This article discusses the relationship between the  Duke spinal cord 
implant research, DBS, and optogenetics research at Stanford
I only guessed at this relationship   - this article is a must-read

Ray

PD Studies Suggest Motor Cortex as Treatment Target

19 March 2009. According to a study in tomorrow's issue of Science, a spinal 
cord procedure less invasive than those that deliver epidural anesthesia can 
restore locomotion in two rodent models of Parkinson disease. The new work 
points to a possible safer alternative to deep brain stimulation (DBS), a 
somewhat risky PD treatment that works in some patients when drugs fail or 
produce nasty side effects. In today's ScienceXpress online, scientists 
apply a new optical tool to uncover surprising insight into the basis for 
DBS's therapeutic effects. Using pulses of light to systematically activate 
or inhibit specific cells within neural circuits, the technology could help 
fine-tune treatments for PD and for other brain stimulation-responsive 
conditions such as epilepsy.

Earlier this year, a large randomized trial (Weaver et al., 2009) backed DBS 
as a promising fallback option for PD patients who receive waning benefit 
from dopamine-boosting drugs. However, the surgical treatment-which relieves 
motor symptoms by sending electrical jolts to disrupted dopaminergic nerve 
circuits in the brain-carries procedure-related side effects that prevent 
widespread use in frail patients with advanced disease (see ARF related news 
story). Led by Miguel Nicolelis at Duke University Medical Center in Durham, 
North Carolina, first author Romulo Fuentes and colleagues have come up with 
a less invasive procedure that rescues motor function in two PD 
models-dopamine-depleted mice, and 6-hydroxydopamine (OHDA)-lesioned rats 
with dopaminergic neuron loss.

Curiously, inspiration for the new PD approach came from epilepsy studies 
done by Nicolelis's group years ago. Epileptic seizures are marked by 
low-frequency, synchronous firing of cortical neurons. Nicolelis and 
colleagues showed they could relieve seizure activity in rats by stimulating 
the trigeminal nerve, the cranial nerve that is responsible for facial 
sensation (Fanselow et al., 2000). It looked as though the nerve stimulation 
was "introducing some noise into the system," Nicolelis told ARF. "The cells 
were basically getting out of their rhythmic firing pattern." Later, while 
investigating disrupted neural activity in dopamine-transporter knockout 
mice, which develop PD-like motor symptoms (Costa et al., 2006), he found a 
striking parallel. "When I looked at the data we were getting in these 
animals, the patterns of brain activity resembled epileptic seizures," 
Nicolelis said.

Putting two and two together, his team initially tried stimulating the 
trigeminal nerve in PD animals. This restored facial movements but not other 
motor capabilities. To trigger more widespread benefit, the researchers took 
a leap and went for the large tactile nerves in the spinal cord. "When you 
stimulate these fibers, they have a very powerful effect on the cortex. They 
get cells to fire asynchronously," Nicolelis said (see image below). The 
stimulation dramatically improved motor function in mice with PD symptoms 
induced by a dopamine synthesis-blocking drug (?-methyl-para-tyrosine, or 
AMPT) and in 6-OHDA-lesioned rats that already had substantial loss of 
dopaminergic neurons. Furthermore, when given along with L-dopa injections 
to dopamine-transporter knockout mice, spinal cord stimulation lowered the 
effective L-dopa dose needed to relieve motor symptoms by 80 percent.

Zapped Back to Asynchrony
Standardized oscillatory brain activity of a parkinsonian mouse before (top) 
and after (bottom) spinal cord electrical stimulation. After stimulation, 
rhythmic activity of neurons in the low-frequency range dramatically 
decreases (blue, left side) while activity in the high-frequency range 
increases (red, right side). This shift in oscillatory activity corresponds 
to a desynchronization of big groups of neurons, a condition that is thought 
to favor or facilitate motor activity. Image credit: Romulo Fuentes

The new technique appears simpler and safer than DBS. "We are not invading 
the brain. We make a little hole in the vertebra and slide these paper-like 
electrodes onto the surface of the spinal cord," Nicolelis said. Because the 
target axons are large and carry no pain signals, he notes, patients should 
not feel much discomfort from the stimulation. Nicolelis said that clinical 
trials of the spinal cord procedure could begin as early as 2010, provided 
that the primate studies his group has planned for this year succeed.

Their findings in rodents suggest that targeting one spot on the spinal cord 
can influence the dynamics of entire circuits-not surprising, as "these 
fibers are very big and converse with many different areas of the brain," 
Nicolelis said. "We are probably having a bulk effect on the motor cortex 
and basal ganglia at the same time. Multiple pathways are being activated in 
a very particular way. That's the reason we think it works."

He admits, though, that not much is understood about what the procedure does 
at the cellular or molecular level. But even DBS, an accepted PD therapy for 
nearly a decade, has remained in large part a black box as far as mechanism. 
Put simply, "the puzzle with Parkinson's DBS is understanding what's really 
being done, and what is different in the brain as a result of what is done," 
said Karl Deisseroth of Stanford University School of Medicine, Palo Alto, 
California, in an interview with ARF.

To figure out which cells mediate the therapeutic effects of DBS, Deisseroth 
tweaked a set of optical tools his lab had previously developed to turn 
specific neuronal populations on or off using laser light. At the heart of 
this technology are microbial light-activated cation channels 
(channelrhodopsins) and chloride pumps (halorhodopsins) that can be targeted 
with cell type-specific promoters to reversibly stimulate or inhibit select 
CNS cells (Boyden et al., 2005; Zhang et al., 2008; Gradinaru et al., 2008). 
As described in a paper published online today in ScienceXpress, Deisseroth, 
first author Viviana Gradinaru, and colleagues have applied these 
optogenetic tools to examine brain activity in 6-OHDA-treated rats with 
PD-like motor deficits.

Activated by light carried through flexible 200-micrometer-wide fiber optics 
placed into target brain areas of freely moving animals (see image below), 
the system overcomes three features that make it hard to figure out how DBS 
works. For starters, DBS electrodes cannot distinguish between the many cell 
types intertwined and intermixed within a given brain region-everything gets 
zapped. Optogenetics, on the other hand, allows precise targeting of 
specific cells. A second problem with electrodes is that "you don't really 
know if you're turning on or turning off," Deisseroth said. To complicate 
matters further, electrical stimulation interferes with electrical 
recording. With optogenetics, however, "we can use light to stimulate and 
also use light to record," Deisseroth said. "That really allows us to see 
what's happening in the circuit and see what's going on in the affected 
brain tissue."

Switching Neurons On and Off
In a rat model of Parkinson disease, movement and motor skills can be at 
least partially restored by either stimulating or inhibiting particular 
regions of the rodents' brains with light. Stimulating axons that project to 
the subthalamic nucleus caused robust and consistent, though also 
reversible, therapeutic effects in the diseased rats. Image credit: Karl 
Deisseroth

Using lentiviruses carrying halorhodopsin or channelrhodopsin genes under 
the control of various promoters, the researchers systematically turned on 
or off different cell types in the rats' subthalamic nucleus (STN), the 
primary region targeted by DBS. "We didn't see any therapeutic effect, which 
was pretty much a shock," Deisseroth told ARF. Instead, the researchers saw 
motor improvement when they selectively stimulated axons projecting to the 
STN. "We were able to trace at least one possible source of those axons to 
the motor cortex, which is in the surface part of the brain," Deisseroth 
said. "This is pretty intriguing insight into brain circuitry. But even 
more, it may suggest that there could be therapies that are less invasive 
because they would target more accessible regions of the brain."
He believes his group's findings may have converged on the same mechanism 
that underlies the spinal cord stimulation reported by Nicolelis and 
colleagues. "The spinal cord is driven in part by the motor cortex. They may 
be recruiting the same cortical neurons that we proved were relevant in the 
optogenetics approach," Deisseroth said. "We implicated the motor cortex by 
directly showing that one could drive those cells and get a therapeutic 
benefit. Basically, all signs may be pointing to motor cortex."

Deisseroth hopes that optogenetics can guide the development of therapies 
that treat a broader range of symptoms than conventional DBS does. In a 
recent study comparing the two DBS target areas-STN and globus pallidus 
interna (GPI)-in 45 PD patients, researchers at the University of Florida, 
Gainesville, found that targeting the STN resulted in greater decline in 
verbal fluency and mood seven months after the DBS procedure. As shown in 
that study, published last week in the Annals of Neurology (Okun et al., 
2009), "DBS can have side effects. It can have incomplete efficacy in 
different patients," Deisseroth said. "Optogenetics will help us understand 
all that and design better treatments. We'll be able to understand which 
cell types contribute to the side effects, which ones contribute to 
efficacy, and the best way to drive each cell type."

Extending their optogenetics strategy to non-electrical cells, Deisseroth's 
group has developed related tools that use light to drive specific 
biochemical pathways. For a study published yesterday in Nature, first 
author Raag Airan and colleagues created hybrid membrane proteins by 
coupling the extracellular part of the light-sensing retinal protein 
rhodopsin with the intracellular portion of a G protein-coupled receptor. 
"The result is that you end up with a G protein-coupled receptor that's not 
activated by chemical anymore but instead by light," Deisseroth said. The 
researchers showed that these photoactivatable G protein signaling pathways 
could drive conditioned place preference in freely moving mice.-Esther 
Landhuis.

References:
Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA. Spinal Cord 
Stimulation Restores Location in Animal Models of Parkinson's Disease. 20 
March 2009. Science 323:1578-82.
Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K. Optical 
Deconstruction of Parkinsonian Neural Circuitry. 19 March 2009. 
ScienceXpress.
Airan RD, Thompson KR, Fenno LE, Bernstein H, Deisseroth K. Temporally 
precise in vivo control of intracellular signaling. 18 March 2009. Nature 
458:1-5.
Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Boweres D, Bova F, Suelter M, 
Jacobson CE 4th, Wang X, Gordon CW Jr, Zeilman P, Romrell J, Martin P, Ward 
J, Rodriguez RL, Foote KD. Cognition

Rayilyn Brown
Director AZNPF
Arizona Chapter National Parkinson Foundation
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