Craig van Horne

Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinsons disease, controversy exists concerning the use of apomorphine- or D-amphetamine-induced rotations as reliable indicators of nigrostriatal dopamine depletion. Our objective was to evaluate which, if either, drug-induced behavior is more predictive of the extent of nigrostriatal dopamine depletion. Fischer 344 and Sprague-Dawley rats were unilaterally injected with 9 micrograms/4 microliters/4 min 6-hydroxydopamine into the medial forebrain bundle. The animals were behaviorally tested with apomorphine (0.05 mg/kg, s.c.) and D-amphetamine (5.0 mg/kg, s.c.). Following testing, the brains were removed and the right and left striata, substantia nigra and ventral tegmental area were dissected free and quickly frozen at -70 degrees C for analysis of catecholamine content by high performance liquid chromatography coupled with electrochemical detection. Our results indicate that an animal which has greater than a 90% depletion of dopamine in the striatum might not rotate substantially on apomorphine, without a concomitant depletion of > 50% of the DA content in the corresponding substantia nigra. No correlations were seen involving depletions of the ventral tegmental area and the extent of the lesions to the striatum. Submaximally lesioned (75-90% depleted) rats were found to rotate on D-amphetamine but not on apomorphine. In addition, control rats that did not receive lesions were often seen to rotate extensively on D-amphetamine. We therefore conclude that maximal lesions of the striatum and substantia nigra are required to generate rotations demonstrable with low dose apomorphine but not with D-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

In VivoMicrodialysis Studies of Somatodendritic Dopamine Release in the Rat Substantia Nigra: Effects of Unilateral 6-OHDA Lesions and GDNF ☆

Dopamine (DA) release and metabolism within the substantia nigra (SN) were studied in normal rats, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions, and 6-OHDA-lesioned rats treated with glial cells line-derived neurotrophic factor (GDNF). Animals with > 99% DA depletions, as determined by apomorphine-induced circling behavior, also showed significant deficits in several measures of spontaneous motor activity. In vivo microdialysis recordings in the SN were carried out in normal and unilaterally 6-OHDA-lesioned rats. Basal levels of DNA were detectable only in the dialysates of normal animals, and basal levels of t he primary DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were found to be significantly reduced in the SN of 6-OHDA-lesioned animals. In the presence of d-amphetamine, either alone or in combination with potassium, significant reductions in DA release were observed in the SN of 6-OHDA-lesioned animals compared to normal animals. Potassium-evoked DA release alone was not significantly different between the groups. A single intranigral administration of GDNF into 6-OHDA-lesioned animals elicited a significant reduction in apomorphine-induced rotation behavior and a significant increase in spontaneous motor activities. These behavioral changes were apparent at 1 week and persisted through 4 weeks following treatment. In vivo microdialysis showed that, although DA metabolism was altered 1 week following GDNF treatment, DA release was not significantly affected until 4 weeks following treatment.

Cognition and Depression Following Deep Brain Stimulation of the Subthalamic Nucleus and Globus Pallidus Pars Internus in Parkinson’s Disease: A Meta-Analysis

Parkinson’s disease (PD) is a common, degenerative disorder of the central nervous system. Individuals experience predominantly extrapyramidal symptoms including resting tremor, rigidity, bradykinesia, gait abnormalities, cognitive impairment, depression, and neurobehavioral concerns. Cognitive impairments associated with PD are diverse, including difficulty with attention, processing speed, executive functioning, memory recall, visuospatial functions, word-retrieval, and naming. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is FDA approved and has been shown to be effective in reducing motor symptoms of PD. Studies have found that stimulating STN and GPi are equally effective at improving motor symptoms and dyskinesias; however, there has been discrepancy as to whether the cognitive, behavioral, and mood symptoms are affected differently between the two targets. The present study used random-effects meta-analytic models along with a novel p-curve analytic procedure to compare the potential cognitive and emotional impairments associated with STN-DBS in the current literature to those associated with GPi-DBS. Forty-one articles were reviewed with an aggregated sample size of 1622 patients. Following STN-DBS, small declines were found in psychomotor speed, memory, attention, executive functions, and overall cognition; and moderate declines were found in both semantic and phonemic fluency. However, GPi-DBS resulted in fewer neurocognitive declines than STN-DBS (small declines in attention and small-moderate declines in verbal fluency). With regards to its effect on depression symptomatology, both GPi-DBS and STN-DBS resulted in lower levels of depressive symptoms post-surgery. From a neurocognitive standpoint, both GPi-DBS and STN-DBS produce subtle cognitive declines but appears to be relatively well tolerated.

Multichannel semiconductor-based electrodes for in vivo electrochemical and electrophysiological studies in rat CNS

Five-channel silicon-based microprobes were sputter-coated with carbon, coated with Nafion, and used for both in vivo electrochemical and single-unit electrophysiological recordings. High-speed electrochemical studies were performed in vitro and in vivo, which demonstrated that these multisite probes were capable of monitoring the evoked overflow of monoamines in selected brain regions of the rat. In addition, action potentials from Purkinje cells in the rat cerebellum, identified electrophysiologically, were recorded from different sites on the same probe. Spontaneous firing rates could be monitored for up to 2 hours in order to investigate the effects of systemic administration of phencyclidine. These results provide preliminary evidence that solid-state multi-site probes can be utilized for both in vivo electrochemical and electrophysiological studies in the rat brain.

Behavioral and electrophysiological correlates of human mesencephalic dopaminergic xenograft function in the rat striatum.

While human fetal xenografts placed into immunocompromised animal hosts have been shown to survive and grow, their ability to function and influence the host tissue has not been fully examined. Therefore, we implanted grafts of human fetal mesencephalic tissue intracranially into rats with unilateral 6-hydroxydopamine lesions of their nigrostriatal dopaminergic innervation and tested the rats behaviorally for reductions in apomorphine-induced rotations. The purpose of this study was to test the ability of these grafts to provide a functional reinnervation by comparing the behavioral changes with the morphology and presence of electrophysiologically active dopaminergic neurons within the graft and with firing rates of host striatal neurons. Adult Sprague-Dawley rats that had been unilaterally lesioned and that showed a stable two peak pattern of apomorphine-induced rotations received grafts of human fetal mesencephalic tissue placed directly into the lesioned striatum. These rats were then further tested each month for five months for reductions in their turning behavior. At 5 to 6 months postgrafting, electrophysiological recordings were made of cells within the graft and within the host striatum. The rats were then examined immunohistochemically to evaluate graft survival and extent of reinnervation of the host tissue. The rats receiving mesencephalic dopaminergic grafts demonstrated a 79% reduction in their apomorphine-induced rotations. Electrophysiological recordings revealed spontaneously active dopaminergic neurons within the graft as well as host striatal cell firing rates consistent with those of dopamine-innervated cells. Furthermore, immunohistochemical studies confirmed graft survival and revealed marked fiber outgrowth from the graft into and throughout the striatum. Taken together these findings provide evidence that grafts of human fetal mesencephalic tissue are able to produce behavioral improvements in lesioned animals which are associated with the presence of dopaminergic neurons within the graft and are consistent with normal host striatal cell activity levels.

Kidney cografts enhance fiber outgrowth from ventral mesencephalic grafts to the 6-OHDA-lesioned striatum, and improve behavioral recovery.

Recent studies have demonstrated the presence of many different neurotrophic factors in the developing and adult kidney. Due to its production of this mixture of neurotrophic factors, we wanted to investigate whether fetal kidney tissue could be beneficial for neuritic fiber growth and/or cell survival in intracranial transplants of fetal ventral mesencephalic tissue (VM). A retrograde lesion of nigral dopaminergic neurons was performed in adult Fischer 344 male rats by injecting 6-hydroxydopamine into the medial forebrain. The animals were monitored for spontaneous locomotor activity in addition to apomorphine-induced rotations once a week. Four weeks following the lesion, animals were anesthetized and embryonic day 14 VM tissue from rat fetuses was implanted stereotaxically into the dorsal striatum. One group of animals received a cograft of kidney tissue from the same embryos in the same needle track. The animals were then monitored behaviorally for an additional 4 months. There was a significant improvement in both spontaneous locomotor activity (distance traveled) and apomorphine-induced rotations with both single VM grafts and VM-kidney cografts, with the VM-kidney double grafts enhancing the motor behaviors to a significantly greater degree. Tyrosine hydroxylase (TH) immunohistochemistry and image analysis revealed a significantly denser innervation of the host striatum from the VM-kidney cografts than from the single VM grafts. TH-positive neurons were also significantly larger in the cografts compared to the single VM grafts. In addition to the dense TH-immunoreactive innervation, the kidney portion of cografts contained a rich cholinergic innervation, as evidenced from antibodies against choline acetyltransferase (ChAT). The striatal cholinergic cell bodies surrounding the VM-kidney cografts were enlarged and had a slightly higher staining density for ChAT. Taken together, these data support the hypothesis that neurotrophic factors secreted from fetal kidney grafts stimulated both TH-positive neurons in the VM cografts and cholinergic neurons in the host striatum. Thus, these factors may be combined for treatment of degenerative diseases involving both dopaminergic and cholinergic neurons.

Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

The proceedings of the 3rd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, imaging, and computational work on DBS for the treatment of neurological and neuropsychiatric disease. Significant innovations of the past year are emphasized. The Think Tanks contributors represent a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers, and members of industry. Presentations and discussions covered a broad range of topics, including policy and advocacy considerations for the future of DBS, connectomic approaches to DBS targeting, developments in electrophysiology and related strides toward responsive DBS systems, and recent developments in sensor and device technologies.

Ophthalmodynamometry for ICP prediction and pilot test on Mt. Everest.

BackgroundA recent development in non-invasive techniques to predict intracranial pressure (ICP) termed venous ophthalmodynamometry (vODM) has made measurements in absolute units possible. However, there has been little progress to show utility in the clinic or field. One important application would be to predict changes in actual ICP during adaptive responses to physiologic stress such as hypoxia. A causal relationship between raised intracranial pressure and acute mountain sickness (AMS) is suspected. Several MRI studies report that modest physiologic increases in cerebral volume, from swelling, normally accompany subacute ascent to simulated high altitudes.Objectives1) Validate and calibrate an advanced, portable vODM instrument on intensive patients with raised intracranial pressure and 2) make pilot, non-invasive ICP estimations of normal subjects at increasing altitudes.MethodsThe vODM was calibrated against actual ICP in 12 neurosurgical patients, most affected with acute hydrocephalus and monitored using ventriculostomy/pressure transducers. The operator was blinded to the transducer read-out. A clinical field test was then conducted on a variable data set of 42 volunteer trekkers and climbers scaling Mt. Everest, Nepal. Mean ICPs were estimated at several altitudes on the ascent both across and within subjects.ResultsPortable vODM measurements increased directly and linearly with ICP resulting in good predictability (r = 0.85). We also found that estimated ICP increases normally with altitude (10 ± 3 mm Hg; sea level to 20 ± 2 mm Hg; 6553 m) and that AMS symptoms did not correlate with raised ICP.ConclusionvODM technology has potential to reliably estimate absolute ICP and is portable. Physiologic increases in ICP and mild-mod AMS are separate responses to high altitude, possibly reflecting swelling and vasoactive instability, respectively.

Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinsons disease, essential tremor, Alzheimers disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this years international Think Tank, with a view toward current and near future advancement of the field.

Survival of Dopaminergic Neurons in Fetal-Tissue Grafts

The possibility of implanting tissue in the brains of patients with Parkinsons disease to alleviate motor deficits has been the focus of multiple international research efforts for the past severa...