Neuroimaging in Patients Undergoing TMS for Depression

Significance: There are few therapeutic options for individuals with treatment resistant
depression (TRD). One recently developed approach is rTMS over left dorsolateral prefrontal
cortex. Recent studies have demonstrated overall antidepressant benefit of rTMS in patients
who fail to respond to a trial of antidepressant medication (1, 2, 3). Nevertheless, for many
patients the response is incomplete, suggesting the need for further optimization. One
potential cause of heterogeneous response might relate to individual differences in brain
anatomy and connectivity patterns. At present, the rTMS stimulation site across subjects is
based upon fixed location relative to motor cortex. Potentially, however, the approach could
be optimized by stimulating based upon individual brain functional connectivity pattern. The
present project will collect pre- and post-treatment brain functional connectivity measures
in a group of patients who will be receiving independent clinical rTMS for resistant
depression, a connectivity-based targeting approach will be applied at the single-subject
level to individualize therapy in those patients who do not respond to standard approaches.

Patients will be divided in 2 groups. Group 1 (N=30) will be depressed patients undergoing
standard TMS for the first time. Group 2 (N=30) constitutes those who have previously
demonstrated that they do not respond to standard TMS. MDD patients prescribed to receive
standard TMS for the first time (group 1) will have resting-state FMRI in order to see if
their responsiveness based on the functional connectivity maps can be predicted.
Non-responders to standard TMS approaches (Group 2) will be randomized (3:2) to either
receive targeted (N=18) or standard (N=12) repetitive TMS (rTMS) treatments. A
connectivity-based targeting strategy will be used on patients undergoing targeted rTMS to
optimize target for focal brain stimulation. Raters and patients in group 2 will be kept
blinded to the treatment assignment. All patients referred from the ongoing treatment study
will be assessed by 3 tesla brain MRI, Magnetic Resonance Spectroscopy (MRS) and Cerebral
Blood Flow/Volume (CBF/CBV) procedures at baseline and immediately following the final
treatment.

General Inclusion Criteria:

1. Male or female outpatients, 18 to 60 years of age.

2. Primary diagnosis of Major Depressive Disorder as confirmed by the Structured Clinical
Interview for Diagnostic and Statistical Manual (DSM-IV-TR) Disorders (SCID-IV-TR).

3. Duration of the index episode of at least 1 month.

4. MDD symptoms, defined as a total HDRS-17 score ≥ 18 despite treatment with an adequate
trial of a serotonin reuptake inhibitor (SRI).

5. Individuals who cannot tolerate medications.

6. Patients currently on medication must be at the same stable dose(s) for 1 month prior
to enrollment and be willing to continue at the same dose(s) through the duration of
the study.

7. Capable and willing to provide informed consent.

8. Signed HIPAA authorization.

9. Right-handed.

10. Willingness to undergo research fMRI scan (3T).

11. Willingness to undergo randomization to either treatment arm.

General Exclusion Criteria:

1. Investigators, and their immediate families (defined as a spouse, parent, child or
sibling, whether by birth or legal adoption).

2. Individuals diagnosed by the investigators with the following conditions: Bipolar
Disorder (lifetime), any Psychotic Disorder (lifetime), history of substance abuse or
dependence within the past year (except nicotine and caffeine).

3. Behavior, which in the judgment of the investigator may hinder the patient in
completing the procedures required by the study protocol.

4. Individuals with a clinically defined neurological disorder including, but not limited
to: tics, space occupying brain lesion; any history of seizures except those
therapeutically induced by electroconvulsive therapy (ECT); history of cerebrovascular
accident; history of fainting; transient ischemic attack within two years; cerebral
aneurysm, Dementia; Parkinson's Disease; Huntington chorea; Multiple Sclerosis.

5. Increased risk of seizure for any reason, including prior diagnosis of increased
intracranial pressure (such as after large infarctions or trauma), or history of
significant head trauma with loss of consciousness for ≥ 5 minutes.

6. Use of any investigational drug within 12 weeks of the randomization visit.

7. Significant acute suicide risk, defined as follow: suicide attempt within the previous
6 months that required medical treatment; or ≥ 2 suicide attempts in the past 12
months; or in the investigator's opinion, has significant risk for suicide based on
the current state or recent history.

8. Cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable
cardiac disease.

9. Intracranial implants (e.g. aneurysms clips, shunts, stimulators, cochlear implants,
or electrodes) or any other metal object within or near the head, excluding the mouth,
that cannot be safely removed.

10. Current illicit drug use (cannabinoid, phencyclidine, amphetamines, barbiturates,
cocaine, methadone, and opiates), defined as drug use during the 6 months before
screening.

11. Known or suspected pregnancy. Urine pregnancy test Women who are breast-feeding.

12. Women of childbearing potential not using a medically accepted form of contraception
when engaging in sexual intercourse.

13. Medicinal patch, unless removed prior to the magnetic resonance (MR) scan.

14. MDD patients with very severe depression, defined as a total HDRS-17 score ≥ 23, will
be excluded and referred to immediate treatment.

15. Risks related to seizures, such as substance abuse or sleep disruptions/insomnia.

SpecificExclusion criteria (group 1):

History of treatment with rTMS therapy for any disorder.

Specific Inclusion criteria (group 2):

History of non-response to rTMS in this depressive episode.