Motor Neurone Disease

Familial forms of Motor neurone disease (MND)

Motor neurone disease is a progressive neurodegenerative disorder that attacks nerves of the brain and spinal cord which gradually inhibits nerve signals from reaching the muscles. This leads to muscle weakness and visible muscle atrophy. As the disease progresses actions such as walking, gripping, swallowing and breathing become increasingly difficult, and eventually impossible. In this article I will be discussing the hereditary forms of MND known as familial motor neurone disease and the symptoms related.

Symptoms of MND

Symptoms of motor neurone disease usually develop slowly and subtly over time and typically fall into 3 stages, the initial stage, advanced stage and the end stage. In two-thirds of cases first symptoms occur in the arm or leg known as limb-onset disease. This can be categorised by a weakened grip or tripping up due to muscle weakness; this can often be accompanied by fasciculation’s (muscle twitching) or muscle cramps. Bulbar-onset disease occurs in around a quarter of cases, this affects the muscles of the throat required for swallowing and speech. Advanced symptoms can display visible muscle atrophy due to the wearing away of muscle from inactivity. Limb function gradually becomes worse due to severe weakness leading to a person becoming unable to move. Joint aches and pain develop due to spasticity; this is a condition where the muscles become stiff and rigid. Breathing becomes progressively difficult as the nerves that control the respiratory muscles become more damaged which can leave a person short of breath after simple day to day tasks. End stage symptoms takes the disease into its final stages. A person will suffer increasing body paralysis and significant shortness of breath to which then non-invasive breathing assistance isn’t enough to compensate for the loss of normal lung function. Sufferers of MND usually become drowsy before falling into a deep sleep where they usually die peacefully.

 

Mentally aware

As MND affects only motor neurones a person’s cognitive function is not lost, meaning they are aware of their condition and symptoms. Although in around 15% of cases people with MND may also suffer with frontotemporal dementia; symptoms include difficulty with planning, concentration and use of language. Some people have additional symptoms that are not directly caused by MND but relate to the reality of living with the disease. These may include anxiety, depression and insomnia.

 

What causes MND?

According to the MND association around 5-10% of cases are caused by hereditary genetic factors known as familial motor neurone disease. Although a person may have a genetic mutation, this alone does not cause the disease but does increase the likelihood of development. There are four major genetic mutations associated with MND. A genetic mutation occurs when the instructions carried within the gene become scrambled in some way which may lead to the body’s processes not functioning accordingly.

One third of the 5-10% have a mutation in the C9ORF72 gene found on chromosome 9. Normal transcription of this gene encodes for a protein found in many tissues including the brain, although its function is unknown. The protein is found in the presynaptic terminals of neurons and in the fluid that surrounds the nucleus. The gene contains a region of 6 DNA nucleotides (the building blocks of DNA) of four guanines and two cytosines and can be repeated several times or just once. When this nucleotide sequence is repeated too many times, in a mutation called a hexanucleotide, it can cause the amyotrophic lateral sclerosis (ALS) form of MND (DeJesus-Hernandez M 2011). It’s not known for certain how many repeats cause MND but it is believed to be over 30. The hexanucleotide mutation has been found to reduce the amount of protein produced by the C9ORF72 gene, which may alter and interfere with the cells’ function; although it is unclear how this protein causes the disease. Mutations in this gene are also responsible for frontotemporal dementia (FTD) although again it is still unclear why some develop MND, FTD or both (Chio, A. et al 2012).

Another gene known to cause MND is the SOD1 gene located on chromosome 21. This gene, under normal function, encodes for an enzyme called superoxide dismutase (SOD) which is abundant in many cells throughout the body. The role of superoxide dismutase is responsible for the breakdown of toxic charged oxygen molecules, called superoxide molecules, by its binding to copper and zinc. The production of these molecules is a by-product of normal functioning cells, although a build-up of them internally can cause the cell damage (Rakhit R. 2006). There are at least 170 mutations of the SOD1 gene known to cause MND. One particular mutation is the changing of an amino acid alanine to valine which causes the enzyme SOD to gain new, but harmful, properties. Researchers are unclear as to why the cells that are affected in MND are sensitive to the SOD1 mutation but it is believed to be due the increased level of toxic free radicals or the formation of aggregates (clumps) of misfolded SOD that cause cell death (Shaw, B. 2007).

The gene TARDBP located on chromosome 1 is responsible for the production of a protein called transactive response DNA binding protein 43 kDa (TDP-43). This protein is found in most tissues and is responsible in regulating transcription (the first step in the production of new proteins) by binding to DNA and mRNA. TDP-43 cuts and rearranges the amino acid building blocks of proteins in different ways leading to the formation of different versions of certain proteins in a process known as alternative splicing. There are around 50 mutations in this gene known to cause MND which affect the region of the TDP-43 that is responsible for the alternative splicing process. The mutations are thought to cause the proteins to misfold and aggregate within motor neurons. Again it is unclear the reasons why motor neurons die and to whether a build-up of aggregated TDP-43 is the cause of death or a by-product of the dying cell (Buratti, E. 2008). The onset of frontotemporal dementia is also associated with mutations in this gene.

Found on chromosome 16, the FUS gene is also responsible in assisting transcription processes by producing a protein called Fused in Sarcoma (FUS). The FUS assists messenger RNA out of the nucleus to be further processed into a mature protein and also helps repair mistakes in DNA. There are around 50 mutations in this gene that can cause MND by interfering with the transport of mRNA which is likely to cause aggregates of FUS within neurons. People who have the FUS gene mutation tend to develop the disease at an earlier age and have a decreased life expectancy. Like the previous 3 genes, mutations in this gene may also cause frontotemporal dementia (Hewitt, C. 2010).

Conclusion

There is currently no cure for motor neuron disease. Extensive research is underway to discover further details about what causes the disease and to find potential life changing medications. The only drug available that has shown to extend survival by two to three months on average is Riluzole which slows the progressive damage to cells by reduction to glutamate sensitivity. Other treatments include physiotherapy to ease cramps, Baclofen medication to ease muscle stiffness, Amitriptyline or botulin injections to stop saliva drooling, and percutaneous endoscopic gastrostomy tube for food intake when dysphagia (swallowing) becomes too difficult. None of these treatments cure MND but may to help improve quality of life.

 

 

 

 

References

Home

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Chio, A. et al 2012

 

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. DeJesus-Hernandez M et al 2011

 

Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis. Rakhit R1Chakrabartty A. 2006

 

How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein? Shaw BF1Valentine JS.

 

Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Buratti E1Baralle FE.

 

Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Hewitt C1Kirby JHighley JRHartley JAHibberd RHollinger HCWilliams TLInce PGMcDermott CJShaw PJ.

 

Author: Laura Ellis

Editor: Rosemary Porter

Music and the Brain

Music has encapsulated individuals across all cultures going back thousands of years. It has been the epicentre of traditional tribal ceremonies across the world. It has been used by the likes of Nas, John Lennon and Lauryn Hill as a form of expression, to inspire the world and as a non-physical emotive weapon. Whether it be on the West End stage, or at your local cinema, music represents the cardinal ingredient used to take an audience on an emotional journey.

Regrettably, we all relate to that feeling associated with exam revision where you ask yourself if you are ever going to be able to remember all of those history dates…all those drug names and classes for the treatment of hypotension…your discussion points on how Marxist interpretations influence how geographers think about economy. Yet have you ever stopped and thought about the number of songs you can completely recall all of the lyrics to? How exactly is it possible to struggle so much to remember so many things, but never forget the lyrics to your favourite songs (sometimes even the songs you hate)? Have you ever listened to the lyrics of a song and sworn that it was written just for you? Or what about that particular motif which takes you straight back to a specific point in time, perhaps with a special person? For the duration of that piece you can recall every last detail and feel the goose bumps return on your skin. This is not a novel topic of interest within neuroscience; it has been explored in books such as ‘Musicophilia’ by Oliver Sacks or ‘This is your brain on music’ by Daniel Levitin for a long time, however I still feel that among the majority it is not something that people really talk or read about.

https://www.youtube.com/watch?v=J4S_FX9bieg

I vividly remember watching a 2009 BBC documentary, ‘The Alzheimer’s Choir’, which revealed – quite beautifully – the healing power of music. Singing for the Brain is a UK-based service composed of Alzheimer’s sufferers and their spouses. They convene to sing a variety of familiar songs in order to stimulate and aid expression by those who have lost their voices. An extraordinary transformation occurred on the screen before me as I watched several sufferers in a nursing home sing along to their favourite songs (where they had previously been unable to recall the names of their children or the day of the week). In some exceptional cases, attempts were made to dance on the spot or get up from their seats. This was a catalytic event in my life; pushing me further towards the field of Neuroscience in a quest to better understand the relationship between music and our brains…how could a string of sound waves be responsible for such a phenomenon? And how many other many other wonderful things is music scientifically accountable for?

Bob Snyder contends that memory and its limitations influence how we perceive and structure events and time sequences. It is very rarely the case that music is not used for communication – be it an idea, an emotion or a story – and where this occurs, musical structure must consider the structure of auditory memory. Echoic memory, short-term memory and long-term memory comprise the three auditory memory processes that correlate accordingly with three different musical levels based on the differences in their time scales. The level of fusion represents the early unconscious processing of frequency and pitch. The level of melodic and rhythmic grouping constitutes the acquisition of melodic and/or rhythmic phrases that last as long as the timescale for short-term memory. Finally, the level of form, associated with the chemical and structural changes in the brain that occur during unconscious processing of long-term memories, correlates with entire sections of musical pieces (Snyder, 2000). What does this mean? Well in short, Snyder is trying to convey the importance of using memory to understand the organisation of music. Can the correlation between music and the neural processes within our brain be the reason that it resonates so strongly within us?

More astoundingly is the recent discovery of a neural population specific to the perception of music as reported by MIT news video:

https://www.youtube.com/watch?v=HhTCOlJ-nh4

Despite the excitement surrounding this discovery, it still leaves a lot of questions unanswered. It isn’t clear whether we respond the way we do to music as a result of having a specific neural population to do so, or whether as a consequence to incorporating music into our lives we have evolved that ability. Equally so, the location of these neurons does not tell us anything more than that they exist…for now. But it is an important starting point necessary to aid this exploration.

Neuroaesthetics is novel area of neuroscience that aims to investigate the neurobiological mechanisms behind our response to art. I believe that we are well on our way to understanding why music is such an integral part of being human and I think we can only do so by increasing awareness of this field of neuroscience – a field I am eager to become a part of. The aim of my blog series is to discuss and ask questions about art and the brain with the ultimate goal of raising awareness, and more importantly interest, in such an exciting area of research. For those who are already intrigued take a look for yourself: http://neuroesthetics.org/

Stay tuned!

References:

Society, A. Singing for the Brain – Alzheimer’s Society. Alzheimers.org.uk [online]. Available from: https://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=760 [Accessed March 3, 2016].

 

Snyder, B. 2000. Music and memory. Cambridge, Mass.: MIT Press.

 

Trafton, A. 2015. Music in the brain. MIT News [online]. Available from: http://news.mit.edu/2015/neural-population-music-brain-1216 [Accessed February 16, 2016].

 Author: Tiffany Quinn

Editor: Molly Campbell

Being Bilingual- What Happens to Your Brain When You Learn a New Language?

One of the most remarkable factors that separate human beings from other species is the ability to communicate through the sophisticated tool of language. It is also true that one of the most extraordinary characteristics of the computational machine in which language is developed, the brain, is modified and structurally influenced by the environment and the experiences we have in our daily life. Interestingly, the process of learning two different languages, whether this be from birth (early or simultaneous bilingualism) or later in adulthood (late or sequential bilingualism), results in structural and functional modifications of the brain. In the last two decades many disciplines have started to investigate these neurostructural changes and the benefits of being bilingual, an example being potentially delayed dementia onset. Here you can find described the last studies and more interesting research outcomes.

 

NEUROSTRUCTURAL AND NEUROFUNCTIONAL MODIFICATIONS

The best way to study whether the assimilation of a second language modifies (at some level) the brain structure is to obtain brain images through Magnetic Resonance Imaging (MRI), and observe if any difference in bilinguals’ brain exist. Indeed, Klein D. et al, did this. In 2013, they compared the thickness of the inferior frontal gyrus (IFG), (Figure 1)- (the area of the frontal lobe which is involved in language articulation) in monolinguals and different types of bilinguals. The study showed that the left pars reticularis and pars orbitalis (the most anterior parts of IFG), are significantly thicker in late bilinguals (age of acquisition from 4 to 13) than in monolinguals. This finding may show that the acquisition of a second language after the most sensitive period of language learning (early childhood), causes quantifiable alterations in brain regions involved in this new task learning. These adaptations are comparable to the acquisition of complex motor tasks such as juggling (Klein D. et al, 2013).

Furthermore, the study illustrated a positive correlation between age of language acquisition and thickness of the aforementioned area, which means that the later the second language is learnt, the thicker the IFG is. This result would suggest that, the highest level of structural modifications are greatly enhanced when the sensitive period for language acquisition is chronologically as far away as the second language is learnt.

Interestingly, this hypertrophic effect of the left IFG is completely reversed in individuals that developed simultaneously two languages since birth. In these type of bilinguals the left IFG is thinner than in monolinguals and the right IFG is thicker. It is widely known that the language is a “lateralised” function of the brain, in simple words: the left hemisphere is responsible for that function. So why do we find an increased structural development in the opposite hemisphere in this case? Well, the most intuitive answer to this phenomenon is that the exposure of these children to two languages since birth probably, not only causes structural brain modifications but also leads to a reorganisation of these areas functionalities.

 

cristina 2

Figure 1. The Inferior Frontal Gyrus in the frontal lobe is anatomically divided in three subregions (from rostral to caudal): pars orbitalis, pars triangularis and opercular pars.

Notle J., Angevine J.B., 2013

Berken A.J. et al, in 2016, studied the correlation between the neural connectivity -the connection between populations of neurons linking the right hemisphere and left hemisphere IFG-, against the level of activation of these areas when producing the same speech in early and late bilinguals.

This comparison used functional MRI, and demonstrated that simultaneous bilinguals, have a higher functional connectivity between the homologous structures (IFG) of both sides. In simple terms, the stronger the neural connection between the left and right structures, the lower the activation of the neurons required to produce the same sentence in the second language (Figure 2). This amazing finding not only demonstrates that the assimilation of two languages since birth leads to enhanced neural connectivity, but it is also a great example of brain functional reorganisation in response to a stimuli received in in early childhood.

cristina 3.png

Figure 2. Graph showing the negative correlation between the neural activation (% BOLD) in simultaneous and sequential bilinguals, against neural connectivity (Fischer’s Z).

Berken J.A. et al, 2016

BILINGUALISM AND DEMENTIA ONSET

By determining the neurostructural and neurofunctional modifications that occur in bilinguals’ brain, scientists have generated controversy regarding the general beneficial effects that bilingualism seems to provide. In particular, the greatest beneficial effect that has been identified is the delay in dementia onset in individuals fluently speaking two languages.

Dementia comprises a wide range of brain disorders that manifest themselves with symptoms that mainly concern progressive and irreversible cognitive decline. The cognitive functions initially affected are generally memory, orientation in space and events and impaired ability to perform everyday tasks ( Argonin M. E., 2008). Bialystok E. et al in 2006 studied 184 patients diagnosed with dementia, of which half ( 51 %) were bilinguals. The amazing finding was that, bilingual individuals developed the first symptoms of dementia on average 4.1 years later than the monolinguals.

One of the major critiques raised to these types of studies, is that the population tested often included immigrated populations and thus the delay in dementia onset could be due other environmental or biological factors rather than the use of two languages. However, a more recent study (Alladi Suvrana D.M. et al 2013), addressed this issue by studying the dementia onset of the indian population, which is mainly bilingual for historical reasons and not for immigration causes. Furthermore, the study compared the monolingual and bilingual groups subdividing further the population based on different variables such as level of education, occupation and severity of dementia. The result of this study showed a delay in dementia onset in bilinguals individuals of 4.5 years, and for three types of dementia: Alzheimer’s, frontotemporal dementia and vascular dementia. However, speculation surrounds the theory of bilingualism delaying dementia onset. The reason being is that, ultimately, not enough information is known about the pathway through which this effect is brought about.

However, it is important to understand that, if bilingualism is responsible for this great delay in dementia onset not only it would be absolutely beneficial for the individual, but it also would represent a great advantage under a socio-economical point of view, and learning a second language should be highly encouraged. For instance, it has been calculated that a delay in dementia onset of 2 years in USA would decrease the prevalence of the disorder of 1.94 millions in 50 years. (Brookmeyer R et al., 1998 as cited in Bialystok E. et al, 2006).

In conclusion…

It is important to take into account the fact that cognitive, structural and functional benefits of bilingualism could widely vary in relation to the type of bilingualism, proficiency and age of learning. It is not possible to state for definite that whoever speaks fluently two languages will undoubtedly preserve his/her cognitive functions better than monolinguals in their lifetime. Furthermore a variety of other environmental, biological and educational factors can support and synergically contribute to the protective effects against many types of dementia. However, there is supporting evidence that infers to bilingualism as being a protective factor. Also, one of the most important benefits of speaking more than one language is without any doubts the ability to communicate and exchange information with more people. and the opportunity to discover new cultures…so, why not give it a try?

If you cannot visualise the IFG from the diagram then take a look at this interesting animation.

https://www.youtube.com/watch?v=lUankRKa0-4

References

 

  • Argonin E.M., 2008, Alzheimer disease and other dementias, second edition, Philadelphia, Lippincot Williams & Wilkins

 

  • Berken A., Chai X., Chen J.K., Gracco V.L., Klein D., 2016, Effects of Early and Late Bilingualism on Resting-State Functional Connectivity, The Journal of Neuroscience, 36(4): 1165-1172

 

  • Hickok G., Small S.L., 2016, Neurobiology of Language, USA, Elsevier Sanders

 

  • Klein, Mok K. , Chen J.A., Watkins K.E., 2013, Age of language learning shapes brain structure: A cortical thickness study of bilingual and monolingual individuals, Brain & Language, 131 (2014) 20–24

 

  • Notle J., Angevine J.B., 2013, The Human brain in Photographs and Diagrams, 4th Edition, Philadelphia USA, Elsevier Sanders

 

  • Stephen, Does bilingualism delay dementia?, 2015, CMAJ Canadian Medical Association Journal, Volume 187(7), 21 April 2015, p E209–E210

 

  • Suvarna , Thomas H.B., Vasanta D., Bapiraju S., Mekala S., Kumar S. A.,; Jaydip Ray C., Subhash K., 2013, Bilingualism delays age at onset of dementia, independent of education and immigration status, Neurology, Volume 81 (22), p1938-1944

 

  • Bialystok E., Craik F.I.M., Freedman M., 2006, Bilingualism as a protection against the onset of symptoms of dementia, Volume 42 Issue 2, Pages 459–464

 

Author: Cristina Cabassi 

Editor: Molly Campbell

Fear: Learning and Conditioning

Introduction

We’ve all experienced the stomach dropping, paralysing feeling of fear, but how many of you have stopped to wonder what it is that makes us feel this way? Many fears are learned during our lifetime, some of which remain with us forever, others fade with time. Yet more fears appear to be more deep-seated and instinctive.

Fear to stimuli can be ‘taught’ in a lab by applying a neutral stimulus (known as the conditioned stimulus) to an animal, alongside something to cause aversion, such as a foot shock (known as the unconditioned stimulus). After multiple trials, the non-scary stimulus will stimulate a fear response without the foot shock. This process is known as fear conditioning.

Fear learning is a very unique neurological process, as it only requires one experience to be ingrained long-term in the brain, and is easily retrieved upon exposure to the same stimulus. The basis of the fear conditioning procedure relies on us having innate fears for the unconditioned stimulus, and the ability to learn new fears via the conditioned stimulus.

Fear association

As a natural part of human functioning, many of our memories are ‘unlearned’ to prevent an overload on the brain. Contextual fears are associated with memories, so can be lost throughout our lifetime, often overlaid by new memories in the presence of the fear-provoking stimulus in a different environment. These kind of fears are often not completely forgotten, so can produce a response in an environment associated with the fear-stimulus, even without the existence of the stimulus itself.

Memories are thought to be stored in an area of the brain known as the hippocampus. Studies have taken place to assess the importance of this region in the storage of contextual fears, and have found that removal of the hippocampus led to a normal fear response during conditioning, but none caused by the environment. This illustrates how closely related the memory and fear systems are.

Another region of the brain involved in fear learning is the amygdala. Damage to an area of this, known as the basolateral nucleus, results in a disruption to the development of fear associated with a particular stimulus.

Contemporary and ancient threats

A puzzling field of fear research is the distinction between innate fears that appear to pass from generation to generation and the fears developed by an individual’s experience. An example of an intrinsic fear is falling from a height; no one has told you to be afraid of this, and if you’re reading this it probably isn’t a fear you’ve learnt yourself, yet something is causing you to avoid jumping from tall buildings.

This kind of instinctive fear has been found to be more difficult to “switch off” compared to contemporary fears learned through conditioning. In one study, people were conditioned to produce a fear response to images of weapons, such as guns and knives, and predators, such as spiders and snakes. Although fear conditioning was similar in both types of image, it was found that fear extinction, aka the loss of fear response to the stimulus, took much longer for the predator images (Fox, E., 2012). This suggests that this kind of ancient threat forms stronger connections within the brain.

An interesting twist on intrinsic fear is a phenomenon known as illusory correlation. Here, volunteers in trials describe a slanted likelihood of an event having taken place during the study. For example, in a study by Sue Mineka, Michael Cook and Andrew Tomarken at Vanderbilt University, volunteers were shown a variety of threatening and non-threatening images, each with an equal likelihood of being accompanied by an electric shock, a loud tone or nothing. Despite this, the volunteers all said that there was a link between seeing a threatening image and getting shocked.

Another study by Richard Viken at Indiana University showed female volunteers images of underweight, normal and overweight women, all equally likely to look happy or sad. The volunteers however thought that the thinner women looked happier. Remarkably, this correlation was particularly pronounced in women with a history of eating disorders. This illusory correlation may play a role in the understanding of our instinctive fears.

The science behind fear

As fear conditioning involves the association of a particular stimulus with one that produces a fear response, it requires the integration of multiple senses. Auditory and somatosensory stimuli are thought to converge in the lateral amygdala, which indirectly sends projections to the brainstem and the hypothalamus. The hypothalamus is a brain region important in expressing defensive behaviour and autonomic response. (Sigurdsson, T. et al., 2007)

Two vital areas of the brain involved in the fear response are the previously mentioned amygdala, and the dorsal medial prefrontal cortex. Rhythmic activity at a specific frequency along the neuronal connections between these regions has been connected to the ‘freezing’ response in laboratory rats exposed to aversive stimuli. This recent discovery may provide a target for therapeutically treating anxiety disorders, by reducing the physiological symptom expression of fear. (Anon., 2016)

 

Conclusion

Fear is something that affects most of us daily, whether it’s nerves for a presentation, shying away from a loud noise or being unable to take a shower because of that large spider lurking in the corner. These can be categorised into innate fears, that we’re born with, and conditioned fears that we learn as we experience life. Fear conditioning in the lab has provided us with information about the pathways within the brain, and the way that responses to different types of fear can change over time.

Untitled

[Sigurdsson, T. et al, 2007]

References

Anon, 2016. Study unravels physiological signature of fear memory within prefrontal-amygdala networks. News Medical. Available at: http://www.news-medical.net/news/20160223/Study-unravels-physiological-signature-of-fear-memory-within-prefrontalc2adamygdala-networks.aspx [Accessed February 23, 2016].

Fox, E., 2012. Rainy Brain, Sunny Brain, London: Arrow Books.

Sigurdsson, T. et al., 2007. Long-term potentiation in the amygdala: A cellular mechanism of fear learning and memory. Neuropharmacology, 52, pp.215–227.

Article Author: Ellie Sanderson

Editor: Molly Campbell