I can’t seem to get away from the theme of Mozart and epilepsy. When I first looked at this, in a blog post titled Mozart and seizures? The links between epilepsy and music, I took the topic rather lightly, more a subscript than a headline you may say. But I have since learnt to take the links between epilepsy and music more seriously.
The major trigger for my ‘road to Damascus’ conversion is a 2018 paper titled Study of the Mozart effect in children with epileptic electroencephalograms, published in the journal Seizure. The paper was an eye-opener because it gave a very helpful comprehensive context to the broader beneficial effect of music…not just in epilepsy, but in other neurological disorders such as Parkinson’s disease, dementia and sleep disorders. The authors, Elyza Grylls and colleagues, started on the established premise that Mozart’s music has a beneficial effect on epilepsy. What they wanted to know was if other forms of music have a similar settling effect on epilepsy, or if only Mozart’s music carries the magic touch. The authors therefore played Mozart’s Sonata for two pianos in D major (K448) to 40 children with epilepsy who were undergoing an EEG (electroencephalogram, or electrical brain wave test). They then compared this with the effect of playing other types of music. Remarkably, they found that only Mozart’s Sonata led to a significant reduction in EEG epileptic discharges.
The authors concluded that there was indeed an anti-epileptic effect of Mozart’s music, the so-called ‘Mozart therapy’. But what is so special about K448? They speculate that it has to do with the structure of Mozart’s music, containing as it does, long periodicities. Interestingly, the music of Yanni, which is similarly structured, has somewhat a similar effect on brain wave activity. On the contrary, and sorry to Beethoven fans, Fur Elisedoesn’t have this effect.
By Bionerd – MRI at Charite Mitte, Berlin (used with permission), CC BY 3.0, Link
You have surely wondered by now whether K448 is the only one of Mozart’s compositions to have an anti-epileptic effect. It doesn’t matter if you haven’t, because the authors of another interesting paper have. They titled their study, published in 2018, Mozart’s music in children with drug-refractory epileptic encephalopathies: comparison of two protocols. Published in the journal Epilepsy and Behaviour, the authors,Giangennaro Coppola and colleagues, compared the effect of K448 with a set of his other compositions. Intriguingly they found that the composition set actually had a greater effect in epilepsy than K448…by a wide margin of 70% to 20%! Furthermore, the set was better tolerated by the children; they were less irritable and had a better nighttime sleep quality.
So, is it all rosy in the garden of music and the brain? No, it’s not! As every rose grows on a thorny tree, so do some forms of music trigger epileptic seizures. This so-called musicogenic epilepsy is well-recognised, and two recent culprits are the music of Sean Paul, discussed in the journal Scientific American , and the music of Ne Yo, explored by NME. Therefore you should craft your playlist wisely.
I recently posted on the role of vagus nerve stimulation (VNS) in epilepsy. Exciting as it is, there are several cutting edge developments in epilepsy that are making VNS ‘old school’. Here is a round-up of 12 such developments
Big Data is spreading its tentacles everywhere and epilepsy is no exception. Take this review in Lancet Neurology for example; titled ‘Epilepsy in 2015: the year of collaborations for big data’, it reviews the impact of big data in five key epilepsy areas such as surgery, effect of epilepsy on pregnancy, and risks if anti-epileptic drugs (AEDs). I was however more impressed by the paper in Neurology titled Predicting frequent ED use by people with epilepsy with health information exchange data‘ which shows how big data may be used to identify frequent emergency department attenders. The authors showed how big data achieves this; the whole aim is to pick out those patients may benefit most from targeted-interventions. The article itself doesn’t mention big data, but the accompanying editorial fortunately does.
The management of epilepsy is very dependent on the accurate assessment of each patient’s day-to-day event pattern. In the simplest form, this is by a seizure diary. Seizures, the abnormal electrical brain activity that result in epilepsy, do not always manifest as recognisable events. Furthermore, many abnormal movements and behaviours do not necessarily arise from seizures. The neurologist therefore often recommends some form of prolonged brain activity monitoring to sort out what is actually happening. This is often done with procedures such as ambulatory electroencephalogram (EEG) and video EEG telemetry. These are all inconvenient and may only be used for a limited period. It is therefore reassuring that there are better techniques on the way. This press release from the World Federation of Neurology titled New epilepsy monitoring devices offer alternatives to inpatient video EEG lists ‘an array’ of devices such as the Brain Sentinel® System and the EEG PatchTM. These go further than just identifying the seizure activity; they‘allow patients to monitor clinical and subclinical seizure activity in the everyday home environment and get advance warning before a seizure strikes‘. What could be better for people with epilepsy?
Epilepsy is a disease with several types and subtypes, and many genetic forms. Treating epilepsy therefore requires a close fit (no pun intended) of the disease type to its treatment. This is however a difficult task because many epilepsies are poorly defined, and the activity of anti-epileptic drugs (AEDs) are poorly understood. Whilst there are general principles of action of AEDs, these may not apply to individual patients. Herein then lies the promise of precision medicines which, making use of the patient’s genetic makeup or genome, offer a better match of AEDs to individuals. It is still early days but the course is being charted; the EpiPM Consortium recently published ‘A roadmap to precision medicines in the epilepsies‘ in Lancet Neurology.
Sudden unexpected death in epilepsy (SUDEP) is a nightmare. It strikes out of the blues, shocking families and neurologists alike. How to predict and prevent this phenomenon is aholy grail in epilepsy care. It is therefore gratifying news in a recent article in the journal Brain that there is a potential SUDEP imaging biomarker. The authors of the paper, titledStructural imaging biomarkers of sudden unexpected death in epilepsy, report that the magnetic resonance imaging (MRI) scans of people at risk of SUDEP show characteristic signs. The main feature is a larger grey matter volume in the right hippocampus and amygdala. The rest of the story is more tricky to understand and involves impaired oxygen regulation leading to the abnormal heart rhythms that presumably cause SUDEP. OK, just take it that this is a potential biomarker to risk-stratify patients for SUDEP!
A generalised tonic-clonic (or grand mal) seizure often self-terminates within 5 minutes. It may however be prolonged, or occur repeatedly, and this is called status epilepsy or status epilepticus. Out-of-hospital care to terminate status epilepticus often involves the use of buccal Midazolam or, thankfully fading into history, rectal Diazepam. The most effective short-term treatment is however intravenous Lorazepam, but this may only be administered in hospital. Is there something as effective as intravenous Lorazepam which could be administered by paramedics in the community? You guessed it, there probably is. A recent trial published in the New England Journal of Medicine (NEJM) shows that pre-hospital intramuscular Midazolam delivered by paramedics is effective. There are safety issues to sort out but this development promises to avert brain damage that may result from prolonged convulsions. Neuroscience News offers a simplified versionof this study.
6. Optogenetics to improve arousal during a seizure
Optogenetics is the use of light to control cell activity in living tissues. I previously listed this in my previous post as one of 10 remarkable breakthroughs that will change neurology. A recent paper in the journal Epilepsia showed how optogenetics may improve epilepsy. Published under the rather unwieldy title Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures…., the authors report the application of optogenetics to stimulate subcortical brainstem cells during a focal epileptic seizure. The story is rather complicated but this technique somehow causes inhibition of the cortical cells that generate seizures. A lot of the physiology remains to be sorted, but hey, its shining a light on a difficult problem!
The electroencephalogram (EEG) is an indispensable tool in the diagnosis of epilepsy. It helps, amongst other things, to localise the site of a seizure discharge, and to classify the epilepsy type. It is however a rather insensitive tool for planning epilepsy surgery compared to imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) scans which are far better. 3D EEG is however set to make its mark in this area if a recent paper in Epilepsia fulfils its promise. Titled ‘The diagnostic utility of 3D electroencephalography source imaging in pediatric epilepsy surgery‘, the authors show that 3-D EEG is comparable to PET and SPECT in planning epilepsy surgery; and it is also cheaper and less risky.
8. Neurotransmitter imaging of epilepsy
By courtesy of Massachusetts General Hospital and Draper Labs [Public domain], via Wikimedia Commons
Epilepsy surgery relies on accurate mapping of the seizure focus. Current techniques are however still suboptimal and scientists are exploring better ways of doing this. One promising field is neurotransmitter-based imaging, and the main neurotransmitter here is glutamate. This MRI technique called glutamate chemical exchange saturation transfer (GluCEST) promises to identify seizure foci that are otherwise difficult to detect. You may read the technical aspects in the original paperin Science Translational Medicine, or go for the layman’s versionin Neuroscience News.
An extension of glutamate imaging uses PET scans and relies on imaging NMDA, one type of glutamate receptor. This technique is reported in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP) in an article titled NMDA receptor binding in focal epilepsies. The principle behind NMDA imaging is the knowledge that NMDA receptor ion channels are overactive in epilepsy. Isn’t it nice when science follows first principles!
Surgery is a very useful tool in treatment of drug-resistant epilepsy. Epilepsy surgery is however not universally successful because localisation of the seizure focus is often imprecise. One promising way to improve the localisation of the seizure focus is to map the changes in oxygen levels that occur in the brain during an epileptic seizure. A paper in the JNNP reports that this is feasible with the use of simultaneous EEG (electroencephalography) and fMRI (functional magnetic resonance imaging). It’s all rather complicated stuff and I recommend this version from the Epilepsy Societywhich offers an excellently simplified summary.
A holy grail of epilepsy (OK, there are many holy grails) is to individualise all types of epilepsy treatment, including surgery. Personalised epilepsy surgery is guided by a simulated model of a patient’s brain neural connections or connectome. This technique is reported in PLOS Computational Biology under the title Predicting surgery targets in temporal lobe epilepsy through structural connectome based simulations. Why scientists love long windy titles baffles me. Anyway, the authors first acquired a map of their subject’s brain connectivity using an MRI technique called diffusion tensor imaging (DTI). They then applied a computerised model of how a seizure propagates to the connectivity map. In this way they are able to establish a more accurate surgical target. The area that is resected at surgery using this technique produced better outcomes than resection using a standard procedure. Makes sense to me.
Although surgery is a good technique for epilepsy, it is an invasive procedure with attendant risks. Endoscopy, using minimal access to perform great feats, reduces this risk significantly. It is widely practiced in medicine and indeed neurosurgeons use it to relieve raised intracranial pressure in some cases. It is therefore a relief to learn that major epilepsy operations may be performed endoscopically. A recent article in the Journal of Neuroscience titled ‘Endoscopic corpus callosotomy and hemispherectomyreports the effectiveness of endoscopy in epilepsy operations such as corpus callosotomy; a procedure that interrupts the large bundle of nerve fibers that connect the two brain hemispheres. You may read the easy versionin Mental Floss.
Deep brain stimulation (DBS) is now routine in many neurological diseases such as Parkinson’s disease (PD). Epilepsy has been slow to catch on but this is changing. A recent piece on the Mayo Clinic website peered into the future treatment options for epilepsyand referred to pacemaker-like devicesto control the seizure focus. There are many studies showing the feasibility and effectiveness of implantable devices which directly stimulate an epileptic focus to abort a seizure. One such system is Responsive Brain Neurostimulator (RNS® System). It may be counterintuitive but stimulation rather than suppression is the key. A review of Responsive neurostimulation in epilepsy says ‘the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or even prevent an upcoming seizure’.
The future is bright for epilepsy care-and it can’t come soon enough for the millions of people whose lives are restricted and compromised by this disease.
The brain is a mystery and that is why neurologists find it fascinating. The more we know, the more it tantalises us with its hidden gems. Great neurologists have waxed lyrical about the ability of the brain to elude all efforts to fully understand it. Santiago Ramon y Cajal for instance says:
“The brain is a world
consisting of a number of unexplored continents
and great stretches of unknown territory”
Non-neurologists are similarly awed by the brain. Emerson M. Pugh for example says:
“If the human brain were so simple that we could understand it,
we would be so simple that we couldn’t”
Neuroscience and neuroanatomy are at the forefront of exploring this great unknown; the research output from these fields is mind-boggling (pardon the intended pun). But which recent findings are most likely to change neurological practice in the near future? Here are my top 6.
The finding however raises hope of better treatments for some neurological diseases. Because the lymphatic system is closely linked to the immune system, multiple sclerosis (MS) is one potential beneficiary of this discovery. Because lymphatics also act as drainage systems, there are implications for conditions such as Alzheimer’s Disease (AD). Hopefully this brain lymphatic system could be manipulated to clear the accumulated abnormal proteins that cause AD and other neurodegenerative diseases.
The brain’s extensive connections is one of its enduring and fascinating mysteries. The winding fibers and tracts, meandering and looping around each other, demonstrate the brain’s complexity. As soon as we think we have grasped it all, along comes a discovery that causes a paradigm shift. This is illustrated by the report of the discovery of a new brain network involved in memory processing. This Parietal Memory Network (PMN), in the brain’s left hemisphere, responds differentially to new and to old information. This may have relevance for cognitive disorders such as Alzheimer’s Disease (AD). For the more technical details of the network, the paper is published in the journal Trends in Cognitive Neuroscience.
In a similar vein is the discovery of previously unknown brain fiber tractscalled the vertical occipital fasciculus (VOF). This new ‘brain corridor‘ is involved in visual processing. The research paper, published in the Proceedings of the National Academy of Science (PNAS), says the VOF is important in the perception of words and faces, amongst other things, and is ‘involved in the control of eye movements, attention, and motion perception‘. The main benefit of this finding is the improvement of our understanding of how the brain learns to read.
The common assumption that the electrical activity of the comatose brain flatlines on the electroencephalogram (EEG) now appears to be a misconception. This is according to a report of the discovery of a previously unknown electrical brain activity in deep comasuggests. One journal reported this as the discovery oflife after brain death!
These electrical waves, seen in deep coma, are called Nu complexes. They are well-described in the original paper in PLoS One. This finding will alter our definition of brain death which relies very much on the absence of organised brain electrical activity. Another implication is for patients whose medical conditions require that they are put into a coma; this finding will potentially guide the anaesthetist to apply the best form of induced coma.
5. Newly discovered brain cell type
I thought I learnt all the different types brain cells or neurones that exist when I was in medical school. The mysterious brain however has a joker at every corner. The report of the discovery of a new type of neuroneshould come as a surprise, but by now we have learnt not to be shocked by new brain discoveries. The strange thing about these cells, found in the hippocampus of the the brains of mice, is that they have direct connections between their axons (the single long tail) and their dendrites (the smaller hair like projections). This connection by-passes the nerve body; this direct connection enhances the strength of the signals the cell generates. The reason for this peculiarity is not clear but, because the hippocampus is the seat of memory, I guess there are implications for cognitive disorders.
6. Newly discovered brain repair enhancers
We know that the brain repairs itself (neuroplasticity), and that brain fibers make new connections even if this occurs very slowly. What is new is that these processes can be enhanced or accelerated by external agents. Two interesting substances recently reported are psilocybin and curry. Yes, healing mushrooms and spices!
It appears that Psilocybin (psychedelic mushrooms) can establish stable connections between parts of the brain which do not normally communicate well. The research on this is published under the title ‘Homological Scaffolds of Brain Functional Networks‘. The paper describes how psilocybin helps in nerve re-wiring with the potential implications for the treatment of depression and addiction. A bit paradoxical, using an addictive substance to treat addiction; but hey, this is the brain we are talking about!
Curry on the other hand contains tumeric which contains tumerone. Tumerone has now been shown to help with nerve growth repair, and it does this by causing proliferation of brain nerve cells. The research itself is titled ‘Aromatic-tumerone induces neural stem cell proliferation in vitro and in vivo‘. It is a study in rats, but are human brains very different? Potential beneficiaries are all the neurodegenerative diseases which neurologists have singularly failed to reverse.
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