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 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.
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 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.
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 description). The targets of the control group are obtained by the average 5-cm method (i.e. (-41, 16, 54))22.
1. Participants' selection
2. Preparation of Magnetic Resonance Imaging (MRI) and TMS
3. Treatment (Figure 1)
4. Clinic data collection (Figure 1b)
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 TMS trial that applied the traditional 5-cm method. This study34 proposed a new treatment protocol, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), a high-dose iTBS regimen with fMRI-guided targeting. The response rate (a MADRS score was 50% lower from the baseline) among 23 MDD patients was 90.48%. 19 of 22 participants (86.4%) met the remission criteria in the intent-to-treat analysis34. Two participants dropped out due to therapeutic intolerances and high motor threshold. Table 1 presents the scores of clinical assessments post-TMS treatment. Therefore, we conjecture that the TMS treatment base on the FC can produce remarkable effectiveness.
Figure 1. Treatment diagram. (a) Process of acquiring stimulation targets and the treatment. See 3.3 for the detailed description on obtaining the target coordinates for the experiment group. The target coordinate for the control group is defined as (-41, 16, 54). (b) Time points of MRI scan and clinical evaluation. Clinical data were collected on the screening, the baseline (i.e., before treatment), as well as Day 1, Day 28, and Day 56 after the treatment. The MRI scan was only performed on the baseline.
*Evaluate patients with M.I.N.I.23 and MADRS24.
**Evaluate patients with all the scales mentioned in Step 4. Please click here to view a larger version of this figure.
Post-SAINT | One Month Post-SAINT | ||||||||||||||||||
Measure | Mean | SD | N | Response(%) | N | Remission(%) | N | Mean | SD | N | Response(%) | N | Remission(%) | N | |||||
MADRS | 5 | 6.37 | 21 | 90.48 | 21 | 90.48 | 21 | 10.95 | 11.76 | 20 | 70 | 20 | 60 | 20 | |||||
HAM-D, 17-item | 4.29 | 4.43 | 21 | 90.48 | 21 | 80.95 | 21 | 8.05 | 8.31 | 20 | 75 | 20 | 65 | 20 | |||||
HAM-D, 6-item | 2.24 | 3.1 | 21 | 85.71 | 21 | 85.71 | 21 | 4.4 | 4.72 | 20 | 75 | 20 | 70 | 20 | |||||
BDI-II (N=18) | 4.47 | 5.76 | 15 | 100 | 12 | 93.33 | 15 | 12.25 | 13.06 | 16 | 57.14 | 14 | 62.5 | 16 | |||||
Suicidal ideation | |||||||||||||||||||
C-SSRS[b] | 0 | 0 | 18 | 100 | 14 | 100 | 18 | 0 | 0 | 19 | 100 | 14 | 100 | 19 | |||||
HAM-D, item 3 | 0.05 | 0.22 | 21 | 100 | 19 | 95.24 | 21 | 0.1 | 0.31 | 20 | 100 | 18 | 90 | 20 | |||||
MADRS, item 10 | 0.1 | 0.44 | 21 | 95.24 | 21 | 95.24 | 21 | 0.35 | 0.75 | 20 | 90 | 20 | 80 | 20 |
Table 1. Clinical assessment scores immediately after and 1 month after the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) for treatment-resistant depression[a] 34
[a] Treatment response was defined as a reduction on total MADRS score by ≥ 50%; remission was defined as a score of < 8 for the 17-item HAM-D, < 5 for the 6-item HAM-D, < 11 for the MADRS, < 13 for the BDI-II, and zero for the C-SSRS.
[b] Suicidal Ideation subscale.
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 should be accurately marked out with the assistance of neuronavigation, and the head should be carefully registered to ensure the accuracy of a head model. Also, note that the 5-cm rule generally stimulates very posterior regions of the frontal brain, while our sgACC-DLPFC targeting protocol usually leads to a very anterior region35,36. Thus, the differential clinical efficacy among targeting methods may be associated with the orientation. Our method should be carefully evaluated by comparison with other approaches that define the stimulation target based on other functional connectivities.
Our protocol has some limitations. First of all, sgACC is located near the sphenoidal sinus, which causes severe signal loss due to the non-uniformity of the magnetic fields37. Besides, the accuracy of the neuronavigation largely depends on the quality of MRI images, which may lead to inaccurate stimulation targets. Improvement of the signal-to-noise ratio of MRI or a better replacement for sgACC may help address this problem. Another limitation is the time-consuming procedures that potentially affect patients' compliance for the treatment, since preparation such as establishing a head model takes a long time, not to mention the whole treatment course that lasts for about two weeks.
Despite these limitations, this method has its strength. Despite the fact that the 5-cm rule has been widely applied in clinical settings, it overlooks the individual differences on the anatomical features, which is considered an important reason for the heterogenous efficacy of TMS38. The neuronavigation system models the head individually by referring to structural MRI images, thus improving the accuracy of coil positioning. Research has proven that a neuronavigated TMS therapy is more effective than a traditional treatment using the 5-cm targeting method38, Furthermore, an operator can adjust the coil in real time under the guidance of the system39,40.
Traditional TMS therapy targets at DLPFC as a whole. In this protocol, the subregion of DLPFC with the strongest negative connectivity with sgACC was selected as the target. Baeken et al.41 found that sgACC is related to suicidal ideation and hopelessness. Patients with treatment-resistance depression show a stronger FC between sgACC and the right lateral frontotemporal cortex, which may be related to the refractory state of the patient42. In addition, strong connectivity between sgACC and DLPFC was found in MDD patients43, and the negative FC between sgACC and default mode network (DMN) was correlated with the clinical improvement. Therefore, we speculate that the connectivity of sgACC is closely related to the therapeutic effect of TMS, and that stimulating a specific region of DLPFC may change its FC with sgACC, which can improve the effectiveness of the treatment25,44.
In summary, the present TMS protocol is operated under the MRI-assisted neuronavigation system and targets the subregion of DLPFC that shows the strongest negative functional connectivity with sgACC. Although no previous studies have applied this targeting method, it may help enhance the accuracy of positioning and possibly improve the treatment response.
The authors have nothing to disclose.
The study was funded by China Postdoctoral Science Foundation funded project (2019M652854) and Natural Science Foundation of Guangdong, China (Grant No. 2020A1515010077).
3T Philips Achieva MRI scanner | Philips | ||
Harvard/Oxford cortical template | http://www.cma.mgh.harva rd.edu/ | ||
MATLAB | MathWorks | ||
SPM12 | http://www.fil.ion.ucl.ac.uk/spm | ||
The Visor2 system | ANT Neuro | The Visor2 software, the optical tracking system, tracking tools and calibration board are part of the visor2 system. | |
TMS device | Magstim, Carmarthenshire, UK |