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.

This study was approved by the Research Ethics Board at the University Health Network.
1. Subject Selection
<ol>
	<li>Conduct an initial assessment on a prospective patient. The inclusion criteria included the presence of a current depressive episode that is resistant to at least 1 adequate trial of medication, and a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) diagnosis of MDD as established by the assessing psychiatrist. Confirm the diagnosis with a standar...

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...

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 &#8216;cortical lesions&#8217;, and establish neural-behavior relationships or functional regions by temporarily disabling the function of a desired cortical region2&#8211;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&#176;-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.

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	<tbody>
		<tr>
			<td>3T GE Signa HDx Scanner</td>
			<td>GE</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>Visor 2.0 Neuronavigation System</td>
			<td>ANT Neuro</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>MagPro R30 Stimulator</td>
			<td>MagVenture</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>Cool-DB80 Coil</td>
			<td>MagVenture</td>
			<td>n/a</td>
			<td></td>
		</tr>
	</tbody>
</table>

mri-guided dmpfc-rtms as a treatment for treatment-resistant 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.

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 &#60;0.0001)27. Using a remission criterion of HamD17 &#8804;7, 8 of 23 subjects remitted following treatme...

Watch this Scientific Journal Video about MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder at JoVE.com

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

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 ...

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13.6K Views.  University of Toronto. 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.