Brain activity supporting alternating speech for semantic words: simultaneous magnetoencephalographic recording.

Communication, especially conversation, is essential for human social life. Many previous studies have examined the neuroscientific underpinnings of conversation, i.e. language comprehension and speech production. However, conversation inherently involves two or more people, and unless two people actually interact with one another, the nature of the conversation cannot be truly revealed. Therefore, in this study, we used two magnetoencephalographs that were connected together, and simultaneously recorded brain activity while two people took turns speaking in a word association/alphabet completion task. We compared the amplitude modulation of the alpha- and beta-band rhythms within each of the 62 brain regions under semantic (word association; less predictable) and non-semantic (alphabet completion; more predictable) conditions. We found that the amplitudes of the rhythms were significantly different between conditions in a wide range of brain regions. Additionally, significant differences were observed in nearly the same group of brain regions after versus before each utterance, indicating that a wide range of brain areas is involved in predicting a conversation partner's next utterance. This result supports the idea that mentalizing, e.g. predicting another person's speech, plays an important role in conversation, and suggests that the neural network implicated in mentalizing extends over a wide range of brain regions.

Itpr1 regulates the formation of anterior eye segment tissues derived from neural crest cells.

Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3'-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1, encoding a 218amino acid isoform. This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after completion of AES formation. Our analyses revealed that the 218-amino acid isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is also possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris.

Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria.

Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

Alpha-actinin-4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas.

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small-cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting ADJ or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages: HR, 1.214; 95% CI, 0.848-1.738; P = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

Reinterpretation of magnetic resonance imaging findings with magnetoencephalography can improve the accuracy of detecting epileptogenic cortical lesions.

OBJECTIVE: This study examined whether the application of magnetoencephalography (MEG) to interpret magnetic resonance imaging (MRI) findings can aid the diagnosis of intractable epilepsy caused by organic brain lesions. METHODS: This study included 51 patients with epilepsy who had MEG clusters but whose initial MRI findings were interpreted as being negative for organic lesions. Three board-certified radiologists reinterpreted the MRI findings, utilizing the MEG findings as a guide. The degree to which the reinterpretation of the imaging results identified an organic lesion was rated on a 5-point scale. RESULTS: Reinterpretation of the MRI data with MEG guidance helped detect an abnormality by at least one radiologist in 18 of the 51 patients (35.2%) with symptomatic localization-related epilepsy. A surgery was performed in 7 of the 51 patients, and histopathological analysis results identified focal cortical dysplasia in 5 patients (Ia: 1, IIa: 2, unknown: 2), hippocampal sclerosis in 1 patient, and dysplastic neurons/gliosis in 1 patient. CONCLUSIONS: The results of this study highlight the potential diagnostic applications of MEG to detect organic epileptogenic lesions, particularly when radiological visualization is difficult with MRI alone.

Brigatinib and lorlatinib: their effect on ALK inhibitors in NSCLC focusing on resistant mutations and central nervous system metastases.

Major issues in anaplastic lymphoma kinase-positive non-small cell lung carcinoma are acquired resistance against anaplastic lymphoma kinase inhibitors and control of central nervous system metastasis. The development of these inhibitors has changed therapeutic strategy in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Brigatinib and lorlatinib were designed to penetrate the blood-brain barrier and to inhibit resistant mutations against anaplastic lymphoma kinase inhibitors. We review the clinical data supporting treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung carcinoma with brigatinib and lorlatinib. Brigatinib has shown promising antitumour activity, including substantial activity against central nervous system metastases, in crizotinib-treated (ALTA trial) patients and crizotinib-naïve (ALTA-1L trial) patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. In addition, brigatinib improved progression-free survival compared with crizotinib in anaplastic lymphoma kinase inhibitor-naïve patients with anaplastic lymphoma kinase-positive non-small cell lung carcinoma. Lorlatinib has demonstrated clinical antitumour activity against both intracranial and extracranial lesions in patients with anaplastic lymphoma kinase- or c-ros oncogene 1 (ROS1)-positive non-small cell lung carcinoma. Ongoing trials and further studies of these agents' biological and clinical properties would provide insight into the optimal therapeutic strategy for administering them to achieve the best survival benefit.

The use of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide-based colorimetric assay in the viability analysis of the filamentous cyanobacterium Arthrospira platensis.

The applicability of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to an industrially valuable filamentous cyanobacterium Arthrospira platensis was examined. When it was applied to A. platensis NIES-39, as few as 10 viable trichomes were quantitatively detected. However, depending on the experimental conditions, it also generated artifactual viability signals. The results should help clarify the scope and limits of the MTT assay in viability analysis.

Treatment of lung cancer using immune checkpoint inhibitors.

The treatment strategy of lung cancer is now significantly changing by the appearance of immune checkpoint inhibitors. Although anti-programmed cell death-1 (PD-1) antibody agents, nivolumab and pembrolizumab, have been already adopted as standard treatments in second line treatment of non-small-cell lung cancer, optimal use is essential due to the high costs and serious adverse effects. Therefore, further investigation of predictive markers in immune checkpoint blockade is ongoing, but robust one has not yet been identified. On the other hand, many clinical trials are now in progress regarding other immune checkpoint in- hibitors, combination therapy with cytotoxic or molecular target agents, different treatment settings and so on.

Cortico-muscular synchronization by proprioceptive afferents from the tongue muscles during isometric tongue protrusion.

Tongue movements contribute to oral functions including swallowing, vocalizing, and breathing. Fine tongue movements are regulated through efferent and afferent connections between the cortex and tongue. It has been demonstrated that cortico-muscular coherence (CMC) is reflected at two frequency bands during isometric tongue protrusions: the beta (ß) band at 15-35Hz and the low-frequency band at 2-10Hz. The CMC at the ß band (ß-CMC) reflects motor commands from the primary motor cortex (M1) to the tongue muscles through hypoglossal motoneuron pools. However, the generator mechanism of the CMC at the low-frequency band (low-CMC) remains unknown. Here, we evaluated the mechanism of low-CMC during isometric tongue protrusion using magnetoencephalography (MEG). Somatosensory evoked fields (SEFs) were also recorded following electrical tongue stimulation. Significant low-CMC and ß-CMC were observed over both hemispheres for each side of the tongue. Time-domain analysis showed that the MEG signal followed the electromyography signal for low-CMC, which was contrary to the finding that the MEG signal preceded the electromyography signal for ß-CMC. The mean conduction time from the tongue to the cortex was not significantly different between the low-CMC (mean, 80.9ms) and SEFs (mean, 71.1ms). The cortical sources of low-CMC were located significantly posterior (mean, 10.1mm) to the sources of ß-CMC in M1, but were in the same area as tongue SEFs in the primary somatosensory cortex (S1). These results reveal that the low-CMC may be driven by proprioceptive afferents from the tongue muscles to S1, and that the oscillatory interaction was derived from each side of the tongue to both hemispheres. Oscillatory proprioceptive feedback from the tongue muscles may aid in the coordination of sophisticated tongue movements in humans.

Remote MEG dipoles in focal cortical dysplasia at bottom of sulcus.

OBJECTIVE: To investigate whether the magnetoencephalography (MEG) single moving dipole (SMD) method could delineate the epileptic zone of focal cortical dysplasia (FCD) at the bottom of sulcus (FCDB). METHODS: We retrospectively analyzed 17 children (11 male; mean age 8.8 years, range 3-17 years) with FCD type II who underwent epilepsy surgery. We compared spatial congruence between the following: (1) MEG cluster and FCDB and (2) MEG cluster and FCD at the brain surface (FCDS). We measured the volume and depth of magnetic resonance imaging (MRI)-visible lesions to investigate whether they affect spatial congruence between MEG cluster and MRI-visible lesion. RESULTS: Eight children had FCDB and the other nine children had FCDS. The volume of MRI-visible lesions for FCDB ranged from 1,632 to 4,707 mm(3) (mean ± standard deviation [SD] 3,095 ± 1,211 mm(3) ). The depth of FCDB ranged from 19 to 33 mm (mean ± SD 26 ± 4 mm). The volume of MRI-visible lesion for FCDS ranged from 2,375 to 57,331 mm(3) (15,470 ± 18,455 mm(3) ). There was a tendency for a smaller volume of MRI-visible lesion for FCDB, relative to FCDS(p = 0.079). In FCDB, six children showed clusters of MEG dipoles and two children showed scattered MEG dipoles for interictal spikes. The spatial congruence between the MEG result and FCDB was partially overlapping in four children and discordant in another four children. In FCDS, eight children had MEG cluster and one child had MEG scatter alone. The spatial congruence between MEG result and FCDS was overlapping in eight of nine children (fully two; partially six) and discordant in one of nine children. Fifteen children (88%; FCDB eight; FCDS seven) became seizure-free after resective surgery. MEG spike dipole resection ratio in the cluster ranged from 4-100% (mean 67%) in 6 FCDB and 23-99% (mean 77%) in 8 FCDS. SIGNIFICANCE: The SMD method may drift MEG spike dipoles for FCDB. Lesionectomy can control seizures for four of eight patients in FCDB despite the remote MEG dipoles. The FCDB or FCDS partially overlapped with MEG cluster may have an extending/invisible epileptogenic zone consecutive to the MRI-visible lesion.

Cryopreservation of the edible alkalophilic cyanobacterium Arthrospira platensis.

Efficient cryopreservation conditions for the edible alkalophilic cyanobacterium Arthrospira (Spirulina) platensis were investigated using a model strain A. platensis NIES-39. As a result, it was found that more than 60% of cells were viable upon thawing, when they had been frozen at a cooling rate of approximately -1 °C min(-1) in the presence of 10% (v/v) dimethyl sulfoxide. Further examination with other Arthrospira strains showed that many of them had strain-dependent optimal conditions for cryopreservation. For example, the best freezing conditions for A. platensis SAG 21.99 were snap-freezing in liquid nitrogen in the presence of 5% (v/v) dimethyl sulfoxide, while they were slow cooling at approximately -1 °C min(-1) in the presence of 10% (v/v) methanol for A. platensis NIES-46, NIES-2308 and UTEX 1926. The variety of successful cryopreservation conditions presented in this study is useful when attempting to cryopreserve various Arthrospira strains.

Modulation of alpha activity in the parieto-occipital area by distractors during a visuospatial working memory task: a magnetoencephalographic study.

Oscillatory brain activity is known to play an essential role in information processing in working memory. Recent studies have indicated that alpha activity (8-13 Hz) in the parieto-occipital area is strongly modulated in working memory tasks. However, the function of alpha activity in working memory is open to several interpretations, such that alpha activity may be a direct neural correlate of information processing in working memory or may reflect disengagement from information processing in other brain areas. To examine the functional contribution of alpha activity to visuospatial working memory, we introduced visuospatial distractors during a delay period and examined neural activity from the whole brain using magnetoencephalography. The strength of event-related alpha activity was estimated using the temporal spectral evolution (TSE) method. The results were as follows: (1) an increase of alpha activity during the delay period as indicated by elevated TSE curves was observed in parieto-occipital sensors in both the working memory task and a control task that did not require working memory; and (2) an increase of alpha activity during the delay period was not observed when distractors were presented, although TSE curves were constructed only from correct trials. These results indicate that the increase of alpha activity is not directly related to information processing in working memory but rather reflects the disengagement of attention from the visuospatial input.

Distinct binding of amyloid imaging ligands to unique amyloid-ß deposited in the presubiculum of Alzheimer's disease.

Non-invasive determination of amyloid-ß peptide (Aß) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aß for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aß deposits lacking interaction with the commonly used amyloid dyes FSB. (11)C-PiB, (3)H-AZD2184, and (125)I-DRK092 showed overt binding to presubicular Aß deposits, while (125)I-DRM106 barely bound to these aggregates despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aß lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aß aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aß deposits. Amyloid radioligands lacking affinity for this component, such as (125)I-DRM106, may selectively capture Aß deposits tightly associated with TSPO neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aß pathologies. Non-invasive determination of amyloid-ß peptide (Aß) serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). We found that there are at least two different amyloid components in hippocampal CA1 and presubiculum providing distinct binding sites for the current amyloid radioligands. Comparative analysis for radioligand binding in these two regions could serve for developing novel imaging agents selectively visualizing neurotoxicity-related Aß pathologies.

Association of heterotrophic bacteria with aggregated Arthrospira platensis exopolysaccharides: implications in the induction of axenic cultures.

Inducing an axenic culture of the edible cyanobacterium Arthrospira (Spirulina) platensis using differential filtration alone is never successful; thus, it has been thought that, in non-axenic cultures, a portion of contaminating bacteria is strongly associated with Arthrospira cells. However, examination of the behavior of these bacteria during filtration revealed that they were not associated with Arthrospira cells but with aggregates of exopolysaccharides present in the medium away from the Arthrospira cells. Based on this finding, a rapid and reliable method for preparing axenic trichomes of A. platensis was established. After verifying the axenicity of the resulting trichomes on enriched agar plates, they were individually transferred to fresh sterile medium using a handmade tool, a microtrowel, to produce axenic cultures. With this technique, axenic cultures of various A. platensis strains were successfully produced. The technique described in this study is potentially applicable to a wider range of filamentous cyanobacteria.

Contralateral dominance of corticomuscular coherence for both sides of the tongue during human tongue protrusion: an MEG study.

Sophisticated tongue movements contribute to speech and mastication. These movements are regulated by communication between the bilateral cortex and each tongue side. The functional connection between the cortex and tongue was investigated using oscillatory interactions between whole-head magnetoencephalographic (MEG) signals and electromyographic (EMG) signals from both tongue sides during human tongue protrusion compared to thumb data. MEG-EMG coherence was observed at 14-36 Hz and 2-10 Hz over both hemispheres for each tongue side. EMG-EMG coherence between tongue sides was also detected at the same frequency bands. Thumb coherence was detected at 15-33 Hz over the contralateral hemisphere. Tongue coherence at 14-36 Hz was larger over the contralateral vs. ipsilateral hemisphere for both tongue sides. Tongue cortical sources were located in the lower part of the central sulcus and were anterior and inferior to the thumb areas, agreeing with the classical homunculus. Cross-correlogram analysis showed the MEG signal preceded the EMG signal. The cortex-tongue time lag was shorter than the cortex-thumb time lag. The cortex-muscle time lag decreased systematically with distance. These results suggest that during tongue protrusions, descending motor commands are modulated by bilateral cortical oscillations, and each tongue side is dominated by the contralateral hemisphere.

Synthesis and biological evaluation of novel radioiodinated imidazopyridine derivatives for amyloid-ß imaging in Alzheimer's disease.

Non-invasive detection for amyloid-ß peptide (Aß) deposition has important significance for the early diagnosis and medical intervention for Alzheimer's disease (AD). In this study, we developed a series of imidazopyridine derivatives as potential imaging agents for single-photon emission computed tomography (SPECT). Two of them, compounds DRK092 and DRM106, showed higher affinity for synthetic human Aß 1-40 fibrils than did the well-known amyloid-imaging agent IMPY. A metabolite analysis revealed brain-permeable radioactive metabolites of (125)I-labeled DRK092 and IMPY; no radioactive metabolites from (125)I-labeled DRM106 ([(125)I]DRM106) were detected. In addition, in vitro autoradiography clearly demonstrated specific binding of [(125)I]DRM106 in the hippocampal region of AD enriched with Aß plaques. Thus, our results strongly suggested that compound DRM106 can be used as an imaging agent for SPECT to detect Aß deposition in AD brain.

Thalamic arteriovenous malformation fed by the artery of Percheron originating from the contralateral posterior cerebral artery in a child.

PURPOSE: Artery of Percheron (AOP) is a rare variant of thalamoperforating artery with a single common trunk feeding both thalami and with or without contribution to the rostral midbrain. We report the first case of thalamic arteriovenous malformation (AVM) fed by AOP with hemorrhagic onset. METHODS: A 12-month-old girl suddenly weakened and developed coma. Left thalamic hemorrhage was detected with the third and both lateral ventricles' hematoma. Thalamic AVM was discovered to be fed by an AOP originating from the contralateral posterior cerebral artery. RESULTS: Endovascular embolization of AVM was impossible due to a risk of bilateral thalamic infarction and anatomical inaccessibility. Thalamic AVM was removed by high superior parietal approach without new neurological symptoms. CONCLUSION: The first case of thalamic AVM fed by AOP originating from the contralateral posterior cerebral artery is reported. Surgical removal of AVM would be at the heart of treatment in order to avoid bilateral thalamic infarction.

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report.

OBJECTIVE: Transcutaneous auricular vagus nerve stimulation (taVNS) was performed in two patients suffering structural focal epilepsy with preserved intellectual ability to show the feasibility of taVNS for specific patient groups. CASE PRESENTATIONS: Patient 1 was a 24-year-old woman with frontal lobe epilepsy who had weekly hyperkinetic seizures despite multiple anti-seizure medications. Patient 2 was a 27-year-old woman with parietal lobe epilepsy and focal cortical dysplasia in the vicinity of the lipoma in the corpus callosum. She experienced weekly focal-impaired awareness seizures even with anti-seizure medication. taVNS was applied to the left earlobe of both patients at 1.5 mA, 25 Hz, 250 µs pulse width, and 30 s stimulation with 30 s rest for 4 h per day. Over an 8-week baseline and 20 weeks of stimulation, the rate of reduction in seizure frequency was evaluated, along with quality-of-life using the Short-Form 36-Item Health survey. RESULTS: At baseline, we measured up to 11 and 12 focal seizures per week in Patient 1 and 2, respectively, with both patients achieving seizure freedom after 4 and 20 weeks taVNS, respectively. Patient 1 and 2 were observed for 18 and 14 months, respectively, including the clinical trial and follow-up observation period. Quality-of-life ratings increased in both patients, and no significant adverse events occurred during the study period. During the maintenance period after 20 weeks, seizures remained absent in Patient 1, and seizures remained reduced in Patient 2. CONCLUSION: Our results demonstrate that taVNS may be a promising tool for structural focal epilepsy with preserved cognitive function. A multicenter double-blind clinical trial is needed to confirm the role of taVNS as an anti-seizure tool.

Genotype-phenotype correlation over time in Angelman syndrome: Researching 134 patients.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of maternal UBE3A. The major cause of AS is a maternal deletion in 15q11.2-q13, and the minor causes are a UBE3A mutation, uniparental disomy (UPD), and imprinting defect (ID). Previous reports suggest that all patients with AS exhibit developmental delay, movement or balance disorders, behavioral characteristics, and speech impairment. In contrast, a substantial number of AS patients with a UBE3A mutation, UPD, or ID were reported not to show these consistent features and to show age-dependent changes in their features. In this study, we investigated 134 patients with AS, including 57 patients with a UBE3A mutation and 48 patients with UPD or ID. Although developmental delay was present in all patients, 20% of patients with AS caused by UPD or ID did not exhibit movement or balance disorders. Differences were also seen in hypopigmentation and seizures, depending on the causes. Moreover, patients with a UBE3A mutation, UPD, or ID tended to show fewer of the specific phenotypes depending on their age. In particular, in patients with UPD or ID, easily provoked laughter and hyperactivity tended to become more pronounced as they aged. Therefore, the clinical features of AS based on cause and age should be understood, and genetic testing should not be limited to patients with the typical clinical features of AS.

Nusinersen induces detectable changes in compound motor action potential response in spinal muscular atrophy type 1 patients with severe impairment of motor function.

BACKGROUND: Most long-term affected spinal muscular atrophy (SMA) type 1 patients have severe impairment of motor function and are dependent on mechanical ventilation with tracheostomy. The efficacy and safety of nusinersen in these patients have not been established. METHODS: We retrospectively evaluated the efficacy of intrathecal nusinersen treatment in patients with SMA type 1 who continued treatment for at least 12 months. There were three patients enrolled in our study (3, 4 and 16 years of age) who had severe impairment of gross motor function without head control or the ability to roll over. All three needed mechanical ventilation with tracheostomy and tube feeding. Motor function was assessed using the Children s Hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND) and the caregivers' evaluations. Concurrently, we examined nerve conduction longitudinally and compared compound motor action potential (CMAP) amplitudes. RESULTS: All patients continued nusinersen administration without significant adverse events for more than three years. While CHOP-INTEND scores did not remarkably increase, according to the caregivers, all three patients had improved finger or facial muscle movements that enabled them to make their intentions understood. Some CMAPs before treatment were not identified but became traces after nusinersen administration. CONCLUSIONS: The improvement in motor function that leads to smoother communication could be a basis for continuing nusinersen treatment. Currently available motor function scorings are not efficient for assessing therapeutic interventions in SMA patients with medical care complexity. Longitudinal nerve conduction studies could be an objective indicator.