Concurrent fMRI-guided rTMS and Cognitive Therapy for the Treatment of Major Depressive Episodes

Objective

Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment
for unipolar major depression, its typical effect sizes have been modest, and both
methodological and conceptual challenges remain regarding how to optimize its efficacy. Two
key elements have been missing from current work: first, to take an RDoC approach and link
the treatment to a comprehensive model of the neurocircuitry underlying depression, where
applying such a model to personalize the site of stimulation is likely to significantly
improve the efficacy of rTMS; and second, to maximize neural changes to the engaged
depression network by utilizing cognitive paired associate stimulation (C-PAS), a technique
we have developed over the last decade in which noninvasive stimulation is applied to the
targeted region while the circuit is engaged in processing related to desired behavior (here,
through the simultaneous use of cognitive behavioral therapy). The concurrent firing in the
emotional regulation circuit caused by TMS pulses and by the CBT will lead to neural
plasticity according to the Hebbian conception of fire together, wire together, while
repeated stimulation over the course of multiple TMS sessions will induce neuroplasticity to
accelerate and strengthen those changes, which are expected to be therapeutic. We thus intend
to test a novel integrative multimodal treatment for MDD consisting of a theory-based
protocol for individualized optimization of rTMS site of stimulation plus concurrent
behavioral interventions targeting the same dysfunctional neural circuitry. Our targeting
procedure is based on recent developments in the psychology and neurobiology of
self-regulation which offer a promising conceptual framework for identifying neural network
mechanisms of action in rTMS for depression, as well as for developing guidelines for
individualized rTMS treatment. As preliminary data, we report initial feasibility data from a
clinical paradigm in which five adults with major depressionreceived TMS to the left middle
frontal gyrus targeted on an individual basis using fMRI, while simultaneously receiving a
previously validated self-regulation-based psychotherapy (self-system therapy or SST). Here,
we will test this individualized method in a larger randomized trial.

Study Population

The study population will consist of 50 individuals between the 18 and 65 years of age, with
a diagnosis of treatment-resistant Major Depressive Disorder (MDD).

Study Design

This single site study is a proof-of-concept clinical trial to test both functional states
associated with an antidepressant response to a six week course of C-PAS using concommitant
SST and 10 Hz rTMS neuronavigated to left DLPFC, as well as the feasibility and safety of
such a course for long-term improvement in depressive symptoms. The proposed study will be
conducted over 3 phases. Phase I will consist of screening, consent, and baseline measures.
Screening will occur under the ETPB screening protocol (01-M-0254). Phase II will consist of
a 6-week double-blind sham controlled trial of neuronavigated TMS/SST. Participants will be
randomized to two groups, one (Active group) using fMRI-guided coil targeting and combined
TMS/SST, the other receiving sham TMS (Sham group) and a sham therapy. Subjects will
participate in 30 daily sessions over 6 weeks, with MRI sessions both prior to and
immediately after the course of TMS. Additionally, MEG will be performed at baseline,
immediately after the first TMS/SST session, and immediately after the entire course of TMS,
and a battery of TMS/EEG excitability and plasticity measures will be performed pre- and
post-TMS/SST course. In Phase III, the study team will provide standard of care for
depression for up to three months, and will prescribe a relapse prevention strategy, in
consultation with the referring physician, including TMS (which is consistent with standard
of care).

Outcome Measures

Primary outcome measures are change in magnitude of BOLD signal recorded in pre- and post-TMS
course MRI sessions, in the DLPFC region targeted with TMS based on individual activations in
that region found at baseline using the priming task, and pre- and post-TMS course
connectivity changes between DLPFC (measured with DTI and resting state functional
connectivity), and other regions associated with the emotional regulation network,
specifically OFC, medial PFC, precuneus, and ACC. Pre and post TMS course change in
depression severity scores (HDRS, MADRS) will also be found, in order to look for
correlations with these MRI measures. Secondary outcome measures will be ratings from the
BSL, C-SSRS, CTQ, HAM-A, NIH-BFI, PANAS, RBANS, RRS, SHAPS, and TLEQ, as well as
electrophysiological changes using MEG and EEG measures.

- INCLUSION CRITERIA:

- 18 to 65 years of age.

- Use of effective method of birth control for women able to become pregnant

- Major Depressive Episode Diagnosis, Severity, and Duration:

- Subjects will meet the DSM-IV-TR primary diagnosis of initial or recurrent Major
Depressive Disorder by DSM-IV-TR criteria -- HAM-D score greater than 17 and Item
1 score greater than or equal to 2. Alternatively: At the initial screening and
beginning of Phase II, subjects must have a baseline score on the MADRS greater
than or equal to 20 and YMRS of less than 12.

- Duration of current episode greater than 8 weeks. The definition of an episode is
demarcated by a period of greater than 2 months when the subject did not meet
full criteria for the DSM-IV-TR definition of Major Depressive Episode. Maximum
duration of current episode cannot exceed 2 years.

- Current or past history of lack of response to at least one adequate antidepressant
trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a
failed adequate trial of ECT would count as an adequate antidepressant trial (unless
the ECT occurred within the last year, in which case the participant will be
excluded).

- If currently on a stable dose of antidepressant medication, the dosage has been
unchanged for at least four weeks prior to study entry. The medication must be
continued, and at the same dosage throughout study participation.

- Each subject must have a level of understanding sufficient to agree to all required
tests and examinations and sign an informed consent document.

- All subjects must have undergone a screening assessment under protocol 01-M-0254, The
Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers .

- Subjects are willing and able to adhere to the intensive treatment schedule and all
required study visits.

EXCLUSION CRITERIA:

- Pregnant or nursing women or women who plan to become pregnant in the next 20 weeks while
in the study.

Persons who are able to get pregnant must be willing to use at least one form of effective
birth control

during the entire period of study participation (or until last clinical labs and rating)
and have a negative pregnancy

test at screening.

- Current or recent (within the past 6 months) diagnosis of substance abuse or
dependence (excluding nicotine and caffeine)

- History of seizure except those therapeutically induced by ECT (childhood febrile
seizures are acceptable and these subjects may be included in the study), history of
epilepsy in self or first degree relatives, stroke, brain surgery, head injury, known
structural brain lesion.

- Diagnosed with the following conditions (current unless otherwise stated):

- Any other current primary Axis I mood or psychotic disorder, including bipolar
disorder, with the exception of most anxiety disorders (including generalized
anxiety disorder (GAD), social anxiety disorder (also known as social phobia),
specific phobia, panic disorder with and without agoraphobia, posttraumatic
stress disorder (PTSD), anxiety secondary to medical condition, acute stress
disorder (ASD), although with .obsessive-compulsive disorder (OCD) and
substance-induced anxiety disorder excluded. While these anxiety disorders can be
comorbid, they must be stable and the MDD must be the primary diagnosis.

- Depression secondary to a general medical condition, or substance-induced.

- Any bipolar disorder or psychotic disorder (lifetime), including schizoaffective
disorder, or major depression with psychotic features in this or previous
episodes.

- Eating disorder (current or within the past year).

- Obsessive compulsive disorder (lifetime).

- ADHD (currently being treated).

- Subjects meeting criteria for Axis II cluster A or B diagnosis based upon DSM-IV
TR criteria, which in the judgment of the Investigator may hinder the subjects in
completing the procedures required by the study protocol.

- Subjects currently engaged or planning to engage in other treatment during the course
of Phases I and II of the study (including behavior therapy, or other types of
individual, family, or group psychotherapy/counseling), or subjects planning to start
an antidepressant medication during the course of Phases I and II.

- Increased risk of seizure for any reason, including prior diagnosis of increased
intracranial pressure (such as after large infarctions or trauma), or currently taking
medication that lowers the seizure threshold. Excluded medications and substances
include: imipramine, amitriptyline, doxepine, nortriptyline, maprotiline,
chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine,
(MDMA, ecstasy), phencyclidine (PCP, angel s dust), ketamine, gamma-hydroxybutyrate
(GHB), alcohol, theophylline.

- Subjects with an unstable or serious medical or neurological disorder

- Presence of any medical illness likely to alter brain morphology and/or physiology
(e.g., hypertension, diabetes) unless if controlled by medications

- Presence of ferromagnetic metal in the body, such as metallic (ferromagnetic) implants
(e.g, heart pacemaker, aneurysm clip).

- Subjects who have hearing loss that has been clinically evaluated and diagnosed

- Participants who are uncomfortable in small closed spaces (have claustrophobia),
unable to lie comfortably supine for up to 90 minutes, and would feel uncomfortable in
the MRI machine (for subjects doing imaging component of the study only).

- Subjects with any of the following treatment histories:

- Lifetime history of TMS treatment.

- Use of any investigational drug or device within 4 weeks of starting the study.

- Clinically significant abnormal lab tests

- Positive HIV test

- Subjects who, in the investigator s judgment, pose a current serious suicidal or
homicidal risk.

- A current NIMH employee/staff or their immediate family member.