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1.
Nature ; 618(7963): 126-133, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37225984

ABSTRACT

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain-spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.


Subject(s)
Brain-Computer Interfaces , Brain , Electric Stimulation Therapy , Neurological Rehabilitation , Spinal Cord Injuries , Spinal Cord , Walking , Humans , Brain/physiology , Electric Stimulation Therapy/instrumentation , Electric Stimulation Therapy/methods , Quadriplegia/etiology , Quadriplegia/rehabilitation , Quadriplegia/therapy , Reproducibility of Results , Spinal Cord/physiology , Spinal Cord Injuries/complications , Spinal Cord Injuries/rehabilitation , Spinal Cord Injuries/therapy , Walking/physiology , Leg/physiology , Neurological Rehabilitation/instrumentation , Neurological Rehabilitation/methods , Male
2.
N Engl J Med ; 391(7): 609-618, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39141853

ABSTRACT

BACKGROUND: Brain-computer interfaces can enable communication for people with paralysis by transforming cortical activity associated with attempted speech into text on a computer screen. Communication with brain-computer interfaces has been restricted by extensive training requirements and limited accuracy. METHODS: A 45-year-old man with amyotrophic lateral sclerosis (ALS) with tetraparesis and severe dysarthria underwent surgical implantation of four microelectrode arrays into his left ventral precentral gyrus 5 years after the onset of the illness; these arrays recorded neural activity from 256 intracortical electrodes. We report the results of decoding his cortical neural activity as he attempted to speak in both prompted and unstructured conversational contexts. Decoded words were displayed on a screen and then vocalized with the use of text-to-speech software designed to sound like his pre-ALS voice. RESULTS: On the first day of use (25 days after surgery), the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. Calibration of the neuroprosthesis required 30 minutes of cortical recordings while the participant attempted to speak, followed by subsequent processing. On the second day, after 1.4 additional hours of system training, the neuroprosthesis achieved 90.2% accuracy using a 125,000-word vocabulary. With further training data, the neuroprosthesis sustained 97.5% accuracy over a period of 8.4 months after surgical implantation, and the participant used it to communicate in self-paced conversations at a rate of approximately 32 words per minute for more than 248 cumulative hours. CONCLUSIONS: In a person with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore conversational communication after brief training. (Funded by the Office of the Assistant Secretary of Defense for Health Affairs and others; BrainGate2 ClinicalTrials.gov number, NCT00912041.).


Subject(s)
Amyotrophic Lateral Sclerosis , Brain-Computer Interfaces , Dysarthria , Speech , Humans , Male , Middle Aged , Amyotrophic Lateral Sclerosis/complications , Amyotrophic Lateral Sclerosis/rehabilitation , Calibration , Communication Aids for Disabled , Dysarthria/rehabilitation , Dysarthria/etiology , Electrodes, Implanted , Microelectrodes , Quadriplegia/etiology , Quadriplegia/rehabilitation
3.
Eur J Neurosci ; 59(5): 1029-1046, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38276915

ABSTRACT

Motor activation in response to perception of action-related stimuli may depend on a resonance mechanism subserving action understanding. The extent to which this mechanism is innate or learned from sensorimotor experience is still unclear. Here, we recorded EEG while people with paraplegia or tetraplegia consequent to spinal cord injury (SCI) and healthy control participants were presented with action sounds produced by body parts (mouth, hands or feet) that were or were not affected by SCI. Non-action sounds were used as further control. We observed reduced brain activation in subjects affected by SCI at both pre- and post-stimulus latencies specifically for those actions whose effector was disconnected by the spinal lesion (i.e., hand sound for tetraplegia and leg sound for both paraplegia and tetraplegia). Correlation analyses showed that these modulations were functionally linked with the chronicity of the lesion, indicating that the longer the time the lesion- EEG data acquisition interval and/or the more the lesion occurred at a young age, the weaker was the cortical activity in response to these action sounds. Tellingly, source estimations confirmed that these modulations originated from a deficit in the motor resonance mechanism, by showing diminished activity in premotor (during prediction and perception) and near the primary motor (during perception) areas. Such dissociation along the cortical hierarchy is consistent with both previous reports in healthy subjects and with hierarchical predictive coding accounts. Overall, these data expand on the notion that sensorimotor experience maintains the cortical representations relevant to anticipate and perceive action-related stimuli.


Subject(s)
Spinal Cord Injuries , Humans , Spinal Cord Injuries/pathology , Paraplegia , Sound , Quadriplegia
4.
N Engl J Med ; 385(3): 217-227, 2021 07 15.
Article in English | MEDLINE | ID: mdl-34260835

ABSTRACT

BACKGROUND: Technology to restore the ability to communicate in paralyzed persons who cannot speak has the potential to improve autonomy and quality of life. An approach that decodes words and sentences directly from the cerebral cortical activity of such patients may represent an advancement over existing methods for assisted communication. METHODS: We implanted a subdural, high-density, multielectrode array over the area of the sensorimotor cortex that controls speech in a person with anarthria (the loss of the ability to articulate speech) and spastic quadriparesis caused by a brain-stem stroke. Over the course of 48 sessions, we recorded 22 hours of cortical activity while the participant attempted to say individual words from a vocabulary set of 50 words. We used deep-learning algorithms to create computational models for the detection and classification of words from patterns in the recorded cortical activity. We applied these computational models, as well as a natural-language model that yielded next-word probabilities given the preceding words in a sequence, to decode full sentences as the participant attempted to say them. RESULTS: We decoded sentences from the participant's cortical activity in real time at a median rate of 15.2 words per minute, with a median word error rate of 25.6%. In post hoc analyses, we detected 98% of the attempts by the participant to produce individual words, and we classified words with 47.1% accuracy using cortical signals that were stable throughout the 81-week study period. CONCLUSIONS: In a person with anarthria and spastic quadriparesis caused by a brain-stem stroke, words and sentences were decoded directly from cortical activity during attempted speech with the use of deep-learning models and a natural-language model. (Funded by Facebook and others; ClinicalTrials.gov number, NCT03698149.).


Subject(s)
Brain Stem Infarctions/complications , Brain-Computer Interfaces , Deep Learning , Dysarthria/rehabilitation , Neural Prostheses , Speech , Adult , Dysarthria/etiology , Electrocorticography , Electrodes, Implanted , Humans , Male , Natural Language Processing , Quadriplegia/etiology , Sensorimotor Cortex/physiology
5.
Neurol Sci ; 45(2): 719-726, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37606743

ABSTRACT

INTRODUCTION: We aimed to describe neurological manifestations and functional outcome at discharge in patients with West Nile neuroinvasive disease. METHODS: This retrospective study enrolled inpatients treated in the University Clinic for Infectious and Tropical Diseases in Belgrade, Serbia, from 1 June until 31 October 2022. Functional outcome at discharge was assessed using modified Rankin scale. RESULTS: Among the 135 analyzed patients, encephalitis, meningitis and acute flaccid paralysis (AFP) were present in 114 (84.6%), 20 (14.8%), and 21 (15.6%), respectively. Quadriparesis/quadriplegia and monoparesis were the most frequent forms of AFP, present in 9 (6.7%) and 6 (4.4%) patients, respectively. Fourty-five (33.3%) patients had cerebellitis, 80 (59.3%) had rhombencephalitis, and 5 (3.7%) exhibited Parkinsonism. Ataxia and wide-based gait were present in 79 (58.5%) patients each. Fifty-one (37.8%) patients had tremor (41 (30.3%) had postural and/or kinetic tremor, 10 (7.4%) had resting tremor). Glasgow coma score (GCS) ≤ 8 and respiratory failure requiring mechanical ventilation developed in 39 (28.9%), and 33 (24.4%) patients, respectively. Quadriparesis was a risk factor for prolonged ventilator support (29.5 ± 16.8 vs. 12.4 ± 8.7 days, p = 0.001). At discharge, one patient with monoparesis recovered full muscle strength, whereas 8 patients with AFP were functionally dependent. Twenty-nine (21.5%) patients died. All of the succumbed had encephalitis, and 7 had quadriparesis. Ataxia, tremor and cognitive deficit persisted in 18 (16.9%), 15 (14.2%), and 22 (16.3%) patients at discharge, respectively. Age, malignancy, coronary disease, quadriparesis, mechanical ventilation, GCS ≤ 8 and healthcare-associated infections were risk factors for death (p = 0.001; p = 0.019; p = 0.004; p = 0.001; p < 0.001; p < 0.001, and p < 0.001, respectively).


Subject(s)
Central Nervous System Viral Diseases , Myelitis , Neuromuscular Diseases , West Nile Fever , Humans , West Nile Fever/complications , West Nile Fever/epidemiology , Retrospective Studies , Tremor/complications , Serbia/epidemiology , Seasons , alpha-Fetoproteins , Quadriplegia/epidemiology , Quadriplegia/etiology , Paresis , Ataxia/complications
6.
Arch Phys Med Rehabil ; 105(1): 75-81, 2024 01.
Article in English | MEDLINE | ID: mdl-37419233

ABSTRACT

OBJECTIVE: To analyze factors associated with malposition that affects function of the thumb in individuals with tetraplegia. DESIGN: Retrospective cross-sectional study. SETTING: Rehabilitation Center for Spinal Cord Injury. PARTICIPANTS: Anonymized data from 82 individuals (68 men), mean age 52.9±20.2 (SD) with acute/subacute cervical spinal cord injury C2-C8 AIS A-D recorded during 2018-2020. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Motor point (MP) mapping and manual muscle test (MRC) of 3 extrinsic thumb muscles (flexor pollicis longus (FPL), extensor pollicis longus (EPL), and abductor pollicis longus (APL)). RESULTS: 159 hands in 82 patients with tetraplegia C2-C8 AIS A-D were analyzed and assigned to "key pinch" (40.3%), "slack thumb" (26.4%), and "thumb-in-palm" (7.5%) positions. There was a significant (P<.0001) difference between the 3 thumb positions depicted in lower motor neuron (LMN) integrity tested by MP mapping and muscle strength of the 3 muscles examined. All studied muscles showed a significantly different expression of MP and the MRC values (P<.0001) between the "slack thumb" and "key pinch" position. MRC of FPL was significantly greater in the group "thumb-in-palm" compared with "key pinch" position (P<.0001). CONCLUSIONS: Malposition of the thumb due to tetraplegia seems to be related to the integrity of LMN and voluntary muscle activity of the extrinsic thumb muscles. Assessments such as MP mapping and MRC of the 3 thumb muscles enable the identification of potential risk factors for the development of thumb malposition in individuals with tetraplegia.


Subject(s)
Spinal Cord Injuries , Thumb , Male , Humans , Adult , Middle Aged , Aged , Cross-Sectional Studies , Retrospective Studies , Hand , Muscle, Skeletal , Quadriplegia/rehabilitation , Spinal Cord Injuries/complications
7.
Childs Nerv Syst ; 40(6): 1943-1947, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38374472

ABSTRACT

BACKGROUND: Chiari malformation type 1 (CM1) is a congenital hindbrain malformation characterized by herniation of the cerebellar tonsils below the foramen magnum. The term Chiari type 1.5 is used when herniation of the brainstem under the McRae line and anomalies of the craniovertebral junction are also present. These conditions are associated with several symptoms and signs, including headache, neck pain, and spinal cord syndrome. For symptomatic patients, surgical decompression is recommended. When radiographic indicators of craniovertebral junction (CVJ) instability or symptoms related to ventral brainstem compression are present, CVJ fixation should also be considered. CASE DESCRIPTION: We report the case of a 13-year-old girl who presented with severe tetraparesis after posterior decompression for Chiari malformation type 1.5, followed 5 days later by partial C2 laminectomy. Several months after the initial surgery, she underwent two fixations, first without and then with intraoperative cervical traction, leading to significant neurological improvement. DISCUSSION AND CONCLUSION: This case report underscores the importance of meticulous radiological analysis before CM surgery. For CM 1.5 patients with basilar invagination, CVJ fixation is recommended, and C2 laminectomy should be avoided. In the event of significant clinical deterioration due to nonadherence to these guidelines, our findings highlight the importance of traction with increased extension before fixation, even years after initial destabilizing surgery.


Subject(s)
Arnold-Chiari Malformation , Decompression, Surgical , Quadriplegia , Traction , Humans , Female , Arnold-Chiari Malformation/surgery , Arnold-Chiari Malformation/complications , Arnold-Chiari Malformation/diagnostic imaging , Adolescent , Decompression, Surgical/methods , Decompression, Surgical/adverse effects , Quadriplegia/etiology , Quadriplegia/surgery , Traction/adverse effects , Traction/methods , Treatment Outcome
8.
Spinal Cord ; 62(7): 357-366, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38519564

ABSTRACT

STUDY DESIGN: Non-randomized clinical trial. OBJECTIVES: Examine the feasibility, physical and psychosocial effects of a high intensity functional training (HIFT) exercise program for people with spinal cord injury (pSCI) and their care partners (CPs). SETTING: Community fitness center in a Medically Underserved Area (Fort Smith, USA.) METHODS: A single-group design with three assessment points (before the program, at midpoint (13 weeks), and post-program (25 weeks) was used to examine the effects of up to 49 HIFT sessions over 25-weeks. Sessions were 60 to 75 min in duration and adapted to the abilities of participants. Feasibility measures included recruitment, retention, attendance, safety and fidelity (exercise intensity rated via session-Rating of Perceived Exertion (RPE). Physical measures included cardiovascular endurance, anaerobic power, and muscular strength. Psychosocial measures included perceived social support for exercise, exercise self-efficacy and health-related quality of life. RESULTS: Fourteen pSCI (7 with paraplegia and 7 with tetraplegia, 2 females) and 6 CPs (4 females) were included (median age = 60) (IQR = 15.8). Recruitment rates were 40% for pSCI and 32% for CPs. On average, participants attended 73% (22%) of exercise sessions with a median session-RPE of 5 (IQR = 1). Retention rates were 83% and 67% for pSCI and CPs, respectively. For pSCI and their CPs, large effect sizes were observed for cardiovascular endurance, anaerobic power, muscular strength, and social support for exercise. CONCLUSIONS: For pSCI and their CPs, HIFT appears feasible and potentially leads to improvements in physical and psychosocial health for both groups.


Subject(s)
Exercise Therapy , Spinal Cord Injuries , Humans , Spinal Cord Injuries/rehabilitation , Spinal Cord Injuries/psychology , Male , Female , Middle Aged , Adult , Exercise Therapy/methods , Aged , Caregivers/psychology , Feasibility Studies , Quality of Life , Paraplegia/rehabilitation , Paraplegia/etiology , Paraplegia/physiopathology , Paraplegia/psychology , Quadriplegia/rehabilitation , Quadriplegia/etiology , Quadriplegia/psychology , Quadriplegia/physiopathology
9.
Spinal Cord ; 62(4): 164-169, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38355660

ABSTRACT

STUDY DESIGN: Retrospective longitudinal cohort study of veterans with SCI. OBJECTIVES: Spinal cord injury (SCI) is associated with an increased risk of developing diabetes mellitus (DM), likely due to body composition alterations and autonomic nervous system dysfunction. These factors are more pronounced in persons with tetraplegia (TP) versus paraplegia (PP). However, the effect of level of injury (LOI) on DM incidence is largely unknown. Therefore, the objective is to examine the effect of LOI on DM incidence in persons with SCI. SETTING: South Texas Veterans Health Care System. METHODS: We obtained electronic record data on age, sex, race/ethnicity, LOI and HbA1c concentration from January 1st 2001 through December 31st 2021. Cox proportional hazard regression analyses were used to assess the association between LOI, DM and all-cause mortality. RESULTS: Among 728 non-diabetic veterans with SCI (350 TP/ 378 PP, 52 ± 15 years, 690 male/38 female) 243 developed DM, of which 116 with TP and 127 with PP. Despite chronological variations between TP and PP, DM risk over the entire follow-up did not differ between the groups (hazard ratio (HR): 1.06, 95% CI: 0.82-1.38). Mortality was higher in TP versus PP (HR: 1.40, 95% CI: 1.09-1.78). However, developing DM did not increase the risk of death, regardless of LOI (HR: 1.07, 95% CI: 0.83-1.37). CONCLUSION: Despite chronological variations between both groups, the level of injury had minimal effect on long-term DM development in this cohort of veterans with SCI. Sponsorship NIH (DK105379; MS), RR&D SPiRE (I21RX003724-01A1; MT and SH).


Subject(s)
Diabetes Mellitus , Spinal Cord Injuries , Humans , Male , Female , Spinal Cord Injuries/complications , Spinal Cord Injuries/epidemiology , Longitudinal Studies , Retrospective Studies , Incidence , Cohort Studies , Diabetes Mellitus/epidemiology , Paraplegia/complications , Quadriplegia/etiology , Quadriplegia/complications
10.
Am J Otolaryngol ; 45(4): 104305, 2024.
Article in English | MEDLINE | ID: mdl-38653085

ABSTRACT

AIM: Iatrogenic acute spinal cord injury with tetraplegia is a serious consequence of non-spinal surgery.We report a case of acute spinal cord injury with tetraplegia after thyroid surgery. METHOD: The patient was pathologically diagnosed with papillary carcinoma, underwent left thyroidectomy, and developed tetraplegia after surgery. RESULT: The patient was diagnosed with acute spinal cord injury with tetraplegia and cured after anti-inflammatory and dehydrating treatment. CONCLUSION: Iatrogenic spinal cord injuries after elective non-spinal surgery can have catastrophic consequences, and clinicians must be alert to this possibility in clinical practice.


Subject(s)
Iatrogenic Disease , Quadriplegia , Spinal Cord Injuries , Thyroid Neoplasms , Thyroidectomy , Humans , Quadriplegia/etiology , Thyroidectomy/adverse effects , Spinal Cord Injuries/complications , Spinal Cord Injuries/etiology , Spinal Cord Injuries/surgery , Thyroid Neoplasms/surgery , Male , Postoperative Complications/etiology , Middle Aged , Carcinoma, Papillary/surgery , Female , Magnetic Resonance Imaging
11.
J Neurosci ; 42(25): 5007-5020, 2022 06 22.
Article in English | MEDLINE | ID: mdl-35589391

ABSTRACT

Consolidation of memory is believed to involve offline replay of neural activity. While amply demonstrated in rodents, evidence for replay in humans, particularly regarding motor memory, is less compelling. To determine whether replay occurs after motor learning, we sought to record from motor cortex during a novel motor task and subsequent overnight sleep. A 36-year-old man with tetraplegia secondary to cervical spinal cord injury enrolled in the ongoing BrainGate brain-computer interface pilot clinical trial had two 96-channel intracortical microelectrode arrays placed chronically into left precentral gyrus. Single- and multi-unit activity was recorded while he played a color/sound sequence matching memory game. Intended movements were decoded from motor cortical neuronal activity by a real-time steady-state Kalman filter that allowed the participant to control a neurally driven cursor on the screen. Intracortical neural activity from precentral gyrus and 2-lead scalp EEG were recorded overnight as he slept. When decoded using the same steady-state Kalman filter parameters, intracortical neural signals recorded overnight replayed the target sequence from the memory game at intervals throughout at a frequency significantly greater than expected by chance. Replay events occurred at speeds ranging from 1 to 4 times as fast as initial task execution and were most frequently observed during slow-wave sleep. These results demonstrate that recent visuomotor skill acquisition in humans may be accompanied by replay of the corresponding motor cortex neural activity during sleep.SIGNIFICANCE STATEMENT Within cortex, the acquisition of information is often followed by the offline recapitulation of specific sequences of neural firing. Replay of recent activity is enriched during sleep and may support the consolidation of learning and memory. Using an intracortical brain-computer interface, we recorded and decoded activity from motor cortex as a human research participant performed a novel motor task. By decoding neural activity throughout subsequent sleep, we find that neural sequences underlying the recently practiced motor task are repeated throughout the night, providing direct evidence of replay in human motor cortex during sleep. This approach, using an optimized brain-computer interface decoder to characterize neural activity during sleep, provides a framework for future studies exploring replay, learning, and memory.


Subject(s)
Learning/physiology , Motor Cortex/physiology , Sleep/physiology , Adult , Brain-Computer Interfaces , Cervical Vertebrae , Electroencephalography/methods , Humans , Male , Pilot Projects , Quadriplegia/etiology , Quadriplegia/physiopathology , Spinal Cord Injuries/complications , Spinal Cord Injuries/physiopathology
12.
Hum Genet ; 142(1): 89-101, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36098810

ABSTRACT

The craniovertebral junction (CVJ) is an anatomically complex region of the axial skeleton that provides protection of the brainstem and the upper cervical spinal cord. Structural malformation of the CVJ gives rise to life-threatening neurological deficits, such as quadriplegia and dyspnea. Unfortunately, genetic studies on human subjects with CVJ malformation are limited and the pathogenesis remains largely elusive. In this study, we recruited 93 individuals with CVJ malformation and performed exome sequencing. Manual interpretation of the data identified three pathogenic variants in genes associated with Mendelian diseases, including CSNK2A1, MSX2, and DDX3X. In addition, the contribution of copy number variations (CNVs) to CVJ malformation was investigated and three pathogenic CNVs were identified in three affected individuals. To further dissect the complex mutational architecture of CVJ malformation, we performed a gene-based rare variant association analysis utilizing 4371 in-house exomes as control. Rare variants in LGI4 (carrier rate = 3.26%, p = 3.3 × 10-5) and BEST1 (carrier rate = 5.43%, p = 5.77 × 10-6) were identified to be associated with CVJ malformation. Furthermore, gene set analyses revealed that extracellular matrix- and RHO GTPase-associated biological pathways were found to be involved in the etiology of CVJ malformation. Overall, we comprehensively dissected the genetic underpinnings of CVJ malformation and identified several novel disease-associated genes and biological pathways.


Subject(s)
Atlanto-Axial Joint , DNA Copy Number Variations , Humans , Atlanto-Axial Joint/pathology , Quadriplegia , Disease Susceptibility/pathology , Bestrophins
13.
Mamm Genome ; 34(4): 572-585, 2023 12.
Article in English | MEDLINE | ID: mdl-37642681

ABSTRACT

Solute carrier family 1 member 4 (SLC1A4), also referred to as Alanine/Serine/Cysteine/Threonine-preferring Transporter 1 (ASCT1), is a sodium-dependent neutral amino acid transporter. It is expressed in many tissues, including the brain, where it is expressed primarily on astrocytes and plays key roles in neuronal differentiation and development, maintaining neurotransmitter homeostasis, and N-methyl-D-aspartate neurotransmission, through regulation of L- and D-serine. Mutations in SLC1A4 are associated with the rare autosomal recessive neurodevelopmental disorder spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM, OMIM 616657). Psychomotor development and speech are significantly impaired in these patients, and many develop seizures. We generated and characterized a knock-in mouse model for the most common mutant allele, which results in a single amino acid change (p.Glu256Lys, or E256K). Homozygous mutants had increased D-serine uptake in the brain, microcephaly, and thin corpus callosum and cortex layer 1. While p.E256K homozygotes showed some significant differences in exploratory behavior relative to wildtype mice, their performance in assays for motor coordination, endurance, learning, and memory was normal, and they showed no significant differences in long-term potentiation. Taken together, these results indicate that the impact of the p.E256K mutation on cognition and motor function is minimal in mice, but other aspects of SLC1A4 function in the brain are conserved. Mice homozygous for p.E256K may be a good model for understanding the developmental basis of the corpus callosum and microcephaly phenotypes observed in SPATCCM patients and assessing whether they are rescued by serine supplementation.


Subject(s)
Microcephaly , Humans , Mice , Animals , Microcephaly/genetics , Microcephaly/complications , Corpus Callosum/metabolism , Brain/metabolism , Quadriplegia/complications , Serine
14.
Am J Med Genet A ; 191(6): 1619-1625, 2023 06.
Article in English | MEDLINE | ID: mdl-36905087

ABSTRACT

The p-21-activated kinase 1 (PAK1) protein, encoded by the PAK1 gene, is an evolutionarily conserved serine/threonine-protein kinase that regulates key cellular developmental processes. To date, seven de novo PAK1 variants have been reported to cause the Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). In addition to the namesake features, other common characteristics include structural brain anomalies, delayed development, hypotonia, and dysmorphic features. Here, we report a de novo PAK1 NM_002576.5: c.1409 T > A variant (p.Leu470Gln) identified by trio genome sequencing (GS) in a 13-year-old boy with postnatal macrocephaly, obstructive hydrocephalus, medically refractory epilepsy, spastic quadriplegia, white matter hyperintensities, profound developmental disabilities, and a horseshoe kidney. This is the first recurrently affected residue identified in the protein kinase domain. Combined assessment of the eight pathogenic PAK1 missense variants reveal that the variants cluster in either the protein kinase or autoregulatory domains. Although interpretation of the phenotypic spectrum is limited by the sample size, neuroanatomical alterations were found more often in individuals with PAK1 variants in the autoregulatory domain. In contrast, non-neurological comorbidities were found more often in individuals with PAK1 variants in the protein kinase domain. Together, these findings expand the clinical spectrum of PAK1-associated IDDMSSD and reveal potential correlations with the affected protein domains.


Subject(s)
Epilepsy , Hydrocephalus , Intellectual Disability , Megalencephaly , Male , Humans , Adolescent , Protein Domains , Protein Kinases , Epilepsy/diagnosis , Epilepsy/genetics , Megalencephaly/diagnosis , Megalencephaly/genetics , Intellectual Disability/genetics , Hydrocephalus/diagnosis , Hydrocephalus/genetics , Quadriplegia/diagnosis , Quadriplegia/genetics , p21-Activated Kinases/genetics , p21-Activated Kinases/chemistry
15.
BMC Neurol ; 23(1): 386, 2023 Oct 26.
Article in English | MEDLINE | ID: mdl-37884876

ABSTRACT

Bickerstaff's brainstem encephalitis is a rare autoimmune disorder that presents with ataxia, ophthalmoplegia, disturbance of consciousness and quadriplegia. A 45-year-old man with a history of ulcerative colitis (UC) taking mesalazine (5-aminosalicylic acid) visited the emergency room presenting with ataxia, ophthalmoplegia and a progressively worsening cognitive impairment. Cerebrospinal fluid analysis showed mild elevation in protein and white blood cell count and increased intracranial pressure. Anti-GQ1b autoantibodies were found positive in the patient's serum and contrast-enhanced brain magnetic resonance imaging showed diffuse leptomeningeal enhancement and pontine lesions. Based on these findings and the patient's clinical course and history, he was diagnosed with Bickerstaff's brainstem encephalitis. Mesalazine was discontinued and high-dose steroid pulse therapy was started, followed by intravenous immunoglobulin, which resulted in gradual improvement of the neurologic symptoms. When an ulcerative colitis patient presents with progressive cognitive impairment, quadriplegia and disturbance of consciousness and gait, Bickerstaff brainstem encephalitis should be considered in the differential diagnosis and prompt immunotherapy may lead to favorable prognosis.


Subject(s)
Autoimmune Diseases of the Nervous System , Colitis, Ulcerative , Encephalitis , Ophthalmoplegia , Male , Humans , Middle Aged , Brain Stem/diagnostic imaging , Brain Stem/pathology , Colitis, Ulcerative/complications , Colitis, Ulcerative/pathology , Mesalamine , Encephalitis/complications , Encephalitis/diagnosis , Quadriplegia , Ataxia/complications , Gangliosides
16.
Neurocase ; 29(5): 160-166, 2023 10.
Article in English | MEDLINE | ID: mdl-38713498

ABSTRACT

This is the case of a 26-year-old male who developed Anton Babinski syndrome (ABS), quadriplegia, and delayed post-hypoxic leukoencephalopathy (DPHL) after an opioid overdose. He exhibited cortical blindness, visual anosognosia, and confabulation upon awakening. Several days later, he experienced acute psychosis and agitation. T2-FSE MRI revealed extensive supratentorial leukoencephalopathy involving both cerebral hemispheres, extending to the posterior corpus callosum due to cerebral anoxia. This case report will discuss different types of encephalopathy from opioid abuse, ABS, visual anosognosia, and confabulation's pathogenic mechanisms. It underscores the necessity of researching substance-induced neuropsychiatric disorders and their pathogenic mechanisms for effective treatments.


Subject(s)
Leukoencephalopathies , Quadriplegia , Adult , Humans , Male , Analgesics, Opioid/poisoning , Hypoxia, Brain/complications , Leukoencephalopathies/chemically induced , Leukoencephalopathies/etiology , Magnetic Resonance Imaging , Opiate Overdose/complications , Quadriplegia/etiology
17.
Arch Phys Med Rehabil ; 104(8): 1209-1218, 2023 08.
Article in English | MEDLINE | ID: mdl-36736805

ABSTRACT

OBJECTIVES: To (1) determine fall characteristics (eg, cause, location, witnesses) of inpatients with spinal cord injury (SCI) and whether they were different for ambulatory persons vs wheelchair users; (2) visualize the total number of daily falls per clock-hour for different inpatients' features (eg, cause of injury, age); (3) compare clinical and demographic characteristics of inpatients who experienced a first fall event vs inpatients who did not experience such event; and (4) identify first fall event predictors. DESIGN: Retrospective observational cohort study. SETTING: Institution for inpatient neurologic rehabilitation. PARTICIPANTS: Persons with SCI (N=1294) admitted to a rehabilitation facility between 2005 and 2022. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional independence measure (FIM), Hospital Anxiety and Depression Scale (HADS), American Spinal Injury Association Impairment Scale (AIS), and Spinal Cord Independence Measure (SCIM) at admission. Kaplan-Meier survival curves and Cox proportional hazards models were used. RESULTS: A total of 502 fall events were experienced by 369 ambulatory inpatients (19.8%) and wheelchair users (80.2%) in 63.9% of cases being alone, with cause, situation, and location significantly different in both groups. Clock-hour visualizations revealed an absolute peak at 12 AM (complete or incomplete injuries, with paraplegia or tetraplegia) but a relative peak at 9 AM mainly including incomplete patients with paraplegia. Of the (n=1294) included patients, 16.8% experienced at least 1 fall. Fallen patients reported higher levels of HADS depression, lower total SCIM, and longer time since injury to admission, with no differences in age, sex, educational level, FIM (quasi-significant), and AIS grade. Multivariable Cox proportional hazards identified time since injury to admission and AIS grade D as significant predictors of first fall event. CONCLUSIONS: Falls identification, characterization, and clock-hour visualization can support decisions for mitigation strategies specifically addressed to inpatients with SCI. Fall predictors were identified as a first step for future research.


Subject(s)
Inpatients , Spinal Cord Injuries , Humans , Retrospective Studies , Spinal Cord Injuries/rehabilitation , Paraplegia/rehabilitation , Quadriplegia
18.
Arch Phys Med Rehabil ; 104(6): 863-871, 2023 06.
Article in English | MEDLINE | ID: mdl-36889373

ABSTRACT

OBJECTIVE: The first aim of this study was to determine whether the use of computers, internet, and computer assistive technology (AT) increased social participation after tetraplegia spinal cord injury. The second aim was to determine whether racial or ethnic disparities of technology use were experienced. DESIGN: A secondary analysis of data collected by the National Spinal Cord Injury Models Systems Study (NSCIMS), an ongoing observational cohort study, was performed on a sample of 3096 participants who experienced a traumatic tetraplegic injury. PARTICIPANTS: Participants included were at least 1-year posttraumatic tetraplegia injury and participated in NSCIMS between 2011 and 2016 (N=3096). SETTING: NSCIMS observational data were originally collected via in-person or phone interviews. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): A binary logistic regression was conducted to determine whether self-reported use of computers or similar device, the internet, computer AT, race, ethnicity, and other demographics predicted high (≥80) vs low/medium (<80) social participation, measured by the Craig Handicap and Reporting Technique social integration standardized measure. RESULTS: Combined use of a computer, AT, and the internet predicted greater social integration by almost 175% (95% confidence interval [CI], 2.0-3.78; P<.001) compared with no device or internet use. Racial and ethnic disparities were discovered. Black participants had 28% lower odds of high social integration than White participants (95% CI, 0.56-0.92; P<.01). Hispanic ethnicity predicted 40% lower odds of high social integration compared with non-Hispanic participants (95% CI, 0.39-0.91; P=.018). CONCLUSIONS: The internet presents an opportunity to reduce barriers to social participation and increase overall social integration after tetraplegia. However, race, ethnic, and income inequities prevent or limit access to the internet, computers, and AT after tetraplegia for Black and Hispanic people.


Subject(s)
Social Participation , Spinal Cord Injuries , Humans , Quadriplegia , Ethnicity , Spinal Cord Injuries/complications , Logistic Models
19.
Childs Nerv Syst ; 39(5): 1323-1328, 2023 05.
Article in English | MEDLINE | ID: mdl-36400977

ABSTRACT

PURPOSE: Patients with mucopolysaccharidosis type IVA (MPS IVA) have many risk factors for myelopathy and paresis. These are spinal cord compression, bone stenosis, and soft tissue thickening with ligament laxity, deformity, odontoid hypoplasia, and atlantoaxial instability. Although most patients with MPS IVA appear generally healthy at birth, patients often show skeletal deformities within a few years. Surgical indications are difficult to determine. Historically, many physicians have used prophylactic decompression and fusion in young, asymptomatic MPS IVA patients to prevent cord compression. Although spinal cord decompression is usually required at the craniocervical junction in patients with MPS IVA, decompression may be required at other spinal cord levels as well. There is a risk of developing neurological damage during surgery. The most common causes are ischemia secondary to cardiac output deteriorated in the prone position or due to artery damage, and local trauma due to neck movements or traction while bringing the patient to the prone position. Neurophysiological monitoring is very important during surgery to reduce the risk of neurological damage in spinal cord surgery. In this case report, a case with loss of lower extremity neuromonitorization motor evoked potential (MEP) responses in the early period of surgery without any intervention to the craniocervical junction after prone positioning will be presented.


Subject(s)
Mucopolysaccharidosis IV , Spinal Cord Compression , Spinal Cord Diseases , Infant, Newborn , Humans , Mucopolysaccharidosis IV/complications , Spinal Cord Compression/etiology , Spinal Cord Diseases/complications , Quadriplegia/etiology , Quadriplegia/prevention & control , Quadriplegia/surgery
20.
BMC Health Serv Res ; 23(1): 1393, 2023 Dec 12.
Article in English | MEDLINE | ID: mdl-38087349

ABSTRACT

BACKGROUND: Persons with spinal cord injury (SCI) living in the community often require care. The boundaries between professional home care and informal care are blurred, and it is unclear who the typical user of home care is. The objective of this study was to describe the characteristics of persons with SCI using professional home care in Switzerland, determine the frequency of home care visits, and investigate the association of sociodemographic factors, SCI-specific characteristics, secondary health conditions, and functional independence with the use of home care. METHODS: We used cross-sectional data from the 2017 community survey of the Swiss Spinal Cord Injury Cohort Study (SwiSCI). Out of 3,959 eligible individuals 1294 completed the questionnaire and were included in the analysis (response rate 33%). Using descriptive statistics, differences between home care users and non-users as well as the frequency of home care visits were investigated. The association between sociodemographic factors, SCI-specific characteristics, secondary health conditions, functional independence and the use of home care was analyzed using multivariable logistic regression. Multiple imputation was used to account for missing data. RESULTS: Of 1,294 participants, 280 (22%) used professional home care. The median weekly professional home care duration was 6 h (Q1 = 2, Q3 = 12). More home care was used in persons with lower functional independence (Odds ratio (OR) 0.30 per 10 unit decrease in the Spinal Cord Independence Measure, 95%-Confidence interval (CI) 0.24-0.37), fewer secondary health conditions (OR 0.96 per unit Spinal Cord Injury Secondary Conditions Scale, 95%-CI 0.94-0.99), tetraplegia (OR 2.77, 95%-CI 1.92-4.00), women (OR 2.42, 95%-CI 1.70-3.43), higher age (OR 1.22 per 10 years increase, 95%-CI 1.06-1.39), living alone (OR 2.48, 95%-CI 1.53-4.03), and those receiving support from an informal caregiver (OR 1.88, 95%-CI 1.27-2.77). CONCLUSIONS: This is the first study to examine the use of professional home care from the perspective of persons with SCI in Switzerland. Lower functional independence strongly predicts increased home care use. The findings showed that professional home care complements informal care and is more likely to be used by individuals with SCI who live alone, have tetraplegia, and are female.


Subject(s)
Home Care Services , Spinal Cord Injuries , Humans , Female , Child , Male , Cross-Sectional Studies , Switzerland/epidemiology , Cohort Studies , Spinal Cord Injuries/therapy , Spinal Cord Injuries/rehabilitation , Quadriplegia
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