instead of the more traditional repeated-measures U.K.). Stimulation site was the left dorsolateral prefrontal analysis of variance, we used a linear mixed-effects model cortex, defined as 5 cm anterior and in a parasagittal plane for data analysis. This class of statistical models allows for from the point of maximum stimulation of the abductor more flexibility in model construction and selection.16 In pollicis muscle. Stimulation intensity was at 90% of motor this context, using this linear mixed-effects model enabled threshold. Sham stimulation was given at the same loca- us to judge whether an order effect of stimulation condi- tion and frequency by using a sham-coil system (Magstim, tions (active stimulation/sham stimulation) should be in- U.K.). The stimulation paradigm was identical with stimu- cluded in the model, on the basis of objective statistical lation conditions leading to a marked dopamine release in criteria. The threshold for significance was set at p < .05.
mesolimbic structures such as the nucleus accumbens.2,3 Two outcome measures were used. Craving was mea- Using a linear mixed-effects model for data analysis, sured with a 10-cm–long, 100-point visual analogue scale group membership (active vs. sham stimulation) was the COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC.
High-Frequency rTMS Decreases Cigarette Smoking fixed-effect covariate and subject ID was included as a support further investigation of high-frequency rTMS for The fixed group effect was found to be significant (p < .01) for “number of cigarettes smoked” (95% Drug names: bupropion (Zyban and others), naltrexone(ReVia and others).
CI = 1.301 to 5.109) but not for “craving.” The directionof the effect indicated that the number of cigarettes smoked was significantly smaller under active stimula-tion conditions compared with sham stimulation condi- 1. Sachdev PS, McBride R, Loo CK, et al. Right versus left prefrontal transcranial magnetic stimulation for obsessive-compulsive disorder:a preliminary investigation. J Clin Psychiatry 2001;62:981–984 Other than complaints of mild headache in 2 cases 2. Keck ME, Sillaber I, Ebner K, et al. Acute transcranial magnetic after active stimulation, patients tolerated rTMS without stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain. Eur JNeurosci 2000;12:3713–3720 3. Keck ME, Welt T, Müller MB, et al. Repetitive transcranial magnetic stimulation increases the release of dopamine in themesolimbic and mesostriatal system. Neuropharmacology 2002;43:101–109 The present study implies that high-frequency rTMS 4. Strafella AP, Paus T, Barrett J, et al. Repetitive transcranial magnetic may reduce cigarette smoking. In contrast, levels of crav- stimulation of the human prefrontal cortex induces dopamine release ing did not change significantly. The failure to find rTMS in the caudate nucleus. J Neurosci 2001;21:RC157 5. Jarvik ME, Madsen DC, Olmstead RE, et al. Nicotine blood levels effects on craving should not be misinterpreted as having and subjective craving for cigarettes. Pharmacol Biochem Behav shown that rTMS does not alter craving. It might be due to methodological issues such as the assessment of craving, 6. Jones RT, Benowitz NL. Therapeutics for nicotine addiction. In: Davis KL, Charney D, Coyle JT, et al, eds. Neuropsychopharmacology: focusing on subject’s desire to smoke, the rating scale be- The Fifth Generation of Progress. Philadelphia, Pa: Lippincott Williams ing less sensitive than the cigarette count, or the actual sample size being too small to show statistically signifi- 7. Di Chiara G. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 2000;393:295–314 8. Epping-Jordan MP, Watkins SS, Koob GF, et al. Dramatic decreases The mechanism of action of high-frequency rTMS in in brain reward function during nicotine withdrawal. Nature 1998;393: cigarette smokers is an object of speculation but may 9. Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release be similar to that of some drugs used to treat smokers.
bupropion and placebo for smoking cessation. N Engl J Med 1997;337: Bupropion is supposed to act by mimicking nicotine’s actions on brain reward systems by blocking neuronal 10. Holm KJ, Spencer CM. Bupropion: a review of its use in the manage- ment of smoking cessation. Drugs 2000;59:1007–1024 uptake of dopamine.6 An identical mechanism might 11. Heatherton TF, Kozlowski LT, Frecker RC, et al. The Fagerström Test account for the action of high-frequency rTMS, since se- for Nicotine Dependence: a revision of the Fagerström Tolerance lective dopamine release in subcortical structures could Questionnaire. Br J Addict 1991;86:1119–1127 12. Cousins MS, Stamat HM, de Wit H. Acute doses of d-amphetamine and be demonstrated after rTMS both in animals2,3 and hu- bupropion increase cigarette smoking. Psychopharmacology (Berl) 2001; mans.4 Especially, immediate marked release of dopa- mine after prefrontal high-frequency rTMS, as indicated 13. King AC, Meyer PJ. Naltrexone alteration of acute smoking response in nicotine-dependent subjects. Pharmacol Biochem Behav 2000;66: by raclopride positron emission tomography,4 may closely resemble pronounced catecholamine-releasing effects 14. Schuh KJ, Stitzer ML. Desire to smoke during spaced smoking intervals.
preferentially resulting from fast forms of nicotine deliv- Psychopharmacology (Berl) 1995;120:289–295 15. Dallery J, Houtsmuller EJ, Pickworth WB, et al. Effects of cigarette ery such as cigarette smoking.17 Moreover, high- nicotine content and smoking pace on subsequent craving and smoking.
frequency rTMS has been shown to influence an array of Psychopharmacology (Berl) 2003;165:172–180 neurotransmitters and biogenic amines including arginine 16. Pinheiro JC, Bates DM. Mixed-Effect Models in S- and S-Plus.
vasopressin2 and serotonin (5-HT),18 which are also 17. Benowitz NL. Pharmacokinetic considerations in understanding altered by nicotine.19 In particular, tobacco smoking is as- nicotine dependence. In: CIBA Foundation Symposium 152. The sociated with reductions in hippocampal serotonin,20 Biology of Nicotine Dependence. Chichester, England: Wiley; 1990:186–209 which may be corrected by rTMS-induced increase in 18. Ben-Shachar D, Belmaker RH, Grisaru N, et al. Transcranial magnetic hippocampal 5-HT concentrations.18 These biological stimulation induces alterations in brain monoamines. J Neural Transm qualities of high-frequency rTMS may explain why even 19. Henningfield JE, Schuh LM, Jarvik ME. Pathophysiology of tobacco daily sessions of active rTMS were able to reduce ciga- dependence. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: rette smoking, whereas acute doses of bupropion failed to The Fourth Generation of Progress. New York, NY: Raven Press; 1995: 20. Balfour DJ, Ridley DL. The effects of nicotine on neural pathways Our data obtained in a small number of cigarette smok- implicated in depression: a factor in nicotine addiction? Pharmacol ers need to be confirmed, but the results of this pilot study COPYRIGHT 2003 PHYSICIANS POSTGRADUA

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