The Emerging Therapeutic Role Of The Non-invasive Brain Stimulation In The Addiction Medicine: Review Of

The Ongoing StudiesAhmed Elaghoury, MD

Psychiatrist at Abbasia Mental Hospital, Cairo, EgyptEmail: dr.aghoury@gmail.com

Introduction• Substance use disorders targeted by NIBS and under current investigation are shown, with their

enrollment numbers (Fig1).

• Targeted brain sites are shown (Table 3)

• There is no registered clinical trial investigating the NIBS use in opioid, hypnotic-sedative, andhallucinogenic use disorders.

• No registered study use transcranial alternating current stimulation, tACS.

TMS

• The TMS protocols registered in the studies are as follows: high-frequency, HF (n=19), low-frequency, LF(n=1), theta-burst stimulation, TBS as continuous cTBS (n=5), and intermittent, iTBS (n=1)

• The only LF TMS study registered targets the SFG in smokers (3).

• The studies registered with the cTBS protocol (n=5) are for smoking, alcohol, and amphetamine over themPFC (44-47) and DMPFC (37), and for cocaine over the DLPFC (46).

• There is a single study sponsored by the NIDA using iTBS protocol for patients (n=170) of cocaine useover the left DLPFC (43).

tDCS

• The transcranial direct current stimulation (tDCS) protocols in the registered studies do not vary widelyregarding the amplitude (1-2 mA) or the duration (20-30 mins). However, they vary as regards the site ofstimulation and cathodal/reference position.

• No high definition (HD) protocols are registered till now.

• The REDSTIM is a large-scale (n=340) randomized, double-blinded study investigating tDCS to reducealcohol consumption in non-abstinent patients and has published its protocol (29).

tRNS

• There is only one registered study, using transcranial random noise stimulation (tRNS), and with largeenrollment (n=225) (17).

• It is for patients with abuse of > 2 substances plus other psychiatric conditions

• The targeted sites for modulation are ACC and DLPFC

Special comments:

• There are only two registered studies for amphetamine use, with large-scale enrollment. The first (26) isopen-label (n=560, HF TMS over DLPFC and parietal), and the second (31) is randomized, single-blinded(n=240, TBS over DMPFC).

• Two studies are trying to investigate the concept of continuation/maintenance treatment with NIBSafter short-term response in patients with both types of stimulant use disorder (cocaine andamphetamine types) (31,48).

• Some studies use NIBS as an add-on to investigate if it will enhance different types of psychotherapy, e.g.use of tDCS with heavy drinking patients during mindfulness sessions is registered (40).

• From the twelve large-scale studies, there are five studies have an enrollment number > 200(17,23,26,29,31)

Credit: Caltech/Todd Hare

• Craving is a central behavior to the drug addiction. It has neurobiological correlates andpsychosocial relations (i-iii).

• The first interest in the use of non-invasive brain stimulation (NIBS) in addiction started in 2003through investigating the use of TMS with the craving of nicotine smokers (iv).

• Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES) have beencommonly investigated to decrease drug craving (v-xii).

• One main challenge for the practice of NIBS is blinding and reproducibility (xiii).

Table 3: Target sites of Neuromodulation in registered studies--------------------------------------------------------------------------------------DLPFC: Lt (n=15), Rt (n=7), BL (n=5) and not determined (n=10)mPFC: n=4Insula: n=2Parietal: n=2ACC: n=2Frontal: n=2DMPFC: n=1SFG: n=1

-------------------------------------------------------------------------------------------DLPFC: dorsolaterprefrontal cortex, mPFC: medial prefrontal cortex, ACC: anterior cingulated cortexal, DMPFC: dorsomedial prefrontal cortex, SFG: superior frontal gyrus

References

Table 1: Factors that can mediate the effects of rTMS or tES on craving (i):--------------------------------------------------------------------------------------o Stimulation parameters, including target siteo Subjects’ brain state: craving vs. restingo How to measure the craving? Cue-induced vs. environmentalo Patient’s characteristics: e.g. motivated or not? Mood disorders or not?

Table 2: The mechanisms underlying/mediating the therapeutic effects of rTMSand tES in drug addiction are still not clear. However, may be (ix):-------------------------------------------------------------------------------------o Modulation of the neural activities in the targeted region: e.g. neuroadaptation and

synaptic plasticityo Network alterations induced by targeted stimulation: effect on distal or corresponding

siteso Release of some neurotransmitters: e.g. dopamine and GABA

MethodThrough use of the keywords “brain stimulation AND addiction” and “Neuromodulation AND addiction,” 55relevant studies are found registered on clinicaltrials.gov : n=50 are reviewed here, n=3 published, n=2withdrawnOnly 39 studies have registered their randomization and double-blinding design

Figure (1) Figur (2)

Figure (3)

Results

1. NCT00284219 2. NCT00543036 3. NCT00901459 4. NCT00951782 5. NCT00973622 6. NCT01031693 7. NCT01093716 8. NCT01259362 9. NCT01288183 10. NCT01397266 11. NCT01523730 12. NCT01567982 13. NCT01569399 14. NCT01593982 15. NCT01702948 16. NCT01729507 17. NCT01876524 18. NCT01930422

19. NCT01973127 20. NCT02045108 21. NCT02091167 22. NCT02091284 23. NCT02126124 24. NCT02146014 25. NCT02228486 26. NCT02285556 27. NCT02401672 28. NCT02446067 29. NCT02505126 30. NCT02534454 31. NCT02557815 32. NCT02567344 33. NCT02570763 34. NCT02624284 35. NCT02643264 36. NCT02691390

37. NCT02713815 38. NCT02776319 39. NCT02810574 40. NCT02861807 41. NCT02862093 42. NCT02867514 43. NCT02927236 44. NCT02939313 45. NCT02939339 46. NCT02939352 47. NCT02948296 48. NCT0298643849. NCT03025321 50. NCT03058276

REVIEWED STUDIES

Discussion and conclusions

i. Hone-Blanchet, Antoine, et al. "Noninvasive brain stimulation to suppress craving in substance use disorders: Review of human evidence andmethodological considerations for future work." Neuroscience & Biobehavioral Reviews 59 (2015): 184-200..

ii. Sayette, Michael A. "The role of craving in substance use disorders: Theoretical and methodological issues." Annual review of clinical psychology 12(2016): 407-433.

iii. Kuhn J, et al. Neuromodulation for Addiction. In: Knotkova, Helena, and Dirk Rasche. Textbook of Neuromodulation. Springer New York, 2015.iv. Johann, Monika, et al. "Repetitive transcranial magnetic stimulation in nicotine dependence." Psychiatrische Praxis 30.Suppl 2 (2003): 129-131.v. Hone-Blanchet, Antoine, and Shirley Fecteau. "The Use of Non-Invasive Brain Stimulation in Drug Addictions." The Stimulated Brain: Cognitive

Enhancement Using Non-Invasive Brain Stimulation (2014): 425.vi. Holtzheimer, Paul, and Andres M. Lozano. Neuromodulation in Psychiatry. John Wiley & Sons, 2016.vii. Kadosh, Roi Cohen, ed. The stimulated brain: cognitive enhancement using non-invasive brain stimulation. Elsevier, 2014.viii. Salling, Michael C., and Diana Martinez. "Brain Stimulation in Addiction." Neuropsychopharmacology (2016)ix. Yavari, Fatemeh, et al. "Noninvasive brain stimulation for addiction medicine: From monitoring to modulation." Progress in brain research 224 (2016):

371-399.x. Brunoni, André, Michael Nitsche, and Colleen Loo, eds. Transcranial Direct Current Stimulation in Neuropsychiatric Disorders: Clinical Principles and

Management. Springer, 2016.xi. Bashir, Shahid, and W-K. Yoo. "Neuromodulation for Addiction by Transcranial Direct Current Stimulation: Opportunities and Challenges." Annals of

neurosciences 23.4 (2016): 241-245.xii. Brunoni, André, Michael Nitsche, and Colleen Loo, eds. Transcranial Direct Current Stimulation in Neuropsychiatric Disorders: Clinical Principles and

Management. Springer, 2016.xiii. Kappenman ES: Establishing Reproducibility and Openness in tES Research. NIMH tES workshop, Sep 2016 [video webinar retrieved from

https://www.eventbrite.com/e/transcranial-electrical-stimulation-tickets-27030688517]

• Smoking craving is the oldest and most common SUD to be under investigation by NIBS• Many current TMS protocols under investigation with patients of SUD are similar to those approved before for

depression.• This can be explained by their well-established safety and tolerability or by the role of distress/depressed mood in

craving.• The optimal modulation protocol for patients with substance use disorders is still not agreed on, and in progress.• The neuroanatomical targets for neuromodulation in patients with SUD are still undetermined, with the DLPFC

being the site to be most investigated.• HF TMS protocols are currently investigated with alcohol and amphetamine, disregarding previous precautions

about seizure occurrence.• Recent interest is rising to investigate NIBS with patients with stimulant use disorders, with both types: cocaine

and amphetamine• Superficial targeting of brain structures and short-term effects are known limitations for NIBS use• These restrictions have opened the door for investigating the use of H-coil and modulating deeper structures e.g.

insula and raised the need of investigating continuation/maintenance tDCS in some registered studies• TBS protocols are getting more common and they are under investigation in large-scale studies.• Large-scale, randomized, and double-blinded studies for the use of TMS, tDCS, and tRNS are in the pipeline for

publishing over the next years.• Many registered studies do not document their modulation protocols in details before publishing, which make

them difficult to replicate.

Acknowledgment to Dr. Amany Ragab, MD for her efforts fornumber figures