Investigation of Plastic Changes in the CNS Associated With Peripheral Neuropathy

Recent neuroimaging literature on neuropathy suggests that chronic pain is characterized by learning-related and memory-related plastic changes of the central nervous system (CNS) with concomitant maladaptive changes in body perception. In particular, it is well accepted that learning-induced functional and structural brain changes involve, in addition to sensorimotor cortex, also limbic and frontal areas that mediate the transition from acute to chronic pain, resulting in pathological processing of body image, impaired multisensory integration and faulty feedback from various interoceptive processes. Interestingly, these alterations share many similarities with brain changes in emotional disorders and the specificity for pain needs to be determined. Moreover, the diagnosis and management of neuropathic pain syndromes remains a major clinical challenge, and this failure is partly attributed to our inability to identify functional brain changes that not only contribute to these syndromes, but also expose the patient to psychological burden that might lead to drug abuse. Although opioids are currently used frequently as first line therapy to alleviate pain caused by the various forms of neuropathies, recent reports indicate that long-term opioid therapy does not improve functional status but rather is associated with a higher risk of depression as well as subsequent opioid dependency and overdose. Thus, in order to improve therapeutic interventions in this patient group, it is imperative to develop a mechanistic model of central processes that could both explain and predict longitudinal changes associated with neuropathic pain syndromes. The identification of the correct sources of pain sensation (i.e. the contribution of central rather than peripheral factors to pain chronicity) is of paramount importance since the clinical course and patient management is likely to differ depending on the exact underlying cause.

Study Overview

• Status: Unknown
• Conditions: Peripheral Neuropathy
• Intervention / Treatment: Procedure: Moderate heat pain

Detailed Description

The goal is to relate non-invasive brain imaging data to clinical parameters in order to develop a mechanistic model of CNS adaptive processes that are produced by a patient-specific disease state. The investigators believe that such a model will have significant predictive value and might provide added value for subsequent patient management. To achieve the stated objectives, the following Specific Aim will be tested:

Aim 1. To assess regional brain changes in patients with polyneuropathies associated with a mild thermal pain challenge and to relate these changes to clinical measures of neuropathy.

Hypothesis 1A. Regional changes in brain glucose metabolism (as measured using FDG PET/CT imaging) associated with thermal pain will differ between patients with polyneuropathy and a group of age-matched controls. Specifically, patients with neuropathy will show a significantly higher increase in glucose metabolism in the medial pain system (affective dimension - brainstem, amygdala, insula) following thermal pain as compared to the control group, indicating increased sensitivity of the interoceptive neural control system for peripheral pain stimulation in patients.

Hypothesis 1B. In patients with neuropathy, regional changes in brain glucose metabolism associated with thermal pain in the medial pain system (affective dimension - brainstem, amygdala, insula) will be inversely related to clinical measures of neuropathic disease state (as measured using quantitative sensory testing, nerve conduction study and standardized pain scale assessment). In contrast, glucose metabolic changes in the lateral pain system (discriminatory dimension - thalamus, area S1) will be directly related to clinical measures. The extent of changes in the medial versus lateral system will also be correlated with the types of polyneuropathies, including idiopathic painful sensory neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth type-1A (CMT1A, the most common type of inherited peripheral nerve disease).

Hypothesis 1C. The increase in functional connectivity (as assessed using fMRI following an oscillatory thermal pain paradigm) will differ between neuropathic patients and controls. Specifically, functional connectivity between the medial pain system (brainstem, amygdala, insula) and the cognitive pain system (VLPFC and FP) will be significantly higher in the patient group as compared to the controls, indicating increased inhibition of the interoceptive brain network by the executive control system. Moreover, functional connectivity between the medial and cognitive pain systems will be directly related with clinical measures.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of a peripheral nerve disease - IPN, CIDP or CMT1A (patient group only)
2. Healthy volunteers with no history of medical conditions known to afflict the nervous system will be recruited as normal controls (control group only)
3. Age 18-60 (Inclusive)
4. Able to undergo PET and MRI
5. Patients who are not on sedative, antidepressant, sedative antihistaminic or narcotic medications.

Exclusion Criteria:

1. Any subject unwilling to undergo genetic testing (DNA sampling)
2. Any subjects with history of conditions known to affect the PNS, such as diabetes, stroke, thyroid disease, chemotherapy, renal failure, alcohol abuse, etc.
3. Subjects with abnormal physical findings suggesting peripheral nerve diseases.
4. Subjects of reproductive potential, who are sexually active but unwilling and/or unable to use medically appropriate contraception, or women who are pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional brain glucose metabolic changes	Changes in brain glucose metabolism associated with thermal pain in the brainstem, amygdala and insula regions. Units are the % change in regional standard uptake value (SUV) between the control and the thermal pain PET scan.	Day 0
Nerve conduction assessment	Electromyography (EMG) study determining nerve conduction velocity (NCV). The unit of NCV is m/s. The lower the NCV values, the more severe is the neuropathy.	Day 0
Pain Scale Assessment	Neuropathy Pain Scale (NPS) instrument. Units is a score between 0 (no pain) and 100 (worst possible pain).	Day 0

Collaborators and Investigators

• Sponsor: Wayne State University

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2019
• Primary Completion (Anticipated): November 30, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: January 8, 2019
• First Submitted That Met QC Criteria: January 12, 2019
• First Posted (Actual): January 16, 2019

Study Record Updates

• Last Update Posted (Actual): January 16, 2019
• Last Update Submitted That Met QC Criteria: January 12, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases
• Other Study ID Numbers: 1811001903

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Results of the study will be published in international journals.

Drug and device information, study documents

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