Spectral Correlation Coefficient-determine TMS for Depression

This study will investigate the feasibility, safety, and tolerability of administering repetitive Transcranial magnetic stimulation(TMS) at frequencies other than standard 10 Hz. This study will enroll 10 subjects who will undergo one quantitative electroencephalograph, one TMS procedure to determine the appropriate frequency and intensity for treatment, weekly mood/symptom assessments, and up to 30 TMS treatments. Subjects will be asked to participate for up to 6 weeks.

STUDY OBJECTIVE

The primary objective of this study is to demonstrate feasibility of repetitive Transcranial Magnetic Stimulation (rTMS) treatment for depression at stimulation frequencies other than 10 Hz. The objectives for this study are:

1. to determine if each subject's frequency response pattern shows one or more distinct frequencies of stimulation that generated increased Spectral Correlation Coefficient;
2. to determine if these frequency response patterns differ across subjects; and,
3. To gather pilot data for an extramural funding application to investigate the efficacy of rTMS treatment at individualized stimulation frequencies as an alternative to the standard 10 Hz protocol.

INCLUSION/EXCLUSION CRITERIA

We will enroll 10 subjects into this study. Subjects must meet all the following inclusion criteria to qualify for enrollment:

1. All subjects must be over between 18-65 years of age.
2. Must have confirmed diagnosis of severe Major Depressive Disorder (single or recurrent episode).
3. Failure to respond to a minimum of 2 trials of antidepressant medication
4. Failure to respond from at least two different agent classes
5. Accompanied by at least two evidence-based augmentation therapies (Benzodiazepines
6. do not count).
7. Must have a trial of psychotherapy known to be effective in the treatment of Major Depressive Disorder of an adequate frequency and duration.

8. Subjects are willing and able to adhere to the treatment schedule and required study visits

   Subjects will be excluded from the study participation if one of the following exclusion criteria applies:

9. Are mentally or legally incapacitated, unable to give informed consent
10. Have an infection or poor skin condition over the scalp where the device will be positioned
11. Have increased risk of seizure because of family history, stroke, or currently use medications that lead to increased risk for seizure
12. Diagnosis of acute or chronic psychotic symptoms or disorders (such as schizophrenia, schizophreniform or schizoaffective disorder) in the current depressive episode.
13. Neurological conditions that include epilepsy, cerebrovascular disease, dementia, increased intracranial pressure, having a history of repetitive or severe head trauma, or with primary or secondary tumors in the central nervous system.
14. Presence of an implanted magnetic-sensitive medical device located less than or equal to 30 centimeters from the transcranial magnetic stimulation magnetic coil or other implanted metal items, including but not limited to a cochlear implant, implanted cardioverter defibrillator, pacemaker, vagus nerve stimulator, or metal aneurysm clips or coils, staples, or stents. (Note: Dental amalgam fillings are not affected by the magnetic field and are acceptable for use with transcranial magnetic stimulation

STUDY PROCEDURES

SUBJECT SCREENING AND ENROLLMENT If a potential TMS patient is evaluated and meets TMS treatment criteria, they will be approached by a study staff member who is not involved in their clinical TMS evaluation to inquire if they would like to participate in the study. If they confirm interest, the study details and their involvement will be discussed with them and the consent form will be reviewed and explained to them. They will have an option to complete the consent form or take it home and complete it when they decide to participate.

A copy of the signed consent form will be provided to the study participant and the original signed consent form will be maintained.

Subjects will be asked to participate in the following procedures:

Qualitative Encephalograph (QEEG) One QEEG will be performed in using ANT Neuro equipment. Recordings will be performed while the subjects are resting in the eye-closed, maximally alert state. Electrodes will be attached to the subjects' scalp using a 64, Ag-Cl electrode nylon electrode cap. These types of electrodes are non-invasive, apply easily and quickly with little or no discomfort to the subject, and are easily removed with minimal clean up. During the recordings, subjects will sit in a comfortable chair while the electrodes are applied. The recording will then be performed and the technicians will alert subjects if any signs of drowsiness appear. A CPz-referential montage will be used with electrodes placed according to the 10-20 system (Leuchter et al., 1992; Dunkin et al, 1995). Signals will be digitally recorded (bandpass 0.3-70 Hz) and analyzed with the Brain Vision Analyzer 2.0 software and MatLab.

Symptom Survey/Mood Assessments

We will administer the following assessments weekly:

• Inventory of Depressive Symptomology (Self-report) (IDS-SR)
• Hamilton Depression Rating Scale (HAMD)
• Profile of Moods (POMS)

The Subjects will be asked about their feelings, thoughts, activities, or emotional well-being. Assessments will be done with study staff and completely individually through self-assessment.

Motor Threshold Determination Before the Spectral Correlation Coefficient is determined, the appropriate intensity will be assigned and used for the Spectral Correlation Coefficient determination and subsequent treatments. The TMS physician(co-investigator/PI) measures the subject's motor threshold by administering several brief pulses. The motor threshold is the minimum amount of power necessary to make the patient's thumb twitch, and varies from individual to individual.

Spectral Correlation Coefficient Determination Prior to the first treatment and following motor threshold determination, subjects will receive stimulation with 68 different stimulation pulse trains of 40 pulses each at frequencies ranging between 3 and 20 Hz in steps of 0.25 Hz, plus intermittent theta burst (iTBS) stimulation, in randomized order. In between pulse trains, 26 s resting period will be recorded. This entire procedure is called "frequency interrogation" and will take forty (40) minutes.

To estimate the optimal individual stimulation frequency, we will compute the spectral correlation coefficient (SCC), which is the the similarity of spectra at two different electrode locations at sliding center frequencies from 3 to 20 Hz in steps of 0.5 Hz and with a 4 Hz band width (+/- 2 Hz). This is computed as a Pearson bivariate correlation coefficient (R) between the seed (F3, stimulation site) and target (posterior locations of the fronto-parietal control network) for each electrode pairing for pre- and post- interrogation resting state. The change in Spectral Correlation Coefficient will be determined by subtracting the post-rTMS from the pre-rTMS SSC, separately for each electrode pair. Only electrodes with an increased SCC will be considered for further analysis.

We next calculate the Spectral Correlation Coefficient density, which is an indicator of a focal increase (clustering) of high Spectral Correlation Coefficient connections to a small topographic area. To calculate density, the Euclidian distance between the remaining target electrodes will be computed and summed. A large cumulative distance indicates that increased targets are widely spread, while a small distance indicates a more focal activation. The SCC and the inversed cumulative target distance then will be z-transformed and combined, such that a large value would indicate a strong increase in connectivity along with a dense distribution of the respective target electrodes, while a small value would indicate a moderate connectivity increase and more dispersed target locations.

In previous work, we have shown that Spectral Correlation Coefficient is a reliable biomarker for 10-Hz rTMS treatment outcome in depression (Corlier et al. 2019) and our preliminary data also indicate that connectivity density post interrogation at 10 Hz is higher for subjects who responded to full rTMS treatment course at 10 Hz.

For the current study, we propose to select the frequency with the largest connectivity density (strong and focal connectivity increase within the fronto-parietal control network) in the range of 3 and 20 Hz as the optimal individual stimulation density.

TMS TREATMENT

Ten patients will be administered 10 and up to 30 acute rTMS treatments at their individual stimulation frequency and up to 6 taper rTMS treatments administered over 2-3 weeks. Weekly evaluations of clinical symptoms (IDS-SR) will be the primary outcome measure, in addition to the assessment of general tolerability and safety issues.

During the treatment, the stimulation coil is placed on the head so that it rests above the front region of the subject's brain. Treatment is then commenced according to the assigned settings. During the treatment, subjects will hear a series of clicking sounds and will feel a tapping sensation under the treatment coil. Per treatment, a total of 3000 pulses will be administered over 75 bursts with 40 pulses delivered per burst. Each treatment will last between 35-50 minutes depending on the treatment parameters.

Treatment will be administered using the Magstim Super Rapid2 Plus1 system, a research device or FDA-approved MagVenture Clinical TMS system.

ANALYSIS

Weekly evaluations of clinical symptoms (IDS-SR) will be the primary outcome measure, in addition to the assessment of general tolerability and safety issues. The assessments will be used to determine feasibility, tolerability, and safety of this treatment assignment method.