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The Use of Neuromodulation in the Treatment of Cocaine Dependence Lucia M

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The Use of Neuromodulation in the Treatment of Cocaine Dependence Lucia M Original Article ADDICTIVE 1 DISORDERS & THEIR TREATMENT Volume 13, Number 1 March 2014 The Use of Neuromodulation 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), deep brain stimulation, 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 dopamine 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 nucleus accumbens (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 forebrain 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 ventral tegmental area 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- substantia nigra (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, hippocampus, 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
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