- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02884674
Repetitive Transcranial Magnetic Stimulation in Obsessive Compulsive Disorder (MAGTOC)
Stimulation magnétique transcrânienne répétitive Dans le Traitement Des Troubles Obsessionnels Compulsifs
Study Overview
Status
Conditions
Detailed Description
This study evaluates the therapeutic effect of a fMRI-guided and robotized neuronavigated theta burst Transcranial Magnetic Stimulation (TMS) targeting right inferior frontal region in resistant obsessive compulsive disorder (OCD) in a double-blind, randomized, placebo-controlled, monocentric study. The study will also assess the interest of some clinical, neuropsychological, neuroimaging, electrophysiological variables in response prediction, besides physiopathological information.
There is an increasing interest in developping treatments for resistant OCD, which are not responding to the conventional treatment, represented by pharmacotherapy associated to cognitive behavioral therapy. Repetitive TMS represents a promising non invasive brain stimulation approach, but efficacy, best available brain target, optimal responder profile and stimulation parameters need to be further documented.
In this study, the included patients will be randomly assigned to an active (theta burst TMS) or sham-placebo treatment group. TMS will be added to their stable pharmacotherapy. The brain target, the right inferior frontal region, involved in the inhibition control brain network, will be defined in a personalized manner via a fMRI paradigm for each patient. TMS will be delivered daily for 2 successive weeks. Measures of different clinical, neuropsychological , electrophysiological (cortical excitability) variables will be performed at baseline, as well as at the end of the TMS course, and 1 week after. Other assessments are planned at 3 and 6 months, in order to highlight the evolution of the potential benefit.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Mircea POLOSAN, Professor
- Email: [email protected]
Study Locations
-
France
-
Rhone Alpes
-
Grenoble, Rhone Alpes, France, 38000
- Recruiting
- CHU de Grenoble - Pavillon Dominique Villars
-
Contact:
- POLOSAN Mircea, Professor
- Email: [email protected]
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Volunteer subjects with Obsessive Compulsive Disorders (OCD) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR) criteria and validated by an experimented clinician following instruments like SCID (Structured Clinical Interview for DSM IV) or MINI (Mini-International Neuropsychiatric Interview)
- with or without associated tics ("Gilles de la Tourette" Syndrome)
- Age > 18 years old
- Y-BOCS score > 20 and CGI (Clinical Global Impression Scale) score ≥ 4
Resistant patients to standard treatments - where treatment resistance is defined by partial but insufficient response (Global Assessment of Functioning score GAF score < 60 and/or reduction of Yale Brown Obsessions and Compulsion Scale score < 35%) or lack of response to previous well conducted treatment including:
- pharmacotherapy : optimal tolerated dose and adequate duration (> 12 weeks) of at least 2 Serotonin Reuptake Inhibitors (selective serotonin reuptake inhibitors, clomipramine), and one augmentation strategy (adjunction of an antipsychotic - such as risperidone or olanzapine or aripiprazole - or lithium or buspirone) ;
- psychotherapy (at least 6 months of cognitive and behavioral therapy)
Exclusion Criteria:
- other primary diagnosis than OCD (comorbid tics and depression are tolerated)
- comorbid diagnosis of schizophrenia/ psychotic disorder, bipolar disorder, substance abuse or dependance
- medical condition involving cognitive decline and affecting brain structures such as Parkinson disease, dementia, multiple sclerosis, HIV (human immunodeficiency virus) infection, lupus etc.
- Magnetic Resonance Imaging exclusion criteria (ferromagnetic implants etc)
- common TMS exclusion criteria (neurological condition with an increased risk of seizure, cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, intracranial implants (e.g. cochlear implants, electrodes, aneurysm clips, stimulators... ) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed will be excluded
- Current use of any investigational drug
- pregnancy / breast feeding patients
- visual or auditive important deficit
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: active Transcranial Magnetic Stimulation
Active Transcranial Magnetic Stimulation (TMS) targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, Using theta burst stimulation and using Transcranial Magnetic Stimulation navigator and robot
|
modulation of the electrical activity of the right inferior frontal gyrus cortex in order to reduce Obsessive Compulsive Disorders symptoms by Active Transcranial Magnetic Stimulation (TMS) targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, using theta burst stimulation and using a TMS neuronavigated robot
|
Placebo Comparator: Placebo
Placebo comparator, using non active magnetic coil, targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, using theta burst stimulation and using Transcranial Magnetic Stimulation navigator and robot
|
Sham rTMS will be delivered using non active magnetic coil, targeting the right frontal inferior gyrus, 2 sessions per day, each session 5min30 day, during 10 consecutive days, using TMS neuronavigated robot.
A subjective sensation will be obtained via frontal dermic electrical stimulation.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change from baseline of the score at the Yale - Brown Obsessive and Compulsive Scale
Time Frame: at baseline and at day 21
|
Evaluation of Obsessive Compulsive Disorder symptoms using the Yale - Brown Obsessive and Compulsive Scale, at day 21, corresponding to 7 days after the end of the TMS cure, compared to baseline.
|
at baseline and at day 21
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Score of Montgomery and Asberg Depression Rating Scale, as a Measure of effects on Mood (depression)
Time Frame: At baseline, at day 21, day 90, day 180
|
Evaluation of Mood using Montgomery Asberg Depression Rating Scale
|
At baseline, at day 21, day 90, day 180
|
Score of Young Mania Rating Scale, as a Measure of effects on Mood (hyperthymia)
Time Frame: At baseline, at day 21, day 90, day 180
|
Evaluation of Mood using Young Mania Rating Scale
|
At baseline, at day 21, day 90, day 180
|
Score of Multidimensional Assessment of Thymic States Scale as a Measure of effects on Emotional Reactivity
Time Frame: At baseline, at day 21, day 90, day 180
|
Evaluation of Emotional Reactivity using Multidimensional Assessment of Thymic States Scale
|
At baseline, at day 21, day 90, day 180
|
Number of patients with Side effects as a measure of Safety and Tolerability
Time Frame: for each session of Transcranial Magnetic Stimulation, at day 15, day 21, day 90, day 180
|
collection of the side effects of the Transcranial Magnetic Stimulation, after each session, during the entire TMS cure
|
for each session of Transcranial Magnetic Stimulation, at day 15, day 21, day 90, day 180
|
Inferior Frontal Region Activity (percentage of the BOLD signal change (parameter estimates beta)
Time Frame: at baseline (day 0)
|
Performing a functional Magnetic Resonance Imaging, looking for biomarkers of response to the TMS cure. Especially studying the right inferior cortex activation in functional Magnetic Resonance Imaging using a Signal Stop Task. |
at baseline (day 0)
|
Fractional Anisotropy (FA), mean and radial diffusivity (MD, RD), tracti integrity of the inhibition network,
Time Frame: at day 0 (baseline)
|
looking for anatomical biomarkers of response, or anatomical differences between the subjects on the inhibition network using Diffusing Tensor Imaging data
|
at day 0 (baseline)
|
Yale - Brown Obsessive and Compulsion Scale score after the TMS treatment as an evaluation of the persistence of the clinical benefit
Time Frame: day 15, day 90 and day 180 after the inclusion.
|
The Yale - Brown Obsessive and Compulsion Scale will also be performed at day 15, day 90 and day 180 after the inclusion in order to assess the kinetics of clinical changes in Obsessive Compulsive symptoms after the TMS cure.
|
day 15, day 90 and day 180 after the inclusion.
|
Cortical Excitability
Time Frame: baseline - day 15 - day 21 - day 90 - day 180
|
assessing a new biomarker linked to OCD and monitoring its evolution with the TMS cure, testing its predictive value for the clinical response
|
baseline - day 15 - day 21 - day 90 - day 180
|
Evaluation of Impulsivity using specific scales
Time Frame: At baseline, at day 21, day 90, day 180
|
Evaluation of impulsivity using UPPS (Urgency, Premeditation, and Sensation Seeking) Impulsive Behavior Scale.
|
At baseline, at day 21, day 90, day 180
|
Evaluation of the Clinical global State
Time Frame: at baseline, day 15, day 21, day 90, day 180
|
Using Clinical Global Impression scale we will assess the evolution of the clinical global status
|
at baseline, day 15, day 21, day 90, day 180
|
type of side effects (pain, paresthesia, other) as a measure of Safety and Tolerability
Time Frame: for each session of Transcranial Magnetic Stimulation, at day 15, day 21, day 90, day 180
|
collection of the side effects of the Transcranial Magnetic Stimulation, after each session, during the entire TMS cure
|
for each session of Transcranial Magnetic Stimulation, at day 15, day 21, day 90, day 180
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Mircea POLOSAN, Professor, Institut National de la Santé Et de la Recherche Médicale, France
Publications and helpful links
General Publications
- Aron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins TW. Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci. 2003 Feb;6(2):115-6. doi: 10.1038/nn1003. No abstract available. Erratum In: Nat Neurosci. 2003 Dec;6(12):1329.
- Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14.
- Li CT, Chen MH, Juan CH, Huang HH, Chen LF, Hsieh JC, Tu PC, Bai YM, Tsai SJ, Lee YC, Su TP. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. 2014 Jul;137(Pt 7):2088-98. doi: 10.1093/brain/awu109. Epub 2014 May 10.
- Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033.
- Verbruggen F, Aron AR, Stevens MA, Chambers CD. Theta burst stimulation dissociates attention and action updating in human inferior frontal cortex. Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13966-71. doi: 10.1073/pnas.1001957107. Epub 2010 Jul 14.
- Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985 May 11;1(8437):1106-7. doi: 10.1016/s0140-6736(85)92413-4. No abstract available.
- Di Lazzaro V, Pilato F, Dileone M, Profice P, Oliviero A, Mazzone P, Insola A, Ranieri F, Meglio M, Tonali PA, Rothwell JC. The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J Physiol. 2008 Aug 15;586(16):3871-9. doi: 10.1113/jphysiol.2008.152736. Epub 2008 Jun 19.
- Plewnia C, Pasqualetti P, Grosse S, Schlipf S, Wasserka B, Zwissler B, Fallgatter A. Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J Affect Disord. 2014 Mar;156:219-23. doi: 10.1016/j.jad.2013.12.025. Epub 2013 Dec 28.
- Sachdev PS, McBride R, Loo CK, Mitchell PB, Malhi GS, Croker VM. Right versus left prefrontal transcranial magnetic stimulation for obsessive-compulsive disorder: a preliminary investigation. J Clin Psychiatry. 2001 Dec;62(12):981-4. doi: 10.4088/jcp.v62n1211.
- Denys D. Pharmacotherapy of obsessive-compulsive disorder and obsessive-compulsive spectrum disorders. Psychiatr Clin North Am. 2006 Jun;29(2):553-84, xi. doi: 10.1016/j.psc.2006.02.013.
- Heyman I, Mataix-Cols D, Fineberg NA. Obsessive-compulsive disorder. BMJ. 2006 Aug 26;333(7565):424-9. doi: 10.1136/bmj.333.7565.424. No abstract available.
- Baxter LR Jr, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM, Selin CE. Local cerebral glucose metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar depression and in normal controls. Arch Gen Psychiatry. 1987 Mar;44(3):211-8. doi: 10.1001/archpsyc.1987.01800150017003. Erratum In: Arch Gen Psychiatry 1987 Sep;44(9):800.
- Prasko J, Paskova B, Zalesky R, Novak T, Kopecek M, Bares M, Horacek J. The effect of repetitive transcranial magnetic stimulation (rTMS) on symptoms in obsessive compulsive disorder. A randomized, double blind, sham controlled study. Neuro Endocrinol Lett. 2006 Jun;27(3):327-32.
- Sarkhel S, Sinha VK, Praharaj SK. Adjunctive high-frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) was not effective in obsessive-compulsive disorder but improved secondary depression. J Anxiety Disord. 2010 Jun;24(5):535-9. doi: 10.1016/j.janxdis.2010.03.011. Epub 2010 Mar 29.
- Sack AT, Cohen Kadosh R, Schuhmann T, Moerel M, Walsh V, Goebel R. Optimizing functional accuracy of TMS in cognitive studies: a comparison of methods. J Cogn Neurosci. 2009 Feb;21(2):207-21. doi: 10.1162/jocn.2009.21126.
- Wu CC, Tsai CH, Lu MK, Chen CM, Shen WC, Su KP. Theta-burst repetitive transcranial magnetic stimulation for treatment-resistant obsessive-compulsive disorder with concomitant depression. J Clin Psychiatry. 2010 Apr;71(4):504-6. doi: 10.4088/JCP.09l05426blu. No abstract available.
- Chambers CD, Bellgrove MA, Stokes MG, Henderson TR, Garavan H, Robertson IH, Morris AP, Mattingley JB. Executive "brake failure" following deactivation of human frontal lobe. J Cogn Neurosci. 2006 Mar;18(3):444-55. doi: 10.1162/089892906775990606.
- Duncan J, Owen AM. Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci. 2000 Oct;23(10):475-83. doi: 10.1016/s0166-2236(00)01633-7.
- Verbruggen F, Schneider DW, Logan GD. How to stop and change a response: the role of goal activation in multitasking. J Exp Psychol Hum Percept Perform. 2008 Oct;34(5):1212-28. doi: 10.1037/0096-1523.34.5.1212.
- Boucher L, Palmeri TJ, Logan GD, Schall JD. Inhibitory control in mind and brain: an interactive race model of countermanding saccades. Psychol Rev. 2007 Apr;114(2):376-97. doi: 10.1037/0033-295X.114.2.376.
- Chambers CD, Bellgrove MA, Gould IC, English T, Garavan H, McNaught E, Kamke M, Mattingley JB. Dissociable mechanisms of cognitive control in prefrontal and premotor cortex. J Neurophysiol. 2007 Dec;98(6):3638-47. doi: 10.1152/jn.00685.2007. Epub 2007 Oct 17.
- Aron AR, Behrens TE, Smith S, Frank MJ, Poldrack RA. Triangulating a cognitive control network using diffusion-weighted magnetic resonance imaging (MRI) and functional MRI. J Neurosci. 2007 Apr 4;27(14):3743-52. doi: 10.1523/JNEUROSCI.0519-07.2007.
- Swann N, Tandon N, Canolty R, Ellmore TM, McEvoy LK, Dreyer S, DiSano M, Aron AR. Intracranial EEG reveals a time- and frequency-specific role for the right inferior frontal gyrus and primary motor cortex in stopping initiated responses. J Neurosci. 2009 Oct 7;29(40):12675-85. doi: 10.1523/JNEUROSCI.3359-09.2009.
- Hampshire A, Chamberlain SR, Monti MM, Duncan J, Owen AM. The role of the right inferior frontal gyrus: inhibition and attentional control. Neuroimage. 2010 Apr 15;50(3):1313-9. doi: 10.1016/j.neuroimage.2009.12.109. Epub 2010 Jan 4.
- Chikazoe J, Jimura K, Asari T, Yamashita K, Morimoto H, Hirose S, Miyashita Y, Konishi S. Functional dissociation in right inferior frontal cortex during performance of go/no-go task. Cereb Cortex. 2009 Jan;19(1):146-52. doi: 10.1093/cercor/bhn065. Epub 2008 Apr 28.
- Luders H, Lesser RP, Dinner DS, Morris HH, Wyllie E, Godoy J. Localization of cortical function: new information from extraoperative monitoring of patients with epilepsy. Epilepsia. 1988;29 Suppl 2:S56-65. doi: 10.1111/j.1528-1157.1988.tb05799.x. Erratum In: Epilepsia 1988 Nov-Dec;29(6):828.
- Johansen-Berg H, Behrens TE, Robson MD, Drobnjak I, Rushworth MF, Brady JM, Smith SM, Higham DJ, Matthews PM. Changes in connectivity profiles define functionally distinct regions in human medial frontal cortex. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13335-40. doi: 10.1073/pnas.0403743101. Epub 2004 Aug 30.
- Marsh R, Horga G, Parashar N, Wang Z, Peterson BS, Simpson HB. Altered activation in fronto-striatal circuits during sequential processing of conflict in unmedicated adults with obsessive-compulsive disorder. Biol Psychiatry. 2014 Apr 15;75(8):615-22. doi: 10.1016/j.biopsych.2013.02.004. Epub 2013 Mar 13.
- de Wit SJ, de Vries FE, van der Werf YD, Cath DC, Heslenfeld DJ, Veltman EM, van Balkom AJ, Veltman DJ, van den Heuvel OA. Presupplementary motor area hyperactivity during response inhibition: a candidate endophenotype of obsessive-compulsive disorder. Am J Psychiatry. 2012 Oct;169(10):1100-8. doi: 10.1176/appi.ajp.2012.12010073. Erratum In: Am J Psychiatry. 2012 Nov 1;169(11):1218.
- Stein DJ, Goodman WK, Rauch SL. The cognitive-affective neuroscience of obsessive-compulsive disorder. Curr Psychiatry Rep. 2000 Aug;2(4):341-6. doi: 10.1007/s11920-000-0079-2.
- Stokes MG, Chambers CD, Gould IC, Henderson TR, Janko NE, Allen NB, Mattingley JB. Simple metric for scaling motor threshold based on scalp-cortex distance: application to studies using transcranial magnetic stimulation. J Neurophysiol. 2005 Dec;94(6):4520-7. doi: 10.1152/jn.00067.2005. Epub 2005 Aug 31.
- Stokes MG, Chambers CD, Gould IC, English T, McNaught E, McDonald O, Mattingley JB. Distance-adjusted motor threshold for transcranial magnetic stimulation. Clin Neurophysiol. 2007 Jul;118(7):1617-25. doi: 10.1016/j.clinph.2007.04.004. Epub 2007 May 23.
- Buch ER, Mars RB, Boorman ED, Rushworth MF. A network centered on ventral premotor cortex exerts both facilitatory and inhibitory control over primary motor cortex during action reprogramming. J Neurosci. 2010 Jan 27;30(4):1395-401. doi: 10.1523/JNEUROSCI.4882-09.2010.
- Neubert FX, Mars RB, Buch ER, Olivier E, Rushworth MF. Cortical and subcortical interactions during action reprogramming and their related white matter pathways. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13240-5. doi: 10.1073/pnas.1000674107. Epub 2010 Jul 9.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 38RC14.156
- 2014-A00668-39 (Other Identifier: ID RCB)
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