Shinya Ohminami

Primary motor cortical metaplasticity induced by priming over the supplementary motor area

Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS‐induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor‐related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico‐cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS‐induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor‐evoked potential sizes on its own but specifically modulated the excitatory I‐wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans.

Bidirectional effects on interhemispheric resting‐state functional connectivity induced by excitatory and inhibitory repetitive transcranial magnetic stimulation

Several recent studies using functional magnetic resonance imaging (fMRI) have shown that repetitive transcranial magnetic stimulation (rTMS) affects not only brain activity in stimulated regions but also resting‐state functional connectivity (RSFC) between the stimulated region and other remote regions. However, these studies have only demonstrated an effect of either excitatory or inhibitory rTMS on RSFC, and have not clearly shown the bidirectional effects of both types of rTMS. Here, we addressed this issue by performing excitatory and inhibitory quadripulse TMS (QPS), which is considered to exert relatively large and long‐lasting effects on cortical excitability. We found that excitatory rTMS (QPS with interstimulus intervals of 5 ms) decreased interhemispheric RSFC between bilateral primary motor cortices, whereas inhibitory rTMS (QPS with interstimulus intervals of 50 ms) increased interhemispheric RSFC. The magnitude of these effects on RSFC was significantly correlated with that of rTMS‐induced effects on motor evoked potential from the corresponding muscle. The bidirectional effects of QPS were also observed in the stimulation over prefrontal and parietal association areas. These findings provide evidence for the robust bidirectional effects of excitatory and inhibitory rTMSs on RSFC, and raise a possibility that QPS can be a powerful tool to modulate RSFC. Hum Brain Mapp 35:1896–1905, 2014.

Cerebellar dysfunction in progressive supranuclear palsy: A transcranial magnetic stimulation study†

Progressive supranuclear palsy (PSP) rarely shows cerebellar signs and symptoms even though the cerebellar dentate nuclei are involved pathologically. This study evaluates cerebellar function using transcranial magnetic stimulation (TMS) to determine whether subclinical cerebellar involvement is present in PSP patients. We studied 11 patients with PSP, 11 patients with Parkinsons disease (PD), and 10 age‐matched controls. Patients were examined with their usual medications and in their relative on state. Motor evoked potentials (MEPs) were recorded from the hand muscle. Cerebellar function was evaluated using suppressive effects of TMS over the cerebellum on MEPs elicited by TMS over the contralateral motor cortex, which we call cerebellar inhibition (CBI). Interstimulus intervals (ISIs) of 4 to 8 ms were used, and the time course of CBI was analyzed. The CBI was reduced in PSP patients. By contrast, the CBI was normal in PD patients in their on state. Although the CBI in their off state should be examined in future studies, the results described herein suggest that Purkinje cells or the dentato–thalamo–cortical pathway assessed by CBI is involved in PSP. Our results are compatible with the pathological findings showing severe dentate nucleus degeneration in PSP patients.

Influence of Short-Interval Intracortical Inhibition on Short-Interval Intracortical Facilitation in Human Primary Motor Cortex

Using the paired-pulse paradigm, transcranial magnetic stimulation (TMS) has revealed much about the human primary motor cortex (M1). A preceding subthreshold conditioning stimulus (CS) inhibits the excitability of the motor cortex, which is named short-interval intracortical inhibition (SICI). In contrast, facilitation is observed when the first pulse (S1) is followed by a second one at threshold (S2), named short-interval intracortical facilitation (SICF). SICI and SICF have been considered to be mediated by different neural circuits within M1, but more recent studies reported relations between them. In this study, we performed triple-pulse stimulation consisting of CS-S1-S2 to further explore putative interactions between these two effects. Three intensities of CS (80-120% of active motor threshold: AMT) and two intensities of S2 (120 and 140% AMT) were combined. The SICF in the paired-pulse paradigm exhibited clear facilitatory peaks at ISIs of 1.5 and 3 ms. The second peak at 3 ms was significantly suppressed by triple-pulse stimulation using 120% AMT CS, although the first peak was almost unaffected. Our present results obtained using triple-pulse stimulation suggest that each peak of SICF is differently modulated by different intensities of CS. The suppression of the second peak might be ascribed to the findings in the paired-pulse paradigm that CS mediates SICI by inhibiting later I waves such as I3 waves and that the second peak of SICF is most probably related to I3 waves. We propose that CS might inhibit the second peak of SICF at the interneurons responsible for I3 waves.

Reduced interhemispheric inhibition in mild cognitive impairment

In mild cognitive impairment (MCI), the corpus callosum is known to be affected structurally. We evaluated callosal function by interhemispheric inhibition (IHI) using transcranial magnetic stimulation (TMS) in MCI patients. We investigated 12 amnestic MCI patients and 16 healthy age-matched control subjects. The IHI was studied with a paired-pulse TMS technique. The conditioning TMS was given over the right primary motor cortex (M1) and the test TMS over the left M1. Motor evoked potentials were recorded from the relaxed first dorsal interosseous muscle. We also studied other motor cortical circuit functions; short-latency afferent inhibition (SAI), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Both the amount of IHI and SAI were significantly reduced in MCI patients as compared with control subjects, whereas SICI or ICF did not differ between them. The degree of IHI significantly correlated with neither the mini-mental state examination score nor the degree of SAI. Our results suggest that transcallosal connection between bilateral M1 is primarily involved in MCI, regardless of SAI dysfunction.

Supramaximal responses can be elicited in hand muscles by magnetic stimulation of the cervical motor roots.

BACKGROUND The amplitude of compound muscle action potentials (CMAPs) evoked in response to magnetic cervical motor root stimulation (MRS) has rarely been used as a diagnostic parameter because of the difficulty in obtaining supramaximal CMAPs. OBJECTIVE To clarify whether supramaximal CMAPs could be elicited by MRS, and if so, whether their amplitude and area could be used to evaluate the conduction of proximal motor roots. METHOD With the use of a custom-made high-power magnetic stimulator, the CMAPs evoked in response to MRS of the first dorsal interosseous, abductor digiti minimi, and abductor pollicis brevis (APB) muscles were compared with those evoked by electrical stimulation at the wrist, brachial plexus, and cervical motor roots. The collision technique was also used to exclude volume conduction. The correlation between MRS-induced CMAP latency and body height was evaluated. RESULTS In 32 of 36 normal subjects, supramaximal CMAPs were obtained in response to MRS. The size of CMAPs occurring in response to MRS was the same as the size of those occurring in response to high-voltage electrical cervical motor root stimulation. The collision technique revealed that the APB muscle was highly contaminated by volume conduction from adjacent muscles. CMAP latency correlated significantly with body height. CONCLUSIONS Supramaximal CMAPs can be obtained in most normal subjects. In subjects exhibiting confirmed supramaximal CMAPs in response to MRS, not only the latency of these CMAPs but also their amplitude and area can be clinically useful, excluding CMAPs in the APB muscle.

Binding of immunoglobulin G antibodies in Guillain-Barré syndrome sera to a mixture of GM1 and a phospholipid: possible clinical implications.

Anti‐GM1 immunoglobulin G (IgG) antibodies are frequently present in sera from patients with Guillain–Barré syndrome (GBS). A previous report on a patient who had a neuropathy with immunoglobulin M (IgM) M‐protein binding to a conformational epitope formed by phosphatidic acid (PA) and gangliosides prompted us to investigate the binding of IgG antibodies in GBS sera to a mixture of GM1 and PA (GM1/PA). Of 121 GBS patients, 32 had anti‐GM1 IgG antibodies. All 32 also had antibody activity against GM1/PA. Twenty‐five (78%) of 32 patients had greater activity against GM1/PA than against GM1 alone. Twelve patients who had no anti‐GM1 IgG antibodies had IgG antibody activity against GM1/PA. No GBS patient had IgG antibody against PA alone. In contrast, two rabbit anti‐GM1 antisera had greater activity against GM1 alone than against GM1/PA. IgG antibody with greater binding activity against a mixture of GM1 and a phospholipid than against GM1 alone may have an important role in the pathogenesis of GBS and has implications for diagnosis. Muscle Nerve 27: 302–306, 2003

Effects of the motor cortical quadripulse transcranial magnetic stimulation (QPS) on the contralateral motor cortex and interhemispheric interactions

Corpus callosum connects the bilateral primary motor cortices (M1s) and plays an important role in motor control. Using the paired-pulse transcranial magnetic stimulation (TMS) paradigm, we can measure interhemispheric inhibition (IHI) and interhemispheric facilitation (IHF) as indexes of the interhemispheric interactions in humans. We investigated how quadripulse transcranial magnetic stimulation (QPS), one form of repetitive TMS (rTMS), on M1 affects the contralateral M1 and the interhemispheric interactions. QPS is able to induce bidirectional plastic changes in M1 depending on the interstimulus intervals (ISIs) of TMS pulses: long-term potentiation (LTP)-like effect by QPS-5 protocol, and long-term depression-like effect by QPS-50, whose numbers indicate the ISI (ms). Twelve healthy subjects were enrolled. We applied QPS over the left M1 and recorded several parameters before and 30 min after QPS. QPS-5, which increased motor-evoked potentials (MEPs) induced by left M1 activation, also increased MEPs induced by right M1 activation. Meanwhile, QPS-50, which decreased MEPs elicited by left M1 activation, did not induce any significant changes in MEPs elicited by right M1 activation. None of the resting motor threshold, active motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation, and short-interval intracortical inhibition in right M1 were affected by QPS. IHI and IHF from left to right M1 significantly increased after left M1 QPS-5. The degree of left first dorsal interosseous MEP amplitude change by QPS-5 significantly correlated with the degree of IHF change. We suppose that the LTP-like effect on the contralateral M1 may be produced by some interhemispheric interactions through the corpus callosum.

Progressive Supranuclear Palsy With Walleyed Bilateral Internuclear Ophthalmoplegia Syndrome

BACKGROUND Walleyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome has mainly been reported in patients with cerebrovascular diseases and multiple sclerosis, but has never been described in patients with neurodegenerative diseases. OBJECTIVE To describe a patient with progressive supranuclear palsy (PSP) who presented with WEBINO syndrome. DESIGN Case report and review of literature. SETTING A university hospital. PATIENT A 72-year-old man began to display akinesia, freezing of gait, postural instability, mild rigidity of the neck, and vertical supranuclear palsy, including downward gaze limitation, at 66 years of age. At 68 years, he started to develop diplopia. At 70 years, he had bilateral medial longitudinal fasciculus syndrome. Later, his eye positions gradually showed alternating exotropia. RESULTS A diagnosis of probable PSP was made based on the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy criteria. He showed alternating exotropia in the forward gaze, and adduction paresis and monocular nystagmus of the abducted eye in the horizontal gaze, 2 clinical symptoms of WEBINO syndrome. CONCLUSION This is the first reported case of a patient with PSP presenting with WEBINO syndrome. Because bilateral medial longitudinal fasciculus lesions are commonly observed in PSP as clinical and pathological findings, particular attention should be given to WEBINO syndrome in patients with PSP.

Modulation of error-sensitivity during a prism adaptation task in people with cerebellar degeneration

Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage.