Original Article ADDICTIVE 1 DISORDERS & THEIR TREATMENT Volume 13, Number 1 March 2014

The Use of in the Treatment of Cocaine Dependence Lucia M. Alba-Ferrara, PhD, Francisco Fernandez, MD, and Gabriel A. de Erausquin, MD, PhD, MSc

reports of craving, which usually pre- Abstract cedes the seeking and taking of drugs. Cocaine-related disorders are currently among the Understanding the pathophysiology of most devastating mental diseases, as they impover- ish all spheres of life resulting in tremendous eco- addiction and the neurobiological basis nomic, social, and moral costs. Despite multiple of craving in particular, is essential for efforts to tackle cocaine dependence, pharmacolog- designing better index of treatment re- ical as well as cognitive therapies have had limited success. In this review, we discuss the use of recent sponse and for developing new thera- neuromodulation techniques, such as conventional peutic interventions. repetitive transcranial magnetic stimulation (rTMS), , and the use of H coils for deep rTMS for the treatment of cocaine dependence. Moreover, we discuss attempts to identify optimal brain targets underpinning cocaine craving and with- THE ANATOMIC BASIS OF drawal for neurodisruption treatment, as well as some weaknesses in the literature, such as the ab- COCAINE DEPENDENCE sence of biomarkers for individual risk classification and the inadequacy of treatment outcome measures, Several investigations have con- which may delay progress in the field. Finally, we present some genetic markers candidates and objec- cluded that the most likely final com- From the Department of tive outcome measures, which could be applied in mon pathway underpinning drugs’ Psychiatry and Neuroscience, combination with transcranial magnetic stimulation treatment of cocaine dependence. We anticipate dependence is neurotrans- Roskamp Laboratory of Brain future research in this area combining genetic and mission. Tonic release of dopamine in Development, Modulation and physiological markers, neurodisruption, and clinical the (NAc) has been Repair, Morsani College of behavioral measures. Medicine, University of South associated with cravings due to sensiti- Florida, Tampa, FL. Key Words: transcranial magnetic stimulation, deep zation, whereas increasing phasic re- rTMS, DBS, addiction, habenula, medial bundle lease in response to consumption is Supported in part by NIMH thought to underlie sustained or in- 7K08MH077220 to G.A.d.E. (Addict Disord Their Treatment creased reinforcement and addictive 2014;13:1–7) behavior.2 The source of dopamine to G.A.d.E. is Steven and Constance Lieber investigator and Sydney R. the NAc is the Baer Jr investigator. He is also ocaine dependence has become a (VTA) of the midbrain, which receives the Roskamp Chair in Biological Csubstantial public health problem, top-down modulation from amygdala Psychiatry at University of South resulting in a significant number of and the prefrontal cortex (PFC) as part Florida. medical, psychological, and social prob- of the valuation of reward process. Con- The authors declare no conflict lems, including the spread of infectious solidation of engrams to obtain rewards of interest. diseases (eg, AIDS, hepatitis, and tuber- depends on the dorsal striatum, which Reprints: Gabriel A. de culosis), crime, violence, and neonatal receives dopamine projections from the Erausquin, MD, PhD, MSc, drug exposure. Prevalence rates for life- (SN), which lies besides Department of Psychiatry and 2 time use of cocaine are typically 1% to the VTA. Neuroscience, Roskamp 3% in developed countries, with higher Importantly, the components of Laboratory of Brain rates in the United States and in the the described network seem to be in- Development, Modulation and Repair, Morsani College of producer countries (WHO). Among volved in drug dependence at different Medicine, University of South people who have taken cocaine on at stages. At the binge or intoxication Florida, 3515 E. Fletcher Avenue, least 1 occasion, cocaine dependence stage, the NAc and the VTA have a Tampa, FL. 33613 (e-mail: develops in an estimated 16% to 17%.1 central role as dopamine release within [email protected]). Relapse to cocaine dependence is fre- these structures in the phasic phase is Copyright r 2012 by Lippincott quently associated with subjective increased, whereas the amygdala plays a Williams & Wilkins www.addictiondisorders.com DOI: 10.1097/ADT.0b013e31827b5a2c 2 ADDICTIVE Alba-Ferrara et al DISORDERS & THEIR TREATMENT Volume 13, Number 1 3 March 2014 role in the withdrawal phase. A more For example, ecopipam, a selective disperse cortico-subcortical network dopamine D1/D5 receptor antagonist, composed by the orbital PFC, amygdala, diminished acute intake of cocaine, , insula, and striatum play however, when administered repeat- a role in craving and relapse processes edly it seems to have the opposite effect as this circuit underlie the subjective increasing D1 dopamine receptor den- experiences of drug such as evaluation sity in the brain.7 Fortunately, there are of the rewarding effect of drugs.3 Paral- nonpharmacological tools of potential lely, disruption within the dorsolateral use for the treatment of drug depend- PFC-cingulate circuit is associated with ence. Transcranial magnetic stimulation poor inhibitory control observable in (TMS) may target the dopaminergic cir- the craving stage such as drug-seeking cuits involved in drug dependency with behaviors.3 Repeated intake of drugs fewer side effects and fewer contraindi- induces long-term neuroadaptations cations than medication treatments.8 caused by hyperactivity of dopamine TMS uses rapidly changing mag- transmission (acute effect of drug), netic fields to induce electric fields in which leads to alteration in cortical the brain, leading to excitation of neu- excitability, leading to heightened mo- rons. TMS has attracted considerable tivation to consume drugs and dimin- interests as a therapeutic option for ished ability to regulate the behavioral various psychiatric and neurological response to drug cues.4 See Figures 1 A disorders. Standard TMS devices induce and B showing the brain circuitry neuronal stimulation in cortical regions underlying addiction. lying mainly superficially under the windings of the coil.9 It should be noted that neuronal stimulation occurs only in TRANSCRANIAL MAGNETIC the vicinity of the scalp surface because the field rapidly decays with increasing STIMULATION ON THE distance from the coil. More recently, THREATMENT OF COCAINE stimulating deeper subcortical brain re- DEPENDENCE gions by deep brain TMS has received increased attention,10 and several re- Pharmacological treatments on drug cent studies have indicated that stimu- dependence have had limited success.5,6 lation of some deep structures may play

FIGURE 1. Model of the neural circuitry underpinning cocaine abuse. A, The neural response during the acute (phasic) cocaine consumption. B, The brain response during cocaine withdrawal. Black pointers indicate DBS targets reported in the literature, and white pointers indicate TMS targets reported in the literature. Boxes in black with small white dots stand for hyperactivity and boxes in white with small back dots stand for hypoactivity. Arrows represent unidirectional connections between structures and arrows crossed by double lines represent disconnectivity. DBS indicates deep brain stimulation; MFB, media forebrain bundle, NAc, nucleus accumbens; PFC, prefrontal cortex; SN, substantia nigra; TMS, transcranial magnetic stimulation; VTA, ventral tegmental area.

r 2012 Lippincott Williams & Wilkins www.addictiondisorders.com Neuromodulation Therapy for Cocaine Dependence ADDICTIVE 3 DISORDERS & THEIR TREATMENT Volume 13, Number 1 a role in the study of reward and moti- lated that the habenula releases GABA March 2014 vation mechanisms. onto dopaminergic cells of the VTA and Although scientific research on SN, resulting in a decrease in midbrain TMS treatments for addictions is still in dopamine.19 Matsumoto and Hikosaka its infancy, some promising studies have observed that midbrain dopamine in- shown moderate success. A recent study creases with unexpected rewards and shows that repeated high-frequency decreases with denied rewards, which is TMS on the left dorsolateral PFC re- exactly the opposite pattern the habe- duced cigarette consumption and nico- nula presents, meaning that these struc- tine craving in smokers, although the tures are anticorrelated.20 Noteworthy, effect tends to disappear over time.11 A cocaine intake conveys a rewarding feel- single case study on an alcoholic patient ing. On the basis of the presented evi- applied TMS on the dorsal anterior dence, it has been proposed that cingulate cortex, which temporarily continuous drug consumption results stopped alcohol cravings but again, the in habenular hyperactivity to counter- TMS effect disappeared over time.12 In balance excessive dopamine release in opposition, a study on healthy women the VTA and SN. Drug withdrawal may found that TMS on the left PFC did not correspond to habenular hyperactivity have an inhibitory effect on food crav- underpinning reward deny.19 It has ing.13 One of the reasons why the pre- been shown that the lateral habenula vious studies show only moderate or electrical stimulation in rats trained to null effects of TMS on craving may lie in self-administered cocaine weakens co- the structures they targeted. Although caine-seeking behavior, probably due to pivotal dopaminergic projections under- extinction of lateral habenula inhibitory lying addictions correspond to the effect on midbrain dopaminergic cells mesolimbic pathway, the cited studies after denied reward.15 However, DBS is targeted more superficial cortical struc- an invasive procedure that may produce tures. Again, traditional TMS performed several and severe adverse effects. Un- with round coils or figure-8 coils has an fortunately, because addiction is often important limitation as it cannot stim- seen as a volitional problem,21 a self- ulate farther than 2 cm from the skull.14 induced condition, or even a life choice,22 reluctance toward the use of invasive techniques such as DBS for the treatment of cocaine addiction is ex- DEEP BRAIN STIMULATION ON pected. THE THREATMENT OF COCAINE DEPENDENCE POSSIBLE TARGET FOR DEEP Deep brain stimulation (DBS) offers the possibility to stimulate deep REPETITIVE TRANSCRANIAL brain structures. Such technique in- MAGNETIC STIMULATION IN volves a neurosurgical intervention in COCAINE DEPENDENCE which implanted electrodes deliver electrical pulses to stereotactically tar- To circumvent the invasiveness of geted areas of the brain. The use of this DBS and the lack of power to stimulate technique in the treatment of addiction deep structures of traditional TMS, H coil has been investigated, revealing that TMS was created. H coils are capable of targeting the NAc and subthalamic nu- stimulating deeper structure and yet, the cleus is effective in reducing drug-seek- technique is noninvasive.10 HcoilTMS ing behavior and drug consumption.3 seem to be optimal for the treatment of Animal models present promising evi- drug dependence, as the most consistent dence on the efficacy of this technique neural nodes underpinning this affection targeting the lateral habenula for addic- are deep and it is a low-risk noninvasive tion treatment.15,16 The lateral habenu- procedure compared with DBS. Surpris- la innervated the VTA and PFC,17 ingly, to the best of our knowledge there providing negative reinforcement sig- are no reported studies applying this nals to midbrain dopamine cells in the technique for the treatment of addiction SN and VTA.18 Specifically, it is postu- in humans. www.addictiondisorders.com 4 ADDICTIVE Alba-Ferrara et al DISORDERS & THEIR TREATMENT Volume 13, Number 1 March 2014 Neuromodulation techniques are newly designed H coils can reach this most effective when using a well-de- track (Fig. 2). fined target region. A well-defined tar- get should be succinct and it should have clear anatomic boundaries, facili- PHYSIOLOGICAL AND GENETIC tating its location on the patient’s struc- TECHNIQUES AS OBJECTIVE tural MR images. Using anatomic or functional mapping/navigation techni- OUTCOME MEASURES AND ques aimed at well-defined targets, re- BIOMARKERS FOR COCAINE searchers should be able to predict the DEPENDENCE TREATMENT stimulation outcome accurately and fa- cilitate replication of findings. More- So far, we have addressed a num- over, the ideal target should be a ber of methodological problems for the central node of the neural network therapeutic use of neuromodulation underlying the behavior to modify. techniques in substance abuse disor- Although the habenula is a structure ders. An additional methodological with clear anatomic boundaries and problem in the addiction treatment lit- strongly connected within the neural erature is that outcomes are too often network underlying cocaine depend- measured by self-reported information ence, it has a remarkably small size and self-reported scales, lacking objec- and thus deep TMS, which has a spatial tivity and with low reliability. In drug resolution of several centimeters, could addiction research, the sensitive not accurately target it. Instead, because of the data collected, the tendency to of its ubiquitous projections to the neu- minimize use and its impact, and lack of ral network underlying cocaine craving, insight or denial, may lead study partic- and its larger size, the media forebrain ipants to misreport their drug use. Con- bundle (MFB) is a privileged target for versely, relying on urine drug screens deep TMS stimulation to treat cocaine alone may miss drug use events occur- use disorders. The MFB connects the ring too far in the past to be detected.27 VTA, the lateral , and A good outcome measure should esti- the NAc.23 Moreover, a connection of mate the prognosis accurately. Sec- the dopamine projecting VTA neuron ondly, the effect of treatment on drug groups with the limbic forebrain is es- dependence must be explained by the tablished directly through the MFB. It is effect of the treatment on the outcome. through the MFB that the VTA connects Thirdly, for an outcome not restricted to to numerous forebrain structures, in- use with a single, specific treatment, cluding the medial hypothalamus, sub- evidence must exist that treatments of lenticular region, lateral and medial various classes affect the outcome in the preoptic region, diagonal band, septal same and predictable manner.28 The nuclei, ventral pallidum, and ventral objective, sensitive, and quantitative parts of the bed nucleus of the stria changes measured using functional MRI terminalis.24 The superolateral branch (fMRI) have made it an attractive tool for of the MFB has direct connections to the measuring outcome of new treatments. ventral striatum and NAc. Upon follow- There is a single case study that collected ing the slMFB anteriorly, the connec- resting state fMRI and qEEG before and tions extend to the orbitofrontal cortex after treatment in an alcoholic patient, and dorsolateral PFC.25 The MFB im- revealing a strong correlation between portance as a central node for addiction the functional imaging data and the clin- and the has been high- ical picture. Precisely, when the patient lighted; in fact, a recent animal study craves for alcohol, activations in the dor- implanted electrodes for intracranial solateral PFC-cingulate circuit is found, self-stimulation on this fiber tract and which also correlates with b activity in the used it as a model of drug-seeking same network. Post–repetitive transcra- behavior.26 It is possible that MFB has nial magnetic stimulation (rTMS), when been excluded as a target for substance- the patient is not craving, activations in related disorders in human studies be- the described network are absent.12 Im- cause it not accessible with standard portantly, it has been proposed that the 8 coils for TMS stimulation; however, use of a combination of psychophysiology

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FIGURE 2. Coronal view showing the middle forebrain bundle as a promising deep rTMS target for cocaine dependence. (1) subtalamic nucleus, (2) substantia nigra, (3) , (4) striatum, (5) ventral tegmental area, and (6) nucleus accumbens. MFB indicates media forebrain bundle; TMS, transcranial magnetic stimulation. and genetics outcome measures is more SLC6A3), the dopamine B hydroxylase reliable than clinical markers and has gene (DBH),32 and the dopamine recep- more potential in establishing treatment tor D2 gene (DRD2)33 have been re- predictors.29,30 Surprisingly, previously ported in the literature. Importantly, obtained potential outcome measures in one of the advantages of rTMS for the substance dependence treatment have treatment of cocaine dependence is that been investigated in isolation. It is reason- this technique can exert persistent effects able to think that integrated fMRI, qEEG, through gene induction. Evidence from 3 and genetic markers would allow to pre- groups, using very different methods, dict treatment outcome more accurately. have reported that rTMS modulates the One of the ultimate goals of personalized expression of immediate early genes.34–36 medicine is to predict the optimal therapy After this strand of research, it might be for each single patient.31 The search for possible that future combined rTMS-ge- psychophysiological and genetic markers netic studies may not only reveal which will make an invaluable contribution to subjects are vulnerable to cocaine de- this goal. pendence but also the use of TMS treat- Identification of gene mutations, ment might trigger genetic modification polymorphisms, or other genetic variants leading to symptoms control. that predispose certain individuals to co- caine addiction would not only provide an ‘‘at-risk’’ diagnostic for substance CURRENT HYPOTHESES AND abuse, but it would also be useful to FURTHER EXPERIMENTS personalize treatments making them pa- tient specific and thus more effective. To date, there is no pharmacolog- There are certain genes that have been ical treatment guidelines for cocaine associated with cocaine dependence, dependence disorder; and a proportion which are also related to dopaminergic of patients do not respond to cognitive functions. Specifically, associations be- behavioral treatment. Alternatively, tween specific genotypes within the of TMS trails only had moderate success the dopamine transporter gene (DAT1/ because it has targeted the surface of the www.addictiondisorders.com 6 ADDICTIVE Alba-Ferrara et al DISORDERS & THEIR TREATMENT Volume 13, Number 1 March 2014 cortex, although the brain circuit under- 4. Feil J, Zangen A. Brain stimulation in the study and pinning addiction is mesial. Future studies treatment of addiction. Neurosci Biobehav Rev. should target mesial structures such as the 2010;34:559–574. 5. Bridge TP, Fudala PJ, Herbert S, et al. 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The dopamine hypothesis of drug addiction tabolites clear out in 3 d) results in poor and its potential therapeutic value. Front Psychiatry. 2011;2:64. assessment of drug intake. Further studies 9. Pascual-Leone A, Walsh V, Rothwell J. Transcranial should combine different measurements magnetic stimulation in cognitive neuroscience— (such as self-reported cocaine use, urine virtual lesion, chronometry, and functional connec- test, and a cocaine craving questionnaire) tivity. Curr Opin Neurobiol. 2000;10:232–237. 10. Zangen A, Roth Y, Voller B, et al. Transcranial mag- to allow to look for inconsistencies in the netic stimulation of deep brain regions: evidence for data.Inaddition,fMRIandqEEGdata efficacy of the H-coil. Clin Neurophysiol. 2005;116: could be collected to improve the reliabil- 775–779. ity of outcome measures. The physiolog- 11. Amiaz R, Levy D, Vainiger D, et al. Repeated high- frequency transcranial magnetic stimulation over the ical data may reveal brain biomarkers, dorsolateral prefrontal cortex reduces cigarette crav- such as intrinsic connectivity patters asso- ing and consumption. Addiction. 2009;104:653–660. ciated with treatment outcome, giving 12. De Ridder D, Vanneste S, Kovacs S, et al. Transient objective empirical support to the efficacy alcohol craving suppression by rTMS of dorsal ante- rior cingulate: an fMRI and LORETA EEG study. of TMS treatment for cocaine depend- Neurosci Lett. 2011;496:5–10. ence. Another weakness in the literature 13. Barth KS, Rydin-Gray S, Kose S, et al. Food cravings consists in that the mechanisms by which and the effects of left prefrontal repetitive transcra- TMS treatment modifies behavior are nial magnetic stimulation using an improved sham condition. Front Psychiatry. 2011;2:9. poorly understood. New studies could 14. Rossi S, Hallett M, Rossini PM, et al. 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