Vibhor Krishna

Tractography‐Based Ventral Intermediate Nucleus Targeting: Novel Methodology and Intraoperative Validation

The ventral intermediate nucleus of the thalamus is not readily visible on structural magnetic resonance imaging. Therefore, a method for its visualization for stereotactic targeting is desirable.

Physiology of freezing of gait

Freezing of gait (FOG) is a common and debilitating, but largely mysterious, symptom of Parkinson disease. In this review, we will discuss the cerebral substrate of FOG focusing on brain physiology and animal models. Walking is a combination of automatic movement processes, afferent information processing, and intentional adjustments. Thus, normal gait requires a delicate balance between various interacting neuronal systems. To further understand gait control and specifically FOG, we will discuss the basic physiology of gait, animal models of gait disturbance including FOG, alternative etiologies of FOG, and functional magnetic resonance studies investigating FOG. The outcomes of these studies point to a dynamic network of cortical areas such as the supplementary motor area, as well as subcortical areas such as the striatum and the mesencephalic locomotor region including the pedunculopontine nucleus (PPN). Additionally, we will review PPN (area) stimulation as a possible treatment for FOG, and ponder whether PPN stimulation truly is the right step forward. Ann Neurol 2016;80:644–659

Spinal Cord Injury: How Can We Improve the Classification and Quantification of Its Severity and Prognosis?

The preservation of functional neural tissue after spinal cord injury (SCI) is the basis for spontaneous neurological recovery. Some injured patients in the acute phase have more potential for recovery than others. This fact is problematic for the construction of clinical trials because enrollment of subjects with variable recovery potential makes it difficult to detect effects, requires large sample sizes, and risks Type II errors. In addition, the current methods to assess injury and recovery are non-quantitative and not sensitive. It is likely that therapeutic combinations will be necessary to cause substantially improved function after SCI, thus we need highly sensitive techniques to evaluate changes in motor, sensory, autonomic and other functions. We review several emerging neurophysiological techniques with high sensitivity. Quantitative methods to evaluate residual tissue sparing after severe acute SCI have not entered widespread clinical use. This reduces the ability to correlate structural preservation with clinical outcome following SCI resulting in enrollment of subjects with varying patterns of tissue preservation and injury into clinical trials. We propose that the inclusion of additional measures of injury severity, pattern, and individual genetic characteristics may enable stratification in clinical trials to make the testing of therapeutic interventions more effective and efficient. New imaging techniques to assess tract injury and demyelination and methods to quantify tissue injury, inflammatory markers, and neuroglial biochemical changes may improve the evaluation of injury severity, and the correlation with neurological outcome, and measure the effects of treatment more robustly than is currently possible. The ability to test such a multimodality approach will require a high degree of collaboration between clinical and research centers and government research support. When the most informative of these assessments is determined, it may be possible to identify patients with substantial recovery potential, improve selection criteria and conduct more efficient clinical trials.

Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: A systematic review

Abstract Context There is considerable interest in translating laboratory advances in neuronal regeneration following spinal cord injury (SCI). A multimodality approach has been advocated for successful functional neuronal regeneration. With this goal in mind several biomaterials have been employed as neuronal bridges either to support cellular transplants, to release neurotrophic factors, or to do both. A systematic review of this literature is lacking. Such a review may provide insight to strategies with a high potential for further investigation and potential clinical application. Objective To systematically review the design strategies and outcomes after biomaterial-based multimodal interventions for neuronal regeneration in rodent SCI model. To analyse functional outcomes after implantation of biomaterial-based multimodal interventions and to identify predictors of functional outcomes. Methods A broad PubMed, CINHAL, and a manual search of relevant literature databases yielded data from 24 publications; 14 of these articles included functional outcome information. Studies reporting behavioral data in rat model of SCI and employing biodegradable polymer-based multimodal intervention were included. For behavioral recovery, studies using severe injury models (transection or severe clip compression (>16.9 g) or contusion (50 g/cm)) were categorized separately from those investigating partial injury models (hemisection or moderate-to-severe clip compression or contusion). Results The cumulative mean improvements in Basso, Beattie, and Bresnahan scores after biomaterial-based interventions are 5.93 (95% CI = 2.41 − 9.45) and 4.44 (95% CI = 2.65 – 6.24) for transection and hemisection models, respectively. Factors associated with improved outcomes include the type of polymer used and a follow-up period greater than 6 weeks. Conclusion The functional improvement after implantation of biopolymer-based multimodal implants is modest. The relationship with neuronal regeneration and functional outcome, the effects of inflammation at the site of injury, the prolonged survival of supporting cells, the differentiation of stem cells, the effective delivery of neurotrophic factors, and longer follow-up periods are all topics for future elucidation. Future investigations should strive to further define specific factors associated with improved functional outcomes in clinically relevant models.

Low-frequency Subthalamic Stimulation in Parkinson's Disease: Long- term Outcome and Predictors

BACKGROUND Parkinsons disease patients undergoing subthalamic nucleus deep brain stimulation (STN DBS) at standard frequency (>100 Hz) often develop gait impairment, postural instability and speech difficulties. Low frequency stimulation (<100 Hz, LFS) can improve such axial symptoms, but there are concerns that improvement may be transient. OBJECTIVE To identify long-term outcome and predictors of low-frequency subthalamic stimulation in Parkinsons disease. METHODS Through a chart review we identified 85 out of 324 STN DBS patients who received a trial of LFS and describe their characteristics and outcome predictors. RESULTS Patients were switched to LFS (<100 Hz) 3.8 ± 3.3 years after surgery. Most patients (64%) attained a subjective improvement of gait, speech or balance for 2.0 ± 1.9 years. Motor scores improved within the first year after the stimulation change and showed a slower progression over time when compared to patients switched back to high frequency stimulation. UPDRS III axial score on medication before surgery and the y-axis coordinate of the active contact were independent predictors of LFS retention. CONCLUSIONS This report provides evidence that the use of LFS yields an enduring benefit in a considerable percentage of patients who develop axial motor symptoms during conventional stimulation.

Surgical technique for spinal cord delivery of therapies: demonstration of procedure in gottingen minipigs.

This is a compact visual description of a combination of surgical technique and device for the delivery of (gene and cell) therapies into the spinal cord. While the technique is demonstrated in the animal, the procedure is FDA-approved and currently being used for stem cell transplantation into the spinal cords of patients with ALS. While the FDA has recognized proof-of-principle data on therapeutic efficacy in highly characterized rodent models, the use of large animals is considered critical for validating the combination of a surgical procedure, a device, and the safety of a final therapy for human use. The size, anatomy, and general vulnerability of the spine and spinal cord of the swine are recognized to better model the human. Moreover, the surgical process of exposing and manipulating the spinal cord as well as closing the wound in the pig is virtually indistinguishable from the human. We believe that the healthy pig model represents a critical first step in the study of procedural safety.

Neuromodulation for Epilepsy

Several palliative neuromodulation treatment modalities are currently available for adjunctive use in the treatment of medically intractable epilepsy. Over the past decades, a variety of different central and peripheral nervous system sites have been identified, clinically and experimentally, as potential targets for chronic, nonresponsive therapeutic neurostimulation. Currently, the main modalities in clinical use, from most invasive to least invasive, are anterior thalamus deep brain stimulation, vagus nerve stimulation, and trigeminal nerve stimulation. Significant reductions in seizure frequency have been demonstrated in clinical trials using each of these neuromodulation therapies.

The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson's disease

Dexmedetomidine (an alpha‐2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep‐brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesised that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analysed microelectrode recording (MER) data from patients with Parkinsons disease who underwent STN DBS. A ‘Dex bolus’ group (dexmedetomidine bolus prior to MER; 27 cells from seven patients) was compared with a ‘no sedation’ group (29 cells from 11 patients). We also performed within‐patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analysed using the Kaneoke–Vitek methodology and local field potential (LFP) oscillatory activity was also investigated. Dexmedetomidine was associated with a slight increase in firing rate (41.1 ± 9.9 vs. 34.5 ± 10.6 Hz, P = 0.02) but a significant decrease in burstiness (number of bursts, P = 0.02; burst index, P < 0.001; percentage of spikes in burst, P = 0.002) of dorsal but not ventral STN neurons. This was not associated with modulation of beta oscillations in the spike‐oscillations analysis(beta peak, P = 0.4; signal‐to‐noise ratio in the beta range for spikes and bursts, P = 0.3 and P = 0.5, respectively) and LFP analysis (Beta power, P = 0.17). As bursting pattern is often used to identify STN and guide electrode placement, we recommend that high‐dose dexmedetomidine should be avoided during DBS surgery.

High long-term symptomatic recurrence rates after Chiari-1 decompression without dural opening: A single center experience

OBJECTIVE We evaluated long-term outcomes of posterior fossa decompression (PFD) without duroplasty in consecutive patients with newly diagnosed Chiari-1 malformation. METHODS We searched the institutional database for all adult patients who underwent Chiari decompression between 1995 and 2007. PFD was offered to all consecutive patients with Chairi-1 malformation during this time period. We excluded patients who underwent re-exploration after initial Chiari-1 decompression elsewhere. Besides the demographic variables, presenting symptoms, neurological and radiographic findings the clinical records were studied for long-term outcomes specifically symptomatic improvement. We defined symptomatic improvement as resolution of all presenting symptoms including pain and/or neurological deficits at the last follow-up. The factors associated with symptom recurrence were also analyzed. RESULTS We identified 47 patients who underwent PFD for Chiari-1 malformation. Syringomyelia was noted in 36.2% of patients and the mean tonsilar herniation was 12.6mm. At a mean follow-up of 9.3 years, the symptomatic improvement rate was 60.6%. There were no operative complications. Repeat posterior fossa decompression was required for 31.9% patients with symptomatic recurrence at an average of 2.6 years after initial decompression. Fibrotic thickening overlying the dura mater was observed in one-third of these patients. CONCLUSIONS This case series reports low complication but high long-term symptomatic recurrence rates adults with symptomatic Chiari-1 malformation undergoing PFD.

Preliminary observations on the vasomotor responses to electrical stimulation of the ventrolateral surface of the human medulla

OBJECT Pulsatile arterial compression (AC) of the ventrolateral medulla (VLM) is hypothesized to produce the hypertension in a subset of patients with essential hypertension. In animals, a network of subpial neuronal aggregates in the VLM has been shown to control cardiovascular functions. Although histochemically similar, neurons have been identified in the retro-olivary sulcus (ROS) of the human VLM, but their function is unclear. METHODS The authors recorded cardiovascular responses to electrical stimulation at various locations along the VLM surface, including the ROS, in patients who were undergoing posterior fossa surgery for trigeminal neuralgia. This vasomotor mapping of the medullary surface was performed using a bipolar electrode, with stimulation parameters ranging from 5- to 30-second trains (20-100 Hz), constant current (1.5-5 mA), and 0.1-msec pulse durations. Heart rate (HR) and blood pressure (BP) were recorded continuously from baseline (10 seconds before the stimulus) up to 1 minute poststimulus. In 6 patients, 17 stimulation responses in BP and HR were recorded. RESULTS The frequency threshold for any cardiovascular response was 20 Hz; the stimulation intensity threshold ranged from 1.5 to 3 mA. In the first patient, all stimulation responses were significantly different from sham recordings (which consisted of electrodes placed without stimulations). Repeated stimulations in the lower ROS produced similar responses in 3 other patients. Two additional patients had similar responses to single stimulations in the lower ROS. Olive stimulation produced no response (control). Hypotensive and/or bradycardic responses were consistently followed by a reflex hypertensive response. Slight right/left differences were noted. No patient suffered short- or long-term effects from this stimulation. CONCLUSIONS This stimulation technique for vasomotor mapping of the human VLM was safe and reproducible. Neuronal aggregates near the surface of the human ROS may be important in cardiovascular regulation. This method of vasomotor mapping with measures of responses in sympathetic tone (microneurography) should yield additional data for understanding the neuronal network that controls cardiovascular functions in the human VLM. Further studies in which a concentric bipolar electrode is used to generate this type of vasomotor map should also increase understanding of the pathophysiological mechanisms of neurogenically mediated hypertension, and assist in the design of studies to prove the hypothesis that it is caused by pulsatile AC of the VLM.