Neurophysiologic Predictors of Outcome With rTMS Treatment of Major Depressive Disorder

A critical challenge in the management of major depressive disorder (MDD) is the selection
of treatment for each individual patient. Although treatments with depression can restore
people's lives, with any treatment modality there are some individuals who do not achieve
complete remission of symptoms, whether the intervention is pharmacological, psychological,
or somatic. While predictors for some treatments have been proposed for groups of patients,
the translation of these predictors to individualized patient care has remained elusive. In
an analysis of data from the NCT 00104611 multi-site, randomized, sham-controlled trial of
TMS, it was found that a larger number of prior treatment failures, longer duration of the
current episode, and the presence of comorbid anxiety were individual patient
characteristics associated with poorer acute outcomes with TMS treatment in the randomized
period (Lisanby et al., in press). This publication did not report standard predictor
metrics (e.g., sensitivity, specificity, positive- or negative-predictive accuracy, ROC
curves), so it is difficult to assess the value of these clinical factors in treatment
planning for individual patients. A predictor that could distinguish between individuals
likely to remit with TMS versus those likely to need a different intervention would be of
great use to clinicians and patients in making treatment decisions.

Our prior work (Cook et al., 2001, 2002, 2005; Leuchter et al. 2002) has studied a new
physiologic biomarker of response to SSRI and mixed-action antidepressants. The EEG-based
cordance biomarker can detect the physiologic effects of successful antidepressant treatment
at 48 hours, 1 week, and 2 weeks of treatment; in contrast, symptom differences between
responders and non-responders did not separate until 4 weeks of treatment in our
placebo-controlled trials. Additionally, the magnitude of early physiologic change was
associated with the completeness of clinical response. Our biomarker has been independently
studied and our findings replicated (Kopecek et al., 2006; Bareš et al., 2007, 2008). The
cordance biomarker can be considered as a leading indicator or predictor of treatment
outcome. As a non-invasive probe of brain physiology, it may detect early neurophysiologic
changes associated with accelerated clinical response from TMS.

More recent work with a related EEG-based measure, the Antidepressant Treatment Response
Index (ATR) has led to a simplified monitoring system; a physician can record
clinically-useful data from a 15-minute in-office procedure with electrodes located on the
forehead and ears (Leuchter et al., in submission). The ATR uses physiologic data collected
prior to treatment and after one week of exposure, and was shown to be predictive of outcome
with antidepressant medication. We are able to assess both cordance and ATR measures with
EEG measurements made prior to treatment and after 5 treatment sessions with TMS to evaluate
the predictive properties of both metrics.

On a related issue, some of the variation in outcome may be related to treatment factors.
Quantitative models and direct in vivo measurements (Wagner et al, 2004, 2008) indicate that
the electrical currents induced by TMS are predominantly confined to a brain region directly
under the treatment coil. The procedure for positioning the coil over the cortical target
is described in the NeuroStar TMS System User Manual (volume 2, sections 6 and 7) and
involves first determining a location where stimulation leads to a contraction of the
abductor policis brevis muscle (visualized with a thumb twitch on the right hand) and then
positioning the coil 5.5 cm anterior to that position along the left Superior Oblique Angle
line. While this target can be located with good reproducibility and was associated with
therapeutic outcome in the NCT trial, it is not clear that this positions the coil over the
best target within the DLPFC for all patients. Indeed, individual differences in gyral
anatomy and in gross brain size both add variability to the specific neuroanatomic region
being stimulated, and this may impact treatment efficiency.

Exposure to even a brief train of TMS pulses can elicit an acute physiologic change (cf
Siebner and Rothwell, 2003), and so a test procedure can be performed that will assess the
distance from the standard treatment position to the point eliciting a maximal acute
physiologic response. We propose a 9-locus mapping procedure, involving the assessment of
changes in brain activity from stimulation at locations including and around the standard
treatment target. The nine locations will be the usual treatment location and 8 other
points, 1.5 and 3.0 cm anterior, posterior, rostral, and caudal of the primary target. Test
stimulation will be for 15 seconds (=150 pulses @ 10 Hz) at each location, followed by 5
minutes of continuous EEG recording to examine acute changes in regional brain activity in
response to a brief stimulation exposure. All therapeutic stimulations will take place in
the standard location, and we will be able to evaluate what proportion of variance in
clinical outcome is explained by distance from the location of maximal acute physiologic
response.

Based on these previous studies, we propose to assess patients during treatment with TMS,
using clinical symptom ratings and brain physiology with EEG.

Inclusion Criteria:

1. Outpatients with non-psychotic, unipolar Major Depressive Disorder (MDD) assessed via
the MINI structured interview

2. A score of ≥ 20 on the HAM-D17 with Item 1 (depressed mood) ≥ 2

3. A history of treatment failure with at least one adequate trial of an antidepressant
and not more than 2 trials, in the current episode, assessed by the ATHF

4. Age range: 18-64.

5. Patients with suicidal ideation are eligible only if the thoughts of death or of life
not being worth living are not accompanied by a plan or intention for self-harm.

Exclusion Criteria:

1. Patient is mentally or legally incapacitated, unable to give informed consent.

2. Patients with psychosis (psychotic depression, schizophrenia, or schizoaffective
diagnoses (lifetime)); bipolar disorder (lifetime); dementia (lifetime); current MMSE
≤ 24; delirium or substance abuse within the past 6 months; eating disorder within
the past year; obsessive-compulsive disorder (lifetime); post-traumatic stress
disorder within the past year; acute risk for suicide or self-injurious behavior.
Patients with diagnostic uncertainty or ambiguity (e.g. rule-out pseudodementia of
depression) will be excluded.

3. Patients with exposure to ECT within the past 6 months, previous TMS treatment for
any condition, or VNS treatment (lifetime).

4. Patients who have met diagnostic criteria for any current substance abuse disorder
at any time in the 6 months prior to enrollment.

5. Past history of skull fracture; cranial surgery entering the calvarium; space
occupying intracranial lesion; stroke, CVA, or TIAs; cerebral aneurysm; Parkinson's
or Huntington's disease; or Multiple Sclerosis.

6. Any history of intracranial implant; implanted cardiac pacemaker, defibrillator,
vagus nerve stimulator, deep brain stimulator; or other implanted devices or objects
contraindicated by product labeling.

7. current pregnancy, breast feeding, or not using a medically accepted means of
contraception.

8. Other medical contraindications to any of the study procedures