Michael C. Ridding

Interaction between intracortical inhibition and facilitation in human motor cortex

1. In seven normal subjects, subthreshold transcranial magnetic conditioning stimuli (using a figure‐of‐eight coil) were applied over the motor cortex in order to evoke activity in intracortical neuronal circuits. The net effect on cortical excitability was evaluated by measuring the effect on the size of EMG responses elicited in the abductor digiti minimi (ADM) muscle by a subsequent suprathreshold test stimulus. 2. A single conditioning stimulus suppressed the size of the test response at interstimulus intervals (ISIs) of 1‐4 ms whereas the response was facilitated at ISIs of 6‐20 ms. The facilitation could be augmented if pairs of conditioning stimuli were given. 3. Inhibition and facilitation appeared to have separate mechanisms. The threshold for inhibition (0.7 active motor threshold) was slightly lower than that for facilitation (0.8 active threshold). Similarly, the inhibitory effect was independent of the direction of current flow induced in the cortex by the conditioning shock, whereas facilitation was maximal with posterior‐anterior currents and minimal with lateromedial current. 4. Direct corticospinal effects were probably not responsible for the results since facilitation of cortical test responses could be produced by conditioning stimuli which had no effect on the amplitude of H reflexes elicited in active ADM muscle. 5. Inhibition and facilitation appeared to interact in a roughly linear manner, consistent with separate inputs to a common neurone. 6. We suggest that subthreshold transcranial magnetic stimulation is capable of activating separate populations of excitatory and inhibitory interneurones in the motor cortex.

Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia.

Transcranial magnetic stimulation has been used in a double pulse paradigm to investigate the excitability of intrinsic motor cortical circuits in 15 patients with focal task specific dystonia of the right hand and a group of eight age matched controls. The left hemisphere was examined in five patients; in the remainder, both hemispheres were tested. There was no significant difference in stimulation threshold between patients and controls nor between the left and right hemispheres in the patients. There was a significant decrease in early corticocortical suppression when comparing stimulation of the left hemisphere in the patients and controls at interstimulus intervals of 1-15 ms (P < 0.01). There was no difference in the amount of suppression in the right and left hemispheres of the patients. It is concluded that in focal task specific dystonia there is shift in the balance between excitation and inhibition in local circuits of the motor cortex which leads to a net decrease in the amount of short latency suppression. These changes reflect disturbed basal ganglia input to the motor cortex. Reduced excitability of cortical inhibitory circuits may be one factor which contributes to the excessive and inappropriate muscle contraction which occurs during fine motor tasks in patients with focal dystonia.

Is there a future for therapeutic use of transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) has in recent years been used to explore therapeutic opportunities in a bewildering variety of conditions. Although there is good evidence that this technique can modify cortical activity, the rationale for its use in many of the conditions investigated so far is not clear. Here we discuss the effects of rTMS in healthy subjects and how it has been used in a number of neurological conditions. We argue that a better understanding of both the effects of rTMS and the pathological processes underlying the conditions for which it is used will reveal whether rTMS really does offer therapeutic potential and, if so, for which conditions.

Determinants of the induction of cortical plasticity by non‐invasive brain stimulation in healthy subjects

The ability to induce cortical plasticity with non‐invasive brain stimulation (NBS) techniques has provided novel and exciting opportunities for examining the role of the human cortex during a variety of behaviours. Additionally, and importantly, the induction of lasting changes in cortical excitability can, under some conditions, reversibly modify behaviour and interact with normal learning. Such findings have driven a large number of recent studies examining whether by using such approaches it might be possible to induce functionally significant changes in patients with a large variety of neurological and psychiatric conditions including stroke, Parkinsons disease and depression. However, even in neurologically normal subjects the variability in the neurophysiological and behavioural response to such brain stimulation techniques is high. This variability at present limits the therapeutic usefulness of these techniques. The cause of this variability is multifactorial and to some degree still unknown. However, a number of factors that can influence the induction of plasticity have been identified. This review will summarise what is known about the causes of variability in healthy subjects and propose additional factors that are likely to be important determinants. A greater understanding of these determinants is critical for optimising the therapeutic applications of non‐invasive brain stimulation techniques.

The effect of voluntary contraction on cortico-cortical inhibition in human motor cortex.

1. It has been previously shown that in a relaxed target muscle, at short interstimulus intervals (ISIs) (up to 6 ms) a conditioning subthreshold transcranial magnetic stimulus can cause suppression of the EMG response evoked by a magnetic test stimulus. At longer ISIs (7‐15 ms) facilitation of the test response is seen. This type of inhibition has been termed ipsilateral cortico‐cortical inhibition. 2. The effect of a minimal tonic contraction on ipsilateral cortico‐cortical inhibition has been investigated in the first dorsal interrosseous (FDI). 3. At short ISIs there was significantly less inhibition of the test response during the maintenance of minimal voluntary tonic contraction of the target muscle (FDI). 4. At longer ISIs (7‐15 ms) there was significantly less facilitation of the test response during a tonic contraction than during relaxation. 5. Minimal activation of an ipsilateral proximal muscle (biceps) had no significant effect on the degree of inhibition seen in the relaxed target muscle (FDI). 6. We suggest that voluntary drive reduces the excitability of inhibitory circuits in cortical areas that project to the active muscle.

Stimulus/response curves as a method of measuring motor cortical excitability in man

We investigated whether input/output curves of human motor cortex could provide similar information to cortical mapping under two conditions where the motor maps are known to change dramatically: ischaemic anaesthesia and amputation. Stimulus/response curves were constructed by recording the size of EMG responses evoked in arm muscles with transcranial magnetic stimulation at a single site using a range of intensities. Changes in the slope of this relationship during ischaemic anaesthesia (6 normal subjects) or amputation (two patients) were compared to changes in cortical motor maps produced by stimulating different sites at the same intensity. At rest both interventions increased map areas, as well as the slope of the stimulus/response curves. During voluntary activity they had no effect. We conclude that stimulus/response curves can detect changes in cortical motor maps, and discuss potential mechanisms for this effect.

Short latency facilitation between pairs of threshold magnetic stimuli applied to human motor cortex

Pairs of threshold magnetic stimuli were applied over the motor cortex at interstimulus intervals of 1-6 ms, and EMG responses recorded from the relaxed or active first dorsal interosseous muscle of 7 normal subjects. In relaxed subjects, when the interval between the stimuli was around 1.0-1.5 ms, 2.5-3.0 ms or 4.5 ms or later, the size of the response to the pair of stimuli was much greater than the algebraic sum of the response to each stimulus alone. During contraction, fewer peaks of facilitation were observed. Facilitation was evident if the stimuli were 0.9-1.1 times threshold in the relaxed state, and 1.0-1.1 times threshold during voluntary contraction. Experiments using either magnetic followed by anodal electric stimulation, or pairs of anodal electric stimuli, suggested that the facilitation most likely occurred within the cerebral motor cortex. Given the timings at which facilitation is prominent, it seems likely that it reflects interactions between circuits normally responsible for production of I-waves.

Changes in corticomotor representations induced by prolonged peripheral nerve stimulation in humans

OBJECTIVE Manipulation of afferent input can induce reorganization within the sensorimotor cortex which may have important functional consequences. Here we investigate whether prolonged peripheral nerve stimulation can induce reorganization within the human motor cortex. METHODS Using transcranial magnetic stimulation, we mapped the scalp representation of the corticospinal projection to hand muscles in 8 normal subjects before and after 2h of simultaneous repetitive electrical stimulation of the ulnar and radial nerves at the wrist. Control mapping experiments were conducted in 6 subjects. RESULTS Following nerve stimulation, larger motor-evoked potentials were evoked from more scalp sites. The induced changes were most apparent in first dorsal interosseous, but were also seen in other hand muscles. The increases in area of the representational maps were accompanied by changes in the location of the optimal site for evoking responses in first dorsal interosseous, and changes in the centres of gravity of the maps. CONCLUSIONS Prolonged afferent stimulation induces an increase in excitability of the corticospinal projection. This is accompanied by a significant shift in the centre of gravity of the stimulated muscles which we propose is evidence of a non-uniform expansion in their cortical representation.

Cortisol Inhibits Neuroplasticity Induction in Human Motor Cortex

We investigated whether plasticity of human motor cortex (M1) is influenced by time of day, and whether changes in circulating levels of cortisol contribute to this effect. Neuroplasticity was induced using paired associative stimulation (PAS), involving electrical stimulation of left median nerve, paired with transcranial magnetic stimulation over the right M1 25 ms later (90 pairs at 0.05 Hz). Surface EMG was recorded from the left abductor pollicis brevis (APB) and first dorsal interosseous muscle. Cortisol levels were assessed from saliva. Time-of-day modulation of PAS effectiveness was assessed in 25 subjects who were tested twice, at 8:00 A.M. and 8:00 P.M. on separate days. In a second double-blind study, 17 subjects were tested with PAS at 8:00 P.M. on two occasions after administration of oral hydrocortisone (24 mg) or placebo. The motor-evoked potential (MEP) in resting APB increased significantly after PAS in the evening (when endogenous cortisol levels were low), but not in the morning. Oral hydrocortisone prevented facilitation of the APB MEP after PAS, and in the drug study, mean salivary cortisol levels were negatively associated with PAS effectiveness. The GABAB-mediated cortical silent period for APB was longer in the morning than in the evening, and was lengthened by PAS and oral hydrocortisone. We conclude that neuroplasticity in human M1 and GABAB-dependent intracortical inhibitory systems are influenced by time of day and modified by circulating levels of cortisol.

Afferent input and cortical organisation: a study with magnetic stimulation

Abstract Previously, we had described a technique for investigating probable GABAergic cortical inhibitory circuits in conscious man using transcranial magnetic stimulation. This type of inhibition has been termed intracortical inhibition. During voluntary contraction, activity in the circuits responsible for this inhibition is reduced. The mechanism by which this reduction in activity is brought about is unknown. However, evidence exists to suggest that afferent input may be, at least in part, responsible for the reduction in inhibition. The experiments described here were designed to investigate this possibility further. The results of these experiments showed that afferent input, produced by electrical peri- pheral-nerve stimulation, reduced the level of intracortical inhibition. Also, motor imagery, which activates similar brain regions as overt movement, but does not result in afferent input, failed to produce significant changes in intracortical inhibition. We conclude from these results that afferent input is capable of altering activity in cortical inhibitory circuits. The relevance of these findings to the mechanisms involved in cortical reorganisation is discussed.