Yuan Bo Peng

The Biopsychosocial Approach to Chronic Pain: Scientific Advances and Future Directions.

The prevalence and cost of chronic pain is a major physical and mental health care problem in the United States today. As a result, there has been a recent explosion of research on chronic pain, with significant advances in better understanding its etiology, assessment, and treatment. The purpose of the present article is to provide a review of the most noteworthy developments in the field. The biopsychosocial model is now widely accepted as the most heuristic approach to chronic pain. With this model in mind, a review of the basic neuroscience processes of pain (the bio part of biopsychosocial), as well as the psychosocial factors, is presented. This spans research on how psychological and social factors can interact with brain processes to influence health and illness as well as on the development of new technologies, such as brain imaging, that provide new insights into brain-pain mechanisms.

Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system

Morphine and surgical cingulotomy, or transection of the anterior cingulate cortex (ACC), provides relief of chronic pain by selectively decreasing the affective dimension of the condition without altering sensory processing. Clinical reports suggest that morphine might be acting at the level of the ACC to alter the complex experience of pain. Therefore, the purpose of this experiment was to directly examine the functional role of the ACC in processing the aversive nature of pain induced by ligation of the L5 spinal nerve. Systemic administration of low dose morphine produced a selective attenuation of pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of mechanical paw withdrawal threshold. Supraspinally, microinjection of morphine into the ACC produced a selective naloxone reversible reduction in pain affect, as indicated by a decrease in the aversiveness of noxious cutaneous stimulation in nerve-damaged animals, with no alteration of response to mechanical stimulation. These data demonstrate the central role of the ACC opioid system in selectively processing the aversive quality of noxious mechanical stimulation in animals with a persistent pain condition.

Spinal dorsal horn neuron response to mechanical stimuli is decreased by electrical stimulation of the primary motor cortex

Motor cortex stimulation (MCS) has been used clinically as a tool for the control for central post-stroke pain and neuropathic facial pain. The underlying mechanisms involved in the antinociceptive effect of MCS are not clearly understood. We hypothesize that the antinociceptive effect is through the modulation of the spinal dorsal horn neuron activity. Thirty-two wide dynamic range spinal dorsal horn neurons were recorded, in response to graded mechanical stimulation (brush, pressure, and pinch) at their respective receptive fields, while a stepwise electrical stimulation was applied simultaneously in the motor cortex. The responses to brush at control, 10 V, 20 V, and 30 V, and recovery were 11.5+/-1.6, 12.1+/-2.6, 11.1+/-2.2, 10.5+/-2.1, and 13.2+/-2.5 spikes/s, respectively. The responses to pressure at control, 10 V, 20 V, and 30 V, and recovery were 33.2+/-6.1, 22.9+/-5.3, 20.5+/-5.0, 17.3+/-3.8, and 27.0+/-4.0 spikes/s, respectively. The responses to pinch at control, 10 V, 20 V, and 30 V, and recovery were 37.2+/-6.4, 26.3+/-4.7, 25.9+/-4.7, 22.5+/-4.3, and 35.0+/-6.2 spikes/s, respectively. It is concluded that, in the rat, electrical stimulation of the motor cortex produces significant transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting their response to an innocuous stimulus.

The anterior cingulate cortex and pain processing

The neural network that contributes to the suffering which accompanies persistent pain states involves a number of brain regions. Of primary interest is the contribution of the cingulate cortex in processing the affective component of pain. The purpose of this review is to summarize recent data obtained using novel behavioral paradigms in animals based on measuring escape and/or avoidance of a noxious stimulus. These paradigms have successfully been used to study the nature of the neuroanatomical and neurochemical contributions of the anterior cingulate cortex (ACC) to higher order pain processing in rodents.

A combined wireless neural stimulating and recording system for study of pain processing

Clinical studies have shown that spinal or cortical neurostimulation could significantly improve pain relief. The currently available stimulators, however, are used only to generate specific electrical signals without the knowledge of physiologically responses caused from the stimulation. We thus propose a new system that can adaptively generate the optimized stimulating signals base on the correlated neuron activities. This new method could significantly improve the efficiency of neurostimulation for pain relief. We have developed an integrated wireless recording and stimulating system to transmit the neuronal signals and to activate the stimulator over the wireless link. A wearable prototype has been developed consisting of amplifiers, wireless modules and a microcontroller remotely controlled by a Labview program in a computer to generate desired stimulating pulses. The components were assembled on a board with a size of 2.5 cm x 5 cm to be carried by a rat. To validate our system, lumbar spinal cord dorsal horn neuron activities of anesthetized rats have been recorded in responses to various types of peripheral graded mechanical stimuli. The stimulation at the periaqueductal gray and anterior cingulate cortex with different combinations of electrical parameters showed a comparable inhibition of spinal cord dorsal horns activities in response to the mechanical stimuli. The Labview program was also used to monitor the neuronal activities and automatically activate the stimulator with designated pulses. Our wireless system has provided an opportunity for further study of pain processing with closed-loop stimulation paradigm in a potential new pain relief method.

Electrical stimulation of the primary somatosensory cortex inhibits spinal dorsal horn neuron activity

Cortical stimulation has been demonstrated to alleviate certain pain conditions. The aim of this study was to determine the responses of the spinal cord dorsal horn neurons to stimulation of the primary somatosensory cortex (SSC). We hypothesized that direct stimulation of the SSC will inhibit the activity of spinal dorsal horn neurons by activating the descending inhibitory system. Thirty-four wide dynamic range spinal dorsal horn neurons were recorded in response to graded mechanical stimulation (brush, pressure, and pinch) at their respective receptive fields while a stepwise electrical stimulation (300 Hz, 0.1 ms, at 10, 20, and 30 V) was applied in the SSC through a bipolar tungsten electrode. The responses to brush at control, 10 V, 20 V, 30 V, and recovery were 16.0 +/- 2.3, 15.8 +/- 2.2, 14.6 +/- 1.8, 14.8 +/- 2.0, and 17.0 +/- 2.2 spikes/s, respectively. The responses to pressure at control, 10 V, 20 V, 30 V, and recovery were 44.7 +/- 5.5, 37.0 +/- 5.6, 29.5 +/- 4.8, 31.6 +/- 5.2, and 43.2 +/- 5.7 spikes/s, respectively. The responses to pinch at control, 10 V, 20 V, 30 V, and recovery were 58.1 +/- 7.0, 42.9 +/- 5.5, 34.8 +/- 3.9, 34.6 +/- 4.4, and 52.6 +/- 6.0 spikes/s, respectively. Significant decreases of the dorsal horn neuronal responses to pressure and pinch were observed during SSC stimulation. It is concluded that electrical stimulation of the SSC produces transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting innocuous stimuli.

A digital wireless system for closed-loop inhibition of nociceptive signals

Neurostimulation of the spinal cord or brain has been used to inhibit nociceptive signals in pain management applications. Nevertheless, most of the current neurostimulation models are based on open-loop system designs. There is a lack of closed-loop systems for neurostimulation in research with small freely-moving animals and in future clinical applications. Based on our previously developed analog wireless system for closed-loop neurostimulation, a digital wireless system with real-time feedback between recorder and stimulator modules has been developed to achieve multi-channel communication. The wireless system includes a wearable recording module, a wearable stimulation module and a transceiver connected to a computer for real-time and off-line data processing, display and storage. To validate our system, wide dynamic range neurons in the spinal cord dorsal horn have been recorded from anesthetized rats in response to graded mechanical stimuli (brush, pressure and pinch) applied in the hind paw. The identified nociceptive signals were used to automatically trigger electrical stimulation at the periaqueductal gray in real time to inhibit their own activities by the closed-loop design. Our digital wireless closed-loop system has provided a simplified and efficient method for further study of pain processing in freely-moving animals and potential clinical application in patients.

An Integrated Flexible Implantable Micro-Probe for Sensing Neurotransmitters

In this work, we have developed an integrated flexible implantable probe on a polyimide-film substrate for sensing neurotransmitters. The flexibility of the probe helps to prevent scar forming in tissues aiming for long-term in vivo monitoring. A micro Ag/AgCl reference electrode was integrated in the same probe with the Au/Cr or Pt/Cr working electrodes providing measurements without the need of a separate reference probe. Several electrode configurations have been considered and designed for implantation at various locations in the central nervous system. The prototype device for proof of principle was an enzyme-based electrochemical L-glutamate sensor using L-glutamate oxidase. A comparison between Au and Pt thin films was conducted by cyclic voltammetry to evaluate their performance as working electrodes. The L-glutamate oxidase was deposited on the working electrodes followed by a meta-Phenylenediamine electropolymerization process to improve the selectivity. The self-referencing technique was also utilized to enhance both the limit of detection and selectivity. The assembled sensors were calibrated and tested at various concentrations of L-glutamate with and without the presence of interfering molecules. The results showed good sensitivity and selectivity. In vivo animal tests were conducted to show the capability of detecting changes of electrochemical signals responding to graded peripheral somatosensory stimuli.

Quantification of light reflectance spectroscopy and its application: determination of hemodynamics on the rat spinal cord and brain induced by electrical stimulation.

Two quantification methods for light reflectance spectroscopy (LRS) were developed and validated to determine absolute and relative values of hemodynamic parameters and light scattering, followed by a specific application using in vivo animal experiments. A single-channel LRS system consisted of a light source, CCD-array detector, and a computer along with a bifurcated, 2-mm-diameter optical probe; this system was utilized to perform laboratory tissue phantoms for validation of the algorithms. In the animal study, a multi-channel, multisite approach was used to measure several reflectance spectra from rat brain and spinal cord on both the ipsi-lateral and contra-lateral sides, using thin 800-μm-diameter optic probes. The neuro-hemodynamic changes were induced by 10-V electrical stimulation in rat hind paw. The LRS data of the animals were analyzed using both absolute and relative methods. The results show that the relative method is computation-efficient and offers a quick estimation of changes in oxy-hemoglobin concentration for real-time monitoring. The absolute quantification method, on the other hand, provides us with an accurate computational tool to calculate absolute values of oxy-, deoxy-, total hemoglobin concentrations, and light scattering coefficients. We also observe that the hemodynamic responses in rat spinal cord were delayed with a few seconds and have an overall broader full width at half maximum, as compared to those from rat somatosensory cortex. LRS as a measurement system provides a robust method for studying local hemodynamic changes and a potential technique to investigate hemo-neural mechanisms in pain processing.

Periaqueductal gray-evoked dorsal root reflex is frequency dependent

The dorsal root reflex (DRR) is an antidromic action potential originating in the spinal cord that propagates toward the periphery. Given that both GABA(A) and 5-HT(3) receptors are involved in the generation of DRRs and stimulation of the periaqueductal gray (PAG) can induce the release of GABA and serotonin within the spinal cord, we investigated the modulation of DRRs by the PAG descending system. The central end of the cut left L5 dorsal root in adult Sprague-Dawley rats was tested with single fiber recording. Stimulating electrodes were placed in the PAG, sciatic nerve, or transcutaneously across hindpaws. Fifty-seven DRRs were recorded for the effect of PAG stimulation in 19 rats, and 51 DRRs from 26 rats and nine DRRs from seven rats were recorded for an effect of ipsilateral and contralateral peripheral stimulation, respectively. The results were expressed as a percentage of the number of DRRs over the number of stimuli. PAG stimulation at 0.2, 0.5, 5, 20, and 50 Hz produced ratios of 113.16+/-9.84, 114.54+/-12.22, 24.6+/-3.23, 17.77+/-4.76, and 12.62+/-3.44 (%), respectively. Stimulation at ipsilateral peripheral nerve evoked DRRs of 103.26+/-8.93, 95.27+/-10.57, 37.66+/-7.55, 11.32+/-4.96, and 5.32+/-3.82 (%), respectively. Stimulation of the contralateral peripheral nerve evoked DRRs of 90.88+/-15.59, 44.30+/-10.77, 6.29+/-1.63, 0.45+/-0.19, and 0.29+/-0.15 (%), respectively. Transection at the thoracic spinal level completely eliminated PAG-induced DRRs. In conclusion, both PAG and peripheral stimulation produced DRRs in a frequency dependent manner. Stimulus intensity has no significant effect on DRRs.