Clinical trial NCT05147142: Low Intensity Focused Ultrasound: a New Paradigm for Depression and Anxiety
Official title: Low Intensity Focused Ultrasound: a New Paradigm for Depression and Anxiety
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Depression
Keywords: Functional Neuroimaging
Acoustic Stimulation
Focused Ultrasound
Lead sponsor: Ocean State Research Institute, Inc.
Sponsor class: OTHER
First posted: 2021-12-07
Enrollment: 25
Sex: ALL
Minimum age (years): 22
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: Objective: Preliminary studies show that low intensity focused ultrasound (LIFU), a new type of non invasive brain stimulation (NIBS), may be able to reach deep structures of the brain involved with depression and anxiety, that remain inaccessible using current forms of NIBS with precision. In this study, the investigators will test if this technique can be used to change brain activity in areas that are connected to depression and anxiety symptoms. The primary objectives of this study are to test the safety and tolerability of LIFU, evaluate the feasibility of using LIFU to reduce brain activity, and evaluate the feasibility of simultaneous fMRI-LIFU. If the results of this study are positive, what the investigators learn will serve as a strong foundation for the future development of innovative treatments for a variety of psychiatric disorders.

Research Procedures: 25 veterans will be recruited. Visits will take place at the VA Providence Healthcare System. During some visits, healthy and patient participants may undergo clinical and research neuroimaging, neuropsychological testing, complete questionnaires, and participate in clinical/neurological assessments. Healthy veterans will not receive LIFU and will only attend 2 study visits. Patients are expected to attend up to 8 visits over 6 weeks. However, some may require up to 6 extended follow-ups after visits 5 or 8, in which case they would attend a total of 11 or 14 visits over 6 months. Two patient visits will include the LIFU application, following FDA safety guidelines. Patients will be assigned either to an experiment in which LIFU stimulation will be delivered immediately prior to a task or to an experiment in which stimulation will be delivered during the task. Within each experiment, patients will be assigned to first receive either LIFU stimulation to the study target or anatomical control. Study staff, but not participants will know which location is being targeted in case safety concerns arise. Safety assessments will be conducted at follow-up visits. A clinician will be available during LIFU administration /follow-up visits. Assuming no injury or other concerns are present, patients will then repeat this process again, receiving stimulation targeting other brain area not previously selected.


Eligibility criteria: Inclusion Criteria:

* Patients must meet DSM-5 criteria for major depressive disorder with and without anxiety symptoms
* Patients must also be symptomatic (i.e. symptom severity above clinical thresholds using standard rating scales) and, if relevant, stable treatment(s) for \>6 weeks.

Exclusion Criteria:

* history of seizure disorder or serious neurologic illness including dementia
* structural or neurologic abnormalities present or in close proximity to sonication site for patients (e.g., clinically significant calcification as might be observed in Fahr disease)
* history of brain surgery, iv) pacemaker or implanted central nervous system device
* greater than mild traumatic brain injury, or any head injury within sixty days of participation
* greater than moderate alcohol or substance use disorders (last six months; excluding nicotine/caffeine)
* active use or withdrawal from alcohol or substances (assessed via breathalyzer/urine testing as indicated)
* metal in the head
* impediment to vision, hearing and/or hand use likely to interfere with assessments
* pregnant or lactating (assessed via pregnancy test)
* unable to follow protocols
* acute suicidality, defined as "Yes" on item 4 of the Columbia Suicide Severity Rating Scale (C-SSRS), (i.e., active suicidal ideation with some intent to act on thoughts), or any endorsement of item 5 (active ideation with specific plan and intent) or any actual, interrupted, aborted attempt or preparatory behavior within the past month.
* symptom threshold considered in the "very severe" range using standard rating scales will be excluded.

Primary outcomes:
measure: Incidence of LIFU-related adverse events as assessed by clinical MRI
timeFrame: up to 6 months post LIFU
measure: Incidence of LIFU-related adverse events as assessed by neurological examinations
timeFrame: up to 6 months post LIFU
measure: Incidence of LIFU-related adverse events as assessed by neuropsychological testing
timeFrame: up to 6 months post LIFU
measure: BOLD fMRI Signal
timeFrame: change from baseline immediately following sonication, at 24 hours, and 1 week
measure: Resting state functional connectivity
timeFrame: change from baseline immediately following sonication, at 24 hours, and 1 week
measure: Perfusion Arterial Spin Labeling (ASL) fMRI Signal throughout Brain
timeFrame: change from baseline immediately following sonication, at 24 hours, and 1 week
Secondary outcomes:
Other outcomes:
Locations:
city: Providence
country: United States
facility: VA Providence Healthcare System
state: Rhode Island
Study officials:
affiliation: VA Providence Healthcare System
name: Noah S Philip, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Korb AS, Shellock FG, Cohen MS, Bystritsky A. Low-intensity focused ultrasound pulsation device used during magnetic resonance imaging: evaluation of magnetic resonance imaging-related heating at 3 Tesla/128 MHz. Neuromodulation. 2014 Apr;17(3):236-41; discussion 241. doi: 10.1111/ner.12075. Epub 2013 May 10.
citation: Monti MM, Schnakers C, Korb AS, Bystritsky A, Vespa PM. Non-Invasive Ultrasonic Thalamic Stimulation in Disorders of Consciousness after Severe Brain Injury: A First-in-Man Report. Brain Stimul. 2016 Nov-Dec;9(6):940-941. doi: 10.1016/j.brs.2016.07.008. Epub 2016 Jul 22. No abstract available.
citation: Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, Thielscher A. Safety of transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both human and animal studies. Brain Stimul. 2019 Nov-Dec;12(6):1367-1380. doi: 10.1016/j.brs.2019.07.024. Epub 2019 Jul 31.
citation: Badran BW, Caulfield KA, Stomberg-Firestein S, Summers PM, Dowdle LT, Savoca M, Li X, Austelle CW, Short EB, Borckardt JJ, Spivak N, Bystritsky A, George MS. Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: A double-blind, sham-controlled study. Brain Stimul. 2020 Nov-Dec;13(6):1805-1812. doi: 10.1016/j.brs.2020.10.007. Epub 2020 Oct 24.
citation: Philip NS, Arulpragasam AR. Reaching for the unreachable: low intensity focused ultrasound for non-invasive deep brain stimulation. Neuropsychopharmacology. 2023 Jan;48(1):251-252. doi: 10.1038/s41386-022-01386-2. No abstract available.
citation: Arulpragasam AR, van 't Wout-Frank M, Barredo J, Faucher CR, Greenberg BD, Philip NS. Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation-A Paradigm Shift in Psychiatric Research. Front Psychiatry. 2022 Feb 24;13:825802. doi: 10.3389/fpsyt.2022.825802. eCollection 2022.