Michael P. Marsh

A carbon nanofiber based biosensor for simultaneous detection of dopamine and serotonin in the presence of ascorbic acid.

A biosensor based on an array of vertically aligned carbon nanofibers (CNFs) grown by plasma enhanced chemical vapor deposition is found to be effective for the simultaneous detection of dopamine (DA) and serotonin (5-HT) in the presence of excess ascorbic acid (AA). The CNF electrode outperforms the conventional glassy carbon electrode (GCE) for both selectivity and sensitivity. Using differential pulse voltammetry (DPV), three distinct peaks are seen for the CNF electrode at 0.13 V, 0.45 V, and 0.70 V for the ternary mixture of AA, DA, and 5-HT. In contrast, the analytes are indistinguishable in a mixture using a GCE. For the CNF electrode, the detection limits are 50 nM for DA and 250 nM for 5-HT.

Carbon nanofiber electrode array for electrochemical detection of dopamine using fast scan cyclic voltammetry

A carbon nanofiber (CNF) electrode array was integrated with the Wireless Instantaneous Neurotransmitter Concentration Sensor System (WINCS) for the detection of dopamine using fast scan cyclic voltammetry (FSCV). Dopamine detection performance by CNF arrays was comparable to that of traditional carbon fiber microelectrodes (CFMs), demonstrating that CNF arrays can be utilized as an alternative carbon electrode for neurochemical monitoring.

Deep brain stimulation induces BOLD activation in motor and non-motor networks: an fMRI comparison study of STN and EN/GPi DBS in large animals.

The combination of deep brain stimulation (DBS) and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. The goal of this study was to trace DBS-induced global neuronal network activation in a large animal model by monitoring the blood oxygenation level-dependent (BOLD) response on fMRI. We conducted DBS in normal anesthetized pigs, targeting the subthalamic nucleus (STN) (n=7) and the entopeduncular nucleus (EN), the non-primate analog of the primate globus pallidus interna (n=4). Using a normalized functional activation map for group analysis and the application of general linear modeling across subjects, we found that both STN and EN/GPi DBS significantly increased BOLD activation in the ipsilateral sensorimotor network (FDR<0.001). In addition, we found differential, target-specific, non-motor network effects. In each group the activated brain areas showed a distinctive correlation pattern forming a group of network connections. Results suggest that the scope of DBS extends beyond an ablation-like effect and that it may have modulatory effects not only on circuits that facilitate motor function but also on those involved in higher cognitive and emotional processing. Taken together, our results show that the swine model for DBS fMRI, which conforms to human implanted DBS electrode configurations and human neuroanatomy, may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS.

Wireless fast-scan cyclic voltammetry to monitor adenosine in patients with essential tremor during deep brain stimulation.

Essential tremor is often markedly reduced during deep brain stimulation simply by implanting the stimulating electrode before activating neurostimulation. Referred to as the microthalamotomy effect, the mechanisms of this unexpected consequence are thought to be related to microlesioning targeted brain tissue, that is, a microscopic version of tissue ablation in thalamotomy. An alternate possibility is that implanting the electrode induces immediate neurochemical release. Herein, we report the experiment performing with real-time fast-scan cyclic voltammetry to quantify neurotransmitter concentrations in human subjects with essential tremor during deep brain stimulation. The results show that the microthalamotomy effect is accompanied by local neurochemical changes, including adenosine release.

Nucleus Accumbens Deep Brain Stimulation Results in Insula and Prefrontal Activation: A Large Animal fMRI Study

Background Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model Methods Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 µsec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan Results We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation Conclusions Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS

Effect of Insulin on Oxidation of Intracellularly and Extracellularly Derived Glucose in Patients With NIDDM: Evidence for Primary Defect in Glucose Transport and/or Phosphorylation but Not Oxidation

Insulin-stimulated glucose oxidation is decreased in patients with non-insulin-dependent diabetes mellitus (NIDDM). It is not known whether this decrease is due to a primary defect in the oxidative pathway or is secondary to impaired glucose transport and/or phosphorylation. To address this issue, glucose oxidation was measured under steady-state conditions at low (∼270 pmol) and high (∼17 μmol) insulin concentrations in seven patients with NIDDM and seven healthy nondiabetic subjects matched for sex, age, and obesity. Glucose oxidation was measured simultaneously by indirect calorimetry and the isotopedilution technique. Although glucose oxidation and nonoxidative storage were lower (P < 0.05) in diabetic than nondiabetic subjects during the low- and highdose insulin infusions, oxidation of intracellularly derived glucose, estimated by subtracting the rate of oxidation measured isotopically (i.e., glucose oxidation derived from the extracellular space) from that measured by indirect calorimetry (i.e., total glucose oxidation), did not differ in diabetic and nondiabetic subjects during the low-dose insulin infusion (3.3 ± 0.1 vs. 3.0 ± 0.1 μmol · kg−1 · min−1). Both techniques provided identical estimates of glucose oxidation during the high-dose insulin infusion. Impaired oxidation of extracellularly but not intracellularly derived glucose strongly suggests that the cause of decreased glucose oxidation in patients with NIDDM is secondary to impaired glucose transport and/or phosphorylation rather than a primary abnormality in the oxidative pathway.

Centromedian-Parafascicular Deep Brain Stimulation Induces Differential Functional Inhibition of the Motor, Associative, and Limbic Circuits in Large Animals

BACKGROUND Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome. Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS. METHODS The combination of DBS and functional magnetic resonance imaging is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. With a within-subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n = 5). RESULTS Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS. CONCLUSIONS Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of Tourette syndrome as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.

Subthalamic Nucleus Deep Brain Stimulation Induces Motor Network BOLD Activation: Use of a High Precision MRI Guided Stereotactic System for Nonhuman Primates

BACKGROUND Functional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS). OBJECTIVE Identify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP). METHOD An in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling. RESULTS STN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001). CONCLUSION Our results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.

Significance of mildly elevated creatine kinase (myocardial band) activity after elective abdominal aortic aneurysmectomy

The clinical significance of mildly elevated creatine kinase (CK) myocardial band (MB) enzyme levels in patients undergoing elective repair of an abdominal aortic aneurysm was evaluated retrospectively in 348 patients. For each patient, preoperative and postoperative electrocardiograms (ECGs) were interpreted blindly for left ventricular hypertrophy, ST segment abnormality, left bundle branch block, right bundle branch block, left axis deviation, atrial fibrillation, T wave abnormality, and Q waves. A total of 107 patients (31%) had postoperative CK-MB elevations of trace or greater; 37 had trace, 35 had 1% to 4%, and 35 had greater than or equal to 5% elevation. There was no difference in survival between those with trace and no CK-MB elevation. Patients with increased CK-MB (greater than or equal to 1%) values were more likely to have ECG abnormalities. The following ECG (either preoperative or postoperative) abnormalities were univariately related to decreased postoperative survival: left ventricular hypertrophy (P less than 0.001), ST segment abnormalities (P less than 0.001), left bundle branch block (P less than 0.001), the combination of right bundle branch block and left axis deviation (P = 0.006), Q wave infarction (P less than 0.001), and atrial fibrillation (P less than 0.001). There were 15 in-hospital deaths, and 333 patients were discharged and followed-up for a median of 4.6 years. There were 97 posthospitalization deaths, 61% of which were due to cardiac causes. Overall survival was associated with the degree of CK-MB elevation; the higher the CK-MB, the worse the survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of Conductive Boron-Doped Diamond Electrode: A microscopic, Spectroscopic, and Voltammetric Study

Building on diamond characteristics such as hardness, chemical inertness and low electron emission threshold voltage, the current microscopic, spectroscopic and voltammetric investigations are directed towards improving the properties of electrode coating materials for their future use in clinical studies of deep brain stimulation via fast-scan cyclic voltammetry (FSCV). In this study we combine the capabilities of confocal Raman mapping in providing detailed and accurate analysis of local distributions of material constituents in a series of boron-doped polycrystalline diamond films grown by chemical vapor deposition, with information from the more conventional techniques of scanning electron microscopy (SEM) and infrared absorption spectroscopy. Although SEM images show a uniform distribution of film crystallites, they have the limitation of being unable to differentiate the distribution of boron in the diamond. Values of 1018–1021 atoms/cm3 of boron content have been estimated from the absorption coefficient of the 1290 cm−1 infrared absorption band and from the 500 cm−1 Raman vibration. The observed accumulation of boron atoms and carbon sp2 impurities at the grain boundaries suggests that very high doping levels do not necessarily contribute to improvement of the material’s conductivity, corroborating with voltammetric data. FSCV results also indicate an enhanced stability of analyte detection.