Ultrasonic Neuromodulation of Cingulate Cortex for Fibromyalgia

Ultrasonic Neuromodulation of Cingulate Cortex for Fibromyalgia: A Blinded Randomized Sham-Controlled Trial

The goal of this clinical trial is to evaluate a new noninvasive brain stimulation intervention for fibromyalgia and to determine its effectiveness in reducing pain. Participants will receive four treatments over the course of one month and will complete surveys at multiple time points throughout the 16-week study.

Study Overview

• Status: Recruiting
• Conditions: Fibromyalgia
• Intervention / Treatment: Device: Focused Ultrasound

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Akiko Okifuji, PhD; Phone Number: 801-585-7690; Email: Akiko.Okifuji@hsc.utah.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Principal Investigator: Daniel Clauw, MD
      • Contact: Katherine Scott, RN, BSN; Phone Number: 734-998-7022; Email: jrsj@med.umich.edu
      • Principal Investigator: Deeba Minhas, MD
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota Medical Center Fairview
      • Principal Investigator: Alik Widge, MD, PhD
      • Contact: Eric Williamson; Phone Number: 612-626-6183; Email: will0188@umn.edu
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University in St. Louis
      • Contact: Cristina Bowman, RN; Phone Number: 314-273-8257; Email: bowmanc@wustl.edu
      • Principal Investigator: Simon Haroutounian, PhD, MSc.Pharm
  • New York
    • Manhasset, New York, United States, 10030
      • Recruiting
      • Northwell Health - The Feinstein Institutes of Clinical Research
      • Principal Investigator: Ashesh Mehta, MD
      • Contact: Clinical Research Team; Phone Number: 516-253-7753; Email: Neuroscienceresearch@northwell.edu
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Recruiting
      • University of Utah
      • Contact: Rachel Douglas, BS, CCRC; Phone Number: 801-587-2811; Email: UltraSound_for_Fibromyalgia_Study@utah.edu
      • Principal Investigator: Rana Jawish, MD
  • West Virginia
    • Morgantown, West Virginia, United States, 26505
      • Recruiting
      • WVU Rockefeller Neuroscience Institute
      • Contact: Tami Deal, CCRC; Phone Number: 304-293-0930; Email: tldeal@hsc.wvu.edu
      • Principal Investigator: Manish Ranjan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing and able to provide informed consent.
2. Age ≥ 22 years.

3. Meets 2016 American College of Rheumatology criteria for fibromyalgia:

   1. Generalized pain, defined as pain in at least 4 of 5 regions, is present, AND
   2. Widespread pain index (WPI) ≥ 7 and symptom severity scale score (SSS) ≥ 5, or WPI of 4-6 and SSS score ≥ 9, AND
   3. Symptoms have been present at a similar level for at least 3 months, AND
   4. A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses.
4. Failure of at least two evidence-based medications (i.e., pregabalin, duloxetine, milnacipran) for the treatment of fibromyalgia.

5. Failure of one or more attempts at physical or Cognitive Behavioral Therapy (CBT) including:

   1. Aerobic exercise like walking, cycling, and swimming,
   2. Water therapy/hydrotherapy with warm water exercises,
   3. Tai Chi involving slow, controlled movements,
   4. Yoga,
   5. Resistance training,
   6. Bodyweight exercises,
   7. Pilates,
   8. Myofascial release therapy applying gentle pressure on trigger points,
   9. Massage therapy,
   10. Trigger point therapy targeting specific pain points,
   11. Joint mobilization,
   12. Postural retraining to correct body alignment,
   13. Balance and coordination exercises,
   14. Feldenkrais method for movement awareness,
   15. Alexander technique to enhance posture and movement efficiency,
   16. Transcutaneous Electrical Nerve Stimulation (TENS) for pain relief,
   17. Heat therapy using hot packs, infrared, or paraffin wax,
   18. Cold therapy with ice packs or cryotherapy,
   19. Ultrasound therapy for deep tissue relaxation,
   20. Biofeedback to control muscle tension and pain response,
   21. Gentle static stretching for prolonged duration,
   22. Active dynamic stretching for full range of motion,
   23. Proprioceptive Neuromuscular Facilitation (PNF) stretching,
   24. Hydrotherapy pool exercises,
   25. Ai Chi (water-based Tai Chi),
   26. Underwater treadmill therapy, aa) Graded motor imagery (GMI), bb) Mirror therapy to retrain brain-body connections, cc) Mindfulness-based stress reduction (MBSR) combining meditation and movement, dd) Balance exercises to improve stability, ee)Gaze stabilization techniques for dizziness and disorientation, ff) CBT.
6. Pain score of ≥ 4 on Numerical Rating Scale (NRS-11) at Screening visit.
7. Pain score of ≥ 4 on NRS-11 at Baseline visit averaged over 3 consecutive calendar days.
8. Stated willingness and ability to comply with all study procedures.
9. Has remained on the same psychiatric treatment regimen (e.g., medication, psychotherapy) for at least one (1) month prior to screening, and has stated willingness to remain on the same regimen for the duration of the study unless a change in treatment is recommended or agreed upon by the site investigator.
10. For participants who could potentially become pregnant: negative urine pregnancy test at screening; agreement to use a highly effective method of contraception (≤ 1% pregnancy rate) including tubal ligation, vasectomized partner, IUD or IUS (intrauterine device or system), or long-acting contraceptives (LARC).

Exclusion Criteria:

1. Any previous diagnosis of bipolar disorder or schizophrenia-spectrum disorder during the participant's lifetime, according to Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5-TR) criteria.
2. New or existing diagnosis of moderate or severe alcohol or other substance use disorder in the past 6 months, according to DSM-5-TR criteria.
3. New or existing diagnosis of obsessive-compulsive disorder and/or posttraumatic stress disorder in the past 30 days, according to DSM-5-TR criteria, and which is unstable in the clinical judgment of the investigator.
4. New or existing primary diagnosis of anorexia nervosa, bulimia nervosa, or binge eating disorder in the past 3 months, according to DSM-5-TR criteria.
5. Clinically significant neurodevelopmental, neurocognitive, or personality disorder, according to DSM-5-TR criteria.
6. Moderate-High Risk of Suicide, according to the Columbia-Suicide Severity Rating Scale (C-SSRS) Screen Version - Recent (i.e., answers YES to Question 3 and NO to Question 6 (Moderate Risk), or YES to Question 4, 5, or 6 (High Risk)), or in the clinical judgement of the site investigator.
7. Lifetime history of a serious suicide attempt in the medical opinion of the site investigator.
8. Changes in treatment for pain in the past 2 months.
9. Treatment with electroconvulsive therapy, transcranial magnetic stimulation, ketamine, or esketamine in the past 30 days.
10. Currently diagnosed progressive neurological disease such as multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, rapid progressive arachnoiditis, brain or spinal cord tumor, or severe/critical spinal stenosis (stenosis).
11. Cancer-related pain.
12. Diagnosis of malignancy other than basal cell carcinoma, or carcinoma in situ of the cervix within the past five years, to include life expectancy less than one year due to advanced malignancy.
13. Autoimmune-related pain.
14. Inadequately managed general medical condition, in the opinion of the site investigator.
15. Lifetime history of cerebral small vessel disease.
16. Lifetime history of intracranial hemorrhage.
17. Pregnant or breast feeding.
18. Implanted medical device in the head or neck.
19. MRI contraindication or intolerance.
20. Previously enrolled in a DIADEM clinical trial. Note: a patient who screen fails is able to be rescreened at most one time.
21. Has a history of any medical or psychiatric disorder, disease, condition, injury, symptoms, or circumstance that, in the opinion of the site investigator, may (1) reduce the participant's ability to fulfill the study requirements as per protocol; (2) adversely impact the integrity of the data or the validity of the study results; or (3) pose an increased risk to the participant during study participation.
22. Participants with braids, dreadlocks, or other hairstyles that prevent access to the side of the head and who are unwilling to temporarily adjust their hairstyle to allow such access.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Focused Ultrasound	Device: Focused Ultrasound; DIADEM device
Sham Comparator: Sham Ultrasound	Device: Focused Ultrasound; DIADEM device

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Numerical Rating Scale - 11 (NRS-11) pain score	The NRS-11 is a scale from 0-10 with higher values representing higher levels of pain.	28 days following initial treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fibromyalgia Impact Questionnaire Revised (FIQR)	The FIQR is a scale ranging from 0 to 100 that evaluates function, overall impact, and symptoms of fibromyalgia over the past 7 days. Higher scores represent more severe impact to the patient.	28 days following initial treatment
Numerical Rating Scale - 11 (NRS-11) pain score response rate	≥ 30% reduction from baseline in NRS-11 score (the NRS-11 is a scale from 0-10 with higher values representing higher levels of pain).	28 days following initial treatment
Patient-Reported Outcomes Measurement Information System (PROMIS-29) - Pain Interference Subscale	The PROMIS-29 is a 29 question survey assessing physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, pain interference, and pain intensity. The Pain Interference Subscale is scored on a 5 point scale and asks how much pain interfered with different activities (1 - Not at all; 2 - A little bit; 3 - Somewhat; 4 - Quite a bit; 5 - Very much). Scores are calculated as T-scores with a mean of 50 and a standard deviation of 10. Higher scores represent more pain interference.	28 days following initial treatment
Numerical Rating Scale - 11 (NRS-11) pain score response rate	≥ 30% reduction from baseline in NRS-11 score (the NRS-11 is a scale from 0-10 with higher values representing higher levels of pain).	7 days following initial treatment
Patient Global Impression of Improvement (PGI-I)	The PGI-I is a scale from 1-7 indicating how the patient has felt overall since beginning treatment. 1 - Very Much Improved; 2 - Much Improved; 3 - Minimally Improved; 4 - No Change; 5 - Minimally Worse; 6 - Much Worse; 7 - Very Much Worse.	28 days following initial treatment
Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a 9-question survey asking "Over the last 2 weeks, how often have you been bothered by any of the following problems?" Each question is scored as: 0: Not at all; Several days;; More than half the days;; Nearly every day. The 9 scores are added together, and the total score ranges from 0 to 27, with higher numbers representing more bothersome problems.	28 days following initial treatment
Numerical Rating Scale - 11 (NRS-11) pain score	The NRS-11 is a scale from 0-10 with higher values representing higher levels of pain.	16 weeks following initial treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs)		Through 28 days following initial treatment
Serious Adverse Events (SAEs)		Through 16 weeks following initial treatment
Patient-Reported Outcomes Measurement Information System (PROMIS-29) - all subscales, excluding Pain Interference	The PROMIS-29 is a 29 question survey assessing physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, pain interference, and pain intensity. Scores for subscales are calculated as T-scores with a mean of 50 and a standard deviation of 10. Higher scores represent worse health than average for anxiety, depression, fatigue, sleep disturbance, and pain interference. Higher scores represent better health than average for physical function and ability to participate in social roles and activities.	28 days following initial treatment
Brief Pain Inventory (BPI) - short form	The BPI includes questions on a scale from 0-10 with higher values representing higher levels of pain or higher levels of pain interference.	28 days following initial treatment
Fibromyalgia Impact Questionnaire Revised (FIQR)	The FIQR is a scale ranging from 0 to 100 that evaluates function, overall impact, and symptoms of fibromyalgia over the past 7 days. Higher scores represent more severe impact to the patient.	16 weeks following initial treatment
Patient-Reported Outcomes Measurement Information System (PROMIS-29) - all subscales	The PROMIS-29 is a 29 question survey assessing physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities, pain interference, and pain intensity. Scores for subscales are calculated as T-scores with a mean of 50 and a standard deviation of 10. Higher scores represent worse health than average for anxiety, depression, fatigue, sleep disturbance, and pain interference. Higher scores represent better health than average for physical function and ability to participate in social roles and activities.	16 weeks following initial treatment
Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a 9-question survey asking "Over the last 2 weeks, how often have you been bothered by any of the following problems?" Each question is scored as: 0: Not at all; Several days;; More than half the days;; Nearly every day. The 9 scores are added together, and the total score ranges from 0 to 27, with higher numbers representing more bothersome problems.	16 weeks following initial treatment
Patient Global Impression of Improvement (PGI-I)	The PGI-I is a scale from 1-7 indicating how the patient has felt overall since beginning treatment. 1 - Very Much Improved; 2 - Much Improved; 3 - Minimally Improved; 4 - No Change; 5 - Minimally Worse; 6 - Much Worse; 7 - Very Much Worse.	16 weeks following initial treatment
Brief Pain Inventory (BPI) - short form	The BPI includes questions on a scale from 0-10 with higher values representing higher levels of pain or higher levels of pain interference.	16 weeks following initial treatment
Columbia Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is a semi-structured interview to assess suicidal ideation and behavior. Based on responses, participants are categorized as Low Risk, Moderate Risk, or High Risk. An increase in risk level will be evaluated.	28 days following initial treatment
Montreal Cognitive Assessment (MoCA)	The MoCA is a neuropsychological screening test with scores ranging from 0-30 with lower scores suggesting higher cognitive impairment.	28 days following initial treatment

Collaborators and Investigators

• Sponsor: SPIRE Therapeutics Inc.
• Collaborators: University of Utah Data Coordinating Center
• Investigators: Principal Investigator: Akiko Okifuji, PhD, University of Utah

Publications and helpful links

General Publications

• Riis TS, Losser AJ, Kassavetis P, Moretti P, Kubanek J. Noninvasive modulation of essential tremor with focused ultrasonic waves. J Neural Eng. 2024 Feb 27;21(1). doi: 10.1088/1741-2552/ad27ef.
• Riis TS, Feldman DA, Losser AJ, Okifuji A, Kubanek J. Noninvasive targeted modulation of pain circuits with focused ultrasonic waves. Pain. 2024 Dec 1;165(12):2829-2839. doi: 10.1097/j.pain.0000000000003322. Epub 2024 Jul 30.
• Riis TS, Feldman DA, Kwon SS, Vonesh LC, Koppelmans V, Brown JR, Solzbacher D, Kubanek J, Mickey BJ. Noninvasive Modulation of the Subcallosal Cingulate and Depression With Focused Ultrasonic Waves. Biol Psychiatry. 2025 Apr 15;97(8):825-834. doi: 10.1016/j.biopsych.2024.09.029. Epub 2024 Oct 11.

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: November 7, 2025
• First Submitted That Met QC Criteria: November 7, 2025
• First Posted (Actual): November 10, 2025

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Rheumatic Diseases; Fibromyalgia
• Other Study ID Numbers: SPIRE1002025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No