Abstract
P. D. Charles,* M. S. Remple,† C. H. Harrison,* T. L. Davis,*‡ C. E. Gill,§ M. J. Bliton,¶ M. G. Tramontana,# R. M. Salomon,# L. Wang,** F. T. Phibbs,* P. Hedera,* C. C. Kao,† J. S. Neimat,† and P. D. Konrad†
*Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
†Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, USA
‡Department of Neurology, Tennessee Valley VA Health Care System, Nashville, TN, USA
§Loyola University of Chicago Stritch School of Medicine, Maywood, IL, USA
¶Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
#Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA
**Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
Parkinson's disease (PD) affects over 4 million people worldwide. PD symptoms result from relentless destruction of nigral dopaminergic neurons, and current treatments do not cure or even slow disease progression. In humans with advanced PD, the subthalamic nucleus (STN) is hyperactive. In primates administered a toxin causing dopaminergic cell death, STN hyperactivity results, and bilateral STN deep brain stimulation (DBS) modifies this activity. We are leading a pilot trial of subthalamic DBS in 30 subjects with early stage PD to gather preliminary safety and tolerability information necessary to launch a large-scale multicenter trial. With approval from the Vanderbilt University IRB and an Investigational Device Exemption from the FDA, 30 subjects with early stage PD were enrolled from our clinic and through advertising. Inclusion criteria were subjects aged 50–75 years old with Hoehn and Yahr Stage II idiopathic PD who had been on PD medications greater than 6 months but less than 4 years, and were without motor fluctuations or dyskinesias. Exclusions included dementia, major psychiatric disease, or previous brain operation or injury. We report here the first evaluation of STN activity in eight subjects with early PD and compare these results to 8 age- and gender-matched controls with advanced PD. The early PD group included seven males and one female, aged 57.4 ± 1.1 years. The advanced PD group were eight age- and gender-matched patients with Hoehn and Yahr Stage ≥ III PD who were treated with DBS as standard of care. The Unified Parkinson's Disease Rating Scale (UPDRS-III) was 27.0 ± 3.1 off medication for the early PD patients, and 42.3 ± 4.0 for the advanced patients. Intraoperative microelectrode recording of firing rates and background activity was utilized during implantation to identify STN and surrounding nuclei. A subsequent analysis of the microelectrode recordings of the STN from both advanced and early PD patients for this study was conducted in a blinded fashion. When compared to the group with advanced PD, the STN firing rate and overall activity were significantly lower (28.7 vs. 38.5 Hz; p < 0.01 and 12.4 vs. 140 mV; p < 0.05, respectively). Based on the results of this preliminary analysis, the STN likely becomes more hyperactive as PD progression occurs. The first detailed analysis of basal ganglia neurophysiology in humans with early stage PD will provide important information about PD pathophysiology. The ongoing trial will also provide safety and tolerability data as well as the necessary preliminary clinical data to design a large-scale clinical trial to determine if DBS in early stage PD slows symptom progression and delays disability.
B. Lin,*† A. Koizumi,† N. Tanaka,‡ S. Panda,‡ and R. H. Masland†
*Department of Anatomy, The University of Hong Kong, Hong Kong
†Harvard Medical School, Boston, MA, USA
‡The Salk Institute for Biological Studies, La Jolla, CA, USA
The principal photoreceptors for image-forming vision in the retina are rod and cone cells. Loss of photoreceptor cells, as happens in a number of human diseases, such as retinitis pigmentosa and age-related macular degeneration, leads to irreversible blindness. Unfortunately, the current therapeutic treatment for retinal degeneration is very limited. Here, we asked whether it is possible to restore any vision by ectopic expression of melanopsin, a newly discovered light-sensitive photopigment, in the surviving ganglion cells. The protein melanopin is normally expressed in 2–3% of the ganglion cell population of the mouse retina. To test this intriguing possibility, we used a viral vector to express mammalian melanopsin in other retinal ganglion cells of rd/rd mice, which suffer an early degeneration of rod photoreceptors and a subsequent degeneration of cones. In each retina, melanopsin was expressed in up to 6,000 retinal ganglion cells, of many morphological types. Whole-cell patch-clamp recording showed intrinsic photoresponses in these cells, even after degeneration of the photoreceptors and additional pharmacological or Cd++ block of synaptic function. The newly melanopsin-expressing ganglion cells provided an enhancement of visual function in the rd/rd mice: the pupillary light reflex returned almost to normal; the mice showed behavioral avoidance of light in an open field test; and they could discriminate a light stimulus from a dark one in a two-choice visual discrimination alley. These results show that an effective signaling pathway for melanopsin is not restricted to the retinal ganglion cells that normally contain melanopsin, or to any particular ganglion cell type. Expression of this or other light-sensitive proteins in the surviving retinal neurons might provide some degree of vision for humans blind due to photoreceptor degeneration.