Ignite Creation Date:
2024-05-06 @ 4:00 PM
Last Modification Date:
2024-10-26 @ 2:01 PM
Study NCT ID:
NCT04832685
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-01-23
First Post:
2021-03-30
Brief Title:
Neuromodulation of Mind-Wandering in Depression
Sponsor:
Massachusetts General Hospital
Organization:
Massachusetts General Hospital
Study Overview
Official Title:
Neuromodulation of Mind-Wandering in Depression
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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 ie mind-wandering and thinking about oneself in the past future and in relation to others Given the DMNs 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 andor 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 ie task-irrelevant thought when individuals are supposed to be focused on a task and rumination ie 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-RV10 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 eg 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 hisher 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 ie 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 35 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 05 ms Duty Cycle 5 ISPPA 144 mWcm2 720 mWcm2 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 individuals 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 mindfulnessmind-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 005 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
MDD is a mood disorder in which people experience a persistent negative mood or loss of interest or pleasure thoughts of worthlessness and guilt andor 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 ie task-irrelevant thought when individuals are supposed to be focused on a task and rumination ie 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-RV10 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 eg 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 hisher 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 ie 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 35 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 05 ms Duty Cycle 5 ISPPA 144 mWcm2 720 mWcm2 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 individuals 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 mindfulnessmind-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 005 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None