Orlando Swayne

Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control.

Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corticospinal tract in humans non‐invasively. Since these early studies, the development of paired‐pulse and repetitive TMS protocols allowed investigators to explore inhibitory and excitatory interactions of various motor and non‐motor cortical regions within and across cerebral hemispheres. These applications have provided insight into the intracortical physiological processes underlying the functional role of different brain regions in various cognitive processes, motor control in health and disease and neuroplastic changes during recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS provides valuable information on functional connectivity between different brain regions, and on the relationship between physiological processes and the anatomical configuration of specific brain areas and connected pathways. More recently, there has been increasing interest in the extent to which these physiological processes are modulated depending on the behavioural setting. The purpose of this paper is (a) to present an up‐to‐date review of the available electrophysiological data and the impact on our understanding of human motor behaviour and (b) to discuss some of the gaps in our present knowledge as well as future directions of research in a format accessible to new students and/or investigators. Finally, areas of uncertainty and limitations in the interpretation of TMS studies are discussed in some detail.

Stages of Motor Output Reorganization after Hemispheric Stroke Suggested by Longitudinal Studies of Cortical Physiology

Reorganization of motor circuits in the cerebral cortex is thought to contribute to recovery following stroke. These can be examined with transcranial magnetic stimulation (TMS) using measures of corticospinal tract integrity and intracortical excitability. However, little is known about how these changes develop during the important early period post-stroke and their influence on recovery. We used TMS to obtain multiple measures bilaterally in a group of 10 patients during the early days and weeks and up to 6 months post-stroke, in order to examine correlations with tests of hand function. Ten age-matched healthy subjects were also studied. After stroke, day-to-day variation in performance was unrelated to physiological measures in the first 3 weeks. Measures of corticospinal integrity averaged over the same period correlated well with hand function, but this relationship became weaker at 3 months. In contrast, most intracortical excitability measures did not correlate acutely but did so strongly at 3 months. Thus in the acute stage, patients’ performance is limited by damage to corticospinal output. Improved performance at 3 months may depend on reorganization in alternative cortical networks to maximize the efficiency of remaining corticospinal pathways—intracortical disinhibition may aid recovery by promoting access to these networks.

Age-dependent changes in the neural correlates of force modulation: An fMRI study

Functional imaging studies in humans have demonstrated widespread age-related changes in cortical motor networks. However, the relative contribution of cortical regions during motor performance varies not only with age but with task parameters. In this study, we investigated whether motor system activity during a task involving increasingly forceful hand grips was influenced by age. Forty right-handed volunteers underwent functional magnetic brain imaging whilst performing repetitive isometric hand grips with either hand in separate sessions. We found no age-related changes in the average size and shape of the task-related blood oxygen level dependent (BOLD) signal in contralateral primary motor cortex (M1), but did observe reduced ipsilateral M1 deactivation in older subjects (both hands). Furthermore, task-related activity co-varied positively with force output in a number of brain regions, but was less prominent with advancing age in contralateral M1, cingulate sulcus (both hands), sensory and premotor cortices (right hand). These results indicate that a reduced ability to modulate activity in appropriate motor networks when required may contribute to age-related decline in motor performance.

The Role of Contralesional Dorsal Premotor Cortex after Stroke as Studied with Concurrent TMS-fMRI

Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. We performed two complementary experiments to explore how cPMd might perform this role in a group of chronic human stroke patients. First, we used paired-coil transcranial magnetic stimulation (TMS) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. We found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, we applied TMS over cPMd during functional magnetic resonance imaging (fMRI) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in either hemisphere and whether these influences changed during affected hand movement. We confirmed that hand grip-related activation in cPMd was greater in more impaired patients. Furthermore, the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment (i.e., less inhibitory/more facilitatory cPMd-iM1 measure at rest as assessed with paired-coil TMS). Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitatory influence of cPMd TMS on blood oxygenation level-dependent signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. cPMd TMS was not found to influence activity in other brain regions in either hemisphere. This state-dependent influence on ipsilesional sensorimotor regions may provide a mechanism by which cPMd supports recovered function after stroke.

The relationship between brain activity and peak grip force is modulated by corticospinal system integrity after subcortical stroke

In healthy human subjects, the relative contribution of cortical regions to motor performance varies with the task parameters. Additionally, after stroke, recruitment of cortical areas during a simple motor task varies with corticospinal system integrity. We investigated whether the pattern of motor system recruitment in a task involving increasingly forceful hand grips is influenced by the degree of corticospinal system damage. Nine chronic subcortical stroke patients and nine age‐matched controls underwent functional magnetic brain imaging whilst performing repetitive isometric hand grips. Target grip forces were varied between 15% and 45% of individual maximum grip force. Corticospinal system functional integrity was assessed with transcranial magnetic stimulation. Averaged across all forces, there was more task‐related activation compared with rest in the secondary motor areas of patients with greater corticospinal system damage, confirming previous reports. However, here we were primarily interested in regional brain activation, which covaried with the amount of force generated, implying a prominent executive role in force production. We found that in control subjects and patients with lesser corticospinal system damage, signal change increased linearly with increasing force output in contralateral primary motor cortex, supplementary motor area and ipsilateral cerebellum. In contrast, in patients with greater corticospinal system damage, force‐related signal changes were seen mainly in contralesional dorsolateral premotor cortex, bilateral ventrolateral premotor cortices and contralesional cerebellum, but not ipsilesional primary motor cortex. These findings suggest that the premotor cortices might play a new and functionally relevant role in controlling force production in patients with more severe corticospinal system disruption.

Human Theta Burst Stimulation Enhances Subsequent Motor Learning and Increases Performance Variability

Intermittent theta burst stimulation (iTBS) transiently increases motor cortex excitability in healthy humans by a process thought to involve synaptic long-term potentiation (LTP), and this is enhanced by nicotine. Acquisition of a ballistic motor task is likewise accompanied by increased excitability and presumed intracortical LTP. Here, we test how iTBS and nicotine influences subsequent motor learning. Ten healthy subjects participated in a double-blinded placebo-controlled trial testing the effects of iTBS and nicotine. iTBS alone increased the rate of learning but this increase was blocked by nicotine. We then investigated factors other than synaptic strengthening that may play a role. Behavioral analysis and modeling suggested that iTBS increased performance variability, which correlated with learning outcome. A control experiment confirmed the increase in motor output variability by showing that iTBS increased the dispersion of involuntary transcranial magnetic stimulation-evoked thumb movements. We suggest that in addition to the effect on synaptic plasticity, iTBS may have facilitated performance by increasing motor output variability; nicotine negated this effect on variability perhaps via increasing the signal-to-noise ratio in cerebral cortex.

What can man do without basal ganglia motor output? The effect of combined unilateral subthalamotomy and pallidotomy in a patient with Parkinson's disease.

We have studied motor performance in a man with Parkinsons disease (PD) in whom thermolytic lesions of the left subthalamic and left globus pallidus nuclei interrupted the basal ganglia (BG)-thalamo-cortical motor circuit in the left hemisphere. This allowed us to study remaining motor capabilities in the absence of aberrant BG activity typical of PD. Movements of the left arm were slow and parkinsonian whereas movement speed and simple reaction times (RT) of the right (operated) arm were within the normal range with no obvious deficits in a range of daily life activities. Two main abnormalities were found with the right hand. (a) Implicit sequence learning in a probabilistic serial reaction time task was absent. (b) In a go/no-go task when the percent of no-go trials increased, the RT superiority with the right hand was lost. These deficits are best explained by a failure of the cortex, deprived of BG input, to facilitate responses in a probabilistic context. Our findings confirm the idea that it is better to stop BG activity than allowing faulty activity to disrupt the motor system but dispute earlier claims that interrupting BG output in PD goes without an apparent deficit. From a practical viewpoint, our observations indicate that the risk of persistent dyskinesias need not be viewed as a contraindication to subthalamotomy in PD patients since they can be eliminated if necessary by a subsequent pallidotomy without producing deficits that impair activities of daily life.

Transcallosal sensorimotor integration: effects of sensory input on cortical projections to the contralateral hand.

OBJECTIVE Low amplitude vibration of forearm or hand muscles predominantly activates proprioceptive inputs that influence corticospinal projections in a focal manner, increasing output to the stimulated muscle while reducing output to neighbouring muscles. Modulation of contralateral forearm muscles by vibration has also been reported on one occasion. The aim of the current investigation was to investigate the effects of proprioceptive input from a hand muscle on corticospinal excitability, intracortical inhibition (SICI) and interhemispheric inhibition (IHI) targeting the homologous contralateral muscle. METHODS Transcranial Magnetic Stimulation (TMS) was delivered to the left cortical hand area of 10 healthy subjects and surface electromyography (EMG) recordings taken from the right First Dorsal Interosseus (FDI) and Abductor Digiti Minimi (ADM). The effect of low amplitude vibration of the left FDI on MEP amplitudes, SICI and IHI targeting the right hand was assessed. RESULTS Vibration of the left FDI caused a significant reduction in MEP amplitudes in the homologous right FDI but not in the right ADM. SICI and IHI targeting both muscles were also significantly increased. CONCLUSIONS We conclude that proprioceptive input from a hand muscle reduces the corticospinal excitability of the contralateral homologous muscle. The increases in SICI and IHI suggest that at least some of this effect occurs in the cortex ipsilateral to the stimulus and this may be mediated via transcallosal fibres. SIGNIFICANCE These results suggest that sensory input can modulate excitability in both motor cortices simultaneously, as well as the relationship between them. Interventions which modulate this transcallosal relationship may become useful in disorders where abnormal IHI is a potential therapeutic target.

Differing effects of intracortical circuits on plasticity

Practice of a motor task leads to an increase in amplitude of motor-evoked potentials (MEP) in the exercised muscle. This is termed practice-dependent plasticity, and is abolished by the NMDA antagonist dextromethorphan and the GABAA agonist lorazepam. Here, we sought to determine whether specific subtypes of GABAA circuits are responsible for this effect by comparing the action of the non-selective agonist, lorazepam with that of the selective GABAA-alpha1 receptor agonist, zolpidem. In seven healthy subjects, transcranial magnetic stimulation (TMS) was used to quantify changes in amplitude of MEP after practice of a ballistic motor task. In addition we measured how the same drugs affected MEP amplitudes and the excitability of a number of cortical inhibitory circuits [short-interval intracortical inhibition (SICI), short-interval afferent inhibition (SAI) and long-interval intracortical inhibition]. This allowed us to explore correlations between drugs effects in measures of cortical excitability and practice-dependent plasticity of MEP amplitudes. As previously reported, lorazepam increased SICI and decreased SAI, while zolpidem only decreased SAI. The new findings were that practice-dependent plasticity of MEPs was impaired by lorazepam but not zolpidem, and that this was negatively correlated with lorazepam-induced changes in SICI but not SAI. This suggests that the intracortical circuits involved in SICI (and not neurons expressing GABAA-alpha1 receptor subunits that are implicated in SAI) may be involved in controlling the amount of practice-dependent MEP plasticity.

The facilitatory effects of intermittent theta burst stimulation on corticospinal excitability are enhanced by nicotine

OBJECTIVE Intermittent theta burst stimulation (iTBS) is increasingly widely used as a means of facilitating corticospinal excitability in the human primary motor cortex. This form of facilitatory plasticity within the stimulated cortex may occur by induction of long term potentiation (LTP). In animal models, agonists of nicotinic acetylcholine receptors have been shown to modulate or induce LTP; we thus sought to test whether nicotine may modulate the effects of iTBS on corticospinal excitability in humans. METHODS A double-blind placebo-controlled cross-over design study was conducted with 10 healthy subjects. iTBS was delivered 60min after subjects took either 4mg nicotine or placebo lozenges, and motor-evoked potentials (MEPs) were then recorded for 40min after the end of stimulation. RESULTS In the placebo arm, iTBS produced an increase in the amplitudes of MEPs which lasted for 5min. In the nicotine arm, iTBS produced a more pronounced facilitation of MEPs that was still present at 40min. In a control experiment, nicotine alone had no effect on MEP amplitudes when given in the absence of iTBS. CONCLUSIONS These data indicate that the effects of iTBS can be enhanced and prolonged by nicotine. SIGNIFICANCE These results are consistent with animal models demonstrating nicotinic modulation of facilitatory plasticity, and will be of interest to investigators seeking to enhance artificially induced changes in cortical excitability.