Interim Safety Profile From the Feasibility Study of the BrainGate Neural Interface System.

BACKGROUND AND OBJECTIVES: Brain-computer interfaces (BCIs) are being developed to restore mobility, communication, and functional independence to people with paralysis. Though supported by decades of preclinical data, the safety of chronically implanted microelectrode array BCIs in humans is unknown. We report safety results from the prospective, open-label, nonrandomized BrainGate feasibility study (NCT00912041), the largest and longest-running clinical trial of an implanted BCI. METHODS: Adults aged 18-75 years with quadriparesis from spinal cord injury, brainstem stroke, or motor neuron disease were enrolled through 7 clinical sites in the United States. Participants underwent surgical implantation of 1 or 2 microelectrode arrays in the motor cortex of the dominant cerebral hemisphere. The primary safety outcome was device-related serious adverse events (SAEs) requiring device explantation or resulting in death or permanently increased disability during the 1-year postimplant evaluation period. The secondary outcomes included the type and frequency of other adverse events and the feasibility of the BrainGate system for controlling a computer or other assistive technologies. RESULTS: From 2004 to 2021, 14 adults enrolled in the BrainGate trial had devices surgically implanted. The average duration of device implantation was 872 days, yielding 12,203 days of safety experience. There were 68 device-related adverse events, including 6 device-related SAEs. The most common device-related adverse event was skin irritation around the percutaneous pedestal. There were no safety events that required device explantation, no unanticipated adverse device events, no intracranial infections, and no participant deaths or adverse events resulting in permanently increased disability related to the investigational device. DISCUSSION: The BrainGate Neural Interface system has a safety record comparable with other chronically implanted medical devices. Given rapid recent advances in this technology and continued performance gains, these data suggest a favorable risk/benefit ratio in appropriately selected individuals to support ongoing research and development. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT00912041. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the neurosurgically placed BrainGate Neural Interface system is associated with a low rate of SAEs defined as those requiring device explantation, resulting in death, or resulting in permanently increased disability during the 1-year postimplant period.

Classification of advanced and early stages of diabetic retinopathy from non-diabetic subjects by an ordinary least squares modeling method applied to OCTA images.

As the prevalence of diabetic retinopathy (DR) continues to rise, there is a need to develop computer-aided screening methods. The current study reports and validates an ordinary least squares (OLS) method to model optical coherence tomography angiography (OCTA) images and derive OLS parameters for classifying proliferative DR (PDR) and no/mild non-proliferative DR (NPDR) from non-diabetic subjects. OLS parameters were correlated with vessel metrics quantified from OCTA images and were used to determine predicted probabilities of PDR, no/mild NPDR, and non-diabetics. The classification rates of PDR and no/mild NPDR from non-diabetic subjects were 94% and 91%, respectively. The method had excellent predictive ability and was validated. With further development, the method may have potential clinical utility and contribute to image-based computer-aided screening and classification of stages of DR and other ocular and systemic diseases.

Improving therapeutic potential of GDNF family ligands.

The last decade has been a frustrating time for investigators who had envisioned major advances in the treatment of Parkinson's disease using neurotrophic factors. The first trials of glial cell line-derived neurotrophic factor for treating Parkinson's disease were very promising. Later blinded control trials were disappointing, not reaching the predetermined outcomes for improvement in motor function. Consideration of the problems in the studies as well as the biology of the neurotrophins used can potentially lead to more effective therapies. Parkinson's disease presents a multitude of opportunities for the cell biologist wanting to understand its pathology and to find possible new avenues for treatment.

Outcomes of hydrocephalus secondary to congenital toxoplasmosis.

OBJECTIVE: Hydrocephalus occurs in children with congenital toxoplasmosis and can lead to severe disability. In these cases, the decision to intervene is often influenced by the expectation of neurological recovery. In this study, clinical responses to neurosurgical intervention in children with hydrocephalus secondary to congenital toxoplasmosis are characterized. METHODS: Sixty-five participants with hydrocephalus due to congenital Toxoplasma gondii infection were evaluated as part of the National Collaborative Chicago-based Congenital Toxoplasmosis Study, and their neuroradiographic findings were reviewed. Clinical outcomes were scored on the basis of cognition and motor skills through the use of IQ scores and Gross Motor Function Classification System (GMFCS) level. Outcomes were then analyzed in relation to approach to management, anatomy of hydrocephalus, and time from diagnosis of hydrocephalus to surgical intervention. RESULTS: There was considerable variation in the outcomes of patients whose hydrocephalus was treated in early life, ranging from normal cognitive and motor function to profound developmental delay and functional limitation. Of the 65 participants included in the study, IQ and GMFCS level were available for 46 (70.8%). IQ and motor score were highly correlated (r = -0.82, p < 0.001). There were people with differing patterns of hydrocephalus or thickness of cortical mantle on initial presentation who had favorable outcomes. Time to neurosurgical intervention data were available for 31 patients who underwent ventriculoperitoneal (VP) shunt placement. Delayed shunt placement beyond 25 days after diagnosis of hydrocephalus was associated with greater cognitive impairment (p = 0.02). Motor impairment also appeared to be associated with shunt placement beyond 25 days but the difference did not achieve statistical significance (p = 0.13). Among those with shunt placement within 25 days after diagnosis (n = 19), the mean GMFCS level was 1.9 ± 1.6 (range 1-5). Five (29.4%) of 17 of these patients were too disabled to participate in formal cognitive testing, after excluding 2 patients with visual difficulties or language barriers that precluded IQ testing. Of the patients who had VP shunt placement 25 or more days after diagnosis (n = 12), the mean GMFCS level was 2.7 ± 1.4 (range 1-4). Of these, 1 could not participate in IQ testing due to severe visual difficulties and 8 (72.7%) of the remaining 11 due to cognitive disability. CONCLUSIONS: VP shunt placement in patients with hydrocephalus caused by congenital toxoplasmosis can contribute to favorable clinical outcomes, even in cases with severe hydrocephalus on neuroimaging. Shunt placement within 25 days of diagnosis was statistically associated with more favorable cognitive outcomes. Motor function appeared to follow the same pattern although it did not achieve statistical significance.

Detection of Subclinical Diabetic Retinopathy by Fine Structure Analysis of Retinal Images.

BACKGROUND AND OBJECTIVE: Diabetic retinopathy (DR) is a major complication of diabetes and the leading cause of blindness among US working-age adults. Detection of subclinical DR is important for disease monitoring and prevention of damage to the retina before occurrence of vision loss. The purpose of this retrospective study is to describe an automated method for discrimination of subclinical DR using fine structure analysis of retinal images. METHODS: Discrimination between nondiabetic control (NC; N = 16) and diabetic without clinical retinopathy (NDR; N = 17) subjects was performed using ordinary least squares regression and Fisher's linear discriminant analysis. A human observer also performed the discrimination by visual inspection of the images. RESULTS: The discrimination rate for subclinical DR was 88% using the automated method and higher than the rate obtained by a human observer which was 45%. CONCLUSIONS: The method provides sensitive and rapid analysis of retinal images and could be useful in detecting subclinical DR.

Automated fine structure image analysis method for discrimination of diabetic retinopathy stage using conjunctival microvasculature images.

The conjunctiva is a densely vascularized mucus membrane covering the sclera of the eye with a unique advantage of accessibility for direct visualization and non-invasive imaging. The purpose of this study is to apply an automated quantitative method for discrimination of different stages of diabetic retinopathy (DR) using conjunctival microvasculature images. Fine structural analysis of conjunctival microvasculature images was performed by ordinary least square regression and Fisher linear discriminant analysis. Conjunctival images between groups of non-diabetic and diabetic subjects at different stages of DR were discriminated. The automated method's discriminate rates were higher than those determined by human observers. The method allowed sensitive and rapid discrimination by assessment of conjunctival microvasculature images and can be potentially useful for DR screening and monitoring.

Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease.

In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in patients. As growth factors do not pass the blood-brain barrier, they have to be delivered intracranially. Therefore their efficient diffusion in brain tissue is of crucial importance. To improve the diffusion of the growth factor neurturin (NRTN), we modified its capacity to attach to heparan sulfates in the extracellular matrix. We present four new, biologically fully active variants with reduced heparin binding. Two of these variants are more stable than WT NRTN in vitro and diffuse better in rat brains. We also show that one of the NRTN variants diffuses better than its close homolog GDNF in monkey brains. The variant with the highest stability and widest diffusion regenerates dopamine fibers and improves the conditions of rats in a 6-hydroxydopamine model of Parkinson's disease more potently than GDNF, which previously showed modest efficacy in clinical trials. The new NRTN variants may help solve the major problem of inadequate distribution of NRTN in human brain tissue.

Patterns of Hydrocephalus Caused by Congenital Toxoplasma gondii Infection Associate With Parasite Genetics.

Four anatomical patterns of hydrocephalus secondary to congenital Toxoplasma gondii infection were identified and characterized for infants enrolled in the National Collaborative Chicago-based Congenital Toxoplasmosis Study. Analysis of parasite serotype revealed that different anatomical patterns associate with Type-II vs Not-Exclusively Type-II strains (NE-II) (P = .035).

A theory of fine structure image models with an application to detection and classification of dementia.

BACKGROUND: Estimation of stochastic process models from data is a common application of time series analysis methods. Such system identification processes are often cast as hypothesis testing exercises whose intent is to estimate model parameters and test them for statistical significance. Ordinary least squares (OLS) regression and the Levenberg-Marquardt algorithm (LMA) have proven invaluable computational tools for models being described by non-homogeneous, linear, stationary, ordinary differential equations. METHODS: In this paper we extend stochastic model identification to linear, stationary, partial differential equations in two independent variables (2D) and show that OLS and LMA apply equally well to these systems. The method employs an original nonparametric statistic as a test for the significance of estimated parameters. RESULTS: We show gray scale and color images are special cases of 2D systems satisfying a particular autoregressive partial difference equation which estimates an analogous partial differential equation. Several applications to medical image modeling and classification illustrate the method by correctly classifying demented and normal OLS models of axial magnetic resonance brain scans according to subject Mini Mental State Exam (MMSE) scores. Comparison with 13 image classifiers from the literature indicates our classifier is at least 14 times faster than any of them and has a classification accuracy better than all but one. CONCLUSIONS: Our modeling method applies to any linear, stationary, partial differential equation and the method is readily extended to 3D whole-organ systems. Further, in addition to being a robust image classifier, estimated image models offer insights into which parameters carry the most diagnostic image information and thereby suggest finer divisions could be made within a class. Image models can be estimated in milliseconds which translate to whole-organ models in seconds; such runtimes could make real-time medicine and surgery modeling possible.

The effect of pulsatile flow on intrathecal drug delivery in the spinal canal.

Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.

Propagating waves in human motor cortex.

Previous studies in non-human primates (NHPs) have shown that beta oscillations (15-30 Hz) of local field potentials (LFPs) in the arm/hand areas of primary motor cortex (MI) propagate as traveling waves across the cortex. These waves exhibited two stereotypical features across animals and tasks: (1) The waves propagated in two dominant modal directions roughly 180° apart, and (2) their propagation speed ranged from 10 to 35 cm/s. It is, however, unknown if such cortical waves occur in the human motor cortex. This study shows that the two properties of propagating beta waves are present in MI of a tetraplegic human patient while he was instructed to perform an instruction delay center-out task using a cursor controlled by the chin. Moreover, we show that beta waves are sustained and have similar properties whether the subject was engaged in the task or at rest. The directions of the successive sustained waves both in the human subject and a NHP subject tended to switch from one dominant mode to the other, and at least in the NHP subject the estimated distance traveled between successive waves traveling into and out of the central sulcus is consistent with the hypothesis of wave reflection between the border of motor and somatosensory cortices. Further, we show that the occurrence of the beta waves is not uniquely tied to periods of increased power in the beta frequency band. These results demonstrate that traveling beta waves in MI are a general phenomenon occurring in human as well as NHPs. Consistent with the NHP data, the dominant directions of the beta LFP waves in human aligned to the proximal to distal gradient of joint representations in MI somatotopy. This consistent finding of wave propagation may imply the existence of a hardwired organization of motor cortex that mediates this spatiotemporal pattern.

Ventricle wall movements and cerebrospinal fluid flow in hydrocephalus.

OBJECT: The dynamics of fluid flow in normal pressure hydrocephalus (NPH) are poorly understood. Normally, CSF flows out of the brain through the ventricles. However, ventricular enlargement during NPH may be caused by CSF backflow into the brain through the ventricles. A previous study showed this reversal of flow; in the present study, the authors provide additional clinical data obtained in patients with NPH and supplement these data with computer simulations to better understand the CSF flow and ventricular wall displacement and emphasize its clinical implications. METHODS: Three NPH patients and 1 patient with aqueductal stenosis underwent cine phase-contrast MR imaging (cine MR imaging) for measurement of CSF flow and ventricle wall movement during the cardiac cycle. These data were compared to data previously obtained in 8 healthy volunteers. The CSF flow measurements were obtained at the outlet of the aqueduct of Sylvius. Calculation of the ventricular wall movement was determined from the complete set of cine MR images obtained axially at the middle of the lateral ventricle. The data were obtained before and after CSF removal with a ventriculoperitoneal shunt with an adjustable valve. To supplement the clinical data, a computational model was used to predict the transmural pressure and flow. RESULTS: In healthy volunteers, net CSF aqueductal flow was 1.2 ml/minute in the craniocaudal direction. In patients with NPH, the net CSF flow was in the opposite direction--the caudocranial direction--before shunt placement. After shunting, the magnitude of the abnormal fluid flow decreased or reversed, with the flow resembling the normal flow patterns observed in healthy volunteers. CONCLUSIONS: The authors' MR imaging-based measurements of the CSF flow direction and lateral ventricle volume size change and the results of computer modeling of fluid dynamics lead them to conclude that the directional pattern and magnitude of CSF flow in patients with NPH may be an indication of the disease state. This has practical implications for shunt design and understanding the mechanisms that produce hydrocephalus.

Fast and slow oscillations in human primary motor cortex predict oncoming behaviorally relevant cues.

Beta oscillations (12-30 Hz) in local field potentials are prevalent in the motor system, yet their functional role within the context of planning a movement is still debated. In this study, a human participant implanted with a multielectrode array in the hand area of primary motor cortex (MI) was instructed to plan a movement using either the second or fourth of five sequentially presented instruction cues. The beta amplitude increased from the start of the trial until the informative (second or fourth) cue, and was diminished afterwards. Moreover, the beta amplitude peaked just prior to each instruction cue and the delta frequency (0.5-1.5 Hz) entrained to the interval between the cues-but only until the informative cue. This result suggests that the beta amplitude and delta phase in MI reflect the subject's engagement with the rhythmically presented cues and work together to enhance sensitivity to predictable and task-relevant visual cues.

An impedance sensor to monitor and control cerebral ventricular volume.

This paper presents a sensor for monitoring and controlling the volume of the cerebrospinal fluid-filled ventricles of the brain. The measurement principle of the sensor exploits electrical conductivity differences between the cerebrospinal fluid and the brain tissue. The electrical contrast was validated using dog brain tissue. Experiments with prototype sensors accurately measured the volume content of elastically deformable membranes and gel phantoms with conductivity properties made to match human brain. The sensor was incorporated into a fully automatic feedback control system designed to maintain the ventricular volume at normal levels. The experimental conductivity properties were also used to assess the sensor performance in a simulated case of hydrocephalus. The computer analysis predicted voltage drops over the entire range of ventricular size changes with acceptable positional dependence of the sensor electrodes inside the ventricular space. These promising experimental and computational results of the novel impedance sensor with feedback may serve as the foundation for improved therapeutic options for hydrocephalic patients relying on volume sensing, monitoring or active feedback control.

The physics of hydrocephalus.

This article reviews our previous work on the dynamics of the intracranial cavity and presents new clinically relevant results about hydrocephalus that can be gained from this approach. Simulations based on fluid dynamics and poroelasticity theory are used to predict CSF flow, pressures and brain tissue movement in normal subjects. Communicating hydrocephalus is created in the model by decreasing CSF absorption. The predictions are shown to reflect dynamics demonstrated by structural MRI and cine-MRI studies of normal subjects and hydrocephalus patients. The simulations are then used to explain unilateral hydrocephalus and how hydrocephalus could occur without CSF pulsations. The simulations also predict the known pressure/volume relationships seen on bolus infusions of CSF, and the small transmural pressure gradients observed in animal experiments and in patients with hydrocephalus. The complications and poor performance of shunts based on pressure-sensitive valves are explained and a system of feedback control is suggested as a solution.

Normal and hydrocephalic brain dynamics: the role of reduced cerebrospinal fluid reabsorption in ventricular enlargement.

CINE phase-contrast MRI (CINE-MRI) was used to measure cerebrospinal fluid (CSF) velocities and flow rates in the brain of six normal subjects and five patients with communicating hydrocephalus. Mathematical brain models were created using the MRI images of normal subjects and hydrocephalic patients. In our model, the effect of pulsatile vascular expansion is responsible for pulsatile CSF flow between the cranial and the spinal subarachnoidal spaces. Simulation results include intracranial pressure gradients, solid stresses and strains, and fluid velocities throughout the cranio-spinal system. Computed velocities agree closely with our in vivo CINE-MRI CSF flow measurements. In addition to normal intracranial dynamics, our model captures the transition to acute communicating hydrocephalus. By increasing the value for reabsorption resistance in the subarachnoid villi, our model predicts that the poroelastic parenchyma matrix will be drained and the ventricles enlarge despite small transmantle pressure gradients during the transitional phase. The poroelastic simulation thus provides a plausible explanation on how reabsorption changes could be responsible for enlargement of the ventricles without large transmantle pressure gradients.

Dystonic storm due to Batten's disease treated with pallidotomy and deep brain stimulation.

To report a novel treatment approach, pallidotomy and deep brain stimulation (DBS), in two sisters with dystonic storm due to Batten's disease. This study is based on long-term follow-up of two sisters, presenting with dystonic storm and their response to pallidotomy and DBS. These sisters, who had visual loss, seizures, and progressive psychomotor decline, experienced progressive disabling abnormal movements culminating in dystonic storm at the age of 15 and 17 years, respectively. In addition to intubation and sedation, multiple medications, including botulinum toxin injections and intrathecal baclofen infusion were tried in both patients without any benefit. The old sister underwent bilateral pallidotomy. Within 10 days postoperatively, there was marked improvement in dystonic storm. She was free of abnormal movements for 9 months. Then she started having opisthotonus lasting 20 seconds to an hour several times/day, but over 6 years abnormal movements are markedly improved, and not returned to pre-pallidotomy level. The young sister underwent both bilateral pallidotomy and DBS, 3 weeks apart. She was free of abnormal movements for 7 months and able to maintain reduction in the abnormal movements by adjusting DBS settings. Pallidotomy and DBS should be considered in dystonic storm due to Batten's disease.

A mathematical model of blood, cerebrospinal fluid and brain dynamics.

Using first principles of fluid and solid mechanics a comprehensive model of human intracranial dynamics is proposed. Blood, cerebrospinal fluid (CSF) and brain parenchyma as well as the spinal canal are included. The compartmental model predicts intracranial pressure gradients, blood and CSF flows and displacements in normal and pathological conditions like communicating hydrocephalus. The system of differential equations of first principles conservation balances is discretized and solved numerically. Fluid-solid interactions of the brain parenchyma with cerebral blood and CSF are calculated. The model provides the transitions from normal dynamics to the diseased state during the onset of communicating hydrocephalus. Predicted results were compared with physiological data from Cine phase-contrast magnetic resonance imaging to verify the dynamic model. Bolus injections into the CSF are simulated in the model and found to agree with clinical measurements.

A prospective blinded evaluation of deep brain stimulation for the treatment of secondary dystonia and primary torticollis syndromes.

OBJECT: The aim of this study was to provide an objective assessment of deep brain stimulation (DBS) for groups of patients with mixed secondary dystonia and primary torticollis syndromes by a blinded evaluation of 13 consecutive patients who underwent ineffective medical treatment and botulinum toxin injections. METHODS: Nine patients with secondary dystonia and 4 with cranial dystonia involving prominent spasmodic torticollis were selected for a DBS implant after they underwent unsuccessful medical treatment. Preoperative videos and neurological assessments were obtained and the DBS implant was inserted into the globus pallidus internus. Postoperatively, DBS parameters were adjusted to provide optimal benefit. Postoperative videotapes and quality of life scores were obtained. Blinded randomized evaluation of videotapes was performed by a neurologist specializing in movement disorders. Videos were scored using the Unified Dystonia Rating Scale, Toronto Western Spasmodic Torticollis Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale, or Abnormal Involuntary Movement Scale. Quality of life scoring was assessed using a standardized 7-point Global Rating Scale. RESULTS: All 13 patients completed preoperative videotaping, medical assessment, and surgery. Optimal DBS programming was completed in 6.5 visits over 5.9 months. Seven patients reported marked improvement, 3 reported moderate improvement, 2 reported slight improvement or no change, and 1 was lost to follow-up. Examiner scores on the Global Rating Scale reflected patient self-reported scores. CONCLUSIONS: Global subjective gains and notable objective improvement were observed in 11 of 13 patients. Although the benefits were variable and not fully predictable, they were of sufficient magnitude to justify offering the procedure when medications and botulinum toxin injections have failed.

Rigorous mathematical modeling techniques for optimal delivery of macromolecules to the brain.

Several treatment modalities for neurodegenerative diseases or tumors of the central nervous system involve invasive delivery of large molecular weight drugs to the brain. Despite the ample record of experimental studies, accurate drug targeting for the human brain remains a challenge. This paper proposes a systematic design method of administering drugs to specific locations in the human brain based on first principles transport in porous media. The proposed mathematical framework predicts achievable treatment volumes in target regions as a function of brain anatomy and infusion catheter position. A systematic procedure to determine the optimal infusion and catheter design parameters that maximize the penetration depth and volumes of distribution will be discussed. The computer simulations are validated with agarose gel phantom experiments and rat data. The rigorous computational approach will allow physicians and scientists to better plan the administration of therapeutic drugs to the central nervous system.