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

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

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

titel Overview Neuromodulation techniques and addiction HF-rTMS and alcohol addiction Alcohol relapse and accelerated HF-rTMS

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

Transcranial direct current stimulation 5

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

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

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

Deep Brain Stimulation 9

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

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

Vagal Nerve Stimulation 12

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

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

Electroconvulsive therapie 15

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

titel Overview Neuromodulation techniques and addiction HF-rTMS and alcohol addiction Alcohol relapse and accelerated HF-rTMS

Transcranial magnetic stimulation (TMS) titel

Repetitive TMS (rTMS) titel Ridding & Rothwell, 2007 DLPFC High Frequency vs Low Frequency

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

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

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

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

Mutiple HF-rTMS sessions titel alcohol craving No difference in anti-craving efficacy in both groups 20 detoxified alcohol- dependent patients Mishra et al, 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

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

Predictors of relapse Craving Stress Severity of alcohol dependence Cognitive dysfunction, especially impaired response inhibition Changes/Adaptations at the neurobiological level titel

Neurobiological predictors of relapse titel ACCACCC vmPFC precuneus Nucleus accumbens Seo et al., 2013De Raedt et al., 2010

titel Overview Neuromodulation techniques and addiction HF-rTMS and alcohol addiction Alcohol relapse and accelerated HF-rTMS

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

Hypothesis 1 titel Hyperactivation during the alcohol-related stimuli => ABSTAINERS

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

Hypothesis 2 titel HF-rTMS only affects the relapse neurocircuit in ABSTAINERS

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

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

titel 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

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

Neurobiological level titel

ANOVA – ROI analysis: Interaction cluster titel P<0.001 AlphaSim corrected

Baseline – Before accelerated HF-rTMS titel dACC Abstainers > Relapsers => cognitive control Hypothesis 1 !

Effect of HF-rTMS Abstainers: dACC activation Relapsers: dACC activation titel ! After HF-rTMS = Hypothesis 2

Rate-dependent effect titel Contrast: alcohol > neutral Rate-dependent effect

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

Limitations No placebo stimulation No control group that received treatment as usual was assessed 4 weeks after discharge Only info about alcohol lapses titel

Future research Patients with low dACC activity larger number of placebo-controlled HF-rTMS interventions Optimize HF-rTMS parameters titel

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

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

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