Freezing of Gait in Parkinson's Disease: Invasive and Noninvasive Neuromodulation.

INTRODUCTION: Freezing of gait (FoG) is one of the most disabling yet poorly understood symptoms of Parkinson's disease (PD). FoG is an episodic gait pattern characterized by the inability to step that occurs on initiation or turning while walking, particularly with perception of tight surroundings. This phenomenon impairs balance, increases falls, and reduces the quality of life. MATERIALS AND METHODS: Clinical-anatomical correlations, electrophysiology, and functional imaging have generated several mechanistic hypotheses, ranging from the most distal (abnormal central pattern generators of the spinal cord) to the most proximal (frontal executive dysfunction). Here, we review the neuroanatomy and pathophysiology of gait initiation in the context of FoG, and we discuss targets of central nervous system neuromodulation and their outcomes so far. The PubMed database was searched using these key words: neuromodulation, freezing of gait, Parkinson's disease, and gait disorders. CONCLUSION: Despite these investigations, the pathogenesis of this process remains poorly understood. The evidence presented in this review suggests FoG to be a heterogenous phenomenon without a single unifying pathologic target. Future studies rigorously assessing targets as well as multimodal approaches will be essential to define the next generation of therapeutic treatments.

Electrical stimulation of the dorsal columns of the spinal cord for Parkinson's disease.

Spinal cord stimulation has been used for the treatment of chronic pain for decades. In 2009, our laboratory proposed, based on studies in rodents, that electrical stimulation of the dorsal columns of the spinal cord could become an effective treatment for motor symptoms associated with Parkinson's disease (PD). Since our initial report in rodents and a more recent study in primates, several clinical studies have now described beneficial effects of dorsal column stimulation in parkinsonian patients. In primates, we have shown that dorsal column stimulation activates multiple structures along the somatosensory pathway and desynchronizes the pathological cortico-striatal oscillations responsible for the manifestation of PD symptoms. Based on recent evidence, we argue that neurological disorders such as PD can be broadly classified as diseases emerging from abnormal neuronal timing, leading to pathological brain states, and that the spinal cord could be used as a "channel" to transmit therapeutic electrical signals to disrupt these abnormalities. © 2017 International Parkinson and Movement Disorder Society.

The role of stimulus periodicity on spinal cord stimulation-induced artificial sensations in rodents.

Objective.Sensory feedback is critical for effectively controlling brain-machine interfaces and neuroprosthetic devices. Spinal cord stimulation (SCS) is proposed as a technique to induce artificial sensory perceptions in rodents, monkeys, and humans. However, to realize the full potential of SCS as a sensory neuroprosthetic technology, a better understanding of the effect of SCS pulse train parameter changes on sensory detection and discrimination thresholds is necessary.Approach.Here we investigated whether stimulation periodicity impacts rats' ability to detect and discriminate SCS-induced perceptions at different frequencies.Main results.By varying the coefficient of variation (CV) of interstimulus pulse interval, we showed that at lower frequencies, rats could detect highly aperiodic SCS pulse trains at lower amplitudes (i.e. decreased detection thresholds). Furthermore, rats learned to discriminate stimuli with subtle differences in periodicity, and the just-noticeable differences from a highly aperiodic stimulus were smaller than those from a periodic stimulus.Significance.These results demonstrate that the temporal structure of an SCS pulse train is an integral parameter for modulating sensory feedback in neuroprosthetic applications.

Regeneration of Propriospinal Axons in Rat Transected Spinal Cord Injury through a Growth-Promoting Pathway Constructed by Schwann Cells Overexpressing GDNF.

Unsuccessful axonal regeneration in transected spinal cord injury (SCI) is mainly attributed to shortage of growth factors, inhibitory glial scar, and low intrinsic regenerating capacity of severely injured neurons. Previously, we constructed an axonal growth permissive pathway in a thoracic hemisected injury by transplantation of Schwann cells overexpressing glial-cell-derived neurotrophic factor (SCs-GDNF) into the lesion gap as well as the caudal cord and proved that this novel permissive bridge promoted the regeneration of descending propriospinal tract (dPST) axons across and beyond the lesion. In the current study, we subjected rats to complete thoracic (T11) spinal cord transections and examined whether these combinatorial treatments can support dPST axons' regeneration beyond the transected injury. The results indicated that GDNF significantly improved graft-host interface by promoting integration between SCs and astrocytes, especially the migration of reactive astrocyte into SCs-GDNF territory. The glial response in the caudal graft area has been significantly attenuated. The astrocytes inside the grafted area were morphologically characterized by elongated and slim process and bipolar orientation accompanied by dramatically reduced expression of glial fibrillary acidic protein. Tremendous dPST axons have been found to regenerate across the lesion and back to the caudal spinal cord which were otherwise difficult to see in control groups. The caudal synaptic connections were formed, and regenerated axons were remyelinated. The hindlimb locomotor function has been improved.

Globus Pallidus Interna and Ventral Intermediate Nucleus of the Thalamus Deep Brain Stimulation for Adductor Laryngeal Dystonia: a Case Report of Blinded Analyses of Objective Voice Outcomes in 2 Patients.

BACKGROUND: Adductor laryngeal dystonia (ADLD) is a substantially debilitating focal progressive neurological voice disorder. Current standard of care is symptomatic treatment with repeated injections of botulinum toxin into specific intrinsic laryngeal muscles with extremely variable and temporary benefits. We report the use of bilateral deep brain stimulation (DBS) of globus pallidus (GPi) for long-term improvement of ADLD voice symptoms. OBJECTIVE: To investigate the effects of bilateral DBS of the GPi and ventral intermediate nucleus (VIM) of the thalamus on vocal function in 2 patients with ADLD associated with voice and hand tremor. METHODS: Blinded objective and quantitative analyses of voice were conducted before and after treatment in 2 female patients (70 and 69 years). Paired t-tests were conducted to compare voice measurements pre-GPi and post-GPi and VIM-DBS. A 2-way analysis of variance was conducted to determine the interaction between target (GPi/VIM) and time (pre/post) for each voice measure. RESULTS: Although the follow-up period differed between patients, the GPi-DBS implanted patient had notable improvement in vowel voicing (%), extent of tremor intensity (%), and overall speech intelligibility (%), compared with preoperative status. GPi-DBS also resulted in significant improvement in cepstral peak prominence (dB). VIM-DBS resulted in a significantly greater change in the tremor rate (Hz). CONCLUSION: Changes in phonatory function provide preliminary support for the use of bilateral GPi-DBS for treatment of ADLD and bilateral VIM-DBS for vocal tremor predominant ADLD. Future studies with larger sample sizes and standardized follow-up periods are needed to better assess the role of DBS for ADLD.

Generating artificial sensations with spinal cord stimulation in primates and rodents.

For patients who have lost sensory function due to a neurological injury such as spinal cord injury (SCI), stroke, or amputation, spinal cord stimulation (SCS) may provide a mechanism for restoring somatic sensations via an intuitive, non-visual pathway. Inspired by this vision, here we trained rhesus monkeys and rats to detect and discriminate patterns of epidural SCS. Thereafter, we constructed psychometric curves describing the relationship between different SCS parameters and the animal's ability to detect SCS and/or changes in its characteristics. We found that the stimulus detection threshold decreased with higher frequency, longer pulse-width, and increasing duration of SCS. Moreover, we found that monkeys were able to discriminate temporally- and spatially-varying patterns (i.e. variations in frequency and location) of SCS delivered through multiple electrodes. Additionally, sensory discrimination of SCS-induced sensations in rats obeyed Weber's law of just-noticeable differences. These findings suggest that by varying SCS intensity, temporal pattern, and location different sensory experiences can be evoked. As such, we posit that SCS can provide intuitive sensory feedback in neuroprosthetic devices.

A Brain to Spine Interface for Transferring Artificial Sensory Information.

Lack of sensory feedback is a major obstacle in the rapid absorption of prosthetic devices by the brain. While electrical stimulation of cortical and subcortical structures provides unique means to deliver sensory information to higher brain structures, these approaches require highly invasive surgery and are dependent on accurate targeting of brain structures. Here, we propose a semi-invasive method, Dorsal Column Stimulation (DCS) as a tool for transferring sensory information to the brain. Using this new approach, we show that rats can learn to discriminate artificial sensations generated by DCS and that DCS-induced learning results in corticostriatal plasticity. We also demonstrate a proof of concept brain-to-spine interface (BTSI), whereby tactile and artificial sensory information are decoded from the brain of an "encoder" rat, transformed into DCS pulses, and delivered to the spinal cord of a second "decoder" rat while the latter performs an analog-to-digital conversion during a sensory discrimination task. These results suggest that DCS can be used as an effective sensory channel to transmit prosthetic information to the brain or between brains, and could be developed as a novel platform for delivering tactile and proprioceptive feedback in clinical applications of brain-machine interfaces.

Spinal cord stimulation and rehabilitation in an individual with chronic complete L1 paraplegia due to a conus medullaris injury: motor and functional outcomes at 18 months.

INTRODUCTION: Epidural electrical stimulation of the conus medullaris has helped facilitate native motor recovery in individuals with complete cervicothoracic spinal cord injuries (SCI). A theorized mechanism of clinical improvement includes supporting central pattern generators intrinsic to the conus medullaris. Because spinal cord stimulators (SCS) are approved for the treatment of neuropathic pain, we were able to test this experimental therapy in a subject with complete L1 paraplegia and neuropathic genital pain due to a traumatic conus injury. CASE PRESENTATION: An otherwise healthy 48-year-old male with chronic complete L1 paraplegia with no zones of partial preservation (ZPP) and intractable neuropathic genital pain presented to our group seeking nonmedical pain relief and any possible help with functional restoration. After extensive evaluation, discussion, and consent, we proceeded with SCS implantation at the conus and an intensive outpatient physical therapy regimen consistent with the recent SCI rehabilitation literature. DISCUSSION: Intraoperatively, no electromyography (EMG) could be elicited with epidural conus stimulation. At 18 months after implantation, his motor ZPPs had advanced from L1 to L5 on the left and from L1 to L3 on the right. Qualitative increases in lower extremity resting state EMG amplitudes were noted, although there was no consistent evidence of voluntary EMG or rhythmic locomotive leg movements. Three validated functional and quality of life (QoL) surveys demonstrated substantial improvements. The modest motor response compared to the literature suggests likely critical differences in the anatomy of such a low injury. However, the change in ZPPs and QoL suggest potential for neuroplasticity even in this patient population.

Improved Dysphagia Outcomes in Anchored Spacers Versus Plate-Screw Systems in Anterior Cervical Discectomy and Fusion: A Systematic Review.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To perform a systematic review of clinical outcomes between stand-alone anchored spacers and traditional cages with plate fixation for dysphagia and pseudoarthrosis using data from clinical trials. METHODS: Our search protocol was added to PROSPERO register and systematic review using PRISMA method was performed. Then, we systematically searched for studies addressing stand-alone anchored spacers in patients who underwent ACDF. Mean Neck Disability Index (NDI), dysphagia incidence % (Dinc%), and Swallowing-Quality of Life (SQOL) scores during preoperative, immediate postoperative and last follow-up visits were extracted. Chi-square and analysis of variance (ANOVA) tests were used for statistical comparisons (P ≤ .05). RESULTS: The initial search generated 506 articles in CENTRAL and 40 articles in MEDLINE. Finally, 14 articles were included. Total number of patients was 1173 (583 anchored stand-alone and 590 plate). Dinc% scores were statistically significantly lower in the stand-alone anchored spacer compared to the plate-screw construct (P ≤ .05). ANOVA showed no statistically significant difference in the comparisons of SQOL. On the other hand, NDI scores were statistically significantly lower in baseline of stand-alone anchored spacer and the plate-screw construct compared with both immediate postoperative and last follow-up visits (P ≤ .05). CONCLUSIONS: Our study results revealed that the stand-alone anchored spacers were associated with less dysphagia in the immediate and last follow-up.

A Closed Loop Brain-machine Interface for Epilepsy Control Using Dorsal Column Electrical Stimulation.

Although electrical neurostimulation has been proposed as an alternative treatment for drug-resistant cases of epilepsy, current procedures such as deep brain stimulation, vagus, and trigeminal nerve stimulation are effective only in a fraction of the patients. Here we demonstrate a closed loop brain-machine interface that delivers electrical stimulation to the dorsal column (DCS) of the spinal cord to suppress epileptic seizures. Rats were implanted with cortical recording microelectrodes and spinal cord stimulating electrodes, and then injected with pentylenetetrazole to induce seizures. Seizures were detected in real time from cortical local field potentials, after which DCS was applied. This method decreased seizure episode frequency by 44% and seizure duration by 38%. We argue that the therapeutic effect of DCS is related to modulation of cortical theta waves, and propose that this closed-loop interface has the potential to become an effective and semi-invasive treatment for refractory epilepsy and other neurological disorders.

Chronic spinal cord electrical stimulation protects against 6-hydroxydopamine lesions.

Although L-dopa continues to be the gold standard for treating motor symptoms of Parkinson's disease (PD), it presents long-term complications. Deep brain stimulation is effective, but only a small percentage of idiopathic PD patients are eligible. Based on results in animal models and a handful of patients, dorsal column stimulation (DCS) has been proposed as a potential therapy for PD. To date, the long-term effects of DCS in animal models have not been quantified. Here, we report that DCS applied twice a week in rats treated with bilateral 6-OHDA striatal infusions led to a significant improvement in symptoms. DCS-treated rats exhibited a higher density of dopaminergic innervation in the striatum and higher neuronal cell count in the substantia nigra pars compacta compared to a control group. These results suggest that DCS has a chronic therapeutical and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients.