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

• 18-60 years old, male or female, any race
• Patients must currently meet sufficient DSM criteria for PTSD and have symptoms of depression; or meet criteria for trauma-induced MDD
• Capacity to give informed consent and follow study procedures
• English speaking

Exclusion criteria

• Outside age range
• Patient does not meet sufficient DSM criteria for PTSD or MDD
• Psychiatric medication use
• Significant handicaps (e.g. mental handicap) that would interfere with testing procedures
• MRI contraindications
• Additional TMS contraindications
• Medication use that substantially reduces seizure threshold to TMS (olanzapine, chlorpromazine, lithium)
• Opiate medication
• Known neurological disorders including multiple sclerosis, encephalopathy, seizure disorder, brain tumors
• Current alcohol or substance abuse disorder (moderate or severe)
• Current schizophrenia or other psychotic disorder, or current bipolar disorder
• Refusal to abstain from illicit drug use for the duration of the study
• Refusal to abstain from alcohol within 24 hours of the MRI scan
• Pregnancy
• Newly initiated psychotherapy (less than 6 weeks)