Focused Ultrasound Stimulation for the Treatment of Chronic Pain

The Brief Pain Inventory - Short Form (BPI-SF) Pain Severity subscale is a 4-item self-report measure (worst pain, least pain, average pain, and current pain), each item rated on a 0 to 10 numeric rating scale anchored at 0 = "No pain" and 10 = "Pain as bad as you can imagine." The subscale score is the arithmetic mean of the 4 items and ranges from a minimum of 0 to a maximum of 10. Higher scores indicate greater pain severity, i.e., a worse outcome. This measure assesses durability of the treatment effect at Month 3, the key secondary timepoint.

The Brief Pain Inventory - Short Form (BPI-SF) Pain Interference subscale is a 7-item self-report measure assessing the degree to which pain interferes with general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Each item is rated on a 0 to 10 scale anchored at 0 = "Does not interfere" and 10 = "Completely interferes." The subscale score is the arithmetic mean of the 7 items and ranges from a minimum of 0 to a maximum of 10. Higher scores indicate greater interference from pain, i.e., a worse outcome.

The Patient Health Questionnaire-9 (PHQ-9) is a 9-item self-report measure of depressive symptom severity over the preceding two weeks. Each item is rated on a 0 to 3 scale anchored at 0 = "Not at all" and 3 = "Nearly every day." The total score is the sum of the 9 items and ranges from a minimum of 0 to a maximum of 27. Higher scores indicate more severe depressive symptoms, i.e., a worse outcome.

The Insomnia Severity Index (ISI) is a 7-item self-report measure of insomnia severity, assessing difficulty falling asleep, difficulty staying asleep, early morning awakening, satisfaction with sleep, interference with daytime functioning, noticeability of impairment, and distress about sleep problems. Each item is rated on a 0 to 4 scale. The total score is the sum of the 7 items and ranges from a minimum of 0 to a maximum of 28. Higher scores indicate more severe insomnia, i.e., a worse outcome.

The Generalized Anxiety Disorder-7 (GAD-7) is a 7-item self-report measure of anxiety symptom severity over the preceding two weeks. Each item is rated on a 0 to 3 scale anchored at 0 = "Not at all" and 3 = "Nearly every day." The total score is the sum of the 7 items and ranges from a minimum of 0 to a maximum of 21. Higher scores indicate more severe anxiety symptoms, i.e., a worse outcome.

The Depression Anxiety Stress Scales-8 (DASS-8) is an 8-item short-form self-report measure of depression, anxiety, and stress symptoms over the preceding week. Each item is rated on a 0 to 3 scale anchored at 0 = "Did not apply to me at all" and 3 = "Applied to me very much or most of the time." The total score is the sum of the 8 items and ranges from a minimum of 0 to a maximum of 24. Higher scores indicate greater depression, anxiety, and stress symptom burden, i.e., a worse outcome.

The Brief Resilience Scale (BRS) is a 6-item self-report measure of the ability to recover from stress. Each item is rated on a 1 to 5 scale anchored at 1 = "Strongly disagree" and 5 = "Strongly agree"; three items are reverse-scored. The scale score is the arithmetic mean of the 6 items and ranges from a minimum of 1 to a maximum of 5. Higher scores indicate greater resilience, i.e., a better outcome.

The Flourishing Scale (FS) is an 8-item self-report measure of perceived success in areas such as relationships, self-esteem, purpose, and optimism. Each item is rated on a 1 to 7 scale anchored at 1 = "Strongly disagree" and 7 = "Strongly agree." The total score is the sum of the 8 items and ranges from a minimum of 8 to a maximum of 56. Higher scores indicate greater psychological well-being, i.e., a better outcome.

Self-reported sleepiness rated on a 100 mm Visual Analog Scale (VAS) administered three times daily via the Attune mobile application. Scores range from a minimum of 0 mm ("Not at all sleepy") to a maximum of 100 mm ("Extremely sleepy"). Higher scores indicate greater sleepiness, i.e., a worse outcome.

Concentration of cortisol in dermal interstitial fluid, measured continuously by the Adaptyx Continuous Biomonitor, a microdialysis-based in-line analyzer, and reported in nanomoles per liter (nmol/L). Change is assessed as the difference from the participant's own baseline concentration. This is a descriptive biomarker measure; neither direction of change is designated a priori as a better or worse outcome.

Absolute spectral power derived from continuous ambulatory electroencephalography (EEG) recorded with the Epitel REMI wireless EEG system in an 8-electrode (10-channel) configuration. Power is computed by fast Fourier transform in five canonical frequency bands, each reported separately in the common unit of microvolts squared per hertz (microV^2/Hz): delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-45 Hz). This is a descriptive biomarker measure; neither direction of change is designated a priori as a better or worse outcome.

Heart rate variability quantified as the root mean square of successive differences between normal RR intervals (RMSSD), derived from photoplethysmography recorded by a consumer smart watch and reported in milliseconds (ms). This is a descriptive physiological measure; higher values reflect greater parasympathetic tone, and neither direction of change is designated a priori as a better or worse outcome.

Self-reported mood rated on a 100 mm Visual Analog Scale (VAS) administered three times daily via the Attune mobile application. Scores range from a minimum of 0 mm ("Worst possible mood") to a maximum of 100 mm ("Best possible mood"). Higher scores indicate better mood, i.e., a better outcome.

Self-reported depressed feeling rated on a 100 mm Visual Analog Scale (VAS) administered three times daily via the Attune mobile application. Scores range from a minimum of 0 mm ("Not at all depressed") to a maximum of 100 mm ("Extremely depressed"). Higher scores indicate greater depressed feeling, i.e., a worse outcome.

Self-reported arousal (alertness and activation) rated on a 100 mm Visual Analog Scale (VAS) administered three times daily via the Attune mobile application. Scores range from a minimum of 0 mm ("Not at all alert or activated") to a maximum of 100 mm ("Extremely alert or activated"). Higher scores indicate greater arousal; this measure is interpreted descriptively and neither direction of change is designated a priori as a better or worse outcome.

Concentrations of the kynurenine pathway metabolites kynurenine, tryptophan, and quinolinic acid in dermal interstitial fluid, measured continuously by the Adaptyx Continuous Biomonitor, a microdialysis-based in-line analyzer. All three analytes share a common unit of measure, micromoles per liter (micromol/L), and each analyte is reported separately within this outcome measure. This is a descriptive biomarker measure; neither direction of change is designated a priori as a better or worse outcome.

Sleep duration parameters derived from continuous ambulatory electroencephalography (EEG) recorded with the Epitel REMI wireless EEG system and scored by a validated automated sleep-staging algorithm. All parameters share a common unit of measure, minutes, and each is reported separately: total sleep time, time in stage N1, time in stage N2, time in stage N3, and time in rapid eye movement (REM) sleep. Higher total sleep time indicates a better outcome; stage-specific durations are interpreted descriptively.

Sleep efficiency derived from continuous ambulatory electroencephalography (EEG) recorded with the Epitel REMI wireless EEG system, defined as total sleep time divided by time in bed and expressed as a percentage (%). Values range from a minimum of 0% to a maximum of 100%. Higher values indicate better sleep continuity, i.e., a better outcome.

Number of nocturnal awakenings per night derived from continuous ambulatory electroencephalography (EEG) recorded with the Epitel REMI wireless EEG system and scored by a validated automated sleep-staging algorithm. Reported as a count of awakenings per night. Higher values indicate more fragmented sleep, i.e., a worse outcome.

Physical activity quantified as the number of steps taken per day, derived from accelerometry (actigraphy) recorded by a consumer smart watch and reported as a count of steps per day. Higher values indicate greater physical activity, i.e., a better outcome.

Gait speed derived from accelerometry recorded by a consumer smart watch and reported in meters per second (m/s). Higher values indicate better ambulatory function, i.e., a better outcome.

Life-space range quantified as the area of the convex hull enclosing all locations visited per day, derived from GPS data recorded by a consumer smart watch and, for participants who opt in, the Beiwe research smartphone application. All coordinates are converted to relativistic coordinates referenced to the participant's modal home location before analysis, and no absolute GPS coordinates are stored or transmitted. Reported in square kilometers (km^2). Higher values indicate greater community mobility, i.e., a better outcome.

Total distance traveled per day, derived from GPS data recorded by a consumer smart watch and, for participants who opt in, the Beiwe research smartphone application, using relativistic coordinates referenced to the participant's modal home location. Reported in kilometers per day (km/day). Higher values indicate greater community mobility, i.e., a better outcome.