Improving Brain Stimulation Through Imaging

Potential participants are first identified and contact is made. Potential participants are
then screened for inclusionary and exclusionary information (see tab 9. Eligibility) that
relate to whether they can safely and comfortably perform the procedures and whether they are
considered healthy or have the disorder for which brain stimulation therapy will be
delivered. They will undergo informed consent that will disclose all the different risks and
benefits for the procedures they will undergo. The list of procedures in which participants
consent to participate is below.

PROCEDURES:

The three procedures conducted at VA Palo Alto are as follows:

1. Psychological / functional assessments:

Interview, computerized, and paper and pencil measures of psychological functioning.
These measures are used to characterize patients' diagnosis and psychological status.
For example, depressed patients will answer questions about depressive symptoms and
potentially comorbid symptoms such as post-traumatic stress disorder. This testing
typically lasts 2 hours.

2. MRI and functional MRI Patients will undergo an MRI that indicates where they receive
stimulation by a marker placed on a cap that displays brightly on an MRI. At Lucas
center or the Palo Alto VA and involves brain imaging that will be related to brain
stimulation techniques either through facilitating image guidance or providing
information that will be correlated to data collected during stimulation. Typically, a
session lasts about 2.5 hours since there is setup time involved.

3. Brain Stimulation:

TMS-transcranial magnetic stimulation which will be collected at the Palo Alto VA. Part of
this procedure may include electromyography (EMG) which involves placing electrodes on the
skin, typically the hand, and measuring indicators of muscle contraction. Sometimes this
information is used to decide stimulation intensity during TMS and sometimes the TMS induced
response will be a source of data in itself. Typically, this is only a measure conducted in
parallel with other procedures and thus will not be given its own consent. MRI Guided TMS. An
MRI will be used to target a selective brain region. To accomplish this, the MRI will be
displayed on a computer screen and an infrared camera enables identification of the
correspondence between the image and the participant's head. To study errors in scalp-based
targeting, the investigators will perform scalp targeting while under MRI guidance but
without the typical visual feedback provided by the MRI. Then this will be compared to scalp
targeting with MRI guidance. The difference will identify typical errors in scalp targeting.
Typically, a session will last approximately 1.5 hours.

Inclusion Criteria:

Capacity and willingness to participant in TMS, and fMRI as well as satisfying criteria for
diagnosis.

1. Between 18 and 80 years of age.

2. Ability to obtain a Motor Threshold (MT) with single pulse TMS.

3. Ability to safely and comfortably undergo an MRI and TMS.

4. Able to read, verbalize, understand and voluntarily sign the Informed Consent Form
prior to participating in any study-specific procedures or assessments.

5. Depression (PHQ-9 >= 10 and functional impairment present indicated with "difficulty"
question).

6. Confirmed diagnosis of Major Depressive Disorder (MDD).

7. Can maintain all existing treatments (e.g. psychopharmacology, psychotherapy, etc.,)
throughout course of the three sessions (psychological / functional assessments, MRI,
and TMS), with modifications only as needed for clinical management.

8. Is a Veteran.

Exclusion Criteria:

- Participants who can not safely and comfortably undergo MRI OR TMS

- If they are left handed or their language is not primarily English they may be
excluded depending on how dependent the imaging and cognitive tasks are on language

- Additionally, participants may be excluded if English is not their primary
language and they therefore do not fully understand the consenting process

- Inability to safely and comfortably undergo an MRI and TMS

- An example of safety screen details for an MRI is detailed in the Stanford
University MRI screening form

- MRI exclusions include having any non-removable device or implant that makes scanning
unsafe, claustrophobia, and size (e.g. weight, girth) beyond the constraints of the
MRI and scanner bed

- For TMS the investigators will follow safety guidelines set by Rossi et. al.,2009

- Specifically, the investigators will not include subjects whose Motor Threshold
(MT) is greater than 84% of maximum device output because mathematically they
would not be able to be safely stimulated using the standard 120% of MT (i.e. the
device cannot stimulate more than 100% of its potential output)

- The investigators will report these high MT data in our secondary analyses.
Additional TMS exclusions include any history or condition that puts patients at
risk for a seizure

- Pregnant or lactating female or planning to become pregnant within the next 3 months

- Lifetime history of moderate or severe traumatic brain injury, current unstable
medical conditions, current (or past if appropriate) significant neurological
disorder, or lifetime history of:

- seizure disorder

- primary or secondary CNS tumors

- stroke

- cerebral aneurysm

- Significant cognitive impairment (Montreal Cognitive Assessment [MoCA] < 26)

- Comorbidities (e.g. PTSD) determined not to be the primary diagnosis

- Have a lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective
disorder, schizophreniform, delusional disorder, or current psychotic symptoms

- Have a diagnosis of obsessive-compulsive disorder, anxiety disorder (generalized
anxiety disorder, social anxiety disorder, panic disorder), or dysthymia assessed by a
study investigator to be primary and causing greater impairment than MDD

- Have active suicidal intent or plan in which case Dr. Rosen will determine whether the
patient needs to be referred for hospitalization

- Presence of any other condition or circumstance that, in opinion of the investigator
team, has the potential to prevent study completion and/or to have a confounding
effect on outcome assessments