Brain Stimulation in the Treatment of Addiction
Corresponding author: Catarine Conti, Programa de Pós-Graduação em Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Av. Marechal Campos, 1468, 29.047-105 Vitória, ES, Brazil, Fax: +55-27-3552-8991, E-mail: firstname.lastname@example.org
Drug dependence is known to be associated with structural and functional damage to the prefrontal cortex (PFC) culminating in the reduction of frontal activity. Besides, the PFC is critically involved in processing the craving of smoking [1,2] and drugs such as alcohol ; opiates  and cocaine [5,6]. Specifically, craving is associated with enhanced activity of this cortical area during drug cue presentation. Once PFC is broadly related to executive functions and to the brain’s reward circuitry [7-9], this imbalance indicates that the cognitive ability to regulate drug-seeking behaviour is decreased, and the risk of consuming the drug increases. Reducing craving and improving cognitive functions constitute great challenges in the treatment of drug addiction and, unfortunately, pharmacological and non-pharmacological approaches have not fully addressed these issues so far.
PFC activation during the exposure of drug-related cues may be specifically related to addiction and associated with an enhanced desire for the drug .
Furthermore, activity enhancement of PFC areas involved in drug-related processes, including emotional responses (medial OFC and ventromedial PFC in craving), automatic behaviors (OFC in drug expectation and ACC in attention bias) and also higher-order executive responses involved in drug-related working memory (DLPFC)  may constitute prominent factors preceding relapses.
The mesocorticolimbic dopamine system and the nigrostriatal dopamine system both contribute to cue-induced drug seeking [12-14] and other behavioral effects of drug use, including reward [15, 16]. Several evidences suggest that an action in dopaminergic neurons may be the mechanism responsible for the reward caused by cocaine consume, or else, the blockade in the dopamine reuptake and subsequent increase of the activity of this neurotransmitter over dopaminergic receptors may be the responsible for the “high” associated with cocaine use . It is well known that some areas from the prefrontal cortex that are involved in these drug-related processes are activated when drug addicted is exposed to either the drug or some drug-cue [1,2,5,6,18-21]. Volkow et al  postulated that this enhanced activity of PFC could contribute to the compulsive self-administration and the lack of control (impaired inhibition) in addicted subjects and also contribute to disruptive cognitive operations that impair judgment and favor relapse .
Neuromodulation as an alternative therapy
Transcranial direct current stimulation (tDCS) is technically a simple method of noninvasive brain stimulation that has been used to modulate neuronal resting membrane potential leading to changes of cortical excitability and other functional parameters [23-25]. It is well established that cathodal current decreases cortical excitability and anodal current increases excitability [26-29]. The potential benefit of this neuromodulation induced by tDCS has been increasingly investigated in neuropsychiatric disorders, such as depression [30-34] and substance abuse and craving including alcohol [35,36], tobacco , Marijuana  and also foods disorders .
The potential use of tDCS in the treatment of drug addiction can be more explored. Assuming that tDCS has been associatedwith working memory enhancement and improvement in other cognitive domains [40-48], brain stimulation over dorsolateral prefrontal cortex (DLPFC) can enhance executive function, providing improved cognitive control over relapsing on drug use . On the other hand, tDCS has demonstrated an important effect in the reduction of craving when applied over the DLPFC. The parameters and results of relevant literature in the field of brain stimulation, especially transcranial direct current stimulation, in the treatment of addiction are discussed below.
Anodal tDCS over the left and right DLPFC was beneficial for reducing cue-provoked smoking craving . In patients with alcohol dependence while being exposed to alcohol cues, both left anodal/right cathodal and right anodal/left cathodal significantly decreased alcohol craving compared to sham stimulation . When tDCS was studied in chronic marijuana smokers, it was observed that right anodal/left cathodal tDCS over the DLPFC (the electrode montage of the present study) was significantly associated with a diminished craving for marijuana .
It has been proposed that cognitive intervention would attenuate the increased cue-induced response in the PFC during drug abstinence . For example, when cocaine abusers purposefully inhibit craving when exposed to conditioned drug-cues, specific changes in brain regions that process reward and prediction of reward occur, or else, regions involved in processing conditioned responses decrease their activities. Interestingly, the increasing of the left DLPFC activity in the P3 segment under crack-related cue presentation observed in crack-cocaine users from non-stimulated group (sham-tDCS) was prevented by the cathodal tDCS applied over the left DLPFC in crack-cocaine users from real tDCS group, suggesting that cathodal tDCS over the DLPFC could be helpful to control the processing of drug-conditioned responses and subsequently the craving response [50,51]. The P3 wave is typically observed in more anterior brain areas  and is sensitive to general and specific arousal, contributing to attention activation and information processing . The association between P3 amplitude and cue-reactivity has been described in volunteers with history of cocaine use [5,54] and other drugs [55,56]. These studies report increased craving after the presentation of drug-related cues, as well as an increased P3 amplitude. In fact, according to Volkow et al “The frontal mediation of a neural circuit involved in the craving response provides a target for top-down cognitive interventions that may be therapeutically beneficial. Interventions that strengthen a weakened but still functional fronto-accumbal circuit may increase the ability of cocaine abusers to block or reduce the drug craving response” .
Transcranial electric activity has been shown to be associated with frontal-related cognitive changes in healthy subjects and several psychiatric conditions [40-48]. Previous study from our lab showed specific clinical and electrophysiological (as indexed by P3) effects of tDCS on patients with alcohol dependencein which we demonstrated that anodal tDCS over left DLPFC resulted in an improved cognitive function . Not only transcranial, but also epidural stimulation was already used to study emotion regulation and the impact of cognitive control on neural response to visual stimuli, for instance, Hajcak et al  studied five patients with treatment-resistant mood disorders stereotactically implanted with stimulating paddles over DLPFC bilaterally. This study corroborated the role of DLPCF in regulating measures of neural activity that have been linked to emotional arousal and attention . Though the number of studies on frontal neuromodulation has been growing in psychiatric disorders, efforts are needed to propose this technique as an effective repetitive therapy in the treatment of such conditions.
Interestingly, we have observed that the effect of anodal tDCS stimulation over the left DLPFC is restricted to the left DLPFC. Besides, when left cathodal tDCS was coupled with right anodal tDCS over the DLPFC, the effect was still restricted to the left DLPFC . These facts bring the issue about inter-hemispheric interaction which occurs via transcallosal fibers that transmit inhibitory influences between the homologous areas of both hemispheres . These fibers are thought to be glutamatergic and to project onto inhibitory GABAergic interneurons . This interaction had already been demonstrated for motor response after stroke through noninvasive brain stimulation over primary motor cortex (M1) [61-63]. Although neuromodulation is discussed here in the cognitive field, motor responses are also the target of several studies. In these cases, M1 receives the stimulation and the expectance is for motor rehabilitation. However, mechanisms through with the current is acting may be similar to those observed in cognitive field. The improved motor function after brain stimulation may be attributed to a suppression of interhemispheric inhibition (down-regulation of the excitability in the intact hemisphere) resulting in an improvement of the damaged function. In subjects with major depressive disorder, 1 Hz rTMS (applied to the left M1) decreased corticospinal excitability in the left hemisphere; however, it induced no significant changes in corticospinal excitability in the contralateral, right hemisphere. In this case, the authors observed a decreased interhemispheric modulation at M1 level contrary to those findings from stroke studies . Knoch et al  used cortical stimulation over PFC and they described the asymmetric role of the PFC in decision-making showing that risk-taking behavior was induced by disruption of the right, but not the left, PFC . Using concurrent tDCS over the PFC, it was demonstrated that left cathodal/right anodal decreases risk-taking behavior compared with left anodal/right cathodal or sham stimulation supporting the idea that differential modulation of DLPFC activity, increasing the right while decreasing the left, might lead to decreased risk taking behaviors .
It has to be considered that many pharmacological treatments for drug dependence are available [67-69], but these treatments have failed to successfully manage the addiction, notably for strong addictive drugs, such as crack-cocaine [70,71]. Though the importance and need of pharmacological treatments, we strongly believe that supplementary alternative tools with proved efficacy could contribute to the treatment. Reducing craving and improving cognitive functions constitute great challenges in the treatment of drug addiction and we suggest that approaches targeted for intervention on the prefrontal cortex would be of great success. Though the number of studies on brain stimulation has been growing in psychiatric disorders involving drug abuse, efforts are needed to propose this technique as an effective repetitive therapy in the treatment of such conditions.
We thank all patients and all colleagues that contributed to our experience acquired in the field of brain stimulation and addiction.
- McBride D, Barrett SP, Kelly JT, Aw A, Dagher A et al. Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokers: an fMRI study. Neuropsychopharmacology. 2006, 31(12): 2728-2738.
- Wilson SJ, MA Sayette, JA Fiez. Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci. 2004,7(3): 211-214.
- Tapert SF, Cheung EH, Brown GG, Frank LR, Paulus MP et al. Neural response to alcohol stimuli in adolescents with alcohol use Archives of General Psychiatry. 2003,60(7): 727-735.
- Sell LA, Morris JS, Bearn J, Frackowiak RS, Friston KJ et al. Neural responses associated with cue evoked emotional states and heroin in opiate addicts. Drug and Alcohol Dependence. 2000,60(2): 207-216.
- Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA. 1996, 93(21): 12040-12045.
- Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L et al. Cue-induced cocaine craving: Neuroanatomical specificity for drug users and drug stimuli. American Journal of Psychiatry. 2000,157(11): 1789-1798.
- Hyman SE, RC Malenka, EJ Nestler. Neural mechanisms of addiction: The role of reward-related learning and memory. Annual Review of Neuroscience. 2006, 29: 565-598.
- Fuster JM. Executive frontal functions. Experimental Brain Research. 2000. 133(1): 66-70.
- Desposito M, Detre JA, Alsop DC, Shin RK, Atlas S et al. The Neural Basis of the Central Executive System of Working-Memory. Nature. 1995,378(6554): 279-281.
- Goldstein RZ, ND Volkow. Oral methylphenidate normalizes cingulate activity and decreases impulsivity in cocaine addiction during an emotionally salient cognitive task. Neuropsychopharmacology. 2011, 36(1): 366-367.
- Goldstein RZ, ND Volkow. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci. 2011,12(11): 652-669.
- Shalev U, JW Grimm, Y Shaham. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev. 2002,54(1): 1-42.
- Feltenstein MW, RE See. The neurocircuitry of addiction: an overview. Br J Pharmacol. 2008, 154(2): 261-274.
- Belin D, Jonkman S, Dickinson A, Robbins TW, Everitt BJ. Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav Brain Res. 2009,199(1): 89-102.
- Pierce, R.C. and V. Kumaresan. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev. 2006, 30(2): 215-238.
- Wise, R.A., Roles for nigrostriatal-not just mesocorticolimbic-dopamine in reward and addiction. Trends Neurosci. 2009,32(10): 517-524.
- Volkow N.D, Fowler JS, Wang GJ, Swanson JM, Telang F. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004,9(6): 557-569.
- Daglish MR, DJ Nutt. Brain imaging studies in human addicts. Eur Neuropsychopharmacol. 2003, 13(6): 453-458.
- Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Angrist B et al. Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction. Am J Psychiatry. 1999, 156(1): 19-26.
- Sell LA, et al. Neural responses associated with cue evoked emotional states and heroin in opiate addicts. Drug Alcohol Depend. 2000,60(2): 207-216.
- Tapert SF, Cheung EH, Brown GG, Frank LR, Paulus MP et al. Neural response to alcohol stimuli in adolescents with alcohol use Arch Gen Psychiatry. 2003,60(7): 727-735.
- Volkow ND, Fowler JS, Wang GJ, Goldstein RZ. Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem. 2002,78(3): 610-624.
- Nitsche MA, et al. Transcranial direct current stimulation: State of the art 2008. Brain Stimul. 2008, 1(3): 206-223.
- Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol. 2003,553(Pt1): 293-301.
- Nitsche MA, Paulus W. Modulation of cortical excitability by weak direct current stimulation-‐-‐technical, safety and functional aspects. Suppl Clin Neurophysiol. 2003, 56: 255-276.
- Nitsche MA, W Paulus. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000,527(Pt 3): 633-639.
- Nitsche MA, W Paulus. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology. 2001,57(10): 1899-1901.
- Nitsche MA, Liebetanz D, Tergau F, Paulus W. Modulation of cortical excitability by transcranial direct current Nervenarzt. 2002,73(4): 332-335.
- Wassermann EM, J Grafman. Recharging cognition with DC brain polarization. Trends Cogn Sci. 2005, 9(11): 503-505.
- Nitsche MA, Loo C. Transcranial direct current stimulation: a new treatment for depression? Bipolar Disord. 2002,4(Suppl 1): 98-99.
- Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP et al. Treatment of major depression with transcranial direct current Bipolar Disord. 2006,8(2): 203-204.
- Fregni F, Paulo S. Boggio, Michael A. Nitsche, Sergio P Rigonatti, Alvaro Pascual-Leone. Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression. Depress Anxiety, 2006.23(8): 482-484.
- Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML, Nitsche MA et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int JNeuropsychopharmacol. 2008, 11(2): 249-254.
- Bikson M, Bulow P, Stiller JW, Datta A, Battaglia F et al. Transcranial direct current stimulation for major depression: a general system for quantifying transcranial electrotherapy dosage. Curr TreatOptions Neurol. 2008. 10(5): 377-385.
- Boggio PS, Sultani N, Fecteau S, Merabet L, Mecca T et al. Prefrontal cortex modulation using transcranial DC stimulation reduces alcohol craving: A double-blind, sham-controlled study. Drug and AlcoholDependence. 2008, 92(1-3): 55-60.
- Nakamura-Palacios EM, de Almeida Benevides MC, da Penha Zago-Gomes M, de Oliveira RW, de Vasconcellos VF et al. Auditory event-related potentials (P3) and cognitive changes induced by frontal direct current stimulation in alcoholics according to Lesch alcoholism typology. Int J Neuropsychopharmacol. 2012,15(5): 601-616.
- Fregni F, Liguori P, Fecteau S, Nitsche MA, Pascual-Leone A et al. Cortical stimulation of the prefrontal cortex with transcranial direct current stimulation reduces cue-‐provoked smoking craving: A randomized, sham-‐ controlled study. Journal of Clinical Psychiatry. 2008,69(1): 32-40.
- Boggio PS, Zaghi S, Villani AB, Fecteau S, Pascual-Leone A et al. Modulation of risk-taking in marijuana users by transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). DrugAlcohol Depend. 2010, 112(3): 220-225.
- Fregni F, Orsati F, Pedrosa W, Fecteau S, Tome FA et al. Transcranial direct current stimulation of the prefrontal cortex modulates the desire for specific foods. Appetite. 2008,51(1): 34-41.
- Kuo MF, Nitsche MA. Effects of transcranial electrical stimulation on Clin EEG Neurosci. 2012,43(3): 192-199.
- Jeon SY, Han SJ. Improvement of the working memory and naming by transcranial direct current stimulation. Ann Rehabil Med. 2012,36(5): 585-595.
- Fertonani A, Rosini S, Cotelli M, Rossini PM, Miniussi C et al. Naming facilitation induced by transcranial direct current Behavioural Brain Research. 2010,208(2): 311-318.
- Fiori V, Hueckel-Weng R, Birbaumer N, Plewnia C et al. Transcranial Direct Current Stimulation Improves Word Retrieval in Healthy and Nonfluent Aphasic Subjects. Journal of Cognitive Neuroscience. 2011,23(9): 2309-2323.
- Dockery CA, Hueckel-Weng R, Birbaumer N, Plewnia C et al. Enhancement of Planning Ability by Transcranial Direct Current Journal of Neuroscience. 2009,29(22): 7271-7277.
- Jo JM, Kim YH, Ko MH, Ohn SH, Joen B, Lee KH et al. Enhancing the Working Memory of Stroke Patients Using tDCS. American Journal of Physical Medicine & Rehabilitation. 2009, 88(5): 404-409.
- Boggio PS, Ferrucci R, Rigonatti SP, Covre P, Nitsche M et al. Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease. Journal of the Neurological Sciences.2006, 249(1): 31-38.
- Fregni F, Boggio PS, Nitsche M, Bermpohl F, Antal A et al. Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Experimental Brain Research. 2005,166(1): 23-30.
- Marshall L, Mölle M, Hallschmid M, Born J. Transcranial direct current stimulation during sleep improves declarative memory. Journal of Neuroscience. 2004,24(44): 9985-9992.
- Batista EK, Klauss J, Fregni F, Nitsche MA, Nakamura-Palacios EM. A Randomized Placebo-‐Controlled Trial of Targeted Prefrontal Cortex Modulation with Bilateral tDCS in Patients with Crack-Cocaine Dependence. Int J Neuropsychopharmacol. 2015, 18(12).
- Conti CL, Moscon JA, Fregni F, Nitsche MA, Nakamura-Palacios EM. Cognitive related electrophysiological changes induced by non-‐ invasive cortical electrical stimulation in crack-‐cocaine addiction. Int JNeuropsychopharmacol. 2014, 17(9): 1465-1475.
- Conti CL, EM Nakamura-Palacios. Bilateral transcranial direct current stimulation over dorsolateral prefrontal cortex changes the drug-cued reactivity in the anterior cingulate cortex of crack-‐cocaine addicts. Brain Stimul. 2014,7(1): 130-132.
- Katayama J, J Polich. Stimulus context determines P3a and P3b. Psychophysiology. 1998, 35(1): 23-33.
- Polich J. Updating P300: an integrative theory of P3a and P3b.Clin Neurophysiol. 2007, 118(10): 2128-2148.
- Franken IH. Two new neurophysiological indices of cocaine craving: evoked brain potentials and cue modulated startle reflex. J Psychopharmacol. 2004,18(4): 544-552.
- Littel M, IH Franken. The effects of prolonged abstinence on the processing of smoking cues: an ERP study among smokers, ex-smokers and never-smokers. JPsychopharmacol. 2007, 21(8): 873-882.
- Namkoong K. Increased P3 amplitudes induced by alcohol-‐related pictures in patients with alcohol dependence. Alcohol Clin Exp Res. 2004,28(9): 1317-1323.
- Volkow ND. Cognitive control of drug craving inhibits brain reward regions in cocaine abusers. Neuroimage. 2010,49(3): 2536-2543.
- Hajcak G. Dorsolateral prefrontal cortex stimulation modulates electrocortical measures of visual attention: evidence from direct bilateral epidural cortical stimulation in treatment-resistant mood disorder. Neuroscience. 2010,170(1): 281-288.
- Meyer BU. Inhibitory and excitatory interhemispheric transfers between motor cortical areas in normal humans and patients with abnormalities of the corpus callosum. Brain. 1995,118(Pt 2): 429-440.
- Chen R. Interactions between inhibitory and excitatory circuits in the human motor Exp Brain Res. 2004,154(1): 1-10.
- Murase N. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol. 2004,55(3): 400-409.
- Fregni F. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 2006, 37(8): 2115-2122.
- Fregni F. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport. 2005,16(14): 1551-1555.
- Bajwa S. Impaired interhemispheric interactions in patients with major J Nerv Ment Dis. 2008,196(9): 671-677.
- Knoch D. Disruption of right prefrontal cortex by low-frequency repetitive transcranial magnetic stimulation induces risk-taking behavior. J Neurosci. 2006, 26(24): 6469-6472.
- Fecteau S. Diminishing risk-taking behavior by modulating activity in the prefrontal cortex: a direct current stimulation study. J Neurosci. 2007, 27(46): 12500-12505.
- Bisaga A, P Popik. In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug Alcohol Depend.2000, 59(1): 1-15.
- Addolorato G. How many cravings? Pharmacological aspects of craving treatment in alcohol addiction: a review. Neuropsychobiology. 2005,51(2): 59-66.
- Andrews T. Pharmacological issues in the treatment of concomitant alcoholism and drug abuse. Adv Alcohol Subst Abuse. 1984,3(4): 1-118.
- Reid MS, V Thakkar. Valproate treatment and cocaine cue reactivity in cocaine dependent individuals. Drug Alcohol Depend. 2009,102(1-3): 144-150.
- Diaper AM, FD Law, JK Melichar. Pharmacological strategies for Br J Clin Pharmacol. 2014,77(2): 302-314.