Circuits In Human Motor Cortex Research Articles

Non-invasive assessment of superficial and deep layer circuits in human motor cortex.

Key points The first indirect (I) corticospinal volley from stimulation of the motor cortex consists of two parts: one that originates from infragranular layer 5 and a subsequent part with a delay of 0.6 ms to which supragranular layers contribute.Non‐invasive probing of these two parts was performed in humans using a refined electrophysiological method involving transcranial magnetic stimulation and peripheral nerve stimulation.Activity modulation of these two parts during a sensorimotor discrimination task was consistent with previous results in monkeys obtained with laminar recordings. Circuits in superficial and deep layers play distinct roles in cortical computation, but current methods to study them in humans are limited. Here, we developed a novel approach for non‐invasive assessment of layer‐specific activity in the human motor cortex. We first conducted brain slice and in vivo experiments on monkey motor cortex to investigate the output timing from layer 5 (including corticospinal neurons) following extracellular stimulation. Neuron responses contained cyclical waves. The first wave was composed of two parts: the earliest part originated only from stimulation of layer 5; after 0.6 ms, stimuli to superficial layers 2/3 could also contribute. In healthy humans we then assessed different parts of the first corticospinal volley elicited by transcranial magnetic stimulation (TMS), by interacting TMS with stimulation of the median nerve generating an H‐reflex. By adjusting the delay between stimuli, we could assess the earliest volley evoked by TMS, and the part 0.6 ms later. Measurements were made while subjects performed a visuo‐motor discrimination task, which has been previously shown in monkey to modulate superficial motor cortical cells selectively depending on task difficulty. We showed a similar selective modulation of the later part of the TMS volley, as expected if this part of the volley is sensitive to superficial cortical excitability. We conclude that it is possible to segregate different cortical circuits which may refer to different motor cortex layers in humans, by exploiting small time differences in the corticospinal volleys evoked by non‐invasive stimulation.

The effect of stimulation interval on plasticity following repeated blocks of intermittent theta burst stimulation

This study assessed the effect of interval duration on the direction and magnitude of changes in cortical excitability and inhibition when applying repeated blocks of intermittent theta burst stimulation (iTBS) over motor cortex. 15 participants received three different iTBS conditions on separate days: single iTBS; repeated iTBS with a 5 minute interval (iTBS-5-iTBS); and with a 15 minute interval (iTBS-15-iTBS). Changes in cortical excitability and short-interval cortical inhibition (SICI) were assessed via motor-evoked potentials (MEPs) before and up to 60 mins following stimulation. iTBS-15-iTBS increased MEP amplitude for up to 60 mins post stimulation, whereas iTBS-5-iTBS decreased MEP amplitude. In contrast, MEP amplitude was not altered by single iTBS. Despite the group level findings, only 53% of individuals showed facilitated MEPs following iTBS-15-iTBS, and only 40% inhibited MEPs following iTBS-5-iTBS. Modulation of SICI did not differ between conditions. These results suggest interval duration between spaced iTBS plays an important role in determining the direction of plasticity on excitatory, but not inhibitory circuits in human motor cortex. While repeated iTBS can increase the magnitude of MEP facilitation/inhibition in some individuals compared to single iTBS, the response to repeated iTBS appears variable between individuals in this small sample.

Selective Suppression of Local Interneuron Circuits in Human Motor Cortex Contributes to Movement Preparation.

Changes in neural activity occur in the motor cortex before movement, but the nature and purpose of this preparatory activity is unclear. To investigate this in the human (male and female) brain noninvasively, we used transcranial magnetic stimulation (TMS) to probe the excitability of distinct sets of excitatory inputs to corticospinal neurons during the warning period of various reaction time tasks. Using two separate methods (H-reflex conditioning and directional effects of TMS), we show that a specific set of excitatory inputs to corticospinal neurons are suppressed during motor preparation, while another set of inputs remain unaffected. To probe the behavioral relevance of this suppression, we examined whether the strength of the selective preparatory inhibition in each trial was related to reaction time. Surprisingly, the greater the amount of selective preparatory inhibition, the faster the reaction time was. This suggests that the inhibition of inputs to corticospinal neurons is not involved in preventing the release of movement but may in fact facilitate rapid reactions. Thus, selective suppression of a specific set of motor cortical neurons may be a key aspect of successful movement preparation.SIGNIFICANCE STATEMENT Movement preparation evokes substantial activity in the motor cortex despite no apparent movement. One explanation for the lack of movement is that motor cortical output in this period is gated by an inhibitory mechanism. This notion was supported by previous noninvasive TMS studies of human motor cortex indicating a reduction of corticospinal excitability. On the contrary, our data support the idea that there is a coordinated balance of activity upstream of the corticospinal output neurons. This includes a suppression of specific local circuits that supports, rather than inhibits, the rapid generation of prepared movements. Thus, the selective suppression of local circuits appears to be an essential part of successful movement preparation instead of an external control mechanism.

P160 Enhanced biasing effect of prior knowledge on perceptual decision processes following continuous theta burst stimulation of motor cortex

Introduction Separate interneuron circuits in human motor cortex (M1) have been suggested to subserve different forms of motor behaviour, but it is not clear what role they play in other aspects such as decision-to-action processes. Objectives We tested whether two distinct interneuron networks in M1 play different roles in perceptual decision-making. Materials & methods 10 participants completed 3 blocks of a decision making task in each of 2 measurement sessions. Participants responded to a left/right visual imperative cue with left/right hand key presses. A random dot kinetogram (RDK) with 2 levels of coherent motion (low, high) preceded the visual cue. In 80% of trials the motion direction of the dots was congruent with that of the imperative cue, and thus could be used to prepare a response in advance. Accuracy and reaction time (RT) associated with correct responses in congruent trials were measured. A controllable pulse parameter transcranial magnetic stimulation (cTMS; Rogue Resolutions Ltd.) device was used to target distinct interneuron circuits in M1 by changing the coil orientation (posterior-anterior, PA; anterior-posterior, AP) and pulse width (45–75 μ s). A continuous theta burst stimulation (cTBS) protocol was applied with AP45 or PA75 pulses, in separate sessions, to the left M1 following the first block of the decision-making task. Results Accuracy of responses was typically ⩾95%, therefore we focus on RTs. As expected, RTs were faster with high versus low RDK coherence (Fig. 1A–D). There was no effect of pulse type on RTs, but ANOVA revealed an interaction of hand, block and coherence (P = 0.029). Calculating the percentage change in RT from low to high coherence trials (Fig. 1E and F) revealed an improvement in RTs for right, but not left, hand responses in high, but not low, coherence trials immediately after cTBS. Conclusion Irrespective of the pulse type, and thus M1 interneuron circuits targeted, cTBS over left M1 enhanced the bias effect for corresponding right hand responses, but only following high coherence RDK. cTBS may have altered the integration in M1 of the sensory evidence from the bias and imperative cue, giving more weight to the bias which normally has a relatively minor influence. Download : Download high-res image (772KB) Download : Download full-size image

Associative plasticity in surround inhibition circuits in human motor cortex.

Surround inhibition is a physiological mechanism that is hypothesised to improve contrast between signals in the central nervous system. In the human motor system, motor surround inhibition (mSI) can be assessed using transcranial magnetic stimulation (TMS). We evaluated whether it is possible to modulate mSI, using a paradigm able to induce plastic effects in primary motor cortex (M1). Fifteen healthy volunteers participated in the experiments. To assess mSI, we delivered single pulses at rest and at the onset of a right thumb abduction. TMS pulses over abductor digiti minimi (ADM; surround muscle) hotspot were delivered when EMG activity in right abductor pollicis brevis (APB; active muscle) > 100 μV was detected. Paired associative stimulation (PAS) was delivered using peripheral median nerve electric stimulation and TMS over APB M1 area at an interstimulus interval of 21.5 ms for the real PAS (PAS21.5) and 100 ms for the sham PAS (PAS100). To verify the effect of PAS21.5 on mSI we collected 20 MEPs from ADM at rest and during APB movements before (T0) and 5 (T1), 15 (T2) and 30 (T3) minutes after PAS21.5. mSI from APB to ADM was present at baseline. PAS21.5 increased the amount of mSI compared with baseline whereas there was no effect after PAS100. Our results suggest that mSI is an adaptable phenomenon depending on prior experience.

Two distinct interneuron circuits in human motor cortex are linked to different subsets of physiological and behavioral plasticity.

How does a single brain region participate in multiple behaviors? Here we argue that two separate interneuron circuits in the primary motor cortex (M1) contribute differently to two varieties of physiological and behavioral plasticity. To test this in human brain noninvasively, we used transcranial magnetic stimulation (TMS) of M1 hand area to activate two independent sets of synaptic inputs to corticospinal neurons by changing the direction of current induced in the brain: posterior-to-anterior current (PA inputs) and anterior-to-posterior current (AP inputs). We demonstrate that excitability changes produced by repetitive activation of AP inputs depend on cerebellar activity and selectively alter model-based motor learning. In contrast, the changes observed with repetitive stimulation of PA inputs are independent of cerebellar activity and specifically modulate model-free motor learning. The findings are highly suggestive that separate circuits in M1 subserve different forms of motor learning.

P1083: Homeostatic metaplasticity of corticospinal excitatory and inhibitory intracortical neural circuits in human motor cortex

P1083: Homeostatic metaplasticity of corticospinal excitatory and inhibitory intracortical neural circuits in human motor cortex

Homeostatic metaplasticity of corticospinal excitatory and intracortical inhibitory neural circuits in human motor cortex

Homeostatic metaplasticity, a fundamental principle for maintaining overall synaptic weight in the physiological range in neuronal networks, was demonstrated at the cellular and systems level predominantly for excitatory synaptic neurotransmission. Although inhibitory networks are crucial for regulating excitability, it is largely unknown to what extent homeostatic metaplasticity of inhibition also exists. Here, we employed intermittent and continuous transcranial magnetic theta burst stimulation (iTBS, cTBS) of the primary motor cortex in healthy subjects for induction of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity. We studied metaplasticity by testing the interactions of priming TBS with LTP/LTD-like plasticity induced by subsequent test TBS. Changes in excitatory neurotransmission were measured by the input-output curve of motor-evoked potentials (IO-MEP), and changes in GABA(A)ergic inhibitory neurotransmission by the IO of short-interval intracortical inhibition (IO-SICI, four conditioning stimulus intensities of 70-100% active motor threshold, interstimulus interval 2.0 ms). Non-primed iTBS increased IO-MEP, while non-primed cTBS decreased IO-MEP. Pairing of identical protocols (iTBSiTBS, cTBScTBS) resulted in suppression of the non-primed TBS effects on IO-MEP, and pairing of different protocols (cTBSiTBS, iTBScTBS) enhanced the test TBS effects on IO-MEP. While non-primed TBS did not result in significant changes of IO-SICI, iTBSiTBS resulted in IO-SICI decrease, and cTBScTBS in IO-SICI increase compared with the non-primed conditions. The changes in SICI induced by priming TBS correlated with the changes in MEP induced by subsequent test TBS. Findings demonstrate that plasticity in both excitatory and inhibitory circuits in the human motor cortex are regulated by homeostatic metaplasticity, and that priming effects on inhibition contribute to the homeostatic regulation of metaplasticity in excitatory circuits.

Associative plasticity in intracortical inhibitory circuits in human motor cortex

Paired associative stimulation (PAS) is a transcranial magnetic stimulation technique inducing Hebbian-like synaptic plasticity in the human motor cortex (M1). PAS is produced by repetitive pairing of a peripheral nerve shock and a transcranial magnetic stimulus (TMS). Its effect is assessed by a change in size of a motor evoked response (MEP). MEP size results from excitatory and inhibitory influences exerted on cortical pyramidal cells, but no robust effects on inhibitory networks have been demonstrated so far. In 38 healthy volunteers, we assessed whether a PAS intervention influences three intracortical inhibitory circuits: short (SICI) and long (LICI) intracortical inhibitions reflecting activity of GABA(A) and GABA(B) interneurons, respectively, and long afferent inhibition (LAI) reflecting activity of somatosensory inputs. After PAS, MEP sizes, LICI and LAI levels were significantly changed while changes of SICI were inconsistent. The changes in LICI and LAI lasted 45 min after PAS. Their direction depended on the delay between the arrival time of the afferent volley at the cortex and the TMS-induced cortical activation during the PAS. PAS influences inhibitory circuits in M1. PAS paradigms can demonstrate Hebbian-like plasticity at selected inhibitory networks as well as excitatory networks.

A common polymorphism in the brain‐derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS

The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: A TMS study

Objective To investigate if different interneuronal circuits in human motor cortex mediate inhibition through different subtypes of the gamma-aminobutyric acid A receptor (GABAAR). Methods Two distinct forms of motor cortical inhibition were measured in 10 healthy subjects by established transcranial magnetic stimulation (TMS) protocols: short interval intracortical inhibition (SICI) and short latency afferent inhibition (SAI). Their modification by a single oral dose of three different positive GABAAR modulators (20 mg of diazepam, 2.5 mg of lorazepam and 10 mg of zolpidem) with different affinity profiles at the various α-subunit bearing subtypes of the GABAAR (diazepam: non-selective, lorazepam: unknown, zolpidem: 10-fold higher affinity to α1- than α2- or α3-subunit bearing GABAARs, no affinity to α5-subunits) was tested in a randomized crossover design. In addition, the sedative drug effects were recorded by a visual analogue scale. Results Diazepam and lorazepam increased SICI, whereas zolpidem did not change SICI. In contrast, diazepam had no effect on SAI, whereas lorazepam and zolpidem decreased SAI. The sedative effects were not different between drugs. Conclusions The dissociating patterns of drug modification of SICI versus SAI strongly suggest that different GABAAR subtypes are involved in SICI and SAI. Significance We provide evidence, for the first time, for a dissociation of effects of diazepam and zolpidem on SAI and confirm the previously reported differential effect of zolpidem and of diazepam and lorazepam on SICI. The differential effects of the three benzodiazepines on SAI and SICI suggest that neuronal circuits in human motor cortex that mediate inhibition through different GABAAR subtypes can be segregated by TMS.

Reply from Vincenzo Di Lazzaro, Fabio Pilato, Michele Dileone, Pietro A. Tonali and Ulf Ziemann

We thank Pompeia and colleagues for their insightful comments on our recent paper (Di Lazzaro et al. 2005b) in which we demonstrate that measures of transcranial magnetic stimulation (TMS) provide an opportunity to segregate physiologically relevant differences of benzodiazepine action in the intact human brain. By using paired pulse TMS protocols, or by coupling of peripheral nerve stimulation with TMS of the contralateral motor cortex, it is possible to recruit specific neuronal circuits of the human brain and to evaluate in vivo the effects of drugs on several neurotransmitter systems (Ziemann, 2004). The short latency inhibitory effect produced by peripheral nerve stimulation on the excitability of the contralateral motor cortex is known as short latency afferent inhibition (SAI). SAI tests an inhibitory circuit in motor cortex (Tokimura et al. 2000) that is controlled by central cholinergic activity: SAI is decreased by the muscarinic receptor antagonist scopolamine in normal subjects (Di Lazzaro et al. 2000b), is significantly reduced in Alzheimer's disease patients and, in these patients, can be increased by acetylcholinesterase inhibitors (Di Lazzaro et al. 2005a). A particular paired pulse TMS protocol (Kujirai et al. 1993) elicits short latency intracortical inhibition (SICI). SICI tests an inhibitory circuit in motor cortex in which neurotransmission through the GABAA receptor is involved (Ziemann et al. 1996; Di Lazzaro et al. 2000a; Ilic et al. 2002) while, in contrast to SAI, this measure is not modified by scopolamine (Di Lazzaro et al. 2000b), and decreased by an acetylcholinesterase inhibitor (Korchounov et al. 2005). Thus, evaluation of the effects of benzodiazepines on SAI and SICI provides a novel and fascinating opportunity to evaluate their effects on distinct inhibitory circuits in human motor cortex. In our recent study (Di Lazzaro et al. 2005b), we provide evidence, for the first time, for a dissociation of lorazepam and a ‘classical benzodiazepine’ (diazepam) on these measures. While both drugs enhance SICI, lorazepam decreases SAI and diazepam increases it. This dissociation may contribute to our understanding of why these two benzodiazepines impair memory function differently. What makes lorazepam different from other benzodiazepines remains unknown though Pompeia and colleagues suggest in their letter that a possible explanation for the atypical effects of lorazepam might be that it has a unique binding profile, possibly to as yet uncharacterized benzodiazepine receptors. This idea bears much similarity with our as yet unproven proposal that lorazepam and diazepam differ in their affinity to subtypes of the GABAA receptor bearing different alpha-units (Di Lazzaro et al. 2005b). If we conceive SAI as a GABAergic cortical inhibition positively controlled by acetylcholine, then the dissociation between lorazepam and diazepam on SAI may be caused by the GABAA receptor that mediates inhibition in the GABAergic motor cortical SAI circuit, or the GABAA receptor that controls release of acetylcholine at brainstem or intracortical levels (Giorgetti et al. 2000). According to the first scenario, which we speculated upon in our recent paper (Di Lazzaro et al. 2005b), lorazepam and diazepam both reduce acetylcholine release to a similar extent, therefore exerting a similar depression on SAI, but diazepam is significantly more effective than lorazepam in enhancing inhibition in the GABAergic motor cortical SAI circuit. This could explain the observed net effect of increased SAI under diazepam but decreased SAI under lorazepam (Di Lazzaro et al. 2005b). The second scenario, which is equally possible, is that lorazepam decreases acetylcholine release more effectively than diazepam while both drugs have similar effects on inhibition in the GABAergic SAI circuit, again resulting in the same dissociating net effects on SAI as above. If true, this would indicate that measures of TMS can be applied to probe cortical inhibition at the level of different subtypes of GABAA receptors. This would be a major advance, not only in comparison to psychophysical studies and less specific electrophysiological studies (Itil et al. 1989; Pompeia et al. 2003), as quoted by Pompeia and colleagues in their letter to the editor, but also in comparison to all previous TMS drug studies (Ziemann, 2004). The significance of this research lies in the fact that cortical GABAergic interneurones are highly diverse and operate with a corresponding diversity of GABAA receptor subtypes in controlling developmental plasticity and behaviour (Fagiolini et al. 2004; Mohler et al. 2004). We agree with Pompeia and colleagues that much more needs to be done, including dose–response curves and testing of other atypical benzodiazepines, to corroborate the view that TMS can distinguish non-invasively and at the systems level of human cerebral cortex between neuronal circuits bearing different GABAA receptor subtypes. However, it appears that a first step towards this important goal has been achieved.

Effects of right unilateral electroconvulsive therapy on motor cortical excitability in depressive patients

Electroconvulsive therapy (ECT) is a widely acknowledged effective treatment for severe major depression. ECT produces considerable anticonvulsant effects that may be related to an increased GABA-ergic neurotransmission. We aimed to explore whether motor cortical excitability as assessed with single and paired pulse transcranial magnetic stimulation (TMS) could be used to investigate these anticonvulsant effects. Therefore, parameters of motor cortical excitability were investigated in 10 patients before and after 10 sessions of right unilateral ECT. After 10 sessions of right unilateral ECT, an enhanced activity of inhibitory circuits in human motor cortex had been observed, as measured by both increased intracortical inhibition and cortical silent period duration, whereas intracortical facilitation and resting motor threshold remained unchanged. The reduction of seizure duration in the course of ECT was associated with clinical improvement and an increase in intracortical inhibition. We interpret this finding as further indirect evidence for changes in inhibitory circuits in the course of ECT in patients with major depression.