Abstract
Sensorimotor control is modulated through complex interactions between descending corticomotor pathways and ascending sensory inputs. Pairing sub-threshold transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS) modulates the Hoffmann’s reflex (H-reflex), providing a neurophysiologic probe into the influence of descending cortical drive on spinal segmental circuits. However, individual variability in the timing and magnitude of H-reflex modulation is poorly understood. Here, we varied the inter-stimulus interval (ISI) between TMS and PNS to systematically manipulate the relative timing of convergence of descending TMS-induced volleys with respect to ascending PNS-induced afferent volleys in the spinal cord to: (1) characterize effective connectivity between the primary motor cortex (M1) and spinal circuits, mediated by both direct, fastest-conducting, and indirect, slower-conducting descending pathways; and (2) compare the effect of individual-specific vs. standard ISIs. Unconditioned and TMS-conditioned H-reflexes (24 different ISIs ranging from −6 to 12 ms) were recorded from the soleus muscle in 10 able-bodied individuals. The magnitude of H-reflex modulation at individualized ISIs (earliest facilitation delay or EFD and individual-specific peak facilitation) was compared with standard ISIs. Our results revealed a significant effect of ISI on H-reflex modulation. ISIs eliciting earliest-onset facilitation (EFD 0 ms) ranged from −3 to −5 ms across individuals. No difference in the magnitude of facilitation was observed at EFD 0 ms vs. a standardized short-interval ISI of −1.5 ms. Peak facilitation occurred at longer ISIs, ranging from +3 to +11 ms. The magnitude of H-reflex facilitation derived using an individual-specific peak facilitation was significantly larger than facilitation observed at a standardized longer-interval ISI of +10 ms. Our results suggest that unique insights can be provided with individual-specific measures of top-down effective connectivity mediated by direct and/or fastest-conducting pathways (indicated by the magnitude of facilitation observed at EFD 0 ms) and other descending pathways that encompass relatively slower and/or indirect connections from M1 to spinal circuits (indicated by peak facilitation and facilitation at longer ISIs). By comprehensively characterizing the temporal profile and inter-individual variability of descending modulation of spinal reflexes, our findings provide methodological guidelines and normative reference values to inform future studies on neurophysiological correlates of the complex array of descending neural connections between M1 and spinal circuits.
Highlights
To determine the influence of transcranial magnetic stimulation (TMS)-induced fastest descending volleys arriving at the spinal motoneurons, we identified the earliest onset of H-reflex facilitation for each participant
At Early facilitation delay (EFD) 0 ms, there the conditioned H-reflex amplitude was significantly larger than unconditioned [p = 0.0018, paired Cohen’s d = 0.709 (95.0%CI 0.471, 1.04)] (Figure 3)
In addition to evaluating the timing and magnitude of the earliest onset of TMS-induced H-reflex facilitation, we evaluated a wide range of longer interval inter-stimulus intervals (ISIs) and determined the ISI that elicits the greatest facilitation in our young able-bodied participant cohort (Figure 2)
Summary
Motor evoked potentials (MEPs) generated in response to transcranial magnetic stimulation (TMS; Barker et al, 1985; Abbruzzese and Trompetto, 2002; Kobayashi and PascualLeone, 2003; Hallett, 2007; Kesar et al, 2018b) and Hoffman reflexes (H-reflexes) elicited in response to peripheral nerve stimulation (PNS; Schieppati, 1987; Pierrot-Deseilligny and Mazevet, 2000; Perez et al, 2007; Burke, 2016) have each been individually used to evaluate the excitability of cortical and spinal sensorimotor circuitry, respectively. Studies using TMS-evoked MEPs have shown modulation of corticospinal excitability with immobilization (Clark et al, 2008, 2010; Leukel et al, 2015; Opie et al, 2016), rehabilitation (Roosink and Zijdewind, 2010; Kantak et al, 2013; Keller et al, 2018), somatosensory stimulation (Meehan et al, 2008; Veldman et al, 2016; Brown et al, 2018), and motor learning (Stefan et al, 2005; Celnik, 2015; Kantak et al, 2018; Palmer et al, 2018). The pairing of sub-threshold TMS and PNS has been used as a neurophysiologic technique to evaluate the strength of descending physiologic connections (i.e., effective connectivity) between M1 and spinal circuits (Crone et al, 2003; Urbin et al, 2017; Keller et al, 2018)
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