Ritsuko Hanajima

Paired-pulse magnetic stimulation of the human motor cortex: differences among I waves.

1 In paired‐pulse cortical stimulation experiments, conditioning subthreshold stimuli suppress the electromyographic (EMG) responses of relaxed muscles to suprathreshold magnetic test stimuli at short interstimulus intervals (ISIs) (1‐5 ms) and facilitate them at long ISIs (8‐15 ms). 2 We made paired‐pulse magnetic stimulation studies on the response of the first dorsal interosseous muscle (FDI) produced by I1 or I3 waves using our previously reported method which preferentially elicits one group of I waves when subjects make a slight voluntary contraction. In some experiments the conditioning and test stimuli were oppositely directed, in the others they were oriented in the same direction. Single motor unit responses were recorded with a concentric needle electrode, and surface EMG responses with cup electrodes. 3 In post‐stimulus time histograms (PSTHs) of the firing probability of motor units, the peaks produced by I3 waves were decreased by a subthreshold conditioning stimulus that preferentially elicited I1 or I3 waves at an ISI of 4 ms. The amount of decrement depended on the intensity of the conditioning stimulus. The stronger the conditioning stimulus, the greater the suppression. In contrast, the peaks produced by I1 waves were little affected by any type of subthreshold conditioning stimulus, given 4 ms prior to the test stimulus. At an ISI of 10 ms, a subthreshold conditioning stimulus slightly decreased the size of the peak produced by the I3 waves, but did not affect the peaks evoked by I1 waves. 4 Surface EMGs showed that a subthreshold conditioning stimulus suppressed the responses produced by I3 waves irrespective of its current direction (anterior or posterior). Both the amount and duration of suppression depended on the intensity of the conditioning stimulus, but not on its current direction. Both parameters increased when the intensity increased. At a high intensity conditioning stimulus, suppression was evoked at ISIs of 1‐20 ms, compatible with the duration of GABA‐mediated inhibition found in animal experiments. Responses produced by I1 waves were little affected by any type of subthreshold conditioning stimulus. 5 We conclude that a subthreshold conditioning stimulus given over the motor cortex moderately suppresses I3 waves but does not affect I1 waves. The duration of suppression of the I3 waves supports the idea that this is an effect of GABAergic inhibition within the motor cortex.

Interhemispheric facilitation of the hand motor area in humans

1 We investigated interhemispheric interactions between the human hand motor areas using transcranial cortical magnetic and electrical stimulation. 2 A magnetic test stimulus was applied over the motor cortex contralateral to the recorded muscle (test motor cortex), and an electrical or magnetic conditioning stimulus was applied over the ipsilateral hemisphere (conditioning motor cortex). We investigated the effects of the conditioning stimulus on responses to the test stimulus. 3 Two effects were elicited at different interstimulus intervals (ISIs): early facilitation (ISI = 4–5 ms) and late inhibition (ISI ≥ 11 ms). 4 The early facilitation was evoked by a magnetic or anodal electrical conditioning stimulus over the motor point in the conditioning hemisphere, which suggests that the conditioning stimulus for early facilitation directly activates corticospinal neurones. 5 The ISIs for early facilitation taken together with the time required for activation of corticospinal neurones by I3‐waves in the test hemisphere are compatible with the interhemispheric conduction time through the corpus callosum. Early facilitation was observed in responses to I3‐waves, but not in responses to D‐waves nor to I1‐waves. Based on these results, we conclude that early facilitation is mediated through the corpus callosum. 6 If the magnetic conditioning stimulus induced posteriorly directed currents, or if an anodal electrical conditioning stimulus was applied over a point 2 cm anterior to the motor point, then we observed late inhibition with no early facilitation. 7 Late inhibition was evoked in responses to both I1‐ and I3‐waves, but was not evoked in responses to D‐waves. The stronger the conditioning stimulus was, the greater was the amount of inhibition. These results are compatible with surround inhibition at the motor cortex.

Bidirectional long‐term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool to induce plastic changes that are thought in some cases to reflect N‐methyl‐d‐aspartate‐sensitive changes in synaptic efficacy. As in animal experiments, there is some evidence that the sign of rTMS‐induced plasticity depends on the prior history of cortical activity, conforming to the Bienenstock–Cooper–Munro (BCM) theory. However, experiments exploring these plastic changes have only examined priming‐induced effects on a limited number of rTMS protocols, often using designs in which the priming alone had a larger effect than the principle conditioning protocol. The aim of this study was to introduce a new rTMS protocol that gives a broad range of after‐effects from suppression to facilitation and then test how each of these is affected by a priming protocol that on its own has no effect on motor cortical excitability, as indexed by motor‐evoked potential (MEP). Repeated trains of four monophasic TMS pulses (quadripulse stimulation: QPS) separated by interstimulus intervals of 1.5–1250 ms produced a range of after‐effects that were compatible with changes in synaptic plasticity. Thus, QPS at short intervals facilitated MEPs for more than 75 min, whereas QPS at long intervals suppressed MEPs for more than 75 min. Paired‐pulse TMS experiments exploring intracortical inhibition and facilitation after QPS revealed effects on excitatory but not inhibitory circuits of the primary motor cortex. Finally, the effect of priming protocols on QPS‐induced plasticity was consistent with a BCM‐like model of priming that shifts the crossover point at which synaptic plasticity reverses from depression to potentiation. The broad range of after‐effects produced by the new rTMS protocol opens up new possibilities for detailed examination of theories of metaplasticity in humans.

Ipsilateral cortico-cortical inhibition of the motor cortex in various neurological disorders

We used a paired-pulse magnetic stimulation technique to study ipsilateral cortico-cortical inhibition of the motor cortex in 48 patients with various neurological disorders and in 20 normal volunteers. In the normal subjects, the first subthreshold conditioning stimulus suppressed responses to the second suprathreshold test stimulus at interstimulus intervals (ISIs) of 1-5 ms (inhibition at short intervals), and facilitated them at ISIs of 8-15 ms (facilitation at long intervals). Patients with motor neuron disease, except those in whom brain stimulation produced control responses that were generated by direct activation of corticospinal neurons (D-waves), had normal inhibition at short intervals. Facilitation at long intervals was not elicited in some patients with amyotrophic lateral sclerosis. Less inhibition at short intervals and normal facilitation at long intervals was found for all the patients with progressive myoclonic epilepsy, a condition in which the excitability of cortical inhibitory interneurons is thought to be affected. Inhibition at short intervals was disturbed, but facilitation at long intervals was intact in the patients with movement disorders (Parkinsons disease, corticobasal degeneration, and Wilsons disease). In these patients, positron emission tomography (PET) studies showed decreased regional cerebral blood flow (rCBF) in the basal ganglia in the relaxed state. However, normal suppression was elicited in the patients with Parkinsons disease with normal rCBF. In four patients with chorea, the time-course of inhibition and facilitation was normal, even though PET studies showed decreased rCBF in the basal ganglia in two of them. Normal inhibition could not be elicited in patients who had a small lesion in the basal ganglia or in the pathway from basal ganglia to the primary motor cortex; the putamen, globus pallidus, and supplementary motor cortex. In contrast, patients who had a lesion in a sensory system (sensory cortex or sensory thalamus) or in the pontine nucleus had normal suppression. We conclude that the results of ipsilateral cortico-cortical inhibition with paired magnetic stimulation reflect the excitability of inhibitory interneurons in the motor cortex and that outputs from the basal ganglia markedly affect this inhibition, but outputs from somato-sensory systems or cerebellum do not. Moreover, dysfunction of the corticospinal tract or spinal motoneurons does not affect results obtained by the paired magnetic stimulation technique when the control responses are generated by I-waves (i.e. descending volleys are produced by transsynaptic activation of the corticospinal tract neurons.

Mechanisms of intracortical I-wave facilitation elicited with paired-pulse magnetic stimulation in humans

In order to elucidate the mechanisms underlying intracortical I‐wave facilitation elicited by paired‐pulse magnetic stimulation, we compared intracortical facilitation of I1‐waves with that of I3‐waves using single motor unit and surface electromyographic (EMG) recordings from the first dorsal interosseous muscle (FDI). We used a suprathreshold first stimulus (S1) and a subthreshold second stimulus (S2). In most experiments, both stimuli induced currents in the same direction. In others, S1 induced posteriorly directed currents and S2 induced anteriorly directed currents. When both stimuli induced anteriorly directed currents (I1‐wave effects), an interstimulus interval (ISI) of 1.5 ms resulted in extra facilitation of the responses to S1 alone. The latency of this effect was equivalent to that of the I2‐wave from S1. When S1 evoked posteriorly directed currents (I3‐wave recruitment), facilitation occurred at a latency corresponding to the I3‐wave from S1. This facilitation occurred at an ISI of 1.5 ms when both S1 and S2 flowed posteriorly, and at an ISI of approximately 3.5 ms when S1 was posteriorly and S2 was anteriorly directed. Based on these findings, we propose the following mechanisms for intracortical I‐wave facilitation. When S1 and S2 induce currents in the same direction, facilitation is produced by summation between excitatory postsynaptic potentials (EPSPs) elicited by S1 and subliminal depolarization of interneurones elicited by S2 directly. When S1 and S2 induce currents in the opposite direction, facilitation is produced by the same mechanism as above or by temporal and spatial summation of EPSPs elicited by two successive stimuli at interneurones or corticospinal neurones of the motor cortex.

RESPONSE OF ANTI-NMDA RECEPTOR ENCEPHALITIS WITHOUT TUMOR TO IMMUNOTHERAPY INCLUDING RITUXIMAB

Paraneoplastic encephalitis with antibodies against NR1/NR2 heteromers of the NMDA receptor associates frequently with ovarian teratoma and has recently been established as a distinct clinical entity.1 Most patients are young women who develop a syndrome with prodromal cold-like illness, intractable seizures, psychosis, dyskinesia, and hypoventilation.1,2 However, about 40% of patients do not have a detectable tumor,3 and the treatment of these patients remains unclear. We report a patient with anti-NR1/NR2 encephalitis without teratoma who showed a nearly complete recovery after intensive immunotherapy including rituximab. ### Case report. A 42-year-old woman had cough and headache for 3 weeks. On the day before admission, she was found to be unresponsive for several minutes, and subsequently developed generalized seizures. On admission, her temperature was 38.2°C, and she had meningeal signs. CSF revealed mild pleocytosis (10/mm3) and slightly elevated protein concentration (45 mg/dL) with normal glucose concentration and IgG index. MRI (figure, A) and EEG were unremarkable. After the seizures were controlled, minimal disorientation was observed. Acyclovir and ceftriaxone were started. Figure MRI and FDG-PET studies of the brain (A) On day 2, the FLAIR MRI was normal. (B) On day 18, the FLAIR image revealed new high-intensity areas in the right temporal cortex, insula, parts of the frontal, parietal, and occipital cortices, and hippocampus. These findings were accompanied by mild edema. High-intensity areas were also observed in the left inferior temporal cortex and hippocampus

Shortening of simple reaction time by peripheral electrical and submotor-threshold magnetic cortical stimulation

Abstract Subthreshold transcranial magnetic stimulation (TMS) over the motor cortex can shorten the simple reaction time in contralateral arm muscles if the cortical shock is given at about the same time as the reaction stimulus. The present experiments were designed to investigate whether this phenomenon is due to a specific facilitatory effect on cortical circuitry. The simple visual reaction time was shortened by 20–50 ms when subthreshold TMS was given over the contralateral motor cortex. Reaction time was reduced to the same level whether the magnetic stimulus was given over the bilateral motor cortices or over other points on the scalp (Cz, Pz). Indeed, similar effects could be seen with conventional electrical stimulation over the neck, or even when the coil was discharged (giving a click sound) near the head. We conclude that much of the effect of TMS on simple reaction time is due to intersensory facilitation, although part of it may be ascribed to a specific effect on the excitability of motor cortex.

Facilitatory effect of tonic voluntary contraction on responses to motor cortex stimulation

To investigate the mechanisms underlying the facilitation of responses to motor cortical stimulation produced by tonic voluntary contraction, we studied the facilitatory effects in 7 normal volunteers during different levels of muscle contraction. Responses were similarly facilitated by voluntary contraction with 3 forms of stimulation: magnetic cortical, electrical cortical, and foramen magnum level stimulation. At a high level of contraction, however, only magnetic responses were markedly facilitated. We conclude that the facilitation of responses to cortical stimulation induced by tonic voluntary contraction occurs mainly at the spinal level, but that cortical excitability changes also contribute to the enlargement of magnetic responses in the case of a high level of contraction.

Interhemispheric facilitation of the hand area of the human motor cortex

We investigated interaction of the human bilateral hand motor area using two magnetic stimulators. A conditioning shock over the motor cortex facilitated the response evoked in the ipsilateral first dorsal interosseous muscle by a test shock over the contralateral motor cortex given under the limiting conditions of a small conditioning shock over a very small area and a small test shock. This effect was so weak that it was not elicited under slightly different conditions. We conclude that an excitatory, but weak, connection between strictly homotopic areas of the bilateral hand motor cortices exists in humans.

Magnetic stimulation over the cerebellum in patients with ataxia

We studied 20 patients with ataxia caused by various disorders using magnetic stimulation over the cerebellum. Results were compared with normal values found for 12 normal volunteers. In normal subjects, a magnetic stimulus over the cerebellum reduced the size of responses evoked by magnetic cortical stimulation when it preceded cortical stimulus by 5, 6 and 7 ms. The grand average of the ratios of the areas of conditioned responses at intervals of 5, 6 and 7 ms to those of control responses was designated the average area ratio (5-7 ms). Suppression of motor cortical excitability was reduced or absent in patients with a lesion in the cerebellum or cerebellothalamocortical pathway, but was normal in patients with a lesion in the afferent pathway to the cerebellum. Normal suppression was observed in Fishers syndrome. The average area ratio (5-7 ms) correlated well with the severity of ataxia in patients with degenerative late-onset ataxia. These results are consistent with those for electrical stimulation of the cerebellum reported previously. We conclude that magnetic stimulation over the cerebellum produces the same effect as electrical stimulation even in ataxic patients. This less painful method can be used clinically to clarify the pathomechanisms for ataxia. Two other clinical uses of this technique were that it revealed clinically undetectable cerebellar dysfunction in patients whose extrapyramidal signs masked cerebellar signs, and that the slow progression of ataxia could be followed quantitatively in patients with degenerative late-onset ataxia.