A Pilot fMRI Study of TMS in Late-Life Severe Worry
Phase: NA
Conditions: Anxiety Disorders Generalized
Sponsor: Carmen Andreescu

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Study Protocol  
 
 
 
 
Official Title: A Pilot fMRI Study of TMS in Late-Life Severe 
Worry 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT03577106 
 
 
 
Initial Protocol Date: 4/16/19 
Last Protocol Update: 12/2/22 
 
 
 
 

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Scientific 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. In our current research (R01 MH108509) we focus on describing the behavior of 
canonical neural networks during resting state and during worry induction in participants with low-to-
high worry. Our 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, we 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. 
 
Study Objectives 
 
In this pilot proposal we intend to test the engagement of therapeutic targets during TBS. Based on our 
preliminary results, the most accessible and relevant target is the parietal cortex – a region that in our 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, we propose to use inhibitory TBS [high frequency TMS at 1 Hz] to modulate cortical 
plasticity and consequently reduce worry severity. To test target engagement, we 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. 
 
 
Study Design & Methods 
 
This is an experimental, cross-sectional study. The estimated total enrollment for this study is 40 
participants. The primary endpoint of this study would be the participant reaching study completion. 
The secondary endpoints include the removal of a participant from the study for the following reasons: 
The investigators may remove someone from the study if we discover that s/he no longer meets study 

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eligibility (e.g., has a surgery involving a metallic implant), for non-compliance with the study protocol, 
or if the study is not believed to be in her/his best interest. 
 
Members of Dr. Andreescu's team will contact those who have participated in the parent protocol 
("FINA" STUDY19050150) and have consented for contact for future studies (via the FINA consent form). 
Recruitment will take place either over the phone or in-person. In-person, this could occur at any of the 
visits associated with STUDY19050150 once it is determined that the participant has a qualifying PSWQ 
score.  
 
A physician investigator who is also a co-investigator will review the consent form with the participant. 
This will occur either in person, via phone call, or via videoconference. The purpose of the research 
study, the procedures involved in the conduct of the study, potential risks and benefits, and the rights of 
study participants will be discussed with the potential subject prior to the attainment of written 
informed consent. Participants will be allowed as much time as they need to consider participation after 
the consent form is reviewed. They will be encouraged to voice any questions or concerns at that time, 
prior to signing the consent form. Participants will be able to ask the physician investigator clarifying 
questions either in person, or via phone call, prior to signing the consent form. Subjects will be provided 
with a clear explanation of the objectives, procedures, risks and benefits of the study and all questions 
will be answered. A Physician Investigator of the study will then obtain consent. All members of our 
research team who have contact with potential participants will receive training in the importance of 
not coercing or otherwise unfairly influencing individuals to participate in this study. Participants will 
also be informed that signing the consent form does not bind them to complete any part of the study- 
they can always change their mind. Participants will sign the consent form prior to beginning any 
screening procedures (excluding the phone screen), clinical assessments, sleep and activity monitoring, 
TMS, or MRI scan as these require completed written informed consent. 
 
Transcranial Magnetic Stimulation Protocol. Theta Burst Stimulation (TBS) will be targeted to the Inferior 
Parietal Cortex based on neural navigation software. TBS will be delivered for about 5-6 minutes, five 
days a week for two weeks, for a total of ten sessions. Accounting for set-up time and possible technical 
issues, participants will be informed that visits may last up to 45 minutes, but on average will take about 
20 minutes. 
 
The following measures will be administered both before and after the TMS intervention:  
1) Penn State Worry Questionnaire (PSWQ) 
2) Montgomery-Asberg Depression Rating Scale (MADRS)  
3) Hamilton Anxiety Rating Scale (HARS) Sleep and Physical Activity Monitoring 
 
As an optional component of the study, participants will be asked to complete a sleep diary and possibly 
wear an actigraphy monitor, depending on availability of the actiwatch, for at least 4 days prior to and 
throughout the TMS intervention. This is to determine their in-and-out of bed times, sleep onset, wake 
times, and how these may change during the TMS intervention. 
 
 The MRI scan will take place within 2 weeks of completion of the TMS sessions and will last 
approximately 1 hour. Scanning will be conducted on a 3 Tesla Siemens PRISMA scanner located in the 
MR Research Center at the University of Pittsburgh, using a 32-channel head coil (the same scanner and 
coil that is used for the current R01 study). We will gather functional MRI data (during rest and task) and 
structural MRI data including gray-matter volumetric estimates from T1-weighted images, white matter 

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hyperintensity volume (WMH) estimated from T2-FLAIR images and white matter microstructure 
integrity estimates from diffusion tensor imaging (DTI). 
 
Functional MRI: The fMRI acquisition includes a 10-minute resting state acquisition (eyes open) followed 
by the worry induction task. We have chosen to use a 10-min acquisition as recent data has showed that 
the reliability is improved by increasing the scan length from 5 to 10 minutes. T2*-weighted BOLD-
contrast functional image acquisition will use multiband (acceleration of 3) gradient-echo echoplanar 
imaging (EPI): TR/TE = 1800ms/30ms, Matrix= 96x96 with 60 slices, Voxel size = 2.5x2.5x2.5 mm3, 
parallel to AC-PC. The most inferior functional scan will be inferior to the most inferior aspect of the 
temporal lobes.  
 
Additionally, a follow-up call will be made 1 month following their last TMS session. The 1-month follow-
up call will include a general assessment of well-being and potential adverse reactions, along with over 
the phone administration of the HARS and MADRS. Research staff will send a copy of the Penn State 
Worry Questionnaire either via a link using Pitt RedCap or mail (including a postage-paid envelope) for 
the participant to complete and return. 
 
 
 
Eligibility Criteria  
 
Participants must have completed Dr. Andreescu's study R01MH108509/STUDY19050150 and have a 
Penn State Worry Questionnaire score of 55 or above. Participants must be 50 years or older. 
Participants must not meet any of the following exclusion criteria: 
1) Any form of psychosis or Bipolar Disorder, dementia, or a history of substance abuse within the last 
six months 
2) Use of antidepressants within the last five to fourteen days (adequate washout interval to be 
determined by the PI based on each specific antidepressant). For fluoxetine, the washout interval will be 
six weeks. However, for participants who are prescribed low dose psychotropics for pain, sleep 
disturbances, and/or medical conditions (e.g. amitriptyline for peripheral neuropathy, low dose 
trazodone as a sleep aid), these will be allowed in most circumstances. We will include participants on 
certain dosages of the most commonly prescribed antidepressants (for medical reasons) as follows: 
amitriptyline up to 50 mg/d, doxepin up to 50 mg/d, trazodone up to 100 mg/d, and imipramine up to 
50 mg/d. We will review other cases individually and the PI will decide if the participants are eligible for 
the study and if they may continue the current medication. 
3) Unable to complete MRI scans: presence of ferromagnetic metal in the body, claustrophobia 
4) Contraindications for TMS: 
a. 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) 
b. Recurrent seizures or epilepsy in participant 
c. Pregnancy 
d. 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). 

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5) 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. 
 
Statistical Considerations 
 
This is a pilot study aiming to explore neural signatures of treatment response. It is not statistically 
powered. Repeated measures ANOVA analysis for responders vs. non-responders using T2- T1 
differences in BOLD changes across MRI task conditions (rest/worry induction) in the region of interest 
(parietal cortex). Response = decrease of 30% in PSWQ. Repeated measures ANOVA, correlation, and 
regression will be used to test changes in sleep patterns and their association with anxiety and fMRI 
response. Analysis of Structural MRI We will collect measures of gray matter volume (MPRAGE), WMH 
load (T2- weighted FLAIR), and white matter micro-structural integrity (DTI). These methods include 
assessment of regional gray matter volume using Automatic Labeling Pathway (ALP), regional WMH 
volume, and tract-based spatial statistics (TBSS) estimates of fractional anisotropy (FA) for the WM 
tracts. Regional WMH volumes: The automated WMH segmentation method is an iterative algorithm 
that automatically selects ‘seeds’ of WMH lesions and applies fuzzy connectedness to segment WMH 
lesions around the seeds (8). Using an automated method, the segmented WMH voxels are localized to 
the different white matter tracts defined on the Johns Hopkins University (JHU) White Matter Atlas (9). 
The same atlas used for localizing the WMH volumes is also used for generating tract-specific DTI 
measures. The DTI data is first preprocessed using tract-based spatial statistics. DTI summary measures 
are then generated using a 4-tissue class model, which treats normal appearing white matter as distinct 
from WMH. The other 2 classes (gray matter and CSF) are included to ensure accurate segmentation, 
but are not part of the planned analyses for this study. The global WMH burden and FA will be included 
as primary variables in Aim 3. As described above, we will also extract regional DTI and WMH measures 
for all white matter tracts. Secondary analyses will explore the role of tract-specific white matter 
alterations in tracts associated with emotion regulation (e.g. uncinate fasciculus, cingulum bundle). 
Analysis of functional MRI Our primary analyses of the BOLD-contrast fMRI dataset will follow an ROI 
approach that has been optimized by our group for analyzing fMRI in the elderly. We will also perform 
full-brain voxelwise secondary analyses. All standard processing steps are done in SPM8 
[http://www.fil.ion.ucl.ac.uk /spm/ software/ spm8]. Additional custom software for alignment of 
elderly brain MRI’s will also be used.