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The potential mechanism of musicogenic epilepsy and future research avenues

The potential mechanism of musicogenic epilepsy and future research avenues BioscienceHorizons Volume 10 2017 10.1093/biohorizons/hzx004 .............................................. .................................................. .................................................. ............... Review article The potential mechanism of musicogenic epilepsy and future research avenues Liddy Ellis School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK *Corresponding author: Cobweb Cottage, New Road, Eckington, Pershore WR10 3AZ, England. Email: le12389@my.bristol.ac.uk Supervisor: Andrew Doherty, Office G.21, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK. Email: a.doherty@bristol.ac.uk .............................................. .................................................. .................................................. ............... Musicogenic epilepsy is a rare form of reflex epilepsy in which seizures are triggered by certain pieces of music. Musical pro- cessing involves interpretation of perceptual elements such as tempo and pitch, and also emotional associations and mem- ory formation. It is hypothesized that the emotional impact of music is more likely to precipitate musicogenic seizures through involvement of the mesolimbic system. This may link these seizures to other types of reflex seizures that also involve emotional responses. Current treatment is restricted to anti-epileptic drugs and surgery, which is not always an option for patients due to eligibility or availability, for example in developing countries. The scientific literature on this topic is very lim- ited. Individual case studies have stated that patients report techniques they use to stop seizures such as distraction, but these have not been explored. Online forums seem to suggest the condition is more common than the scientific literature states, and so may be a useful resource to consider. After describing the normal processing of music and how this pathway may be affected in musicogenic epilepsy, the review discusses the potential relationship between musicogenic and other sei- zures, and why this is relevant. New avenues for research into alternative interventions for patients could be opened by con- sidering information on forums and case reports, and methods of doing this are discussed. Key words: epilepsy, music, seizures, reflex, treatments, emotion Submitted on 3 October 2016; editorial decision on 24 February 2017 .............................................. .................................................. .................................................. ............... by addressing current gaps in the knowledge and how they Introduction could be investigated to provide novel information about both musicogenic and other reflex seizures. Musicogenic epilepsy is a type of reflex epilepsy in which sei- zures are induced by ‘sounds in melodic or harmonic combin- ation, without stylistic or cultural restraint and excluding other non-startling sounds’ (Avanzini, 2003). First reported by Epileptic seizures Critchley (1937), this rare condition only affects 1 in 10 000 000 Epilepsy is diagnosed following two unprovoked seizures less people (Avanzini, 2003), yet the literature brings to light than 24 h apart, or two seizures occurring in response to a trigger some interesting concepts. This review aims to highlight these (Fisher et al., 2014). They result from synchronous firing of action points and discuss how they can be used as future avenues for potentials (APs) by groups of neurons, leading to overexcitation research into alternative treatments for seizures where surgery in selective parts of the brain. There are a wide range of potential and pharmacological interventions may not be suitable or causes, including genetic predisposition (Berg et al., 2010), infec- accessible. After a general overview on seizure mechanisms, tions, structural/metabolic conditions, idiopathic causes (Bhalla music processing and the potential ways this is affected in et al., 2011) and birth complications (Golomb et al., 2007). musicogenic epilepsy will be focussed on. The review will end ............................................................................................... .................................................................. © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. Different types of seizure occur depending on the underlying pathology and the area of the brain affected. The International League against Epilepsy (ILAE) classifies seizures as focal, where activity is restricted to one hemisphere of the brain, or generalized, which affects the entire cortex. Focal seizures can be described by the manifestation of their effects or by where they originate. For example, temporal lobe epilepsy (TLE) can origin- ate in the temporal lobe of the brain or can present with major behavioural effects on temporal lobe function. In contrast gener- alized seizures present more stereotypically, involving both hemispheres of the brain throughout the seizure (Berg et al., 2010). Generalized seizures can also begin focally and secondarily spread to the contralateral hemisphere, usually as tonic–clonic seizures (Browne and Holmes, 2008). Additionally, seizures can be described as simple or complex; in the latter a patient experi- ences an alteration of consciousness. The exact pathogenesis of seizure development is not com- pletely known, however, a basic mechanism has been out- lined. The transition of a normal neuron into one supporting epileptic activity is termed epileptogenesis. The neuron becomes hyperexcitable, making it easier to become and remain depolarized (Scharfman, 2007). Consequently, there Figure 1. (A) PDS. Initially the neuron has a resting membrane is a prolonged depolarization of the neuron, which occurs due potential of ≈−60 mV, then by epileptogenesis the PDS occurs. The to activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepro- membrane potential increases for a prolonged time and so a burst of pionic acid (AMPA) receptors and N-methyl-D-aspartate APs fire. Follow this, inhibition begins to overtake and so a hyperpolarization follows. Adapted from (Holmes and Ben-Ari, 2003) (NMDA) receptors (Westbrook, 2000). This results in a burst with kind permission from Nature Publishing Group. (B) The of APs (de Curtis and Avanzini, 2001), shown in Fig. 1A. mechanism of surround inhibition. Green neurons are excitatory, black Following a plateau phase, repolarization occurs leading to are inhibitory interneurons. When the middle neuron is activated, it an afterhyperpolarization of the neuron (Westbrook, 2000). stimulates the neurons both sides and the inhibitory neurons. This sequence of events is known as the paroxysmal depolar- Feedback inhibition is purple, and feedforward inhibition is red. When izing shift (PDS) (Matsumoto and Marsan, 1964), and it is the interneurons are activated, these pathways activate and shut down this that is associated with the initiation of seizure activity. the neurons. Loss of this means the excitatory green pathways are active, so APs are transmitted to neighbouring neurons. The PDS in a single neuron can then spread to local neu- rons through local synaptic transmission (Jeffreys, 2015), extracellular ion concentration changes (Jiruska et al., 2013), neurons to be inhibited simultaneously, overcoming it synchro- via gap junctions between neurons and glial cells (Rozental nizes neuronal firing (Trevelyan, Sussillo and Yuste, 2007). et al., 2001) or electric field transmission (Zhang et al., 2014). Neural circuits then allow synchronisation of other areas of As a result a seizure focus develops. It was thought the focus the brain. In TLE, there is a multifocal initiation in different parts originated from one specific place, but lately this has been dis- of the temporal lobe, especially very plastic areas, e.g. the hippo- puted instead suggesting seizures begin from multiple micro- campus (Bertram, 2013). The midline nuclei (MN) in the thal- seizures which amalgamate to form a larger focus (Stead, amus allow propagation of epileptic activity through ‘a divergent- Bower and Brinkmann, 2010). convergent-excitatory system,’ spreading both directly to other Synchronisation of the neurons exhibiting PDS leads to cortical regions, and indirectly via the MN. Excitation in this summation of burst firing APs. However, in order for a seizure region stimulates neurons in other areas of the cortex to syn- to occur, more neurons need to be recruited and the afterhy- chronize, which repeats resulting in a seizure (Bertram, 2013). perpolarisation needs to be diminished. The loss of surround The mechanism behind termination of a seizure is more inhibition (Trevelyan et al.,2006), explained in Fig. 1B, is key. uncertain. There are many theories as to how this may occur, Many excitatory cells have feedback and feedforward inhib- including hypersynchrony (Timofeev and Steriade, 2004) and ition to prevent hyperexcitation via activation of surrounding recovery of inhibition in susceptible areas which subsequently GABA-ergic inhibitory interneurons (Jiruska et al., 2013). spreads. Overcoming this surround inhibition recruits other excitatory neurons (Trevelyan et al., 2006), spreading the seizure to the Reflex versus spontaneous seizures next ‘line’ of connected neurons where it is limited until inhib- ition here is overwhelmed. This is termed the ‘wave of inhibition’ The majority of seizures occur spontaneously. However reflex (Jiruska et al., 2013) and because this causes large numbers of epilepsy describes an abnormal predisposition to seizures ............................................................................................... .................................................................. 2 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. following exposure to a stimulus, affecting around 7% patients (Symonds, 1959). The type of seizure occurring var- ies depending on the precipitant, such as reading or music (Kasteleijn-Nolst Trenite, 2012). Distinguishing reflex epi- lepsy has been difficult for many reasons, including overlap with patients experiencing both spontaneous and reflex sei- zures, discrepancies in defining a trigger (Irmen, Wehner and Lemieux, 2015), and variations in time delays between expos- ure to a stimulus and a seizure. This disagreement has led to a theory that epileptic seizures are in fact on a spectrum ranging from reflex to spontaneous, including patients who experi- ence both, have factors that increase the likelihood of a seiz- ure, or have more than one trigger (Nakken et al., 2005). But why do reflex seizures occur? It is possible that general precipitating factors lower the threshold for more specific stimuli to cause seizures in certain people, resulting in differ- ent types of reflex epilepsies. In addition to this an initial event altering a particular brain network and predisposing it to hypersynchrony could allow a specific stimulus to overcome the threshold for seizure activity (Irmen, Wehner and Lemieux, 2015). A genetic component has also been sug- gested for certain seizures (Ratnapriya et al., 2009). There are many different stimuli that can precipitate seiz- ure activity. They can be intrinsic or extrinsic, and can involve higher processing centres (Irmen, Wehner and Lemieux, 2015) such as the mesolimbic pathway. The involvement of this pathway in many triggers (Wilkins et al., 1982) supports an idea that different seizures may actually be part of a group of epilepsies involving dysfunction in decisive, associative and emotional circuits. The reason they present differently could be due to the exact connection within the limbic system that is affected by epileptogenesis. These seizures could therefore be classed together rather than segregated. It is here that the phenomenon of musicogenic epilepsy is relevant. However, before exploring the mechanisms by which music may result in epileptic seizures, one must first consider how music is processed in the brain. Music processing The mechanisms behind the processing of music in the brain have been studied extensively. Many aspects remain uncertain, due to both limitations in animal experiments (Zatorre and Figure 2. Pathway involved in transmitting vibrations from music (green) into action potentials (orange) before reaching the auditory Salimpoor, 2013) and the issue that altering music can result in cortex (blue) for further processing. it becoming sound, which case reports suggest involves different circuits (Peretz et al., 1994, 2002; Griffiths et al., 1997). The current understanding is that vibrations in the air hit auditory cortex, which is arranged tonotopically (Talavage the tympanic membrane and are transmitted through the ossi- et al., 2004). This sequence is displayed in Fig. 2. cles in the middle ear, causing movement of the oval window and fluid in the cochlea. Here the basilar membrane allows The processing of pitch in music differs from speech, lan- conversion of fluid vibrations into APs in the cochlear nerve, guage and environmental sounds in a variety of ways, as in which travels via the cochlear nucleus and inferior colliculus speech pitch continuously changes while in music it is orga- to the medial geniculate body in the thalamus (Griffiths et al., nized and consists of specific notes, requiring more accuracy 2001). From here information is relayed to the primary to detect pitch. This may be a feature of the right cerebral ............................................................................................... .................................................................. 3 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. hemisphere as it dominates in music. Humans are likely born with this lateralization to enable different interpretation of sounds, meaning that as the brain develops if a car alarm, speech or music all have the same pitch people can distinguish between them (Levitin, 2007). Tonality, tempo and harmonies are also integrated to form melodies, and as more components of melodies are processed activity spreads outwards from the primary auditory cortex (Zatorre, Evans and Meyer, 1994; Griffiths et al., 2001; Patterson et al., 2002). Previous knowledge is required about how different notes combine to form a melody, and to recognize when something is ‘out of tune’. This must be based on prior retention of audi- tory information, in which the inferior frontal cortices, the right parietal and insular cortices have a role (Zatorre, Evans and Meyer, 1994; Maess et al., 2001). Numerous functional loops integrate other functions such as movement, activating the basal ganglia, premotor cortex and frontal regions in response to timing (Grahn and Brett, 2007). Emotional associations of music Figure 3. Activation of brain regions in response to music associated In addition to the perceptual side of music processing there is with different emotions. Emotions categorized as high or low valence also the affective side, where the emotional impact of music and high or low arousal show different regions of increased activity. develops. The mesolimbic system is considered responsible While emotions such as tenderness activate more medial and frontal for emotion, reward and motivation (Haber and Knutson, areas, wonder, joy and power also activate the lateral temporal lobe. Taken from (Trost et al., 2012). Open Access, Creative Commons 2010), and associations between dopamine release in this sys- Attribution Non-Commercial License. tem and listening to pleasurable music suggest its involvement in applying an emotional characteristic to music (Salimpoor et al., 2011). to music, highlighting the occurrence of reward processing. The amygdala has projections to the nucleus accumbens Involvement of the orbitofrontal cortex and inferior frontal (Lehne, Rohrmeier and Koelsch, 2014), auditory cortex and cortex with the nucleus accumbens also indicates connections medial geniculate body (Koelsch and Skouras, 2014), connect- between emotional effects of music and cognitive functions ing the auditory and reward systems. By determining positive such as decision making and expectation. Connections and negative reward values it acts as a major input of auditory between the prefrontal cortex, mesolimbic system and audi- information into the mesolimbic system. Hippocampal con- tory cortex allow the brain to relate music to dopamine nections then encode these in memory (Koelsch and Skouras, release and surrounding events, resulting in retention of this 2014). information and how it is perceived (Zatorre and Salimpoor, 2013). This may extend into more specific emotions shown in Right hippocampal activation increases more in specificfeel- Fig. 3 (Trost et al., 2012). ings (Trost et al.,2012), implying both connections to the reward system and a role in encoding specificemotions. The complex interactions between many regions of the Pleasant music results in better recognition of songs (Eschrich, brain both in perceptual and affective mechanisms are pre- Munte and Altenmuller, 2008), therefore the hippocampus sented in Fig. 4, although undoubtedly many more connec- may be pivotal in linking emotions and memory. Similarly, the tions exist between the areas. It is dysfunction in these superior temporal gyrus is thought to contain information networks that could cause hyperexcitability of excitatory about previous experiences of music and link this with neurons. reward (Zatorre and Salimpoor, 2013). Unpleasant music is The hippocampus and limbic system are likely to be par- associated with increased right parahippocampal gyrus ticularly vulnerable. The hippocampus is susceptible due to its response, while the reverse sees right prefrontal cortex acti- extensive connections with other parts of the brain, its high vation (Blood et al., 1999) also suggesting coding of positive degree of plasticity and ability to undergo neurogenesis and negative emotions. throughout life (Bertram, 2013). A particular pathway of A functional Magnetic Resonance Imaging (fMRI) study interest is the hippocampal-prefrontal cortex (H-PFC) path- (Menon and Levitin, 2005) corroborated significant correla- way, which has been implicated in a number of psychiatric tions between activation of the nucleus accumbens and the disorders (Godsil et al., 2013). It undergoes NMDA receptor ventral tegmental area, hypothalamus and insula in response dependent long-term potentiation (LTP), regulated by both ............................................................................................... .................................................................. 4 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. Figure 5. (A) The H-PFC pathway (blue) and the connections to and from the amygdala (black). Orange denotes direct regulation by the amygdala to prevent overexcitation. Red highlights the pathways that stress can affect. (B) Epileptogenesis causes synchronisation in this pathway, allowing spread to other areas of the cortex. Dysregulation of the amygdala (red) may be a mechanism for this. Musicogenic epilepsy Musicogenic seizures are usually complex focal, affecting the temporal lobe in 75% cases and the right side in 61%, with some secondarily generalizing to tonic–clonic seizures (Wieser et al., 1997). The average age of onset of musicogenic epilepsy is 28 (Wieser et al., 1997), however, the age of presentation is not until 39 (Pittau et al., 2008), indicating the prevalence could be underestimated. This could be due to the difficulties in recognising music as a trigger and also a lack of knowledge of health professionals. Only 17% of patients have seizures exclusively triggered by music (Wieser et al., 1997), while 53% report having other stimuli (Pittau et al., 2008), adding Figure 4. Diagram representing anatomical connections of regions weight to the earlier idea of a spectrum of epilepsies. Many of the brain involved in the emotional processing of music. ACC = cases report latencies of several minutes between hearing anterior cingulate cortex; ant Ins = anterior insula; Am (BL) = music and a seizure (Avanzini, 2003), making it harder to rec- basolateral amygdala; Am (CM) = corticomedial amygdala; Hipp = hippocampus; NAc = nucleus accumbens; OFC = orbitofrontal ognize music as the precipitant. Consequently, the scientific cortex; PH = parahippocampal gyrus; Temp P = auditory cortex. literature is limited to mostly case reports. These are still valu- Reproduced from (Koelsch, 2010) with kind permission from Elsevier. able though in trying to determine the nature and extent of this condition. dopaminergic D1 receptor transmission (Gurden, Takita and When investigating the pathogenesis of musicogenic epi- Jay, 2000) and through input to and from the amygdala lepsy no correlations have been found between perceptual (Richter-Levin and Maroun, 2010). This pathway is highly components of triggering music such as tempo and pitch susceptible to stress, with studies showing disruptions to (Wieser et al., 1997). Triggers instead range from specific lines neural plasticity here in rats (Rocher et al., 2004). Stress is a in songs (Tayah et al., 2006) to repertoires of composers. The common trigger in epilepsy and is experienced during events tendency of patients to either have an interest in music or be such as brain trauma, therefore it is plausible that dysfunction musicians (Wieser et al., 1997), who perhaps have more of an in the H-PFC pathway could precipitate seizure activity. emotional response to music than non-music listeners, sup- Stimulation of the amygdala prevents LTP induction in this ports the hypothesis that seizures are associated with emo- pathway (Godsil et al., 2013) and so dysregulation of emo- tional responses to music rather than music itself. Feelings tions may also be a mechanism to precipitate seizure activity including fear and anxiety before seizure onset are often here, as LTP at the H-PFC connection is less well regulated, reported as well as autonomic responses (Morocz et al., 2003; shown in Fig. 5. Pittau et al., 2008; Diekmann and Hoppner, 2014). It is less likely that the auditory cortex is susceptible to The notion that musicogenic seizures are linked to emo- damage as the critical period, where there is heightened plasti- tional responses towards the music concerned is supported by city and therefore susceptibility to epileptogenesis, finishes functional imaging studies aimed at detecting altered activity relatively early in life (Moore, Hutchings and Meyer, 1991; following epileptogenic music. For instance, augmented acti- de Villers-Sidani et al., 2007). vation in the right gyrus rectus with secondary activation of ............................................................................................... .................................................................. 5 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. the left anterior temporal lobe has been reported during seen in reading epilepsy (Vaudano et al., 2012), when compar- music-induced aura (Morocz et al., 2003) using fMRI, while ing epileptic triggers to neutral music This region is involved in a positron emission tomography scan study showed activa- early cognitive processes for regulating emotions (Goldin et al., tion of the orbitofrontal cortex and paralimbic areas prior to 2008), and so Diekmann and Hoppner proposed that musico- seizure onset but after a stimulus (Blood et al., 1999). In a genic seizures may arise because of dysfunction in regulation of single-photon emission computed tomography (SPECT) emotions rather than the music itself. This could explain why study, Wieser et al. (1997) found after listening to Italian music over half of patients have seizures triggered by other stimuli their patient stopped moving and went pale, describing an aura besides music (Pittau et al., 2008), and supports the idea of of ‘delightful feelings’ 30 s before. Complementary electro- some reflex epilepsies actually being part of a group of limbic encephalogram (EEG) recordings showed seizure activity begin- system epilepsies that present differently. ning in the right frontotemporal region. The regions of the brain involved in these studies are key structures in the process- Treatments ing of emotional components of music, supporting the idea they could be involved in the induction of musicogenic seizures. Epilepsy affecting the temporal lobe is more likely to be fMRI studies comparing neutral and emotional music have refractory to drug treatment (Semah et al., 1998), which is found that in addition to frontal areas, right posterior tem- likely due to the numerous connections of the temporal lobe poral lobe and auditory association cortex activity increase with the rest of the brain (Thom et al., 2010). Current treat- before a seizure (Pittau et al., 2008). These regions corres- ment options for musicogenic epilepsy are limited to pharma- pond to the superior temporal gyrus which could relate to cological or surgical interventions. Pharmacological agents dysfunction in the acoustic memory function of this region. are usually prescribed depending on the type of seizure a patient has and so this varies between patients. For focal seizures with Additional activity in limbic regions, cingulate cortex or without generalization, carbamazepine and lamotrigine are (Marrosu et al., 2009), and the hippocampus (Diekmann and first line agents, with oxcarbazepine, sodium valproate and Hoppner, 2014), indicate increased emotional processing. levetiracetam alone or in combination as alternatives (British The limbic system provides a plausible way for abnormal Medical Journal Group and the Royal Pharmaceutical Society activity to occur in both hemispheres due to its numerous con- of Great Britain, 2016). nections to areas involved in music processing, potentially explaining why musicogenic seizures show activity in both For patients with refractory epilepsy there are a few options. temporal lobes. Those eligible for surgery can undergo partial resection of the temporal lobe or seizure focus if identified by intracranial EEG, Differences between studies could be because of limitations although often without curing patients completely (Wiebe et al., of surface EEG recordings. Intracranial EEGs (Tayah et al., 2001). In those unsuitable for surgery other options including 2006) provide higher spatial resolution and better differenti- deep brain stimulation (Fisher et al., 2010) and vagus nerve ation between seizure onset and spread. They have shown dif- stimulation (Ryvlin et al., 2014) have been effective in some but ferent initial activity in patients, both in the right lateral and again do not always completely stop seizures. medial temporal lobes, with propagation to either the right lateral temporal lobe or ACC. Although the gold standard for These treatments, however, are not universally available locating foci, the invasive nature of intracranial EEG limits its due to lack of resources for example, creating a need for alter- use in studies to patients being considered for surgery. natives to drugs and surgery. A total of 85% of patients with epilepsy live in developing countries, and of these around The involvement of the many structures distal to the audi- 90% receive insufficient treatment (Scott, Lhatoo and Sander, tory cortex corroborates with patient reports that it is the 2001). It is for these reasons that research into another option emotions and memories associated with music that are the for patients to try and control their seizures is relevant. key factors causing seizures. What is not known is why music specifically triggers the seizures. Consistent involvement of If the findings of Diekmann and Hoppner are correct it the superior temporal gyrus, hippocampus, orbitofrontal cor- potentially provides a window for research into finding tex and limbic system suggests that in musicogenic epilepsy behavioural interventions to more generally regain this emo- there may be epileptic activity in connections specifically tional control, as patients may be able to stop a ‘snowballing’ between the limbic system and memory recall areas involved effect of emotions and therefore seizure precipitation. Case in music, lowering the threshold for activation of excitatory reports have described patients saying they can abort seizures neurons here. Specific music then creates an emotional state (Critchley, 1937; Wieser et al., 1997; Sacks, 2007) and it is that sufficiently activates these pathways and triggers a seiz- possible this could involve preventing this snowballing. ure, which could present through autonomic and agitated There is, however, very limited research into the methods signs seen in patients following associated activation of the patients use to stop seizures and what is happening in the frontal and limbic areas (Avanzini, 2003). brain at this time. Finding out if this suppression actually In addition to these areas Diekmann and Hoppner (2014) stops seizures is key to discovering if it has a use as a future showed Brodmann area 6 showed increased activation, also behavioural therapy, and also if there are connections in the ............................................................................................... .................................................................. 6 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. brain which could potentially be up regulated in musicogenic all be variants of the same problem, and would provide evi- epilepsy patients to stop seizures. In photosensitive epilepsy, dence to rethink the current system of segregating each trig- techniques have been found to allow certain patients to pre- ger. Furthermore, findings of a region more likely to show vent seizures, including covering one eye and being a certain seizure activity in musicogenic seizures will open avenues to distance from a television (Italiano et al., 2014). Additionally, focus research into connections and receptors that may be a multicentre study (Capovilla et al., 2006) investigating the specific in this area. It will also aid knowledge of how music is effect of a blue lens observed a disappearance of photoparox- processed in the brain, which is still not completely under- ysmal responses in 76% patients with a particular photosensi- stood. Alternatively finding that foci are individual to patients tive epilepsy. The successes of such techniques highlight that would support exploration into more non-pharmacological behavioural interventions can be effective and may have a treatments for epilepsy, which have a less specific mechanism place in musicogenic epilepsy management, but further research of action. is needed. This is where the phenomenon of aborting seizures becomes relevant, because if it is found that success of these techniques is linked to actually suppressing a seizure and that this can be Current gaps and the future applied to other patients, then it provides a novel non- As discussed there are extensive gaps in the literature about pharmacological way for controlling seizures. This would be an musicogenic epilepsy. Little is known about the specific exceptionally valuable tool to improve their quality of life. mechanisms involved in seizure onset and propagation, also Questionnaires may have a role here in gathering information limited because of uncertainties in normal musical processing. as to what current patients do, whether these methods work and the events surrounding them. Epilepsy forums may also be There is also a lot of focus on the professional but not useful. The idea of suppressing a seizure also suggests that once patient side of reporting seizures. Online forums are popular some types start they can be stopped, contradictory to current with many epilepsy patients but are rarely referred to in the understandings of epileptic mechanisms. Additional research literature. They are very useful in understanding patient investigating aborting seizures could also study the areas of the experiences and beliefs about their musicogenic epilepsy and brain activated during these techniques at rest, to try and locate provide a resource of information that scientific articles may where this occurs. EEG could be used to assess in patients who miss. Studies have found patients are accurate in predicting report an ability to abort their seizures whether firstly epileptic seizures (Haut et al., 2013) demonstrating patient knowledge activity has actually begun when attempting to stop them, and can be reliable. Using these websites may provide further secondly if patients are successful. Taking this further one could information and also an alternative method to contact more see if these techniques can also be taught to other patients and if patients who may not necessarily be included in studies using they have the same effect. conventional methods. Indeed, it is interesting that musico- genic seizures tend to appear more frequently on epilepsy sup- Additional research investigating aborting seizures, espe- port websites, such as Epilepsy Society, than one would cially if studies showed this suppression happened after seiz- expect for such a rare condition. A potential method to reach ure activity had begun, could also use fMRI to study the areas more patients therefore could be by posting recruitment noti- of the brain activated during these techniques at rest. fications for studies on these sites. Another fundamental gap is how musicogenic epilepsy Conclusion may link with other types of reflex epilepsies, particularly complex forms. Studies state but do not investigate patients Expanding our knowledge of musicogenic epilepsy is needed, who have seizures triggered by multiple stimuli including as for the patients and their families it can make simple daily music, and so information such as whether onset and spread activities a challenge, limiting their lifestyle. There are inter- of these seizures are related or not remains unknown. If they esting findings within the current literature which potentially are related this could open up an avenue for research into open new concepts in the field of reflex epilepsy. Further reflex epilepsy that is applicable to larger numbers of patients. research could lead to the use of new therapies before having Experiments exploring seizure initiation would be relevant to consider invasive treatments such as surgery. These therap- following the trends in the literature towards the idea of a ies could also provide an alternative in places where current group of reflex epilepsies. These concepts could be explored interventions are not available. using EEG and fMRI to investigate firstly whether in multiple patients certain regions of the brain are more likely to be acti- Author biography vated than others. Secondly in patients with multiple triggers one could compare, using Statistical Parametric Mapping Liddy Ellis wrote this article and has primary responsibility (Friston et al., 1994, Patterson et al., 2002), a patient’s musi- for the final content. She is a fourth year medical student who cogenic seizures to their others. intercalated in BSc neuroscience in 2015. Being drawn to the If the results showed that onset of musicogenic seizures clinical side of neuroscience she chose to research triggers of show similarities to other triggers this suggests that they may epilepsy as part of her dissertation, and became particularly ............................................................................................... .................................................................. 7 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. processes in seizure generation: an fMRI-EEG study, Epileptic interested in the role of music. Liddy is now completing her Disorders: International Epilepsy Journal With Videotape, 16 (1), medical degree and although currently unsure hopes to special- 31–44. ize in an area related to neurology or development. Outside of medicine she enjoys playing hockey and other sports. Eschrich, S., Munte, T. F. and Altenmuller, E. O. (2008) Unforgettable film music: the role of emotion in episodic long-term memory for music, BMC Neuroscience, 9, 48. Acknowledgements Fisher, R., Salanova, V., Witt, T. et al. (2010) Electrical stimulation of the I would like to thank Charlotte Carter and Anastasia anterior nucleus of thalamus for treatment of refractory epilepsy, Riordan-Eva for their valuable contributions to our group Epilepsia, 51 (5), 899–908. discussions at supervisor meetings. I would especially like to thank my supervisor Dr Andrew Doherty for his fantastic Fisher, R. S., Acevedo, C., Arzimanoglou, A. et al. (2014) ILAE official report: support, continued enthusiasm for teaching and help format- a practical clinical definition of epilepsy, Epilepsia, 55 (4), 475–482. ting the figures for which I am exceptionally grateful. Friston, K. J., Holmes, A. P., Worsley, K. J. et al. 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The potential mechanism of musicogenic epilepsy and future research avenues

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BioscienceHorizons Volume 10 2017 10.1093/biohorizons/hzx004 .............................................. .................................................. .................................................. ............... Review article The potential mechanism of musicogenic epilepsy and future research avenues Liddy Ellis School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK *Corresponding author: Cobweb Cottage, New Road, Eckington, Pershore WR10 3AZ, England. Email: le12389@my.bristol.ac.uk Supervisor: Andrew Doherty, Office G.21, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK. Email: a.doherty@bristol.ac.uk .............................................. .................................................. .................................................. ............... Musicogenic epilepsy is a rare form of reflex epilepsy in which seizures are triggered by certain pieces of music. Musical pro- cessing involves interpretation of perceptual elements such as tempo and pitch, and also emotional associations and mem- ory formation. It is hypothesized that the emotional impact of music is more likely to precipitate musicogenic seizures through involvement of the mesolimbic system. This may link these seizures to other types of reflex seizures that also involve emotional responses. Current treatment is restricted to anti-epileptic drugs and surgery, which is not always an option for patients due to eligibility or availability, for example in developing countries. The scientific literature on this topic is very lim- ited. Individual case studies have stated that patients report techniques they use to stop seizures such as distraction, but these have not been explored. Online forums seem to suggest the condition is more common than the scientific literature states, and so may be a useful resource to consider. After describing the normal processing of music and how this pathway may be affected in musicogenic epilepsy, the review discusses the potential relationship between musicogenic and other sei- zures, and why this is relevant. New avenues for research into alternative interventions for patients could be opened by con- sidering information on forums and case reports, and methods of doing this are discussed. Key words: epilepsy, music, seizures, reflex, treatments, emotion Submitted on 3 October 2016; editorial decision on 24 February 2017 .............................................. .................................................. .................................................. ............... by addressing current gaps in the knowledge and how they Introduction could be investigated to provide novel information about both musicogenic and other reflex seizures. Musicogenic epilepsy is a type of reflex epilepsy in which sei- zures are induced by ‘sounds in melodic or harmonic combin- ation, without stylistic or cultural restraint and excluding other non-startling sounds’ (Avanzini, 2003). First reported by Epileptic seizures Critchley (1937), this rare condition only affects 1 in 10 000 000 Epilepsy is diagnosed following two unprovoked seizures less people (Avanzini, 2003), yet the literature brings to light than 24 h apart, or two seizures occurring in response to a trigger some interesting concepts. This review aims to highlight these (Fisher et al., 2014). They result from synchronous firing of action points and discuss how they can be used as future avenues for potentials (APs) by groups of neurons, leading to overexcitation research into alternative treatments for seizures where surgery in selective parts of the brain. There are a wide range of potential and pharmacological interventions may not be suitable or causes, including genetic predisposition (Berg et al., 2010), infec- accessible. After a general overview on seizure mechanisms, tions, structural/metabolic conditions, idiopathic causes (Bhalla music processing and the potential ways this is affected in et al., 2011) and birth complications (Golomb et al., 2007). musicogenic epilepsy will be focussed on. The review will end ............................................................................................... .................................................................. © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. Different types of seizure occur depending on the underlying pathology and the area of the brain affected. The International League against Epilepsy (ILAE) classifies seizures as focal, where activity is restricted to one hemisphere of the brain, or generalized, which affects the entire cortex. Focal seizures can be described by the manifestation of their effects or by where they originate. For example, temporal lobe epilepsy (TLE) can origin- ate in the temporal lobe of the brain or can present with major behavioural effects on temporal lobe function. In contrast gener- alized seizures present more stereotypically, involving both hemispheres of the brain throughout the seizure (Berg et al., 2010). Generalized seizures can also begin focally and secondarily spread to the contralateral hemisphere, usually as tonic–clonic seizures (Browne and Holmes, 2008). Additionally, seizures can be described as simple or complex; in the latter a patient experi- ences an alteration of consciousness. The exact pathogenesis of seizure development is not com- pletely known, however, a basic mechanism has been out- lined. The transition of a normal neuron into one supporting epileptic activity is termed epileptogenesis. The neuron becomes hyperexcitable, making it easier to become and remain depolarized (Scharfman, 2007). Consequently, there Figure 1. (A) PDS. Initially the neuron has a resting membrane is a prolonged depolarization of the neuron, which occurs due potential of ≈−60 mV, then by epileptogenesis the PDS occurs. The to activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepro- membrane potential increases for a prolonged time and so a burst of pionic acid (AMPA) receptors and N-methyl-D-aspartate APs fire. Follow this, inhibition begins to overtake and so a hyperpolarization follows. Adapted from (Holmes and Ben-Ari, 2003) (NMDA) receptors (Westbrook, 2000). This results in a burst with kind permission from Nature Publishing Group. (B) The of APs (de Curtis and Avanzini, 2001), shown in Fig. 1A. mechanism of surround inhibition. Green neurons are excitatory, black Following a plateau phase, repolarization occurs leading to are inhibitory interneurons. When the middle neuron is activated, it an afterhyperpolarization of the neuron (Westbrook, 2000). stimulates the neurons both sides and the inhibitory neurons. This sequence of events is known as the paroxysmal depolar- Feedback inhibition is purple, and feedforward inhibition is red. When izing shift (PDS) (Matsumoto and Marsan, 1964), and it is the interneurons are activated, these pathways activate and shut down this that is associated with the initiation of seizure activity. the neurons. Loss of this means the excitatory green pathways are active, so APs are transmitted to neighbouring neurons. The PDS in a single neuron can then spread to local neu- rons through local synaptic transmission (Jeffreys, 2015), extracellular ion concentration changes (Jiruska et al., 2013), neurons to be inhibited simultaneously, overcoming it synchro- via gap junctions between neurons and glial cells (Rozental nizes neuronal firing (Trevelyan, Sussillo and Yuste, 2007). et al., 2001) or electric field transmission (Zhang et al., 2014). Neural circuits then allow synchronisation of other areas of As a result a seizure focus develops. It was thought the focus the brain. In TLE, there is a multifocal initiation in different parts originated from one specific place, but lately this has been dis- of the temporal lobe, especially very plastic areas, e.g. the hippo- puted instead suggesting seizures begin from multiple micro- campus (Bertram, 2013). The midline nuclei (MN) in the thal- seizures which amalgamate to form a larger focus (Stead, amus allow propagation of epileptic activity through ‘a divergent- Bower and Brinkmann, 2010). convergent-excitatory system,’ spreading both directly to other Synchronisation of the neurons exhibiting PDS leads to cortical regions, and indirectly via the MN. Excitation in this summation of burst firing APs. However, in order for a seizure region stimulates neurons in other areas of the cortex to syn- to occur, more neurons need to be recruited and the afterhy- chronize, which repeats resulting in a seizure (Bertram, 2013). perpolarisation needs to be diminished. The loss of surround The mechanism behind termination of a seizure is more inhibition (Trevelyan et al.,2006), explained in Fig. 1B, is key. uncertain. There are many theories as to how this may occur, Many excitatory cells have feedback and feedforward inhib- including hypersynchrony (Timofeev and Steriade, 2004) and ition to prevent hyperexcitation via activation of surrounding recovery of inhibition in susceptible areas which subsequently GABA-ergic inhibitory interneurons (Jiruska et al., 2013). spreads. Overcoming this surround inhibition recruits other excitatory neurons (Trevelyan et al., 2006), spreading the seizure to the Reflex versus spontaneous seizures next ‘line’ of connected neurons where it is limited until inhib- ition here is overwhelmed. This is termed the ‘wave of inhibition’ The majority of seizures occur spontaneously. However reflex (Jiruska et al., 2013) and because this causes large numbers of epilepsy describes an abnormal predisposition to seizures ............................................................................................... .................................................................. 2 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. following exposure to a stimulus, affecting around 7% patients (Symonds, 1959). The type of seizure occurring var- ies depending on the precipitant, such as reading or music (Kasteleijn-Nolst Trenite, 2012). Distinguishing reflex epi- lepsy has been difficult for many reasons, including overlap with patients experiencing both spontaneous and reflex sei- zures, discrepancies in defining a trigger (Irmen, Wehner and Lemieux, 2015), and variations in time delays between expos- ure to a stimulus and a seizure. This disagreement has led to a theory that epileptic seizures are in fact on a spectrum ranging from reflex to spontaneous, including patients who experi- ence both, have factors that increase the likelihood of a seiz- ure, or have more than one trigger (Nakken et al., 2005). But why do reflex seizures occur? It is possible that general precipitating factors lower the threshold for more specific stimuli to cause seizures in certain people, resulting in differ- ent types of reflex epilepsies. In addition to this an initial event altering a particular brain network and predisposing it to hypersynchrony could allow a specific stimulus to overcome the threshold for seizure activity (Irmen, Wehner and Lemieux, 2015). A genetic component has also been sug- gested for certain seizures (Ratnapriya et al., 2009). There are many different stimuli that can precipitate seiz- ure activity. They can be intrinsic or extrinsic, and can involve higher processing centres (Irmen, Wehner and Lemieux, 2015) such as the mesolimbic pathway. The involvement of this pathway in many triggers (Wilkins et al., 1982) supports an idea that different seizures may actually be part of a group of epilepsies involving dysfunction in decisive, associative and emotional circuits. The reason they present differently could be due to the exact connection within the limbic system that is affected by epileptogenesis. These seizures could therefore be classed together rather than segregated. It is here that the phenomenon of musicogenic epilepsy is relevant. However, before exploring the mechanisms by which music may result in epileptic seizures, one must first consider how music is processed in the brain. Music processing The mechanisms behind the processing of music in the brain have been studied extensively. Many aspects remain uncertain, due to both limitations in animal experiments (Zatorre and Figure 2. Pathway involved in transmitting vibrations from music (green) into action potentials (orange) before reaching the auditory Salimpoor, 2013) and the issue that altering music can result in cortex (blue) for further processing. it becoming sound, which case reports suggest involves different circuits (Peretz et al., 1994, 2002; Griffiths et al., 1997). The current understanding is that vibrations in the air hit auditory cortex, which is arranged tonotopically (Talavage the tympanic membrane and are transmitted through the ossi- et al., 2004). This sequence is displayed in Fig. 2. cles in the middle ear, causing movement of the oval window and fluid in the cochlea. Here the basilar membrane allows The processing of pitch in music differs from speech, lan- conversion of fluid vibrations into APs in the cochlear nerve, guage and environmental sounds in a variety of ways, as in which travels via the cochlear nucleus and inferior colliculus speech pitch continuously changes while in music it is orga- to the medial geniculate body in the thalamus (Griffiths et al., nized and consists of specific notes, requiring more accuracy 2001). From here information is relayed to the primary to detect pitch. This may be a feature of the right cerebral ............................................................................................... .................................................................. 3 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. hemisphere as it dominates in music. Humans are likely born with this lateralization to enable different interpretation of sounds, meaning that as the brain develops if a car alarm, speech or music all have the same pitch people can distinguish between them (Levitin, 2007). Tonality, tempo and harmonies are also integrated to form melodies, and as more components of melodies are processed activity spreads outwards from the primary auditory cortex (Zatorre, Evans and Meyer, 1994; Griffiths et al., 2001; Patterson et al., 2002). Previous knowledge is required about how different notes combine to form a melody, and to recognize when something is ‘out of tune’. This must be based on prior retention of audi- tory information, in which the inferior frontal cortices, the right parietal and insular cortices have a role (Zatorre, Evans and Meyer, 1994; Maess et al., 2001). Numerous functional loops integrate other functions such as movement, activating the basal ganglia, premotor cortex and frontal regions in response to timing (Grahn and Brett, 2007). Emotional associations of music Figure 3. Activation of brain regions in response to music associated In addition to the perceptual side of music processing there is with different emotions. Emotions categorized as high or low valence also the affective side, where the emotional impact of music and high or low arousal show different regions of increased activity. develops. The mesolimbic system is considered responsible While emotions such as tenderness activate more medial and frontal for emotion, reward and motivation (Haber and Knutson, areas, wonder, joy and power also activate the lateral temporal lobe. Taken from (Trost et al., 2012). Open Access, Creative Commons 2010), and associations between dopamine release in this sys- Attribution Non-Commercial License. tem and listening to pleasurable music suggest its involvement in applying an emotional characteristic to music (Salimpoor et al., 2011). to music, highlighting the occurrence of reward processing. The amygdala has projections to the nucleus accumbens Involvement of the orbitofrontal cortex and inferior frontal (Lehne, Rohrmeier and Koelsch, 2014), auditory cortex and cortex with the nucleus accumbens also indicates connections medial geniculate body (Koelsch and Skouras, 2014), connect- between emotional effects of music and cognitive functions ing the auditory and reward systems. By determining positive such as decision making and expectation. Connections and negative reward values it acts as a major input of auditory between the prefrontal cortex, mesolimbic system and audi- information into the mesolimbic system. Hippocampal con- tory cortex allow the brain to relate music to dopamine nections then encode these in memory (Koelsch and Skouras, release and surrounding events, resulting in retention of this 2014). information and how it is perceived (Zatorre and Salimpoor, 2013). This may extend into more specific emotions shown in Right hippocampal activation increases more in specificfeel- Fig. 3 (Trost et al., 2012). ings (Trost et al.,2012), implying both connections to the reward system and a role in encoding specificemotions. The complex interactions between many regions of the Pleasant music results in better recognition of songs (Eschrich, brain both in perceptual and affective mechanisms are pre- Munte and Altenmuller, 2008), therefore the hippocampus sented in Fig. 4, although undoubtedly many more connec- may be pivotal in linking emotions and memory. Similarly, the tions exist between the areas. It is dysfunction in these superior temporal gyrus is thought to contain information networks that could cause hyperexcitability of excitatory about previous experiences of music and link this with neurons. reward (Zatorre and Salimpoor, 2013). Unpleasant music is The hippocampus and limbic system are likely to be par- associated with increased right parahippocampal gyrus ticularly vulnerable. The hippocampus is susceptible due to its response, while the reverse sees right prefrontal cortex acti- extensive connections with other parts of the brain, its high vation (Blood et al., 1999) also suggesting coding of positive degree of plasticity and ability to undergo neurogenesis and negative emotions. throughout life (Bertram, 2013). A particular pathway of A functional Magnetic Resonance Imaging (fMRI) study interest is the hippocampal-prefrontal cortex (H-PFC) path- (Menon and Levitin, 2005) corroborated significant correla- way, which has been implicated in a number of psychiatric tions between activation of the nucleus accumbens and the disorders (Godsil et al., 2013). It undergoes NMDA receptor ventral tegmental area, hypothalamus and insula in response dependent long-term potentiation (LTP), regulated by both ............................................................................................... .................................................................. 4 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. Figure 5. (A) The H-PFC pathway (blue) and the connections to and from the amygdala (black). Orange denotes direct regulation by the amygdala to prevent overexcitation. Red highlights the pathways that stress can affect. (B) Epileptogenesis causes synchronisation in this pathway, allowing spread to other areas of the cortex. Dysregulation of the amygdala (red) may be a mechanism for this. Musicogenic epilepsy Musicogenic seizures are usually complex focal, affecting the temporal lobe in 75% cases and the right side in 61%, with some secondarily generalizing to tonic–clonic seizures (Wieser et al., 1997). The average age of onset of musicogenic epilepsy is 28 (Wieser et al., 1997), however, the age of presentation is not until 39 (Pittau et al., 2008), indicating the prevalence could be underestimated. This could be due to the difficulties in recognising music as a trigger and also a lack of knowledge of health professionals. Only 17% of patients have seizures exclusively triggered by music (Wieser et al., 1997), while 53% report having other stimuli (Pittau et al., 2008), adding Figure 4. Diagram representing anatomical connections of regions weight to the earlier idea of a spectrum of epilepsies. Many of the brain involved in the emotional processing of music. ACC = cases report latencies of several minutes between hearing anterior cingulate cortex; ant Ins = anterior insula; Am (BL) = music and a seizure (Avanzini, 2003), making it harder to rec- basolateral amygdala; Am (CM) = corticomedial amygdala; Hipp = hippocampus; NAc = nucleus accumbens; OFC = orbitofrontal ognize music as the precipitant. Consequently, the scientific cortex; PH = parahippocampal gyrus; Temp P = auditory cortex. literature is limited to mostly case reports. These are still valu- Reproduced from (Koelsch, 2010) with kind permission from Elsevier. able though in trying to determine the nature and extent of this condition. dopaminergic D1 receptor transmission (Gurden, Takita and When investigating the pathogenesis of musicogenic epi- Jay, 2000) and through input to and from the amygdala lepsy no correlations have been found between perceptual (Richter-Levin and Maroun, 2010). This pathway is highly components of triggering music such as tempo and pitch susceptible to stress, with studies showing disruptions to (Wieser et al., 1997). Triggers instead range from specific lines neural plasticity here in rats (Rocher et al., 2004). Stress is a in songs (Tayah et al., 2006) to repertoires of composers. The common trigger in epilepsy and is experienced during events tendency of patients to either have an interest in music or be such as brain trauma, therefore it is plausible that dysfunction musicians (Wieser et al., 1997), who perhaps have more of an in the H-PFC pathway could precipitate seizure activity. emotional response to music than non-music listeners, sup- Stimulation of the amygdala prevents LTP induction in this ports the hypothesis that seizures are associated with emo- pathway (Godsil et al., 2013) and so dysregulation of emo- tional responses to music rather than music itself. Feelings tions may also be a mechanism to precipitate seizure activity including fear and anxiety before seizure onset are often here, as LTP at the H-PFC connection is less well regulated, reported as well as autonomic responses (Morocz et al., 2003; shown in Fig. 5. Pittau et al., 2008; Diekmann and Hoppner, 2014). It is less likely that the auditory cortex is susceptible to The notion that musicogenic seizures are linked to emo- damage as the critical period, where there is heightened plasti- tional responses towards the music concerned is supported by city and therefore susceptibility to epileptogenesis, finishes functional imaging studies aimed at detecting altered activity relatively early in life (Moore, Hutchings and Meyer, 1991; following epileptogenic music. For instance, augmented acti- de Villers-Sidani et al., 2007). vation in the right gyrus rectus with secondary activation of ............................................................................................... .................................................................. 5 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. the left anterior temporal lobe has been reported during seen in reading epilepsy (Vaudano et al., 2012), when compar- music-induced aura (Morocz et al., 2003) using fMRI, while ing epileptic triggers to neutral music This region is involved in a positron emission tomography scan study showed activa- early cognitive processes for regulating emotions (Goldin et al., tion of the orbitofrontal cortex and paralimbic areas prior to 2008), and so Diekmann and Hoppner proposed that musico- seizure onset but after a stimulus (Blood et al., 1999). In a genic seizures may arise because of dysfunction in regulation of single-photon emission computed tomography (SPECT) emotions rather than the music itself. This could explain why study, Wieser et al. (1997) found after listening to Italian music over half of patients have seizures triggered by other stimuli their patient stopped moving and went pale, describing an aura besides music (Pittau et al., 2008), and supports the idea of of ‘delightful feelings’ 30 s before. Complementary electro- some reflex epilepsies actually being part of a group of limbic encephalogram (EEG) recordings showed seizure activity begin- system epilepsies that present differently. ning in the right frontotemporal region. The regions of the brain involved in these studies are key structures in the process- Treatments ing of emotional components of music, supporting the idea they could be involved in the induction of musicogenic seizures. Epilepsy affecting the temporal lobe is more likely to be fMRI studies comparing neutral and emotional music have refractory to drug treatment (Semah et al., 1998), which is found that in addition to frontal areas, right posterior tem- likely due to the numerous connections of the temporal lobe poral lobe and auditory association cortex activity increase with the rest of the brain (Thom et al., 2010). Current treat- before a seizure (Pittau et al., 2008). These regions corres- ment options for musicogenic epilepsy are limited to pharma- pond to the superior temporal gyrus which could relate to cological or surgical interventions. Pharmacological agents dysfunction in the acoustic memory function of this region. are usually prescribed depending on the type of seizure a patient has and so this varies between patients. For focal seizures with Additional activity in limbic regions, cingulate cortex or without generalization, carbamazepine and lamotrigine are (Marrosu et al., 2009), and the hippocampus (Diekmann and first line agents, with oxcarbazepine, sodium valproate and Hoppner, 2014), indicate increased emotional processing. levetiracetam alone or in combination as alternatives (British The limbic system provides a plausible way for abnormal Medical Journal Group and the Royal Pharmaceutical Society activity to occur in both hemispheres due to its numerous con- of Great Britain, 2016). nections to areas involved in music processing, potentially explaining why musicogenic seizures show activity in both For patients with refractory epilepsy there are a few options. temporal lobes. Those eligible for surgery can undergo partial resection of the temporal lobe or seizure focus if identified by intracranial EEG, Differences between studies could be because of limitations although often without curing patients completely (Wiebe et al., of surface EEG recordings. Intracranial EEGs (Tayah et al., 2001). In those unsuitable for surgery other options including 2006) provide higher spatial resolution and better differenti- deep brain stimulation (Fisher et al., 2010) and vagus nerve ation between seizure onset and spread. They have shown dif- stimulation (Ryvlin et al., 2014) have been effective in some but ferent initial activity in patients, both in the right lateral and again do not always completely stop seizures. medial temporal lobes, with propagation to either the right lateral temporal lobe or ACC. Although the gold standard for These treatments, however, are not universally available locating foci, the invasive nature of intracranial EEG limits its due to lack of resources for example, creating a need for alter- use in studies to patients being considered for surgery. natives to drugs and surgery. A total of 85% of patients with epilepsy live in developing countries, and of these around The involvement of the many structures distal to the audi- 90% receive insufficient treatment (Scott, Lhatoo and Sander, tory cortex corroborates with patient reports that it is the 2001). It is for these reasons that research into another option emotions and memories associated with music that are the for patients to try and control their seizures is relevant. key factors causing seizures. What is not known is why music specifically triggers the seizures. Consistent involvement of If the findings of Diekmann and Hoppner are correct it the superior temporal gyrus, hippocampus, orbitofrontal cor- potentially provides a window for research into finding tex and limbic system suggests that in musicogenic epilepsy behavioural interventions to more generally regain this emo- there may be epileptic activity in connections specifically tional control, as patients may be able to stop a ‘snowballing’ between the limbic system and memory recall areas involved effect of emotions and therefore seizure precipitation. Case in music, lowering the threshold for activation of excitatory reports have described patients saying they can abort seizures neurons here. Specific music then creates an emotional state (Critchley, 1937; Wieser et al., 1997; Sacks, 2007) and it is that sufficiently activates these pathways and triggers a seiz- possible this could involve preventing this snowballing. ure, which could present through autonomic and agitated There is, however, very limited research into the methods signs seen in patients following associated activation of the patients use to stop seizures and what is happening in the frontal and limbic areas (Avanzini, 2003). brain at this time. Finding out if this suppression actually In addition to these areas Diekmann and Hoppner (2014) stops seizures is key to discovering if it has a use as a future showed Brodmann area 6 showed increased activation, also behavioural therapy, and also if there are connections in the ............................................................................................... .................................................................. 6 Bioscience Horizons � Volume 10 2017 Review article ............................................................................................... .................................................................. brain which could potentially be up regulated in musicogenic all be variants of the same problem, and would provide evi- epilepsy patients to stop seizures. In photosensitive epilepsy, dence to rethink the current system of segregating each trig- techniques have been found to allow certain patients to pre- ger. Furthermore, findings of a region more likely to show vent seizures, including covering one eye and being a certain seizure activity in musicogenic seizures will open avenues to distance from a television (Italiano et al., 2014). Additionally, focus research into connections and receptors that may be a multicentre study (Capovilla et al., 2006) investigating the specific in this area. It will also aid knowledge of how music is effect of a blue lens observed a disappearance of photoparox- processed in the brain, which is still not completely under- ysmal responses in 76% patients with a particular photosensi- stood. Alternatively finding that foci are individual to patients tive epilepsy. The successes of such techniques highlight that would support exploration into more non-pharmacological behavioural interventions can be effective and may have a treatments for epilepsy, which have a less specific mechanism place in musicogenic epilepsy management, but further research of action. is needed. This is where the phenomenon of aborting seizures becomes relevant, because if it is found that success of these techniques is linked to actually suppressing a seizure and that this can be Current gaps and the future applied to other patients, then it provides a novel non- As discussed there are extensive gaps in the literature about pharmacological way for controlling seizures. This would be an musicogenic epilepsy. Little is known about the specific exceptionally valuable tool to improve their quality of life. mechanisms involved in seizure onset and propagation, also Questionnaires may have a role here in gathering information limited because of uncertainties in normal musical processing. as to what current patients do, whether these methods work and the events surrounding them. Epilepsy forums may also be There is also a lot of focus on the professional but not useful. The idea of suppressing a seizure also suggests that once patient side of reporting seizures. Online forums are popular some types start they can be stopped, contradictory to current with many epilepsy patients but are rarely referred to in the understandings of epileptic mechanisms. Additional research literature. They are very useful in understanding patient investigating aborting seizures could also study the areas of the experiences and beliefs about their musicogenic epilepsy and brain activated during these techniques at rest, to try and locate provide a resource of information that scientific articles may where this occurs. EEG could be used to assess in patients who miss. Studies have found patients are accurate in predicting report an ability to abort their seizures whether firstly epileptic seizures (Haut et al., 2013) demonstrating patient knowledge activity has actually begun when attempting to stop them, and can be reliable. Using these websites may provide further secondly if patients are successful. Taking this further one could information and also an alternative method to contact more see if these techniques can also be taught to other patients and if patients who may not necessarily be included in studies using they have the same effect. conventional methods. Indeed, it is interesting that musico- genic seizures tend to appear more frequently on epilepsy sup- Additional research investigating aborting seizures, espe- port websites, such as Epilepsy Society, than one would cially if studies showed this suppression happened after seiz- expect for such a rare condition. A potential method to reach ure activity had begun, could also use fMRI to study the areas more patients therefore could be by posting recruitment noti- of the brain activated during these techniques at rest. fications for studies on these sites. Another fundamental gap is how musicogenic epilepsy Conclusion may link with other types of reflex epilepsies, particularly complex forms. Studies state but do not investigate patients Expanding our knowledge of musicogenic epilepsy is needed, who have seizures triggered by multiple stimuli including as for the patients and their families it can make simple daily music, and so information such as whether onset and spread activities a challenge, limiting their lifestyle. There are inter- of these seizures are related or not remains unknown. If they esting findings within the current literature which potentially are related this could open up an avenue for research into open new concepts in the field of reflex epilepsy. Further reflex epilepsy that is applicable to larger numbers of patients. research could lead to the use of new therapies before having Experiments exploring seizure initiation would be relevant to consider invasive treatments such as surgery. These therap- following the trends in the literature towards the idea of a ies could also provide an alternative in places where current group of reflex epilepsies. These concepts could be explored interventions are not available. using EEG and fMRI to investigate firstly whether in multiple patients certain regions of the brain are more likely to be acti- Author biography vated than others. Secondly in patients with multiple triggers one could compare, using Statistical Parametric Mapping Liddy Ellis wrote this article and has primary responsibility (Friston et al., 1994, Patterson et al., 2002), a patient’s musi- for the final content. She is a fourth year medical student who cogenic seizures to their others. intercalated in BSc neuroscience in 2015. Being drawn to the If the results showed that onset of musicogenic seizures clinical side of neuroscience she chose to research triggers of show similarities to other triggers this suggests that they may epilepsy as part of her dissertation, and became particularly ............................................................................................... .................................................................. 7 Review article Bioscience Horizons � Volume 10 2017 ............................................................................................... .................................................................. processes in seizure generation: an fMRI-EEG study, Epileptic interested in the role of music. Liddy is now completing her Disorders: International Epilepsy Journal With Videotape, 16 (1), medical degree and although currently unsure hopes to special- 31–44. ize in an area related to neurology or development. Outside of medicine she enjoys playing hockey and other sports. Eschrich, S., Munte, T. F. and Altenmuller, E. O. (2008) Unforgettable film music: the role of emotion in episodic long-term memory for music, BMC Neuroscience, 9, 48. Acknowledgements Fisher, R., Salanova, V., Witt, T. et al. (2010) Electrical stimulation of the I would like to thank Charlotte Carter and Anastasia anterior nucleus of thalamus for treatment of refractory epilepsy, Riordan-Eva for their valuable contributions to our group Epilepsia, 51 (5), 899–908. discussions at supervisor meetings. I would especially like to thank my supervisor Dr Andrew Doherty for his fantastic Fisher, R. S., Acevedo, C., Arzimanoglou, A. et al. (2014) ILAE official report: support, continued enthusiasm for teaching and help format- a practical clinical definition of epilepsy, Epilepsia, 55 (4), 475–482. ting the figures for which I am exceptionally grateful. Friston, K. J., Holmes, A. P., Worsley, K. J. et al. 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