Jonathan M. Bledsoe

Wireless instantaneous neurotransmitter concentration system-based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring - laboratory investigation

OBJECT In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. METHODS The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal model, the pig. RESULTS The WINCS, which is designed in compliance with FDA-recognized consensus standards for medical electrical device safety, successfully measured dopamine, glutamate, and adenosine, both in vitro and in vivo. The WINCS detected striatal dopamine release at the implanted CFM during DBS of the MFB. The DBS-evoked adenosine release in the rat thalamus and MCS-evoked glutamate release in the pig cortex were also successfully measured. Overall, in vitro and in vivo testing demonstrated signals comparable to a commercial hardwired electrochemical system for FPA. CONCLUSIONS By incorporating FPA, the chemical repertoire of WINCS-measurable neurotransmitters is expanded to include glutamate and other nonelectroactive species for which the evolving field of enzyme-linked biosensors exists. Because many neurotransmitters are not electrochemically active, FPA in combination with enzyme-linked microelectrodes represents a powerful intraoperative tool for rapid and selective neurochemical sampling in important anatomical targets during functional neurosurgery.

Development of the Wireless Instantaneous Neurotransmitter Concentration System for intraoperative neurochemical monitoring using fast-scan cyclic voltammetry: Technical note

OBJECT Emerging evidence supports the hypothesis that modulation of specific central neuronal systems contributes to the clinical efficacy of deep brain stimulation (DBS) and motor cortex stimulation (MCS). Real-time monitoring of the neurochemical output of targeted regions may therefore advance functional neurosurgery by, among other goals, providing a strategy for investigation of mechanisms, identification of new candidate neurotransmitters, and chemically guided placement of the stimulating electrode. The authors report the development of a device called the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for intraoperative neurochemical monitoring during functional neurosurgery. This device supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially and chemically resolved neurotransmitter measurements in the brain. METHODS The FSCV study consisted of a triangle wave scanned between -0.4 and 1 V at a rate of 300 V/second and applied at 10 Hz. All voltages were compared with an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single carbon fiber (r = 2.5 mum) into a glass capillary and pulling the capillary to a microscopic tip by using a pipette puller. The exposed carbon fiber (that is, the sensing region) extended beyond the glass insulation by approximately 100 microm. The neurotransmitter dopamine was selected as the analyte for most trials. Proof-of-principle tests included in vitro flow injection and noise analysis, and in vivo measurements in urethane-anesthetized rats by monitoring dopamine release in the striatum following high-frequency electrical stimulation of the medial forebrain bundle. Direct comparisons were made to a conventional hardwired system. RESULTS The WINCS, designed in compliance with FDA-recognized consensus standards for medical electrical device safety, consisted of 4 modules: 1) front-end analog circuit for FSCV (that is, current-to-voltage transducer); 2) Bluetooth transceiver; 3) microprocessor; and 4) direct-current battery. A Windows-XP laptop computer running custom software and equipped with a Universal Serial Bus-connected Bluetooth transceiver served as the base station. Computer software directed wireless data acquisition at 100 kilosamples/second and remote control of FSCV operation and adjustable waveform parameters. The WINCS provided reliable, high-fidelity measurements of dopamine and other neurochemicals such as serotonin, norepinephrine, and ascorbic acid by using FSCV at CFM and by flow injection analysis. In rats, the WINCS detected subsecond striatal dopamine release at the implanted sensor during high-frequency stimulation of ascending dopaminergic fibers. Overall, in vitro and in vivo testing demonstrated comparable signals to a conventional hardwired electrochemical system for FSCV. Importantly, the WINCS reduced susceptibility to electromagnetic noise typically found in an operating room setting. CONCLUSIONS Taken together, these results demonstrate that the WINCS is well suited for intraoperative neurochemical monitoring. It is anticipated that neurotransmitter measurements at an implanted chemical sensor will prove useful for advancing functional neurosurgery.

Accuracy of upper thoracic pedicle screw placement using three-dimensional image guidance

BACKGROUND CONTEXT Pedicle screw malposition rates using conventional techniques have been reported to occur with a frequency of 6% to 41%. The upper thoracic spine (T1-T3) is a challenging area for pedicle screw placement secondary to the small size of the pedicles, the inability to visualize this area with lateral fluoroscopy, and significant consequences for malpositioned screws. We describe our experience placing 150 pedicle screws in the T1-T3 levels using three-dimensional (3D) image guidance. PURPOSE The aim of this study was to assess the accuracy of 3D image guidance for placing pedicle screws in the first three thoracic vertebrae. STUDY DESIGN The accuracy of pedicle screw placement in the first three thoracic vertebrae was evaluated using postoperative thin-section computed tomography (CT) scans of the cervicothoracic region. PATIENT SAMPLE Thirty-four patients who underwent cervicothoracic fusion were included. OUTCOME MEASURES Radiological investigation with CT scans was performed during the postoperative period. METHODS Thirty-four consecutive patients underwent cervicothoracic instrumentation and fusion for a total of 150 pedicle screws placed in the first three thoracic vertebrae. All screws were placed using 3D image guidance. Medical records and postoperative imaging of the cervicothoracic junction for each patient were retrospectively reviewed. An independent radiologist reviewed the placement of the pedicle screws and assessed for pedicle breach. All cortical violations were reported as Grade 1, 0 to 2 mm; Grade 2, 2 to 4 mm; and Grade 3, greater than 4 mm. RESULTS Overall, 140 (93.3%) out of 150 screws were contained solely in the desired pedicle. All 10 pedicle violations were Grade 1. The direction of pedicle violation included three medial, four inferior, two superior, and one minor anterolateral vertebral body. No complication occurred as a result of screw placement or the use of image guidance. CONCLUSIONS Upper thoracic pedicle screw placement is technically demanding as a result of variable pedicle anatomy and difficulty with two-dimensional visualization. This study demonstrates the accuracy and reliability of 3D image guidance when placing pedicle screws in this region. Advantages of this technology in our practice include safe and accurate placement of spinal instrumentation with little to no radiation exposure to the surgeon and operating room staff.

Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy

Deep brain stimulation (DBS) provides therapeutic benefit for several neuropathologies, including Parkinson disease (PD), epilepsy, chronic pain, and depression. Despite well‐established clinical efficacy, the mechanism of DBS remains poorly understood. In this review, we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies (e.g., human electrometer and closed‐loop smart devices) for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.

Rheumatoid arthritis of the craniovertebral junction.

BACKGROUNDRheumatoid arthritis (RA) is the most common inflammatory disease involving the spine. It has a predilection for involving the craniocervical spine. Despite widespread involvement of the cervical spine with RA, few patients need surgery. The 3 major spinal manifestations of RA in the cervical spine are basilar invagination, atlantoaxial instability, and subaxial subluxations. Surgical management of RA involving the craniovertebral junction remains a challenge despite a decline in severe cases and an improvement in surgical techniques. METHODSWe conducted an exhaustive review of English-language publications discussing RA involving the craniovertebral junction. We paid special attention to publications detailing modern surgical management of these conditions. In addition, we outline our own surgical experience with such patients. RESULTSWe discuss alternative surgical methods for treating basilar invagination, atlantoaxial instability, and concurrent subaxial subluxations. We detail our surgical technique for transoral odontoidectomy, occipital cervical fusion, and atlantoaxial fusion. We detail the use of spinal surgical navigation in both of these procedures. CONCLUSIONSurgical management of RA remains a challenging field. There clearly has been a decrease in cases of mutilating RA involving the craniovertebral junction. Surgical techniques for managing these conditions have steadily improved.BACKGROUND Rheumatoid arthritis (RA) is the most common inflammatory disease involving the spine. It has a predilection for involving the craniocervical spine. Despite widespread involvement of the cervical spine with RA, few patients need surgery. The 3 major spinal manifestations of RA in the cervical spine are basilar invagination, atlantoaxial instability, and subaxial subluxations. Surgical management of RA involving the craniovertebral junction remains a challenge despite a decline in severe cases and an improvement in surgical techniques. METHODS We conducted an exhaustive review of English-language publications discussing RA involving the craniovertebral junction. We paid special attention to publications detailing modern surgical management of these conditions. In addition, we outline our own surgical experience with such patients. RESULTS We discuss alternative surgical methods for treating basilar invagination, atlantoaxial instability, and concurrent subaxial subluxations. We detail our surgical technique for transoral odontoidectomy, occipital cervical fusion, and atlantoaxial fusion. We detail the use of spinal surgical navigation in both of these procedures. CONCLUSION Surgical management of RA remains a challenging field. There clearly has been a decrease in cases of mutilating RA involving the craniovertebral junction. Surgical techniques for managing these conditions have steadily improved.

Radiosurgery for large-volume (> 10 cm3) benign meningiomas

OBJECT Stereotactic radiosurgery (SRS) has proven to be a safe and effective treatment for many patients with intracranial meningiomas. Nevertheless, the morbidity associated with radiosurgery of larger meningiomas is poorly understood. METHODS The authors performed a retrospective review of 116 patients who underwent SRS for meningiomas (WHO Grade I) > 10 cm3 between 1990 and 2007, with a minimum follow-up of 12 months. Patients with atypical or malignant meningiomas and those who received prior radiotherapy were excluded. The average tumor volume was 17.5 cm3 (range 10.1-48.6 cm3); the average tumor margin dose was 15.1 Gy (range 12-18 Gy); and the mean follow-up duration was 70.1 months (range 12-199 months). RESULTS Tumor control was 99% at 3 years and 92% at 7 years after radiosurgery. Thirty complications after radiosurgery were noted in 27 patients (23%), including 7 cases of seizures, 6 cases of hemiparesis, 5 cases of trigeminal injury, 4 cases of headaches, 3 cases of diplopia, 2 cases each of cerebral infarction and ataxia, and 1 case of hearing loss. Patients with supratentorial tumors experienced a higher complication rate compared with patients with skull base tumors (44% compared with 18%) (hazard ratio 2.9, 95% CI 1.3-6.7, p = 0.01). CONCLUSIONS The morbidity associated with SRS for patients with benign meningiomas > 10 cm(3) is greater for supratentorial tumors compared with skull base tumors. Whereas radiosurgery is relatively safe for patients with large-volume skull base meningiomas, resection should remain the primary disease management for the majority of patients with large-volume supratentorial meningiomas.

Wireless instantaneous neurotransmitter concentration sensing system (WINCS) for intraoperative neurochemical monitoring

The Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) measures extracellular neurotransmitter concentration in vivo and displays the data graphically in nearly real time. WINCS implements two electroanalytical methods, fast-scan cyclic voltammetry (FSCV) and fixed-potential amperometry (FPA), to measure neurotransmitter concentrations at an electrochemical sensor, typically a carbon-fiber microelectrode. WINCS comprises a battery-powered patient module and a custom software application (WINCSware) running on a nearby personal computer. The patient module impresses upon the electrochemical sensor either a constant potential (for FPA) or a time-varying waveform (for FSCV). A transimpedance amplifier converts the resulting current to a signal that is digitized and transmitted to the base station via a Bluetooth® radio link. WINCSware controls the operational parameters for FPA or FSCV, and records the transmitted data stream. Filtered data is displayed in various formats, including a background-subtracted plot of sequential FSCV scans — a representation that enables users to distinguish the signatures of various analytes with considerable specificity. Dopamine, glutamate, adenosine and serotonin were selected as analytes for test trials. Proof-of-principle tests included in vitro flow-injection measurements and in vivo measurements in rat and pig. Further testing demonstrated basic functionality in a 3-Tesla MRI unit. WINCS was designed in compliance with consensus standards for medical electrical device safety, and it is anticipated that its capability for real-time intraoperative monitoring of neurotransmitter release at an implanted sensor will prove useful for advancing functional neurosurgery.

Mechanisms of Action of Deep Brain Stimulation

Publisher Summary This chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.Publisher Summary This chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.

Intramedullary melanotic schwannoma.

We present a case of an intramedullary melanotic schwannoma (IMS) of the thoracic spinal cord. To our knowledge, this is the seventh reported case of an IMS of the central nervous system. Schwannomas are benign nerve sheath tumors of neural crest origin composed entirely of well differentiated Schwann cells that typically occur in peripheral nerves. Both the intramedullary location and the melanotic component of the reported lesion make it exceedingly rare. We will present our case, theories as to the origin of these tumors, clues in radiographic identification, and current clinical follow-up recommendations.

Mechanisms of Action of Deep Brain Stimulation: A Review

Publisher Summary This chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.Publisher Summary This chapter focuses on the five mechanisms of action of deep brain simulation (DBS), which have gained widest acceptance form the scientific community. These hypothesis include depolarization block hypothesis, synaptic modulation hypothesis, synaptic depression hypothesis, neural jamming/modulation hypothesis, and synaptic facilitation hypothesis. Depolarization block hypothesis originated from the observation that the clinical effects of DBS are similar to those of a surgical lesion suggesting that this type of stimulation acts by silencing neurons of the stimulated structure. The synaptic modulation hypothesis states that DBS activates neuronal elements that are in close proximity to the stimulating electrode, which results in local synaptic inhibition via activation of axonal terminals within the stimulated nuclei that release inhibitory neurotransmitters such as GABA. The synaptic depression hypothesis is related to the synaptic modulation hypothesis and it states that a neuron that is activated by DBS is unable to sustain high frequency action on efferent targets due to depletion of terminal vesicular stores of neurotransmitters. The neural jamming or modulation hypothesis states that DBS regulates and corrects pathological activity in the basal ganglia network. Understanding the fundamental principles of neural jamming requires a detailed knowledge of neuronal ionic conductances, as well as normal firing patterns within the thalamocortical basal ganglia network. According to the synaptic facilitation hypothesis, DBS results in the release of dopamine from surviving dopaminergic neurons projecting to the basal ganglia to contribute to the therapeutic action of STN HFS in PD patients.