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.

A closed loop feedback system for automatic detection and inhibition of mechano-nociceptive neural activity.

Clinical studies have shown that spinal or cerebral neurostimulation can significantly relieve pain. Current neurostimulators work in an open loop; hence, their efficacy depends on the patient's or physician's comprehension of pain. We have proposed and developed a real-time automatic recognition program with signal processing functions to detect action potentials. By using a wireless neurorecording module, spinal neuronal responses to mechanical stimuli (brush, pressure, and pinch) applied to rats' hind paws were recorded. Nociceptive spinal responses were detected and suppressed by our automated module through delivering electrical stimulation to the periaqueductal gray (PAG). The interspike intervals (ISIs) of the fired action potentials were used to distinguish among the three different mechanical stimuli. Our system was able to detect the neuronal activity intensities and deliver trigger signals to the neurostimulator according to a pre-set threshold in a closed-loop feedback configuration, thereby suppressing excessive activity in spinal cord dorsal horn neurons.

Detection of thermal pain in rodents through wireless electrocorticography.

In an effort to detect pain in an objective way, Electrocorticography (ECoG) signals were acquired from male Sprague-Dawley rats in response to thermally induced pain. A wearable, wireless multichannel system was utilized to acquire signals from freely-behaving animals during the experiments. ECoG signals were recorded before (baseline) and during the heat exposure for which animals withdrew their paws in response to the painful feeling. Analysis of the signals revealed a clear, high-amplitude peak at the moment of the paw withdrawal across all four recording channels in each test. Analysis in the frequency domain found the peaks coincided with an abrupt increase of delta rhythms (under 4 Hz). In the baseline, heating, and post-withdrawal segments, these rhythms were relatively low, indicating that the sharp increase in delta activity might be associated with pain. Theta, alpha, beta, and gamma rhythms were also measured, but no significant differences were found between each phase of the signals. These preliminary results are promising; however, more animal models will need to be tested to provide statistically significant results with high confidence.

Inhibition of spinal cord dorsal horn neuronal activity by electrical stimulation of the cerebellar cortex.

The cerebellum plays a major role in not only modulating motor activity, but also contributing to other functions, including nociception. The intermediate hemisphere of the cerebellum receives sensory input from the limbs. With the extensive connection between the cerebellum to brain-stem structures and cerebral cortex, it is possible that the cerebellum may facilitate the descending system to modulate spinal dorsal horn activity. This study provided the first evidence to support this hypothesis. Thirty-one wide-dynamic-range neurons from the left lumbar and 27 from the right lumbar spinal dorsal horn were recorded in response to graded mechanical stimulation (brush, pressure, and pinch) at the hind paws. Electrical stimulation of the cerebellar cortex of the left intermediate hemisphere significantly reduced spinal cord dorsal horn neuron-evoked responses bilaterally in response to peripheral high-intensity mechanical stimuli. It is concluded that the cerebellum may play a potential antinociceptive role, probably through activating descending inhibitory pathways indirectly.

Septal stimulation inhibits spinal cord dorsal horn neuronal activity.

Deep brain stimulation (DBS) has been used for relieving chronic pain in patients that have been through other existing options. The septum has been one of the targets for such treatment. The purpose of this study was to determine the inhibitory effect of electrical stimulation in the medial septum diagonal band of broca (MSDB) on neuronal activity in the spinal cord of rats anesthetized with sodium pentobarbital. While unilaterally stimulating the MSDB, wide dynamic range neurons in the lumbar region of the spinal cord were recorded in response to graded mechanical stimulation of the hind paws (brush, pressure, and pinch). Stimulation was at 1, 5, 10, and 20V, at 100Hz, and 0.1ms duration. Significant bilateral reduction was observed in response to pressure (ipsilaterally: 0.90±0.05, 0.48±0.06*, 0.55±0.05*, 0.40±0.05*; and contralaterally: 0.70±0.06*, 0.59±0.08*, 0.75±0.05*, 0.49±0.07*) and pinch (ipsilaterally: 0.89±0.08, 0.46±0.05*, 0.54±0.04*, 0.50±0.05*; and contralaterally: 0.78±0.05, 0.61±0.07*, 0.64±0.04*, 0.53±0.06*). Data were expressed as a fraction of control. Significant changes were also found in responses to brush in certain groups (ipsilaterally: 1.08±0.08, 0.72±0.06*, 1.00±0.12, 0.65±0.06*; and contralaterally: 0.93±0.05, 0.77±0.07*, 0.98±0.05, 0.84±0.07). Further analysis suggested that 5V was adequate for achieving optimal inhibition. It is concluded that the MSDB can be used as alternative target for DBS in the treatment of pain.

Recognition and inhibition of dorsal horn nociceptive signals within a closed-loop system.

We implemented an integrated system that can acquire neuronal signals from spinal cord dorsal horn neurons, wirelessly transmit the signals to a computer, and recognize the nociceptive signals from three different mechanical stimuli (brush, pressure and pinch). Positive peak detection method was chosen to distinguish between signal spikes. The inter spike intervals (ISIs) were calculated from the identified action potentials (APs) and fed into a numerical array called cluster. When the sum of the ISIs in the cluster reached a critical level, the program recognized the recorded signals as nociceptive inputs. The user has the flexibility to tune both the cluster size and critical threshold for individual's need to reach optimization in pain signal recognition. The program was integrated with a wireless neurostimulator to form a feedback loop to recognize and inhibit nociceptive signals.

Contributions of dorsal root reflex and axonal reflex to formalin-induced inflammation.

The dorsal root reflex (DRR) and the axonal reflex (AR) are antidromic activities in primary afferents and are involved in neurogenic inflammation. DRRs and/or ARs lead to release of neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). CGRP causes blood vessels to dilate leading to an increase in blood perfusion, whereas SP causes plasma extravasation, leading to edema. Both DRR and AR can be evoked by noxious stimuli. The goal of this study was to determine the role of DRR and AR in neurogenic inflammation by examining the blood perfusion (BP) change in hindpaws in response to formalin injection (an acute inflammatory agent). Laser Doppler images were collected simultaneously in both hindpaws in anesthetized rats to determine the level of BP. Local lidocaine was applied to the left sciatic nerve to block both orthodromic signals and antidromic DRRs without affecting ARs. All rats then received a subcutaneous formalin injection to the left hindpaw. Our results showed that (1) the mean BP of the left paw increased significantly following formalin injection, with or without lidocaine; (2) application of lidocaine in the left sciatic nerve alone significantly increased BP ipsilaterally; (3) formalin injection following lidocaine application significantly increased BP more than the group without lidocaine; and (4) there was delayed significant BP increase in the right (contralateral) hindpaw following formalin injection with or without lidocaine. It is concluded that ARs play a more important role than DRRs in formalin-induced neurogenic inflammation.

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.

Near infrared and visible spectroscopic measurements to detect changes in light scattering and hemoglobin oxygen saturation from rat spinal cord during peripheral stimulation.

In this study, we investigated dynamic changes in light scattering and hemoglobin oxygen saturation (S(sc)O(2)) on the rat spinal cord due to peripheral electrical stimulation by measuring near infrared (NIR) and visible spectroscopy, respectively. The spectral slope in the wavelength region between 700 and 900 nm is used as an index (S(NIR)) to quantify light scattering. With a 100-mum (source-detector separation) fiber-optic needle probe, optical reflectance was measured from the left lumbar region, specifically LL5, of the spinal cord surface at a height of 575 mum from the spinal cord surface. Graded electrical stimulations from 20 to 50 V, in increments of 10 V, were given to the plantar surface of the rat left hind paw for a period of 20 s. Changes in both light scattering (S(NIR)) and S(sc)O(2) were determined as a difference between the baseline and the maximum of slope value and hemoglobin oxygen saturation, respectively, during the stimulation period. There were significant differences in both S(NIR) and S(sc)O(2) during stimulation, with the average percentage changes of 10.9% and 15.5%, respectively. We observed that both S(NIR) and S(sc)O(2) measured at the spinal cord are insensitive to the intensity of the electrical stimulus, which is possibly caused by the nonlinear process of neurovascular coupling. Our finding essentially indicates that peripheral electrical stimulation results in significant changes in both light scattering and hemoglobin oxygen saturation on the rat spinal cord, and ignoring light scattering changes could lead to possible negative offsets of hemodynamic parameters (oxy-, deoxy-, and total hemoglobin concentrations) obtained in the functional optical imaging in the brain.