Frontal allographic agraphia in a patient with behavioral variant frontotemporal dementia.

We report a patient with behavioral variant frontotemporal dementia who developed agraphia, irritability, perseverative and stereotyped behavior, and dietary changes. MRI revealed bilateral frontal convexity atrophy. Neuropsychological examination showed fluent aphasia with perseverative allographic agraphia, mild semantic impairment, and dysexecutive syndrome. Allographic agraphia featured unidirectional conversion from hiragana (cursive form of Japanese phonograms) and kanji (Japanese morphograms) to katakana (square form of Japanese phonograms), as opposed to mutual (bidirectional) conversion between hiragana and katakana in parieto-occipital gyri lesions. Furthermore, all letters of the word were converted and this whole-word conversion may be characteristic of perseverative behavior in frontotemporal dementia.

Expanded clinical spectrum of oculopharyngodistal myopathy type 1.

INTRODUCTION/AIMS: Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited. METHODS: This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed. RESULTS: Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens were collected from the biceps brachii and tibialis anterior muscles of three patients. Myopathic changes were more severe with more atrophic fibers forming clusters in the tibialis anterior than the biceps brachii muscles of these three patients. No rimmed vacuoles were observed in the biceps brachii muscles in two of the three patients. DISCUSSION: This study shows the expanded clinical spectrum of OPDM1, highlighting the importance of axial muscle evaluation in OPDM1. Considering patients with very subtle oculopharyngeal symptoms, genetic analysis of LRP12 should be considered in patients with isolated distal myopathy.

Structure of χ3-Borophene Studied by Total-Reflection High-Energy Positron Diffraction (TRHEPD).

We have investigated the structure of χ3-borophene on Ag(111), a monolayer material of boron atoms, via total-reflection high-energy positron diffraction (TRHEPD). By comparing the experimental rocking-curves with ones for several structures calculated by using dynamical diffraction theory, we confirmed that the χ3-borophene layer has a flat structure. The distance from the topmost layer of the metal crystal is 2.4 Å, which is consistent with results reported by X-ray standing wave-excited X-ray photoelectron spectroscopy. We also demonstrated that the in-plane structure of χ3-borophene is compatible with the theoretical predictions. These structural properties indicate that χ3-borophene belongs to a group of epitaxial monolayer sheets, such as graphene, which have weak interactions with the substrates.

Plasticity and dystonia: a hypothesis shrouded in variability.

Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques which aim to induce and quantify plasticity, the mechanisms and nature of their inherent variability and use such observations to review the idea that excessive and abnormal plasticity is a pathophysiological substrate of dystonia. We have tried to define the tone of our review by a couple of Professor John Rothwell's many inspiring characteristics; his endless curiosity to refine knowledge and disease models by scientific exploration and his wise yet humble readiness to revise scientific doctrines when the evidence is supportive. We conclude that high variability of response to non-invasive brain stimulation plasticity protocols significantly clouds the interpretation of historical findings in dystonia research. There is an opportunity to wipe the slate clean of assumptions and armed with an informative literature in health, re-evaluate whether excessive plasticity has a causal role in the pathophysiology of dystonia.

Modulation of I-wave generating pathways by theta-burst stimulation: a model of plasticity induction.

KEY POINTS: Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of transcranial magnetic stimulation applied to primary motor cortex (M1) at different coil orientations. We found an association between late I-wave recruitment [reflected by anterior-posterior (AP)-lateromedial (LM) latency; i.e. the excess latency of motor-evoked potentials generated by transcranial magnetic stimulation with an AP orientation over the latency of motor-evoked potentials evoked by direct activation of corticospinal axons using LM stimulation] and changes in cortical excitability following iTBS, confirming previous studies. AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. Plasticity in the motor network may in part derive from a modulation of excitability and the recruitment of late I-wave generating cortical pathways. ABSTRACT: Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and the underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor-evoked potentials elicited by transcranial magnetic stimulation with an anterior-posterior (AP) orientation over the latency of motor-evoked potentials evoked by direct activation of corticospinal axons using lateromedial (LM) stimulation, referred to as the 'AP-LM latency' difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. In 20 healthy subjects, we investigated whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced AP-LM latency, and that this reduction significantly correlated with changes in cortical excitability observed following iTBS: subjects with larger reductions in AP-LM latencies featured larger increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating pathways may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel repetitive transcranial magnetic stimulation protocols.

Latency shift in compound muscle action potentials during electroneurography in facial palsy.

OBJECTIVE: Electroneurography (ENoG) reliably predicts the prognosis of facial palsy. However, the results of ENoG are dependent on the location, where the wave is detected, as a compound muscle action potential (CMAP) arising from the facial muscles. To minimize errors in prognostic prediction, we analysed the latencies of facial CMAPs. MATERIALS AND METHODS: Fifty-seven patients with unilateral peripheral facial palsy and 24 healthy volunteers were enrolled. Amplitudes, negative peak latencies (NPL), and rise latencies (RL) of CMAPs were measured on the paralysed and healthy sides in patients and in healthy volunteers. The relationships of these latencies with ENoG values and the lowest House-Brackmann (H-B) scores were also analysed. RESULTS: The amplitude of CMAP on the paralysed side was smaller, and NPL and RL were longer, than those on the healthy side in patients and healthy volunteers (p < 0.01). In patients, there was no difference in NPL between the ENoG < 40% group and the ENoG ≥ 40% group. Conversely, there was a significant difference in RL between the ENoG < 40% group and ENoG ≥ 40% group (p = 0.03). No relationships were observed between NPL or RL and the lowest H-B score. CONCLUSIONS: NPL and RL of CMAP on the paralysed side were equivalent or longer than those on the healthy side. During ENoG for facial palsy, CMAP should be measured on the healthy side first, and then detected (and the amplitude measured) on the paralysed side with reference to CMAP latency on the healthy side, to reduce errors in detecting facial CMAPs.

The effect of age on the homotopic motor cortical long-term potentiation-like effect induced by quadripulse stimulation.

The reduction of plasticity with age has been shown by many previous papers in animal experiments. This issue can be studied in humans because several non-invasive brain stimulation techniques induce synaptic plasticity in the human brain. We investigated the influence of individuals' age on the responder rate of the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS). The participants were 107 healthy volunteers: 53 older participants (Mean ± SD 65.0 ± 1.5 years) and 54 younger participants (37.2 ± 8.7). The quadripulse stimulation with 5-ms inter-pulse interval (QPS5) was applied over the primary motor cortex (M1). We measured motor evoked potentials (MEPs) before QPS, and at five time points after QPS for up to 25 min. In each participant, average MEP amplitude (size) ratios were quantified. We first classified participants as responders and non-responders simply by comparing the size ratio with 1.0 for consistency with previous studies, then as "significant responders", "non-responders", and "opposite responders" for more detailed analysis by comparing the size ratio with the mean and standard deviation of the MEP size ratios of the sham condition. The degree of LTP-like effects induced by QPS5 was significantly smaller in the older group compared to the younger group. Also, the rates of responders and significant responders were lower in the older group (58 and 47%, respectively) compared to the younger group (80 and 76%, respectively). The age of the participants significantly affected the LTP-like effect induced by QPS5, which suggests that brain plasticity decreases with age.

Tacrolimus-Induced Reversible Cerebral Vasoconstriction Syndrome with Delayed Multi-Segmental Vasoconstriction.

Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular syndrome characterized by multi-segmental constrictions of the cerebral arteries that resolves spontaneously within 3 months. Although RCVS is considered to be due to transient dysregulation of vascular tone, the exact pathomechanism remains unclear. We describe the case of a 15-year-old girl with RCVS induced by tacrolimus, who developed generalized seizure during the postoperative course of orthotropic heart transplantation. Magnetic resonance imaging at symptom onset showed a few vasoconstrictions accompanying brain edema and convexity subarachnoid hemorrhage. Although her neurological conditions rapidly improved after discontinuing tacrolimus, a repeat magnetic resonance angiogram demonstrated delayed progression of the multi-segmental vasoconstrictions followed by subsequent resolution. Our case demonstrates that cautious observation of the cerebral arteries using magnetic resonance angiography and careful management of vasoconstrictions with vasodilators are necessary for delayed vasoconstrictions even when the clinical symptoms improve.

What Makes the Muscle Twitch: Motor System Connectivity and TMS-Induced Activity.

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) evokes several volleys of corticospinal activity. While the earliest wave (D-wave) originates from axonal activation of cortico-spinal neurons (CSN), later waves (I-waves) result from activation of mono- and polysynaptic inputs to CSNs. Different coil orientations preferentially stimulate cortical elements evoking different outputs: latero-medial-induced current (LM) elicits D-waves and short-latency electromyographic responses (MEPs); posterior-anterior current (PA) evokes early I-waves. Anterior-posterior current (AP) is more variable and tends to recruit later I-waves, featuring longer onset latencies compared with PA-TMS. We tested whether the variability in response to AP-TMS was related to functional connectivity of the stimulated M1 in 20 right-handed healthy subjects who underwent functional magnetic resonance imaging while performing an isometric contraction task. The MEP-latency after AP-TMS (relative to LM-TMS) was strongly correlated with functional connectivity between the stimulated M1 and a network involving cortical premotor areas. This indicates that stronger premotor-M1 connectivity increases the probability that AP-TMS recruits shorter latency input to CSNs. In conclusion, our data strongly support the hypothesis that TMS of M1 activates distinct neuronal pathways depending on the orientation of the stimulation coil. Particularly, AP currents seem to recruit short latency cortico-cortical projections from premotor areas.

Two distinct interneuron circuits in human motor cortex are linked to different subsets of physiological and behavioral plasticity.

How does a single brain region participate in multiple behaviors? Here we argue that two separate interneuron circuits in the primary motor cortex (M1) contribute differently to two varieties of physiological and behavioral plasticity. To test this in human brain noninvasively, we used transcranial magnetic stimulation (TMS) of M1 hand area to activate two independent sets of synaptic inputs to corticospinal neurons by changing the direction of current induced in the brain: posterior-to-anterior current (PA inputs) and anterior-to-posterior current (AP inputs). We demonstrate that excitability changes produced by repetitive activation of AP inputs depend on cerebellar activity and selectively alter model-based motor learning. In contrast, the changes observed with repetitive stimulation of PA inputs are independent of cerebellar activity and specifically modulate model-free motor learning. The findings are highly suggestive that separate circuits in M1 subserve different forms of motor learning.

Cerebellar stimulation fails to modulate motor cortex plasticity in writing dystonia.

BACKGROUND: Primary dystonia is characterized neurophysiologically by reduced inhibitory mechanisms and abnormal regulation of plasticity responses. The potential of anodal cerebellar transcranial direct current stimulation as a therapeutic tool in writing dystonia was examined, after the observation that cerebellar stimulation reduces responses to an associative plasticity protocol in healthy subjects. METHODS: Ten patients with writing dystonia completed a two-part study (sham and anodal) in which cerebellar stimulation was given simultaneously with paired associative stimulation. Electrophysiological and clinical parameters were measured before and after stimulation. RESULTS: Clinical symptoms were unchanged by cerebellar stimulation. Patients exhibited much variability in the size and direction of their plasticity responses. Excessive or topographically abnormal plasticity responses were not observed. In the subgroup of patients with facilitatory responses to paired associative stimulation in the sham condition, anodal cerebellar stimulation retained its ability to reduce the magnitude of plasticity response. CONCLUSIONS: Our limited understanding of intersubject variability of plasticity responses in writing dystonia currently undermines cerebellar stimulation as a novel treatment in this subset of dystonia. Cerebellar stimulation may be beneficial in other neurological disorders with consistently exaggerated plasticity.

A reflection on plasticity research in writing dystonia.

Much attention has focused on the hypothesis that there is enhanced plasticity of sensorimotor circuits in patients with dystonia. A common experimental method to assess plasticity in dystonia research is paired associative stimulation (PAS). Excessive, nonfocal effects of PAS were observed in early studies of dystonia; however, these large effects have not been uniformly replicated. In this viewpoint, data from 15 patients with writing dystonia are presented. We suggest that, as in healthy individuals, the effects of PAS are highly variable. A review of previous studies examining PAS in writing dystonia highlights the range of results that have been observed. We conclude that current experimental evidence cannot be fully explained by the notion that PAS responses in writing dystonia are consistently excessive or nonspecific. The variability of PAS responses is such that enhanced plasticity should not be considered a dystonic fingerprint, because the direction of response can vary, and there is overlap between patient and healthy data. We also discuss evidence questioning the assumption that PAS responses are a clear correlate to levels of synaptic plasticity; we need to define more specifically what PAS responses signify in the dystonic brain. Our conclusions are limited to PAS in writing dystonia; however, much variation exists with other plasticity protocols. Large multicenter studies of both focal and generalized forms of dystonia, probing variability of individual neurophysiological profiles, are encouraged. This will reveal the true role of plasticity in the pathophysiology of dystonia and may expose subject-specific therapeutic interventions that are currently concealed.

The role of interneuron networks in driving human motor cortical plasticity.

The after-effects of repetitive transcranial magnetic stimulation (rTMS) are highly variable between individuals. Because different populations of cortical neurons are stimulated more easily or are more excitable in different people at different times, the variability may not be due to differences between individuals in the plasticity of cortical synapses, but may instead be due to individual differences in the recruitment of cortical neurons. In this study, we examined the effects of rTMS in 56 healthy volunteers. The responses to excitatory and inhibitory theta burst stimulation (TBS) protocols were highly variable between individuals. Surprisingly, the TBS effect was highly correlated with the latency of motor-evoked potentials (MEPs) evoked by TMS pulses that induced an anterior-posterior (AP) directed current across the central sulcus. Finally, we devised a new plasticity protocol using closely timed pairs of oppositely directed TMS current pulses across the central sulcus. Again, the after-effects were related to the latency of MEPs evoked by AP current. Our results are consistent with the idea that variation in response to rTMS plasticity probing protocols is strongly influenced by which interneuron networks are recruited by the TMS pulse.

An Elderly Woman with Complaints of Pain and Hearing Loss, Diagnosed with CMT1A with PMP22 Duplication.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous hereditary motor and sensory neuropathy of the peripheral nervous system, with CMT1A in particular being the most common form. We encountered a 76-year-old woman with CMT1A who had a history of pain attacks and hearing loss from a young age, with motor symptoms manifesting late in life. Her pain and hearing loss may have been related to CMT. Our case also raises the possibility that neuropathic pain and hearing loss may precede the classic motor symptoms of CMT1A.

Extremely Longitudinally Extensive Transverse Myelitis in a Patient With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Longitudinally extensive myelitis with 15 or more vertebrae in length is extremely rare, with limited evidence regarding clinical features and therapeutic response. We report a case of a 29-year-old male patient with extremely longitudinally extensive myelitis ultimately diagnosed as myelin oligodendrocyte glycoprotein-associated disease (MOGAD). The patient presented with an acute onset of meningismus, limb weakness, sensory disturbance below the C5 level, ataxia, and urinary retention. T2-weighted imaging on MRI showed an extremely longitudinally extensive spinal cord lesion ranging from C2 to the medullary conus, together with a left pontine lesion. Positive anti-myelin oligodendrocyte glycoprotein antibodies were serologically detected, which led to the diagnosis of MOGAD. Intravenous methylprednisolone followed by 1 mg/kg oral prednisolone with taper resulted in complete symptomatic and radiological resolution. The striking complete resolution despite the symptomatic and radiological severity observed in this case has been described in a few previously reported MOGAD cases. Extremely longitudinally extensive myelitis with excellent therapeutic response may be a characteristic presentation of MOGAD.

Adrenomyeloneuropathy with Later Development of Cerebral Form Caused by a Hemizygous Splice-site Variant in ABCD1.

Adrenomyeloneuropathy (AMN)/adrenoleukodystrophy (ALD) is an X-linked genetic disorder caused by pathogenic variants in ABCD1. We treated a 54-year-old man with slowly progressive spastic paraparesis with later development of the cerebral form. A pathogenic splice-site variant of ABCD1 (c.1489-1G>A, p.Val497Alafs*51) and elevated levels of very long-chain fatty acids were found, leading to the diagnosis of AMN. Detailed ABCD1 mRNA expression analyses revealed decreased levels of ABCD1 mRNA accompanied by deletion of the first 31 bp in exon 6. The altered mRNA transcriptional patterns associated with splice site variants are diverse and may provide important insights into ALD pathogenesis.

Recovery after Prolonged Disturbance of Consciousness and Repeated Cerebral Perfusion Changes in Neuronal Intranuclear Inclusion Disease.

Encephalitic episodes are a clinical manifestation of neuronal intranuclear inclusion disease (NIID) and often show transient disturbance of consciousness. We herein report a genetically confirmed patient with NIID who initially presented progressive dementia and showed prolonged disturbance of consciousness preceded by an acute-onset headache. During that time, we performed N-isopropyl-p-[123I] iodoamphetamine single-photon-emission computed tomography twice and found that the blood flow increased in different regions. Prolonged disturbance of consciousness following an encephalitic episode may be associated with repeated hyperperfusion in various regions resulting from mitochondrial dysfunction. NIID patients presenting with encephalitic episodes can recover gradually and spontaneously even after prolonged disturbances of consciousness.

Treatment of cryptogenic new-onset refractory status epilepticus (C-NORSE) with tocilizumab: A case report.

A 35-year-old woman with no prior history of epilepsy developed status epilepticus (SE), which was highly resistant to multiple antiseizure medications and sedatives. The etiology of SE was not identified despite extensive investigation, and the patient was diagnosed with cryptogenic new-onset refractory status epilepticus (C-NORSE). Although first-line immunotherapies such as high-dose corticosteroids and plasma exchange were ineffective, the patient manifested a resolution of SE after the administration of tocilizumab, which inhibits interleukin-6. Non-antibody-mediated inflammation has been hypothesized to be a probable pathophysiology of C-NORSE in recent studies, and tocilizumab may be a plausible second-line treatment.

Global Perceptions and Utilization of Clinical Neurophysiology in Movement Disorders.

BACKGROUND: Clinical neurophysiology (CNP) involves the use of neurophysiological techniques to make an accurate clinical diagnosis, to quantify the severity, and to measure the treatment response. Despite several studies showing CNP to be a useful diagnostic tool in Movement Disorders (MD), its more widespread utilization in clinical practice has been limited. OBJECTIVES: To better understand the current availability, global perceptions, and challenges for implementation of diagnostic CNP in the clinical practice of MD. METHODS: The International Parkinson and Movement Disorders Society (IPMDS) formed a Task Force on CNP. The Task Force distributed an online survey via email to all the members of the IPMDS between August 5 and 30, 2021. Descriptive statistics were used for analysis of the survey results. Some results are presented by IPMDS geographical sections namely PanAmerican (PAS), European (ES), African (AFR), Asian and Oceanian (AOS). RESULTS: Four hundred and ninety-one IPMDS members (52% males), from 196 countries, responded. The majority of responders from the AFR (65%) and PAS (63%) sections had no formal training in diagnostic CNP (40% for AOS and 37% for ES). The most commonly used techniques are electroencephalography (EEG) (72%) followed by surface EMG (71%). The majority of responders think that CNP is somewhat valuable or very valuable in the assessment of MD. All the sections identified "lack of training" as one of the biggest challenges for diagnostic CNP studies in MD. CONCLUSIONS: CNP is perceived to be a useful diagnostic tool in MD. Several challenges were identified that prevent widespread utilization of CNP in MD.