Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04832685 |
| Other study ID # |
2021P000704 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 20, 2023 |
| Est. completion date |
April 2025 |
Study information
| Verified date |
January 2024 |
| Source |
Massachusetts General Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The specific aim of this proposed study is to investigate the feasibility and therapeutic
potential of LIFUP in changing negative cognition in depression. Specifically, the
investigators will study if modulating DMN activity can change maladaptive mind-wandering.
The investigators hypothesize that DOWN-modulation of the posterior cingulate cortex (PCC), a
key DMN node, will decrease DMN resting state functional connectivity, perfusion, and
activation during a cognitive-affective task (description below). The investigators also
hypothesize that DOWN-modulation of the PCC will be associated with decreased mind-wandering
and increased mindfulness. Finally, the investigators hypothesize that the opposite will be
true for UP-modulation of the PCC.
Description:
The default mode network (DMN) is a network of structurally and functionally connected brain
regions that was first identified during "passive" states. Since its initial discovery, the
conceptualization of the DMN has evolved over time; the DMN has now been linked with a range
of higher-order cognitive processes such as spontaneous, self-generated thoughts (i.e.
mind-wandering) and thinking about oneself in the past, future, and in relation to others.
Given the DMN's involvement in cognition, researchers have investigated its role in
psychiatric disorders associated with cognitive issues, such as Major Depressive Disorder
(MDD).
MDD is a mood disorder in which people experience a persistent negative mood or loss of
interest or pleasure, thoughts of worthlessness and guilt, and/or suicidal ideation. The
majority of literature suggests that currently depressed individuals have increased DMN
resting-state functional connectivity at rest and greater DMN activation when processing
negative stimuli. Researchers have suggested that this DMN hyperactivity reflects the
tendency for depressed individuals to engage in negative cognition, such as maladaptive
mind-wandering (i.e. task-irrelevant thought when individuals are supposed to be focused on a
task) and rumination (i.e. negative, repetitive, self-focused thinking). Mind-wandering, in
general, has been linked to unhappiness. Rumination is associated with the maintenance of a
current depressive episode and is a predictor of future depressive episodes. Therefore,
changing these forms of negative cognition, via modulation of DMN activity, could be of
benefit to individuals with MDD.
One way of modulating DMN activity is to use brain stimulation. The investigators have
previously used transcranial Direct Current Stimulation (tDCS) of a DMN brain region to
effect a small yet significant reduction in mind-wandering behavior in a community sample.
However, tDCS has low spatial specificity and neuroimaging was not used to determine if tDCS
was actually changing mind-wandering via changes in DMN activity. Low Intensity Focused
Ultrasound Pulsation (LIFUP) is a novel non-invasive brain stimulation method which has high
spatial specificity, unlike other non-invasive brain stimulation methods such as Transcranial
Magnetic Stimulation (TMS) and tDCS. Specifically, LIFUP can deliver acoustic energy to a
brain region of a few millimeters in diameter. This method has been applied to the thalamus
to restore consciousness to patients in minimally conscious states, and the investigators
have been using this method in multiple IRB-approved studies as applied to the amygdala,
ventral striatum, and entorhinal cortex.
Specific Aims:
The specific aim of this proposed study is to investigate the feasibility and therapeutic
potential of LIFUP in changing negative cognition in depression. Specifically, the
investigators will study if modulating DMN activity can change maladaptive mind-wandering.
The investigators hypothesize that DOWN-modulation of the posterior cingulate cortex (PCC), a
key DMN node, will decrease DMN resting state functional connectivity, perfusion, and
activation during a cognitive-affective task (description below). The investigators also
hypothesize that DOWN-modulation of the PCC will be associated with decreased mind-wandering
and increased mindfulness. Finally, the investigators hypothesize that the opposite will be
true for UP-modulation of the PCC.
Subject Selection:
Twenty participants (n = 40 healthy controls, n = 40 individuals with MDD) aged 18-64 years
old will be recruited. The Structured Clinical Interview for DSM-5 Disorders, Research
Version (SCID-5-RV)10 will be used to determine eligibility.
Subject Enrollment:
Participants will be recruited through email announcements at MGH, postings to college
websites, and flyers (see attached flyer) posted at MGH and in the community (e.g., community
centers, public libraries, coffee shops, restaurants, and laundromats). A phone screening
will be performed to efficiently confirm likelihood that subjects will meet inclusion and
exclusion criteria prior to committing time for further evaluation of eligibility.
Informed consent will be obtained prior to the performance of any protocol procedures. The
informed consent document will be used to explain in simple terms the risks and benefits of
study participation to the subject. The nature of the study will be fully explained to the
subject by the PI, co-investigators or specially-trained study staff. The subject will be
encouraged to ask questions pertaining to their participation in the study and the subject
may take as much time as they feel necessary to consider his/her participation in the study
as well as consult with family members or their physicians. Participation in this study is
voluntary and the subjects may withdraw from the study at any time. The IRB-approved informed
consent documents will be signed and dated by the subject and the person obtaining consent.
Study Procedures:
After providing study information and obtaining IRB approved informed consent, participants
will complete up to five study visits on five different days.
Visit 1 (up to 1 hour):
For participants who are recruited as healthy controls, the SCID-5-RV will be administered to
determine if the participant has no current or past history of any psychiatric disorders. For
participants who are recruited as individuals with MDD, the SCID-5-RV will be administered to
determine if the participant meets criteria for a current MDD diagnosis. Participants will be
excluded from further study procedures if they do not meet the above-described criteria.
Visit 2 (up to 1 hour):
Participants will complete questionnaires assessing depressive symptoms, anxiety,
mindfulness, and rumination.
After completing questionnaires, participants will practice the cognitive task they will be
performing in the MRI scanner. Participants will complete a self-attribution task (Ghaznavi,
Chou, Dougherty, & Nierenberg, 2023). Participants will see a series of trait adjectives and
be asked to make a judgment about whether that personality trait applies to them (i.e. press
a button indicating "Me" or "Not Me"). This task has been used by our lab to assess cognition
and DMN activation in bipolar disorder.
After completing the practice computer task, participants will complete the MR Screening
Safety form. After confirming the participant does not have MRI contraindications, they will
be scanned using a 3 Tesla Siemens MRI scanner at the Athinoula A. Martinos Center for
Biomedical Imaging. At baseline, we will collect a T1 MEMPRAGE structural scan,
blood-oxygen-level-dependent (BOLD) resting state scan, Arterial Spin Labelled (ASL) scan,
and a BOLD functional MRI scan paired with the task (described above). Participants will then
exit the MRI scanner and will be asked to retrospectively report on their mind-wandering
thoughts during the task. Participants will not receive LIFUP during this visit.
Visits 3 and 4 (up to 3.5 hours each; spaced 1 week apart):
At Visits 3 and 4, participants will complete the same questionnaires (described in Visit 2).
To assess the subjective experience of LIFUP and its effects on mood, participants will rate
their negative and positive mood on Visual Analog Scales as well as complete the 11-factor
Altered States of Consciousness questionnaire (ASC) after LIFUP.
Participants will be scanned again with the same MRI sequences and complete the same computer
task described in Visit 2, pre and post LIFUP.
LIFUP Sonication:
Participants will be fitted with the LIFUP device, the BX Pulsar 1002 (BrainSonix
Corporation). The transducer will be placed on the head using landmarks and will be targeting
the cluster in the PCC that was activated during the computer task in Visit 2. Participants
will then receive either active or sham DOWN-modulation (Pulse Repetition Frequency = 10 Hz,
Pulse-Width = 0.5 ms, Duty Cycle = 5%, ISPPA = 14.4 mW/cm2, 720 mW/cm2). The order will be
counterbalanced across subjects. The sonications will be delivered in a 30-seconds on,
30-seconds off block design, for a total duration of 10 minutes. We are using the same LIFUP
parameters in other IRB-approved LIFUP studies (IRB protocol #2019P000562 and IRB protocol
#2019P001458) and these parameters have been safely used at other research collaborator sites
at UCLA and MUSC. For sham sonication, a gel pad that absorbs ultrasound will be used with
the transducer so that the ultrasound will not go through the skull and into the brain. For
active sonication, a gel pad that allows the transmission of ultrasound waves will be used
with the transducer. These gel pads look identical; this study will be double-blinded where
study staff will not know which gel pad corresponded with active or sham LIFUP.
Visit 5 (up to 1 hour; spaced 1 week after Visit 4):
During this visit, participants will complete the same questionnaires (described in Visit 2).
Biostatistical Analysis:
fMRI data during the task will be analyzed using SPM12 software (Wellcome Department of
Cognitive Neurology, London, UK). Individual subject-level data will be slice-time corrected,
realigned and unwarped, coregistered to the individual's structural images, normalized, and
smoothed. For LIFUP targeting, first-level contrast images will be created to identify BOLD
activation in the PCC during self-judgments. To study the effects of LIFUP, first-level
contrast images will be created comparing BOLD activation during the task before and after
LIFUP. These contrast images will then be entered into a 2nd level random effects flexible
factorial model. We will investigate whether there is a group (MDD versus healthy control) by
condition (sham vs. active modulation) interaction on BOLD activation in DMN regions. Beta
signal values will be extracted from DMN regions and we will investigate if there are
significant correlations between DMN activation and our behavioral measures of depressive
symptoms, anxiety, and mindfulness/mind-wandering.
BOLD resting state scan data will be similarly preprocessed and entered into CONN toolbox.
The PCC will be used as a seed region and Fischer-transformed functional connectivity beta
values with other DMN regions will be extracted for each individual subject.
Repeated-measures ANOVAs will be conducted to again investigate whether there is a group by
condition interaction on DMN resting state functional connectivity. Correlational analyses
will also be performed to explore correlations with behavioral measures.
ASL data will be analyzed using Bayesian Inference for Arterial Spin Labeling MRI. Perfusion
maps corresponding to pre and post LIFUP will be subtracted from each other to determine if
there is decreased or increased perfusion in DMN regions associated with active modulation.
An updated statistical power analysis from our recent LIFUP study of the amygdala suggests
that 40 participants will be necessary to achieve statistical significance (p < 0.05) in a
voxel-based analysis. To increase our statistical power for comparing two groups, we will
recruit 40 participants in each group (total n = 80).
