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.

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 or medications that are commonly used in clinical practice to treat fibromyalgia (e.g., pregabalin, duloxetine, milnacipran, sublingual cyclobenzaprine hydrochloride, tricyclics (e.g., amitriptyline, nortriptyline, desipramine),gabapentin, gabapentinoids, NSAIDS (including Cox-2 inhibitors), acetaminophen, SSRIs, SSNIs, muscle relaxants, non-sublingual forms of cyclobenzaprine hydrochloride, opioids, benzodiazepines), at least 1 of which is FDA-approved for the treatment of fibromyalgia (e.g., pregabalin, duloxetine, milnacipran, and sublingual cyclobenzaprine hydrochloride).

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 either abstain from heterosexual intercourse or use an acceptable contraceptive method during study participation. Acceptable contraceptive methods include hormonal contraception, including oral contraceptive pills, tubal ligation, vasectomized partner, IUD or IUS (intrauterine device or system), or long-acting reversible 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 prescribed treatments for pain in the past 2 months that could confound study outcome assessments, in the opinion of the site investigator.
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 conditions that are known to cause 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. MRI contraindication or electrically sensitive implants such as pacemakers, implanted cardioverter defibrillators, or neurostimulators. Routine dental hardware is not exclusionary.
19. MRI 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 a 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.