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CRCNS: Computational Model of Chronic Pain Analgesia via Closed-Loop Peripheral Nerve Stimulation

Award Number: R01AT011844
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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CRCNS: Computational Model of Chronic Pain Analgesia via Closed-Loop Peripheral Nerve Stimulation - Acute pain is important to survival, however, if the pain system becomes hypersensitive to non-painful and painful stimuli this can result in conditions called allodynia and hyperalgesia, respectively, and with time, chronic pain. Chronic pain is a significant burden on society, with an estimated prevalence of 11.2% in the U.S., and is a significant contributor to the opioid epidemic. Neuromodulation, via electrical stimulation of nerve fibers, has shown promise as an alternative pain treatment to pharmaceuticals with less side effects. but is still limited in efficacy for many patients. The programming (selective delivery of pulse width, frequency, and amplitude) of the stimulation is often performed by trial-and-error, and is kept constant (i.e., is open loop) between programming sessions. Closed-loop (CL) stimulation, in contrast, adapts over time to the system needs by automatically adjusting the parameters in response to a measured pain signal in the body. CL approaches in engineering systems are often designed based on models that mathematically characterize how a system responds to an actuation signal. Current CL approaches for pain, however, are model-free and simply wait for measured pain activity in the spinal cord to cross a threshold before activating suppressive stimulation. This acts as a local anesthetic, suppressing pathological pain, but unfortunately it also suppresses acute pain that alerts the body to damaging stimuli. In the proposed program, we will address these limitations by building a computational framework for a novel adaptive, model-based closed-loop peripheral nerve stimulation (PNS) approach for the correction of the dysfunctional pain system back to a normal physiological state. This will be accomplished by designing “model-matching” feedback PNS strategies, which match the response to exogenous stimuli (e.g. paw rub) of the CL pain system in a nerveinjured animal to that of a naïve, healthy animal. In order to match responses, we propose to build pseudolinear time invariant (pLTI) models of the response to stimulation in healthy and nerve injured conditions by collecting data and performing system identification. We will then optimize controllers to minimize the error between the responses. These controllers will be designed and optimized in silico then tested in vivo by continuously recording the electrophysiological response and responding by changing the amplitude and polarity of PNS pulses held at a constant frequency. This framework will be developed and tested using novel electrophysiological recordings from wide dynamic range (WDR) neurons in the dorsal horn of the spinal cord in naïve and nerve-injured rats in response to PNS and stimuli (e.g. stroke of a paw). WDR neurons are a cell type selected for its well documented deviation from its baseline in pain syndromes and role as a relay station between pain receptors in the periphery and the thalamus in the brain. The thalamus is the gateway for pain information to enter the brain for perception and can be accessed and recorded from using deep brain stimulation (DBS) electrodes in humans, making it an ideal location for pain therapies designed for translation in the future. Thus, we will simultaneously record from WDR neurons and pain sensitive populations of neurons in the thalamus.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research and Training in Complementary and Integrative Health	000	5	4/7/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $335,514 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research and Training in Complementary and Integrative Health	000	5	6/26/2025	NON-COMPETING CONTINUATION	$335,514
														Subtotal = $335,514

Issue Date FY: 2024 ( Subtotal = $374,699 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research and Training in Complementary and Integrative Health	000	4	6/25/2024	NON-COMPETING CONTINUATION	$374,699
														Subtotal = $374,699

Issue Date FY: 2023 ( Subtotal = $390,028 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research and Training in Complementary and Integrative Health	000	3	6/28/2023	NON-COMPETING CONTINUATION	$390,028
														Subtotal = $390,028

Issue Date FY: 2022 ( Subtotal = $399,845 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research and Training in Complementary and Integrative Health	000	2	7/1/2022	NON-COMPETING CONTINUATION	$399,845
														Subtotal = $399,845

Issue Date FY: 2021 ( Subtotal = $409,375 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research and Training in Complementary and Integrative Health	000	1	6/23/2021	NEW	$406,103
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Research and Training in Complementary and Integrative Health	001	1	7/16/2021	NEW	$3,272
														Subtotal = $409,375

Grand Total All Awards = $1,909,461

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CRCNS: Computational Model of Chronic Pain Analgesia via Closed-Loop Peripheral Nerve Stimulation

Award Number: R01AT011844

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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