Wednesday, 26 September 2012

On the Pursuit of Curing Blindness

This is the second of two posts about Macular Degenerative Disease, from the patient's symptoms to the researchers pursuing the cure. 

Advances in science have increased life expectancy in the Western world, yet this progress has come with a cost: the human body is not designed to maintain such a long life. Our population has more elderly members who endure a very low quality of life, suffering from degenerating bodies. As Bette Davis famous quote goes: Old age ain’t for sissies. Wouldn’t it be wonderful if we could repair or replace the malfunctioning body components? Design a new body that could keep up with our thirst for life? 

Age-related Macular Degenerative Disease (AMD) is the leading cause of blindness in the Western world. According to the Macular Disease Society, only in the UK 250.000 people suffer from AMD. This condition usually affects people over 60, but macular degeneration can also appear at young age. 

What Causes AMD? 
One of the main causes of AMD is the degeneration and loss of the retinal pigmented epithelium cells (RPE). These RPE cells have several functions: 
  • keep the retinal layer alive
  • get rid of the waste material
  • transport water
  • act as a barrier preventing blood to enter the retina
  • keep photoreceptors alive (cells that respond to light). 
  • RPE growth is closely linked to the photoreceptors during nervous system development. 
The London Project is a research endeavour that aims to restore the damaged RPE cells before it causes complete blindness to the AMD patient. Regenerating damaged tissue is ambitious, but regenerating tissue in the central nervous system is mind blowing. 

Schematic of the cellular organization of the retina showing the area where the RPE cells are being replaced
(image from Carr et al. PLoS ONE 2009) 




Three groups coordinate in The London Project: one specialized in developing cells ready for transplant working in the Institute of Ophthalmology, University College London (UCL), a clinical group of surgeons and eye specialists based at Moorfields Eye Hospital and a human embryonic stem cell group in the University of Sheffield’s Centre for Stem Cell Biology.

Dr Amanda Carr, one of the neuroscientists working in the UCL group in The London Project, takes us for a peek inside the lab and tells us about her fascinating work.

“We generate new RPE cells by using either human embryonic stem cells or the patient’s own somatic stem cells”Amanda explains.


"Our project aims to start treating the other eye of the patient with AMD, where RPE cells most probably have started to degenerate too, but the rest of the cells in the retina are still healthy. If we replace the RPE cells in time, before the other cell types in the retina are affected, then the patient will have a functional retina and will not go blind.  

Being able to know in advance that a subject’s RPE cells will degenerate offers a chance to start treatment in time to preserve both eyes. If your parents have had AMD there is a chance that you will suffer from it too".


Amanda Carr in a laboratory in the Institute of Opthalmology (University College London)

"When a patient goes blind in one eye, usually the other eye will degenerate too. Once the first symptoms appear it is usually too late for treatment because it means that not only have the RPE cells have degenerated, the seeing part of the eye, the photoreceptors, have also been affected. We are not able to replace photoreceptors at the moment, although promising research in animals is currently being developed and this might be an option in the future (Pearson et al., 2012)". 

Human embryonic stem cells (HESC) are isolated from a fertilized human egg which has not been implanted in the mother’s uterus.

HESC have the capacity of being pluripotent (they can differentiate into any type of cell) and unlimited self-renewal. This last capacity of self-renewal makes them cancerous, so when undifferentiated HESC cells should not be used for transplants.  Once the cell has differentiated to a certain type of cell, then they remain stable and are safe to use for transplants.

“We work with a group from the University of Sheffield’s Centre for Stem Cell Biology who provides us with the HESC cells. The HESC cells we use were derived in Sheffield over 10 years ago from a single fertilized embryo, which was donated after in vitro fertilization. These cells divide unlimitedly so we have a constant supply of stem cells". 


Diagram by Amanda Carr explaining the process of generating RPE cells using human embryonic stem cells (HSC). 


Induced pluripotent somatic cells (iPS) are cells originated from adult human tissue, contrary to HESC which can turn into any type of cell, iPS cells can only turn into certain types of cells, they are multipotent.

Amanda explains, “Generating iPS cells is a long process, it takes around 6 months from the extraction of a sample of the patient’s skin to the production of mature RPE cells. In theory, if these cells were to be used as a therapeutic, because these cells are from the own patient, he/she won’t have an immune response to the implant [...]The iPS technology is still under development, it is a plausible treatment for the future, but current implants are using the RPE cells generated from the HESC cells”.   


Diagram by Amanda Carr explaining the process of generating induced pluripotent somatic cells (iPSC)  using the patients own skin cells.



"Generating iPS cells takes several stages. First, we take a sample of the patient’s skin, which is composed by somatic cells. When the sample is kept under appropriate culture conditions fibroblasts will grow from the biopsy.  Fibroblasts are still somatic but will divide to form even more fibroblasts. Using viruses encoding embryonic transcription factors, we can manipulate these fibroblasts. We use four different transcription factors to reprogram the somatic fibroblasts so that they look and behave like pluripotent embryonic stem cells".

Checking samples of iPS cells under the microscope

"Within a couple of days the reprogrammed fibroblast cells start to look different: they turn from long thin spindly cells, into round cells which grow in packed colonies that expand and get bigger. A sample of these cells is tested to see if it has the capacity to differentiate into different types of cells, if they are pluripotent or not. If successful, the remaining sample in the petri dish - the one we have not allowed to differentiate - will be used as a stem cell line for developing differentiated RPE cells". 



Under the microscope the samples of cells are seen as these dots.
On the top left image shows the long spindly fibroblast cells researchers begin with. On the top right image shows differentiated iPS cells, which are disposed in very small cells tightly packed into defined colonies. 
The bottom image shows the RPE cell monolayer.  


"RPE cells are pigmented, which is really useful for experimenters as they are visually very distinctive. They look dark brown and it is easy to separate them from the rest of the non-pigmented sample".

Samples of iPS cells that are started to differentiate into retinal pigment epithelium (RPE) cells.
The dark brown spots in the petri dish are RPE cells.

As if generating new RPE cells and testing their functionality was not enough, researchers encountered another challenge: RPE cells don’t stick to the membrane that usually supports them in the retina (the Bruchs membrane). The researchers had to develop an artificial membrane, porous enough to let water in, keep the new RPE cells in place and not degenerate inside the eye. Amanda smiles and says “This membrane is as thin as kitchen cling film”. 




Amanda Carr with samples of induced pluripotent skin cells (iPS)  

Amanda argues that because the eye is the only directly observable part of the central nervous system, the implanted stem cells in the eye can be checked easily and non-invasively. This is not the case for the rest of the nervous system.

The clinical group at Moorfields Eye Hospital also set an ambitious goal:  what if the restoration of RPE cells in AMD patients could be done as an outpatient procedure? The aim is to develop a procedure as simple as cataract surgery. 

The Moorfields Eye Hospital in London

In 2012 the London Project completed the large animal safety study trials using RPE cells originating from HESC cells. Currently the cells are being prepared for Phase I/II clinical trials which are expected to commence in 2013 at Moorfields Eye Hospital in London. The London Project is now using iPS cell technologies to derive RPE cells from patients with various eye diseases. The cells will be used to model disease development and will also provide a new in vitro cell system for drug discovery.
  
The London Project seems to be ahead of the current pioneering stem cell research - which is starting to successfully recover lost functions in animals, but are not ready for human pilot trials. An example of these works have been recently published in the journal Nature: scientists at the University of Sheffield could partially restore hearing loss in gerbils after stem cell implants in their cochlea (this work was also commented in The Guardian newspaper) and scientists at the University College London, Cornell and Johns Hopkins could restore vision in mice after stem cell implants in the photoreceptors in their retina.

All the advances in regenerative medicine will not make us immortal, yet they can push the boundaries for a better and a longer life, provide a better future for the next generations and make old age suitable for “sissies”.  It is science at its best.

I would like to thank Dr Amanda Carr for sharing her work, her constant help and generosity. I would also like to thank Dr Carlos Gias for his helpful comments on this and other articles of the blog. 

References

Bull ND, Martin KR (2011) Concise Review: Stem Cell-Based Therapies for Retinal Neurodegenerative Diseases. Stem Cells Aug;29(8):1170-5.

Carr AJ, Vugler AA, Hikita ST, Lawrence JM, Gias C, Chen LL, Buchholz DE, Ahmado A, Semo M, Smart MJK, Hasan S, da Cruz L, Johnson LV, Clegg DO, Coffey P (2009) Protective Effects of Human iPS-Derived Retinal Pigment Epithelium Cell Transplantation in the Retinal Dystrophic Rat. PLoS One, Dec 3; 4(12):e8152

Chen W, Jongkamonwiwat N, Abbas L, Eshtan SJ, Johnson SL, Kuhn S, Milo M, Thurlow JK, Andrews PW, Marcotti W, Moore HD, Rivolta MN(2012) Restorationof auditory evoked responses by human ES-cell-derived otic progenitors. Nature Sep 12 doi:10.1038/nature 11415

Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, Duran Y, Smith AJ, Chuang JZ, Azam SA, Luhmann UF, Benucci A, Sung CH, Bainbridge JW, Carandini M, Yau KW, Sowden JC, Ali RR. (2012) Restoration of vision after transplantation of photoreceptors. Nature May 3; 485(7396): 99-103.

Strauss O (2005) The Retinal Pigment Epithelium in Visual Function Physiol Rev Jul; 85(3): 845-881

Vugler A, Lawrence J, Walsh J, Carr A, Gias C, Semo M, Ahmado A, Da Cruz L, Andrews P, Coffey P (2007) Embrionic Stem Cells and Retinal Repair Mech Dev Nov-Dec;124(11-12).

Press Articles

"Human stem cells partially restore hearing to deaf gerbils"article by Ian Sample published in the The Guardian newspaper on the 12th of September 2012 .


Visual Hallucinationsof the Blind

This is the first of two posts about Macular Degenerative Disease, from the patient's symptoms to the research pursuing the cure. 

Visual Hallucinations  of the Blind

An hallucination mimics perception and is produced by the brain, it happens in the absence of an external stimulus.

Having hallucinations can be quite disturbing - realizing that nobody else is seeing, hearing or feeling what you perceive is a great cause of concern - as it is usually linked to mental illness. With the great social stigma that having a mental illness carries specially in the Western society, it is understandable that people who have hallucinations would rather keep it as a secret. Organizations such as Rethink Mental Illness are working on changing prejudges towards mental illness. Yet hallucinations are not necessarily an indication of mental illness: migraines, drug consumption or epilepsy are examples of conditions that can produce hallucinations.

A percentage of patients with visual impairment also report having visual hallucinations. These patients have no neurological condition other than their visual deficit, they are capable of distinguishing their hallucinations from reality, exceptionally - it might be disguised in normal perception - when the hallucination fits congruently with the rest of what is being perceived. The incidence of this phenomenon is difficult to estimate as many patients do not document their disease. Their condition is called Charles Bonnet Syndrome.

It seems paradoxical that someone who is partially or completely blind can have visual hallucinations.




Charles Bonnet 1720-1793
Image taken from wikipedia

The first to describe this phenomenon was Charles Bonnet - a Swiss naturalist and philosopher from the eightieth century- who observed that some visually impaired patients presented hallucinations. Charles Bonnet's initial encounter with the syndrome was through the case of his grandfather, who was a lucid man who had lost nearly all of his vision due to cataracts, his hallucinations were rich varied and quite complex, he perceived people, animals, buildings, geometric shapes or objects. 


In the following TEDtalk video, Oliver Sacks explains the Charles Bonnet Syndrome through the individual experiences of his patients. Oliver Sacks - neurologist and professor at the New York University School of Medicine - is one of the best science communicators in the area of neuroscience, his books about rare neurological cases have transcended the scientific community becoming bestselling novels amongst the general public. He has a new book ready to come out this coming November on hallucinations.




What causes Charles Bonnet Syndrome? 

Still today scientists have not quite unravelled the causes behind the Charles Bonnet Syndrome, although they have proposed two main theories: 
  • The release theory which suggests that having any form of lesion in the visual system would produce abnormal and faulty communication within the visual areas of the brain, hence generating hallucinations. As if visual hallucinations were attempts of the brain of turning an interrupted message into something coherent. 
  • The deprivation theory which suggests that a reduction in sensory stimulation leads to the production of spontaneous images from the brain, resulting in visual hallucinations. In other words, our brain relies on the information that our senses convey to interact with the world, with others, and also to be able to think, act and wonder. An isolated brain can start doing strange things: it generates hallucinations.
Although both theories might be partially correct, the deprivation theory seems also to serve as a plausible explanation to hallucinatory events different from the ones reported in the Charles Bonnet Syndrome.

An isolated brain can generate hallucinations

Isolating a subject from his/her normal environment, and confining them to a sensory reduced, poor and stereotyped habitat has a great impact in his/her brain.

History is filled with anecdotes from sailors, explorers, mountaineers, astronauts, shepherds ... who after being exposed to long term isolation or being surrounded by a monotonous landscape describe having had hallucinations. The tales relating to these hallucinations have been feeding popular stories for generations: fantastic marine beasts and mermaids encountered by sailors through their travels, mystic apparitions giving a message to hermit isolated characters.

1866 unknown Russian artist.
Image taken from wikipedia
1544 illustration from Carta Magna.
Image taken from wikipedia

Sensory deprivation and solitary confinement have been studied in laboratory conditions. The conclusions of these studies are limited by the time volunteers are exposed to this conditions, the amount of subjects participating in them. Yet, these studies have been able to replicate hallucinations in sensory deprived subjects. For example, in the thirties, Donald O. Hebb reported that after seven days, volunteers showed distressful symptoms like body illusions, anxiety and hallucinations. In the fifties, Bexton, Heron and Scott reported similar findings, their volunteers presented disturbances in thinking, had trouble estimating time, delusions and also had hallucinations.

It is no secret that today sensory deprivation is used as a form of torture, called "the white torture". We are familiar with newspaper articles and photos taken of Guantánamo prisoners with their eyes and ears covered, with gloved and handcuffed hands. By reducing the environmental stimulation - like blindfolding, hoods, poor lighting, earmuffs, monotonous diet or limb constraint - victims generate distortions of perception. In a recent paper published in the journal PLoS Medicine, researchers Iacopino and Xenakis reported how some of prisoners in Guantánamo were having audiovisual hallucinations.

Solitary confinement, an extreme form of isolation, used in prisons as severe punishment, frequently generates psychosis as well as hallucinations. The torturers seek to weaken the victim, by inducing helplessness, guilt and fear.

Because normal people seek sensory stimulation and contact with others, the reasoning behind having sensory deprived captives is that the victim will cling to the interrogator and become an informant. This practice might be far from efficient as the information provided from a delusional prisoner is most likely to be unreliable.

Under sensory deprived conditions, subjects loose track of time, captors firstly take away the victims watches, which contributes to generate lack of control. Gordon Turnbull explains aspects of the debriefing of british soldiers who had been prisoners during the Gulf War and Lebanon 1991 in his paper "Hostage retrieval", he argues that by giving these soldiers wrist watches, they seem to regain a sense of orientation, independence and control.

If healthy individuals who are exposed to short term sensory deprivated environments report hallucinations, it is plausible that subjects who are in some extent - long term sensory deprived due to loss or degeneration of their sensory physiology might also have hallucinations.


Age-related Macular Degeneration Patients often present Charles Bonnet Syndrome

The Age-related Macular Degenerative Disease (AMD) is a chronic illness characterized by a progressive degeneration of the central retina that produces a gradual loss of vision. It is the major cause of blindness in older adults, affecting people over 60. In the early stages of AMD patients loose only their central vision of one eye and the capacity of seeing through peripheral vision still remains fine. The impact on the quality of life of patients with AMD is severe, depending on the stage of the disease, patients might have to cease their professional activities, depend physically and economically on family members and have limitations in their everyday life. The estimated economic cost of AMD only in the United States is 575-733 million dollars per year. With an aging population the incidence of AMD is likely to double in the next decades. Lim and collaborators - in their recent article published in the Lancet - estimate that 20% of the population will suffer from AMD in the next decades. According to the Macular Disease Society, in the UK, 20% of people over 90 already have AMD.

Picture of the back of the eye showing early stages of macular degeneration.
The yellow lighter area is the optic disc, the browner central area represents the macula.
In this case the macula is affected by early stages of degeneration.
Image taken from wikipedia

Any individual with visual impairment is susceptible of experiencing Charles Bonnet Syndrome, patients with AMD are no exception. Subjects might experience complex non-stereotyped visual hallucinations that can have a sudden appearance and last for hours. Because the onset of AMD - around 60 years of age- coincides with other very frequent degenerative disease, dementia, hallucinations in AMD patients are often regarded as symptoms of early stages of dementia rather than Charles Bonnet Syndrome, this is why patients are frequently misdiagnosed. The difference between the hallucinations in dementia and in Charles Bonnet Syndrome resides in the capacity of the patient to distinguish hallucinations from reality. Charles Bonnet Syndrome patients are lucid, their hallucinations are mainly visual - there is currently some debate of whether or not there might also have an auditory component - and are not context congruent. Patients with dementia can not distinguish hallucinations from reality, they incorporate them with delusional thoughts and try to interact with them.

As explained earlier, the incidence of Charles Bonnet Syndrome in AMD patients is difficult to estimate as many patients do not report their hallucinations due to fear of being regarded as having mental problems.

What causes AMD? 

To understand the causes behind AMD, I talk with Dr Amanda Carr - from the Institute of Opthalmology, University College London - who's research aims to find a cure for AMD. Amanda is part of the team of researchers working in the The London Project to Cure Blindness who are doing pioneering work in this field. Three groups work collaborate in The London Project: one specialized in developing cells ready for transplant working in the Institute of Ophthalmology, University College London (UCL), a clinical group of surgeons and eye specialists based at Moorfields Eye Hospital and a human embryonic stem cell group in the University of Sheffield’s Centre for Stem Cell Biology.


Detail of the Moorfields Eye Hospital building
"In the retina, there is a thin layer of cells in the pigment epithelium, formed by retinal epithelium (RPE) cells. These cells serve different functions, like keeping the retinal layers alive,transporting water and nutrients to the retina or getting rid of the metabolic debris that the retina generates. The AMD can be caused by the degeneration of the RPE cells" says Amanda.  

Amanda explains that the AMD has two forms, both of which end up having in some stage, RPE degeneration and can ultimately cause blindness: 

a) The dry form of AMD is caused by the inability of the RPE cells to get rid of debris properly. The debris is composed by fatty deposits that accumulate, detaching the retinal epithelium from the rest of the retina. With no nutrient support, the retina degenerates and eventually dies. 

b) The wet form of AMD is caused by the inability of the RPE cells to function as a barrier, so there is blood vessel infiltration, which enters the retina and bleeds. 

Although the wet form of AMD has treatment, the dry form of AMD which is the most common one (9 in 10 patients show this form of AMD), currently does not have a treatment.   

The RPE cells keep the retinal layers alive, including the photoreceptors, which are specialized neurons - fundamental for vision -  responsible for detecting luminance. There are two types of photoreceptors: rods, which are responsible for nocturnal vision, and cones, which are responsible for colour vision.  AMD patients can present in the early stages of the macular degeneration gradual loss of colour perception, which is an indication that the cones have degenerated. 



Watercolour painting of photoreceptors by Laura González López-Briones.
There are two types of photoreceptors (specialized cells that detect light): rods and cones.
Second to the left represents a cone and the rest represent rods 
Testing for Macular Disease 

There is a simple way to test if you might have AMD by using the Amsler Grid test. By focusing on the central point of the Amsler Grid, people with no visual impairments see the grid as a regular pattern with no differences along the grid, people with AMD see a distortion of the grid in the visual field that corresponds to the degenerated area in the retina.

Amsler Grid as seen by a person with no vision problems
Amsler Grid as seen by a person who has macular degenerative disease
Both images taken from wikipedia

For more information about AMD please visit The Macular Disease Society website.

I would like to thank Laura González López-Briones for letting me publish her work in this post. Laura - a neuroscientist and also a painter - her work illustrates the heading of my blog with watercolours of neurons. I would also like to thank Dr Amanda Carr, who's work features in further detail in the post "On the Pursuit of Curing Blindness" which follows this post.

In order to avoid problems with copyright, images taken from wikipedia.

References

Hebb DO (1968) Concerning Imagery Psychol Rev 75(6): 466-477

Ffytche DH (2009) Visual Hallucinations in Eye Disease Curr Opin Neurol Feb; 22 (1):28-35.

Iacopino V, Xenakis S.N (2011) Neglet of Medical Evidence of Torture in Guantánamo Bay: A Case Series. PLoS Med Apr;8(4):e1001027.

Lim LS, Mitchel P, Seddon JM, Holz FG and Wong TY(2012) Age-related macular degeneration Lancet 379:1729-38.

Manford M, Andermann F (1998) Complex visual hallucinations. Clinical and neurobiological insight. Brain Oct 121 (10): 1819-1840.

Schadlu AP, Schadlu R, Shepherd JB 3rd (2009) Charles Bonnet syndrome: a review. Curr Opin Ophthalmol May; 20(3): 219-22

Turnbull G (1997) Hostage Retrieval J R Soc Med 90(9): 478-483.

Smith S, Kenna JC, Reed GF (1962) Effects of Sensory Deprivation Proc R Soc Med Dec, 55(12): 1003-1014.










Thursday, 21 June 2012

A Pilot Experiment to Aid Musician's Cramp

We have all had the uncomfortable experience of involuntary eye twitching, eye lid tics or muscle spasm. Gemma Correll is a professional illustrator who often refers to these eye twitches in the series of her daily diaries, attributing them to stress, fatigue or too much caffeine intake.

Illustration belonging to Gemma Correll's daily diaries where she explains an episode of eye twitching.
 Image posted with permission of Gemma Correll 

For professionals who rely on fine motor skills such as athletes or musicians, suffering from regular and consistent muscle twitches can have a great impact in their performance and truncate their careers. Traditionally these twitches have been linked to performance anxiety, or to lack of training, but increasing evidence is pointing that it is produced by faulty neural connections. What might have started as involuntary muscle twitches or muscle incoordination could be symptoms of a complex neurological movement disorder called dystonia. According to the  Dystonia Society it is estimated that only in the UK there are over 70,000 people suffer from this condition of which 8,000 are children. 

Focal dystonia can present itself as task specific, for example when writing (writer's cramp) or when playing an instrument (musician's cramp). It is estimated that 1% of professional musicians suffer from musician's cramp. 

Gemma Correll posing next to a mural she has painted. Image posted with permission from Gemma Correll
Dr Mark Edwards from the Institute of Neurology at University College London is currently piloting an experiment using transcranial direct current stimulation (TDCS) and transmagnetic cranial stimulation (TMS) to target faulty neural connections in musicians who suffer from focal hand dystonia. 

"There are musicians out there who are struggling and giving up their careers because of dystonia" Mark explains. 


Dr Mark Edwards in the Institute of Neurology, showing an old model of TMS with one coil

So are musicians relieved to learn that they have a medical condition rather a psychological condition? 


"That’s true, it speaks to the overlap they are told that it has to do with performance anxiety, which is not exactly true. What it is true is that musicians with dystonia tend to have higher levels of anxiety who musicians who do not have dystonia.



It is a very interesting interphase, but in society as soon as something is psychological, there is a sense that it is something that you are doing yourself and that you could snap out of it, as if it is something not real, and that you are weak. Psychological conditions are also generated by the brain, so it would be quite surprising that if the brain went wrong it wouldn’t have an impact on those aspects too. It is a matter of trying to explain to people that cognitive psychological issues are involved, so treatment can help".


What do we know today about dystonia? 

"The strongest theory is that dystonia is a product of abnormal brain plasticity. There are children who have dystonia that affects their whole body and adults that only have eye and head muscles affected, previously they were classified as different conditions when we know today that they are the same condition"

Nobody is born a professional music player, it takes years of practice and learning in order to play an instrument well. "Practice makes perfect", learning to do something new eventually gets easier and performance improves after training and repetition. The neural connections in the brain of the student have to undergo changes to establish a new skill, this capacity is called brain plasticity



Brain plasticity refers to any change in the neural system, from learning to aging, from memorizing to adapting to brain damage. Brain plasticity is the result of the formation of new connections between neurons or from changes in the strength of those connections. The strength and effectiveness of a neural connection is both activity and experience dependent. The more a neural connection is in use the more efficient it will become. This implies that the more you train doing something the better you get at it.   



Hence the phrase of the 1906 Nobel Prize winner Ramon y Cajal "All man can be, if it is his purpose, be the sculpturer of his own brain".



Professional musicians present an adaptive plastic reorganization of the neural connections in the motor and sensory cortical areas in the brain which are responsible for the coordination and muscle movements required to play an instrument. This allows musicians to perform precision movements at higher speed than a normal individual can do. The activation of the neural command to move a finger will trigger the inhibition of movements of the fingers next to it, so the musician can aim precisely at a note and not at another.

Photo of the modern model of TMS with two coils 

What happens in the brain of musicians with dystonia?

"In case of the musicians, they have pushed that particular body part to an extreme, which is the way your motor system changes, but in vulnerable people to this dystonia, this system is set in a different way, it is more sensitive, so these changes trigger complexity in the neuronal communication producing a spill over of muscle control".

Musician's cramp affects different muscles depending on the instrument that is played, for example violinists and pianists may present problems with finger, hand or arm movement, and wind players frequently present tongue or lip coordination problems. Because the prevalence of musician's cramp is not equivalent among all the distribution of instrumental groups this condition might be triggered by certain movements.

Musician playing the cello. In order to avoid copyright problems, image taken from wikipedia

Why musician's who have dystonia don't improve when training?  The more you practice the more efficient those particular neural connections should be.

"TMS stimulation protocols can induce plastic changes in the motor cortex, but when they are applied to individuals that have dystonia they show that their brain plasticity is affected. The excitation gets spread outside, so areas which are topographically near get excitation as well". 

"We don’t really know how plasticity works in abnormal situations, so TMS can help us understand how the brain works in these conditions". 

"With a simple associative thing, if you are playing the piano and you want to move one finger, the excitation in the motor cortex makes you move the finger next to it, so you might not play the note that you are aiming for. Your linking sensations with movement, you are thinking that you are doing a specific movement when actually the excitability is spreading to other muscles of nearby".

Prokofiev and Rostropovich. Image taken from wikipedia
So it’s a problem of balance between excitatory and inhibitory connections?

"Yes. Dystonia as a group they don’t have enough activity of their inhibitory circuits, so you can show that at cortical level, spinal cord level, brainstem level. There is a loss of inhibitory control. This was the idea but it seems that the problem is more complex. When observing people with dystonia caused by genetic problems, it is quite common to find people that carry the genetic mutation but do not have dystonia, they also have a similar loss of inhibition but they are clinically unaffected. So the argument is that the loss of inhibition is not enough".

Surround inhibition

"When moving just one finger, the contractions of the muscles are never really isolated, the whole forearm and hand also have certain degree of muscle contractions, to produce a fine movement, some degree of control over the excitability over these body parts is needed. When you are doing a small movement with one finger, the excitability of the surrounding fingers is reduced. People who suffer from focal hand dystonia seem to loose this surround inhibition, so the muscles from the neighbor fingers also contract" Mark explains.

The nervous system is capable of generating focused neural activity through a physiological mechanism called surround inhibition. Surround inhibition or lateral inhibition seems to result from a general organization pattern in neural connectivity, where excitatory neurons are surrounded by local inhibitory neurons, so the activation of one area also produces the inhibition of the neighboring areas.

The cytoarchitectonic structure of the mammal brain cortex presents a matrix of excitatory and inhibitory neurons. Mice cortex. Stained in green are pyramidal neurons which are excitatory and on the back stained in red, GABA-ergic neurons which are inhibitory.  Image taken from wikipedia.


People who suffer from dystonia show an abnormal surround inhibition, where activation of certain motor commands produce an involuntary activation of other movements resulting in poor motor control. The abnormal surround inhibition observed in the motor cortex might be derived by abnormal motor signals coming other motor regions in the brain, such as the basal ganglia.


Pilot treatment of hand dystonia targeting muscles


Surround inhibition is also present in sensorimotor interaction, so moving one finger while stimulating adjacent fingers enhances surround inhibition. Mark and his team have applied this protocol to people who suffer from hand dystonia.


"A postdoctoral researcher Dr Panagiotis Kassaveti has studied nerve periphery issues in dystonia. He has given subjects stimulation in the surrounding muscle spindles at the same time they were performing the task related to their dystonia. The effect was short lived, but the surrounding inhibition of these subjects was enhanced improving their symptoms".

Dr Mark Edwards with a TMS (unplugged) device.

Pilot treatment of hand dystonia targeting the cerebellum.

Mark and his team are targeting faulty neural connections in the cerebellum that underlie the involuntary muscle twitches and block them with TDCS while the musicians are playing their instrument. Mark and his team expect that this protocol will allow the system to form a new adaptive neural network.


"When you are playing an instrument you are recalling a memory of the motor pattern necessary to play that instrument. During recollection, the memory becomes vulnerable to change. That is the basic idea", Mark says. 


Mark's first subject, a classic guitarist whos hand dystonia has affected his career, reported some mild shortlived benefit from the TDCS treatment. Encouraged by this, Mark and his team are working on a longer TDCS treatment that could produce changes in the long term.  


"We are currently doing a pilot, the first subject reported benefit after applying a stimulation protocol to his cerebellum. We might have found a effect but it is still short lived. We need to start running proper placebo controls" Mark explains.


"We don’t really know how plasticity works in abnormal situations, so TMS can help us understand how the brain works in these conditions".

Dr. Andrew Spence ( see previous post) who works in robots says that the cockroach is able to move better than any other robot that the NASA has been capable of designing ...

"If you think about robots and artificial intelligence, they can learn how they can play chess but when it comes to basic motor skills, they can hardly perform simple motor movements. 

In the video of the final of the robots playing football, the States against Japan, which is the pinnacle of technology, they display such a low level of performance when compared to a professional football player like Ronaldinho. Ronaldinho's skills are beyond what a robot can ever do".





I would like to thank Mark Edwards for his time and for sharing his work with the curious neuron's readers, and hope his pilot treatment can aid musician's with dystonia.  I would also like to thank Gemma Correll for letting me publish her work in this post. Without them this post wouldn't have been possible.

References

Altenmüller E, Baur V, Hofmann A, Lim V.K., Jabush H.C. "Musician's cramps as a manifestation of maladaptative brain plasticity: arguments from instrumental differences" Ann N YAcad Sci. 2012 Apr; 1252:259-65.

Beck S and Hallet M "Surround inhibition in the motor cortex" Exp Brain Res 2011; 210:165-172. 

Berlucchi G and Butchel H.A. "Neuronal plasticity: historical roots and evolution of meaning" Exp Brain Res 2009; 192:07-319

Edwards MJ, Talelli P,  Rothwell JC "Clinical applications of transcranial magnetic stimulation in patients with movement disorders". Lancet Neurol 2008; 7: 827–40

Galea JM,Vazquez A, Pasricha N, Orban de Xivry J.J. And Celnik P. “Dissociating the roles of the cerebellum and motor cortex during adaptative learning: the motor cortex retains what the cerebellum does” Cereb Cortex 2011;21:1761-1770

Wednesday, 6 June 2012

Visiting "Brains. The Mind as Matter" at the Wellcome Collection


Collecting brains for scientific study started at the end of the 18th century and became common practice in the 19th and 20th century. Although the brains were first gathered in medical faculties, soon these collections were also available in museums for the general public to see. The general public gathered with amazement to observe human brains for the first time. 

Until the 17th of June Londoners have the opportunity of visiting the exhibition The Wellcome Collection "Brains. The Mind as Matter" an approach to the brain as a physical entity, allowing the visitor to learn how this viscera is collected, classified, stored and treated. 

The amazement that the encounter with the human brain provoked in the 19th century citizen is still present today, as the exhibition "Brains. The Mind as Matter" has attracted the most visitors per day of any exhibition so far held at The Wellcome Collection.  

The curators Marius Kwint (University of Postsmouth) and Lucy Shanahan (Wellcome Collection) have gathered an impressive collection of objects from human brains and surgical instruments used to study the brain, to historical manuscripts and artwork, all of which help to contextualize and tell the story of those individuals who's brains have been part of the history and progress of neuroscience. The main characters of these stories are not just the scientists or neurosurgeons but also the patients, the brain donors and their families.






As a neuroscientist visiting the exhibit feels a bit bizarre, although it is flooded with familiar objects and images, the perspective is so different as if the brain was completely new, as if it were a stranger. As neuroscience PhD student Benjamin Towse says “It’s about the practice of neuroscience more than it is about neuroscience itself", or how the curator Marious Kwint defines it "this exhibition is not about what the brain does for us, but what we do to the brain". 


With 150 objects displayed in the exhibition, including all of them would require a dedicated post in itself. Here is a brief summary to give you at taste of the exhibition, but the nothing would substitute the experience of visiting it for yourself.

Brainbow  Jean Livet, Joshua R Sanes and Jef Lichtman 2007 Digital photograph.
Living neurons altered to express fluorescent proteins from genes taken from coral and jellyfish.
 Image posted with permission from The Wellcome Collection. 

Lucy Shanahan curator of the Wellcome Trust goes through the exhibition with us today:

In this exhibit there is no information about brain function. Why mind as matter?

"We are not doing a straight science exhibition. We are more interested in giving it a cultural and a historical context. Looking at the brain from a humanistic point of view" Lucy explains. 



What was the idea behind this exhibition? 

"It was an idea that had been circulating for some time. Initially there was a particular fascination with the idea of having a series of famous brains on display, such as Einstein's. We even considered requesting Lenin's brain, but we were unable to pursue it in the end".


"The idea started to evolve from that initial concept when Marius Kwint was invited to start researching the project further. He began by visiting brain collections in the US at Cornell University and the Cushing Centre in Yale and subsequently travelled to brain collections in Europe in particular Germany. I think he was particularly struck by the vision of so many brains in the same room, which inspired him to explore the motivations behind collecting brains and to consider whether these motivations have changed over the last century. As a result, the scope of the exhibit started to broaden" says Lucy.



Photograph of the cellars of the Charité hospital in Berlin. Photograph taken by Daniel Alexander, 2011.
 Image posted with permission from The Wellcome Collection.


The reason behind collecting brains was to find some type of correlation between talent or intellectual capacity and the size and structure of the brain. A systematic postmortem study of the brains of geniuses but also criminals, mentally retarded or pathological started in Europe in the 19th century. The brains were weighed, convolutions and gyri measured, cerebral lobes compared.  In Russia, the brains of the most talented were collected such as the creator of the periodic table Mendeleev, the writer Turgenev, the neuroanatomist Betz or the musician and conductor Rubinstein. In USA, the most notorious brain collected for scientific study was Einstein's brain.  

Preserved brain of Helen H Gardner, writer, civil servant and suffragist who died in 1925.
Wilder Brain Collection Cornell University.
Image posted with permission from The Wellcome  Collection. 


As appealing as the idea of finding a neuroanatomical substrate for talent might be, none has really been found. Although some studies report to have found slight cytoarchitectonical differences in certain cortical areas of the brains of more gifted individuals, yet these studies have not been conclusive. There are no specific qualities that the brains of the gifted seem to have when compared to others.

However, it has been the pathological and injured brains which have provided a better understanding of how the brain works. One of the most famous and recent cases of postmortem study has been the brain of Henry Molaison (patient H.M.) who's case of memory impairment has been key to understanding   memory function. To find out more about the case of H.M click here: H.M. patient

In the exhibition "Brains: The Mind as Matter" visitors have the chance to see samples of Einstein's brain and a video of the H.M's brain being cryoprotected and sliced for neuroanatomical study.


Image by Hellen Pynor “Headache”.

"We chose this piece by Helen Pynor as our lead image because it encapsulated perfectly well the theme of the exhibition: it confronted us with  brain as a visceral object, but also with it's ethereal beauty" says Lucy. 

Headache (detail) by Helen Pynor, 2008.
Image courtesy of the artist and GV Art
Have you had the chance of seeing a craniotomy in real life? 

"Not this time, but in the past for a prevoius exhibit about the heart, the team had the chance to see a live heart surgery as part of the research process. We certainly do not shy away for putting ourselves in the forefront to gather information and conduct research for our exhibitions.

In the last section of the exhibition "Giving/Taking" there is a film called "Brain Bank" which was shot at Hammersmith Hospital in London, where several colleagues had the opportunity to observe the brain being sliced for the Imperial College Tissue Bank. The film provides a unique window for visitors who may never have the chance to see something like that for themselves". 

"A number of artists also attended these dissection sessions, on various occasions, such as David Marron, who made the piece of work seen alongside the "Brain Bank" film, in response to his own visit and makes fantastic analogies with the brain and other organic materials such as a walnut, a raw chicken, or a cauliflower...it is curious how easy it is to oscillate between seeing the brain as something quintessentially human and then as something completely inanimate". 


"Nervous Tissue Note Panel" by David Marron, 2010.
Image courtesy of the artist and GV Art 

Preserving brain tissue


It wasn't until the 18th century, when proper preservation techniques were developed, that the brain could be successfully collected and stored for study. There are very few brain samples prior to this time.

"One of the things that I found particularly interesting is that the brain is not naturally solid. There is a wonderful photograph taken at the Cambridge University Brain Bank which is a remarkable view of the real material quality of the brain which is surprisingly gelatinous, not like the perfect form that holds it's shape within the confines of our skulls. Once it is removed, it becomes flabby and flaccid, slightly resembling a squid! This was a real revelation. Brains deteriorate very quickly and they are  difficult to dissect as a result of their jelly-like texture - hence the need to preserve and solidify the specimens".  

"Unusually, there is an early Egyptian brain on display" Lucy points out. "The ancient Egyptians considered the brain to be irrelevant after death, os it is extremely rare to have come across one that has been preserved. Normally they discarded the brain but preserved other viscera like the heart.".  

Cerebral hemisphere of an ancient Egyptian brain (2010 BCE)  Dry Specimen.
Hunterian Museum Royal College of Surgeons of England, London.
 Image posted with the permission of the Wellcome Collection.




Ancient egyptians must have found some form of managing tissue fixation to preserve internal organs during the mummification process. According to the book "Brains. The Mind over Matter" this mummified brain was found in a burial ground of the Dynasty XI in the temple of Mentuhotep II at Deir el-Bahari. 
How did you find the artwork related to the brain? How did you choose the artwork? 

"All of the artists featured in the exhibition have had a very close personal relationship to the subject either through their own experiences, that of a family member or other individuals with whom they have built a real relationship through involving them in their work. There is nothing arbitrary in the selection of artists in the exhibition, nobody's work is here just because it happens to have a brain in it, there is a very poignant story behind each piece. 


We were already aware of the work of several artists who have been working with this topic for many years. We learnt about the work of several other artists through a private gallery called GV Art London, which holds a license to display human tissue.


For example, the work of Helen Pynor has been recently exhibited there and a number of artists whose work share a common interest in the intersection of "Where science meets art".  

To find more about the GV Art London exhibitions about Art and Neuroscience, there is an interesting article in Arts Magazine

What did the artists say?

"The artists were very happy to have their work juxtaposed with real brains, providing the perfect context for their work".   

Artist Katharine Dowson created this work inspired by the successful laser treatment of her cousin's cerebral arteriovenous malformation.

"Memory of a Brain Malformation" by Katharine Dowson, 2006 Laser-etched lead crystal glass
Image courtesy of the artist and GV Art

Comparative neuroanatomy

"We were tempted to include more animal brains but in the end chose a select few. The model of the alligator brain is a great example of how well the brain fits the relative shape and size of the skull. We also have on display the left hemisphere from the brain of a female bottle nose dolphin, which is interesting because it is considered to be quite similar to the human brain. although it has very specific features including a large cerebellum and impressive, highly intricate, convolutions" Lucy explains.

Wax model with wooden handle of an alligator brain. Ziegler studio 1887.
 Image posted with permission of the Wellcome Trust Collection.  


Brain donation 

Neuroscience relies on the generosity of the people who volunteer to donate their brains for research. This process is usually anonymous, which makes donation specially altruistic. The lack of contact between scientists and donors might be one of the reasons why scientists tend to impose a great emotional distance when studying human tissue. The work done by Ania Davrowska and Browyn Parry in "Mind Over Matter" is especially moving, as it approaches brain donation from the donor's point of view. It is a fantastic work as many people don't consider the possibility of donating their brains unless they are asked and the project also helps scientists to gain some perspective. 

The stories and faces behind brain donation are fascinating and touching.  Two of the brain donors involved in this project - Albert Webb and Eddie Holden - have had close relationship with people who have suffered from Alzheimer's disease.

Mr Albert Webb was a soldier during the Second World War, he fought in Naples, where he developed a great passion for opera. His wife suffered from Alzheimer's disease and this encouraged him to donate his brain "I shall be doing a bit of good perhaps to somebody". 

Mr Eddie Holden volunteered as a soldier in the Parachute Regiment, and participated in the liberation of war prisoners in Japan. He donates his brain in the hope it will help finding a treatment for Alzheimer's disease "Losing memory, where you are, not knowing who you are, is a terrible thing".  


Mr Albert Webb.
Photograph from the  project "Mind Over Matter: The Brain Donors"
by Ania Drabrowska, 2008-2011.
Image courtesy of the artist and GV Art

Mr Eddie Holden.
Photograph from the project "Mind Over Matter: The Brain Donors"
by Ania Drabrowska, 2008-2011.
Image courtesy of the artist and GV Art

After seeing the exhibition, do you think visitors would consider donating their brains to science?

"It was certainly a message that I hoped visitors would take away from this exhibition, though each person might have a different reaction  [...] When you are curating an exhibition in your mind there is a narrative that you are trying to convey and you hope others will have the same understanding of the story you have set out to tell, but of course each person is going to encounter it slightly differently". 

What has been the public response to the exhibition? 

"We have been overwhelmed by the public's reaction and interest. It's probably the most overtly medical exhibit we ever produced and it shows that there is an appetite for very graphic and visceral matterial. However, confronting a real brain in a jar is quite a different experience to seeing a brain on television". 


"In one of the first press interviews we organised for the BBC Radio Four, there was an interesting dialogue between Marius Kwint and a neuroscientist about how much we still don't understand about the brain. Although much has been learned over the past 500 years, there is still a lot that remains a mystery".


Ganglionic cells of the trigeminal nucleus of the mouse. Microscope slide by Santiago Ramón y Cajal, 1900. Photograph by Virginia García Marín. Cajal Legacy, Instituto Cajal (CSIC), Madrid.
Image posted with permission from The Wellcome Collection. 




Interview with the tour guides that work in the Wellcome Trust Collection

Aishling Holdbrooke and Steve Britt are tour guides in the Wellcome Trust Collection, they are the ones who are in close contact with the visitor of the exhibitions. Here they talk about their experience with the public. 

What type of preparation do the tour guides have before an exhibition? 

"Usually we have a month of preparation, we meet the curator of the exhibit. In case of this particular exhibition we had the chance of visiting the Wellcome Trust Image Centre and I had the opportunity to participate in an fMRI study and see my own brains"says Steve. 

Is there a particular element that people are more interested in?

"It is varied: the video of the craniotomy,  the piece of Einstein's brain, the fact that there is a shortage of brains for current research... " Steve points put. 
"Scan" by Nina Sellars, 2012.

Image courtesy of the artist and GV Art


The Nina Sellars artwork provides visitors who have a smart phone with the chance to scan a QR (quick response) code to view online images of her MRI scanned brain. scan.ninasellars.com. Aishling explained the work by Nina Sellars and helped me scan the QR for the curious neuron readers to access.  

What type of questions do people usually ask? 

"Usually people like to share their experience, if they or members of their families have had neurosurgery. The public is very interested in this subject, they ask questions about neuroanatomy and brain function" says Steve.  

What type of visitors come to see the exhibitions in the Wellcome Trust Collection? 

"In the past it was mainly young professionals, a lot of artists. Since we are located next to University College London and to a big hospital (UCLH) we also had scientists and doctors visiting. This has changed, now our public is very wide, and the profile is variable".  


"At the weekends it gets so crowded people have to wait outside in the street. We were not expecting so many people" says Steve. 

This exhibition will be running until the 17th of June, I encourage scientists and non-scientists to take the opportunity of experiencing an encounter with the human brain. This might be an exhibition you will never forget.

From the 19th of June until the 16th of October The Wellcome Collection will be showing "Superhuman" an exhibit about the different ways humans have been able to adapt, improve and enhance their bodies. From prosthetics to biotechnology, from science fiction to medicine. An exciting approach that combines artwork, medicine and history. Don't miss it!

I would like to thank Aishling Holdbrooke, Steve Britt, Alasdair McCartney and Tim Morley. I would like to specially thank Lucy Shanahan for her time, for her tailored tour through the exhibition and for answering my questions. Without them this post wouldn't have been published.

References

Vein AA, Maat-Schieman ML "Famous Russian brains: historical attempts to understand intelligence" Brain 2008 Feb 131:583-90.

Marius Kwint and Richard Wingate Brains. The Mind as Matter London: Wellcome Collection; 2012