Determinants of resting M1 excitability

The induction of plasticity in M1 is strongly influenced by the excitability state of the target neurons at the time of induction. This section outlines some of the determinants of resting excitability in the motor cortex.

1.6.1 Individual characteristics

25

There can be substantial inter-individual variability in resting excitability levels in M1 as measured by TMS. A number of factors can influence the capacity for plasticity induction, including anatomical characteristics. Increased cortical thickness is associated with greater facilitation following paired-associative stimulation [130], and individual differences in intracortical circuitry appears to be a key source of variability in the response to TBS. Differences in which neuronal pools are recruited by single TMS pulses may determine the response to TBS. Specifically, those individuals that demonstrate late rather than early I-waves in response to single TMS pulses are more likely to show the expected responses to cTBS and iTBS [131]. Fibre orientation in pyramidal tracts appears to contribute substantially to variance in motor thresholds, as does the skull-to cortex distance [132].

In addition to structural differences, there are a number of state-related determinants of excitability. MEP amplitudes are influenced by the phase of cortical oscillations, particularly in the alpha and beta frequency bands, and strong cortico-muscular coherence at the time of stimulation increases MEP amplitude [133]. High pre-stimulation activity in the beta band is correlated with decreased MEP amplitude

[133,134]. Similarly, responses to TMS are stronger when alpha power is low (i.e.

desynchronized) prior to stimulus delivery [135]. As M1 forms a key component of motor networks, it is also influenced by activity in connected regions, such as the dorsal premotor cortex [136].

The ability of a given technique to induce plasticity is dependent on a number of different characteristics, such as gender, age, time of day, attention and diet. In female participants, excitability levels may be dependent on phase of menstrual cycle, as high

26

circulating estradiol is associated with increased excitability [137]. In addition, females display a prolonged response to the induction of LTD-like plasticity [138]. Females exhibit a linear relationship between testosterone levels and PAS-induced plasticity while in males, levels of circulating insulin-like growth factor 1 (IGF-1) are more predictive [139]. Muller-Dalhaus et al. [140] report that the response to PAS decreases linearly with age, possibly due to the degeneration of neuronal circuits or a decline in neurotransmitter levels. The response to PAS also appears to be influenced by circadian rhythms, as plasticity induction is greater in the afternoon than in the morning [141], likely due to lower cortisol levels [142,143]. Multiple reports also suggest that plasticity is enhanced by directing attention to the stimulated limb [45,144,145]. In contrast, high trait-level anxiety is associated with decreased intracortical inhibition [146]. While chronic nicotine usage is associated with a reduction in M1 excitability [147], neither caffeine nor sleep deprivation appear to

influence the resting motor threshold [148–150]. Finally, there is strong evidence that the individual response to plasticity is influenced by genetic factors, and particularly by

variation in the BDNF gene. This is discussed in more depth in Section 1.9.5.

1.6.2 History of synaptic activity

The concept of metaplasticity is used to describe “higher order” plasticity, or a change in the state of the neurons that generate LTP and LTD. Homeostatic metaplasticity refers to a mechanism by which synaptic strength can be adjusted. According to the Bienenstock-Cooper-Munro (BCM) theory of synaptic plasticity, synapses that have recently undergone LTP are resistant to further LTP induction and are more likely to undergo LTD [151]. It is now well-established that the ability to induce plasticity at a given synapse is strongly

27

influenced by the prior activity of the synapse. Thus, the threshold for the induction of LTP and LTD is not fixed, but instead varies according to the integrated post-synaptic activity [152–154]. Low levels of prior activity favour the induction of LTP, whereas higher levels make LTD induction more likely [154–156]. The role of homeostatic metaplasticity appears to be to prevent the saturation of LTP/LTD and to stabilize neuronal networks [156,157]. At the neuronal level, metaplasticity is likely governed by a range of

mechanisms, including presynaptic neurotransmitter release, postsynaptic glutamate receptor trafficking, and the secretion of modulators such as BDNF and cell adhesion

proteins [158]. The activity of NMDA receptors and their downstream signalling molecules are also likely to play a key role [157].

The BCM principle can be demonstrated quite readily using non-invasive brain stimulation. While PAS reliably induces LTP in M1, this effect is abolished if two

consecutive PAS sessions are administered [159]. Indeed, a number of studies have shown a suppression of excitability when two LTP-inducing interventions are delivered

sequentially [160–164]. Evidence suggests that rather than a complete inhibition, priming instead elevates the threshold for subsequent induction [165,166]. In contrast, this

principle can be used to enhance plasticity. Applying iTBS prior to cTBS results in a greater suppression of cortical excitability than cTBS alone [167,168], and iTBS-induced

excitability is enhanced when primed with cTBS [161,162]. Using quadripulse stimulation, Hamada et al. [169] demonstrated that priming the motor cortex with brief high-frequency (excitatory) repetitive TMS increases the threshold for further LTP induction. This study was the first to demonstrate homeostatic metaplasticity using a priming technique that did not affect cortical excitability on its own.

28

Metaplasticity can also be demonstrated behaviourally, as multiple studies have reported that following motor learning, the trained M1 is much more likely to undergo LTD than LTP [170–172]. Homeostatic effects appear to be critically dependent on the time interval between stimuli [163,164], which may depend on the specific protocols that are administered [154].