Clinical trial NCT06320028: Altering Default Mode Network Activity With Transcranial Focused Ultrasound to Reduce Depressive Symptoms
Official title: Altering Default Mode Network Activity to Reduce Depressive Symptoms
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Depressive Disorder, Major
Depression
Keywords: Non-invasive Transcranial Focused Ultrasound Stimulation
Depression
Mood disorders
Lead sponsor: University of Arizona
Sponsor class: OTHER
Collaborators: name: Openwater
First posted: 2024-03-20
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All participants will receive the same treatment protocol.
Primary purpose: TREATMENT

Brief summary: Depression is a leading cause of disability worldwide, affecting roughly 21 million adults. Repetitive Negative Thought (RNT) has been identified as a potential maintaining factor in depression, such that those who exhibit higher degrees of RNT endorse greater symptoms. Research also suggests that the Default Mode Network (DMN), responsible for self-referential processing, plays an important role in depression wherein it has been linked to RNT. In depressed individuals, this network appears to be hyper-connected, or "too connected", within itself which, in turn, is thought to promote RNT.

Half of depressed individuals are treatment-resistant, creating a critical need to identify more effective interventions derived from a better mechanistic understanding of the development and maintenance of depression. Non-invasive Transcranial-Focused Ultrasound Stimulation (tFUS) is promising for the treatment of depression. tFUS directs a low-intensity (nonthermal) focused ultrasound beam that passes safely through the skull. Compared to other noninvasive neuromodulation approaches, tFUS can target deeper brain regions with high spatial precision.

The present study is an exploratory non-blinded single treatment study to investigate whether tFUS targeting a major hub of the DMN, the anterior-medial prefrontal cortex, can improve depression symptoms and reduce RNT. Twenty depressed individuals with high RNT (75th percentile) will complete up to eleven ultrasound sessions targeting the anterior medial prefrontal cortex, a hub of the brain's default mode network that has been found to be hyper-connected in depression. MRI scans will be obtained before the first and after the last ultrasound sessions. Based on previous literature, it is predicted that depression interview ratings and self-report symptoms will decrease after the intervention, and also that DMN connectivity will decrease following intervention.

Detailed description: Participants will first complete the online screening to identify those who may meet criteria of major depressive disorder and have high RNT. Those meeting these criteria will be contacted for a formal diagnostic interview, consisting of the consent process and a structured clinical interview using the DSM-5. Once deemed eligible, participants will complete baseline interviews, self-report surveys, and an MRI session. Then, they will complete up to three weeks of ultrasound treatment, wherein the first week consists of five ultrasound sessions. Upon completion of week one, participants will complete the same interview, self-report surveys, and MRI session. Participants' symptom improvement will be determined by whether they meet remission criteria, defined as a Beck Depression Inventory Score - II (BDI-II) of \<13 and a Hamilton Depression Rating Scale (HDRS) score of \<8. If remission criteria are not met, participants will continue ultrasound sessions for two more weeks, three sessions per week. Following completion, participants will complete a final interview, self-report surveys, and MRI session. In each treatment session, the ultrasound device will be placed on the participants' forehead with the aid of the customized headset co-localized to the participant's structural MR image. Each ultrasound treatment lasts ten minutes.

Eligibility criteria: Inclusion Criteria:

* Participants must be between the ages of 18-50
* Participants must have normal or corrected vision (glasses, contacts, etc)
* Must be proficient in English in order to read the consent form (Spanish speakers are included, as long as they are also proficient in English)
* Must be right-handed
* Upper 25% of distribution on perseverative thinking scores based on local norms (score ≥ 37)
* Participants meeting DSM-5 criteria for current major depressive episode

Participants may be excluded from the MRI portion of the experiment if they are pregnant or are unsure if they may be pregnant or have any contraindications for MRI, including severe claustrophobia, non-MRI compatible cardiac pacemakers; implantable defibrillators; aneurysm clips; neural stimulators; artificial heart valves; ear implants; insulin pumps; drug infusion devices; IUDs; magnetic dental appliances; metal fragments or foreign objects in the eyes, skin or body; metal plates, screws, and prosthetics; non-removable metal piercings; tattoos on the head and neck, other certain older tattoos or permanent makeup (eyeliner) using metal-containing inks, some medicated patches, or any other condition, metal implant or other injury or device that is contraindicated for MRI. If a subject has any of these, the experimenter will evaluate whether it is safe for them to participate in the MRI portion of the experiment.

Exclusion Criteria:

* History of head injury with loss of consciousness for more than 5 min
* Uncorrected hearing or vision impairment severe enough to interfere with participation.
* Currently have or history of brain or mental illness judged likely to interfere with testing, including drug and/or alcohol dependence
* Sleep disorder (e.g., insomnia)
* Current drug, alcohol, or prescription drug intoxication
* History of epilepsy
* History of diagnosed migraines
* Metal implants in their head or face, including dental retainers that cannot be removed
* History of cardiac problems that could impact brain function (e.g., atrial fibrillation)
* Current active suicidal potential necessitating immediate treatment

Primary outcomes:
measure: Beck Depression Inventory - II (BDI-II)
timeFrame: Before ultrasound treatment, daily after each ultrasound session, after completion of week 1 of treatment, after completion of week 3 of treatment (if applicable)
measure: Perseverative Thinking Questionnaire (PTQ)
timeFrame: Before ultrasound treatment, daily after each ultrasound session, after completion of week 1 of treatment, after completion of week 3 of treatment (if applicable)
measure: Hamilton Depression Rating Scale (HDRS)
timeFrame: Before ultrasound treatment, after completion of week 1 of treatment, after completion of week 3 of treatment (if applicable)
measure: Default Mode Network (DMN) Connectivity
timeFrame: Before ultrasound treatment, after completion of week 1 of treatment, after completion of week 3 of treatment (if applicable)
Secondary outcomes:
measure: The Montgomery-Åsberg Depression Rating Scale (MADRS)
timeFrame: Before ultrasound treatment, after completion of week 1 of treatment, after completion of week 3 of treatment (if applicable)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
Study officials:
affiliation: University of Arizona Psychology Department
name: John JB Allen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Arizona Psychology Department
name: Jessica N Schachtner, BA
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fini M, Tyler WJ. Transcranial focused ultrasound: a new tool for non-invasive neuromodulation. Int Rev Psychiatry. 2017 Apr;29(2):168-177. doi: 10.1080/09540261.2017.1302924. Epub 2017 Apr 21.
citation: Kubanek J. Neuromodulation with transcranial focused ultrasound. Neurosurg Focus. 2018 Feb;44(2):E14. doi: 10.3171/2017.11.FOCUS17621.
citation: Samantha J. Reznik, Joseph L. Sanguinetti, William J. Tyler, Chris Daft, John J.B. Allen. (2020) A double-blind pilot study of transcranial ultrasound (TUS) as a five-day intervention: TUS mitigates worry among depressed participants, Neurology, Psychiatry and Brain Research, 37(60-66), ISSN 0941-9500, https://doi.org/10.1016/j.npbr.2020.06.004.
citation: Sanguinetti JL, Hameroff S, Smith EE, Sato T, Daft CMW, Tyler WJ, Allen JJB. Transcranial Focused Ultrasound to the Right Prefrontal Cortex Improves Mood and Alters Functional Connectivity in Humans. Front Hum Neurosci. 2020 Feb 28;14:52. doi: 10.3389/fnhum.2020.00052. eCollection 2020.
citation: Sanguinetti, J. L., Smith, E., Allen, J. J. B., Hameroff, S. (2014). Human brain stimulation with transcranial ultrasound (TUS); Potential applications for mental health. In Bioelectromagnetic Medicine. New York, NY: Taylor & Francis.
citation: Sheline YI, Barch DM, Price JL, Rundle MM, Vaishnavi SN, Snyder AZ, Mintun MA, Wang S, Coalson RS, Raichle ME. The default mode network and self-referential processes in depression. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1942-7. doi: 10.1073/pnas.0812686106. Epub 2009 Jan 26.