Parag G. Patil

Learning to Control a Brain–Machine Interface for Reaching and Grasping by Primates

Reaching and grasping in primates depend on the coordination of neural activity in large frontoparietal ensembles. Here we demonstrate that primates can learn to reach and grasp virtual objects by controlling a robot arm through a closed-loop brain–machine interface (BMIc) that uses multiple mathematical models to extract several motor parameters (i.e., hand position, velocity, gripping force, and the EMGs of multiple arm muscles) from the electrical activity of frontoparietal neuronal ensembles. As single neurons typically contribute to the encoding of several motor parameters, we observed that high BMIc accuracy required recording from large neuronal ensembles. Continuous BMIc operation by monkeys led to significant improvements in both model predictions and behavioral performance. Using visual feedback, monkeys succeeded in producing robot reach-and-grasp movements even when their arms did not move. Learning to operate the BMIc was paralleled by functional reorganization in multiple cortical areas, suggesting that the dynamic properties of the BMIc were incorporated into motor and sensory cortical representations.

Ensemble recordings of human subcortical neurons as a source of motor control signals for a brain-machine interface

OBJECTIVE:Patients with severe neurological injury, such as quadriplegics, might benefit greatly from a brain-machine interface that uses neuronal activity from motor centers to control a neuroprosthetic device. Here, we report an implementation of this strategy in the human intraoperative setting to assess the feasibility of using neurons in subcortical motor areas to drive a human brain-machine interface. METHODS:Acute ensemble recordings from subthalamic nucleus and thalamic motor areas (ventralis oralis posterior [VOP]/ventralis intermediate nucleus [VIM]) were obtained in 11 awake patients during deep brain stimulator surgery by use of a 32-microwire array. During extracellular neuronal recordings, patients simultaneously performed a visual feedback hand-gripping force task. Offline analysis was then used to explore the relationship between neuronal modulation and gripping force. RESULTS:Individual neurons (n = 28 VOP/VIM, n = 119 subthalamic nucleus) demonstrated a variety of modulation responses both before and after onset of changes in gripping force of the contralateral hand. Overall, 61% of subthalamic nucleus neurons and 81% of VOP/VIM neurons modulated with gripping force. Remarkably, ensembles of 3 to 55 simultaneously recorded neurons were sufficiently information-rich to predict gripping force during 30-second test periods with considerable accuracy (up to R = 0.82, R2 = 0.68) after short training periods. Longer training periods and larger neuronal ensembles were associated with improved predictive accuracy. CONCLUSION:This initial feasibility study bridges the gap between the nonhuman primate laboratory and the human intraoperative setting to suggest that neuronal ensembles from human subcortical motor regions may be able to provide informative control signals to a future brain-machine interface.

National trends in surgical procedures for degenerative cervical spine disease: 1990-2000.

OBJECTIVE:Degenerative cervical spine disease is one of the most common indications for spinal surgical intervention. The impact of the unprecedented changes in healthcare technology and delivery over the past decade is unknown. We examined this issue using the Nationwide Inpatient Sample database, a representative sample of all United States inpatient hospitalizations. METHODS:All adult patients undergoing spinal procedures with a principal diagnosis of cervical spine disease were selected for analysis according to International Classification of Diseases 9th Revision clinical modification codes. Patients diagnosed with infection, neoplasia, fracture, or trauma, as well as those with noncervical or nonspecific principal diagnoses, were excluded. RESULTS:The total number of cervical spine procedures in the sampled population rose twofold, from 53,810 in 1990 to 112,400 in 2000. Anterior fusion procedures rose (17.8–69.5% of procedures), whereas nonfusion decompressions declined sharply (70.5–24.6%). Patient diversity increased with increasing rates of surgery among women (25.0–51.0 per 100,000) and minorities (18.4–45.7 per 100,000). Although average age (47.5–49.2 yr) and medical comorbidities (8.7–13.5% of patients) increased, mortality (0.21–0.14% of hospitalizations) and average length of stay (5.2–2.2 d) declined. Inflation-adjusted hospital charges rose by 48% to a total exceeding

The Development of Brain-Machine Interface Neuroprosthetic Devices

2 billion in 2000. CONCLUSION:Compared with one decade ago, the surgical treatment of degenerative cervical spine disease has evolved to include a higher percentage of anterior and fusion procedures performed on a more diverse, older, and comorbid patient population, with shortened hospital stay and improved morbidity and mortality, although at substantially increased cost.

A Fully Self-Contained Logarithmic Closed-Loop Deep Brain Stimulation SoC With Wireless Telemetry and Wireless Power Management

SummaryThe development of brain-machine interface technology is a logical next step in the overall direction of neuro-prosthetics. Many of the required technological advances that will be required for clinical translation of brain-machine interfaces are already under development, including a new generation of recording electrodes, the decoding and interpretation of signals underlying intention and planning, actuators for implementation of mental plans in virtual or real contexts, direct somatosensory feedback to the nervous system to refine actions, and training to encourage plasticity in neural circuits. Although pre-clinical studies in nonhuman primates demonstrate high efficacy in a realistic motor task with motor cortical recordings, there are many challenges in the clinical translation of even simple tasks and devices. Foremost among these challenges is the development of biocompatible electrodes capable of long-term, stable recording of brain activity and implantable amplifiers and signal processors that are sufficiently resistant to noise and artifact to faithfully transmit recorded signals to the external environment. Whether there is a suitable market for such new technology depends on its efficacy in restoring and enhancing neural function, its risks of implantation, and its long-term efficacy and usefulness. Now is a critical time in brain-machine interface development because most ongoing studies are science-based and noncommercial, allowing new approaches to be included in commercial schemes under development.

In vivo performance of a microelectrode neural probe with integrated drug delivery.

Although closed-loop deep brain stimulation (DBS) promises treatment of many neurological disorders, an implantable system-on-chip (SoC) implementing an effective closed-loop DBS algorithm has not been demonstrated. This work introduces a logarithmic, closed-loop DBS system that detects and processes low-frequency brain field signals to control and adapt stimulation currents. The system records and processes neural signals with four low-noise neural amplifier (LNA) channels, a multiplexed logarithmic ADC, and two high-pass and two low-pass digital logarithmic filters. Logarithmic processing saves power and achieves high dynamic range. A logarithmic domain digital signal processor (DSP) and PI-controller controls eight current stimulator channels and enables closed-loop stimulation. An RF transceiver, a clock generator, and a power harvester are also included in the system to achieve a complete implantable SoC. The 4 mm2 180 nm CMOS prototype consumes a total of 468 μW for recording and processing neural signals, for stimulation, and for two-way wireless communication.

Deep brain stimulation for movement disorders.

OBJECT The availability of sophisticated neural probes is a key prerequisite in the development of future brain-machine interfaces (BMIs). In this study, the authors developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery promises to extend dramatically the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology. METHODS To form the multifunctional neural probe, the authors affixed a 16-channel microfabricated silicon electrode array to a fused silica catheter. Three experiments were conducted in rats to characterize the performance of the device. Experiment 1 examined cellular damage from probe insertion and the drug distribution in tissue. Experiment 2 measured the effects of saline infusions delivered through the probe on concurrent electrophysiological measurements. Experiment 3 demonstrated that a physiologically relevant amount of drug can be delivered in a controlled fashion. For these experiments, Hoechst and propidium iodide stains were used to assess insertion trauma and the tissue distribution of the infusate. Artificial CSF (aCSF) and tetrodotoxin (TTX) were injected to determine the efficacy of drug delivery. RESULTS The newly developed multifunctional neural probes were successfully inserted into rat cortex and were able to deliver fluids and drugs that resulted in the expected electrophysiological and histological responses. The damage from insertion of the device into brain tissue was substantially less than the volume of drug dispersion in tissue. Electrophysiological activity, including both individual spikes as well as local field potentials, was successfully recorded with this device during real-time drug delivery. No significant changes were seen in response to delivery of aCSF as a control experiment, whereas delivery of TTX produced the expected result of suppressing all spiking activity in the vicinity of the catheter outlet. CONCLUSIONS Multifunctional neural probes such as the ones developed and validated within this study have great potential to help further understand the design space and criteria for the next generation of neural probe technology. By incorporating integrated drug delivery functionality into the probes, new treatment options for neurological disorders and regenerative neural interfaces using localized and feedback-controlled delivery of drugs can be realized in the near future.

Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial

Deep brain stimulation (DBS) is a widely employed therapeutic modality for the treatment of movement disorders. Full FDA approval or humanitarian device exemption has been made for Parkinsons disease, tremor, and dystonia. In this review, we describe the indications and selection criteria, target selection, and outcomes for each of these conditions. In addition, we describe the operative techniques utilized in DBS surgery and look forward to new developments in DBS on the horizon.

Transplantation of spinal cord–derived neural stem cells for ALS Analysis of phase 1 and 2 trials

BACKGROUND Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING Abbott (previously St Jude Medical).

The MDS−UPDRS tracks motor and non-motor improvement due to subthalamic nucleus deep brain stimulation in Parkinson disease

Objective: To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers. Methods: This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale–Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups. Results: Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression. Conclusions: Intraspinal transplantation of human spinal cord–derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers. Classification of evidence: This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues.