Emergence of Radial Nerve Dominance in Median Nerve Cortex After Median Nerve Transection in an Adult Squirrel Monkey

C. E. Schroeder1, S. Seto1, and P. E. Garraghty2

1 Departments of Neuroscience and Neurology, Albert Einstein College of Medicine, Bronx, New York 10461; and 2 Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana 47401

    ABSTRACT
Abstract
Introduction
Methods
Results
Discussion
References

Schroeder, C. E., S. Seto, and P. E. Garraghty. Emergence of radial nerve dominance in median nerve cortex after median nerve transection in an adult squirrel monkey. J. Neurophysiol. 77: 522-526, 1997. Throughout the glabrous representation in Area 3b, electrical stimulation of the dominant (median or ulnar) input produces robust, short-latency excitation, evident as a net extracellular "sink" in the Lamina 4 current source density (CSD) accompanied by action potentials. Stimulation of the collocated nondominant (radial nerve) input produces a subtle short-latency response in the Lamina 4 CSD unaccompanied by action potentials and followed by a clear excitatory response 12-15 ms later. Laminar response profiles for both inputs have a "feedforward" pattern, with initial activation in Lamina 4, followed by extragranular laminae. Such corepresentation of nondominant radial nerve inputs with the dominant (median or ulnar nerve) inputs in the glabrous hand surface representation provides a likely mechanism for reorganization after median nerve section in adult primates. To investigate this, we conducted repeated recordings using an implanted linear multi-electrode array straddling the cortical laminae at a site in "median nerve cortex" (i.e., at a site with a cutaneous receptive field on the volar surface of D2 and thus with its dominant afferent input conveyed by the median nerve) in an adult squirrel monkey. We characterized the baseline responses to median, radial, and ulnar nerve stimulation. We then cut the median nerve and semi-chronically monitored radial nerve, ulnar nerve and median nerve (proximal stump) evoked responses. The radial nerve response in median nerve cortex changed progressively during the weeks after median nerve transection, ultimately assuming the characteristics of the dominant nerve profile. During this time, median, and ulnar nerve profiles displayed little or no change.

    INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References

The glabrous hand surface representation in somatosensory cortical Area 3b of primates appears to be divisible into median and ulnar nerve "territories" based on which peripheral nerve provides the dominant or obvious cutaneous input (Wall et al. 1993). Recently, Garraghty et al. (1994) and Schroeder et al. (1995) suggested that, in addition to its dominant input, the cortex within the glabrous surface representation also receives cryptic or nondominant inputs from the dorsal hand surface, conveyed by the radial nerve. In the latter report, the suggestion was based on the direct observation that in locations dominated by median or ulnar nerve inputs from the glabrous hand surfaces, either cutaneous stimulation of the hand dorsum or electrical stimulation of the radial nerve could produce a "nondominant" pattern of response. Dominant and nondominant responses were characterized by their local postsynaptic potential and action potential patterns, as indexed by laminar profiles of current source density (CSD) and multi-unit activity, sampled using linear array multi-electrodes. Throughout the glabrous representation in Area 3b, electrical stimulation of the dominant (median or ulnar) input produced robust, short-latency excitation, evident as a large current sink accompanied by action potentials in Lamina 4. Stimulation of the collocated nondominant (radial nerve) input produced a subtle short-latency response in the Lamina 4 CSD, unaccompanied by action potentials, and followed by a clear excitatory response 12-15 ms later. Laminar response profiles for both dominant and nondominant inputs had a "feedforward" pattern, with initial activation in Lamina 4, followed by extragranular laminae.

The normal corepresentation of nondominant dorsum hand (radial) inputs with the dominant (median or ulnar) inputs in the glabrous hand surface representation would seem to provide a clear vehicle for the biased patterns of reorganization found after peripheral nerve section (Garraghty and Muja 1996; Garraghty et al. 1994; Merzenich et al. 1983a,b). The present experiment tested the prediction that in median nerve cortex, after removal of the dominant input, the nondominant, radial nerve input would acquire the physiologic characteristics of the dominant input.

    METHODS
Abstract
Introduction
Methods
Results
Discussion
References

Using previously described methods (Schroeder et al. 1995), one squirrel monkey (Saimiri sciureus) weighing 0.6 kg was implanted with a plastic cranial pedestal to provide for head restraint and stabilization of the multi-electrode during repeated measurements. To approximate the conditions of micro-electrode mapping experiments, during recording, the monkey was anesthetized with a mixture of xylazine (10 mg/kg) and ketamine (30 mg/kg). Depth of anesthesia was monitored using palpebral and pad withdrawal reflexes. Body temperature was kept within normal limits using a water heating blanket.

Laminar CSD and multi-unit activity profiles were obtained by recording with a linear array multicontact electrode, positioned so as to straddle the cortex from the pial surface to the white matter. Tactile stimulation was used to define the cutaneous representation at the recording site and electrical stimulation then was used to quantify the strength, laminar distribution, and temporal pattern of median, ulnar, and radial nerve inputs. Electrical stimulation was provided by 100 µs, constant-current, square-wave pulses applied with bipolar electrodes to the skin of the forearm at points determined to permit isolated stimulation of individual nerves. Stimulation sites and appropriate current levels (2-3 mA) were determined from preliminary studies of nerve stimulation concurrent with recording of electromyographic responses from appropriate distal musculature (see also Schroeder et al. 1995). For median nerve, the optimal stimulation point was found to be at the ventral forearm, 1-2 cm proximal to the wrist, whereas that for the radial nerve was at the mid-dorsal forearm. Current settings were adjusted to produce isolated suprathreshold activation of the appropriate distal musculature, With this level of stimulation, it is safest to assume that no type of fiber within the target nerve was excluded from stimulation. This could pose a problem for the present study if the "nondominant" radial nerve response in median nerve cortex was actually a long-latency response to cutaneous input, stemming from the shock evoked hand twitch and conveyed by the median nerve. However, there was a built-in control for this possibility in that the "nondominant" radial nerve response observed at baseline was unchanged in the acute phase of recording after the median nerve was cut and the route of cutaneous inputs in question was removed.

After mapping penetrations, the multi-electrode was permanently affixed at a site in Area 3b, having a cutaneous representation on the proximal volar surface of D2 and displaying a "median nerve dominant" electrical stimulation profile. Baseline median, radial, and ulnar nerve responses were measured before the median nerve was cut and ligated in the mid-forearm (see Garraghty and Muja 1996). Recordings were taken immediately after nerve section and then, beginning on the fifth postoperative day, three times weekly for 4 wk. The monkey then was killed and the brain was removed for histologic analysis.

    RESULTS
Abstract
Introduction
Methods
Results
Discussion
References

Figure 1, A and B, displays laminar CSD and multi-unit activity profiles produced by electrical stimulation of the median and radial nerves, recorded with the multi-electrode array implanted in the median nerve representation in Area 3b. The collocated median and radial nerve profiles conform precisely to earlier descriptions (Schroeder et al. 1995). In this site, median nerve stimulation produced the largest short-latency activity and a "classic" sensory cortical laminar activation sequence (Fig. 1A). Initial response in Lamina 4 (arrow) is indicated by a current sink with a concomitant increase in multi-unit activity (MUA) and this is followed by similar excitatory response configurations in the extragranular laminae. The largest excitatory response is centered in Lamina 3. Throughout the laminae, large current sinks and MUA increases (indicative of net depolarization of local neurons) are followed by current sources with MUA reductions (indicative of hyperpolarization). In the radial nerve response profile (Fig. 1B), the initial short-latency response in the middle laminae is subtle; there is a small transmembrane current flow component without a discernable MUA correlate. The laminar sequence and distribution of activity are similar to those of the median nerve profile, but the clear excitatory response, signaled by transmembrane current flow and associated MUA activity, begins 12-15 ms later. Ulnar nerve stimulation produces a very poor response in this site (not shown). In sum, the median nerve provides the dominant input to this site, as indicated by the robust, short-latency activity; the radial nerve provides a substantial, but nondominant, input; and the ulnar nerve provides little or no input.


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FIG. 1. A: laminar CSD and multi-unit activity (MUA) profiles elicited by electrical stimulation of the median nerve. Profiles were obtained using a linear array, multicontact electrode, fixed in a position covering sites extending from approximately Lamina 2/3 border down into white matter. Position of Lamina 4 is indicated by arrow (left). A functional indicator of ventral (white matter) border of cortex is a rapid drop in current source density (CSD) amplitude, often accompanied by high-amplitude MUA (see Schroeder et al. 1995); this is most evident in D. B: a laminar activity profile evoked by radial nerve stimulation in the same site. C and D: radial nerve-evoked activity profiles sampled at +7 and +21 days post median nerve section.

Median nerve section induced a progressive change in the radial nerve profile. Figure 1, C and D, display the radial nerve-evoked profile at 7 and 21 days after median nerve section. The notable change from the presection profile is that the +7 day profile displays clear short-latency excitation, beginning with the initial response in Lamina 4 and continuing with the subsequent responses in supra- and infragranular sites. At +21 days, the pattern of change clearly has progressed, in that response amplitudes, as indexed by both CSD and multi-unit activity, have increased. Despite these changes, the basic feedforward laminar activation sequence is maintained; there is initial response in Lamina 4, followed by activation of the extragranular laminae.

To summarize the time course of the change in the radial nerve-evoked response, Fig. 2 (left) presents radial nerve-evoked responses at baseline (precut) along with those sampled acutely and at intervals after median nerve section. The data format is a condensed representation of the CSD profile, the average rectified current flow (AVREC) waveform, which is derived by full-wave rectifying each CSD waveform and averaging them together (Schroeder et al. 1995). Because the AVREC is derived from the CSD, it has a more direct relationship to postsynaptic potentials, than to action potentials. Thus response features noted in the AVREC waveform may be manifested poorly or absent in concomitant MUA patterns (for detailed discussion of this point, see Schroeder et al. 1995). On the right are median nerve stump and ulnar nerve-evoked waveforms at selected time points (i.e., at precut baseline and at 5 and 28 days postmedian nerve section).


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FIG. 2. A condensed representation of the laminar CSD profile, the average rectified current flow (AVREC) waveforms evoked by electrical stimulation of the radial nerve, sampled at time points before and after section of median nerve (left). Right: AVREC waveforms elicited by electrical stimulation of ulnar and median nerves (proximal stump) at selected time points. Arrows indicate corresponding radial nerve-evoked responses taken at these time points.

In the baseline and acute postcut recordings, the prominent initial response to radial nerve stimulation begins at ~30 ms poststimulus. It is preceded by an epoch of smaller response that begins at 7-10 ms poststimulus (described above) and is often not evident in the AVREC waveform. The obvious change in the radial nerve AVREC waveform after median nerve transection is a decrease in the latency and increase in the amplitude of the prominent excitatory response. No change was observed on the day of the median nerve section, but a decrease in the excitatory response latency was apparent in the first postcut recording on day 5. Thereafter, there was a progressive amplitude increase that appeared to asymptote by 21 days postcut. The median and ulnar nerve responses in this site appeared largely unchanged throughout the postcut period.

    DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References

The main finding of the present study is that in median nerve cortex, after removal of the "dominant," median nerve input, the pre-existing, "nondominant," radial nerve response undergoes progressive increase in amplitude and decrease in latency, eventually assuming the physiologic characteristics of the dominant input. The time course of reorganization, as studied in one subject here, parallels that outlined by micro-electrode mapping of several subjects in the experiments of Merzenich et al. (1983b). This time course is consistent with a use-dependent "Hebbian-like" potentiation of inputs, such as that implicated by the finding that similar reorganization is prevented by N-methyl-D-aspartate (NMDA)-receptor blockade (Garraghty and Muja 1996). Also consistent with earlier work (Garraghty and Muja 1996; Merzenich et al. 1983a,b), we find little evidence of an expansion of ulnar nerve representation in the deprived cortex. The overall pattern of results supports the view (Garraghty and Kaas 1991; Garraghty et al. 1994; Schroeder et al. 1995) that pre-existing anatomic circuitry can account for the more protracted, as well as the immediate, phase of reorganization (see e.g., Cusick et al. 1990) that follows nerve injury.

It is noteworthy that the radial nerve response, in its baseline (precut) form and throughout reorganization, maintains a characteristic "feedforward" laminar activation profile, with an initial response in Lamina 4, and subsequent responses in the extragranular laminae (see also Schroeder et al. 1995). This observation is inconsistent with the notion that adult plasticity, in contrast to developmental plasticity, uses "associative" (feedback and lateral) circuits rather than feedforward circuits (Singer 1995).

Our results provide an additional extension of previous work by demonstrating that the injured median nerve retains its access to cortex after reorganization. This is important because it indicates that the reorganization that follows peripheral median nerve transection is not enabled by any substantial reduction in the central connections of dorsal root ganglion neurons whose peripheral processes comprise the median nerve. Thus the elimination of "normal" patterns of peripheral sensory activation by cutting the median nerve is sufficient to permit the emergence of the underlying radial nerve inputs to "median nerve cortex." The elimination of the afferents themselves is not necessary.

    ACKNOWLEDGEMENTS

  We thank Drs. J. C. Arezzo and D. C. Javitt for helpful comments and discussion and for facilities support. We thank R. Lindsley, J. P. Noonan, and M. Litwak for technical assistance and H. Rubin for photography.

  This work was supported by National Institute of Mental Health Grants MH-47939 and MH-06723 and by Indiana University Grant 22-314-31.

    FOOTNOTES

  Present address and address for reprint requests: C. Schroeder, Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Bldg. 37, Orangeburg, NY 10962.

  Received 8 August 1996; accepted in final form 17 October 1996.

    REFERENCES
Abstract
Introduction
Methods
Results
Discussion
References

0022-3077/97 $5.00 Copyright ©1997 The American Physiological Society