Effects of L-DOPA on quadripulse magnetic stimulation-induced long-term potentiation in older adults.

Reduced cortical plasticity has been previously reported in older adult as compared with young adults. However, the effects of dopamine on this plasticity reduction remain unknown. Here, we assessed the effects of high-dose (200 mg) and medium-dose (100 mg) L-3,4-dihydroxyphenylalanine (L-DOPA) intake on the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS) in older adults (aged ∼65 years). The subjects were 32 (200 mg) and 20 (100 mg) healthy older adult volunteers. This study was designed as a double-blind, crossover and placebo-controlled trial on one dose of L-dopa. Two hours after taking L-DOPA or placebo-drug, QPS was applied over the motor cortex. Motor evoked potentials were recorded to evaluate the motor cortical excitability changes. We found that both doses of L-DOPA enhanced LTP after QPS in older adults as one group. We classified subjects into QPS responders and QPS nonresponders. Both L-DOPA doses produced significant LTP enhancement in QPS nonresponders, whereas either of doses did not produce significant LTP enhancement in QPS responders. Collectively, our findings suggest that the neural plasticity reductions observed in older adults could be partly improved by dopamine.

Increased facilitation of the primary motor cortex in de novo Parkinson's disease.

INTRODUCTION: Paired-pulse transcranial magnetic stimulation (TMS) is useful to estimate the balance between inhibitory and facilitatory circuits of the primary motor cortex (M1) in Parkinson's disease (PD). Results of earlier studies are, however, incongruent: some reports describe normal short-interval intracortical inhibition (SICI), but others describe reduced SICI. We hypothesize that exaggerated intracortical facilitation masks normal inhibition, and that a triple-pulse method can reveal masked inhibition in PD. METHODS: Ten PD patients who had not been exposed to dopaminergic medications were enrolled. Results were compared with those obtained from 10 age-matched healthy volunteers. We measured TMS-elicited motor evoked potential (MEP) as an index of M1 excitability. We tested SICI, intracortical facilitation (ICF), and short-interval intracortical facilitation (SICF), which has three distinct facilitatory peaks, using the paired-pulse TMS paradigm. A triple-pulse protocol, SICI + SICF, was investigated as described in our earlier study. This protocol examined SICF in the presence of SICI, thereby allowing our test of true inhibitory influence on a specific component of MEP-generating mechanism known as I3 wave. RESULTS: In PD patients, SICI estimated using the conventional method was decreased, whereas SICF was enhanced around its second peak out of the three. Results for SICI + SICF were comparable between PD patients and healthy controls, suggesting normal inhibition of I3 waves in PD patients. CONCLUSION: We confirmed the SICF enhancement in drug naïve PD patients. We propose that I3 wave inhibition by a subthreshold pulse shown by SICI paradigm is unaffected in PD. The triple-pulse method can reveal masked inhibition.

Supplementary motor area plays a causal role in automatic inhibition of motor responses.

BACKGROUND: The masked-priming paradigm is used to test unconscious inhibitory processes of the brain. A tendency towards responses that are incompatible with the prime, designated as negative compatibility effect (NCE), emerges when the perception of a priming visual stimulus is "masked" afterwards. This effect presumably stems from a subliminal inhibitory process against the masked-prime. Prior lesions as well as activation studies suggest a key role of SMA in this effect. OBJECTIVE: This study was conducted to elucidate a causal role of SMA in the subliminal response inhibition represented by the NCE. METHODS: Using a repeated-measures pre-post design with a group of healthy people, physiological measures (resting and active motor thresholds and motor evoked potential (MEP) amplitude) and behavioral ones (choice reaction time (CRT), positive compatibility effect (PCE) and NCE) were obtained before and after three quadripulse stimulation (QPS), namely sham, M1-QPS, and SMA-QPS, on different days. CRT and PCE served as indices for different aspects of motor execution. RESULTS: Motor thresholds were not altered after any QPS, although the M1-QPS increased MEP amplitude. Neither CRT nor PCE was altered significantly after QPS protocols. NCE was abolished after the SMA-QPS. CONCLUSIONS: Abolished NCE after the SMA-QPS in the absence of MEP changes suggests that (1) SMA plays a cardinal role in the NCE, and (2) the network involved in NCE is different from that of MEP generation.

Somatosensory-evoked potential modulation by quadripulse transcranial magnetic stimulation in patients with benign myoclonus epilepsy.

OBJECTIVE: In patients with benign myoclonus epilepsy (ME), giant sensory-evoked potential (SEP) reflects the hyperexcitability of the sensory cortex. The aim of this study was to compare the effect of quadripulse transcranial magnetic stimulation (QPS) on the median nerve SEP between ME patients and healthy subjects. METHODS: Ten healthy volunteers and six ME patients with giant SEP participated in this study. QPSs at interpulse intervals (IPIs) of 5, 30, 50, 100, 500 and 1250 ms were applied over the left primary motor cortex (M1) for 30 min. The peak-to-peak amplitudes of N20 to P25 (N20-P25) and P25 to N33 (P25-N33) components were measured at the left somatosensory cortex. RESULTS: In healthy participants, the P25-N33 was bidirectionally modulated by QPS over M1, following the Bienenstock-Cooper-Munro (BCM) theory. The N20-P25 was not affected by any QPSs. In ME patients, the giant P25-N33 was potentiated after any QPSs. Furthermore, the N20-P25 was also potentiated after QPS at IPIs of 5, 30, 50 100 or 500 ms. CONCLUSIONS: In ME patients, the cascade for long-term depression-like effects may be impaired. SIGNIFICANCE: The giant SEP was furthermore enhanced by QPS.

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.

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.

Triad-conditioning transcranial magnetic stimulation in Parkinson's disease.

BACKGROUND: Transcranial magnetic stimulation (TMS) has been used to reveal excitability changes of the primary motor cortex (M1) in Parkinson's disease (PD). Abnormal rhythmic neural activities are considered to play pathophysiological roles in the motor symptoms of PD. The cortical responses to external rhythmic stimulation have not been studied in PD. We recently reported a new method of triad-conditioning TMS to detect the excitability changes after rhythmic conditioning stimuli, which induce facilitation by 40-Hz stimulation in healthy volunteers. OBJECTIVE: We applied a triad-conditioning TMS to PD patients to reveal the motor cortical response characteristics to rhythmic TMS. METHODS: The subjects included 13 PD patients and 14 healthy volunteers. Three conditioning stimuli over M1 at an intensity of 110% active motor threshold preceded the test TMS at various inter-stimulus intervals corresponding to 10-200 Hz. RESULTS: The triad-conditioning TMS at 40 Hz induced no MEP enhancement in PD patients in either the On or Off state, in contrast to the facilitation observed in the normal subjects. Triad-conditioning TMS at 20-33 Hz in the beta frequency elicited significant MEP suppression in PD patients. The amount of suppression at 20 Hz positively correlated with the UPDRS III score. CONCLUSION: We observed abnormal M1 responses to rhythmic TMS in PD. The suppression induced by beta frequency stimulation and no facilitation by 40-Hz stimulation may be related to abnormal beta and gamma band activities within the cortical-basal ganglia network in PD patients. The motor cortical response to rhythmic TMS may be an additional method to detect physiological changes 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.

Conditioning intensity-dependent interaction between short-latency interhemispheric inhibition and short-latency afferent inhibition.

The relationship between sensory and transcallosal inputs into the motor cortex may be important in motor performance, but it has not been well studied, especially in humans. The aim of this study was to reveal this relationship by investigating the interaction between short-latency interhemispheric inhibition (SIHI) and short-latency afferent inhibition (SAI) in humans with transcranial magnetic stimulation. SIHI is the inhibition of the primary motor cortex (M1) elicited by contralateral M1 stimulation given ∼10 ms before, and it reflects transcallosal inhibition. SAI is the inhibition of M1 elicited by contralateral median nerve stimulation preceding M1 stimulation by ∼20 ms. In this investigation, we studied the intensity dependence of SIHI and SAI and the interaction between SIHI and SAI in various conditioning intensities. Subjects were 11 normal volunteers. The degree of effects was evaluated by comparing motor evoked potential sizes recorded from the first dorsal interosseous muscle between a certain condition and control condition. Both SIHI and SAI were potentiated by increment of the conditioning stimulus intensity and saturated at 1.4 times resting motor threshold for SIHI and 3 times sensory threshold for SAI. No significant interaction was observed when either of their intensities was subthreshold for the inhibition on its own. Only when both intensities were strong enough for their inhibition did the presence of one inhibition lessen the other one. On the basis of these findings, we conclude that interneurons mediating SIHI and SAI have mutual, direct, and inhibitory interaction in a conditioning intensity-dependent manner.

Increased primary motor cortical excitability by a single-pulse transcranial magnetic stimulation over the supplementary motor area.

The supplementary motor area (SMA) is a secondary motor area that is involved in various complex hand movements. In animal studies, short latency and probably direct excitatory inputs from SMA to the primary motor cortex (M1) have been established. Although human imaging studies revealed functional connectivity between SMA and M1, its electrophysiological nature has been less studied. This study explored the connection between SMA and M1 in humans using a single-pulse transcranial magnetic stimulation (TMS) over SMA. First, TMS over SMA did not alter the corticospinal tract excitability measured by the size of motor evoked potential elicited by single-pulse TMS over M1. Next, we measured short-interval intracortical facilitation (SICF), which reflects the function of a facilitatory circuit within M1, with or without a single-pulse TMS over SMA. When the intensity of the second pulse in the SICF paradigm (S2) was as weak as 1.0 active motor threshold for a hand muscle, SMA stimulation significantly enhanced the SICF. Furthermore, this enhancement by SMA stimulation was spatially confined and had a limited time window. On the other hand, SMA stimulation did not alter short-interval intracortical inhibition or contralateral silent period duration, which reflects the function of an inhibitory circuit mediated by gamma-aminobutyric acid A (GABA(A)) or GABA(B) receptors, respectively. We conclude that a single-pulse TMS over SMA modulates a facilitatory circuit within M1.

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.

Inter-individual variation in the efficient stimulation site for magnetic brainstem stimulation.

OBJECTIVE: To investigate inter-individual variation in the efficiency of magnetic brainstem stimulation (BST) with regard to the stimulation site. METHODS: We studied 31 healthy subjects, using a right hand muscle as a recording site. Three stimulation sites were compared: BST over the inion (inion BST), and BST over the midpoint between the inion and the right (ipsilateral BST) or left (contralateral BST) mastoid process. Five suprathreshold BSTs were performed for each stimulation site using the same stimulation intensity. The mean peak-to-peak amplitudes of motor evoked potential (MEP) were compared. The active motor threshold (AMT) and onset latency for inion BST and ipsilateral BST were also measured and compared. RESULTS: Contralateral BST did not evoke discernible MEPs in most subjects. In 21 subjects (67.7%), ipsilateral BST elicited larger MEPs than inion BST did, and AMT for ipsilateral BST was lower than or equal to the AMT for inion BST in all subjects. Ipsilateral BST elicited shorter latency in such subjects. CONCLUSIONS: The suitable stimulation site for BST differed among subjects. About two-thirds showed larger MEP to ipsilateral BST. SIGNIFICANCE: These findings might help us to find an efficient stimulation site for BST in each subject.

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 Parkinson's 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.

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.

Cortico-conus motor conduction time (CCCT) for leg muscles.

OBJECTIVE: To measure the conduction time from the motor cortex to the conus medullaris (cortico-conus motor conduction time, CCCT) for leg muscles using magnetic stimulation. METHODS: Motor evoked potentials (MEPs) were recorded from tibialis anterior muscles in 51 healthy volunteers. To activate spinal nerves at the most proximal cauda equina level or at the conus medullaris level, magnetic stimulation was performed using a MATS coil. Transcranial magnetic stimulation of the motor cortex was also conducted to measure the cortical latency for the target muscle. To obtain the CCCT, the latency of MEPs to conus stimulation (conus latency) was subtracted from the cortical latency. RESULTS: MATS coil stimulation evoked reproducible MEPs in all subjects, yielding CCCT data for all studied tibialis anterior muscles. CONCLUSIONS: MATS coil stimulation provides CCCT data for healthy subjects. SIGNIFICANCE: This novel method is useful for evaluation of corticospinal tract function for leg muscles because no peripheral component affects the CCCT.

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.

Prominent cauda equina involvement in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), it has not been well known which segment of the peripheral nerves, distal or proximal, is more often involved in electrophysiological examination. This study compares nerve conductions at proximal segments with those at distal segments in 11 patients with CIDP. To obtain cauda euqina conduciton time (CECT), compound muscle action potentials (CMAPs) were elicited by magnetic stimulation using a MATS coil from the abductor hallucis muscle. CECT was prolonged in 9 patients (81.8%), whereas the ankle-knee conduction was delayed in 4 (36.4%). The proximal segments are more frequently involved than the distal segments in this disorder.

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.

Motor cortical epilepsia partialis continua in a patient with a localized sensory cortical lesion.

We describe a 33-year-old man with cyclosporine encephalopathy who showed continuous jerking in the left upper limb due to epilepsia partialis continua. Jerk-locked back averaging (JLA) of magnetoencephalogram disclosed a spike preceding the jerk localized at the hand motor area, whereas JLA of electroencephalogram revealed no premyoclonus spikes. The paired-pulse motor cortical transcranial magnetic stimulation revealed motor cortical hyperexcitability, while the paired-pulse somatosensory evoked potential showed no sensory cortical hyperexcitability. The brain MRI showed a high intensity lesion localized at the hand sensory area. These results suggest that the jerks were produced by discharges at the motor cortex probably disinhibited by the sensory cortical lesion.

Progressive supranuclear palsy with wall-eyed 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.