Neuromodulation of Mind-Wandering in Depression
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed 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 = 10 healthy controls, n = 10 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 three study visits on three 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 mood 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.
Visits 2 and 3 (up to 3.5 hours each; spaced 1 week apart) Questionnaires At Visits 2 and 3, participants will complete questionnaires assessing depressive symptoms (Beck Depression Inventory), anxiety (The State-Trait Anxiety Inventory), mindfulness (Five Facet Mindfulness Questionnaire), and rumination (Ruminative Responses Scale of the Response Styles Questionnaire). 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.
Computer Task After completing questionnaires, participants will practice the cognitive-affective task they will be performing in the MRI scanner before and after LIFUP. Participants will complete a modified version of the Multi-Source Interference Task (MSIT) overlaid on negative, neutral, and positive images from the International Affective Picture System (IAPS). Subjects must identify the number in a three digit number that is different. For example, if the participant sees "010" the correct answer would be "1" since it is the different number. This MSIT-IAPS task has been used to assess cognitive-affective deficits in bipolar disorder.
During this task, participants will also be randomly interrupted. Instead of seeing a digit on the screen, participants will be asked if they were thinking about the task or something else. Participants respond by pressing one key if they were having Task-related thoughts (Task) and another key for task unrelated (Not Task) thoughts. Participants then see other screens asking if they were thinking about themselves, the past, present, or future, and if they were having positive, neutral, or negative thoughts. After answering these questions, participants resume seeing digits on the screen. The investigators have used these random thought probes during the MSIT in a previous tDCS study.
MRI Scan 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, 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 MSIT-IAPS task (described above) will be collected. Participants will then exit the MRI scanner and will be asked to retrospectively report on their mind-wandering thoughts during the MSIT-IAPS task, using the Thought Sampling Questionnaire.
LIFUP Sonication Participants will next 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 positioned using their structural MRI scan to localize the PCC. Participants will then receive either DOWN-modulation (Pulse Repetition Frequency = 10 Hz, Pulse-Width = 0.5 ms, Duty Cycle = 5%, ISPPA = 14.4 mW/cm2, 720 mW/cm2) or UP-modulation (Pulse Repetition Frequency = 100 Hz, Pulse-Width = 0.5 ms, Duty Cycle = 5%, ISPPA = 14.4 mW/cm2, ISPTA = 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. The investigators are using the same LIFUP parameters in other IRB-approved LIFUP studies and these parameters have been safely used at other research collaborator sites at UCLA and MUSC.
After receiving LIFUP, participants will then be scanned again using the same MRI protocol as described above.
Biostatistical Analysis fMRI data during the MSIT-IAPS 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. First-level contrast images will be created comparing BOLD activation during the MSIT-IAPS task before and after LIFUP. These contrast images will then be entered into a 2nd level random effects flexible factorial model. The investigators will investigate whether there is a group (MDD versus healthy control) by condition (UP vs. DOWN modulation) interaction on BOLD activation in DMN regions. Beta signal values will be extracted from DMN regions and the investigators will investigate if there are significant correlations between DMN activation and 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 UP vs. DOWN modulation.
Previous studies have demonstrated that 20 participants are sufficient to achieve statistical significance (p < 0.05) in a voxel-based analysis.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: UP and DOWN-Modulation All participants will receive UP- and DOWN-modulation of the posterior cingulate cortex (PCC). |
Device: UP- and DOWN-Modulation
All participants in both groups will receive UP- and DOWN-modulation of the PCC.
|
Outcome Measures
Primary Outcome Measures
- Mind-wandering frequency during task [3 hours]
Changes in reported frequency of negative mind-wandering thoughts during the MSIT-IAPS task before and after UP- and DOWN-modulation
- Default mode network activation during task [3 hours]
Changes in Blood-Oxygen-Level Dependent activation in the default mode network during the MSIT-IAPS task before and after UP- and DOWN-modulation
Secondary Outcome Measures
- Depressive symptoms [1 week]
Depressive symptoms as measured by the Beck Depression Inventory in the week after the UP- and DOWN-modulation sessions
- Default mode network connectivity [3 hours]
Changes in default mode network resting state functional connectivity before and after UP- and DOWN-modulation
Eligibility Criteria
Criteria
Inclusion Criteria:
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Male or female
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Age 18-64
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Right-handed
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Normal or corrected-to normal vision and hearing
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For group with depression, current diagnosis of depression
Exclusion Criteria:
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Active significant medical illness or neurological disorder
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MRI scan contraindications (e.g., metal implant, claustrophobia, weigh over 250 pounds, etc.)
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For healthy control group, any current or past history of mood disorders
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
Sponsors and Collaborators
- Massachusetts General Hospital
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2021P000704