Method of Treating Parkinson\u27s Disease in Humans by Convection-Enhanced Infusion of Glial Cell-Line Derived Neurotrophic Factor to the Putamen

A method of treating Parkinson\u27s disease in humans is disclosed, wherein glial cell-line derive neurotrophic factor (GDNF) is chronically administered directly to one or both putamen of a human in need of treatment thereof via convection-enhanced infusion using at least one implantable pump and at least one catheter. In one aspect of the present invention the GDNF is infused directly into one or both putamen through one or more indwelling intraparenchymal multiport brain catheters connected to one or more implantable pumps wherein the flow rate is pulsed

Method of Treating Parkinson\u27s Disease in Humans by Convection-Enhanced Infusion of Glial Cell-Line Derived Neurotrophic Factor to the Putamen

A method of treating Parkinson\u27s disease in humans is disclosed, wherein glial cell-line derive neurotrophic factor (GDNF) is chronically administered directly to one or both putamen of a human in need of treatment thereof via convection-enhanced infusion using at least one implantable pump and at least one catheter. In one aspect of the present invention the GDNF is infused directly into one or both putamen through one or more indwelling intraparenchymal mutitiport brain catheters connected to one or more implantable pumps wherein the flow rate is pulsed

Amidated Dopamine Neuron Stimulating Peptides for CNS Dopaminergic Upregulation

The present invention relates to novel proteins, referred to herein as amidated glial cell line-derived neurotrophic factor (GDNF) peptides (or Amidated Dopamine Neuron Stimulating peptides (ADNS peptides) ), that are useful for treating brain diseases and injuries that result in dopaminergic deficiencies

Amidated Dopamine Neuron Stimulating Peptide Restoration of Mitochondrial Activity

The present invention relates to the use of novel proteins, referred to herein as amidated glial cell line-derived neurotrophic factor (GDNF) peptides (or “Amidated Dopamine Neuron Stimulating peptides (ADNS peptides)”), for treating brain diseases and injuries that result in dopaminergic deficiencies and mitochodrial dysfunction, e.g., reduced complex I enzyme activity

Disruption of Columnar and Laminar Cognitive Processing in Primate Prefrontal Cortex Following Cocaine Exposure

Prefrontal cortical activity in primate brain plays a critical role in cognitive processes involving working memory and the executive control of behavior. Groups of prefrontal cortical neurons within specified cortical layers along cortical minicolumns differentially generate inter- and intra-laminar firing to process relevant information for goal oriented behavior. However, it is not yet understood how cocaine modulates such differential firing in prefrontal cortical layers. Rhesus macaque nonhuman primates (NHPs) were trained in a visual delayed match-to-sample (DMS) task while the activity of prefrontal cortical neurons (areas 46, 8 and 6) was recorded simultaneously with a custom multielectrode array in cell layers 2/3 and 5. Animals were reinforced with juice for correct responses. The first half of the recording session (control) was conducted following saline injection and in the second half of the same session cocaine was administered. Prefrontal neuron activity with respect to inter- and intra-laminar firing in layers 2/3 and 5 was assessed in the DMS task before and after the injection of cocaine. Results showed that firing rates of both pyramidal cells and interneurons increased on Match phase presentation and the Match Response (MR) in both control and cocaine halves of the session. Differential firing under cocaine vs. control in the Match phase was increased for interneurons but decreased for pyramidal cells. In addition, functional\u27 interactions between prefrontal pyramidal cells in layer 2/3 and 5 decreased while intra-laminar cross-correlations in both layers increased. These neural recordings demonstrate that prefrontal neurons differentially encode and process information within and between cortical cell layers via cortical columns which is disrupted in a differential manner by cocaine: administration

Maternal separation affects dopamine transporter function in the Spontaneously Hypertensive Rat: An in vivo electrochemical study

<p>Abstract</p> <p>Background</p> <p>Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR) is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT) in ways that distinguish SHR from control rat strains.</p> <p>Methods</p> <p>SHR and control Wistar-Kyoto (WKY) rats were subjected to maternal separation for 3 hours per day from postnatal day 2 to 14. Rats were tested for separation-induced anxiety-like behaviour followed by <it>in vivo </it>chronoamperometry to determine whether changes had occurred in striatal clearance of dopamine by DAT. The rate of disappearance of ejected dopamine was used as a measure of DAT function.</p> <p>Results</p> <p>Consistent with a model for ADHD, SHR were more active than WKY in the open field. SHR entered the inner zone more frequently and covered a significantly greater distance than WKY. Maternal separation increased the time that WKY spent in the closed arms and latency to enter the open arms of the elevated plus maze, consistent with other rat strains. Of note is that, maternal separation failed to produce anxiety-like behaviour in SHR. Analysis of the chronoamperometric data revealed that there was no difference in DAT function in the striatum of non-separated SHR and WKY. Maternal separation decreased the rate of dopamine clearance (k_-1) in SHR striatum. Consistent with this observation, the dopamine clearance time (T100) was increased in SHR. These results suggest that the chronic mild stress of maternal separation impaired the function of striatal DAT in SHR.</p> <p>Conclusions</p> <p>The present findings suggest that maternal separation failed to alter the behaviour of SHR in the open field and elevated plus maze. However, maternal separation altered the dopaminergic system by decreasing surface expression of DAT and/or the affinity of DAT for dopamine, increasing the time to clear dopamine from the extracellular fluid in the striatum of SHR.</p

Neurometabolic and Electrophysiological Changes During Cortical Spreading Depolarization: Multimodal Approach Based on a Lactate-Glucose Dual Microbiosensor Arrays

Spreading depolarization (SD) is a slow propagating wave of strong depolarization of neural cells, implicated in several neuropathological conditions. The breakdown of brain homeostasis promotes significant hemodynamic and metabolic alterations, which impacts on neuronal function. In this work we aimed to develop an innovative multimodal approach, encompassing metabolic, electric and hemodynamic measurements, tailored but not limited to study SD. This was based on a novel dual-biosensor based on microelectrode arrays designed to simultaneously monitor lactate and glucose fluctuations and ongoing neuronal activity with high spatial and temporal resolution. In vitroevaluation of dual lactate-glucose microbiosensor revealed an extended linear range, high sensitivity and selectivity, fast response time and low oxygen-, temperature- and pH- dependencies. In anesthetized rats, we measured with the same array a significant drop in glucose concentration matched to a rise in lactate and concurrently with pronounced changes in the spectral profile of LFP-related currents during episodes of mechanically-evoked SD. This occurred along with the stereotypical hemodynamic response of the SD wave. Overall, this multimodal approach successfully demonstrates the capability to monitor metabolic alterations and ongoing electrical activity, thus contributing to a better understanding of the metabolic changes occurring in the brain following SD

Electrochemical Evaluation of a Multi-Site Clinical Depth Recording Electrode for Monitoring Cerebral Tissue Oxygen

The intracranial measurement of local cerebral tissue oxygen levels—PbtO2—has become a useful tool for the critical care unit to investigate severe trauma and ischemia injury in patients. Our preliminary work in animal models supports the hypothesis that multi-site depth electrode recording of PbtO2 may give surgeons and critical care providers needed information about brain viability and the capacity for better recovery. Here, we present a surface morphology characterization and an electrochemical evaluation of the analytical properties toward oxygen detection of an FDA-approved, commercially available, clinical grade depth recording electrode comprising 12 Pt recording contacts. We found that the surface of the recording sites is composed of a thin film of smooth Pt and that the electrochemical behavior evaluated by cyclic voltammetry in acidic and neutral electrolyte is typical of polycrystalline Pt surface. The smoothness of the Pt surface was further corroborated by determination of the electrochemical active surface, confirming a roughness factor of 0.9. At an optimal working potential of −0.6 V vs. Ag/AgCl, the sensor displayed suitable values of sensitivity and limit of detection for in vivo PbtO2 measurements. Based on the reported catalytical properties of Pt toward the electroreduction reaction of O2, we propose that these probes could be repurposed for multisite monitoring of PbtO2 in vivo in the human brain