Transcranial Magnetic Stimulation for Addictive disorders 인천 참사랑병원 천 영 훈

S. Rossi et al. / Clinical Neurophysiology 120 (2009) 2008–2039

Technical Overview of TMS 1831 Michael Faraday : changing electrical field produces a changing magnetic field that, consistent with Faraday’s law. approved by some countries for treatment of medication-refractory depression : i.e., Canada and Israel October 2008 : specific rTMS device 가 미국에서 medication- refractory unipolar depression 에 대한 치료법으로 FDA 승인 획득

Technical Overview of TMS Variations in stimulation parameters include  orientation of the induced magnetic field,  single or repeated stimulation,  frequency of stimulation,  number of pulses,  intensity and site of stimulation  shape of coil  Stereotactic or navigated TMS

Technical Overview of TMS Shape of Coil 1) round coils: powerful but not focal 2) figure-8 coil: more focal but superficial 3) H-coil: newly developed, with complex windings more deeper structures s excessive field strengths, but less focal Frequency of stimulation pulse  low-frequency rTMS (approximately 1 Hz) : induce a transient inhibition of cortical excitability  high frequency rTMS (>5 Hz) : transiently enhance cortical excitability

Technical overview of tDCS transcranial direct current stimulation (tDCS) : neuronal resting membrane potential 과 cortical excitability 를 변화시킴 weak constant electric current, delivered via two surface electrodes -> subthreshold modulation of neuronal resting membrane potential -> modulation of spontaneous brain activity (Nitsche et al., 2003c, 2005; Nitsche and Paulus, 2000, 2001).  Related to voltage gated channel & NMDA re. blocking  Sustained effectiveness?

Previous studies of tDCS Cognition (Bermpohl et al., 2005; Boggio et al., 2007; Fregni et al., 2006; Kincses et al., 2004), Memory (Fregni et al., 2005; Sparing and Mottaghy, 2008) Impulsivity (Fecteau et al., 2007). Depression (Boggio et al.,2007, 2008a; Fregni et al., 2006), Food craving (Fregni et al.,2008b) Nicotine dependence (McBride et al., 2006; Fregni et al., 2008) Alcohol dependence (Boggio et al., 2008)

chronic drug use : ass w neuroadaptations within several sites in the mesocorticolimbic reward circuitry ( Everitt et al., 2008; Kalivas & O’Brien, 2007; Volkow et al., 2003). => altered DA activity and cortical excitability (Kalivas and O’Brien, 2007; Kauer and Malenka, 2007; Wise, 1996b) => persistence of drug seeking behaviors, difficulties regulating drug-seeking behaviors heightened likelihood of relapse (Everitt et al., 2008; Jentsch and Taylor, 1999).

Brain Stimulation in Addiction Research Investigative tool : altered cortical excitability by drug To assess changes in excitability in motor cortex Therapeutic tool Repetitive brain stimulation => modulate cortical excitability (e.g. in the PFC) => alter neuronal activity of circuits ass w craving

Brain stimulation to assess cortical excitability in addiction Balance of inhibitory and excitatory neurotransmission : crucial to maintaining the optimal balance of cortical excitability (Torregrossa and Kalivas, 2008) : glutamate & GABA activity  Alterations in balance – related to deficits in brain Fx.  Psychiatric & neurologic disorders Motor threshold : measure of cortical excitability : single pulse stimulation -> primary cortex -> Corticospinal pathway -> Muscle twitch (contralat.) = MEP(muscle evoked potential) by EMG

TMS studies of cortical excitability in addiction

Brain stimulation to assess cortical excitability in addiction Cocaine & Nicotine dependent : decreased excitability in motor cortex. (Boutros et al., 2001, 2005; Sundaresan et al., 2007; Lang et al, 2008) Ecstasy : increased excitability of the visual cortex (Oliveri and Calvo, 2003) Alcohol  acute exposure : decreased excitability in the motor cortex & PFC  chronic consumption : alter glutamate mechanisms involved in cortical excitability (Conte et al., 2008; Kahkonen, 2005; Kahkonen et al., 2001, 2003; Ziemann et al., 1995).

Brain stimulation to assess cortical excitability in addiction Wohlfarth K et al : Acamprosate 가 excitability of cortical motor neurons 에 효과가 있는지 : 12 male healthy volunteers : ACP 6T or placebo for 1 week - randomized cross-over design - TMS: paired stimulation paradigm => MEPs: no differences but MT : increased in the acamprosate group (verum: 61.5% (SD = 7.9) vs. placebo: 58.9% (SD = 8.8), p = 0.036). ACP 는 motor cortex 의 hypoexcitability 를 유발하는 것으로 결론

Therapeutic tool for drug addiction Hallett, 2007; Rossini and Rossi, 2007; Ziemann, 2004 : rTMS can alter excitability in the stimulated cortex, and interconnected brain regions, beyond the period of stimulation Animal studies rTMS to the frontal regions of rats : ↑ release of DA in both the mesolimbic & mesostriatal pathways (Kanno et al., 2004; Keck et al., 2002; Zangen and Hyodo, 2002) Human studies : using PET to assess the effects of rTMS on DA transmission.  rTMS of PFC : induces release of DA in the caudate nucleus (Strafella et al. 2001)

Therapeutic tool for drug addiction Depression (Fitzgerald et al., 2003, 2006a, 2007; Kito et al., 2008; Lisanby et al., 2008) OCD (Greenberg et al., 1997, 2000) Schizophrenia (Cohen et al.,1999; Jin et al., 2006; Lee et al., 2005; Stanford et al., 2008) Food craving (Uher et al., 2005) Drug addiction (Amiaz et al., 2009; Camprodon et al., 2007; Eichhammer et al., 2003; Johann et al., 2003; Politi et al., 2008)

Effect of neuromodulation on craving and substance use

Nicotine Johann et al. (2003) - over Lt. DLPFC, high frequency rTMS - tobacco craving tobacco dependent individual - either active or sham at 90% of MT. : Craving levels by VAS (both 30 min prior to, and following)  levels of tobacco craving ↓

Nicotine Eichhammer et al. (2003) - 14 treatment-seeking heavy smokers : required to abstain from smoking 12 h before the rTMS -double-blind crossover trial. randomized order, each pt received 2 active trials + 2 shams over 4 consecutive days. - high frequency (20 Hz) rTMS to the left DLPFC (90% of MT) - 1) craving by VAS (baseline and 30 min after) 2) cigarette consumption - No of cigarettes smoked in 6 h after Tx  cigarette consumption ↓ but craving levels remained unchanged.

Nicotine Amiaz et al. (2009) : exposure to visual smoking cues (prior to rTMS) : 48 nicotine-dependent randomly divided into 4 groups - active TMS + smoking cues or + neutral cues, - sham TMS + smoking cues or + neutral cues. : 10 daily sessions of high frequency (10 Hz), 100% of MT over DLPFC + weekly maintenance sessions during the following month. : VAS, standard questionnaires on nicotine consumption, craving and dependence.  cigarette consumption ↓ & nicotine dependence ↓ => rTMS blocked craving induced by smoking cues but 이러한 효과들은 10 daily session 후 사라지기 시작 치료 종료 후 6 개월 이후에는 흡연량의 감소가 유의하지 않았음.

Cocaine Camprodon et al. (2007) : single session of high frequency rTMS over either Rt. or Lt. DLPFC : 6 males cocaine dependence. : two sessions of high frequency (10 Hz) rTMS at 90% of MT, once over the right, and once over the left DLPFC, with a week break between the two sessions. : Craving by VAS (10 min before, immediately, 4hr after)  single session right DLPFC (but not Lt) reduced cocaine craving. Politi et al. (2008) : 10 daily sessions of high frequency (15 Hz) rTMS over the left DLPFC at 100% of MT : 36 cocaine dependence post-detox. : daily clinical evaluation of symptoms associated with cocaine craving. => cocaine craving ↓ esp. cocaine cravings reduced gradually throughout the sessions

Alcohol Mishra et al. (2010) * aim: anticraving efficacy of high-frequency rTMS in Rt. DLPFC (10 Hz frequency, 4.9 seconds per train, inter-train interval of 30 seconds, 20 trains per session, total 10 sessions). * prospective, single-blind, sham-controlled study * 45 patients with AD c CIWA-Ar scores <or=10. * active and sham in a 2 : 1 ratio (30 pts vs 15 pts) * Alcohol Craving Questionnaire (ACQ-NOW) : baseline, after the last rTMS session and after 1 month of the last rTMS => Active group 에서 post-rTMS ACQ-NOW score 가 유의하게 감소

Alcohol Herremans et al. (2010) : prospective, single-blind, sham-controlled study involving 36 hospitalized patients : 최소 2 주이상 입원 중인 환자들을 대상 : obsessive-compulsive drinking scale (OCDS) : HF-rTMS 직전 및 직후에 측정 금요일날 시행 후 주말 외박 보낸 후 월요일 귀원 - 1 st naturalistic study : stimulation intensity of 110% of the subject’s resting MT 20 Hz rTMS session, 40 trains of 1.9 s duration intertrain interval of 12 s (1560 pulses per session). => 갈망의 감소는 없었음.

Alcohol De Ridder et al. (2011) Case report: 46 yrs female : rTMS targeting the dACC using a double cone coil 시행 fMRI 와 EEG 를 rTMS 전후와 재발 후 시행 => Craving 은 dADD 와 PCC 간의 EEG beta activity and connectivity 와 연관 & rTMS 시행 후 소실 rTMS 전 유발 인자에 의한 갈망은 ACC-vmPFC 및 PCC, NC 를 activation 시켰으나 rTMS 후에는 이러한 activation 이 사라짐.

Safety Issues of TMS TMS guidelines  1 st Wassermann, 1998  2 nd Safety of TMS Consensus Group, 2009

Safety Issues of TMS TMS guidelines  1 st Wassermann, 1998  2 nd Safety of TMS Consensus Group, 2009 Sz. : rare, but the main risk of rTMS : less than 0.1% of the subjects following rTMS, - in most cases when high frequency and intensity were used in patients taking medications that lower the seizure threshold (Tassinari et al., 2003).  따라서 alcoholics, cocaine, amphetamine user 에게 high- intensity rTMS 사용시 주의. Long-term effects of repeated rTMS: yet unknown.

S. Rossi et al. / Clinical Neurophysiology 120 (2009) 2008–2039

Safety Issues of TMS Cognitive changes : rTMS for therapy 의 경우 cumulative effects 로 인해 발생가능  Machii et al., 2006 : meta-analysis of 173 papers published from January 1998 to December 2003 (more than 3000 subjects/patients) that reported application of rTMS to non-motor areas, => excessive tiredness, concentration difficulties, memory difficulties 대개는 mild & transient, very rare  Loo et al., 2008 : comprehensive review of sham-controlled rTMS studies in major depression 39 studies (more than 1200 patients) 12 reported cognitive improvement. 3 개의 연구에서는 적어도 1 가지 인지검사에서 악화된 소견을 보고

Issues of lateralization in addiction DLPFC unilateral stimulation => same effect on contra-lateral site via transcallosal connection (George et al., 1999) beneficial effects on craving were observed with -bilateral tDCS stimulation (Boggio et al., 2008; Fregni et al., 2008) - high-frequency rTMS over the left DLPFC : (Eichhammer et al., 2003; McBride et al., 2006) right DLPFC : (George et al., 2002; Camprodon et al., 2007).