Online speech synthesis using a chronically implanted brain-computer interface in an individual with ALS.

Brain-computer interfaces (BCIs) that reconstruct and synthesize speech using brain activity recorded with intracranial electrodes may pave the way toward novel communication interfaces for people who have lost their ability to speak, or who are at high risk of losing this ability, due to neurological disorders. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a man with impaired articulation due to ALS, participating in a clinical trial (ClinicalTrials.gov, NCT03567213) exploring different strategies for BCI communication. The 3-stage approach reported here relies on recurrent neural networks to identify, decode and synthesize speech from electrocorticographic (ECoG) signals acquired across motor, premotor and somatosensory cortices. We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the participant from a vocabulary of 6 keywords previously used for decoding commands to control a communication board. Evaluation of the intelligibility of the synthesized speech indicates that 80% of the words can be correctly recognized by human listeners. Our results show that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words while preserving the participant's voice profile, and provide further evidence for the stability of ECoG for speech-based BCIs.

A click-based electrocorticographic brain-computer interface enables long-term high-performance switch-scan spelling.

Background: Brain-computer interfaces (BCIs) can restore communication in movement- and/or speech-impaired individuals by enabling neural control of computer typing applications. Single command "click" decoders provide a basic yet highly functional capability. Methods: We sought to test the performance and long-term stability of click-decoding using a chronically implanted high density electrocorticographic (ECoG) BCI with coverage of the sensorimotor cortex in a human clinical trial participant (ClinicalTrials.gov, NCT03567213) with amyotrophic lateral sclerosis (ALS). We trained the participant's click decoder using a small amount of training data (< 44 minutes across four days) collected up to 21 days prior to BCI use, and then tested it over a period of 90 days without any retraining or updating. Results: Using this click decoder to navigate a switch-scanning spelling interface, the study participant was able to maintain a median spelling rate of 10.2 characters per min. Though a transient reduction in signal power modulation interrupted testing with this fixed model, a new click decoder achieved comparable performance despite being trained with even less data (< 15 min, within one day). Conclusion: These results demonstrate that a click decoder can be trained with a small ECoG dataset while retaining robust performance for extended periods, providing functional text-based communication to BCI users.

Stable Decoding from a Speech BCI Enables Control for an Individual with ALS without Recalibration for 3 Months.

Brain-computer interfaces (BCIs) can be used to control assistive devices by patients with neurological disorders like amyotrophic lateral sclerosis (ALS) that limit speech and movement. For assistive control, it is desirable for BCI systems to be accurate and reliable, preferably with minimal setup time. In this study, a participant with severe dysarthria due to ALS operates computer applications with six intuitive speech commands via a chronic electrocorticographic (ECoG) implant over the ventral sensorimotor cortex. Speech commands are accurately detected and decoded (median accuracy: 90.59%) throughout a 3-month study period without model retraining or recalibration. Use of the BCI does not require exogenous timing cues, enabling the participant to issue self-paced commands at will. These results demonstrate that a chronically implanted ECoG-based speech BCI can reliably control assistive devices over long time periods with only initial model training and calibration, supporting the feasibility of unassisted home use.

Online speech synthesis using a chronically implanted brain-computer interface in an individual with ALS.

Recent studies have shown that speech can be reconstructed and synthesized using only brain activity recorded with intracranial electrodes, but until now this has only been done using retrospective analyses of recordings from able-bodied patients temporarily implanted with electrodes for epilepsy surgery. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a clinical trial participant (ClinicalTrials.gov, NCT03567213) with dysarthria due to amyotrophic lateral sclerosis (ALS). We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the user from a vocabulary of 6 keywords originally designed to allow intuitive selection of items on a communication board. Our results show for the first time that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words that are intelligible to human listeners while preserving the participants voice profile.

Medical therapies for amyotrophic lateral sclerosis-related respiratory decline: an appraisal of needs, opportunities and obstacles.

A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.

Amyotrophic lateral sclerosis-specific quality of life-short form (ALSSQOL-SF): A brief, reliable, and valid version of the ALSSQOL-R.

INTRODUCTION: The Amyotrophic Lateral Sclerosis (ALS)-Specific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOL-R) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOL-SF) suitable for limited clinic time and patient stamina. METHODS: The ALSSQOL-SF was created using Item Response Theory and confirmatory factor analysis on 389 patients. A cross-validation sample of 162 patients assessed convergent, divergent, and construct validity of the ALSSQOL-SF compared with psychosocial and physical functioning measures. RESULTS: The ALSSQOL-SF consisted of 20 items. Compared with the ALSSQOL-R, optimal precision was retained, and completion time was reduced from 15-25 minutes to 2-4 minutes. Psychometric properties for the ALSSQOL-SF and its subscales were strong. DISCUSSION: The ALSSQOL-SF is a disease-specific global QOL instrument that has a short administration time suitable for clinical use, and can provide clinically useful, valid information about persons with ALS. Muscle Nerve 58: 646-654, 2018.

A randomized controlled trial of resistance and endurance exercise in amyotrophic lateral sclerosis.

OBJECTIVE: Evaluate the safety and tolerability of resistance and endurance exercise in ALS participants as measured by their ability to complete this six-month study. METHODS: Participants were randomized to Resistance, Endurance, or Stretching/Range of Motion (SROM the exercise regimen prescribed for most ALS patients) exercises. All exercises were performed at home with an individualized regimen designed by a physical therapist trained in ALS management. Primary outcome measures were tolerability of the exercises at 24 weeks defined by 50% of participants completing at least 50% of the prescribed exercise regimen. Secondary outcome measures included the ALSFRS-R, pulmonary FVC, and other measures of ALS function. RESULTS: At 12 and 24 weeks, all three exercise regimens were tolerated according to our pre-specified criteria. Compliance to the prescribed exercise regimen was the highest in the resistance and SROM arms of the study. All three forms of exercise were considered safe as there were no differences in the rates of disease progression among groups. There were no differences in the secondary outcome measures and feasibility for evaluating these measures was successful. In a post-hoc analysis, there was a trend towards fewer falls in the Resistance and Endurance groups. CONCLUSIONS: This study demonstrates that SROM, resistance, and endurance exercise are all safe to be performed with the specified regimen without any worsening of outcomes as related to ALS function. All three forms of exercise were tolerated with resistance and SROM exercises showing the highest compliance over the 24 week-period.

Medical history of chemotherapy or immunosuppressive drug treatment and risk of amyotrophic lateral sclerosis (ALS).

A recent population-based analysis demonstrated lower risk of the lethal degenerative neuromuscular disease, amyotrophic lateral sclerosis (ALS) associated with history of the use of 'antineoplastic agents' and 'immunosuppressants'. To see if this finding was generalizable to other ALS cohorts, we examined associations between use of these agents and ALS risk in an independent case-control study of n = 414 ALS patients and n = 361 controls in an Eastern US population. Controls were sampled from the general population and among non-neurodegenerative disease patients. A history of chemotherapy treatment was significantly associated with a decreased ALS risk (OR 0.46, 95% CI 0.22-0.89, P = 0.026). We did not observe an association between risk of ALS and immunosuppressant therapy use (OR 0.78, 95% CI 0.50-1.02, P = 0.23). Analyses were adjusted for age, gender, and smoking. Our results support the prior report for chemotherapy treatment and lead to further discussion of the underlying mechanism.

High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial.

IMPORTANCE: No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE: To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN: A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING: Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS: One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS: Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS: The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE: Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00484510.

Electrical impedance myography as a biomarker to assess ALS progression.

Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.

Recombinant expression of the AChR-alpha1 subunit for the detection of conformation-dependent epitopes in Myasthenia Gravis.

Detection of autoantibodies associated with neurological disease typically involves immunoprecipitation of radioactively labeled native proteins. We explored whether single receptor subunits, fused to Renilla luciferase (Ruc), could detect patient autoantibodies in Luciferase Immunoprecipitation Systems. Myasthenia Gravis patient sera were tested for conformational autoantibodies to only the α1-subunit of the nicotinic acetylcholine receptor (AChR). Using a panel of 10 AChR-α1 fragments, AChR-α1-Δ5-Ruc demonstrated the highest immunoreactivity with a conformational-specific antibody and the highest sensitivity in a pilot cohort. Testing a larger cohort with AChR-α1-Δ5-Ruc demonstrated 21% sensitivity and 97% specificity. A point mutation within Ruc increased the diagnostic performance of AChR-α1-Δ5 (32% sensitivity, 97% specificity). The (125)I-α-bungarotoxin multi-subunit AChR assay demonstrated 63% sensitivity and 97% specificity. These findings highlight the difficulty in detecting Myasthenia Gravis conformational epitopes across assay formats and lay the foundation for detecting autoantibodies to defined recombinant chains of the AChR and potentially other neurotransmitter receptors.

A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis.

Our objective was to determine if chronic treatment with the non-competitive AMPA antagonist talampanel is efficacious and safe in subjects with ALS. A double-blind, placebo-controlled, multicenter, randomized clinical trial of nine months treatment duration was conducted in 59 subjects with ALS, with 40 subjects receiving talampanel 50 mg p.o. t.i.d, and 19 subjects receiving placebo. Primary outcome measure was rate of decline in isometric arm strength (as measured by change in arm strength megaslope of the Tufts Quantitative Neuromuscular Exam (TQNE)). Other efficacy endpoints included rate of decline in respiratory function, isometric leg strength, bulbar function, fine motor function, the ALS Functional Rating Scale (ALSFRS), and survival. Secondary safety outcome measures were frequency of adverse events, neurological status, plasma concentration of talampanel, vital signs, routine laboratory tests, and electrocardiograms. Decline in muscle strength was 15% less in talampanel treated subjects, and decline in ALSFRS was 30% slower in talampanel treated subjects. Talampanel was safe in subjects with ALS. Mortality rates (8% talampanel, 5% placebo) and drug discontinuation rates (25% talampanel, 16% placebo) were similar in active treatment and placebo groups. Dizziness and somnolence occurred significantly more often in talampanel treated subjects. Although no efficacy measure reached statistical significance, there was a repeated trend toward slower decline in ALSFRS and isometric muscle strength in talampanel treated subjects. Talampanel was well tolerated in subjects with ALS. Although certain adverse events occurred more frequently in the active treatment group, the rate of subject drop-out after nine months did not exceed that seen in other trials. These findings provide strong support for a phase III trial to determine the efficacy of talampanel in subjects with ALS.

Development and validation of the Family Decision-Making Self-Efficacy Scale.

OBJECTIVE: Several studies have reported high levels of distress in family members who have made health care decisions for loved ones at the end of life. A method is needed to assess the readiness of family members to take on this important role. Therefore, the purpose of this study was to develop and validate a scale to measure family member confidence in making decisions with (conscious patient scenario) and for (unconscious patient scenario) a terminally ill loved one. METHODS: On the basis of a survey of family members of patients with amyotrophic lateral sclerosis (ALS) enriched by in-depth interviews guided by Self-Efficacy Theory, we developed six themes within family decision making self-efficacy. We then created items reflecting these themes that were refined by a panel of end-of-life research experts. With 30 family members of patients in an outpatient ALS and a pancreatic cancer clinic, we tested the tool for internal consistency using Cronbach's alpha and for consistency from one administration to another using the test-retest reliability assessment in a subset of 10 family members. Items with item to total scale score correlations of less than .40 were eliminated. RESULTS: A 26-item scale with two 13-item scenarios resulted, measuring family self-efficacy in decision making for a conscious or unconscious patient with a Cronbach's alphas of .91 and .95, respectively. Test-retest reliability was r = .96, p = .002 in the conscious senario and r = .92, p = .009 in the unconscious scenario. SIGNIFICANCE OF RESULTS: The Family Decision-Making Self-Efficacy Scale is valid, reliable, and easily completed in the clinic setting. It may be used in research and clinical care to assess the confidence of family members in their ability to make decisions with or for a terminally ill loved one.

Accurate ALSFRS-R scores can be generated from retrospective review of clinic notes.

Retrospective studies are important in ALS but require markers of disease severity to enable risk adjustment and to allow fair comparisons between patient groups. The ALSFRS-R could be used as such a measure. This study aimed to determine if accurate ALSFRS-R scores could be generated by reviewing clinic notes. Five investigators reviewed 100 de-identified clinic notes to generate estimated ALSFRS-R scores. These scores were compared to ALSFRS-R scores completed by patients within three months of the clinic note. The retrospective ALSFRS-R scores did not differ significantly from the actual scores (mean retrospective score 38.7+/-5 vs. actual score 38.4+/-6, p =0.5). The intra-class correlation coefficient between actual and retrospective scores confirmed reasonable agreement (rho = 0.53, p <0.001). Bland Altman analysis also confirmed good agreement between the actual and retrospective scores. This study indicates that ALSFRS-R scores can be accurately reproduced from information in clinic notes and should be considered as a marker of disease severity for use in retrospective studies.

Family health care decision making and self-efficacy with patients with ALS at the end of life.

OBJECTIVE: Persons with ALS differ from those with other terminal illnesses in that they commonly retain capacity for decision making close to death. The role patients would opt to have their families play in decision making at the end of life may therefore be unique. This study compared the preferences of patients with ALS for involving family in health care decisions at the end of life with the actual involvement reported by the family after death. METHODS: A descriptive correlational design with 16 patient-family member dyads was used. Quantitative findings were enriched with in-depth interviews of a subset of five family members following the patient's death. RESULTS: Eighty-seven percent of patients had issued an advance directive. Patients who would opt to make health care decisions independently (i.e., according to the patient's preferences alone) were most likely to have their families report that decisions were made in the style that the patient preferred. Those who preferred shared decision making with family or decision making that relied upon the family were more likely to have their families report that decisions were made in a style that was more independent than preferred. When interviewed in depth, some family members described shared decision making although they had reported on the survey that the patient made independent decisions. SIGNIFICANCE OF RESULTS: The structure of advance directives may suggest to families that independent decision making is the ideal, causing them to avoid or underreport shared decision making. Fear of family recriminations may also cause family members to avoid or underreport shared decision making. Findings from this study might be used to guide clinicians in their discussions of treatments and health care decision making with persons with ALS and their families.

Early use of non-invasive ventilation prolongs survival in subjects with ALS.

Non-invasive positive pressure ventilation (NPPV) can improve survival in ALS patients with advanced respiratory impairment, but it is not known if it is beneficial earlier in the disease course. A retrospective cohort study of patients with ALS was performed comparing survival from time of diagnosis in subjects who started NPPV use when their FVC was >or=65% predicted (Early NPPV) with subjects who started NPPV when their FVC was below 65% predicted (Standard NPPV). The Early group (n = 25) and the Standard group (n = 67) were similar except for pulmonary function (mean FVC in Early NPPV group = 74.3+/-10.1% predicted and 48.3+/-11.3 in Standard group, p<0.001). The median time from ALS diagnosis to death was significantly longer in the Early NPPV group (2.7 years vs. 1.8 years, p = 0.045). This remained significant after adjustment for potential confounding factors (H.R. = 0.55, 95% CI 0.31-0.98). Survival from time of diagnosis was nearly one year longer in the Early group. Until more definitive data are available from randomized trials, our findings suggest that clinicians either encourage earlier use of NPPV or use more sensitive tests for respiratory muscle impairment than upright FVC.

Supramaximal inflation improves lung compliance in subjects with amyotrophic lateral sclerosis.

RATIONALE: Lung compliance has been found to be low in patients with chronic diaphragmatic weakness or paralysis but has not been well-studied in patients with amyotrophic lateral sclerosis (ALS). Noninvasive positive-pressure ventilation (NPPV) prolongs survival in ALS patients but may also have additional beneficial effects. OBJECTIVES: This study evaluated static expiratory lung compliance (CL) in subjects with ALS and determined the effect of lung inflation with supramaximal inflation on CL. DESIGN: This was a prospective trial comparing CL before and after supramaximal lung inflation via mouthpiece-delivered positive pressure. SETTING: A single university medical center with an multidisciplinary ALS center. PARTICIPANTS: Fourteen subjects with ALS were compared to 4 healthy volunteers. INTERVENTIONS: Subjects underwent a battery of pulmonary function tests including for CL. Then they used positive pressure administered via a mouthpiece set to 10 cm H2O above their maximal static recoil pressure for 5 min. The CL measurement was then repeated. RESULTS: The mean (+/- SD) baseline CL was reduced (164.1 +/- 82.1 mL/cm H2O) in subjects with ALS and was significantly lower than that in healthy volunteers (237.5 mL/cm H2O; p = 0.04). CL increased significantly in subjects with evidence of diaphragm weakness (change in CL, 11.3 +/- 16.7 mL/cm H2O; p = 0.03). Healthy volunteers did not have an increase in CL. CONCLUSIONS: Patients with ALS and diaphragmatic weakness have reduced CL, and brief supramaximal inflation increases CL. These findings suggest that atelectasis or increased alveolar surface forces are present in ALS patients and that these patients will have increased work of breathing. Some of the beneficial effects demonstrated with NPPV therapy may be through its effects on CL and the work of breathing.

Pulmonary predictors of survival in amyotrophic lateral sclerosis: use in clinical trial design.

The rapidity of progression of amyotrophic lateral sclerosis (ALS) to death or respiratory failure impacts patients, clinicians, and clinical investigators. This study compared the abilities of various pulmonary function tests to predict tracheostomy-free survival. We evaluated 95 ALS patients by determining upright and supine forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, arterial partial pressure of carbon dioxide (PaCO2), and transdiaphragmatic sniff pressures (Pdi-sniff). Tracheostomy-free survival time was measured from the date of spirometry. Supine FVC, upright FVC, MIP, MEP, and Pdi-sniff were significantly associated with tracheostomy-free survival after controlling for nonpulmonary factors, whereas PaCO2 was not. A normal supine FVC, MIP, or MEP was highly predictive for one-year survival. These tests are well suited to predict survival for trial enrollment and patient counseling. Supine FVC's simplicity of use and availability to ALS investigators makes it a particularly attractive predictor of one-year survival in ALS.

Promoting excellence in end-of-life care in ALS.

The type and quality of end-of-life care varies greatly in ALS; the time to initiate end-of-life care is not defined, and decision making is hampered by logistical and financial barriers. There has been no systematic review of these issues in ALS. The goals of this initiative are to: 1) improve end-of-life care for patients with ALS and families based on what limited evidence is available; 2) increase awareness, interest, and debate on the end-of-life care in ALS; and 3) identify areas needed for new prospective clinical research. The ALS Peer Workgroup reviewed the literature and 1) identified the current state of knowledge, 2) analysed the gaps in care, and 3) provided recommendations for standard of care and future research. It was shown that areas of investigation are needed on the incorporation of an interdisciplinary approach to care in ALS that includes: psychosocial evaluation and spiritual care; the use of validated instruments to assess patient and caregiver quality of life; and the establishment of proactive caregiver programs. Several public policy changes that will improve coverage for medical care, hospice, and caregiver costs are also reviewed. More clinical evidence is needed on how to provide optimal end-of-life care specifically in ALS.

Use of noninvasive ventilation in patients with amyotrophic lateral sclerosis.

INTRODUCTION: Noninvasive positive pressure ventilation (NIPPV) is associated with improved survival in amyotrophic lateral sclerosis (ALS) and has been widely recommended. The extent of NIPPV use in ALS patients and the factors associated with its use have not been studied. METHODS: A cross-sectional study using the ALS Patient Care Database. Analyses were performed to assess the association of patient and care characteristics with use of ventilatory support. RESULTS: 1458 patients were studied. 15.6% used NIPPV and 2.1% used invasive mechanical ventilation. Patients who used NIPPV were significantly more likely to be male and have higher income than those who did not. They were also more likely to have a gastrostomy tube, lower vital capacity, more severe disease, bulbar involvement and poorer general health status as measured by the SF-12 and Sickness Impact Profile. Multivariate analysis revealed that lower FVC, higher income and use of gastrostomy tube were independently associated with use of NIPPV. CONCLUSIONS: NIPPV is used more than seven times as frequently as invasive ventilation in ALS patients. Patients who use NIPPV have more severe disease than those who do not use any respiratory intervention. Patients with lower income are less likely to use NIPPV, which raises concerns about disparities in the care of patients with ALS.