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

Neuroimaging Age-related Versus Pain-related Changes in Pain Modulation

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.

Study Overview

• Status: Completed
• Conditions: Musculoskeletal Pain; Pain, Chronic
• Intervention / Treatment: Other: MRI Neuroimaging; Other: Quantitative Sensory Testing; Other: Questionnaires; Other: Physical and Cognitive Function Testing

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 Type: Observational
• Enrollment (Actual): 105

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32607
      • UF & Shands Orthopaedics and Sports Medicine Institute
    • Gainesville, Florida, United States, 32608
      • UF Health Science Center
    • Gainesville, Florida, United States, 32611
      • McKnight Brain Institute of the University of Florida
    • Gainesville, Florida, United States, 32611
      • Clinical Translational Research Building

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Older adults (60+ years old) who experience musculoskeletal pain as well as those who do not experience musculoskeletal pain; healthy young adults (18-25 years old).

Description

Inclusion Criteria:

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

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Older Adults with Musculoskeletal Pain; Older adults (60+ years old) experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.	Other: MRI Neuroimaging; MRI scans utilized to measure the structural and functional integrity of the brain.; Other Names: Functional Magnetic Resonance Imaging (fMRI); Other: Quantitative Sensory Testing; Vibratory Detection Thresholds; Tactile Detection Thresholds; Thermal Detection Thresholds, Pain Thresholds, and Temporal Summation; Allodynia and Temporal Summation; Punctate Pain Testing and Temporal Summation; and Pressure Pain Thresholds.; Other Names: QST; Other: Questionnaires; The Modified Mini-Mental State Examination (3MS), the Montreal Cognitive Assessment (MoCA), the Center for Epidemiologic Studies Depression Scale (CES-D), the Geriatric Depression Scale (GDS), the Edinburg Handedness Inventory, the Ten-Item Personality Inventory (TIPI), the Pittsburgh Sleep Quality Index (PSQI), the state and trait versions of the State-Trait Anxiety Inventory (STAI), the state and trait versions of the Positive and Negative Affect Schedule (PANAS), pain questionnaires (the Graded Chronic Pain Scale (GCPS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Pain-Detect, the short-form McGill Pain Questionnaire (SF-MPQ-2), and the Coping Strategies Questionnaire-Revised (CSQ-R)), a standardized paper and pencil cognitive battery (Hopkins Verbal Learning Test (HVLT), Trail Making A&B, Boston Naming Test, Controlled Oral Word Association Test (COWAT), Stroop Interference Test, Ruff Figural Fluency Test, and Raven's Progressive Matrices Test).; Other: Physical and Cognitive Function Testing; Upper Limb Isometric Strength, Short Physical Performance Battery (SPPB), GAITRite Instrumented Walking, Galvanic Skin Response, Knee Extension Isokinetic Strength, the Pepper Assessment Tool for Disability (PAT-D), and an electronic NIH Toolbox Cognitive Battery.
Older Adults without Musculoskeletal Pain; Older adults (60+ years old) not experiencing musculoskeletal pain will undergo: MRI Neuroimaging, Quantitative Sensory Testing, Physical and Cognitive Function Testing, and questionnaire batteries.	Other: MRI Neuroimaging; MRI scans utilized to measure the structural and functional integrity of the brain.; Other Names: Functional Magnetic Resonance Imaging (fMRI); Other: Quantitative Sensory Testing; Vibratory Detection Thresholds; Tactile Detection Thresholds; Thermal Detection Thresholds, Pain Thresholds, and Temporal Summation; Allodynia and Temporal Summation; Punctate Pain Testing and Temporal Summation; and Pressure Pain Thresholds.; Other Names: QST; Other: Questionnaires; The Modified Mini-Mental State Examination (3MS), the Montreal Cognitive Assessment (MoCA), the Center for Epidemiologic Studies Depression Scale (CES-D), the Geriatric Depression Scale (GDS), the Edinburg Handedness Inventory, the Ten-Item Personality Inventory (TIPI), the Pittsburgh Sleep Quality Index (PSQI), the state and trait versions of the State-Trait Anxiety Inventory (STAI), the state and trait versions of the Positive and Negative Affect Schedule (PANAS), pain questionnaires (the Graded Chronic Pain Scale (GCPS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Pain-Detect, the short-form McGill Pain Questionnaire (SF-MPQ-2), and the Coping Strategies Questionnaire-Revised (CSQ-R)), a standardized paper and pencil cognitive battery (Hopkins Verbal Learning Test (HVLT), Trail Making A&B, Boston Naming Test, Controlled Oral Word Association Test (COWAT), Stroop Interference Test, Ruff Figural Fluency Test, and Raven's Progressive Matrices Test).; Other: Physical and Cognitive Function Testing; Upper Limb Isometric Strength, Short Physical Performance Battery (SPPB), GAITRite Instrumented Walking, Galvanic Skin Response, Knee Extension Isokinetic Strength, the Pepper Assessment Tool for Disability (PAT-D), and an electronic NIH Toolbox Cognitive Battery.
Young Controls; 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.	Other: MRI Neuroimaging; MRI scans utilized to measure the structural and functional integrity of the brain.; Other Names: Functional Magnetic Resonance Imaging (fMRI); Other: Quantitative Sensory Testing; Vibratory Detection Thresholds; Tactile Detection Thresholds; Thermal Detection Thresholds, Pain Thresholds, and Temporal Summation; Allodynia and Temporal Summation; Punctate Pain Testing and Temporal Summation; and Pressure Pain Thresholds.; Other Names: QST; Other: Questionnaires; The Modified Mini-Mental State Examination (3MS), the Montreal Cognitive Assessment (MoCA), the Center for Epidemiologic Studies Depression Scale (CES-D), the Geriatric Depression Scale (GDS), the Edinburg Handedness Inventory, the Ten-Item Personality Inventory (TIPI), the Pittsburgh Sleep Quality Index (PSQI), the state and trait versions of the State-Trait Anxiety Inventory (STAI), the state and trait versions of the Positive and Negative Affect Schedule (PANAS), pain questionnaires (the Graded Chronic Pain Scale (GCPS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Pain-Detect, the short-form McGill Pain Questionnaire (SF-MPQ-2), and the Coping Strategies Questionnaire-Revised (CSQ-R)), a standardized paper and pencil cognitive battery (Hopkins Verbal Learning Test (HVLT), Trail Making A&B, Boston Naming Test, Controlled Oral Word Association Test (COWAT), Stroop Interference Test, Ruff Figural Fluency Test, and Raven's Progressive Matrices Test).; Other: Physical and Cognitive Function Testing; Upper Limb Isometric Strength, Short Physical Performance Battery (SPPB), GAITRite Instrumented Walking, Galvanic Skin Response, Knee Extension Isokinetic Strength, the Pepper Assessment Tool for Disability (PAT-D), and an electronic NIH Toolbox Cognitive Battery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short Physical Performance Battery (SPPB)	The Short Physical Performance Battery (SPPB) Total Score is a measure of physical function. It is calculated by summing three measures of lower-extremity function: standing balance (side-by-side, semi-tandem, and tandem stance), 4-meter walking speed, and ability to rise from a chair. Each task is rated on a 0-4 scale, with increasing scores indicating better physical performance. The SPPB Total scores range from 0-12.	At baseline-physical function visit

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA)
• Investigators: Principal Investigator: Yenisel Cruz-Almeida, MSPH, PhD, University of Florida

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): February 4, 2024
• Study Completion (Actual): February 4, 2024

Study Registration Dates

• First Submitted: December 23, 2014
• First Submitted That Met QC Criteria: July 1, 2015
• First Posted (Estimated): July 2, 2015

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Chronic Pain; Older adults; Musculoskeletal
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Pain; Chronic Pain
• Other Study ID Numbers: IRB201401056-N; K01AG048259 (U.S. NIH Grant/Contract); P30AG059297 (U.S. NIH Grant/Contract); Pepper Grant (Other Grant/Funding Number: National Institute of Health)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No