Validating inborn error of immunity prevalence and risk with nationally representative electronic health record data.

BACKGROUND: The 10 Warning Signs of Primary Immunodeficiency were created 30 years ago to advance recognition of inborn errors of immunity (IEI). However, no population-level assessment of their utility applied to electronic health record (EHR) data has been conducted. OBJECTIVE: We sought to quantify the value of having ≥2 warning signs (WS) toward diagnosing IEI using a highly representative real-world US cohort. A secondary goal was estimating the US prevalence of IEI. METHODS: In this cohort study, we accessed normalized and de-identified EHR data on 152 million US patients. An IEI cohort (n = 41,080), in which patients were defined by having at least 1 verifiable IEI diagnosis placed ≥2 times in their record, was compared with a matched set of controls (n = 250,262). WS were encoded along with relevant diagnoses, relative weights were calculated, and the proportion of IEI cases versus controls with ≥2 WS was compared. RESULTS: The proportion of IEI cases with ≥2 WS significantly differed from controls (0.33 vs 0.031; P < .0005, χ2 test). We also estimated a US IEI prevalence of 6 per 10,000 individuals (41,080/73,165,655; 0.056%). WS 9 (≥2 deep-seated infections), 7 (fungal infections), 5 (failure to thrive) and 4 (≥2 pneumonias in 1 year) were the most heavily weighted among the IEI cohort. CONCLUSIONS: This nationally representative US-based cohort study demonstrates that presence of WS and associated clinical diagnoses can facilitate identification of patients with IEI from EHR data. In addition, we estimate that 6 in 10,000, or approximately 150,000 to 200,000 individuals are affected by IEI across the United States.

Braided multi-electrode probes: mechanical compliance characteristics and recordings from spinal cords.

OBJECTIVE: To test a novel braided multi-electrode probe design with compliance exceeding that of a 50 µm microwire, thus reducing micromotion- and macromotion-induced tissue stress. APPROACH: We use up to 24 ultra-fine wires interwoven into a tubular braid to obtain a highly flexible multi-electrode probe. The tether-portion wires are simply non-braided extensions of the braid structure, allowing the microprobe to follow gross neural tissue movements. Mechanical calculation and direct measurements evaluated bending stiffness and axial compression forces in the probe and tether system. These were compared to 50 µm nichrome microwire standards. Recording tests were performed in decerebrate animals. MAIN RESULTS: Mechanical bending tests on braids comprising 9.6 or 12.7 µm nichrome wires showed that implants (braided portions) had 4 to 21 times better mechanical compliance than a single 50 µm wire and non-braided tethers were 6 to 96 times better. Braided microprobes yielded robust neural recordings from animals' spinal cords throughout cord motions. SIGNIFICANCE: Microwire electrode arrays that can record and withstand tissue micro- and macromotion of spinal cord tissues are demonstrated. This technology may provide a stable chronic neural interface into spinal cords of freely moving animals, is extensible to various applications, and may reduce mechanical tissue stress.

Microphysiology of epileptiform activity in human neocortex.

The authors report the use of dense two-dimensional microelectrode array recordings to characterize fine resolution electrocortical activity ("microEEG") in epileptogenic human cortex. A 16-mm(2) 96 microelectrode array with 400-mum interelectrode spacing was implanted in five patients undergoing invasive EEG monitoring for medically refractory epilepsy. High spatial resolution data from the array were analyzed in conjunction with simultaneously acquired data from standard intracranial electrode grids and strips. microEEG recorded from within the epileptogenic zone demonstrates discharges resembling both interictal epileptiform activity ("microdischarges") and electrographic seizures ("microseizures") but confined to cortical regions as small as 200 microm(2). In two patients, this activity appeared to be involved in the initiation or propagation of electrographic seizures. The authors hypothesize that microdischarges and microseizures are generated by small cortical domains that form the substrate of epileptogenic cortex and play important roles in seizure initiation and propagation.

Neuronal ensemble control of prosthetic devices by a human with tetraplegia.

Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclinical results from intact animals to a clinically useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a 'neural cursor' with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multi-jointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnology to restore independence for humans with paralysis.

Long-term stimulation and recording with a penetrating microelectrode array in cat sciatic nerve.

We studied the consequences of long-term implantation of a penetrating microelectrode array in peripheral nerve over the time course of 4-6 mo. Electrode arrays without lead wires were implanted to test the ability of different containment systems to protect the array and nerve during contractions of surrounding muscles. Treadmill walking was monitored and the animals showed no functional deficits as a result of implantation. In a different set of experiments, electrodes with lead wires were implanted for up to 7 mo and the animals were tested at 2-4 week intervals at which time stimulation thresholds and recorded sensory activity were monitored for every electrode. It was shown that surgical technique highly affected the long-term stimulation results. Results between measurement sessions were compared, and in the best case, the stimulation properties stabilized in 80% of the electrodes over the course of the experiment (162 days). The recorded sensory signals, however, were not stable over time. A histological analysis performed on all implanted tissues indicated that the morphology and fiber density of the nerve around the electrodes were normal.

Capabilities of a penetrating microelectrode array for recording single units in dorsal root ganglia of the cat.

The recording capability of a microelectrode array in the cat dorsal root ganglion (DRG) was studied in 11 acute experiments, 373 single, discriminable sensory units were recorded on 587 electrodes (0.64 units/electrode). Sensory action potentials as large as 1750 microV were obtained (mean=132 microV). These were comparable to literature reports of the best DRG extracellular recordings made with conventional electrodes. We were able simultaneously to activate and record over 50 discriminable, time-varying units from L6 and L7 DRGs during a cyclic ankle displacement. We also successfully recorded stable, phase dependent multiple sensory units with very little artifact or electromyographic (EMG) contamination during decerebrate walking. Thus, the array is capable of recording more effectively from more DRGs neurons than has been achieved by conventional recording techniques. The recording selectivity and stability of the array, coupled with the large number of neurons that can be recorded simultaneously, provide attractive features for better understanding sensorimotor control principles.