Enhanced action performance following TMS manipulation of associative plasticity in ventral premotor-motor pathway

Highlights

• Paired associative TMS of PMv and M1 affects the human motor system.

• TMS aimed at strengthening PMv-to-M1 connections increases corticomotor excitability.

• This TMS manipulation also improves object-oriented hand action performance.

• Greater motor gains are found in participants with more excitable motor system.

• No effects are observed on a control task or when stimulating M1-to-PMv connections.

Abstract

Skillful goal-directed manual actions such as grasping and manipulating objects are supported by a large sensorimotor network. Within this network, the ventral premotor cortex (PMv) transforms visual information about objects into motor commands that are conveyed to the primary motor cortex (M1), allowing fine control of finger movements. However, it is unknown whether transcranial magnetic stimulation (TMS) of this PMv-to-M1 hierarchical pathway improves action performance. To fill in this gap, here, we used cortico-cortical paired associative stimulation (ccPAS) with the aim of manipulating synaptic efficacy in the human PMv-to-M1 pathway. We found that repeatedly pairing TMS of pre-and post-synaptic nodes of the PMv-to-M1 pathway (i.e., PMv-to-M1 ccPAS) increased motor excitability and enhanced performance on the 9-Hole Peg Test (9-HPT), which taps into PMv-M1 functioning. These effects were specific to the ccPAS protocol consistent with the direction of the PMv-to-M1 hierarchy, as no effects were observed when reversing the order of the paired TMS pulses (i.e., following a M1-to-PMv ccPAS) or when administering sham ccPAS. Additionally, the effect of PMv-to-M1 ccPAS appeared functionally specific, as no behavioral enhancement was observed in a visuomotor control task. We therefore provide novel causal evidence that the PMv-to-M1 pathway, which is instrumental to object-oriented hand actions, is sensitive to TMS manipulations of associative plasticity. Our study highlights the causal role of the PMv-to-M1 pathway in controlling skillful object-oriented hand actions and suggests that ccPAS might be a useful tool for investigating the functional relevance of directional connectivity in humans. These findings may have implications for designing novel therapeutic strategies based on the manipulation of associative plasticity in cortico-cortical networks.

Introduction

Goal-directed manual actions such as grasping, manipulating and moving objects are the result of complex interactions within dorsal occipito-parieto-frontal streams involved in sensorimotor transformations (Jeannerod et al., 1995; Castiello, 2005; Grol et al., 2007; Cavina-Pratesi et al., 2010; Davare et al., 2011). At least part of this process is thought to occur in a serial, hierarchical fashion: monkey studies have suggested that, within a dorsolateral stream, the ventral premotor cortex (PMv) transforms visual information about object properties (e.g., their shape, size, etc.) into appropriate motor commands; these commands are conveyed to the primary motor cortex (M1), allowing fine control of individual finger movements (Muir and Lemon, 1983; Murata et al., 1997; Fagg and Arbib, 1998; Fogassi et al., 2001; Lang and Schieber, 2004; Raos et al., 2006). Although alternative/parallel pathways also exist (e.g., Dum and Strick, 1991; He et al., 1993), these monkey studies point to a pivotal role of the PMv-to-M1 hierarchy in performing skilled, visually guided, object-oriented manual actions such as grasping observed objects (Prabhu et al., 2009; Rizzolatti et al., 2014; Borra et al., 2017; Gerbella et al., 2017).

Neuroimaging and transcranial magnetic stimulation (TMS) studies suggest that the human brain is endowed with neural systems for goal-directed actions analogous to those of monkeys (Castiello, 2005; Cavina-Pratesi et al., 2007; Króliczak et al., 2007; Tunik et al., 2007; Davare et al., 2008, 2009, 2010). These studies have shown that visually guided, object-oriented manual actions are at least partly underpinned by neural interactions within the dorsolateral stream (e.g., Davare et al., 2010, 2011; for further involvement of dorsomedial areas see Vesia et al., 2017). For example, Grol and colleagues reported increased connectivity between occipito-parieto-frontal nodes of the dorsolateral stream (i.e., V3A, AIP and PMv) during precision grasping (Grol et al., 2007). In addition, Davare and colleagues have shown that, during grasp preparation, short-latency PMv-to-M1 connections are facilitated in a muscle-specific manner (i.e., grasp-related facilitation is specific to those circuits controlling the muscles involved in the upcoming grasp; see Davare et al., 2008, 2009, 2010). These studies converge with monkey findings and support the notion of a human PMv-to-M1 hierarchy in fine motor control of object-oriented manual actions.

A variety of experiences ranging from learning new motor skills to experiencing a stroke in motor areas have been associated with neuroplastic changes in premotor and motor areas and the connection between them (Nelles et al., 2001; Sun et al., 2007; Albert et al., 2009; Taubert et al., 2011; Wiestler and Diedrichsen, 2013; Horn et al., 2016). For example, training in a fine motor task involving grasping and moving pegs and marbles strengthened functional connectivity between PMv and primary sensorimotor representations of the hand (Hamzei et al., 2012). Increased functional connectivity between PMv and sensorimotor cortex was also found following training in a precision drawing task (Philip and Frey, 2016). Moreover, performing skillful hand actions after extensive training was associated with increased premotor-motor connectivity (Dayan and Cohen, 2011). However, these previous studies used a correlational approach that does not address the critical question of whether direct strengthening of premotor-motor connectivity (e.g., via exogenous brain manipulation) would cause an enhancement in hand motor functions. Answering this outstanding question is the goal of the present study.

Recent advances in TMS allow us to directly address this question through a protocol called cortico-cortical paired associative stimulation (ccPAS) (Rizzo et al., 2009, 2011; Koganemaru et al., 2009; Arai et al., 2011; Buch et al., 2011; Lu et al., 2012; Koch et al., 2013; Veniero et al., 2013; Johnen et al., 2015; Romei et al., 2016a; Casula et al., 2016; Chiappini et al., 2018). This protocol consists of repeated paired stimulation of two interconnected brain areas with the aim of mimicking patterns of neuronal stimulation shown to induce spike-timing-dependent plasticity (STDP) – a form of synaptic plasticity meeting the Hebbian principle that synapses are potentiated if the presynaptic neuron fires immediately before the postsynaptic neuron in a coherent and repeated manner (Jackson et al., 2006; Caporale and Dan, 2008; Markram et al., 2011). In the ccPAS protocol, pre- and post-synaptic coupling is achieved by repeatedly administering pairs of TMS pulses. In each pair, a first pulse over a target area is followed by a second pulse over an interconnected target area with an inter-stimulus interval (ISI) consistent with the activation of short-latency connections between the two areas. In a relevant study, Buch et al. (2011) administered a ccPAS protocol by delivering the first pulse in each pair over PMv and the second over M1 using an ISI of 8 ms, i.e., the critical ISI at which the PMv exerts a short-latency physiological effect on the excitability of the ipsilateral M1 (see dual-site TMS studies of Davare et al., 2008, 2009, 2010; Bäumer et al., 2009 pointing to an ISI of 6–8 ms). Thus, with this protocol, the cortico-cortical volley elicited by PMv stimulation (first pulse) would reach M1 slightly before/at the same time as the exogenous M1 stimulation (second pulse), resulting in convergent M1 activation. This repeated stimulation of the PMv-to-M1 pathway enhanced the physiological effect of PMv conditioning over M1 excitability, and the time-course of the long-term potentiation (LTP)-like effect resembled that of STDP effects observed in animal studies (Buch et al., 2011). In a further study, the PMv-to-M1 ccPAS protocol was found to increase the functional connectivity of the stimulated pathway, as measured by functional magnetic resonance imaging (fMRI). Increased connectivity was anatomically specific and did not occur in non-stimulated parallel motor pathways (Johnen et al., 2015).

These physiological studies provided direct evidence that ccPAS can transiently strengthen PMv-to-M1 connections by increasing synaptic efficiency in a hierarchical motor pathway involved in visually guided object grasping and manipulation. However, these studies did not answer the critical question of whether exogenous enhancement of PMv-to-M1 synaptic efficiency also causes an improvement in performing object-oriented manual actions.

In the present study, we sought to investigate the malleability and behavioral relevance of PMv-to-M1 connectivity by combining a ccPAS PMv-to-M1 protocol with two behavioral tasks. Based on the notion that the PMv is a key region for visually guided, object-oriented manual actions (Binkofski et al., 1999; Ehrsson et al., 2000; Kuhtz-Buschbeck et al., 2001; Horn et al., 2016) and the PMv-to-M1 hierarchy is involved in the implementation of such actions (Prabhu et al., 2009; Rizzolatti et al., 2014; Borra et al., 2017; Gerbella et al., 2017), we hypothesized that administering a ccPAS protocol aimed at enhancing PMv-to-M1 connectivity would improve performance on the Nine-Hole Peg Test (9-HPT; Mathiowetz et al., 1985; Grice et al., 2003), a well-established manual dexterity task tapping into the ability to grasp and manipulate small objects.

We hypothesized this behavioral enhancement would be specific. No improvement was expected following a M1-to-PMv ccPAS protocol –controlling for the directionality of the stimulated pathway– or a sham ccPAS protocol –controlling for nonspecific effects of TMS. Additionally, we expected no ccPAS-induced changes in performance on a visual choice reaction time (cRT) task. Although both 9-HPT and cRT are visuomotor tasks, the latter does not tap into the ability to efficiently shape the hand to manipulate objects, and it was thus expected to be less sensitive to manipulation of PMv-M1 connectivity.

Lastly, based on prior work reporting that global measures of motor excitability predict the magnitude of LTP effects in the motor system (Müller-Dahlhaus et al., 2008) and TMS-induced behavioral effects (Kaminski et al., 2011), we expected to find a positive relationship between behavioral changes induced by PMv-to-M1 ccPAS and motor excitability as assessed before ccPAS.