Executive function deficits are common in late life depression (LLD) and are associated with resistance to antidepressants, poor quality of life, considerable disability and increased suicidal risk. This study uses a novel type of Transcranial Magnetic Stimulation called intermittent Theta Burst Stimulation (iTBS). iTBS delivers high frequency (50Hz) magnetic pulses in "bursts" of 3 stimuli. It is posited that this intervention induces plasticity in the human cortex. Theoretical and empirical evidence from research studies informs that iTBS can improve depression and executive deficits, however, this has not been examined in older adults.

This project examines iTBS's ability to improve depression and executive impairment in LLD. It also tests the effects of iTBS on brain connectivity within the Cognitive Control Network (CCN). This study will enhance understanding of LLD, providing critical pilot data to develop future randomized controlled clinical trials.

Both active and sham interventions are administered sequentially to the left and right dorso-lateral prefrontal cortex. The total stimulation time is about 7 minutes. These interventions are administered for 6 weeks (Monday-Friday). 20 subjects will be randomized. Changes in mood from baseline to the end of study are measured with the Montgomery-Asberg Depression Rating Scale. Executive function at baseline and end of study are evaluated with the National Institutes of Health Toolbox executive domain battery. Safety assessments include: the 21 item Scale for suicidal ideation SSI. The frequency, intensity and burden of side effects rating (FIBSER) and the Altman Self Rating Mania scale (ASRM). Ancillary depression measures include the Quick Inventory of Depressive Symptoms (QIDS) and the Clinical Global Impression of Improvement scale.

Subjects undergo functional Magnetic Resonance Imaging (fMRI) before and after the study interventions to test the effects of iTBS on the brain's functional connectivity.

This research will provide meaningful information about the effects of iTBS on mood and executive function in older adults as well as information regarding its effects on brain function. Results of this pilot study will inform a grant submission and allow investigators to calculate power for a definitive randomized controlled clinical trial to test the efficacy of iTBS versus placebo.

Inclusion Criteria:

1. Age ≥ 60 - 85 years old
2. Diagnosis of major depressive disorder (MDD), single or recurrent, with a current Major depression episode as diagnosed by the Mini-international Neuropsychiatric Interview (MINI 6.0)
3. Montgomery Asberg Depression Scale score greater than or equal to 15 at baseline.
4. Evidence of decreased executive function as evidenced by either of the following conditions: a) scoring below the mean normative scaled score on the average of the NIH Toolbox executive function measures: Flanker inhibitory control and attention test and the Dimensional sort card test, approximate score 70 - 100 as per PI discretion. b) Discrepancy of at least 10 points between the average of the picture vocabulary score and the reading recognition test score and the average of the Flanker inhibitory control and dimensional card sort test score. c) Frontal Systems Behavior Scale (FRSBE) T scores above 60 (indicative of borderline to clinically significant impairment) and at least 10 points (1 Standard Deviation) above subject's premorbid (pre-depression) scores.

Exclusion Criteria:

1. Inability to complete NIH tool box cognitive testing
2. Inability to provide informed consent
3. <22 score on the Montreal Cognitive Assessment MoCA indicative of moderate to severe cognitive impairment per PI discretion
4. Lifetime diagnosis of bipolar I or II disorder or psychotic disorder as per the MINI interview
5. current psychotic symptoms
6. alcohol or other substance use disorder per DSM V criteria in the past 6 months
7. High risk for suicide (active suicidal ideation/intent or plan and patient is unsafe to be in the outpatient setting), an urgent psychiatric referral will be made in those cases
8. Have a diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), assessed by a study investigator to be primary
9. Previous history of TMS
10. history of failure to an adequate course of electroconvulsive therapy (ECT) such as equal or more than 7-9 electroconvulsive therapy treatments, per PI discretion
11. Major unstable medical illness including advanced/uncontrolled diabetes, hypertension, renal disease or advanced cancer, per PI discretion
12. Psychotropic use other than antidepressants (e.g., Benzodiazepines [more than 2mg of lorazepam equivalent daily], anticonvulsants [except low dose of Neurontin approximately 600mg/day] or cognitive enhancers such as N-Methyl D - Aspartate (NDMA) receptor antagonists [Memantine HCL], psychostimulants [such as methylphenidate or modafinil]) per PI discretion
13. Recent changes or initiation of antidepressant therapy approximately in the last 4 weeks prior to intervention delivery, per PI discretion
14. if participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study
15. contraindications for TMS including the presence of metallic objects within 30 cm of the TMS coil, intracranial implants (e.g., aneurysm 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; presence of intracardiac lines, defibrillators or a cardiac pacemaker and unable to assess safety; presence of implanted electronic devices that control physiologic functions and unable to assess safety
16. have a personal history of a primary seizure disorder or a seizure associated with an intracranial lesion
17. History of severe head trauma or neurological disorders that substantially increase seizure risk, per PI discretion
18. non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).

Individual participant data may be available upon request to be shared with other researchers interested in geriatric depression and resting state functional connectivity analysis.

Upon publication pf study results

to request information e-mail PI: Pilar Cristancho at cristanchopimiento.l@wustl.edu

Each participant was assessed for adverse events from baseline (pre-intervention) to the end of of six weeks of the intervention.