A Pilot Functional Magnetic Resonance Imaging (fMRI) Study of TMS in Late-Life Severe Worry

Background:

Twenty percent of older adults in the community report severe worry. While worry is a
universal human experience, severe and excessive worry in older adults has been recently
linked to increased risk of stroke and other cardiovascular diseases, increased risk of
conversion to Alzheimer's disease as well as to higher risk of all-cause mortality. As worry
is a transdiagnostic construct, it is present in several mood and anxiety disorders,
including major depressive disorder and generalized anxiety disorder. Current treatment
choices in late-life (antidepressant/anxiolytic medications and psychotherapeutic
interventions) have been proven moderately efficacious in reducing anxiety/depression burden,
but ineffective in reducing worry severity, a phenomenon that may contribute to the high
relapse rates associated with mood and anxiety disorders in the geriatric population. These
elements support the need for novel, experimental interventions specifically designed to
target the neural basis of severe worry in late-life. Through a pre-existing study (R01
MH108509), investigators focus on describing the behavior of canonical neural networks during
resting state and during worry induction in participants with low-to-high worry. The research
indicates that simple induction of worry activates a distinct set of regions
(caudate/thalamus, visual cortex, dorsal anterior cingulate). Given the universality and
potential evolutionary benefits of worry, investigators believe that the neural network
associated with worry induction supports a normal, physiologic experience. However, the
regions involved in maintaining worry (hippocampus, thalamus) as well as those associated
with severe worry (orbitofrontal cortex, superior parietal gyrus, amygdala, parahippocampal
gyrus) support a pathological phenomenon and may represent ideal targets for interventions.

This pilot study will test the engagement of therapeutic targets during TBS. Based on the
investigators' preliminary results, the most accessible and relevant target is the parietal
cortex - a region that in the investigators K 23 sample remained significantly associated
with severe worry after controlling for effects of comorbid depression or overall anxiety. As
parietal cortex cerebrovascular flow increased in association with worry severity, the
investigators will use inhibitory TBS [high frequency TMS at 1 Hz] to modulate cortical
plasticity and consequently reduce worry severity. To test target engagement, the research
team will use the in-scanner worry induction paradigm designed by Dr. Andreescu and her
mentors during her K23 award and currently use to probe worry induction in the R01 MH108509.
Given the exploratory nature of this proposal and based on our preliminary data, we will use
two measures of target engagement: 1) the relative decrease in BOLD signal in the parietal
cortex and 2) the relative decrease in rSPG-dACC functional connectivity.

Significance:

1. Severe worry in late-life carries a significant health care risk. Worry is defined as a
complex affective and cognitive process, negative-affect laden, and relatively
uncontrollable [6]. While worry is a universal human experience that may confer an
evolutionary advantage by modifying threat-related decision-making, severe and excessive
worry has been recently linked to increased risk of conversion from mild cognitive
impairment to Alzheimer's disease [7], and with increased risk of stroke and other
cardiovascular events, after controlling for depression and vascular risk factors.
Severe worry is also associated with interruption in functioning and reduced quality of
life and with a higher risk of all-cause mortality in midlife and late-life.

2. Severe worry in late-life responds poorly to traditional interventions. Traditionally,
severe worry has been confined to categories such as Generalized Anxiety Disorder (GAD)
and Major Depressive Disorder (MDD), multiple lines of research support the presence of
severe worry in other several other anxiety and mood disorders. Thus, while GAD is built
around the concept of severe, uncontrollable worry, only 20% of severe older worriers
qualify for a GAD diagnosis. This evidence supports a major recent shift in the
conceptualization of worry as a transdiagnostic entity most suitable for dimensional
investigations. Current late-life GAD treatment choices, including cognitive-behavioral
therapy (CBT) and antidepressant pharmacotherapy, have proven moderately efficacious in
reducing overall burden of anxiety but ineffective in reducing worry severity. The
ineffectiveness of current treatments in reducing worry severity may be at the root of
the chronic, relapsing course of late-life GAD, which is one of the least likely mental
disorders to remit and most likely to relapse.

3. Novel circuit-based targets for intervention. Several neuroimaging studies have
investigated both activation and functional connectivity among various brain regions
involved in GAD - in adolescents and young adults. This research team has published
exclusively on the neural markers of GAD in older adult participants. Also, very few
studies used fMRI paradigms specifically tailored to induce worry or analyzed
specifically the effect of worry severity at rest or during task. The investigators'
current results point toward two different networks that may benefit from targeted
interventions: the one associated exclusively with severe worry
(amygdala-parahippocampus- rOFC- rSPG) and the one associated with maintenance/the
protracted quality of worry (insula-caudate/thalamus-amygdala-parahippocampus).

The investigators decided to target the network associated with worry severity due to both
the richer literature regarding the pernicious effect of severe worry on both public health
and treatment response but also due to accessibility for TMS of the rSPG. Overall, the worry
severity network seems to implicate excessive limbic/paralimbic activation potentially
amplified by the cognitive anticipation of the negative affective value of future events
processed through the OFC as well as probable attempts to cognitively control the arousal and
dysphoria through structures such as dACC and SPG. This speculation is in line with newer
interpretations of pathologic worry that suggest severe worriers both maintain arousal in
order to seek out potential solutions to the anxiogenic source while attempting to inhibit
representations of the potential bad outcomes.

Inclusion Criteria:

- Participants must have completed Dr. Andreescu's study R01MH108509/PRO15080120.

- Penn State Worry Questionnaire score of 55 or above.

Exclusion Criteria:

- Any form of psychosis or Bipolar Disorder, dementia, a history of substance abuse
within the last six months, or subjects treated with psychotropic medications
(Selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake
inhibitors (SNRIs), and similar; benzodiazepines okay) within the past two weeks (six
weeks for fluoxetine).

- Unable to complete MRI scans: presence of ferromagnetic metal in the body,
claustrophobia

- Contraindications for TMS:

1. Presence of a neurologic disorder or medical condition known to alter seizure
threshold(e.g., stroke, aneurysm, brain surgery, structural brain lesion, brain
injury, frequent/severe headaches)

2. Recurrent seizures or epilepsy in participant

3. Pregnancy

4. Metallic implants in body located at 30 cm or less from the position of the
magnetic coil; presence in the body of other devices that may be affected by
magnetic field (e.g. pacemakers).

- Unable to temporarily discontinue benzodiazepines 48 hours prior to MRI scan.
Participants on high doses of benzodiazepines (e.g., greater than or equivalent to 2
mg of lorazepam) will be excluded, given the complexity and potential complications of
benzodiazepine taper/withdrawal.