Robotically Delivered fMRI-Guided Personalized Transcranial Magnetic Stimulation Therapy for Treatment-Resistant Depression

This protocol demonstrates the workflow of FMRI-guided, robotically delivered, personalized TMS for depression. FMRI-guided TMS addresses the accuracy and precision problems associated with standard scalp-based targeting. After converting the patient's MRI DICOM files into NIFTI format and performing RSFC analysis, identify the standard space brain coordinates, located at the center of gravity of the left dorsolateral prefrontal cortex or DLPFC anti-correlated cluster in X, Y, Z format.

Then, obtain the standard space DLPFC SGC functional connectivity map produced in NIFTI format. Identify the standard space brain coordinate corresponding to the right abductor pollicis brevis motor area to approximate the target for resting motor threshold, or RMT testing. Warp the DLPFC, and M1 coordinates, and DLPFC SGC functional connectivity map from standard space to the patient's native space using transforms generated by the initial pre-processing pipeline prepared earlier.

Provide the psychiatrist performing the TMS targeting with the native space brain coordinates for DLPFC, and M1, and DLPFC SGC functional connectivity map. To navigate to the storage location of the patient's native T1W images, click file and select new session in the Neuronavigation. Create a session folder and select either DICOM or NIFTI, depending on the storage format of the T1W images.

Adjust the surface threshold on the scalp on the T1W image using the adjust surface threshold option located in the menu bar in the Neuronavigation software. Using the adjust scalp threshold option, adjust the scalp surface threshold to inflate or deflate. Ensure minimization of epidural space or scalp over inflation from the scalp surface definition.

To segment brain tissues from non-brain tissues, using the brain segmentation option, select a large white matter tract and click calculate, so the software determines relative contrast values of brain and non-brain tissue, then check that the defined brain surface adequately aligns with the gray matter surface. Then, using the patient registration option, predefine anatomical landmarks. Mark the left tragus, right tragus, and nasion onto the patient's native space T1W image in preparation for co-registration with the patient's actual scalp landmarks.

The tragus, tragus helix junction, or any easily identifiable landmark can be used as long as co-registration at a later step is closely matched. Next, enter the native space DLPFC target and the M1 coordinates in X, Y, Z format using right anterior superior orientation with the planning option in the menu bar. Reposition the DLPFC target to the nearest gyrus if it falls within a sulcus.

To verify that the repositioned brain coordinate remains within the selected anti-correlated cluster, overlay the native space DLPFC SGC functional connectivity map onto the patient's native space T1W image and enter the coordinates of the repositioned brain target in the MRI visualization software. Reposition the M1 coordinate to the precentral gyrus if necessary. Calculate the perpendicular entry points of the TMS coil on the scalp for the DLPFC and M1 coordinates.

Ensure the approach angle of the TMS coil, relative to the left side of the head, is set to 45 degrees during calculation of the entry point. Overlay a six by four entry or target grid spaced at five by five millimeter intervals in the entry or target option in the control area to create additional targets for RMT testing. Seat the patient in a motorized treatment chair with a neck rest, ensuring proper support of the head and neck.

Recline the patient and raise the legs to a comfortable position. Using a headband or double-sided tape, fix the patient reference tracker to the patient's right forehead. Position the patient's head using the motorized chair so that it is within the visual field of the Neuronavigation camera.

Then, return to the patient registration option in the menu bar to coregister the patient's anatomical landmarks and scalp surface to the predefined anatomical landmarks and scalp surface on the T1W image. Touch the pointer to the patient's actual scalp landmarks and acquire each landmark by pressing the green button on the foot or hand switch. Touch the pointer to the scalp and gently run it across the patient's scalp to acquire 300 scalp landmarks while pressing the green button on the foot or hand switch.

Check the spatial alignment accuracy between the actual and predefined anatomical landmarks and scalp surface at the end of the patient registration procedure, reported as root mean square deviation in millimeters. Ensure that the root mean square values are below three millimeters, otherwise, repeat the registration steps until this is achieved. Reposition the cobot so the patient reference tracker is at an optimal distance and angle within the visual field of the Neuronavigation camera.

Ensure the visual field of the Neuronavigation camera can also detect one of the cobot reference points. Check the visual field by selecting Check Tracking System in the menu bar. The purple crosshairs indicate visible reference points.

Enable manual mode in the cobot option in the control area to manually move the coil-mounted robotic arm into the workspace. Click move to park position in the cobot option panel to move the coil into the neutral position. Manually position the cobot, or adjust the motorized chair, so the coil is directly above the patient's head with a separation of several centimeters.

Then calibrate the coil force sensor function in the cobot option within the control area of the Neuronavigation software to trigger a sensor popup window with four pressure lights. Place a finger on the coil and gradually increase, then decrease pressure so all four pressure lights turn on and then off in sequence. Ensure the lights activate left to right, then deactivate right to left to make the okay button clickable.

Place three electromyograph electrodes connected to the MEP monitor along the ventral length of the right abductor pollicis brevis. Select the MEP protocol on the TMS machine and set the sensitivity to 200 microvolts per division. Select recall, and then select timing to display the MEP interface.

To instruct the coil-mounted robotic arm to move to the first M1 target in the grid, select the target in the entry and target option panel in the control area. Select coil alignment in the cobot option panel to position the coil on the patient's scalp. Select the stimulator option in the control area of the Neuronavigation software and set the initial stimulation intensity to 40%in the amplitude option.

Click single pulse to deliver a pulse while moving sequentially to each of the targets in the M1 grid. Precise positioning of the TMS coil is not required for motor targets. Increase the stimulation intensity as needed to observe an MEP or visible thumb flexion.

Identify the target that produces the strongest MEP along with the largest amplitude flexion of the right thumb, fingers, or wrist. Select the optimal M1 target in the entry and target panel and click coil alignment in the cobot option panel to position the coil on the patient's scalp. Adjust the stimulation intensity of single pulses at this target at set intervals until the RMT is determined.

In the stimulation panel, MEP max values above 50 millivolts indicate an MEP. Identify the RMT as the minimum stimulation intensity required to evoke five out of 10 movements with an MEP greater than 50 millivolts on electromyography. Instruct the patient to close the eyes, relax, and avoid focusing on any specific thought to maintain consistent brain states across FMRI and TMS.

Instruct the coil-mounted robotic arm to move to the DLPFC target by selecting the target in the entry and target option panel in the control area. Select coil alignment in the cobot option panel to position the coil on the patient's scalp. Select the programmed three minute intermittent theta burst stimulation protocol in the menu option on the TMS machine.

Select recall and then timing to prepare the machine to deliver the three minute intermittent theta burst stimulation protocol. Select the stimulator option in the control area and set the stimulation intensity to 80%of RMT for the first session, 100%for the second session, and 120%for subsequent sessions. Click start or stop trains to deliver the full train of repetitive TMS pulses.

Each pulse is indicated in the stimulation panel. Perform left dorsolateral prefrontal cortex stimulation daily for up to 20 to 30 weekday sessions. In an open-label study using this protocol, there was an overall response rate of 52%and a remission rate of 33%The a priori subgroups showed distinct response and remission rate profiles, indicating that the depression group without comorbidity, group one, responded better than the groups with comorbidity or bipolar depression, groups two and three respectively.

Pretreatment, the group average functional connectivity of the SGC DLPFC was minus 0.25. The functional connectivity between the DLPFC and the rest of the brain did not alter as a function of TMS treatment. In the subset of patients who underwent pre and post TMS FMRI, a specific reduction in anti-correlated RSFC was observed from pre-treatment to post-treatment, with the negative resting state functional connectivity approaching zero.

This protocol demonstrates the feasibility of using functional connectivity to personalize the treatment target for TMS in depression. This protocol requires substantial resources and specialized expertise, particularly for MRI, imaging analysis, and the use of Neuronavigation and robotic systems. Future protocols will improve feasibility using technology that integrates Neuronavigation, robotics, and imaging workflows.