In a recent study published in Nature Medicine, researchers designed a neuroprosthesis replicating the natural lumbosacral spinal activation during walking for Parkinson's disease (PD) patients.
Study: A spinal cord neuroprosthesis for locomotor deficits due to Parkinson’s disease. Image Credit: taniascamera/Shutterstock.com
Late-stage PD patients often suffer from debilitating locomotor deficits that are resistant to existing therapies. Researchers have identified a complementary treatment known as epidural electrical stimulation (EES) to alleviate these deficits. EES modulates motor neuron activity by activating large-sized afferents, allowing real-time regulation of leg motor neuronal activity.
This strategy has restored activities like standing, cycling, walking, and swimming among individuals with spinal cord injuries. The approach could be used to create a prosthesis to alleviate PD-related locomotor deficits.
About the study
In the present study, researchers designed a neuroprosthetic device to alleviate locomotion deficits in PD patients.
The neuroprosthesis was developed in a non-human primate (NHP) model to replicate locomotion difficulties resulting from Parkinson's disease. Walking was recorded in nine rhesus monkeys before and after a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment that modeled late-stage PD, coinciding with the severe depletion of striatal dopaminergic terminals and nigral neurons. The researchers intended to develop a prosthesis based on EES to restore the natural spatiotemporal activation of leg motor neurons disrupted during walking among PD patients.
The spinal cord anatomy of rhesus monkeys was studied to guide prosthesis development. The electrodes were spatially distributed in two arrays of eight electrodes each to gain access to the targeted regions. The electrodes were placed in four non-human primates, and single EES pulses were delivered to elicit muscle response and leg motion. The location and timing of epidural electrical stimulation bursts were to correlate with walking-related hotspot stimulation.
The researchers investigated whether the timing at which EES would correlate with hotspot activity based on ongoing movements could be deciphered from primary motor cortical neuronal activity among MPTP-treated primates. The microelectrode arrays were interfaced with modules enabling broadband neural activity recording synchronized with electromyography (EMG) and kinematics.
Subsequently, the team interfaced motor cortical neuronal activity with EES burst location and timing to develop the wire-free, brain-regulated, closed-loop prosthesis and investigated whether the prosthesis alleviated gait impairment and balancing difficulties observed among MPTP-treated non-human primates. The team also investigated whether the prosthesis could complement deep brain stimulation (DBS) to address PD-associated motor signs. Electrodes were implanted into the bilateral subthalamic nuclei in addition to the brain-controlled prosthesis in the MPTP-treated non-human primates, and structural magnetic resonance imaging (MRI) was performed.
The team verified the feasibility of detecting events from motor cortex activity in PD patients to harmonize EES with ongoing movements. Two individuals with idiopathic PD and motor fluctuations received bilateral subdural electrodes placed in the primary motor cortical region. The prosthesis was implanted in an elderly male (P1) aged 62 years with a 30-year history of Parkinson's disease who presented with severe gait impairments that were refractory to available medical treatments. A personalized neuro-biomechanical model actuated by a reflex-based circuit was generated, allowing the estimation of the optimal activation of muscles during walking expected by P1 in PD absence.
Results
The NHP model was appropriate for prosthesis development. The prosthesis interacted with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to promote longer steps, improve balance, and reduce gait freezing in P1. The spatiotemporal mapping of leg motor neuronal activation showed that walking involved the sequential stimulation of six hotspots in the right and left hemicords.
The team reasoned that targeting the dorsal root entry regions relaying to the six hotspots would improve balance and gait. The electrode arrays targeted relevant pools of leg motor neurons, and postmortem anatomical evaluations confirmed the appropriate and stable location of the electrode arrays.
The NHPs displayed a highly regular neuronal firing phase-locked with the gait cycles in the experiments. The team reasoned that the firing patterns should allow real-time identification of hotspot activation-related events. Since muscle activity was altered during the gait phases of weight acceptance, momentum, and leg lifting, the associated hotspots were targeted using EES in the hemicords.
Motor intentions were decoded from the activity of motor cortical neurons while walking in the non-human primate model, with appropriate predictions to coordinate the location and timing of EES spurts and reduce locomotion-related deficits.
The prosthesis reduced gait difficulties in non-human primates and restored the natural activation of leg motor-type neurons during walking, which translated into improvements in gait quality and balance. The prosthesis also reduced spine curvature during walking and improved posture. The prosthesis also improved gait and balance during skilled locomotion while negotiating the rungs of a horizontal ladder.
On concomitant use of the prosthesis and DBS, MPTP-treated NHPs showed increased alertness and walking speeds closer to those quantified before MPTP administration and gait improvements that enabled higher steps. The findings indicated the feasibility of decoding events from primary motor cortex activity to synchronize EES to the ongoing movements in PD patients. The prosthesis also reduced gait freezing, with and without DBS, and the closed-loop operations of the prosthesis remained highly accurate.
Rehabilitation supported by the prosthesis improved gait and quality of life. Locomotor deficit quantification using well-established clinical scores and tests [including the Movement Disorder Society (MPS) Unified PD Rating Scale UPDRS III] revealed improvements in endurance and balance. The prosthesis supported mobility in community settings, enabling P1 to enjoy recreational walks in nature over several kilometers without additional assistance.
Based on the study findings, the neuroprosthesis could decrease the severity of locomotor deficits among PD patients.
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