The study was funded by China Postdoctoral Science Foundation funded project (2019M652854) and Natural Science Foundation of Guangdong, China (Grant No. 2020A1515010077).

Inform all participants about the study and ask them to sign the informed consent form prior to the start of the study. The present protocol was approved by the Research Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University.
NOTE: In this double-blind study, patients with depression were randomly divided into two groups. In the experimental group, stimulation targets are located by the DLPFC-sgACC-based individualized location method (Please see 3.3 for detailed des...

The sgACC is responsible for emotional processing and plays an important role in stress regulation16,17,18. A study suggests that targeting on a subregion of DLPFC that shows strongest functional anti-connectivity with sgACC (6, 16, -10) may enhance the antidepressant effect25. Therefore, precisely locating this target is the critical step of this protocol. Before the stimulation, the borders of the brain...

Major depressive disorder (MDD) is characterized by significant and persistent depression, and in more severe cases, patients can encounter hallucinations and/or delusions1,2. Compared with the general population, the risk of suicide among MDD patients is approximately 20 times higher3. While medication is currently the most used treatment for MDD, 30% - 50% of the patients lack adequate response to antidepressants4. For the responders, the symptom improvement tends to appear after a relatively long latent period and is accompanied by side effects. Psychotherapy, although effective for some patients, is costly and time-consuming. A safer and more effective treatment for MDD is therefore urgently required.
Repetitive transcranial magnetic stimulation (rTMS)is a non-invasive and safe technique and has been approved for the treatment of various mental disorders5,6,7. Although its therapeutic mechanism remains unclear, rTMS was speculated to work by regulating the activity of the stimulated brain regions and the neural plasticity8,9,10, thus normalizing specific functional networks10,11,12. rTMS also causes network effect, which evokes changes in remote brain areas through connection pathways, leading to an amplified therapeutic effect13. Although rTMS changes brain activity immediately and robustly, its response rate in the treatment of MDD is only about 18%14. The main reason may be the inaccurate location of stimulation targets15.
The subgenual anterior cingulate cortex (sgACC) is mainly responsible for emotional processing and plays a role in regulating the response to stressful events, emotional response to internal and external stimuli, and emotional expression16,17,18. This subregion of ACC shares substantial structural and functional connectivity with the cerebral cortex and the limbic system19,20. Interestingly, studies have shown that the post-stimulation activity of this area is closely related to the clinical efficacy of TMS. For instance, the blood flow of sgACC decreased after a course of TMS targeted on the right dorsolateral prefrontal cortex (DLPFC), which was associated with the alleviation of depressive symptoms21. Vink et al.8 found that stimulation targeted on DLPFC was propagated to sgACC, and suggested that sgACC activity can be a biomarker of the treatment response of TMS. According to previous researches, Fox and colleagues22&#160;proposed that targeting on a subregion of DLPFC that shows strongest functional anti-connectivity with sgACC (MNI coordinate: 6, 16, -10) enhances the antidepressant effect. Here, we demonstrate a study protocol aimed to examine this hypothesis.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>3T Philips Achieva MRI scanner</td>
			<td>Philips</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Harvard/Oxford cortical template</td>
			<td>http://www.cma.mgh.harva rd.edu/</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>MATLAB</td>
			<td>MathWorks</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>SPM12</td>
			<td>http://www.fil.ion.ucl.ac.uk/spm</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>The Visor2 system</td>
			<td>ANT Neuro</td>
			<td></td>
			<td>The Visor2 software, the optical tracking system, tracking tools and calibration board are part of the visor2 system.</td>
		</tr>
		<tr>
			<td>TMS device</td>
			<td>Magstim, Carmarthenshire, UK</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

individualized rtms treatment for depression using an fmri-based targeting method

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and safe neuromodulation technique that immediately changes brain activity. Despite its wide application in the treatment for MDD, the treatment response remains different among individuals, which may be attributable to the inaccurate positioning of the stimulation target. Our study aims to examine whether the functional magnetic resonance imaging (fMRI)-assisted positioning improves the efficacy of rTMS in treating depression. We intend to identify and stimulate the subregion of dorsolateral prefrontal cortex (DLPFC) in MDD with strongest anti-correlation with the subgenual anterior cingulate cortex (sgACC), and to conduct a comparative investigation of this novel method and the traditional 5-cm rule. To achieve more precise stimulation, both methods were applied under the guidance of neuronavigation system. We expected that the TMS treatment with individualized positioning based on resting state functional connectivity may show better clinical efficacy than the 5-cm method.

ROI-wise FC analysis should show that sgACC is significantly anti-correlated with DLPFC, in which the strongest negative correlation is the stimulus target to be chosen. Significant anti-correlation between the sgACC-DLPFC functional connectivity and the treatment response should be found in the correlation analysis33.
The current protocol is based on an innovative TMS targeting method that no previous studies have applied. Here we present results from an fMRI-guided TM...

Watch this Scientific Journal Video about Individualized rTMS Treatment for Depression using an fMRI-Based Targeting Method at JoVE.com

Individualized rTMS Treatment for Depression using an fMRI-Based Targeting Method

The present protocol describes the application of repetitive transcranial magnetic stimulation (rTMS), where a subregion of the dorsolateral prefrontal cortex (DLPFC) with the strongest functional anticorrelation with the subgenual anterior cingulate cortex (sgACC) was located as the stimulation target under the assistance of a fMRI-based neuronavigation system.

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial ...

The variation of stimulated targets across the DLPFC may account for most of the efficacy heterogeneity of rTMS. This method helps in locating the effective target precisely. The differences between individual brains may lead to inaccurate stimulation target by the traditional five cm rule.This protocol provides a strategy to acquire the individual stimulate target for each subject. This technique may help enhance the accuracy of positioning and possibly improve the treatment response of depression. Demonstrating the procedure will be Min Zhang and Xin Luo, a couple of members from my laboratory.Begin by selecting the subgenual anterior cingulate cortex, or sgACC, as the region of interest, or ROI, with a 10-millimeter radius. Remove the white matter and cerebrospinal fluid in the ROI based on the Harvard-Oxford cortical atlas. using a gray matter probability threshold of 0.25.Extract the average time course of the ROI. To generate the functional connectivity, or FC, map, compute Pearson's correlation coefficients between the ROI and dorsolateral prefrontal cortex, or DLPFC, in a voxel-wise manner. Normalize each correlation coefficient using Fisher's r-to-z transformation.According to the FC map, identify the peak coordinate in DLPFC with the largest Pearson's anti-correlation coefficient with sgACC. This is the subregion of DLPFC with the strongest negative FC with sgACC, which will be later targeted in the transcranial magnetic stimulation, or TMS, treatment for the experimental group. To begin determining the resting motor threshold, or RMT, and recording the hotspot for each subject, instruct the patient to sit back and relax.Then, put two recording electrodes on the thenar of the right hand and a reference electrode on the bony part of the wrist. Stimulate the motor hotspot with 10 consecutive stimulations with different intensities, meanwhile recording the number of thenar muscle contractions. Identify the minimum TMS intensity at which a motor-evoked potential of greater than or equal to 50 microvolts is recorded at least five times, and define it as the patient's RMT.Assess the severity of depression using clinical scales as described in Clinical Data Collection. Perform the TMS treatment two times a day for 10 days. To create a new patient entry, select the Create New Patient option.Input the patient's ID number or name in the text box. Then, to overlay the structural MRI images onto the navigation system, select Import patient MRI, and then import the structural image of the patient and select the image type. Create an individual head model, and define the stimulation target by first pressing the Specify MRI Fiducials button.Place the crosshair on different spots in the MRI image as mentioned in the manuscript. Press Create Head Model, and select Manual Brain Segmentation. And adjust the threshold of the scalp, the lower brain, and the upper brain.Click on Define Target to proceed. Select the Target Marker page, and click Go to MRI Coordinates to input the coordinate of the treatment target as identified previously, and then press Go to. Press Add Marker to name the point.To calibrate the coil, first click Proceed to Neuronavigation. In the text box, select the right type of tools to be used in the treatment. Ensure all the tools of reference are in the view of the infrared camera.Then press Validate Coil, and put the tip of the pointer on the marked coil point. Press Validate when the indicator of each tool turns green. Select the patient's name or ID on the Select Patient page.Then, click on Select Targets on the next page. Choose Read target markers to browse the file of targets. Import the file, and select the target.Click on Define Coordinate System. Put a headband with a reference tool on the patient. Ensure the coil tracker and the reference tool are in the vision of the navigation system.Place the pointer's tip on nasion and both tragi in turn. Press the green button on the remote control each time the indicator of a marker turns green. Continuously move the pointer's tip over the top of the head.Press the button on the remote control to continue. Press Neuronavigation, and on the Active Coil page, set the stimulation intensity to 100%RMT. Choose Stimulate at targets to see the target on the head model online.When the coil matches the target crosshair and the indicator text turns green, stimulate. Prepare and start the treatment directly from the coil calibration step if the patient's entry has been created before. Conduct follow-up assessments on day one, day 28, and day 56 after the whole treatment course.The response rate among 23 MDD patients was found to be 90.48%19 of 22 participants met the remission criteria in the intent-to-treat analysis. The scores of clinical assessments post-TMS treatment were calculated for all the patients. By precisely locating the effective target of rTMS, this technique may improve the treatment of depression and also provide new ideas for treatment of treatment-resistant depression.

Individualized rTMS Treatment for Depression using an fMRI-Based Targeting Method

Abstract