NEPAL (Neuromodulatory Examination of Pain and Mobility Across the Lifespan)

Completed

• Conditions: Pain, Chronic; Musculoskeletal Pain
• Interventions: Other: MRI Neuroimaging; Other: Quantitative Sensory Testing; Other: Questionnaires; Other: Physical and Cognitive Function Testing

• Registration Number: NCT02488863
• Lead Sponsor: University of Florida

Brief Summary

Musculoskeletal pain represents the leading cause of disability worldwide. It has been traditionally attributed to peripheral mechanisms, but peripheral damage, inflammation, and psychological factors have failed to significantly account for the presence, absence, or severity of chronic musculoskeletal pain (CMP). Recent studies show that individuals with CMP exhibit dysfunctional pain modulation supporting a significant central nervous system (CNS) contribution. However, the CNS mechanisms underlying these changes in pain modulation are not currently known, nor is their relation to clinical pain progression. The proposed pilot examines brain circuits recently described in predicting the transition from acute to chronic pain, in predicting clinical and experimental pain changes as well as physical performance and mobility changes in older persons with musculoskeletal pain over a one year period. The findings will provide novel and important information regarding the mechanisms underlying aberrant pain processing and its functional consequences in older adults with musculoskeletal pain. The information learned can be subsequently used to target treatment and prevention strategies in future studies of older adults. The central hypothesis is that increased functional and structural connectivity of cortico-striatal regions will be significantly associated with baseline clinical and experimental pain and decreased physical function in persons with CMP and will account for more rapid clinical pain and disability progression over time.

Detailed Description

Chronic musculoskeletal pain (CMP) is the most common, non-malignant disabling condition that affects at least one in four older people. The most common painful musculoskeletal conditions among older adults are osteoarthritis, low back pain, fibromyalgia, chronic shoulder pain, knee pain, myofascial pain syndrome and previous fracture sites. Recent studies demonstrate generalized alterations of pain processing among older individuals with CMP. An improved understanding of the mechanisms underlying CMP-related changes in pain modulation will provide a basis for the development of targeted preventive and rehabilitative strategies. In light of evidence emphasizing plasticity of white matter connections, and the potential pain relieving effects of non-invasive brain stimulation interventions, it seems reasonable to identify these connections as potential targets for future treatment approaches. Given the expected growth of the older population, such strategies could have a monumental impact in reducing healthcare expenditures and improving the quality of life of older adults.

Study Timeline

• Study First Submitted: 2014-12-23
• Study Start: 2015-07
• Study First Submitted QC: 2015-07-01
• Study First Posted: 2015-07-02
• Primary Completion: 2024-02-04
• Study Completion: 2024-02-04
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-21
• Last Update Posted: 2024-06-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 195

Inclusion Criteria

• older adults over 60 years of age with and without musculoskeletal pain
• healthy young adults between the ages of 18-25

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Exclusion Criteria

• pregnant women
• history of alcohol/drug abuse in the past
• known intra-cerebral pathology or epilepsy
• significant cognitive impairment as evidenced by the 3MS
• hospitalizations for mental health reasons in the past year
• not meeting MRI screening requirements (implants, prosthesis, artificial limb/joint, shunt, metal rods, hearing aid, claustrophobia or anxiety)
• chronic/current use of narcotic medications
• serious systemic (uncontrolled diabetes; self reported A1C>7), neurological , or cardiovascular disease (uncontrolled hypertension >155/90)
• liver or kidney disease
• inability to consent for study participation

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Older Adults with Musculoskeletal Pain	Quantitative Sensory Testing	Older adults (60+ years old) experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Older Adults with Musculoskeletal Pain	Questionnaires	Older adults (60+ years old) experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Older Adults without Musculoskeletal Pain	Questionnaires	Older adults (60+ years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Older Adults without Musculoskeletal Pain	MRI Neuroimaging	Older adults (60+ years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Older Adults without Musculoskeletal Pain	Quantitative Sensory Testing	Older adults (60+ years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Young Controls	MRI Neuroimaging	Healthy young adults (18-25 years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Young Controls	Physical and Cognitive Function Testing	Healthy young adults (18-25 years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Older Adults with Musculoskeletal Pain	MRI Neuroimaging	Older adults (60+ years old) experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Older Adults with Musculoskeletal Pain	Physical and Cognitive Function Testing	Older adults (60+ years old) experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Older Adults without Musculoskeletal Pain	Physical and Cognitive Function Testing	Older adults (60+ years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Young Controls	Quantitative Sensory Testing	Healthy young adults (18-25 years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.
Young Controls	Questionnaires	Healthy young adults (18-25 years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.

Primary Outcome Measures

Name	Time	Method
Quantitative Sensory Testing (QST), Vibratory Detection Thresholds	At the QST visit (2 hrs)	The "TSA Thermal Sensory and Vibratory Sensory Analyzer (Model TSA II, VSA 3000) (Medoc. LTD)" will be used in this study to quantify nerve fiber dysfunction with measurements of vibratory thresholds. Vibratory threshold is tested with a vibratory pin, which presses the measured area with a consistent pressure of 50g. The vibratory sense analysis will be performed with upward-moving stimuli, which increases in intensity until a sensation is perceived. Several vibrations will be given sequentially and the mean end variance will be determined to verify the consistency of the test.
Quantitative Sensory Testing (QST), Punctate Pain Testing and Temporal Summation	At the QST visit (2 hrs)	We will apply punctate mechanical stimuli to the test sites with a series of weighted probes. Probes of different weights will be applied to participants' skin to determine the level that produces slight discomfort or pain. Two measures are obtained: 1) Pain threshold is determined by applying probes of different weights in ascending and descending sequences and participants are asked to tell the examiner which probes produce pain; 2) A weighted probe is applied either once or several times in a row and participants are asked to rate the pain they experience from the probe. In addition, a standardized plastic MediPin ® commonly used in neurological examinations will be applied to testing areas and participants will be asked to rate the intensity of any pain that is experienced.
Quantitative Sensory Testing (QST), Thermal Detection Thresholds, Pain Thresholds, and Temporal Summation	At the QST visit (2 hrs)	The "TSA Thermal Sensory and Vibratory Sensory Analyzer (Model TSA II, VSA 3000) (Medoc. LTD)" will also be used in this study to quantify nerve fiber dysfunction with measurements of thermal sensory thresholds (warm, cold, heat-induced pain, and cold-induced pain). Several trials will be performed for the sensory modality and a mean threshold will be calculated. For threshold determination, the investigators will use a "reaction time-inclusive" method, the method of limits, consisting of continuously changing intensities of stimuli halted automatically by the subject at the moment that the requested sensation is perceived. The following thresholds will be evaluated using the TSA II: (1) cool sensation; (2) warm sensation; (3) cold pain; and (4) heat pain. Subjects will also be asked to qualify the sensation after it has been quantified. Temporal summation of heat pain will be assessed by administering brief repetitive suprathreshold heat stimuli to test sites.
Upper Limb Isometric Strength	At the Physical and Cognitive Function visit (2 hrs)	This is a handgrip strength test using a dynamometer. The subject will be instructed to squeeze the dynamometer with maximum isometric effort for about 5 seconds. No other body movement will be allowed.
Knee Extension Isokinetic Strength	At the Physical and Cognitive Function visit (2 hrs)	An isokinetic dynamometer modified with increased sensitivity force transducers will be used to record Total work (Joules) and maximal force production (Biodex System 3, Shirley, NY). Participants will move through a full range of motion (if no contraindications are present), performing contractions at 60, 90 and 120 degrees/second to document potential effects on the velocity of movement.
Quantitative Sensory Testing (QST), Pressure Pain Thresholds	At the QST visit (2 hrs)	Pressure is delivered by a hand-held algometer (FDX, Wagner Instruments and/or Algomed, Medoc LTD), which is a spring-controlled device that delivers calibrated pressure via a flat 10mm diameter rubber tip. Pressure is delivered at an approximate rate of 1 kg/sec. Participants respond when they first feel pain, at which time the pressure is removed.
Short Physical Performance Battery (SPPB)	At the Physical and Cognitive Function visit (2 hrs)	The SPPB is based on a timed short distance walk, repeated chair stands and a balance test, which will be administered by a well-trained study team member.
Galvanic Skin Response	At the Physical and Cognitive Function visit (2 hrs)	Changes in participants' skin conductance will be measured (Biograph® ProComp5TM Infinity) during mobility assessments. Conductive electrodes will be attached to participants' fingers to measure any emotional arousal elicited by obstacles and/or cognitive tasks.
MRI Neuroimaging	At the imaging visit (2 hrs)	Brain connectivity, white matter connectivity indices.
Quantitative Sensory Testing (QST), Tactile Detection Thresholds	At the QST visit (2 hrs)	Thresholds for light touch will be assessed with von Frey monofilaments, using two ascending and two descending stimulus series, according to the method of limits. Detection threshold at each test site will be determined by the obtaining the geometric mean across these four test series.
Quantitative Sensory Testing (QST), Allodynia and Temporal Summation	At the QST visit (2 hrs)	Dynamic mechanical allodynia will be investigated using a soft brush and lightly brushing the skin of the hands and feet as well as any reported painful areas. If pain is evoked in the test area, the participant will be asked to rate the intensity of the pain. If an allodynic area is detected, temporal summation will be evoked by repetitively tapping the skin of the allodynic area with von Frey hairs (100g) at 1 Hz for 10 seconds. If temporal summation is evoked in the allodynic test area the participant will be asked to rate the intensity of the pain.
Pepper Assessment Tool for Disability (PAT-D)	At the Physical and Cognitive Function visit (2 hrs)	The PAT-D is a validated questionnaire which consists of 5 subscales: mobility, transferring, upper extremity, instrumental and basic activities of daily living.
NIH Cognition Toolbox	At the Physical and Cognitive Function visit (2 hrs)	The NIH Cognition toolbox assesses cognitive functions.
Mobility Assessments	At the Physical and Cognitive Function visit (2 hrs)	Participants will be asked to walk over a mat without any obstacles, as well as stepping over an obstacle, and while performing a cognitive task. Some tests will be performed while walking over a GAITRite ® instrumented walking mat, which measures spatiotemporal gait parameters.

Secondary Outcome Measures

Name	Time	Method
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)	At the baseline/screening visit and at 12 month follow-up	The WOMAC questionnaire evaluates the condition of osteoarthritis, including pain, stiffness, and physical functioning of the joints.
Short Form-McGill Pain Questionnaire (SF-MPQ)	At the baseline/screening visit and at 12 month follow-up	The SF-MPQ consists of 15 sensory and affective descriptors of pain that are rated on an intensity scale.
The Modified Mini-Mental State Examination (3MS)	At the baseline/screening visit (2 hrs)	The 3MS screens for cognitive impairment.
Edinburg Handedness Inventory	At the baseline/screening visit (2 hrs)	The Edinburg Handedness Inventory assesses which hand is dominant.
The Pittsburgh Sleep Quality Index (PSQI)	At the baseline/screening visit and at 12 month follow-up	The PSQI is an instrument used to measure the quality and patterns of sleep in adults.
The state version of the Positive and Negative Affect Schedule (PANAS)	At the baseline/screening visit, at each experimental visit, and at 12 month follow-up	The PANAS is a self-report questionnaire that consists of two 10-item scales to measure both positive and negative affect.
Pain DETECT	At the baseline/screening visit and at 12 month follow-up	The Pain DETECT questionnaire screens for neuropathic components of pain.
Hopkins Verbal Learning Test (HVLT)	At the baseline/screening visit (2 hrs)	The HVLT measures verbal memory.
Trail Making A & B	At the baseline/screening visit (2 hrs)	The Trail Making Test measures set shifting and psychomotor speed.
Raven's Standard Progressive Matrices (SPM)	At the baseline/screening visit (2 hrs)	The SPMs were developed to assess, as simply and unambiguously as possible, the two components of "g"--or "general" factor in mental ability--identified by Spearman as eductive ability and reproductive ability.
Center for Epidemiologic Studies Depression Scale (CES-D)	At the baseline/screening visit and at 12 month follow-up	The CES-D screens for depression.
The Ten-Item Personality Inventory (TIPI)	At the baseline/screening visit (2 hrs)	The TIPI is a 10-item measure of the Big Five (or Five-Factor Model) dimensions.
The trait version of the State-Trait Anxiety Inventory (STAI)	At the baseline/screening visit (2 hrs)	The STAI is an introspective psychological inventory consisting of 40 self-report items pertaining to anxiety affect.
Coping Strategies Questionnaire- Revised (CSQ-R)	At the baseline/screening visit and at 12 month follow-up	The Coping Strategies Questionnaire measures pain coping strategies on a 7-point Likert Scale.
Boston Naming Test	At the baseline/screening visit (2 hrs)	The Boston Naming test includes 60 line drawings ranging from simple, high frequency vocabulary (i.e. tree) to rare words (abascus).
The Montreal Cognitive Assessment (MoCA)	At the baseline/screening visit (2 hrs)	The MoCA assesses multiple domains of cognitive functions.
Controlled Oral Word Association (COWA) Test	At the baseline/screening visit (2 hrs)	The COWA Test is a verbal fluency test that measures spontaneous production of words belonging to the same category or beginning with some designated letter.
The Ruff Figural Fluency test	At the baseline/screening visit (2 hrs)	The Ruff Figural Fluency test is a nonverbal measure of initiation, planning, and divergent reasoning.
Geriatric Depression Scale (GDS)	At the baseline/screening visit and at 12 month follow-up	The GDS is a 30-item self-report assessment used to identify depression in the elderly.
The trait version of the Positive and Negative Affect Schedule (PANAS)	At the baseline/screening visit (2 hrs)	The PANAS is a self-report questionnaire that consists of two 10-item scales to measure both positive and negative affect.
Knee X-ray	At the baseline/screening visit (2 hrs)	For older adult cohorts (ages 60+), an x-ray of the dominant knee will be taken to measure presence/severity of osteoarthritis.
The state version of the State-Trait Anxiety Inventory (STAI)	At the baseline/screening visit, at each experimental visit, and at 12 month follow-up	The STAI is an introspective psychological inventory consisting of 40 self-report items pertaining to anxiety affect.
The Graded Chronic Pain Scale (GCPS)	At the baseline/screening visit, at each experimental visit, and at 12 month follow-up	The GCPS is a seven-item instrument designed to evaluate overall severity of chronic pain based on two dimensions, pain intensity and pain-related disability.
The Stroop Interference test	At the baseline/screening visit (2 hrs)	The Stroop Interference test assesses cognitive functions.

Trial Locations

Locations (4)

UF Health Science Center; 🇺🇸 Gainesville, Florida, United States

UF & Shands Orthopaedics and Sports Medicine Institute; 🇺🇸 Gainesville, Florida, United States

Clinical Translational Research Building; 🇺🇸 Gainesville, Florida, United States

McKnight Brain Institute of the University of Florida; 🇺🇸 Gainesville, Florida, United States