A pilot study of fMRI targeted rTMS for obsessive compulsive disorder

Obsessive compulsive disorder (OCD) is a relatively common disorder, with a lifetime prevalence of 2–3% [[1]Ruscio A.M. Stein D.J. Chiu W.T. Kessler R.C. The epidemiology of obsessive-compulsive disorder in the national comorbidity survey replication.Mol Psychiatr. 2010; 15: 53-63Google Scholar]. Morbidity arising from this chronic condition is extremely high and often leads to significant impairment in affected individuals [[2]Hollander E. Stein D.J. Fineberg N.A. Marteau F. Legault M. Quality of life outcomes in patients with obsessive-compulsive disorder: relationship to treatment response and symptom relapse.J Clin Psychiatr. 2010; 71: 784-792Google Scholar,[3]Koran L.M. Thienemann M.L. Davenport R. Quality of life for patients with obsessive-compulsive disorder.Am J Psychiatr. 1996; 153: 783-788Google Scholar]. Neuroimaging studies have implicated dysfunction in frontostriatal circuitry in the pathophysiology of OCD [[4]Graybiel A.M. Rauch S.L. Toward a neurobiology of obsessive-compulsive disorder.Neuron. 2000; 28: 343-347Google Scholar], showing that there is abnormal resting activity and functional connectivity of the orbitofrontal cortex, the anterior cingulate cortex (ACC), medial prefrontal cortex (PFC) and the caudate nucleus in people living with OCD. Repetitive transcranial magnetic stimulation (rTMS) it is increasingly being investigated as a potential therapeutic option for treatment resistant OCD with one form of treatment, deep TMS, now approved for clinical use in the US. One of the more promising forms of rTMS for the treatment of OCD involves the stimulation of regions of medial PFC, including the ACC and the bilateral supplementary motor area (SMA) with several preliminary studies supporting the potential efficacy of rTMS applied to this site (for example [[5]Mantovani A. Lisanby S.H. Pieraccini F. Ulivelli M. Castrogiovanni P. Rossi S. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS).Int J Neuropsychopharmacol. 2006; 9: 95-100Google Scholar,[6]Mantovani A. Simpson H.B. Fallon B.A. Rossi S. Lisanby S.H. Randomized sham-controlled trial of repetitive transcranial magnetic stimulation in treatment-resistant obsessive-compulsive disorder.Int J Neuropsychopharmacol. 2010; 13: 217-227Google Scholar]) with a suggestion that treatment effects are mediated through right-lateralized effects [[7]Mantovani A. Rossi S. Bassi B.D. Simpson H.B. Fallon B.A. Lisanby S.H. Modulation of motor cortex excitability in obsessive-compulsive disorder: an exploratory study on the relations of neurophysiology measures with clinical outcome.Psychiatr Res. 2013; 210: 1026-1032Google Scholar]. Therefore, it may be possible to substantially enhance the efficacy of rTMS treatment of OCD by specifically targeting the right SMA. In particular, it may be of value to target an area within motor planning regions (SMA or premotor cortex (PMC)) most strongly functionally coupled with the striatum, especially the ventral caudate which has been strongly implicated in the pathophysiology of OCD [[8]Harrison B.J. Soriano-Mas C. Pujol J. Ortiz H. Lopez-Sola M. Hernandez-Ribas R. et al.Altered corticostriatal functional connectivity in obsessive-compulsive disorder.Arch Gen Psychiatr. 2009; 66: 1189-1200Google Scholar], as a method of maximising the likelihood of secondary effects on OCD related basal ganglia circuitry arising from motor system stimulation. Therefore, we conducted a small pilot study to investigate whether stimulation specifically targeted to the right-sided SMA/premotor region most strongly anti-correlated (measured via spontaneous resting-state activity fluctuations) with the ventral caudate would yield greater symptom reduction than stimulation applied to the standard midline SMA target site. Our study included a group of patients with treatment resistant OCD (a DSM-IV diagnosis of OCD plus a failure to respond to at least two trials of adequate dose and duration of either serotonin retake reuptake inhibitor medications or clomipramine) who had not started a new medication or had any change in medication dose in the six weeks prior to screening (trial registration ACTRN12613000780752). Patients with standard rTMS contraindications were excluded. All patients received 20 TMS sessions administered five days per week over four weeks. Each treatment session involved a single 30-min 1Hz rTMS train at 120% of the resting motor threshold. Treatment used a MagVenture R30 stimulator and DB70 70mm figure of 8 coil and was applied at either 1) the SMA as identified by 15% of the distance between inion and nasion anterior to the vertex on the sagittal midline (as per [[5]Mantovani A. Lisanby S.H. Pieraccini F. Ulivelli M. Castrogiovanni P. Rossi S. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS).Int J Neuropsychopharmacol. 2006; 9: 95-100Google Scholar]), or 2) rTMS targeted to the site of optimal anti-correlated resting-state activity between the right sided SMA/PMC and ventral caudate nucleus, based on an 8 minute resting state fMRI scan conducted on the Monash Biomedical Imaging (MBI) center Siemens widebore 3.0 T MRI scanner (with 32-channel headcoil). The “seed” region in the right ventral caudate nucleus was defined as a 3.5-mm radial sphere (sampling approximately 25 voxels) and located at the central border of the ventral caudate and nucleus accumbens as per [[8]Harrison B.J. Soriano-Mas C. Pujol J. Ortiz H. Lopez-Sola M. Hernandez-Ribas R. et al.Altered corticostriatal functional connectivity in obsessive-compulsive disorder.Arch Gen Psychiatr. 2009; 66: 1189-1200Google Scholar]. Treatment localization used an Ascension MINIBIRD and the MRIcro/MRIreg package [[9]Rorden C. Brett M. Stereotaxic display of brain lesions.Behav Neurol. 2000; 12: 191-200Google Scholar]. A series of patients referred for rTMS therapy for OCD were recruited to the study and randomised using a single random number list. However, 2 patients randomised to the MRI based condition were unable to receive an MRI scan due to scan access issues and were provided treatment in the SMA group. Nineteen patients were randomised and 17 received treatment for the full 4-week course (2 patients discontinued as they were not willing to continue study procedures). Two further patients withdrew at the end of treatment (without completing outcome assessments) and for one additional patient an end of trial YBOCS assessment could not be completed due to scheduling issues. Of the 15 patients who received treatment and for who outcome data was available for analysis, 10 patients received SMA stimulation and 5 fMRI targeted therapy. There was no difference between the groups in age, sex, age of illness onset, duration of illness or baseline OCD or depression severity. There was a small, statistically significant within-group improvement in symptoms for the SMA group on the total YBOCS (Baseline: 28.8+/-5.4, End treatment: 23.6+/-7.9, p < 0.05) but not the QIDS or BAI. For the fMRI-targeted group, no significant improvements were seen across measures. There were no differences in baseline-post treatment change scores between the groups. Two patients in the SMA group and none in the fMRI-targeted group achieved a >30% reduction in YBOCS score (both had a reduction of >50%). In this small pilot trial, we found confirmatory evidence that SMA stimulation may produce therapeutic effects in patients with OCD. However, we found no initial indications that fMRI-targeted treatment based on connectivity with the ventral caudate would produce any additional benefit. In contrast, and contrary to our hypothesis, we saw no meaningful therapeutic benefits in the group receiving the targeted therapeutic approach. This result could be related to the fMRI targeting method failing to identify the critical nodes in a network relevant to the treatment of OCD. It is also possible that 1Hz stimulation does not result in sufficiently significant propagation of effects through this network to produce meaningful therapeutic effects, and the benefits of SMA stimulation arise from a different therapeutic mechanism. In addition, especially given the modest effects seen overall, treatment efficacy in OCD may well require stimulation that is less focal and modulates broader areas of the prefrontal cortex. Regardless, approaches to neuronavigationally based treatment of OCD should explore alternative targets and methods of localization to potentially enhance response to rTMS treatment of OCD. PBF is supported by a NHMRC Investigator Grant ( 1193596 ).