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Behavioral recovery from spinal cord injury following delayed application of polyethylene glycol

Richard B. Borgens^*, Riyi Shi and Debra Bohnert

Center for Paralysis Research, Institute for Applied Neurology, Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907-1244, USA

View larger version (56K): [in a new window]   Fig. 1. The circuitry of the cutaneus trunci muscle (CTM) reflex and its interruption by injury. Afferent sensory axons project from nociceptive and mechanosensory receptors in the skin into the spinal cord at the dorsal root of each vertebral segment on both the left and right sides via the dorsal cutaneous nerves, as shown in red. These synapse on second- and third-order neurons whose long-tract projections ascend the spinal cord in the ventrolateral funiculus to synapse on CTM motor neurons clustered as bilateral nuclei at the cervical–thoracic junction. There is no anatomical connection between the left- and right-side motor neuron pools. Efferent axons (blue) project out of the spinal cord as a component of the brachial plexus terminating on the cutaneus trunci muscle beneath the skin of the back via the lateral thoracic branch of the plexus. In the intact animal, the green and yellow/green area represents the entire normal bilateral receptive fields of the CTM sensory neurons. Tactile stimulation of this region produces skin contractions, but contractions are not elicited outside this region. Note that a lesion to the spinal cord blocks ascending conduction of the afferent sensory tracts of the CTM. This produces a region of areflexia below the level of the lesion in which tactile stimulation no longer produces CTM contractions (highlighted in yellow/green); the rostral fields are unaffected by the injury. The orange-shaded area represents a region of partial recovery within the area of areflexia below the level of the lesion. This drawing is not to scale and, for clarity, does not include every component in the CTM circuit (such as commissural or contralateral projections) (see Blight et al., 1990; Borgens et al., 1990).

View larger version (47K): [in a new window]   Fig. 2. Dot matrix evaluation of the cutaneus trunci muscle (CTM) reflex. (A) An overlay drawing of superimposed video images of a guinea pig. Black dots are permanent markers tattooed onto the shaved back and pink dots show the positions of the markers at the peak of skin contraction, captured by stop- frame video analysis (see Materials and methods). The exact point of tactile stimulation producing these CTM contractions is shown by the position of the monofilament probe used to stimulate the skin. During the period of testing, a boundary line was drawn on the back of the animal with a marker (highlighted in green) to reveal the total CTM receptive field. Stimulation within the circumscribed area produced skin contractions; stimulation outside the area did not. The actual video image source of the drawing is shown in C. The box in A is magnified in B, showing that the direction of skin contraction is generally towards the probe (arrow); the distance moved by a marker during contraction is also shown (hatched lines). This distance (2 mm) divided by the time required to produce it (0.12 s) gives the velocity of skin contraction (16.7 mm s–1).

View larger version (31K): [in a new window]   Fig. 3. Somatosensory evoked potentials (SSEPs). (A,B) Complete recordings of SSEP tests. In the pre-injury recording (A), the bottom three overlapping traces were produced by three separate sets of standard stimulations (refer to Materials and methods). These signals were averaged to produce the single top trace revealing two peaks of early-arriving (P1) and late-arriving (P2) evoked potentials at the brain (refer to Materials and methods). The peaks shown are characteristic SSEPs produced by tibial nerve stimulation in adult guinea pigs. The double-headed arrow shows the stimulus artifacts. A similar recording is shown in B, but this was taken within 30 min of a standardized compression to the mid-thoracic spinal cord. Note the complete loss of all ascending SSEPs. In C, a single averaged trace is shown of a median nerve stimulation recorded in this same animal, as a control procedure, within minutes of the traces shown in B.

View larger version (43K): [in a new window]   Fig. 4. The loss and recovery of cutaneus trunci muscle (CTM) receptive fields. (A) A normal, complete receptive field is shown highlighted in green on the tracing of a control guinea pig, as shown in Fig. 2 and described in Materials and methods. The region of areflexia is outlined in red on the next image, 24 h post-injury to the spinal cord. Note that approximately half the total CTM receptive field is lost as a result of severe spinal cord compression. One month later, this region remains unchanged. The video image used to produce the last drawing is shown on the far right. (B) From left to right, a similar set of images to those in A. The normal receptive field (green) and the region of areflexia (red) after spinal cord injury are marked. The region of CTM recovery in response to PEG application is outlined in blue in the last drawing and demonstrates a region of recovery of CTM sensitivity comprising approximately 42 % of the original region of areflexia. (C) Note the modest region of PEG-mediated CTM recovery outlined in blue. In the magnified section shown in D, note the position of the probe within the region of recovery and the movement of the skin marker dots towards the probe (arrow). Probing outside the region circumscribed in blue did not produce CTM reflex movements, but probing in the region marked in green (above the level of the injury), did elicit contractions. E shows the actual video images collapsed in layers to produce C and D.

View larger version (22K): [in a new window]   Fig. 5. Evoked potentials. (A; from top to bottom) Averaged traces of evoked potentials are shown, all obtained from the same animal, from the pre-injury electrical recording to those obtained 1 month post-injury. Note the complete absence of somatosensory evoked potentials (SSEPs) following spinal cord injury. This was characteristic in 100 % of the control population at all times tested. A median nerve control stimulation was also carried out at these times, but only the 1 month recording is shown in the bottom trace, the arrow pointing to a strong early-arriving evoked potential (for an explanation of P1 and P2, refer to Fig. 3). (B) Recovery of SSEP conduction in a PEG-treated animal. The characteristic double SSEP peaks are present in the uninjured animal. Note the complete loss of these peaks following injury and the positive median nerve control procedure carried out at this time point. One day post-injury to 1 month post-injury recordings show the recovery of SSEP conduction. The dotted line marks the approximate peak magnitude of the early-arriving SSEP. Note that the latency to peak contraction is reduced over time (refer to Fig. 6). Such recovering SSEPs were characteristic of 100 % of the PEG-treated animals and are in contrast to the complete absence of such conduction in all control animals.

View larger version (52K): [in a new window]   Fig. 6. Amplitude and latency of recovered somatosensory evoked potentials (SSEPs) in PEG-treated animals. The peak normalized amplitude of the early-arriving SSEP is plotted for all time points together with the mean latency (100 % represents the pre-injury value). Note that the mean magnitude of the SSEP is approximately 50 % of its pre-injury level, while the latency declines incrementally. The latency at 1 month was statistically significantly reduced compared with day 1 measurements. Values are means + S.E.M. Measurements from 13 animals are shown for all points except at 2 weeks, where nine animals were used for recordings.