Functional Brain Imaging Study of Response to Repetitive TMS (rTMS) Treatment of Major Depression

I. BACKGROUND AND SIGNIFICANCE (including progress report and preliminary studies).

1. Historical background

Repetitive transcranial magnetic simulation (rTMS) has been used extensively to treat
patients with major depression [1]. However, its efficacy varies. Biomarkers which can
quantify, objectively assess, or even predict the efficacy of the rTMS treatment for
each patient are necessary in order to establish more effective and individualized
treatment, as well as to save cost and time. TMS is a noninvasive technique that
stimulates the brain by using an externally applied magnetic field to induce electric
currents at surface of the cortex without causing pain. rTMS has been used to treat
depression for close to 20 years, and the FDA recently approved the use of rTMS in 2007
for treatment.

2. Previous pre-clinical or clinical studies leading up to, and supporting the proposed
research

Despite its potential, rTMS has limitations such as a variable rate of effectiveness
[1, 2]. It requires daily on-site treatment for duration of 4-6 weeks, and it is
commonly paid for with private patient funds. Therefore, there is a need to assess the
efficacy of rTMS more objectively and accurately. Importantly, patients would benefit
from an ability to predict the likely outcome of the treatment (4-6 weeks) within the
first few sessions. Thus, the investigators propose to study two corresponding
biomarkers by employing two imaging modalities, functional MRI (fMRI) and functional
near infrared spectroscopy (fNIRS). Success of this project will result in the
identification of quantitative biomarkers that are responsive to rTMS treatment of
depression and predict its outcomes. This will greatly improve and individualize the
treatment for depression in the future.

3. Rationale behind the proposed research, and potential benefits to patients and/or
society

Unlike functional activation studies, which are mainly focused on brain regions in
isolation, functional connectivity studies quantify the dynamic interactions between
functionally related brain regions. This is likely to be more relevant in complex
psychiatric disorders such as major depression. Resting state (RS) network activity reflects
intrinsic brain function in the absence of a task. It has shown a remarkable overlap with
patterns of task-induced activity [3]. The main benefit to using RS fMRI to investigate the
effect of psychiatric disorders on the brain is that it assesses brain state, rather than
response to a complicated experimental task. This is especially critical in studying the
patients with depression, since the trademark of the disease is lack of willingness to
participate in any activity. There is mounting evidence of atypical RS functional network
activity in depression [2, 4- 6]. Among these networks, the cognitive control network (CCN)
is particularly important due to its role in mood regulation and attention. Because of this,
the dorsolateral prefrontal cortex (DLPFC), an important part of the CCN, is the target of
standard rTMS treatment. Thus it is critical to understand the changes in the CCN before and
after rTMS treatment; this could be used as clinical marker of the efficacy of the
treatment.

RS fMRI is advantageous for the assessment of the efficacy of rTMS treatment: it is
brain-based, objective and potentially more specific. fNIRS is a noninvasive optical imaging
tool, which measures oxy-, deoxy-, and total hemoglobin concentration changes (Δ[HbO], Δ[Hb]
and Δ[tHb], respectively) at the cortex through the intact skull [7]. fNIRS is the ideal
accompaniment for rTMS research, because:

1. The instrumentation is immune to magnetic field changes

2. It is most sensitive to the brain regions most affected by rTMS

3. It has a wide temporal dynamic range (from ms to hours), which allows the measurement
of single TMS pulses as well as an entire rTMS session

4. The probe hardware is compact and adaptable so that measurements can be made without
affecting rTMS equipment placement Recently, various labs have demonstrated the ability
of fNIRS to monitor the effect of rTMS in healthy subjects [8, 9]. In this study,
patients that will receive rTMS as part of their clinical treatment for depression will
be monitored for up to 30 sessions. Investigators will focus on the correlations
between the changes in hemodynamic response from session to session with the final
outcomes, especially the correlation between the hemodynamic changes in the first few
sessions and the treatment outcome. This will help us to understand if the early trend
of hemodynamic responses of rTMS can predict the long-tern effectiveness.

II. SPECIFIC AIMS (Research Objectives)

a. Specify objectives and hypotheses to be tested in the research project

In this proposal, the investigators will employ two imaging modalities to assess
quantitatively the rTMS treatment and establish the early biomarker to predict the outcome
by exploring:

1. The RS functional connectivity within 10 days before and within 10 days after a course
of treatment (up to 30 treatments; however, a typical course of treatment is likely one
treatment 5 times a week for 4-6 weeks: total 20 sessions) using blood oxygen
level-dependent functional MRI (BOLD fMRI).

2. The real time hemodynamic response of the brain to rTMS during each treatment session
using fNIRS. A number of studies report a decrease in functional connectivity in the
CCN in subjects with major depression [4-6]. Furthermore, studies indicate the DLPFC, a
major part of CCN, exhibits relatively low activation in depression.

To this end, our specific hypotheses are as follows:

1. Primary Hypothesis: In patients with a positive response to rTMS, the investigators
will observe an increase in the strength of connectivity as measured by fMRI among
brain regions in the CCN after 4 weeks treatment.

2. Secondary Hypothesis: Brain activation measured by fNIRS in the DLPFC during rTMS will
increase as the number of treatments increase. Detection of this increase in brain
activity at the beginning of the treatment may be a marker for positive treatment
outcome.

Inclusion Criteria:

1. Subjects must be 21-45 years old.

2. Current episode of depression must be of a duration of three years or less

3. Participants must have a score of 18 or more on the 24-item version of the HDRS

4. Participants must have failed at least one adequate trial of antidepressant
medication in this or the most recent depressive episode, but not more than four
medications.

•Alternatively, they can have shown an inability to tolerate four such agents due to
side effects

5. Participants may be medicated or un-medicated.

•Medication adjustments may be introduced during the course of the TMS treatment by
his or her primary psychiatrist in consultation with Dr. Morales. At the discretion
of the PI and study physician, subjects that begin taking or undergo a change in
certain medications known to influence mood or vascular circulation may be excluded
from the study analysis. Exclusion from the analysis will not affect their clinical
treatment.

6. Women entering this study must complete a urine pregnancy screen prior to fMRI
scanning unless they are post-menopausal, clinically defined as no menses in greater
than 12 months or having had surgical removal of the ovaries.

7. Subjects must be in inpatient/outpatient treatment with a prescribing mental health
clinician.

8. Subjects will meet DSM-IV criteria for or Major Depressive Disorder and be currently
depressed.

9. Subject must have a HAM-D score ≥ 18 and a MADRS score > 18.

•At the discretion of a study psychiatrist or PI, a HAM-D/MADRS score of less than 18
may be accepted if enough depressive symptoms are present and the subject meets DSM
criteria for depression.

10. Capable of giving informed consent, including compliance with restrictions and
restrictions listed on consent form.

Exclusion Criteria:

1. Currently pregnant or planning to be pregnant during the course of the study, as
verified by positive pregnancy test on fMRI scan days, or childbearing potential and
not using adequate contraception. Adequate contraception includes birth control
pills, birth control shots, or a non-metallic, MRI-compatible intrauterine device
(IUD). Those not of childbearing potential include post-menopausal for more than 6
months, surgically sterilized, or male participants.

2. Active neurological diseases, history of seizure disorder, dementias, or acute
medically unstable or unmanaged physical illnesses.

3. Failed more than four antidepressant medications in this or the most recent
depressive episode

4. Any contraindication to MRI scanning as assessed by pre-screening MRI questionnaire
(including, but not limited to, the presence of ferrous implant, pacemaker, etc…).

5. History of clinically significant claustrophobia.

6. Weight greater than 250 pounds (>113.4kg).

7. Evidence of drug use, nicotine use, alcohol use, or caffeine use by participant
and/or clinical observation on the fMRI scanning days.

8. Any clinically significant brain structural abnormalities per patient's medical
history or per report generated from the clinical structural scan performed during
baseline scanning. Per the discretion of the study physician and the principal
investigator, subjects who meet this exclusion criterion may be included in the
research study and excluded from the study analysis.

9. Patients who, in the investigators' judgment, will not likely be able to comply with
the study protocol.