Sensorimotor integration within the primary motor cortex by selective nerve fascicle stimulation

Abstract

The integration of sensory inputs in the motor cortex is crucial for dexterous movement. We recently demonstrated that a closed-loop control based on the feedback provided through intraneural multichannel electrodes implanted in the median and ulnar nerves of a participant with upper limb amputation improved manipulation skills and increased prosthesis embodiment. Here we assessed, in the same participant, whether and how selective intraneural sensory stimulation also elicits a measurable cortical activation and affects sensorimotor cortical circuits. After estimating the activation of the primary somatosensory cortex evoked by intraneural stimulation, sensorimotor integration was investigated by testing the inhibition of primary motor cortex (M1) output to transcranial magnetic stimulation, after both intraneural and perineural stimulation. Selective sensory intraneural stimulation evoked a low-amplitude, 16 ms-latency, parietal response in the same area of the earliest component evoked by whole-nerve stimulation, compatible with fast-conducting afferent fibre activation. For the first time, we show that the same intraneural stimulation was also capable of decreasing M1 output, at the same time range of the short-latency afferent inhibition effect of whole-nerve superficial stimulation. The inhibition generated by the stimulation of channels activating only sensory fibres was stronger than that due to intraneural or perineural stimulation of channels activating mixed fibres. We demonstrate in a human subject that the cortical sensorimotor integration inhibiting M1 output previously described after the experimental whole-nerve stimulation is present also with a more ecological selective sensory fibre stimulation. KEY POINTS: Cortical integration of sensory inputs is crucial for dexterous movement. Short-latency somatosensory afferent inhibition of motor cortical output is typically produced by peripheral whole-nerve stimulation. We exploited intraneural multichannel electrodes used to provide sensory feedback for prosthesis control to assess whether and how selective intraneural sensory stimulation affects sensorimotor cortical circuits in humans. Activation of the primary somatosensory cortex (S1) was explored by recording scalp somatosensory evoked potentials. Sensorimotor integration was tested by measuring the inhibitory effect of the afferent stimulation on the output of the primary motor cortex (M1) generated by transcranial magnetic stimulation. We demonstrate in humans that selective intraneural sensory stimulation elicits a measurable activation of S1 and that it inhibits the output of M1 at the same time range of whole-nerve superficial stimulation.

Keywords: evoked potentials; intraneural double-sided filament electrodes (ds-FILE); short-latency afferent inhibition; somatosensory peripheral stimulation; transcranial magnetic stimulation (TMS).

Figure 1. Schematic representation of ds‐FILE and Cuff electrodes and their placement in the nerve trunk

Electrodes were implanted in the middle third of the left arm (left panel: a single nerve is represented). A Cuff electrode wraps the nerve trunk at a proximal site. Two ds‐FILEs are inserted into the nerve trunk with an angle of approximately 45°. Active sites of the electrodes are represented in the right panels. The ds‐FILE active area has a thickness of 360 μm and a total length of 3 mm and it bears 16 contacts (area: 150 × 50 μm²), arranged on both sides of the electrode. [Image created with BioRender.com.] [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2. Recruitment of motor fibres with median nerve ds‐FILE and Cuff electrode contacts

A, example of recruitment of compound muscle action potentials (CMAPs) after stimulation with IM16 and IM12 contacts at increasing intensities. At increasing stimulation intensities, IM16 elicits CMAPs of increasing amplitude (left panels); stimulation with IM12 does not evoke EMG responses in forearm muscles (right panels) while it evokes somatosensory perceptions and hence it is considered to be selective for sensory afferents. Each EMG trace (top panels) is the average of three trials. CMAP amplitude (bottom panels) is measured as peak‐to‐peak amplitude of the EMG signal. B, thick lines represent the average stimulus–response curves for tested contacts of ds‐FILE (left curve, dark red) and Cuff (right curve, light blue) electrodes. Thin dashed lines represent the ±1 SD limits of the average curve. Circles represent the actual CMAPs (average of three stimuli). Curves are derived from actual and interpolated CMAPs obtained from contacts 14, 15 and 16 of the ds‐FILE and from contacts 1–8 and 11–14 of the Cuff electrode, in the range of tested stimulation intensities. Contacts that did not evoke muscle responses are not represented. Stimulation was delivered as a biphasic square wave pulse, with a total duration of 160 μs for the ds‐FILE and of 400 μs for the Cuff electrode contacts. Stimulation charge (nC) is calculated as stimulus intensity (μA) × duration (ms). Note the different charge scale for ds‐FILE and Cuff. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3. Comparison of sensory perception thresholds between median nerve ds‐FILE and Cuff electrode contacts

Sensory thresholds for individual active sites evoking sensory perceptions within the tested stimulation range are represented. Threshold values are measured as stimulation charge, i.e. stimulation intensity (μA) × stimulus duration (ms). Boxplots summarize the lower quartile, median and upper quartile of the sample distribution for both electrodes. Thresholds with ds‐FILE stimulation (n = 15) are significantly lower than with Cuff stimulation (n = 12) (P < 0.0001; Mann–Whitney test). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4. Somatosensory evoked potentials from transcutaneous left ulnar nerve stimulation (A–C) and from left intraneural median nerve stimulation (D)

See Results for details. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 5. SAI values obtained by delivering the conditioning afferent pulse with different electrodes and contacts, at different inter‐stimulus intervals (ISIs)

Boxplots represent MEP amplitudes by single pulse TMS (test condition, n = 12) and by paired pulse TMS, normalized to the average test MEP amplitude (n = 6 for each ISI). All stimulation sites of ds‐FILE and Cuff electrodes are associated with a reduction of the test MEP amplitude in the target muscle across tested ISIs from 15 to 21 ms (i.e. SAI < 1.0). SAI was analysed by grouping ISIs of 15–16 ms (white boxes), 17–19 ms (light grey) and 20–21 ms (dark grey). The ISI of 8 ms (n = 14) was used as a control condition that is not expected to generate SAI. Boxplots represent the lower quartile, median and upper quartile of the sample distribution; whiskers extend up to 1.5 times the interquartile range; circles indicate outliers; and black diamonds indicate the mean of the sample. Significant P values of comparisons between conditioned and test MEPs (Mann–Whitney tests) are reported. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 6. Effect of stimulation site and ISI on SAI

A, effect of stimulation site on SAI. Boxplots represent SAI values obtained by delivering the conditioning afferent pulse with different electrodes and contacts, by grouping ISIs of 15–21 ms. P values indicate significant differences for each site compared with IM12 (Mann–Whitney tests; individual P values reported in the Results). B, effect of ISI on SAI. Boxplots represent SAI values obtained by delivering the conditioning afferent pulse at different ISIs, by grouping all contacts indicated in A. P values indicate significant differences for each ISI compared with the ISI of 15–16 ms (Mann–Whitney tests; individual P values reported in the Results). SAI values below 1.0 indicate inhibition of the test MEP. Boxplots represent the lower quartile, median and upper quartile of the sample distribution; whiskers extend up to 1.5 times the interquartile range; circles indicate outliers; and black diamonds indicate the mean of the sample.

Figure 7. Boxplots of SAI values obtained in different muscles of the right (intact) and left (amputated) side after conditioning by transcutaneous ulnar nerve stimulation at the elbow

Values below 1.0 indicate inhibition of the test MEP. SAI was analysed by grouping ISIs of 19–21 ms. SAI is significantly lower for muscles of the amputated side (Mann–Whitney tests). Boxplots represent the lower quartile, median and upper quartile of the sample distribution; whiskers extend up to 1.5 times the interquartile range; circles indicate outliers; and black diamonds indicate the mean of the sample.