Design and protocol for the decompression-plus trial: a phase 1 clinical study of dorsal myelotomy and expansive duroplasty with or without autologous nerve grafting in acute traumatic spinal cord injury.

Background: Traumatic spinal cord injury (tSCI) is a devastating condition marked by persistent neurologic deficits. Secondary injury processes following tSCI, including progressive hemorrhagic necrosis and elevated intraspinal pressure (ISP), contribute to ongoing neurologic deterioration. Existing therapeutic strategies have shown limited efficacy, emphasizing the critical need for innovative interventions.

Age-related differences in resting glutamate levels and glutamate uptake in the hippocampus and frontal cortex of C57BL/6 mice.

In normal aging, little is known in human and animal models about functional changes to glutamate neuronal systems that may contribute to age-related cognitive differences. The present studies investigated glutamate neuronal signaling in the hippocampus (dentate gyrus) and frontal cortex (infralimbic) of young adult (3-8 months), middle-aged (10-13 months), and aged (15-27 months) male and female C57BL/6 mice using microelectrode electrode array (MEA) recording technology to measure second-by-second resting levels of glutamate in anesthetized mice. Glutamate regulation was investigated in vivo by inhibiting the uptake of glutamate by local application of the competitive non-transportable blocker of excitatory amino acid transporters DL-threo-beta-benzyloxyaspartate (TBOA).

Two-year feasibility and safety of open-label autologous peripheral nerve tissue implantation during deep brain stimulation in patients with Parkinson's disease.

BackgroundMotor dysfunction in Parkinson's disease (PD) is characterized by a loss of functioning neurons in the substantia nigra. Two options exist when encountering damaged neurons: replace or support. We implemented a strategy of using autologous peripheral nerve tissue, in a reparative state, to provide a collection of neurorestorative support to unhealthy neurons with the goal of modifying the motor progression of PD.

Identification of cellular and noncellular components of mature intact human peripheral nerve.

Background And Aims: The goal of this study was to define basic constituents of the adult peripheral nervous system (PNS) using intact human nerve tissues.

Methods: We combined fluorescent and chromogenic immunostaining methods, myelin-selective fluorophores, and routine histological stains to identify common cellular and noncellular elements in aldehyde-fixed nerve tissue sections. We employed Schwann cell (SC)-specific markers, such as S100β, NGFR, Sox10, and myelin protein zero (MPZ), together with axonal, extracellular matrix (collagen IV, laminin, fibronectin), and fibroblast markers to assess the SC's relationship to myelin sheaths, axons, other cell types, and the acellular environment.

A Plant Model of -Synucleinopathy: Expression of -Synuclein A53T Variant in Hairy Root Cultures Leads to Proteostatic Stress and Dysregulation of Iron Metabolism.

Synucleinopathies, typified by Parkinson's disease (PD), entail the accumulation of -synuclein (Syn) aggregates in nerve cells. Various Syn mutants, including the Syn A53T variant linked to early-onset PD, increase the propensity for Syn aggregate formation. In addition to disrupting protein homeostasis and inducing proteostatic stress, the aggregation of Syn in PD is associated with an imbalance in iron metabolism, which increases the generation of reactive oxygen species and causes oxidative stress.

Recipient Reaction and Composition of Autologous Sural Nerve Tissue Grafts into the Human Brain.

Parkinson's disease (PD) is a severe neurological disease for which there is no effective treatment or cure, and therefore it remains an unmet need in medicine. We present data from four participants who received autologous transplantation of small pieces of sural nerve tissue into either the basal forebrain containing the nucleus basalis of Meynert (NBM) or the midbrain substantia nigra (SN). The grafts did not exhibit significant cell death or severe host-tissue reaction up to 55 months post-grafting and contained peripheral cells.

Amperometric bio-sensing of lactate and oxygen concurrently with local field potentials during status epilepticus.

Epilepsy is a prevalent neurological disorder with a complex pathogenesis and unpredictable nature, presenting limited treatment options in >30 % of affected individuals. Neurometabolic abnormalities have been observed in epilepsy patients, suggesting a disruption in the coupling between neural activity and energy metabolism in the brain. In this study, we employed amperometric biosensors based on a modified carbon fiber microelectrode platform to directly and continuously measure lactate and oxygen dynamics in the brain extracellular space.

Visualization of the Movement Disorder Society Unified Parkinson's Disease Rating Scale Results.

We sought to design a data visualization platform to represent the Movement Disorder Society- Unified Parkinson's Disease Rating Scale (MDS-UPDRS) item scores in an easy-to-use display without modification of the raw data or summary scores. Score items for Parts I, II, and IV were arranged as separate inline blocks, while Part III item blocks were arranged in an anatomical fashion. A color scale was created to represent symptom severity and changes observed from one exam to another.

Inhibition of monoamine oxidase-a increases respiration in isolated mouse cortical mitochondria.

Monoamine oxidase (MAO) is an enzyme located on the outer mitochondrial membrane that metabolizes amine substrates like serotonin, norepinephrine and dopamine. MAO inhibitors (MAOIs) are frequently utilized to treat disorders such as major depression or Parkinson's disease (PD), though their effects on brain mitochondrial bioenergetics are unclear. These studies measured bioenergetic activity in mitochondria isolated from the mouse cortex in the presence of inhibitors of either MAO-A, MAO-B, or both isoforms.

Transection injury differentially alters the proteome of the human sural nerve.

Regeneration after severe peripheral nerve injury is often poor. Knowledge of human nerve regeneration and the growth microenvironment is greatly lacking. We aimed to identify the regenerative proteins in human peripheral nerve by comparing the proteome before and after a transection injury.

Using a Transection Paradigm to Enhance the Repair Mechanisms of an Investigational Human Cell Therapy.

One promising strategy in cell therapies for Parkinson's disease (PD) is to harness a patient's own cells to provide neuroprotection in areas of the brain affected by neurodegeneration. No treatment exists to replace cells in the brain. Thus, our goal has been to support sick neurons and slow neurodegeneration by transplanting living repair tissue from the peripheral nervous system into the substantia nigra of those with PD.

In-vitro and in-vivo performance studies of a porous infusion catheter designed for intraparenchymal delivery of therapeutic agents of varying size.

Background: Limitations have previously existed for the use of brain infusion catheters with extended delivery port designs to achieve larger distribution volumes using convection-enhanced delivery (CED), due to poor transmittance of materials and uncontrolled backflow. The goal of this study was to evaluate a novel brain catheter that has been designed to allow for extended delivery and larger distribution volumes with limited backflow of fluid. It was characterized using a broad range of therapeutic pore sizes both for transmittance across the membranes to address possible occlusion and for distribution in short term infusion studies, both in-vitro in gels and in-vivo in canines.

Target-directed evolution of novel modulators of the dopamine transporter in Lobelia cardinalis hairy root cultures.

The dopamine transporter (DAT) is targeted in substance use disorders (SUDs), and "non-classical"" DAT inhibitors with low abuse potential are therapeutic candidates. Lobinaline, from Lobelia cardinalis, is an atypical DAT inhibitor lead. Chemical synthesis of lobinaline is challenging; thus, "target-directed evolution" was used for lead optimization.

Gait and Balance Changes with Investigational Peripheral Nerve Cell Therapy during Deep Brain Stimulation in People with Parkinson's Disease.

Background: The efficacy of deep brain stimulation (DBS) and dopaminergic therapy is known to decrease over time. Hence, a new investigational approach combines implanting autologous injury-activated peripheral nerve grafts (APNG) at the time of bilateral DBS surgery to the globus pallidus interna.

Objectives: In a study where APNG was unilaterally implanted into the substantia nigra, we explored the effects on clinical gait and balance assessments over two years in 14 individuals with Parkinson's disease.

Surgical methodology and protocols for preventing implanted cerebral catheters from becoming obstructed during and after neurosurgery.

Background: Convection Enhanced Delivery (CED) into targeted brain areas has been tested in animal models and clinical trials for the treatment of various neurological diseases.

New Method: We used a series of techniques, to in effect, maintain positive pressure inside the catheter relative to the outside, that included a hollow stylet, a high volume bolus of solution to clear the line, a low and slow continuous flow rate during implantation, and heat sealing the catheter at the time of implantation.

Results: 120 catheters implanted into brain parenchyma of 89 adult female rhesus monkeys across four sets of experiments.

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

The intracranial measurement of local cerebral tissue oxygen levels-PbtO-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 PbtO 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.

RNA Sequencing of Human Peripheral Nerve in Response to Injury: Distinctive Analysis of the Nerve Repair Pathways.

The development of regenerative therapies for central nervous system diseases can likely benefit from an understanding of the peripheral nervous system repair process, particularly in identifying potential gene pathways involved in human nerve repair. This study employed RNA sequencing (RNA-seq) technology to analyze the whole transcriptome profile of the human peripheral nerve in response to an injury. The distal sural nerve was exposed, completely transected, and a 1 to 2 cm section of nerve fascicles was collected for RNA-seq from six participants with Parkinson's disease, ranging in age between 53 and 70 yr.

Invited review: Utilizing peripheral nerve regenerative elements to repair damage in the CNS.

An ongoing question in neuroscience is how the peripheral nervous system can repair itself following an injury or insult whereas the central nervous system has a profoundly limited ability for repair. The recent and rapid advancement of our understanding of the gene expression and corresponding biochemical profiles of Schwann cells, within the distal segments of injured peripheral nerves, has helped elucidate the potential mechanisms underlying the unique ability for these cells to enable regeneration of peripheral nerve tissue. Meanwhile, with a new understanding and appreciation for the capabilities of the peripheral nervous system, we are beginning to unlock the potential for neural regeneration and repair within the central nervous system.

Modulation of epileptogenesis: A paradigm for the integration of enzyme-based microelectrode arrays and optogenetics.

Background: Genesis of acquired epilepsy includes transformations spanning genetic-to- network-level modifications, disrupting the regional excitatory/inhibitory balance. Methodology concurrently tracking changes at multiple levels is lacking. Here, viral vectors are used to differentially express two opsin proteins in neuronal populations within dentate gyrus (DG) of hippocampus.

Challenges of simultaneous measurements of brain extracellular GABA and glutamate in vivo using enzyme-coated microelectrode arrays.

Background: Although GABA is the major inhibitory neurotransmitter in the CNS, quantifying in vivo GABA levels has been challenging. The ability to co-monitor both GABA and the major excitatory neurotransmitter, glutamate, would be a powerful tool in both research and clinical settings.

New Method: Ceramic-based microelectrode arrays (MEAs) were used to quantify gamma-aminobutyric acid (GABA) by employing a dual-enzyme reaction scheme including GABase and glutamate oxidase (GluOx).

Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance.

In Parkinson's disease, degeneration of substantia nigra dopaminergic neurons is accompanied by damage on other neuronal systems. A severe denervation is for example seen in the locus coerulean noradrenergic system. Little is known about the relation between noradrenergic and dopaminergic degeneration, and the effects of noradrenergic denervation on the function of the dopaminergic neurons of substantia nigra are not fully understood.

Costs of Implementing Quality in Research Practice.

Using standardized guidelines in preclinical research has received increased interest in light of recent concerns about transparency in data reporting and apparent variation in data quality, as evidenced by irreproducibility of results. Although the costs associated with supporting quality through a quality management system are often obvious line items in laboratory budgets, the treatment of the costs associated with quality failure is often overlooked and difficult to quantify. Thus, general estimations of quality costs can be misleading and inaccurate, effectively undervaluing costs recovered by reducing quality defects.

GDNF revisited: A novel mammalian cell-derived variant form of GDNF increases dopamine turnover and improves brain biodistribution.

Parkinson's disease (PD) is a disorder affecting dopamine neurons for which there is no cure. Glial cell line-derived neurotrophic factor (GDNF) and the closely related protein neurturin are two trophic factors with demonstrated neuroprotective and neurorestorative properties on dopamine neurons in multiple animal species. However, GDNF and neurturin Phase-2 clinical trials have failed to demonstrate a significant level of improvement over placebo controls.