ARTICLE Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study Marco Ceccanti, Maurizio Inghilleri, Maria Luisa Attilia, Ruggero Raccah, Marco Fiore, Abraham Zangen, and Mauro Ceccanti Abstract: The hypothalamic pituitary adrenal axis and dopamine have a key role in transition from alcohol social use to addiction. The medial prefrontal cortex was shown to modulate dopaminergic activity and cortisol releasing factor (CRF) release in hypothalamic and extra-hypothalamic systems. The recent advancements in non-invasive neurostimulation technologies has enabled stimulation of deeper brain regions using H-coil transcranial magnetic stimulation (TMS) in humans. This randomized double-blind placebo-controlled pilot study aims to evaluate H-coil efficacy in stimulating the medial prefrontal cortex. Corti- solemia and prolactinemia were evaluated as effectiveness markers. Alcohol intake and craving were considered as secondary outcomes. Eighteen alcoholics were recruited and randomized into 2 homogeneous groups: 9 in the real stimulation group and 9 in the sham stimulation group. Repetitive TMS (rTMS) was administered through a magnetic stimulator over 10 sessions at 20 Hz, directed to the medial prefrontal cortex. rTMS significantly reduced blood cortisol levels and decreased prolactinemia, thus suggesting dopamine increase. Craving visual analogic scale (VAS) in treated patients decreased, as well as mean number of alcoholic drinks/day and drinks on days of maximum alcohol intake (DMAI). In the sham group there was no significant effect observed on cortisolemia, prolactinemia, mean number of alcoholic drinks/day, or drinks/DMAI. Thus, deep rTMS could be considered a potential new treatment for alcoholism. Key words: alcohol, prefrontal cortex, transcranic magnetic stimulation, cortisol, prolactin. Résumé : L’axe hypothalamo–hypophyso–surrénalien et la dopamine jouent un rôle clé dans la transition d’une consommation sociale d’alcool vers une dépendance a ` l’alcool. Le cortex préfrontal interne module l’activité dopaminergique et la libération de corticolibérine (CRF) dans les systèmes hypothalamique et extra-hypothalamique. Un progrès récent sur le plan des technologies de neurostimulation non-invasive permet de stimuler ces régions profondes du cerveau a ` l’aide de la stimulation magnétique trans-crânienne (SMT) chez l’humain. Cet essai pilote aléatoire a ` double aveugle comparatif avec placebo visait a ` évaluer l’efficacité de stimulation du cortex préfrontal interne de la bobine solénoïde. La cortisolémie et la prolactinémie ont été évaluées en tant que marqueurs d’efficacité. La consommation d’alcool et l’état de besoin ont été considérés comme résultats secondaires. Dix-huit personnes alcooliques ont été recrutées et réparties de manière aléatoire en deux groupes homogènes, 9 personnes avec stimulation réelle et 9 personnes avec stimulation simulée. La STM répétitive (STMr) a été appliquée au moyen d’un stimulateur magnétique en 10 sessions de 20 Hz, et dirigée sur le cortex préfrontal interne. La STMr pouvait réduire significativement le niveau de cortisol sanguin et la prolactinémie, suggérant ainsi un accroissement de la dopamine. L’échelle visuelle de l’état de besoin chez les patients traités diminuait, de même que le nombre moyen de consommations par jour et le nombre de consommations lors des jours de consommation d’alcool maximale. Chez le groupe simulé, aucun effet significatif n’était observé sur la cortisolémie, la prolactinémie, le nombre moyen de consommations par jour et le nombre de consomma- tions lors des jours de consommation maximale. Le STMr profonde pourrait être considérée comme un outil supplémentaire pour traiter l’alcoolisme. [Traduit par la Rédaction] Mots-clés : alcool, cortex préfrontal, stimulation magnétique trans-crânienne, cortisol, prolactine. Introduction Background Impulse-control disorders and antisocial personality disorders are very common in patients affected by substance dependence, particularly alcoholics (Hasin et al. 2011; Lewis 2011). In the context of alcohol consumption there are different categories of consum- ers. In the United States, 65% of the adult population are alcohol consumers (National Institute on Alcohol Abuse and Alcoholism 1997), and 12% of them can be classified as abusers or addicts (Merikangas and McClair 2012). According to Koob (Koob and Le Moal 1997), addiction is char- acterised by (i) compulsive substance seeking and intake, (ii) loss of control over the amount of substance that is consumed, and (iii) the emergence of a negative emotional state when access to the substance is prevented. In terms of clinical interventions, it is also beneficial to identify addiction as a cycle consisting of 3 stages (Koob et al. 2009): intox- ication, withdrawal, and preoccupation–anticipation (craving). The first stages are dominated by impulsivity, characterised by gratification or relief after committing an act. In the later stages, Received 14 May 2014. Accepted 20 December 2014. Marco Ceccanti and M. Inghilleri. Department of Neurology and Psychiatry, Sapienza University of Rome, Viale dell’Universita ` 30, 00161 Rome, Italy. M.L. Attilia and Mauro Ceccanti. Department of Clinical Medicine, Sapienza – University of Rome, Via del Policlinico 155, 00161 Rome, Italy. R. Raccah. ATID (Advanced Technology Innovation Distribution), Via Dora 1, 00198 Rome, Italy. M. Fiore. EBRI-CNR, Via del Fosso di Fiorano 64, 00143 Rome, Italy. A. Zangen. Department of Life Sciences, Ben-Gurion University, P.O. Box 653 Beer-Sheva 84105, Israel. Corresponding author: Marco Ceccanti (e-mail: marco.ceccanti@yahoo.it). 283 Can. J. Physiol. Pharmacol. 93: 283–290 (2015) dx.doi.org/10.1139/cjpp-2014-0188 Published at www.nrcresearchpress.com/cjpp on 20 January 2015.