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

1. BACKGROUND AND SIGNIFICANCE (including progress report and preliminary studies).
2. 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.
3. 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.
4. 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)

1. 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.