Tag Archives: retina

Interfacing with the nervous system: Studies in mice and rats show the way.

As fundamental scientific knowledge about how the nervous system works has increased over the past few decades, the possibility has emerged that we may one day be able to use electrical stimulation (or inhibition) to treat – even to functionally cure – conditions where it has been damaged by disease or injury.  Scientists are now working hard to make this dream a reality, indeed we have recently discussed the role of animal research in developing deep brain stimulation to treat Parkinson’s disease, and in the work being done to enable quadriplegic patients to operate robotic limbs, and even to restore voluntary control of their own limbs.

But these are not the only examples of how animal research is advancing the use of neural interfaces in medicine, today Nature News carries two articles on how groundbreaking research is paving the way for advances in optical prosthesis and the treatment of epilepsy.

Recent years have seen a number of innovative treatments for different types of blindness move from the lab to the clinic, including monoclonal antibodies, gene therapy and embryonic stem cells, Another approach that has been studied in patients for some time, and which may be useful in patients whose retina is too badly damaged to benefit from the techniques mentioned above,  is the use of neural prosthesis which replace damaged photoreceptor cells in the retina and directly stimulate the optic nerve, an approach discussed by Speaking of Research committee member Dario Ringach on his blog in 2010.

A prosthetic retina that can translate an image into neural signals was tested using a picture of a baby’s face. A is the original image. B is the image after it passes through the coding software. C is after it has been processed by the mouse retinal ganglion cells. D is the processed image without coding. Credit: Sheila Nirenberg, Nirenberg, S. & Pandarinath, C. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1207035109 (2012).

Nature news reports that scientists at Cornell University have solved one of the greatest challenges facing this technology, how to encode the electrical signal so that the light hitting the prosthesis is turned into a signal that the brain can understand. This problem has meant that current retinal prosthesis only allow patients to discern edges or lines, but not to be able to see movement or recognize faces. Now Sheila Nirenberg and her colleagues report the development of a code that enables mice that are blind due to severe retinal degeneration to see with far greater acuity than was possible with earlier prosthesis, the Nature News article noting that:

After receiving the encoded input, the mice were able to track moving stripes, something that they hadn’t been able to do before. The pair then looked at the neural signals that the mice were producing and used a different, ‘untranslate’, code to figure out what the brain would have been seeing. The encoded image was clearer and more recognizable than the non-encoded one”

It’s an exciting discovery that combines advanced visual prosthetic technology – which converted the light into a pattern that the brain can understand –  and genetic modification to introduce the Channelrhodopsin-2 gene into the retinal ganglion cells of the optic nerve, thus enabling them to respond to the light pattern emitted by the prosthetic and pass it to the brain. They hope to take into clinical trials in the near future, and may well do so as variations on the techniques required for this approach – including gene therapy of the eye – are already well developed, and several have already proven successful when evaluated in human patients.

The second item in Nature news is a very interesting discussion of the potential to use of a different technology – transcranial electrical stimulation (TES) – to stimulate neurons using electrodes implanted in the skull of epilepsy patients. Deep Brain Stimulation has been used to treat patients with epilepsy who don’t respond to anti-epileptic drugs, but while it has proven to be effective in many cases its use has been limited by the risks inherent in the surgery required to implant the electrodes, and the side effects due to the electrodes being continually on.

In an article published this week in the journal Science, György Buzsáki and colleagues at the New York University School of Medicine reported the development of a TES implant that was able to detect epileptic seizures in rats and then turn on to limit the reduce the duration of the seizure. Dr. Buzsáki and his colleagues have so far only studies this technique in “petit mal” or absence seizures, and are now planning to study its effectiveness for other types of epileptic seizures, but the potential of an electrostimulation technique that can control epileptic seizures but requires less invasive surgery than DBS and turns on only when requires is great.

All in all, they are two articles that highlight both the advances being made in this field, and how those advances depend on animal research.

Paul Browne

Understanding migraines: The blind leading the…err…rats

Chances are that you have either suffered from migraine yourself or have a family member or close friend who have, after all about 1 in 8 of us will suffer from migraine at some stage in our lifetime, and some sufferers experience repeated debilitating episodes over many years . While headache on one side of the brain is typical other symptoms such as nausea are very common, indeed in some migraine victims nausea is the primary symptom of the disorder.  Through a combination of studies in animals and clinical research using techniques such as fMRI and PET scans scientists have learned a lot in recent years about what happens before and during migraine episodes but we do not yet fully understand what ultimately causes the attacks, and debate rages over the relative importance of some mechanisms originating deep in brain regions such as the hypothalamus and others that start in membranes that surround the brain, (1,2).  Current treatments can help prevent migraine, reduce suffering and hasten recovery they do not work for all patients, and a better understanding of what exactly is happening before and during a migraine attack will aid the development of really effective treatments and preventative measures.  A study published in Nature Neuroscience combines clinical research with studies of rats to provide clues about a key characteristic of migraines that has until now remained unexplained, the exacerbation of the pain experienced by sufferers by light (3).

The team, lead by Rami Burnstein of Beth Israel Deaconess Medical Centre in Boston, decided to concentrate of the role of a particular subset of nerve cells in the retina known as intrinsically photosensitive retinal ganglion cells (ipRGCs) which they knew from previous mouse research to be involved in eye functions that are not image forming, such as setting the biological clock to the day night cycle.  The ipRGCs are stimulated by light both indirectly via the rods and cones and directly through a pigment called melanopsin that they themselves contain.  In order to discover if the ipRCGs are important to light sensitivity in migraine they performed a very neat clinical study involving 20 blind patients who also suffered from migraine. Six of these patients lacked any light perception due to removal of their eyes or damage to the optic nerve, while in the remaining 14 the damage to the eyes was less total, affecting the rods and cones but not ipRGCs, so that while they were unable to see images they could detect light. The results were clear, blue and grey light made the headaches of those who retained light sensitivity worse, while having no effect on the six blind individuals who lacked light perception.

Determining that the ipRGCs are involved in the exacerbation of migraine headaches by light is of course only part of the story, and Professor Burnstein’s team next turned to tracing the nerve pathways that are responsible for the increased pain, knowledge that might help to develop new treatments.  This they could not do in human subjects because the available imaging techniques do not have the precision to determine the connections between individual neurons.  In a series of studies they injected labels including Green Fluorescent Protein into particular areas of the eyes and brain, and in some cases even individual nerve cells, of anesthetized rats with and followed the path of the neurons.  They were also able to use tiny electrodes to record the effect of light on the firing of individual nerves in the brain, something that cannot yet be done in human subjects. An exciting observation was that the ipRCGs connected to cells in a region of the brain known as the posterior thalamus, itself part of the trigeminovascular pathway that is strongly implicated in migraine headache through transmission of nerve signals from the irritated outer brain membranes to the deep brain. When they examined the electrical activity of these cells they discovered that the majority of the cells within the posterior thalamus that are involved in mediating migraine pain are also light sensitive.  Finally they demonstrated that the light-sensitive pain-mediating neurons of the posterior hypothalamus connect to nerve cells in several regions of the somatosensory region of the cortex, an intriguing discovery since abnormalities in this region have previously been seen in migraine patients. This discovery is likely to encourage scientists to study the role of the somatosensory cortex in migraine in more detail.

So how important is this study? Well it’s unlikely that this discovery will lead to any treatment breakthrough in the immediate future, though the discovery that grey light can exacerbate migraine headache is new and may help patients to avoid it.  Despite a perhaps natural tendency for the news media to look for “breakthroughs” the majority of scientific papers published are like this one, providing valuable new insights into biology that contribute to our overall understanding of how biological systems work and happens when they go awry but not indicating an easy fix.  I’ve no doubt that this and many similar basic science studies will contribute to better treatments for migraine in the future, but perhaps not tomorrow!

Regards

Paul Browne

1)      Olesen J. et al “Origin of pain in migraine:evidence for peripheral sensitization” The Lancet Neurology Volume 8, Issue 7, Pages 679-690 (2009) doi:10.1016/S1474-4422(09)70090-0

2)      Alstadhaug K.B.  “Migraine and the hypothalamus” Cephalalgia Volume 29, Issue 8, Pages 809-817 doi: 10.1111/j.1468-2982.2008.01814.x

3)      Noseda R. et al. “A neural mechanism for exacerbation of headache by light” Nature neuroscience Advance Publication Online 10 January 2010 doi: 10.1038/nn.2475

Blind Dogs Lead Researchers to Treatments

Leber’s congenital amaurosis (LCA) is a form of blindness that affects about 1 in 80,000 people.  This inherited disease, in which the retina progressively degenerates, results in severe loss of vision, and frequently patients can only see well enough to count fingers or see bright lights.  Unfortunately, many of these patients also experience eye pain from bright lights.  LCA is caused by mutations in a number of genes, including the RPE65 gene.  Currently, there is no treatment for this disease but clinical trials using gene therapy have recently shown some promise.

Today, Lancelot (shown) continues to see well after a single gene therapy treatment in 2000. Credit: Foundation Fighting Blindness.

Today, Lancelot (shown) continues to see well after a single gene therapy treatment in 2000. Credit: Foundation Fighting Blindness.

The ability to deliver a gene using viral gene therapy was successfully demonstrated in rats and mice in the 1990’s.  Given these technical capabilities, it seemed that LCA might be a good target for gene therapy – delivery of the vector to the small space below the retina could deliver a normal copy of the gene exactly where it is needed.  The next question was, could vision loss be prevented in animal models of LCA?   Briards, a type of sheepdog, are predisposed to blindness, and genetic testing showed they often have mutations in RPE65, just like LCA patients.  Delivery of RPE65 using viral gene therapy to these afflicted dogs gave encouraging results:  the dogs had improved vision as shown by their electroretinograms and their ability to navigate obstacle courses in dim light (Acland et al., 2001).

Now, a report in the Human Gene Therapy and a commentary appearing in both the New England Journal of Medicine and Scientific American highlight a Phase 1 clinical trial to treat LCA using viral delivery of a normal copy of RPE65(Cideciyan et al., 2009).  Within weeks of receiving the vector, all three patients could detect dim light, a task they could not previously do.  Importantly, these visual improvements were still apparent 1 year after treatment. Phase 1 clinical trials are specifically designed to test safety of a treatment and to date, viral gene delivery of RPE65 has passed this test.  These three patients have not developed an immune response to the viral delivery system, a critical aspect for efficacy and safety of the treatment.

Studies in animals are also helping to clarify how and when the treatment will be effective. An important consideration is that people or animals need to have a good number of retinal cells left if the gene therapy is to be effective:  this treatment only works before retinal degeneration has progressed too far.  The patients in the clinical trials were adults with some intact photoreceptors, however most LCA patients lose photoreceptors in early childhood.  Studies using mice or dogs of various ages have shown promising results indicating that the younger the animal is treated, they more effective treatment is (Dejneka et al., 2004) .  Consequently, early intervention, before extensive degeneration has occurred, will likely be critical to preventing the severe loss of vision that characterizes this disease.  Additional Phase 1 clinical trials are ongoing and include children with LCA.

Can thes patients that have received RPE65 through gene therapy expect the same prognosis as their canine counterparts?  Only time will tell, but they should be optimistic about their long-term outcomes.  The LCA briard dogs, including Lancelot who was one of the first dogs treated, have shown functional recovery that lasting for more than 7 years.

Regards

Anna Matynia

Acland, G.M., Aguirre, G.D., Ray, J., Zhang, Q., Aleman, T.S., Cideciyan, A.V., Pearce-Kelling, S.E., Anand, V., Zeng, Y., Maguire, A.M., et al. (2001). Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28, 92-95.

Cideciyan, A.V., Hauswirth, W.W., Aleman, T.S., Kaushal, S., Schwartz, S.B., Boye, S.L., Windsor, E.A., Conlon, T.J., Sumaroka, A., Pang, J.J., et al. (2009). Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year. Hum Gene Ther.

Dejneka, N.S., Surace, E.M., Aleman, T.S., Cideciyan, A.V., Lyubarsky, A., Savchenko, A., Redmond, T.M., Tang, W., Wei, Z., Rex, T.S., et al. (2004). In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther 9, 182-188.