Unravelling homeostatic interactions in inhibitory and excitatory networks in human motor cortex

Homeostatic plasticity has emerged as a fundamental regulatory principle that helps to stabilize neuronal and circuit activity within optimal ranges (Bienenstock et al. 1982; Abbott & Nelson, 2000). Using a priming-test approach, transcranial brain stimulation techniques have been successfully employed to study regional homeostatic metaplasticity in the intact human motor cortex (M1) (Iyer et al. 2003; Lang et al. 2004; Siebner et al. 2004; Muller et al. 2007; Nitsche et al. 2007; Todd et al. 2009). In these studies, a priming stimulation protocol triggers a homeostatic response in M1, which then is captured by a second test stimulation protocol. Usually, the motor evoked potential (MEP) elicited by single-pulse transcranial magnetic stimulation (TMS) is used as read-out to trace homeostatic metaplasticity. The MEP represents a complex excitability measure, which is influenced by the excitability levels of various intracortical circuits that project on to the corticospinal motor neuron as well as excitability at the spinal level (Groppa et al. 2012). More specific measures of intracortical excitability can be obtained by using paired-pulse paradigms, which apply a conditioning (CS) and test stimulus (TS) through the same coil (Reis et al. 2008). Paired-pulse TMS studies have shown that motor training is accompanied by lasting changes in the excitability of intracortical inhibitory circuits (Classen et al. 1998; Rosenkranz et al. 2007), but it has been unclear whether homeostatic mechanisms are also expressed in these inhibitory circuits. The few studies investigating homeostatic mechanisms in intracortical connections have so far yielded inconsistent results (Siebner et al. 2004; Doeltgen & Ridding, 2011).

In this issue of The Journal of Physiology, Murakami and colleagues (2012) applied ‘facilitatory’ intermittent theta-burst stimulation (iTBS) or ‘inhibitory’ continuous theta-burst stimulation (cTBS) to induce a homeostatic response in intracortical inhibitory circuits in M1 underlying short interval intracortical inhibition (SICI) (Kujirai et al. 1993). They found that a priming TBS sensitized the responsiveness of the inhibitory SICI circuits to a test TBS: after priming with iTBS at 80% active motor threshold (aMT), iTBS decreased SICI (i.e. the iTBS→iTBS condition). After priming with cTBS at 70% aMT, cTBS increased SICI (i.e. the cTBS→cTBS condition) when compared to non-primed iTBS. No such effects were observed after non-primed iTBS or cTBS.

This sensitization of intracortical SICI circuits to a second identical TBS protocol most likely reflects a homeostatic mechanism. The majority of previous studies reported an increase in SICI after a single iTBS session and a decrease in SICI after a single cTBS session (Huang et al. 2005, Huang et al. 2008, Suppa et al. 2008). The normal direction of TBS-induced after-effects was reversed by TBS priming: Primed iTBS decreased SICI and primed cTBS increased SICI, suggesting homeostatic counter regulation.

TBS at stimulation intensity (SI) of 80% AMT triggered a parallel homeostatic regulation of excitability in the intracortical inhibitory circuits mediating SICI and the intracortical excitatory circuits determining corticospinal excitability. The cTBS→cTBS protocol enhanced excitatory corticospinal output and intracortical inhibition. Likewise, the iTBS→iTBS protocol weakened the excitatory corticospinal output and intracortical inhibition. This finding ties in with the concept that an important aspect of homeostatic plasticity is to maintain a proper balance between excitation and inhibition within neural networks (Turrigiano, 2011).

Interestingly, homeostatic metaplasticity was less consistently expressed in the intracortical inhibitory circuits mediating SICI than in the excitatory corticospinal pathway: All four TBS→TBS interventions consistently revealed homeostatic regulation of corticospinal excitability. In contrast, only identical TBS protocols (the iTBS→iTBS or cTBS→cTBS protocol) targeting the same cortical circuits caused a homeostatic modulation of SICI, whereas alternating TBS protocols (the iTBS→cTBS or cTBS→iTBS protocols) failed to trigger a homeostatic response. Moreover, the homeostatic inhibitory response depended on the SI of the priming TBS. The iTBS→iTBS protocol only produced a priming effect on SICI when the priming iTBS was given at an SI of 80% aMT. Likewise, the cTBS→cTBS protocol only produced a priming effect on SICI when SI of the priming cTBS was set to 70% AMT.

The seminal study by Murakami and colleagues (2012) motivates several lines of future research. Homeostatic effects are likely to exist in other intracortical circuits as well, for instance in cortical circuits mediating short-latency facilitation and long-latency inhibition and facilitation (Reis et al. 2008). A pertinent question is how these different intracortical circuits interact to control intracortical and corticospinal excitability. One possible way to disentangle the interactions between different intracortical circuits and the corticospinal output is to pharmacologically manipulate synaptic neurotransmission or ion channel function and to examine how this alters the homeostatic regulation of paired-pulse intracortical inhibition and facilitation.

The possibility to trace homeostatic metaplasticity within intracortical inhibitory circuits has considerable potential for studying the cortical pathophysiology of neurological diseases that are associated with a dysregulation of cortical excitability such as focal hand dystonia. Patients with focal dystonia show both, abnormal homeostatic metaplasticity in the corticospinal output tract (Quartarone et al. 2005) and a consistent decrease in SICI (Ridding et al. 1995), which has been suggested as the source of their impaired surround inhibition of neighbouring muscles (Sohn & Hallett, 2004). The investigation of homeostatic control within the SICI circuitry might provide a direct link between deficient intracortical inhibition and reduced homeostatic plasticity in focal hand dystonia. This might significantly advance the understanding of the mechanisms underlying this complex disease.