Moving Forward: Advances in the Treatment of Movement Disorders with Deep Brain Stimulation

The modern era of stereotactic and functional neurosurgery has ushered in state of the art technologies for the treatment of movement disorders, particularly Parkinson’s disease (PD), tremor, and dystonia. After years of experience with various surgical therapies, the eventual shortcomings of both medical and surgical treatments, and several serendipitous discoveries, deep brain stimulation (DBS) has risen to the forefront as a highly effective, safe, and reversible treatment for these conditions. Idiopathic advanced PD can be treated with thalamic, globus pallidus internus (GPi), or subthalamic nucleus (STN) DBS. Thalamic DBS primarily relieves tremor while GPi and STN DBS alleviate a wide range of Parkinsonian symptoms. Thalamic DBS is also used in the treatment of other types of tremor, particularly essential tremor, with excellent results. Both primary and various types of secondary dystonia can be treated very effectively with GPi DBS. The variety of anatomical targets for these movement disorders is indicative of the network-level dysfunction mediating these movement disturbances. Despite an increasing understanding of the clinical benefits of DBS, little is known about how DBS can create such wide sweeping neuromodulatory effects. The key to improving this therapeutic modality and discovering new ways to treat these and other neurologic conditions lies in better understanding the intricacies of DBS. Here we review the history and pertinent clinical data for DBS treatment of PD, tremor, and dystonia. While multiple regions of the brain have been targeted for DBS in the treatment of these movement disorders, this review article focuses on those that are most commonly used in current clinical practice. Our search criteria for PubMed included combinations of the following terms: DBS, neuromodulation, movement disorders, PD, tremor, dystonia, and history. Dates were not restricted

The Role of Functional Neuroanatomy of the Lumbar Spinal Cord in Effect of Epidural Stimulation

In this study, the neuroanatomy of the swine lumbar spinal cord, particularly the spatial orientation of dorsal roots was correlated to the anatomical landmarks of the lumbar spine and to the magnitude of motor evoked potentials during epidural electrical stimulation (EES). We found that the proximity of the stimulating electrode to the dorsal roots entry zone across spinal segments was a critical factor to evoke higher peak-to-peak motor responses. Positioning the electrode close to the dorsal roots produced a significantly higher impact on motor evoked responses than rostro-caudal shift of electrode from segment to segment. Based on anatomical measurements of the lumbar spine and spinal cord, significant differences were found between L1-L4 to L5-L6 segments in terms of spinal cord gross anatomy, dorsal roots and spine landmarks. Linear regression analysis between intersegmental landmarks was performed and L2 intervertebral spinous process length was selected as the anatomical reference in order to correlate vertebral landmarks and the spinal cord structures. These findings present for the first time, the influence of spinal cord anatomy on the effects of epidural stimulation and the role of specific orientation of electrodes on the dorsal surface of the dura mater in relation to the dorsal roots. These results are critical to consider as spinal cord neuromodulation strategies continue to evolve and novel spinal interfaces translate into clinical practice

Volatile diagnostic techniques for ventilator associated pneumonia

Ventilator associated pneumonia (VAP) is a significant challenge for the Intensive Care doctors worldwide. It is both difficult to diagnose accurately and quickly and to treat effectively once the diagnosis has been established. Current diagnostic microbiological methods of diagnosis can take up to 48 hours to yield results. Early diagnosis and treatment remain the best way of improving outcome for patients with VAP. In this study we look at novel diagnostic techniques for VAP. Electronic nose (Enose) technology was used to identify to identify the presence of microorganisms in bronchoalveolar lavage (BAL) fluid samples taken from the respiratory tracts of ventilated patients. The results were compared with standard microbiological culture and sensitivities. The Enose was able to discriminate 83% of samples into growth or no growth groups on samples grown in the lab. When the technique was employed to samples taken directly from patients the accuracy fell to 68.2%. This suggests that patient related factors may be reducing the accuracy of the Enose classification. The use of antimicrobial drugs prior to patient sampling is likely to have played a major role. The second part of this study used Gas Chromatography-Mass Spectrometry (GC-MS) analysis of patient’s breath in an attempt to identify patients with VAP. Breath samples were taken at the same time as the bronchoalveolar lavage samples described above. The use of this technique did show differences between the breath samples of patients who did not have any microbiological growth from their BAL samples and those that did. Leave one out cross validation of a PC fed LDA model showed 84% correct classification between healthy volunteers, no growth and growth groups. Finally, we evaluated the Breathotron, which is a breath analysis device designed and built at Cranfield Health. It allows for analysis of breath samples using a single sensor system as opposed to a sensor array employed in traditional Enose devices. This allows it to be more portable and cheaper to build. The Breathotron also allows collection of breath onto sorbent cartridges for GC-MS analysis. Its single sensor did not allow for accurate discrimination between samples.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Combat-Related Intradural Gunshot Wound to the Thoracic Spine: Significant Improvement and Neurologic Recovery Following Bullet Removal

The vast majority of combat-related penetrating spinal injuries from gunshot wounds result in severe or complete neurological deficit. Treatment is based on neurological status, the presence of cerebrospinal fluid (CSF) fistulas, and local effects of any retained fragment(s). We present a case of a 46-year-old male who sustained a spinal gunshot injury from a 7.62-mm AK-47 round that became lodged within the subarachnoid space at T9-T10. He immediately suffered complete motor and sensory loss. By 24-48 hours post-injury, he had recovered lower extremity motor function fully but continued to have severe sensory loss (posterior cord syndrome). On post-injury day 2, he was evacuated from the combat theater and underwent a T9 laminectomy, extraction of the bullet, and dural laceration repair. At surgery, the traumatic durotomy was widened and the bullet, which was laying on the dorsal surface of the spinal cord, was removed. The dura was closed in a water-tight fashion and fibrin glue was applied. Postoperatively, the patient made a significant but incomplete neurological recovery. His stocking-pattern numbness and sub-umbilical searing dysthesia improved. The spinal canal was clear of the foreign body and he had no persistent CSF leak. Postoperative magnetic resonance imaging of the spine revealed contusion of the spinal cord at the T9 level. Early removal of an intra-canicular bullet in the setting of an incomplete spinal cord injury can lead to significant neurological recovery following even high-velocity and/or high-caliber gunshot wounds. However, this case does not speak to, and prior experience does not demonstrate, significant neurological benefit in the setting of a complete injury

Electrophysiological Guidance of Epidural Electrode Array Implantation over the Human Lumbosacral Spinal Cord to Enable Motor Function after Chronic Paralysis.

Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis attributed to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in 2 human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating that array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first 5 days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI

Microvascular cerebral hemodynamics in pediatric sickle cell disease with Diffuse Correlation Spectroscopy

Sickle cell disease is a genetic blood disorder that has profound effects on the brain. Chronic anemia combined with both macro- and micro-vascular perfusion abnormalities that arise from stenosis or occlusion of blood vessels, increased blood viscosity, adherence of red blood cells to the vascular endothelium, and impaired autoregulatory mechanisms in sickle cell disease patients all culminate in susceptibility to cerebral infarction. Indeed, the risk of stroke is 250 times higher in children with sickle cell disease than in the general population. Unfortunately, while transcranial Doppler ultrasound (TCD) has been widely clinically adopted to longitudinally monitor macrovascular perfusion in these patients, routine clinical screening of microvascular perfusion abnormalities is challenging with current modalities (e.g., positron emission tomography, magnetic resonance imaging) given their high-cost, requirement for sedation in children \u3c 6y, and need for trained personnel. In this pilot study, we first assess the feasibility of a low-cost, noninvasive optical technique known as Diffuse Correlation Spectroscopy (DCS) to quantify an index of resting-state cortical cerebral blood flow in 11 children with SCD along with 11 sex- and age-matched healthy controls. As expected, blood flow index was significantly higher in sickle subjects compared to healthy controls (p \u3c 0.001). Within sickle subjects, blood flow index was inversely proportional to resting-state arterial hemoglobin levels (p = 0.012), consistent with expected anemia-induced compensatory vasodilation that aims to maintain adequate oxygen delivery to the tissue. Further, in a subset of patients measured with transcranial Doppler ultrasound, DCS-measured blood flow was correlated with TCD-measured blood flow velocity in middle cerebral artery (Rs = 0.68), although the trend was not statistically significant (p=0.11). These results are consistent with those of several previous studies using traditional neuroimaging techniques to quantify cerebral blood flow, suggesting that DCS may be a promising low-cost tool for assessment of tissue-level cerebral blood flow in pediatric sickle cell disease. Finally, given that sickle cell disease is often associated with severe anemia, we next assessed the potentially confounding effects of hematocrit on the DCS-measured blood flow index using a microfluidic tissue-simulating phantom. For a fixed flow rate in the microfluidic channels, we show that blood flow index is inversely correlated with hematocrit, and we present a means to correct the measured blood flow index for hematocrit in anemic conditions

Functional Ultrasound Imaging of Spinal Cord Hemodynamic Responses to Epidural Electrical Stimulation: A Feasibility Study

This study presents the first implementation of functional ultrasound (fUS) imaging of the spinal cord to monitor local hemodynamic response to epidural electrical spinal cord stimulation (SCS) on two small and large animal models. SCS has been successfully applied to control chronic refractory pain and recently was evolved to alleviate motor impairment in Parkinson's disease and after spinal cord injury. At present, however, the mechanisms underlying SCS remain unclear, and current methods for monitoring SCS are limited in their capacity to provide the required sensitivity and spatiotemporal resolutions to evaluate functional changes in response to SCS. fUS is an emerging technology that has recently shown promising results in monitoring a variety of neural activities associated with the brain. Here we demonstrated the feasibility of performing fUS on two animal models during SCS. We showed in vivo spinal cord hemodynamic responses measured by fUS evoked by different SCS parameters. We also demonstrated that fUS has a higher sensitivity in monitoring spinal cord response than electromyography. The high spatial and temporal resolutions of fUS were demonstrated by localized measurements of hemodynamic responses at different spinal cord segments, and by reliable tracking of spinal cord responses to patterned electrical stimulations, respectively. Finally, we proposed optimized fUS imaging and post-processing methods for spinal cord. These results support feasibility of fUS imaging of the spinal cord and could pave the way for future systematic studies to investigate spinal cord functional organization and the mechanisms of spinal cord neuromodulation in vivo

Iron abundances of B-type post-Asymptotic Giant Branch stars in globular clusters: Barnard 29 in M 13 and ROA 5701 in omega Cen

High resolution optical and ultraviolet spectra of two B-type post-Asymptotic Giant Branch (post-AGB) stars in globular clusters, Barnard 29 in M 13 and ROA 5701 in omega Cen, have been analysed using model atmosphere techniques. The optical spectra have been obtained with FEROS on the ESO 2.2-m telescope and the 2d-Coud\'e spectrograph on the 2.7-m McDonald telescope, while the ultraviolet observations are from the GHRS on the HST. Abundances of light elements (C, N, O, Mg, Al and S) plus Fe have been determined from the optical spectra, while the ultraviolet data provide additional Fe abundance estimates from Fe III absorption lines in the 1875-1900 {\AA} wavelength region. A general metal underabundance relative to young B-type stars is found for both Barnard 29 and ROA 5701. These results are consistent with the metallicities of the respective clusters, as well as with previous studies of the objects. The derived abundance patterns suggest that the stars have not undergone a gas-dust separation, contrary to previous suggestions, although they may have evolved from the AGB before the onset of the third dredge-up. However, the Fe abundances derived from the HST spectra are lower than those expected from the metallicities of the respective clusters, by 0.5 dex for Barnard 29 and 0.8 dex for ROA 5701. A similar systematic underabundance is also found for other B-type stars in environments of known metallicity, such as the Magellanic Clouds. These results indicate that the Fe III ultraviolet lines may yield abundance values which are systematically too low by typically 0.6 dex and hence such estimates should be treated with caution.Comment: 15 pages, 3 figures. Accepted for publication in MNRA