Principal Investigator/Program Director (Last, First, Middle): Peng, Yuan Bo / Devarajan, Venkat / Subbarao, Kamesh

Development of Implantable Wireless Sensor and Stimulator for Chronic Pain Control

A. BACKGROUND AND SPECIFIC AIMS

Pain is a significant national health problem. It is the most common reason individuals seek medical care, with 40 millions of medical visits annually, costing the American public more than $100 billion each year. Sensory signals, including pain, are transmitted from periphery to the spinal cord and then up to higher centers. Pain signals are carried by small myelinated A-delta and unmyelinated C-fibers of the primary afferents to spinal cord dorsal horn neurons, where the information is then relayed to the thalamus, and further up to the primary somatosensory cortex. With this ascending pathway, a noxious stimulus can be perceived as pain. These ascending signals also activate descending inhibitory systems in the midbrain and medulla, which project to the spinal cord. Together with the large myelinated A-beta afferent inputs, they modulate the information processing at the dorsal horn projection neurons to relieve pain. There is a relatively better control of acute pain, such as postoperative pain can be managed by morphine. However, there are not enough tools to treat chronic pain, such as neuropathic pain, back pain, cancer pain. It is the chronic pain that changes the psychological status of the patient and make them suffer. Stimulation of certain area of the nervous system (e.g., motor cortex, and periaqueductal gray) is one of the options to those patient with chronic pain conditions.

Our long-range goal is to provide new tools that can be used to relieve chronic pain. The objective of this application is to develop an implantable neural sensor and stimulator system that can identify and decode the signals in the somatosensory cortex and transmit the signal to a stimulator over the spinal cord.

We plan to develop this system in two phases:

  1. Phase 1.Develop the sensor that can be implanted in the somatosensory cortex. It is postulated that there will be an increased response in the somatosensory cortex when different intensity of natural stimuli are applied.
  2. Phase 2. Develop the spinal cord stimulator that can receive signals from the implanted sensor and deliver stimulating current based on the intensity of signal from the sensor. It is expected that this stimulator can adjust the current to reach the optimal stimulation.
  3. Phase 3. Animal experiment. The sensor and spinal cord stimulator will be implanted in the rat. Following recovery from surgery, the free moving animals will be stimulated with innocuous and noxious stimuli (mechanical, thermal, and chemical). Signals from the sensor will be analyzed to correlate the level of stimuli, and the “painful” signals will be transmitted to the spinal cord stimulator. The intensity of stimulation will be adjusted to the optimal combination (frequency, duration, and amplitude) in the same animal under the same noxious stimulus condition to determine how much pain can be relieved (Fig. 1).

It is our expectation that this project is feasible because spinal cord stimulator has been used in the clinic for the treatment of chronic pain (Ahmed, 2003; Cata et al., 2004; Hautvast et al., 1997; Hunter and Ashby, 1994; Kavar et al., 2000; Kemler et al., 2000a; Kemler et al., 2000b; Mironer and Somerville, 2000; North et al., 2003; Rushton, 2002; Spincemaille et al., 2000; Tseng, 2000; Turner et al., 2004). The resultant research will be significant, because with this innovative collaborative research between psychology and engineering, we will be the first to innovate an automatic feed forward stimulation system that will deliver optimal level of stimulation to the spinal cord. Compare to medical schools, UTA has the advantage to combine expertise from both engineers and neuroscientists to achieve this goal.

B. EXPERIMENTAL DESIGN AND METHODS

Sensor Development.

Stimulator Development.

In Vivo Animal Test. Male Sprague-Dawley rats, weighing 200 – 250 g, will be surgically prepared using aseptic techniques. In brief, animals will be anesthetized using isoflurene anesthesia (3% induction; 1.5% - 2% maintenance). Craniotomoty will be performed over the primary somatosensory area and the sensor will be implanted. Laminectomy will be performed over the lumbar spinal cord region to implant the spinal cord stimulator. After 7-day postoperative recovery, animals will be tested in the following three behavioral paradigms. Simultaneous recording of signals from the somatosensory sensor will be correlated with these behavioral responses.

Thermal Paw Withdrawal Threshold Latency TestingThe measurement of thermal paw withdrawal threshold latency utilizes an infrared heat source applied to the plantar surface of both hindpaws (Ugo Basile, Plantar Test #7370). The beam intensity will be adjusted during baseline testing to produce withdrawal threshold latencies of 6 – 7 sec. Following a 15-minute habituation period, threshold testing will be performed three times per paw with at least 2-min separating each measurement. The average value of the three latency measurements for each paw will be used to calculate the withdrawal latency.

Mechanical Paw Withdrawal Threshold Testing Following a 15-min habituation period, calibrated von Frey filaments are pressed upward against the plantar surface of each hind paw for approximately 1 sec. Four von Frey filaments (43, 64, 106, and 202 mN) are employed and administered in an ascending series to establish response threshold. The stimulus series consist of alternately testing the left and right hind paws with each of the four filaments beginning with the least (43mN) and progressing in order to the greatest (202 mN) force von Frey. A withdrawal response is recorded when the animal actively lifts the stimulated paw during the stimulation period. The ascending stimulus series is repeated over 10 trials and the frequency of withdrawal response is converted to percent response: % response = (frequency of response/20)*100.

Formalin test Animal will be injected with 50 l of 3% formaldehyde into left planter skin of the hindpaw. The number of seconds tha animal spends licking the paw, elevating the paw, and resting the paw on the floor surface will be recorded over 60 min.

REFERENCES

1. Ahmed SU (2003) Complex regional pain syndrome type I after myocardial infarction treated with spinal cord stimulation. Reg Anesth Pain Med 28: 245-247.

2. Cata JP, Cordella JV, Burton AW, Hassenbusch SJ, Weng HR, Dougherty PM (2004) Spinal cord stimulation relieves chemotherapy-induced pain: a clinical case report. J Pain Symptom Manage 27: 72-78.

3. Hautvast RW, Ter Horst GJ, DeJong BM, DeJongste MJ, Blanksma PK, Paans AM, Korf J (1997) Relative changes in regional cerebral blood flow during spinal cord stimulation in patients with refractory angina pectoris. Eur J Neurosci 9: 1178-1183.

4. Hunter JP, Ashby P (1994) Segmental effects of epidural spinal cord stimulation in humans. J Physiol (Lond ) 474: 407-419.

5. Kavar B, Rosenfeld JV, Hutchinson A (2000) The efficacy of spinal cord stimulation for chronic pain. J Clin Neurosci 7: 409-413.

6. Kemler MA, Barendse GA, van Kleef M, De Vet HC, Rijks CP, Furnee CA, van den Wildenberg FA (2000a) Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 343: 618-624.

7. Kemler MA, Barendse GA, van Kleef M, De Vet HC, Rijks CP, Furnee CA, van den Wildenberg FA (2000b) Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy [see comments]. N Eng J Med 343: 618-624.

8. Mironer YE, Somerville JJ (2000) Pain tolerance threshold: a pilot study of an objective measurement of spinal cord stimulator trial results. Pain Med 1: 110-115.

9. North RB, Calkins SK, Campbell DS, Sieracki JM, Piantadosi S, Daly MJ, Dey PB, Barolat G (2003) Automated, patient-interactive, spinal cord stimulator adjustment: a randomized controlled trial. Neurosurg 52: 572-580.

10. Rushton DN (2002) Electrical stimulation in the treatment of pain. Disabil Rehabil 24: 407-415.

11. Spincemaille GH, Klomp HM, Steyerberg EW, van Urk H, Habbema JD (2000) Technical data and complications of spinal cord stimulation: data from a randomized trial on critical limb ischemia. Stereotact Funct Neurosurg 74: 63-72.

12. Tseng SH (2000) Treatment of chronic pain by spinal cord stimulation. J Formos Med Assoc 99: 267-271.

13. Turner JA, Loeser JD, Deyo RA, Sanders SB (2004) Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 108: 137-147.

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