1. Sarah Herremans Addiction Therapy 2015 Florida, USA August 03-08, 2015

2. The predictive value of alcohol- related cues for relapse after accelerated HF-rTMS treatment in alcohol addiction Herremans Sarah

3. titel 3 25-10-2015 Overview Neuromodulation techniques and addiction HF-rTMS and alcohol addiction Alcohol relapse and accelerated HF-rTMS

4. Neuromodulation techniques Non-invasive techniques transcranial direct current stimulation (tDCS) transcranial magnetic stimulation (TMS) Invasive techniques deep brain stimulation (DBS) vagal nerve stimulation (VNS) electroconvulsive therapy (ECT) titel 4 25-10-2015

5. Transcranial direct current stimulation 5

6. tDCS and substance dependence Nicotine: Fregni et al., 2008: 24 subjects, stimulation of DLPFC (dorsolateral prefrontal cortex) Each subject: 1 placebo, 1 anodal left/cathodal right and 1anodal right/cathodal left stimulation =>  craving (cue-exposure) in both active stimulation conditions Boggio et al., 2009: 27 subjects, randomized, double blind, placebo-controlled Stimulation of the DLPFC, during 5 consecutive days (anodal left/cathodal right) => Increasingly  craving (cue-exposure) over time 6 8-9-2012

7. tDCS and substance dependence Alcohol: Boggio et al., 2009: 13 subjects, stimulation of DLPFC, randomized placebo-controlled Each subject: 1 placebo, 1 anodal left/cathodal right & 1 anodal right/cathodal left stimulation   craving (cue-exposure) in both ACTIVE stimulation conditions Cannabis: Boggio et al., 2010: 25 cannabis users – 3 groups -randomized placebo - an anodal left/cathodal right - an anodal right/cathodal left =>  craving only for anodal right/cathodal left stimulation 7 8-9-2012

8. Neuromodulation techniques Non-invasive techniques transcranial direct current stimulation (tDCS) transcranial magnetic stimulation (TMS) Invasive techniques deep brain stimulation (DBS) vagal nerve stimulation (VNS) electroconvulsive therapy (ECT) titel 8 25-10-2015

9. Deep Brain Stimulation 9

10. DBS and substance dependence DBS in substance dependence as a comorbid disorder => case reports (Kuhn, 2007, 2009; Mantione, 2010) DBS in substance dependence as primary disorder Voges, 2013 : 5 treatment-resistant alcohol-dependent pts => decrease in relapse rate or abstinence Kuhn, 2011: 2 TR heroïne dependent patients => decrease in relapse rate Stimulation place: nucleus accumbens In animals: nucleus accumbens, insula, medial forebrain bundle, subthalamic nucleus, lateral habenula 10 8-9-2012

11. Neuromodulation techniques Non-invasive techniques transcranial direct current stimulation (tDCS) transcranial magnetic stimulation (TMS) Invasive techniques deep brain stimulation (DBS) vagal nerve stimulation (VNS) electroconvulsive therapy (ECT) titel 11 25-10-2015

12. Vagal Nerve Stimulation 12

13. VNS and substance dependence No human case studies Liu et al., 2011: study with heroine dependent rats: inhibition of heroine reinstatement after heroine priming and after exposure to heroin cues 13 8-9-2012

14. Neuromodulation techniques Non-invasive techniques transcranial direct current stimulation (tDCS) transcranial magnetic stimulation (TMS) Invasive techniques deep brain stimulation (DBS) vagal nerve stimulation (VNS) electroconvulsive therapy (ECT) titel 14 25-10-2015

15. Electroconvulsive therapie 15

16. ECT and substance dependence Outdated!!! 1966: Roper et al.: effective in 4 of 6 cases, most of them were morphine-dependent After that nothing was published …Reason??? Possibly because APA did not specify addiction as an indication in ECT guidelines 16 8-9-2012

17. titel 17 25-10-2015 Overview Neuromodulation techniques and addiction HF-rTMS and alcohol addiction Alcohol relapse and accelerated HF-rTMS

18. Transcranial magnetic stimulation (TMS) titel 18 25-10-2015

19. Repetitive TMS (rTMS) titel 19 25-10-2015 Ridding & Rothwell, 2007 DLPFC High Frequency vs Low Frequency

20. Previous research (2012,2013) 1 HF-rTMS session at Right DLPFC Craving Cognition Response Inhibition Attentional Control Randomized placebo controlled cross-over Detoxified alcohol-dependent patients

21. Go-NoGo task (Zimmerman & Fimm, 1992) GoNoGo OCDS RESPONSE INHIBITION ATTENTIONAL CONTROL

22. Study Design 50 pts29 pts Active HF-rTMS Placebo HF-rTMS Go-NoGo task OCDS 1 WEEK OCDS until three days after the stimulation

23. Results No effect on craving (until three days after the stimulation) No effect on response inhition Increase in attentional control => distractibility

24. Mutiple HF-rTMS sessions titel 24 25-10-2015 alcohol craving No difference in anti-craving efficacy in both groups 20 detoxified alcohol- dependent patients Mishra et al, 2015 10 daily sessions left DLPFC 10 daily sessions right DLPFC Mishra et al, 2010: 14% relapsed in the active stimulation 33% in the placebo stimulation Höppner et al, 2011

25. Relapse Often (80 -> 92% in one year ) Definition:binary (yes or no drink) different outcomes Pharmacological/psychotherapy not always beneficial only 30% in actual treatment; reasons for this treatment gap: - problem is not acknowledged - the desire to not involve outside help/ that the treatment is not effective - the belief that the problem will pass by itself - stigma - financial problems,… titel 25 25-10-2015

26. Predictors of relapse Craving Stress Severity of alcohol dependence Cognitive dysfunction, especially impaired response inhibition Changes/Adaptations at the neurobiological level titel 26 25-10-2015

27. Neurobiological predictors of relapse titel 27 25-10-2015 ACCACCC vmPFC precuneus Nucleus accumbens Seo et al., 2013De Raedt et al., 2010

28. titel 28 25-10-2015 Overview Neuromodulation techniques and addiction HF-rTMS and alcohol addiction Alcohol relapse and accelerated HF-rTMS

29. Goal 1 Can we predict alcohol relapse after accelerated HF-rTMS treatment based on baseline brain activation during a cue-exposure? titel 29 25-10-2015

30. Hypothesis 1 titel 30 25-10-2015 Hyperactivation during the alcohol-related stimuli => ABSTAINERS

31. Goal 2 How does 15 ACCELERATED HF-rTMS sessions influence the relapse neurocircuitry in detoxified alcohol-dependent patients? titel 31 25-10-2015

32. Hypothesis 2 titel 32 25-10-2015 HF-rTMS only affects the relapse neurocircuit in ABSTAINERS

33. Study design titel 33 25-10-2015 15 accelerated sessions over 1 week Four weeks after the last fMRI: “have you already consumed an alcoholic beverage?” Right DLPFC 20 Hz 1560p/session

34. 29 recently detoxified (benzodiazepines) alcohol-dependent patients were included over one year 10 patients were lost to follow-up 19 patients: 13 relapsers, 6 abstainers titel 34 25-10-2015

35. titel 35 25-10-2015 Relapsers (13 patients) Abstainers (6 patients) Significance Gender (M/F)7/64/2P>0.99 Age (years)M=43.6; SD=7.3M=47.7; SD=13.6P=0.40 BZD free days before stimulation M=13.0; SD=6.0M=12.0; SD=4.1P=0.72 Heavy Drinking Days during the last month M=17.7; SD=10.6M=20.0; SD=10.0P=0.68 Duration of alcohol addiction M=14.5; SD=9.9M=9.8; SD=9.6P=0.35

36. Relapse rate 68% High! Compared to Mishra et al, 2010 much higher! Not easy to compare since we used accelerated protocol Accelerated protocol less efficient? Mean duration of alcohol addiction of our patients +/- 5 years longer Comparable to studies assessing naltrexone, acamprosate (Laaksonen et al., 2008) titel 36 25-10-2015

37. Neurobiological level titel 37 25-10-2015

38. ANOVA – ROI analysis: Interaction cluster titel 38 25-10-2015 P<0.001 AlphaSim corrected

39. Baseline – Before accelerated HF-rTMS titel 39 25-10-2015 dACC Abstainers > Relapsers => cognitive control Hypothesis 1 !

40. Effect of HF-rTMS Abstainers: dACC activation Relapsers: dACC activation titel 40 25-10-2015 ! After HF-rTMS = Hypothesis 2

41. Rate-dependent effect titel 41 25-10-2015 Contrast: alcohol > neutral Rate-dependent effect

42. How can we interpret?  In detoxified hospitalized patients  During exposure to alcohol stimuli Is HF-rTMS relevant in patients with high baseline dACC activation (abstainers)? Patients with a low baseline dACC activation (relapsers) have a larger proportional increase of dACC activation, but without a clinical effect? short duration of action? dosage? titel 42 25-10-2015

43. Limitations No placebo stimulation No control group that received treatment as usual was assessed 4 weeks after discharge Only info about alcohol lapses titel 43 25-10-2015

44. Future research Patients with low dACC activity larger number of placebo-controlled HF-rTMS interventions Optimize HF-rTMS parameters titel 44 25-10-2015

45. Take away message 15 accelerated HF-rTMS sessions in detoxified alcohol-dependent patients: High relapse rate (68%) Abstaining patients: more cognitive control (dACC) Accelerated HF-rTMS has a rate-dependent effect on dACC activation Only a limited effect at the clinical level (HF- rTMS effect probably short-lived) titel 45 25-10-2015

46. Thank you for your attention! Collaborators: Chris Baeken, MD, PHD Frieda Matthys, MD, PHD Peter Van Schuerbeek, MSc Rudi De Raedt, PhD, Johan De Mey, MD, PhD Daniele Marinazzo, PhD titel 46 25-10-2015

47. Addiction Therapy 2016 Website: addictiontherapy.conferenceseries.com Meet the eminent gathering once again at Addiction Therapy 2016 Miami, USA October 06-08, 2016