Dennis A. Turner

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open‐label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).

Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial

BACKGROUND In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinsons disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. METHODS We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinsons disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4 × 10¹¹ vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinsons disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. RESULTS Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0·31 [SE 2·63], 95% CI -5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. INTERPRETATION Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. FUNDING Ceregene and Michael J Fox Foundation for Parkinsons Research.

Reactive astrocytes express the embryonic intermediate neurofilament nestin.

Nestin is a neurofilament protein expressed by the immediate precursors to neurons and glia in rats and humans. Nestin immunoreactivity in the rat CNS was studied following kainic acid (KA) hippocampal lesions. Numerous nestin positive cells within the KA lesion were confirmed to be reactive astrocytes by their immunoreactivity for glial fibrillary acidic protein (GFAP). The number of these cells decreased with time after the KA lesion and no astrocyte immunostaining for nestin was observed in control animals. A subset of nestin-positive cells in the ventricular subependymal region appeared to be radial glial cells, extending to cell body layers. Nestin is one of several embryonic markers expressed by reactive astrocytes, suggesting an embryonic reversion induced by the KA lesion, possibly to enhance functional recovery.

Age-related alterations in potentiation in the CA1 region in F344 rats

F344 rats of various ages (2-3 months, 15-16 months, and 24-25 months) were tested on a spatial memory task. The 15- and 24-month-old rat groups showed impaired acquisition and retention of the memory task, compared to the young animals. Extracellular field potential recordings in the CA1 region were subsequently performed in vitro, using hippocampal slices from both these tested rats and similar but untested F344 young and aged rats. Findings included: a) a positive correlation between baseline dendritic EPSP slope values and retention scores across age groups; b) a more rapid decay of both somatic and dendritic short-term potentiation in aged slices; c) decreased somatic but not dendritic long-term potentiation overall in aged slices, regardless of bath Mg2+ level; and d) decreased paired-pulse facilitation in slices from aged rats bathed in 4.0 mM Mg2+ media compared to young controls. These findings suggest an age-related alteration in both presynaptic and postsynaptic potentiation mechanisms, which may relate to the poor spatial memory acquisition and retention in the aged rats. These age-related differences point to substantial changes in neuronal signal processing capabilities and local circuit function in the hippocampus as a function of aging.

Ensemble recordings of human subcortical neurons as a source of motor control signals for a brain-machine interface

OBJECTIVE:Patients with severe neurological injury, such as quadriplegics, might benefit greatly from a brain-machine interface that uses neuronal activity from motor centers to control a neuroprosthetic device. Here, we report an implementation of this strategy in the human intraoperative setting to assess the feasibility of using neurons in subcortical motor areas to drive a human brain-machine interface. METHODS:Acute ensemble recordings from subthalamic nucleus and thalamic motor areas (ventralis oralis posterior [VOP]/ventralis intermediate nucleus [VIM]) were obtained in 11 awake patients during deep brain stimulator surgery by use of a 32-microwire array. During extracellular neuronal recordings, patients simultaneously performed a visual feedback hand-gripping force task. Offline analysis was then used to explore the relationship between neuronal modulation and gripping force. RESULTS:Individual neurons (n = 28 VOP/VIM, n = 119 subthalamic nucleus) demonstrated a variety of modulation responses both before and after onset of changes in gripping force of the contralateral hand. Overall, 61% of subthalamic nucleus neurons and 81% of VOP/VIM neurons modulated with gripping force. Remarkably, ensembles of 3 to 55 simultaneously recorded neurons were sufficiently information-rich to predict gripping force during 30-second test periods with considerable accuracy (up to R = 0.82, R2 = 0.68) after short training periods. Longer training periods and larger neuronal ensembles were associated with improved predictive accuracy. CONCLUSION:This initial feasibility study bridges the gap between the nonhuman primate laboratory and the human intraoperative setting to suggest that neuronal ensembles from human subcortical motor regions may be able to provide informative control signals to a future brain-machine interface.

An on-line archive of reconstructed hippocampal neurons

We have developed an on-line archive of neuronal geometry to encourage the use of realistic dendritic structures in morphometry and for neuronal modeling, located at web address www.neuro.soton.ac.uk. Initially we have included full three-dimensional representations of 87 neurons from the hippocampus, obtained following intracellular staining with biocytin and reconstruction using Neurolucida. The archive system includes a structure editor for correcting any departures from valid branching geometry and which allows simple errors in the digitisation to be corrected. The editor employs a platform-independent file format which enforces the constraints that there should be no isolated branches and no closed loops. It also incorporates software for interconversion between the archive format and those used by various neuronal reconstruction and modelling packages. The raw data from digitisation software can be included in the archive as well as edited reconstructions and any further information available. Cross-referenced tables and indexes are updated automatically and are sorted according to a number of fields including the cell type, contributor, submission date and published reference. Both the archive and the structure editor should facilitate the quantitative use of full three-dimensional reconstructions of neurons from the hippocampus and other brain regions.

Altered cortical visual processing in PD with hallucinations: An fMRI study

Objective: To compare fMRI activation during two visual stimulation paradigms in Parkinson disease (PD) subjects with chronic visual hallucinations vs PD patients who had never hallucinated. Methods: Twelve pairs of PD subjects, matched for age, PD duration, and dopaminergic drug exposure duration, participated in this study. The authors examined group differences in activation during stroboscopic (flashing) vs no visual stimulation and kinematic (apparent motion) vs stationary visual stimulation. Results: During stroboscopic stimulation, non-hallucinating PD subjects showed significantly greater activation in the parietal lobe and cingulate gyrus compared to hallucinating PD subjects. In contrast, the hallucinating subjects showed significantly greater activation in the inferior frontal gyrus and the caudate nucleus. During kinematic stimulation, non-hallucinating PD subjects showed significantly greater activation in area V5/MT, parietal lobe, and cingulate gyrus compared to hallucinating PD subjects. Hallucinating PD subjects showed significantly greater activation in the superior frontal gyrus. Conclusions: PD patients with chronic visual hallucinations respond to visual stimuli with greater frontal and subcortical activation and less visual cortical activation than non-hallucinating PD subjects. Shifting visual circuitry from posterior to anterior regions associated primarily with attention processes suggests altered network organization may play a role in the pathophysiology of visual hallucinations in PD.

Sustained release of nerve growth factor from biodegradable polymer microspheres.

Although grafted adrenal medullary tissue to the striatum has been used both experimentally and clinically in parkinsonism, there is a definite need to augment long-term survival. Infusion of nerve growth factor (NGF) or implantation of NGF-rich tissue into the area of the graft prolongs survival and induces differentiation into neural-like cells. To provide for prolonged, site-specific delivery of this growth factor to the grafted tissue in a convenient manner, we fabricated biodegradable polymer microspheres of poly(L-lactide)co-glycolide (70:30) containing NGF. Biologically active NGF was released from the microspheres, as assayed by neurite outgrowth in a dorsal root ganglion tissue culture system. Anti-NGF could block this outgrowth. An enzyme-linked immunosorbent assay detected NGF still being released in vitro for longer than 5 weeks. In vivo immunohistochemical studies showed release over a 4.5-week period. This technique should prove useful for incorporating NGF and other growth factors into polymers and delivering proteins and other macromolecules intracerebrally over a prolonged time period. These growth factor-containing polymer microspheres can be used in work aimed at prolonging graft survival, treating experimental Alzheimers disease, and augmenting peripheral nerve regeneration.

Age and Dose-Dependent Effects of Ethanol on the Induction of Hippocampal Long-Term Potentiation

Hippocampal long-term potentiation (LTP) is strongly associated with the acquisition of spatial memory and is attenuated by ethanol. Recent studies have shown that the inhibitory potency of ethanol against n-methyl-d-aspartate (NMDA) receptor-mediated synaptic activity is enhanced in hippocampal slices taken from juvenile rats compared to those taken from adults. In addition, ethanol has been reported to impair spatial memory acquisition at lower doses in adolescent rats compared to adults. We therefore hypothesized that the suppression of hippocampal LTP by ethanol would be more potent in hippocampal slices taken from adolescent rats compared to those taken from adults. The potency of ethanol against NMDA receptor-mediated LTP was assessed in area CA1 of hippocampal slices taken from adolescent (30 days old) and adult (90 days old) rats. In slices from adolescent rats, theta-burst stimulus trains reliably induced robust LTP in the absence of ethanol, but when the stimulus trains were presented in the presence of either 10 mM or 30 mM ethanol, LTP induction was significantly suppressed relative to controls. In contrast, there was no effect of these ethanol concentrations on the induction of LTP in hippocampal slices from adult rats. These observations indicate that ethanol suppresses LTP in the adolescent hippocampus at concentrations that do not affect than it suppresses in the adult slices, suggesting a much greater sensitivity to ethanol in adolescence.

Relative risks of ventriculostomy infection and morbidity

SummaryVentricular catheter placement is a common procedure for the management of increased intracranial pressure. Hypotheses regarding the etiology of infection of catheters center on two alternative assumptions: 1) contamination leading to infection occurs at the time of catheter insertion, implying that catheter duration has minimal effect on infection risk; and 2) infection of catheters derives from catheter contamination after insertion, suggesting that duration of catheter use may significantly affect infection risk.We have studied the relative complication rate of ventricular catheter insertions using a retrospective approach (n=161 patients and 253 catheter insertion procedures). The overall infection rate was 4.1%, but the daily infection hazard increased exponentially with time, to a maximum daily rate of 10.3% by day 6 of catheter insertion. This increasing risk appears most consistent with the second hypothesis. The risk of non-infectious complications was 5.6%, including hemorrhagic occurrences and misplacement severe enough to require a new catheter insertion. The daily hazard of infection approximately equalled the non-infectious risk of routine catheter replacement by day 5.Additional prospective data on the daily risk of CSF infection and the appropriateness of antibiotic prophylaxis either at the time of ventricular catheter insertion or continued through the catheters-presence may be required to both definitively identify which hypothesis of infection risk is correct and whether antibiotics can significantly ameliorate this risk.