Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.
Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.
Repetitive transcranial magnetic stimulation (rTMS) is a form of indirect focal cortical stimulation. rTMS employs brief, focal electromagnetic field pulses that penetrate the skull to stimulate target brain regions. rTMS is thought to engage the mechanisms of synaptic long-term potentiation and long-term depression, thereby increasing or decreasing the cortical excitability of the region stimulated1. Generally, the rTMS pulse frequency determines its effects: higher frequency stimulation tends to be excitatory, while lower frequency is inhibitory. Non-invasive stimulatory procedures are also widely used as a causal probe to induce temporary ‘cortical lesions’, and establish neural-behavior relationships or functional regions by temporarily disabling the function of a desired cortical region2–4.
Therapeutic rTMS involves multiple stimulation sessions, usually applied once daily over several weeks, to treat a variety of disorders, including major depressive disorder (MDD)5, eating disorders6, and obsessive-compulsive disorder7. rTMS for MDD is a potential option for medically refractory patients, and allows the clinician to noninvasively target and alter the excitability of a cortical region directly involved with depressive etiology or pathophysiology. The conventional cortical target for MDD-rTMS is the dorsolateral prefrontal cortex (DLPFC)8. However, convergent evidence from neuroimaging, lesion, and stimulation studies identifies the dorsomedial prefrontal cortex (dmPFC) as a potentially important therapeutic target for MDD9 and a variety of other psychiatric disorders characterized by deficits in self-regulation of thoughts, behaviors, and emotional states10. The dmPFC is a region of consistent activation in emotional regulation11, behavioral regulation12,13. The dmPFC is also associated with neurochemical14, structural15, and functional16 abnormalities in MDD
Described here is the procedure for 20 sessions (4 weeks) of magnetic resonance imaging (MRI) guided rTMS to the dmPFC bilaterally, as a treatment for major depressive disorder. In addition to a conventional 10 Hz protocol applied over 30 min, an intermittent theta burst stimulation protocol (TBS) is discussed, which applies 50 Hz triplet bursts at 5 Hz over a 6 min session17. Both protocols are thought to be excitatory, with the TBS protocol having the potential to achieve comparable effects using a much shorter session18. In both protocols, anatomical MRIs as well as clinical assessments are acquired prior to rTMS. Neuronavigation uses the anatomical scans to account for anatomical variability of dmPFC and optimize the location of rTMS. A relatively new 120°-angled fluid-cooled rTMS coil was also used in order to stimulate deeper midline cortical structures. Finally, rTMS intensity titration was used over the first week of rTMS sessions to ensure that patients could habituate to the higher pain levels associated with dmPFC stimulation as compared to conventional DLPFC stimulation.
This study was approved by the Research Ethics Board at the University Health Network.
1. Subject Selection
2. Acquiring Magnetic Resonance Images
3. Preprocessing Anatomical Scans for Real-time Neuronavigation
4. Motor Threshold Assessment
5. rTMS Treatment & Adaptive Titration
6. Clinical Data Collection
In previous work, HamD17 was used as a measure of treatment response for 10 Hz dmPFC-rTMS. Table 1 displays the pre- and post-treatment HamD17 scores in a previously published case series27. Among all subjects, pre-treatment HamD17 score was 21.66.9 that significantly decreased by 4,331% to 12.58.2 post-rTMS (t22 = 6.54, p <0.0001)27. Using a remission criterion of HamD17 ≤7, 8 of 23 subjects remitted following treatment. Table 2 displays the pre- and post-treatment BDI-II scores in the same case series27. Pre-treatment BDI-II was 32.59.9 and significantly decreased by 34.231.7% to 22.012.8 post-rTMS (t22 = 5.11, p <0.001). HamD17 and BDI-II percent improvement was correlated to determine whether the same subjects responded on both measures (r = 0.72, p = 0.0001).
Adaptive titration was reported in a larger subset of 47 MDD patients undergoing 10 Hz dmPFC-rTMS23. In a case series that included this subset of patients, subjects achieved the target stimulus intensity in 0.91.8 sessions and were able to complete an entire rTMS session at the intended intensity at 4.53.7 sessions23. Adaptive titration was not correlated to treatment improvement.
A comparison of TBS to 10 Hz dmPFC stimulation was recently performed in a recent 185-subject chart review18. Outcomes did not differ significantly between groups. On the HamD17, 10 Hz patients had a 50.6% response and 38.5% remission rate, while TBS patients achieved a 48.5% response and 27.9% remission rate. On the BDI-II, 10 Hz patients had a 40.6% response an 29.2% remission rate, while TBS patients achieved a 43.0% response and 31.0% remission rate18.
Subject # | Pre-Treatment HAMD | Post-Treatment HAMD | % Improvement |
11 | 21 | 1 | 95.24 |
6 | 18 | 2 | 88.89 |
4 | 28 | 4 | 85.71 |
2 | 12 | 2 | 83.33 |
9 | 22 | 4 | 81.82 |
25 | 19 | 4 | 78.95 |
12 | 20 | 5 | 75.00 |
10 | 20 | 5 | 75.00 |
14 | 14 | 4 | 71.43 |
16 | 26 | 10 | 61.54 |
7 | 19 | 8 | 57.89 |
24 | 17 | 9 | 47.06 |
3 | 19 | 11 | 42.11 |
8 | 21 | 14 | 33.33 |
5 | 36 | 24 | 33.33 |
17 | 23 | 16 | 30.43 |
15 | 37 | 27 | 27.03 |
23 | 12 | 9 | 25.00 |
19 | 28 | 21 | 25.00 |
13 | 29 | 22 | 24.14 |
1 | 12 | 10 | 16.67 |
21 | 13 | 12 | 7.69 |
18 | 23 | 22 | 4.35 |
22 | 21 | 22 | -4.76 |
20 | 22 | 24 | -9.09 |
Mean | 21.28 | 11.68 | 46.28 |
Standard Dev. | 6.68 | 8.24 | 31.81 |
Table 1: Individual subject HamD17 improvement, using baseline and post-treatment HamD17 scores.
Subject # | Pre-rTMS BDI | Post-rTMS BDI | % Improvement |
11 | 26 | 3 | 88.46 |
6 | 21 | 4 | 80.95 |
4 | 45 | 9 | 80.00 |
2 | 17 | 4 | 76.47 |
16 | 36 | 13 | 63.89 |
5 | 35 | 17 | 51.43 |
3 | 30 | 15 | 50.00 |
12 | 26 | 14 | 46.15 |
14 | 22 | 12 | 45.45 |
1 | 33 | 19 | 42.42 |
10 | 34 | 20 | 41.18 |
23 | 32 | 19 | 40.63 |
9 | 22 | 15 | 31.82 |
15 | 57 | 40 | 29.82 |
19 | 38 | 28 | 26.32 |
7 | 25 | 22 | 12.00 |
18 | 45 | 41 | 8.89 |
20 | 45 | 43 | 4.44 |
17 | 25 | 24 | 4.00 |
13 | 44 | 44 | 0.00 |
22 | 36 | 37 | -2.78 |
21 | 30 | 32 | -6.67 |
8 | 24 | 31 | -29.17 |
Mean | 32.52 | 22.00 | 34.16 |
Standard Dev. | 9.86 | 12.83 | 31.70 |
TTEST | 3.99713E-05 | 5.114221135 |
Table 2: Individual subject BDI-II improvement, using baseline and post-treatment BDI-II scores.
Here, MRI-guided dmPFC-rTMS was applied for treatment-resistant MDD. In general, rTMS at this site was well tolerated, with mild scalp discomfort and pain at the site of stimulation that was adequately managed using adaptive titration. In open-label trials and a chart review, both 10 Hz and theta burst stimulation resulted in significant improvements in depressive severity as measured by the HamD17 and BDI-II.
There are two critical steps worth noting in the rTMS treatment procedure for optimal dmPFC stimulation. First, an angled, double-cone coil allows for optimal stimulation of deeper structures within the medial aspect of the prefrontal cortex28. Second, a treatment stimulation intensity of 120% resting motor threshold at this medial site is well-tolerated and without serious adverse events, despite the relatively high intensity of the applied stimulation in absolute terms when compared to the lower absolute intensities required for conventional DLPFC-rTMS. This same intensity also appears to be safe and tolerable for TBS protocols with dmPFC-rTMS, notwithstanding the significantly lower values of 80% active motor threshold more commonly used with TBS18. As previously mentioned, significant pain and discomfort is associated with anterior medial prefrontal stimulation at higher intensities29. Adaptive titration was quickly and successfully used to aide in rTMS-related discomfort adaptation. In sum, the use of an angled rTMS coil and relatively high stimulation intensity (with adaptive titration) may allow for deeper penetration of stimulation to the medial prefrontal and underlying cingulate cortices28, without incurring higher risks of seizure of intolerable scalp pain.
Neuronavigation is often used for precise individualized anatomical landmarking for coil vertex placement. However, one problem with MRI-guided neuronavigation is that it potentially omits the functional relationships of the desired stimulation target to other brain regions in favor of anatomical specificity across subjects. Indeed, there is significant functional connectivity variability found in association cortices, including regions of prefrontal cortex, which may impede treatment efficacy30. For example, a recent study used resting-state functional connectivity to show that left DLPFC-rTMS treatment efficacy in MDD was dependent on left DLPFC connectivity to the subgenual cingulate cortex31. Patients that improved with left DLPFC-rTMS tended to have anticorrelated functional connectivity between the DLPFC and the subgenual cingulate cortex at baseline. Therefore, resting-state functional connectivity could be harnessed to further optimize target placement and identify potential biomarkers once the functional characteristics of response are identified32.
One major limitation of rTMS as a treatment is that it is unclear how certain stimulation parameters influence its treatment efficacy. There is substantial variability in the parameters of conventional left DLPFC stimulation for MDD across studies, and there is also increasing evidence of substantial inter-individual variability in how some rTMS parameters affect cortical excitation and inhibition or treatment efficacy33,34. For example, the effects of 10 Hz stimulation on motor evoked potential (MEP) was recently shown to vary considerably across subjects, with some showing decreases rather than increases in MEP strength after stimulation35. Other rTMS treatment parameters that potentially require further optimization (or individualization) to maximize treatment efficacy include the number of pulses per session, the number of sessions per day, stimulation intensity and the duty cycle (how many seconds stimulation is on and off per cycle).
There are also general limitations to rTMS as a treatment. These include the logistical requirements for patients to make multiple visits to hospital for treatment, limited access to treatment for patients in remote areas, the high cost of treatment (>$250 per session) with conventional parameters, and the low volumes of patients who can be treated per device using conventional parameters (1-2 per hr at most). Parameter optimization may help to address some of these problems in future. Other forms of non-invasive stimulation, such as transcranial direct current stimulation (tDCS), may also come to serve as a less expensive alternative to rTMS, suitable for use at home rather than in the clinic36.
Despite its technical limitations, dmPFC-rTMS is clinically promising for treatment-resistant MDD. rTMS, and dmPFC-rTMS in particular, may also probe to be a promising option in other medication-resistant psychiatric illnesses including eating disorders10, obsessive-compulsive disorder37, and post-traumatic stress disorder38. Identifying good treatment candidates for these disorders may require additional tools other than traditional symptom-based diagnostic classification schemas – in particular, neuroimaging. Acquiring patient neuroimaging data before and after treatment allows for the identification of potential biological pre-treatment predictors and mechanisms of treatment response. Dorsomedial and subgenual cingulate resting-state functional connectivity have been identified as potential predictors to treatment response27. Additionally, graph theoretical measures such as betweenness centrality have been shown to differentiate dmPFC-rTMS responders and non-responders at baseline based on subscales for hedonic responses23. Neuroimaging also points to anterior mid-cingulate cortex and dorsomedial thalamic resting state functional connectivity change that correlates to treatment response27. In sum, functional neuroimaging may become a useful clinical tool as potential predictors and mechanisms of treatment response are identified.
Since current dmPFC-rTMS studies have used an open-label design, future directions should include the creation of a sham-controlled trial to assess its therapeutic efficacy in MDD versus sham and conventional stimulation. However, creating a convincing sham-control arm is technically challenging, particularly for simulating somatosensory or nociceptive sensations, as well as convincingly blinding the rTMS technician39. In a recent meta-analysis, over half of patients were able to correctly guess their treatment arm39. In another meta-analysis, placebo effects were large, but comparable to escitalopram trials40. Future studies involving a rTMS sham arm should consider a design that addresses all sensory aspects of rTMS for both the patient and the technician. Nonetheless, augmenting magnetic stimulation techniques through TBS41, priming stimulation42 or adjunctive cognitive behavioral therapy43 or pharmacotherapy44 may also help to optimize the therapeutic effects of rTMS. TBS in particular has the potential to achieve significant improvements in treatment duration and thus in patient volumes, access times, and treatment cost, while achieving equivalent outcomes to much longer conventional protocols18,45.
In summary, rTMS of the dmPFC is a promising novel approach to therapeutic brain stimulation for treatment-resistant MDD. By incorporating the use of a MRI-guided neuronavigation system, a fluid-cooled, 120° angled stimulation coil, a high stimulation intensity and an adaptive titration schedule, dmPFC-rTMS can be safely and accurately delivered to deep targets in the medial prefrontal cortex. As these regions are central to the pathophysiology of many neuropsychiatric disorders, this approach may have promising applications not only for MDD, but also for a variety of other psychiatric conditions that are resistant to standard treatments.
The authors have nothing to disclose.
The authors wish to thank Aisha Dar, Vanathy Niranjan, and Dr. Umar Dar for technical assistance with rTMS delivery and data collection. The authors also wish to acknowledge the generous support of the Toronto General and Western Hospital Foundation, the Buchan Family Foundation, and the Ontario Brain Institute in funding this work.
3T GE Signa HDx Scanner | GE | n/a | |
Visor 2.0 Neuronavigation System | ANT Neuro | n/a | |
MagPro R30 Stimulator | MagVenture | n/a | |
Cool-DB80 Coil | MagVenture | n/a |