Accelerated TMS to a Novel Brain Target in MDD and PTSD

Non-invasive transcranial magnetic stimulation (TMS) is now FDA-approved for the treatment of
major depressive disorder (MDD). However, there is growing evidence that the targeting
strategy for delivering TMS treatment would yield superior clinical outcomes if it were more
tailored to individual neuroanatomy. The current study take this idea one step further and
suggest that functional MRI guided TMS might yield an even greater leap forward in promoting
optimal clinical outcomes.

The sgACC has been well established as a brain area sensitive to negative mood inductions and
implicated in neural abnormalities associated with affective and stress disorders. It is
therefore one of the primary targets for deep brain stimulation (DBS) treatment of MDD using
surgically implanted DBS devices. Recent posthoc imaging studies of patients who have
undergone TMS treatment for depression suggest that treatment outcomes tended to be better
when patients were by chance stimulated in an area of lateral prefrontal cortex that had high
levels of functional connectivity with sgACC. Based on this finding and on interleaved
TMS/fMRI probe data, the investigators contend that targeting delivery of TMS to the brain
surface non-invasively as indicated by sgACC resting functional connectivity may be
especially effective in downregulating sgACC and thereby producing superior clinical
outcomes.

Researchers have used TMS/fMRI to better understand causal communication among circuits
typically examined with resting fMRI alone. Recent work suggests that there are specific
sites that, when stimulated, influence subcortical brain areas implicated in affective
disorders such as the sgACC. Previously, TMS targets were based on brain atlases mapped onto
individual brain surfaces. This proposal will utilize more individualized targeting from
participants' own resting connectivity data to guide stimulation that we show is especially
effective in influencing downstream brain areas of interest. The investigators will focus on
a target region of the lateral prefrontal cortex (LPFC) that data suggest is particularly
effective at influencing the sgACC. As an alternative brain target, we will also test the
efficacy of the dorsolateral prefrontal cortex as a target given its precedence in the
literature as an effective stimulation site for remediating depressive symptoms. The target
will be chosen based on an atlas and will adjust the target coordinates based on the inverse
of a nonlinear normalization of each participant's brain to standard brain space. Thus,
individual anatomical differences will be taken account with this target though without
guidance from individual functional imaging data.

To increase generalizability to other disorders and to patients with comorbid anxiety and
depression (the typical clinical profile), the investigators will recruit patients who are
diagnosed PTSD and have symptoms of depression or those who experience trauma-induced MDD.
Participants will be scanned in an MRI to get anatomical and resting fMRI data to guide TMS,
then participants will be invited to participate in two rounds of two week TMS treatment to
each site (order counterbalanced) with one month between treatments. Participants will be
monitored to assess PTSD symptoms, depressive symptoms,and quality of life before, acutely
after, and one month following TMS treatments to evaluate the effectiveness of each site in
mitigating symptoms or improving functioning.

Inclusion Criteria:

1. 18-60 years old, male or female, any race

2. Patients must currently meet sufficient DSM criteria for PTSD and have symptoms of
depression; or meet criteria for trauma-induced MDD

3. Capacity to give informed consent and follow study procedures

4. English speaking

Exclusion Criteria:

1. Outside age range

2. Patient does not meet sufficient DSM criteria for PTSD or MDD

3. Psychiatric medication use

4. Significant handicaps (e.g. mental handicap) that would interfere with testing
procedures

5. MRI contraindications

6. Additional TMS contraindications

7. Medication use that substantially reduces seizure threshold to TMS (olanzapine,
chlorpromazine, lithium)

8. Opiate medication

9. Known neurological disorders including multiple sclerosis, encephalopathy, seizure
disorder, brain tumors

10. Current alcohol or substance abuse disorder (moderate or severe)

11. Current schizophrenia or other psychotic disorder, or current bipolar disorder

12. Refusal to abstain from illicit drug use for the duration of the study

13. Refusal to abstain from alcohol within 24 hours of the MRI scan

14. Pregnancy

15. Newly initiated psychotherapy (less than 6 weeks)