Myo-cortical crossed feedback reorganizes primate motor cortex output

Abstract

The motor system is capable of adapting to changed conditions such as amputations or lesions by reorganizing cortical representations of peripheral musculature. To investigate the underlying mechanisms we induced targeted reorganization of motor output effects by establishing an artificial recurrent connection between a forelimb muscle and an unrelated site in the primary motor cortex (M1) of macaques. A head-fixed computer transformed forelimb electromyographic activity into proportional subthreshold intracortical microstimulation (ICMS) during hours of unrestrained volitional behavior. This conditioning paradigm stimulated the cortical site for a particular muscle in proportion to activation of another muscle and induced robust site- and input-specific reorganization of M1 output effects. Reorganization was observed within 25 min and could be maintained with intermittent conditioning for successive days. Control stimulation that was independent of muscle activity, termed "pseudoconditioning," failed to produce reorganization. Preconditioning output effects were gradually restored during volitional behaviors following the end of conditioning. The ease of changing the relationship between cortical sites and associated muscle responses suggests that under normal conditions these relations are maintained through physiological feedback loops. These findings demonstrate that motor cortex outputs may be reorganized in a targeted and sustainable manner through artificial afferent feedback triggered from controllable and readily recorded muscle activity. Such cortical reorganization has implications for therapeutic treatment of neurological injuries.

Figure 1.

Conditioning paradigm. a, ICMS testing before and after conditioning documented the muscle and torque responses at movement threshold for different cortical sites with the forelimb in a resting, neutral position. Right, Example TTAs of rectified EMG and torque responses evoked from one cortical site. b, During ADC the neurochip discriminated Mrec raw EMG and delivered proportional intracortical subthreshold stimuli at cortical site Nstim while the animal engaged in unrestrained behavior. Right, Mrec EMG activity exceeding threshold (horizontal dashed line)-triggered current pulses noted in the Nstim raster (blue).

Figure 2.

Torque vector analysis. TTA plots show torques evoked by trains of ICMS stimuli, called torque TTAs, computed for each manipulandum axis and aligned on onset of stimulus train (0 ms). Torque axes were combined to generate the torque trajectory (curved line) and mean torque vector (green arrow) in 3D torque space for 120 ms following onset (*). Data represent average of 41 ICMS responses at movement threshold evoked from a cortical site associated with forelimb pronation. Stimulus intensity 80 μA. Rad, radial deviation; Uln, ulnar deviation; Pro, pronation; Sup, supination; Flex, flexion; Ext, extension.

Figure 3.

ICMS torque responses as a function of stimulus intensity. Torque trajectories (colored curved lines) and mean torque vectors (colored straight lines) for different stimulus intensities delivered to a cortical site associated with forelimb extension plotted in 3D torque space. Data represent 120 ms following stimulus onset. To permit serial comparisons and angular measurements between torques, shadows of the torque vectors are projected (in gray) onto the major plane capturing the torque directions. Subsequent comparisons are made on the major planes.

Figure 4.

EMG Response to ICMS. TTAs of rectified EMG evoked during ICMS at two stimulation intensities in animal A. Response onsets were defined as times when the mean response over a 6 ms sliding window exceeded 3 SDs above baseline mean. Baseline means were calculated from the 500 ms immediately preceding stimulus onset (vertical line). Stimulus train is shown as horizontal dark gray bar. Higher stimulation intensity evokes larger TTA response (arrows). Red bars show baseline and response mean.

Figure 5.

ICMS responses from a cortical site associated with forelimb extension. Muscle responses and torque responses are shown for different stimulus intensities delivered at a single cortical site in animal A. Torque responses, shown at the right, increase with stimulus intensity beginning at movement threshold (120 μA). Small muscle responses were observed at subthreshold stimulation intensities but failed to generate consistent torques. Horizontal gray bars represent stimulus trains and train onset shown as vertical line. Calibration lines represent 50 mV (EMG) or 0.05 N · m (torque). ED 4/5, extensor digitorum digits 4 and 5; EDC, extensor digitorum communis; FDP, flexor digitorum profundus; Rad, radial deviation; Uln, ulnar deviation; Pro, pronation; Sup, supination; Flex, flexion; Ext, extension.

Figure 6.

Location of microwire tracks during conditioning experiments. a, Schematic of lateral cerebral hemisphere. b, Experiment 1, animal Z. c, Experiment 2, animal Y. d, Experiment 3, animal Z. e, f, Experiments 4 and 5, animal A. Experiment numbers correspond to table entries.

Figure 7.

Motor cortex output reorganization during conditioning. a, Average wrist torque vectors (colored arrows) and trajectory traces (curved lines) plotted in torque space in the plane that captured dominant torque directions during ICMS at three cortical sites. Nrec vector (red arrow) shifts 92°after the first 24 h conditioning session (* in b). The initial 50 ms segment of the Nrec trajectory (indicated by gray arrows) reverses direction following Conditioning, aligning with the trajectory of Nstim. F, flexion; E, extension; G, grip; R, release. b, Direction of mean torques over 11 consecutive days. The mean conditioning effect during 3 d of conditioning (gray regions) was 61.0 ± 26.7°. Dashed red line shows mean Nrec at baseline. Error bars indicate SEM. c, Rates of stimuli triggered by Mrec muscle activity during free movement during first conditioning session. Mean rate for all three conditioning sessions was 6.9 ± 6.8 Hz. Data concatenated in 100 ms bins. d, Muscle responses evoked by ICMS. Red arrows indicate the appearance of responses in EDC (Mstim) evoked by ICMS at Nrec following a single conditioning session (* in b). e–g, A separate conditioning experiment in another animal. Following 5.8 h of conditioning, Nrec torque vectors shifted 78.2° toward Nstim responses (* in f). P, pronation; S, supination; F, flexion; E, extension. f, Mean conditioning effect was 73.3 ± 16.6° across five conditioning sessions. g, Stimulation rates (over 1 min bins) during all ADC sessions. h, The relative location of microwires for the two animals. C.S., central sulcus.

Figure 8.

ADC is necessary and sufficient to induce reorganization. a, Direction of mean torques in separate conditioning experiment. Conditioning for 25 min produced a 46.7° shift in Nrec torque responses (*). The mean conditioning effect across three conditioning sessions (ADC) in block 1 was 67.1°. Torque responses returned to near-baseline levels (dashed red line) following termination of artificial feedback. In the second block Nrec underwent pseudoconditioning (PC) using identical stimulation parameters as in *, including the behavioral condition, conditioning duration (25 min), current intensity (44 μA; 49% of movement threshold), and mean frequency (9 Hz). The total number of stimuli administered during ADC and PC was nearly identical (1.39 × 10⁴ and 1.35 × 10⁴, resp.). No reorganization was observed during PC (arrow). All sessions were 24 h in duration, except as noted above. b, The observed stimulation rate during the initial conditioning session of block 1 was 9.0 ± 0.8 Hz. c, The programmed stimulation rate during PC was 9.0 Hz.

Figure 9.

Sustaining plasticity by conditioning anatomical antagonists with intermittent reinforcement. a, Torque responses at baseline and following 3.2 h of conditioning in animal Z. Nrec mean torque vectors (red arrows) shifted 59° above baseline. This shift was explained by significant change in the initial segment of the torque trajectories (gray arrows), and reversal of the direction of torque trajectory at its inflection point (†). Data represent first conditioning session shown in b (*). b, Direction of mean torque during an experiment with two conditioning blocks. The first block (ADC-1) tested effects of local current spread by decreasing current intensity (indicated by intensity of gray shading in calibration bar). The second block (ADC-2) tested the sustainability of plasticity by introducing intermittent reinforcement with a decreasing reinforcement schedule. The Nstim stimulation ratio (indicated by the height of the calibration bar) was incrementally decreased by a factor of 4 while the stimulation intensity was held constant (18 μA). Intermittent reinforcement maintained cortical reorganization throughout block 2. Nrec baseline torque shown by dashed red line. Ctrl microwire was lost to mechanical breakage between blocks. c, Stimulation rates during conditioning block 1 (left) and 2 (right). Stimulation rates were highly phasic, reflecting the animal's unrestrained limb movements. During block 2, the stimulation rate was reduced in two steps (§) by increasing the ratio of EMG triggers-to-intracortical stimuli during conditioning. Rate data plotted for 1 min bins.

Figure 10.

Reorganization is site specific and input specific. a, Change in mean torque direction for each cortical site for all stages of the experiments. ADC (black bars) produced significant reorganization of torque output at Nrec, but not Nstim or Ctrl sites. Pseudoconditioning (red bars) failed to induce reorganization at any cortical site. Pooled data from all experiments in four animals; number of observations shown in each bar. Baseline variability in torque output shown in white. Data represent mean ± SEM. ***p < 0.001, ns, not significant. b, Summary of ADC results illustrated by the angular separation of Nrec and Ctrl ICMS effects from the direction of Nstim mean torque (inset). Nrec ICMS effects (♦) fall below the dashed line of identity in every instance, indicating a consistent shift toward Nstim after conditioning. c, Baseline and conditioned mean ICMS effects for Nrec (filled bars) and Ctrl (open bars). Conditioning resulted in reduced separation of torque responses between Nrec and Nstim (***p < 0.001, independent samples t test, t = 6.825). There were no significant differences between baseline and conditioning Ctrl means.

Figure 11.

Proposed mechanism of reorganization. a, ICMS testing defines baseline responses. b, Nstim ADC evokes postsynaptic depolarization synchronized to presynaptic inputs from Nrec horizontal connections normally activity during movement (dashed red arrow). c, Following conditioning, ICMS at Nrec activates strengthened pathways to produce responses that incorporate Nstim projections. Similar mechanisms could occur at other sites of convergence. d, Putative convergent sites for synaptic strengthening. The projections of separate motor cortex populations are illustrated in a hypothetical conditioning experiment pairing anatomical agonists FCR and FDP. A stimulating microwire terminates in the proximity of Nstim. ADC strengthens synapses shown in red (“x”) that mediate connections from Nrec during volitional movements. A proportion of the population is activated directly by focal current injection (yellow region). Subcortical and spinal sites of convergence are illustrated by red boutons (y and z). e, Corticomuscle loop. A schematic of the minimal corticomuscle pathways (left) and response patterns of involved neurons (right). CM cells have the most direct, monosynaptic connections on spinal motoneurons (MN), although polysynaptic linkages via other corticospinal cells exist. The afferent pathway begins with Ia afferents whose somas are located in the DRG. The predominant response type of these cell populations recorded during a ramp-and-hold wrist movement is shown at right (Adapted from Fetz et al., 2002b). Additional inputs to the CM cell, including central cells driving the CM cell, are represented by the pre-CM cell.