The bidirectional role of music effect in epilepsy: Friend or foe?

Abstract

Epilepsy is a prevalent neurological disease that impacts around 70 million individuals globally. Anti‐seizure medications (ASMs) are the first choice for clinicians to control unprovoked epileptic seizures. Although more than 30 ASMs are available in the market, patients with epilepsy (PWEs) still show poor responses to adequate drug treatment. Meanwhile, long‐term medications not only bring heavy financial burdens but also lead to undesirable side effects. Music, a ubiquitous art form throughout human history, has been confirmed as therapeutically effective in various neurological conditions, including epilepsy. This alternative therapy offers convenience and a relatively safe approach to alleviating epileptic symptoms. Paradoxically, besides anti‐convulsant effect, some particular music would cause seizures inversely, indicating the pro‐convulsant effect of it. Considering that investigating the impact of music on epilepsy emerges as a compelling subject. In this review, we tried to present the following sections of content on this topic. Initially, we overviewed the impact of music on the brain and the significant progress of music therapy in central neurological disorders. Afterward, we classified the anti‐convulsant and pro‐convulsant effects of music in epilepsy, relying on both clinical and laboratory evidences. Finally, possible mechanisms and neural basis of the music effect were concluded, and the translational potentials and some future outlooks about the music effect in epilepsy were proposed.

Plain Language Summary

Epilepsy is an extremely severe neurological disorder. Although anti‐seizure medications are preferred choice to control seizures, the efficacy is not satisfied due to the tolerance. Anecdotal music effect had been deemed functional diversity but not clarified on epilepsy, pro‐convulsive, or anti‐convulsive. Here, we reviewed this interesting but puzzling topic, as well as illustrating the potential mechanisms and its translational potential.

Key points.

• This review seeks to concisely describe and trace historical “music effect” for neurological functions.

• The effect of music on epilepsy by analyzing the available literature, focusing on its potential anti‐convulsant effects as well as its pro‐convulsant abilities were summarized.

• The possible neural mechanisms including dopamine theory and auditory system of music effect were concluded.

1. INTRODUCTION

Epilepsy, a prevalent and severe neurological disease, is characterized by unprovoked, recurrent spontaneous seizures. ¹ An increasing number of researches have suggested epilepsy as a brain dysfunctional disorder resulting from neuronal hyperexcitability and hypersynchronization. ² Anti‐seizure medications (ASMs) are the first choice for seizure control in patients with epilepsy (PWEs). Despite over 30 ASMs being available on the market, around one‐third of PWEs continue to exhibit an inadequate response to pharmacological treatment. ³ , ⁴ Regrettably, individuals suffering from pharmacoresistant epilepsy not only encounter a greater susceptibility to sudden unexpected death in epilepsy (SUDEP) but also have constraints in being able to choose alternative therapies. For long, brain surgery has been highly effective in about 65% of pharmacoresistant patients, while accompanying high rate of seizure remission. ⁵ Thus, there is an imperative need to explore non‐invasive alternative treatments for epilepsy.

The environment around us is filled with a multitude of acoustic information. It is widely acknowledged that acoustic stimuli might influence brain activity through the auditory system (Figure 1). Typically, the auditory system in the brain operates in two stages: (1) sound spreads through the air at a specific frequency, and as air particles fluctuate, the cochlea detects external sound leading to vibrations in the tympanic membrane. These vibrations then stimulate the auditory ossicles, converting mechanical signals into electrical signals. (2) Nerve fiber hair cells receive these vibrations and transmit them through the cochlear nucleus to the inferior colliculus and the superior olivary nucleus. From there, the signals are relayed to the medial geniculate nucleus in the thalamus, and finally, received by the auditory cortex (Figure 1). ⁶ , ⁷ Crucially, humans and other mammals respond differently to sound stimuli with different frequencies, tones, and pitches. One lyrical gentle piece of music may make people pleasant, soothing, and bring positive effect, while one shrill and frightening piece of sound may contribute to people's negative mood. With such evidence, non‐invasive music therapy is an attractive topic for both basic researchers and neurologists. Randomized clinical trials have proven that music‐based interventions have the comprehensive capacity for rehabilitation of dementia, Parkinson's disease, stroke, dementia, and multiple sclerosis. ⁸ Inversely, once some other specific music or sound occurs, it may trigger the hyperexcitation within the auditory network and cause seizures, defined as musicogenic epilepsy. It is classified as a rare form of complex reflex epilepsy by the International League Against Epilepsy (ILAE). ⁹ This phenotype is particularly rare as the prevalence is of 1 in 10 million. It is associated with characteristic sounds as melody or harmony features which trigger individual's epileptic seizures. Clinical cases reported various musicogenic triggers and epileptogenic zones due to the specific affected patients. ¹⁰ , ¹¹ , ¹² , ¹³ Neuroimage and EEG recording data have demonstrated the right mesial temporal lobe region is the most active in either ictal or interictal discharges in musicogenic epilepsy individuals. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ Evidences from clinical studies also demonstrated that the autoimmunity systems were disordered in musicogenic patients. ¹⁸ , ¹⁹ , ²⁰ However, there is no clear definition for music that was pro‐ or anti‐convulsant, and the mechanisms underlying music's bidirectional effects on epilepsy remain unillustrated.

FIGURE 1.

The auditory pathway transmits audio signals from the ear to the brain. Once reaching the eardrum, a sound triggers a sequence of mechanical, chemical, and neurological events in several parts of the auditory system, including the cochlea, cochlear nucleus, inferior colliculus, superior olivary nuclei, medial geniculate nucleus, and the auditory cortex.

Here, in this review, we aim to provide a concise overview of the current research regarding the effect of music on epilepsy. Initially, this review seeks to concisely describe the regulatory effects of music on the brain. Next, we want to examine the effect of music on epilepsy by analyzing the available literature, focusing on its potential anti‐convulsant effects as well as its pro‐convulsant abilities. In conclusion, our review presented a forward‐looking perspective on the utilization of music therapy, aiming to provide a more robust basis for its clinical implementation in the future.

2. METHODOLOGY

This review focused on music's effect on epilepsy. The criteria include (i) musicogenic epilepsy (carried out 60 literatures, 8 reviews, 34 case reports, and 18 research articles); (ii) music effect on epilepsy (154 literatures, 40 reviews, 12 clinical trials, and 4 meta‐analyses and research articles from the rest part); and (iii) Mozart effect on epilepsy (52 literatures, 11 reviews, 7 clinical trials, 3 meta‐analyses, and 31 research articles). All literatures enrolled were carried out on PubMed, using the search term “musicogenic epilepsy,” “music effect on epilepsy,” and “Mozart effect on epilepsy.”

3. HISTORICAL “MUSIC EFFECT” FOR NEUROLOGICAL FUNCTIONS

Since time immemorial, the famous philosopher Pythagoras has proposed the concept of “musical medicine,” which suggested that harmonious music could soothe the mind and benefit physical diseases. More importantly, it has been shown that the principle of harmony in playing musical instruments possesses the ability to evoke a diverse range of emotions. After that, music information processing in the brain takes place in several neural circuits and affects higher levels of sensory, cognitive, motor, and emotional functions. Due to its broad effect on brain function, music‐based adjunctive therapies have been used since the 1960s to alleviate symptoms of Parkinson's disease, epilepsy, and multiple sclerosis. ⁸ , ²¹ Further study has demonstrated that music exerts a diverse array of impacts on brain function (Table 1). Clinical trials have proved that music‐facilitated psychoeducational strategies could alleviate symptoms of depression and distress. ²² Even in palliative care, music therapy intervention did not alleviate pain, but it led to a significantly greater reduction in the fatigue score on the quality‐of‐life scale. ²³ In addition, other studies have demonstrated the efficacy of music therapy in alleviating postoperative pain. ²⁴ , ²⁵ , ²⁶ , ²⁷ It is also proposed that music additionally diminished the requirement for sedation and analgesia during surgical and endoscopic procedures, lessened anxiety in mechanically ventilated patients, and lowered endogenous stress levels following myocardial infarction. ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ Research has indicated that listening to music could alleviate anxiety levels through a complex set of effects in a neurohumoral pathway that involves multiple brain regions and the autonomic system, which in turn alters the levels of endorphins, cytokines, and endogenous hormones. This may partly explain why music influences the mood. Also, listening to personalized music which causes negative emotions while driving could hinder participants' ability to simulate driving. Fairclough's research has shown that playing music with low levels of psychological activation, as proposed by the Circumplex model, could attenuate changes in contractile reactivity in response to simulated traffic congestion, suggesting that the emotional properties of music may mediate cardiovascular responses to negative emotions. ²⁹ Subjects in the positive mood induction group who listened to Bach's “Brandenburg Concerto No. 3” for 3 min exhibited a greater rate of false memories than those in the negative mood induction group who listened to Prokofiev's “Alexander Nevsky: Russia under the Mongolian Yoke.” ³⁰ Similarly, dissonant music showed greater efficacy in disrupting cognitive tasks than harmonic music when performed concurrently, indicating that music with different compositions may have different effects. ³¹ These results may be due to the complexity of the auditory system and the fact that music may modulate the release of some hormones. Similarly, music therapy also plays a role in Parkinson's disease. Research has demonstrated that rhythmic auditory stimulation, a frequently employed therapy during nighttime, has the potential to address walking difficulties in individuals with Parkinson's disease. Additionally, it may also have beneficial effects on other non‐motor symptoms associated with Parkinson's disease, such as cognitive decline and memory impairment. ³²

TABLE 1.

Pioneers of music effect on human brain.

Effect	Sound	Sample size	Reference
Decrease seizure activity	A pure tone burst of 1000 HZ or loud music	15	Fernandez et al. 85
Musicogenic Epilepsy	Bach's organ music	22	Joynt et al. 59
Break the vicious cycles of pain	Various instruments and soothing music	6	Munro and Mount 15
Evokes thrills	Not specified	15	Goldstein 13
Decrease neuronal discharge rate	1. Simple familiar or unknown classical tunes 2. Orchestrated folk music 3. Drumming without a tune	34	Creutzfeldt and Ojemann 86
Improve spatial reasoning ability	Mozart piece	36	Rauscher et al. 34
Alleviate symptons of depression and distress	Not specified	30	Hanser and Thompson 22
Release of stress hormones and cardiac function	1. A part of “Rosen aus dem Stiden” by Johann Strauss 2. “Viertes Streichquartett, 4. Satz: Rondo improvisato” by Hans Werner Henze 3. A part of “Raga Ramdas Malhar” by Ravi Shankar	20	Mockel et al. 87
Reduce anxiety	Country Western Instrumental, “Fresh Aire” by Mannheim Steamroller, “Winter Into Spring” by George Winston, and “Prelude” and “Comfort” Zone, both by Steven Halpern	96	Barnason and Zimmerman 126
Improve sleeping	Baroque and New Age music	25	Mornhinweg and Voignier 127
Decrease seizure frequencies	The Sonata for two pianos in D major (K.448)	29	Hughes et al. 35
Reduce seizure frequency in patients with Lennox–Gastaut syndrome	Mozart K.448	1	Hughes et al. 36

In summary, music has diverse modulatory impact on the brain. Using new technology to systematically study the cell types and neural circuitry mechanisms involved in the effects of music on the brain has provided a deeper understanding in the differences and similarities in the consequences of different sounds. Before that time, we may continue to be puzzled as to whether replicating the modulation of music on the brain can achieve the intended outcome.

4. MUSIC IN EPILEPSY: A BI‐EDGED SWORD

4.1. The potential anti‐convulsant effect of music

A growing percentage of clinical research indicated that music can be used as an adjunctive therapy which could greatly improve both mood and cognitive performance. Among these music, the “Mozart effect” was the most attractive and valuable, which was first proposed by Rauscher et al. as improving spatial reasoning ability. ³⁴ Exposure to these pieces of music can reduce epileptiform discharges and seizure frequencies, which may act as a hypersynchronization disturber. To explore and test this therapeutical hypothesis, multiple clinical and preclinical trials were based on the Piano Concerto No.20 in D Minor, K.488: Mozart.

In 1995, Hughes et al. reported that listening to Mozart K448 resulted in a drastic decrease in clinical seizure frequencies and epileptiform activities of some patients. ³⁵ One Lennox–Gastaut syndrome patient was reported to have fewer seizures and generalized bilateral spikes when exposed to long‐term Mozart music during wakefulness. ³⁶ Patients who exposed to Mozart also exhibited a decrease in interictal epileptic discharges (IEDs) and seizures. ⁸ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ Moreover, listening to Mozart's music even led to 72.7% effectiveness of seizure‐free or control in children with intractable epilepsy. ⁴¹ The impact of music on epileptic interictal condition was documented, and also acute medically refractory non‐convulsive status epilepticus (SE) patients were reported a good response to music. ⁴² , ⁴³ In addition, regular exposure to Mozart, as an add‐on treatment, improved refractory epilepsy patients' response to ASMs and seizure control. ³⁸ , ⁴⁴ The findings of this study suggest that utilizing music as a complementary therapy may be beneficial for epileptic patients, especially those unresponsive to conventional ASMs. Besides, meta‐analysis confirmed the effectiveness and safety of Mozart's music for drug‐resistant epilepsy systematically and comprehensively, which highlighted the translational potential of music in epilepsy management. ⁴⁵ As is known that Mozart's music could reduce epileptiform discharge (EDs), whether other music could exhibit an equal or better efficacy than Mozart's music becomes an interesting topic. Some researchers found another music that has gender discrimination in treating epilepsy: listening to Haydn's music led to a decrease in EDs in women only, while increased EDs in men. ⁴⁶ And the musical features may account for this diversity, of which harmonic spectrum and tempo in high‐frequency parts may matter. Except for EEG changes under musical stimuli, the patient experienced marked clinical and neurophysiological improvements once adding music to one's conventional treatment. ⁴² , ⁴⁷

Further research has also proposed the potential anti‐convulsant benefits of Mozart's music in experimental epilepsy models. In amygdala and hippocampus kindling‐induced temporal lobe epilepsy (TLE) mice models, sub‐dose ASMs were ineffective for kindled seizures. However, seizure severity was reduced by sub‐dose ASMs after 14 consecutive days of listening to Mozart K.448 for 12 h per day. ⁴⁸ Particularly, Lin et al. found that seizure frequencies and high‐voltage rhythmic spikes were attenuated during and after Mozart music exposure in spontaneous absence epilepsy animal model. ⁴⁹ Furthermore, regarding epileptic comorbidities, Mozart's music was able to improve cognitive impairment in rats that experienced SE. ⁵⁰ However, with the exception of Mozart's Piano Sonata in C major (K.545), other music episodes including Mozart's own legacies and Beethoven's to Alice, as well as K448's string version, could not achieve the equal potential anti‐convulsant effect of K.448, highlighting the underlying acoustics mechanisms. ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ Analyzing the “Mozart effect's” acoustic properties reveals long‐term periodicity, which probably resonates in the cerebral cortex and may be connected to the auditory information encoding in the brain. ⁵⁶ It is worth noting that Mozart K.448 and K.545 share many similar spectral characteristics, having a greater concentration of energy in the fundamental and lower harmonics, and both peak at about 1 kHz. While the melodic structure of music created by Haydn, Liszt, and Mozart share similarities. Despite the substantial supportive evidence of music therapy as an adjuvant therapy for epilepsy, further study is still needed. Furthermore, some individuals with emotional deficiencies do not benefit from music therapy, which may be connected to the individualized music add‐on therapy. ⁵⁷ , ⁵⁸

The majority of studies mentioned above supported the positive anti‐convulsant effects of music in epilepsy (Figure 2), while the evidence is not convincible enough. Small sample sizes, multi‐criteria, and diverse outcome measurements were used across these studies. Mostly effective music was not systematically categorized and unrepeated in patients due to the heterogeneity of patients' responses. Furthermore, the procedure of epilepsy treatment evaluation was time wasting and effort consuming. Even the positive outcome of music therapy is likely doubtable and unacceptable for some professional clinicians. Thus, it is urgently needed to carry out multi‐center and double‐blinded randomized controlled trials to validate the efficacy of music therapy. Also, potential bias caused by patients' preference for different music should not be ignored.

FIGURE 2.

The anti‐convulsant music effect. Particular musical stimuli exhibit specific clinical adjunctive anti‐convulsant benefits. Mozart's sonatas K.448 and K.545 have a beneficial impact on decreasing the frequency of epileptic seizures. Furthermore, they have been found to improve cognitive function in both humans and rats. In rats, these sonatas have also been observed to boost the effectiveness of low‐dose anti‐seizure medications.

In general, music therapy, as a potentially effective, convenient, and non‐invasive adjuvant treatment without obvious side effects, has a promising effect to alleviate the symptoms of chronic neurological diseases such as epilepsy. However, the effects of these adjuvant therapies may vary due to the limitations of the sample size and the individualization of parameters and treatment regimens. Moreover, the application of music in neurological diseases still has certain limitations, especially in the field of epilepsy, and the main treatment of music is limited to Mozart K448 and K545. Therefore, it is urgent to conduct further research on music therapy to optimize parameters and explore mechanisms to provide solid foundation for broader clinical application.

4.2. The potential pro‐convulsant effect of music

Despite its potential anti‐convulsant efficiency, musicogenic epilepsy (ME) cannot be disregarded due to its prevalence rate of around 1 case per 10 000 000 persons. The ILAE categorizes it as a rare kind of complicated reflex epilepsy. ⁹ In reported cases, seizures following musical stimulation are typically delayed by several minutes. During this latency period, patients may experience various symptoms. Musical exposure has been proven to be beneficial for some individuals with epilepsy, whereas some may experience increased epileptic susceptibilities.

Critchley first found that music could be an epileptogenic factor, neither for simple partial seizure nor complex partial seizure, in 1937. Joynt et al. further reported that a patient experienced seizures while listening to certain organ music in 1962. ⁵⁹ Poskanzer et al. also reported a case of epilepsy induced by music where the patient experienced seizures triggered by certain songs. The guttural and “metallic” quality of voice may be the core of epileptogenic music. Even exposed to the ringing of the British Broadcasting Corporation church interval bells, a 62‐year‐old patient experienced three episodes of loss of consciousness. ⁶⁰ A woman developed the seizure symptoms of “ringing in the ears” during her first violin lesson when she was 10 and the seizures did not vanish till her death. ⁶¹ Because music has specific sound characteristics like rhythm, melody, and harmony, it elicits emotions and can be analyzed intellectually. Long‐term observations and recordings showed that sensory and cognitive factors such as light stimulation, geometric patterns, and mathematical calculations do not induce seizures. Thus, it may be inferred that seizures are linked to the cognitive processing of music or rhythmic noises. Simultaneously, a 67‐year‐old clergyman and musician encountered unanticipated or deliberate convulsions while playing a certain song on the organ. ⁶² A recent review documented observations from 110 cases of epilepsy triggered or facilitated by music published between 1884 and 2007, of which 53% (49 of 93) patients experienced music‐induced seizures. In 34 of these patients (37%), the seizures were exclusively due to music stimuli. Five patients (5%) initially experienced seizures without a musical trigger, but later developed seizures that were entirely musical in nature, while five patients (5%) had only music‐induced seizure onset first, and then progressed to spontaneous seizures, which indicates the complexity of musicogenic seizures. Structural and functional data found that active lesions were found predominantly in the right temporal lobe in 60 patients who underwent ictal electroencephalograms (EEGs), indicating the temporal lobe may predominate during ME. ¹⁵ , ¹⁶ , ⁶³ , ⁶⁴

Generally, music episodes are composed with rhythms, melodies, tones, and harmonies. The precise cause of musicogenic epilepsy in these basic music components remains ambiguous, and there are divergent viewpoints. Wieser and his colleagues investigated a case of musicogenic epilepsy using ictal single‐photon emission computed tomography (SPECT) in their study. ⁶⁵ Their findings suggested that the role of music as a precipitating factor is neither exclusive nor specific to most patients generally. Overall, mood and emotion seem to be important influences in triggering musicogenic epilepsy. Of 83 reported patients in total, only 14 (17%) experienced seizures triggered by music alone. Precise data on the onset of music‐triggered seizures were not available in 33 cases, leaving 36 patients who experienced both types of seizures, one triggered by music and the other not. To investigate the specificity of the acoustic stimuli, the researchers found that 4% of the 83 patients were exposed to tones only, while 14% were exposed to “all kinds of music and sounds.” The remaining 4% of the patients were exposed to sounds only. In addition, the “familiarity and/or affective content” of the acoustic stimuli was considered a significant factor for 15 patients. They discovered that 4 patients (11%) were professional musicians, while 11 (31%) were amateurs. In addition, 5 patients (14%) were categorized as “music enthusiasts,” while 7 (20%) exhibited an above‐average level of interest in music. Only 8 patients (23%) with musicogenic epilepsy reported not being particularly interested in music. The evidence indicates that people with a heightened sensitivity to music are more likely to develop musicogenic epilepsy, particularly if they possess a high level of musical aptitude. ⁶⁵ This suggests that the emotional component of music may play a role. Nevertheless, research had documented instances of seizures being provoked by music in newborns as young as 6 months old, indicating that the emotional aspect may not be the sole cause. ⁶⁶ In brief, the causes underlying musicogenic epilepsy may be multifaceted and intricate.

Besides clinical evidence, laboratory findings also indicate a correlation between sound exposure and epileptic seizures. A well‐studied model of generalized epileptic seizures in mice is sensitive to audiogenic seizures. In this model, mice exhibited generalized seizures when exposed to harmful auditory stimuli. Many genetic variants have been previously identified in musicogenic epilepsy. Genomic alterations in some mouse strains resulting in susceptibility to musicogenic seizures have also been partially investigated using DNA sequencing and immunosuppression. The dilute brown agouti coat color (DBA) mouse is commonly used as an animal model for sound‐induced seizures due to its high susceptibility. Mice of the DBA/2 strain suffered an age‐related progression of seizures when exposed to a loud sound with a mixture of frequencies. This included a phase of uncontrolled running, followed by clonic seizures, and a prolonged tonic phase that culminated in respiratory arrest. This condition could frequently end in respiratory arrest that is often fatal or leads to full recovery. ⁶⁷ The mouse audiogenic epilepsy susceptibility locus was localized into chromosomes 4, 7, and 12 of the DBA/2 J strain. ⁶⁸ The DBA/2 strain was used to investigate the anticonvulsant effects of clobazam, benzodiazepines, adenosine type 1 receptors (A1Rs), and their ligands, potentiators of the 5‐HT system, and structurally diverse positive allosteric modulators of GABAB receptors. ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ The Frings mouse, which is vulnerable to musicogenic epilepsy, is also genetically susceptible to sound‐induced seizures, making it a reliable model for reflex epilepsy. ⁷⁴ , ⁷⁵ The underlying genetic locus responsible for the ME phenotype has been named monogenic audiogenic seizure susceptible (MASS1), which is one of the only two identified seizure mutations that are not associated with the ion channel mutations. Similarly, immunohistochemical data proved auditory process brain regions were also hyperexcitable in the Frings mouse seizures. ⁷⁶ The effects of new analogs of topiramate, the novel cholesterol 24‐hydroxylase inhibitor soticlestat, and the synaptic and extra‐synaptic GABA transporter inhibitors have been investigated in Frings mice. ⁷⁷ , ⁷⁸ In a previous study, Minyoung Shin et al. have identified the genetical basis for other monogenic seizure phenotypes, such as juvenile audiogenic monogenic seizure (jams1) in the Black Swiss mouse strain delimited by the gene basigin (Bsg) and the marker D10Mit140. This strain experiences seizures that are not related to hearing loss and its encoding hyperpolarization‐activated cyclic nucleotide‐gated channel subunit 2 (HCN2) may provide an ideal model for human reflex epilepsy. ⁷⁹ The mouse model of audiogenic epilepsy enables genetic analysis and allows for extensive biochemical and electrophysiological investigations that are not feasible in human patients. Typically, this animal model of audiogenic epilepsy is naturally susceptible to experiencing convulsive seizures when exposed to sound stimuli, without the need for genetic or chemical manipulation. This distinguishes it from other models used in epilepsy research, which require the suppression of epilepsy‐related genes through genetic techniques. Consequently, these models show the potential to be extensively utilized in the evaluation of both existing and novel ASMs.

The current clinical signs of the condition are still not clearly described, and deeper investigations are still needed. Neuroimages and successful mesial temporal lobe rection supported musicogenic epilepsy as a limbic epilepsy. The effect of music in precise modulation on limbic system is still unillustrated. Additionally, given that limbic system is closely related to memory consolidation, it suggests that the music‐experienced memory may be also the inducement of musicogenic epilepsy. However, this was not involved or mentioned in the literature. Also, due to the limitations of retrospective study, musicogenic epilepsy may not be captured in time, leading to the potentially biased comment on the outcome. Preclinical research of musicogenic epilepsy shows diverse manners in which seizures were triggered by extrinsic or intrinsic factors. Animal models suggested the musicogenic epilepsy as a focal seizure, while anti‐focal seizure medications cannot achieve seizure control. Thus, we considered that in‐depth investigations combining both clinical and laboratory efforts are urgently needed to illustrate the characteristics, etiologies, pathogenesis, and potential mechanisms of musicogenic epilepsy.

To sum up, music seems to be a double‐edged sword for epilepsy (Table. 2). Both anti‐convulsant and pro‐convulsant efficacy of music can be found in clinical and laboratory settings, suggesting that the music effect on epilepsy seems to be partly related to the basic sound characteristics. However, one has to admit that the process by which music affects epilepsy in humans may be more intricate, as music has the ability to induce high‐level mood changes due to the music experiences, which are barely observed in rodents. The complexity of the music effect in epilepsy pushed researchers to analyze the mechanisms by which a music episode influences brain functions in both animals and humans. By doing so, neurologists would be clearer about which music can be selected as adjunctive therapy for epilepsy.

TABLE 2.

The double‐edged music in epilepsy.

Year	Author	Sound	Animal/human	Sample size	Epileptogenic/therapeutic	Effect
1962	Poskanzer et al. 60	The ringing of the B. B. C. church interval bells	Human	1	E	Experienced three episodes of loss of consciousness
1962	Joynt et al. 59	Organ music	Human	1	E	Experienced seizures
1980	Sutherling et al. 62	Performing a particular hymn on the organ	Human	1	E	Experienced spontaneous or induced seizures
1993	Ogunyemi and Breen et al. 61	Rhythmical sounds and music	Human	1	E	Seizures occur when singing, listening to music, or even thinking about music
1995	Rauscher et al. 34	Mozart piece	Human	36	T	Improve people's spatial reasoning ability
1998	Hughes et al. 35	The Sonata for two pianos in D major (K.448)	Human	29	T	Reduce the frequency of seizures
1999	Hughes et al. 36	The Sonata for two pianos in D major (K.448)	Human	1	T	Patients with Lennox‐Gastaut syndrome had fewer cliical seizures
2007	Lahiri et al. 44	Mozart	Human	1	T	A patient with a refractory form of gelastic epilepsy never had another seizure during 3 months of music therapy
2010	Miranda et al. 43	Mozart (not specifically the sonata for two pianos, K.448) and J.S. Bach	Human	1	T	Electrographic status epilepticus remitted in comatose patients
2010	Kuester et al. 42	Sonata for two pianos by Mozart K 448	Human	1	T	Music itself can modify brain activity objectively and this effect may influence the reduction in epileptic activity, even in medically refractory non‐convulsive status epilepticus
2010	Lin et al. 55	The Sonata for two pianos in D major (K.448)	Human	58	T	Decreases in epileptic discharges
2011	Lin et al. 41	The Sonata for two pianos in D major (K.448)	Human	11	T	Decreasing seizure frequency in children with refractory epilepsy
		The Sonata for two pianos in D major (K.448)				Significant decreases
2012	Lin et al. 5	Mozart K.448 and K.545	Human	39	T	Decrease in the frequency of epileptic discharges
2013	Lin et al. 49	Mozart K.448	Rat	5	T	Reduced the number of seizures in rats as well as the frequency of spike discharges
2014	Lin et al. 66	Mozart K.448	Human	48	T	Decreased seizure recurrence and epileptic discharges in children with first unprovoked seizures
2016	Xing et al. 95	Mozart's Piano Sonata K.448	Rat	30	T	Improve cognitive impairment in rats with status epilepticus induced by pilocarpine
2021	Štillová et al. 46	The first movement of Mozart's Sonata for Two Pianos K. 448 and the first movement of Haydn's Symphony No. 94	Human	18	T	Mozart music could reduce epileptiform discharge of EEG in the brain, but Haydn's music led to a decrease in EDs in women only; and increased EDs in men
2022	Xu et al. 48	Mozart K.448	Mice		T	Enhance the anti‐seizure efficacy of sub‐dose drugs

Abbreviations: EDs, epileptic discharges; EEG, electroencephalography.

5. THE POSSIBLE MECHANISMS OF MUSIC EFFECT FOR EPILEPSY—“SCENES IN THE MIST”

The music consists of well‐organized sounds that reflect and influence the intricate emotions of human beings. Contemporary neuroimaging data have revealed alterations in the activity of many regions of the human brain when exposed to music. Also, recent studies have identified specific brain structural and functional reorganization in musicians, further suggesting that music would influence crucial brain regions and circuitries to exhibit complex influences on brain function. ⁸⁰ , ⁸¹ , ⁸² It can be imagined that diverse branches of music have the heterogeneous capacity to modulate neural activity, and personally preferred music activated the prefrontal lobe especially. ⁸³ Emotional and motivational processes exert a significant influence on the neuronal activity in the auditory cortex, enabling these neurons to distinguish between positive and negative sounds that share distinct characteristics.

5.1. The possible musical mechanisms

In 2020, Zheng et al. investigated the effect of music style on cognitive activity by measuring the level of conceptualization and activation in the prefrontal cortex, where two music styles (i.e., soothing and invigorating) were presented to the audience in the experiment. Behavioral studies then determined the audience's subjective conceptualization levels, and functional near‐infrared spectroscopy measured the activation levels in prefrontal cortex functional areas. The findings indicated that soothing music led to higher levels of subjective conceptualization among the audience, in contrast to uplifting music. Additionally, uplifting music resulted in greater activation levels in forebrain functional areas compared to soothing music. The first scientific practitioner of music therapy is considered by the psychological community to be Aluthura's in the late 18th century, who firstly used music with patients to match emotional and mental rhythms and found that music had a facilitating effect on the responses of psychiatric patients. ⁸⁴ Fermandez and colleagues found that when the brain was exposed to a pure or loud sound at 1000 Hz, there was an increase in the amplitude of brain wave activity and a significant decrease in the duration of the discharges following the onset of epilepsy. ⁸⁵ Creutzfeldt and Ojemann subsequently found that exposure to three distinct genres of music might change the rates at which neurons fire in individuals with pharmacoresistant epilepsy. It was observed by means of microelectrodes positioned in the lateral temporal lobe during the course of the experiment. ⁸⁶ Mockel et al. found three different types of music, including a section of Johann Strauss's “Rosen aus dem Stiden,” Hans Werner Henze's “Viertes Streichquartett Satz: Rondo improvisato,” the music piece “Rondo improvisato” by Hans Werner Henze, and Ravi Shankar's “Raga Ramdas Malhar” which may regulate the release of stress hormones and related cardiac functions. ⁸⁷ In fact, there have been efforts to uncover the mechanism of this significant effect of meditative music on stress hormones as well as left ventricular diastolic function, and this mechanism may be due to direct neural connections between the cerebral cortex, brainstem, reticular system, and other autonomic regulatory structures. ⁸⁸ Studies have shown that listening to Mozart's Piano Sonata K.448 improved spatial reasoning. Recent in vivo research has demonstrated that listening to Mozart K.448 music for 12 hour daily improves the effectiveness of ASMs. Furthermore, Mozart K.448 therapy not only boosts the impact of ASMs at therapeutic dosages but also reduces the minimum dosage required for ASMs. ⁴⁸ Furthermore, reports suggest that Mozart's Piano Sonata K.545 can significantly reduce epileptic discharges. Spectral analysis showed that Mozart's Piano Sonata K.545 shares the common frequency and low harmonics (peaks at 1 KHz) with K448. The low harmonics of K545 may be the core of alleviating seizure discharges in children with epilepsy. ⁵¹ Additionally, Hughes et al. discovered through the implementation of computer technology that Haydn, Liszt, and Mozart's compositions share comparable musical structures and display common characteristics, which may potentially contribute to decreased EDs. Thus, music therapy has gained attention as a distinct field within alternative medicine in numerous Western nations due to its effective and well‐tolerated characteristics. Although some of these fundamental mechanisms have been partially uncovered, contradictions still exist. Clinical evidence has demonstrated the beneficial role of Mozart's sonata K.448 in helping reduce EDs and control seizures in genetic epilepsy. Although the potential for music therapy is promising, there is still a limited understanding of its underlying mechanisms. Music therapy's mechanism of action encompasses various areas of brain activity. Given that music could elicit responses in many regions of the human brain that are involved in the processing of pain, these response to music indicated the involved midbrain dopaminergic system. ⁸⁹ , ⁹⁰ , ⁹¹ , ⁹²

Furthermore, the utilization of music as a supplementary therapy for epilepsy, particularly Mozart K.448, has distinct characteristics compared to other forms of music. Several studies have demonstrated the presence of a rhythmic synchronization effect. Rhythmic synchronization refers to the phenomenon where the activity of neurons or the rhythms of the heart are influenced by the beat of other rhythmic stimuli or auditory input. For example, music is used clinically to promote gait rehabilitation in patients with neurological disorders such as Parkinson's disease, stroke, traumatic brain injury, and cerebral palsy by inducing a rhythmic synchronization effect. ⁹³ , ⁹⁴ Another study showed that K448 differed from the music of other composers in that it had a higher repetition rate. The inverse relationship between the cognitive effects of Mozart's music and playing the same music backward in mice and humans suggests that the nature of the Mozart effect should be attributed to its specific rhythms. ⁹⁵

According to these analyses, Mozart, Bach, and J. C. Bach had a distinctive long‐term periodicity. They assumed that these periodicities were consistent with the general theme that Mozart's music is highly organized and may resonate with the organizing cerebral cortex. ⁹⁶ Compared to the music of other composers, Mozart's work seems to have some different characteristics. When it comes to the effects of classical music on brain function, K.448 is the most studied chapter of Mozart's pieces. The anti‐convulsant effects of the Piano Sonata K. 545 in C major have been reported and have been found to have spectral characteristics similar to those of K.448.

In 2017, Arjmand and colleagues discovered unexpected changes in musical characteristics, such as intensity and rhythm, that activated the frontal regions of the brain associated with positive emotional responses. ⁹⁷ Similarly, research has revealed that the musical structure of K448 may contribute to its potential anti‐convulsant effect, and elucidated a new theory of the “Mozart K448 effect” in epilepsy: the musical structure defined by the sonata form may trigger a positive emotional response, which may be important for the anti‐convulsant effect. Also, Quon et al. demonstrated that the frequency component of the stimulus has an equally important role, as the filtered version of K448 failed to elicit an anti‐convulsant response. Thus, although the filtered version of K448 has a similar structure, it may have reduced its emotional salience and led to dismissed anti‐convulsant effect. This may also be a rhythmic synchronization of the “Mozart effect” in music, which is a subject for further research. ⁹⁸

5.2. The brain regions involved in music

Prior research indicates that music exerts a wide‐ranging influence on the function of the nervous system. Apart from providing pleasure and motivation, music can also impact the extensive auditory circuits and contribute to the production and release of various neurotransmitters. Consequently, the potential mechanism of music therapy is likely to be complex and multifaceted. New neuroimaging studies have shown the effect of music on mood‐related brain regions, with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) showing that pleasant music stimulation can activate brain regions closely linked to pleasure or reward, such as the ventral striatum, orbitofrontal cortex, and forebrain insular. ⁹² , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ , ¹⁰² In contrast, research has shown that sad music can activate areas of the brain associated with negative emotions, including the hippocampus, amygdala, and medial temporal lobe. ¹⁰³ , ¹⁰⁴

Nevertheless, the emotional responses triggered by music are intricate, going beyond a straightforward division of positive and negative feelings. Music has the capacity to evoke multifaceted emotional experiences, as indicated by psychological studies that propose a wider and more intricate variety of emotional reactions. Moreover, music inherently possesses subjectivity, which may also be linked to the emotional alterations it can elicit. In another way, due to individual differences in mood states, some people are “pleasure deprived” of music; that is, they do not experience the pleasure when exposed to music. ⁹² Music has been empirically shown to be effective in eliciting highly pleasurable emotional responses, and as listening to music activates areas of the brain that are strongly associated with pleasure or reward, it has been reported in the literature that exposure to music increases the release of dopamine in the brain and that neurotransmitter pathways may be involved in the effects of Mozart's music on epilepsy. ¹⁰⁵ And the pleasure produced by music is associated with changes in the brain's neurochemicals, such as dopamine (DA), and endogenous opioids, as several studies have confirmed. ¹⁰⁶ , ¹⁰⁷

5.2.1. Dopamine theory of music effects

Calcium lowered blood pressure in spontaneously hypertensive rats (SHRs) by increasing brain dopamine synthesis through a calmodulin‐dependent system and that increased DA levels lowered systolic blood pressure in SHRs by listening to Mozart's music (K.205), which also significantly increased serum calcium and neo‐striatal DA levels. ⁹⁰ , ¹⁰⁵ , ¹⁰⁸ These results suggest that music may also increase calcium‐related DA synthesis in the brain and reduce blood pressure, revealing that the DA transmitter system may be an evolved pathway of the music effect, and further PET studies have shown that dopamine is released during music listening. In autosomal dominant nocturnal frontal lobe epilepsy, alterations in inter‐striatal dopaminergic circuitry may be associated with nocturnal paroxysmal motor activity. ¹⁰⁹ In cases of juvenile myoclonic epilepsy, there is a decrease in D2/3 receptor binding, which is only observed in the bilateral posterior shell nuclei. This indicates that there are particular changes in the dopaminergic system. ¹¹⁰ Furthermore, decreased D2/D3 receptor binding in the polar and lateral epileptogenic temporal lobes of individuals with TLE and hippocampal sclerosis (HS) in close proximity to the median temporal lobe was confirmed. ¹¹¹ Similar findings were later reported in the animal models. ¹¹² , ¹¹³ Collectively, it can be deduced that listening to Mozart K.448 may alter the dopaminergic pathways in subcortical structures, which in turn helps in controlling seizures. Besides, the cortico‐basal ganglia loops, which play an inhibitory role in focal epilepsy, are known to be part of the reward system. ¹¹⁴ Yet, there is currently no concrete evidence to support connections among music, activation of the basal ganglia, and control of convulsions; it still needs further investigation.

5.2.2. Auditory and emotional memory circuitry involved in music effect

Also, research has indicated that music can alleviate the psychological distress associated with illness, primarily by diminishing stress and regulating levels of arousal. Specifically, listening to calming music has been shown to decrease anxiety and stress in individuals undergoing traumatic medical procedures, such as surgery, as well as in patients with coronary artery disease. ¹¹⁵ , ¹¹⁶ In some ways, reports indicate that music can help regulate stress, arousal, and mood by activating responses in the brainstem. ¹¹⁷ Music has been found to elicit brainstem reactions that control cholinergic and dopaminergic neurotransmission through noradrenergic neurons. This, in turn, regulates various physiological and psychological factors in humans, such as heart rate, pulse, blood pressure, mood, skin conductance, and muscle tone. ¹¹⁸ And a literature review shows that these effects were largely related to music rhythm: soothing music is associated with lower heart rate, breathing, and blood pressure, while fast‐beat music increases those activities inversely. ¹¹⁹ This suggests that music may achieve positive and negative feedback of emotional memories through the auditory circuit in response to sound, and it has also been reported in the literature that a depressed individual had a seizure due to emotional stimulation, involving modulation of amygdala enlargement and emotion‐related neural circuity. ¹²⁰

Clinical studies indicate that music‐induced seizures have an emotional and cognitive component. Interestingly, the amygdala has been linked to emotion and motivation for a long time. It processes fear and positive environmental cues, and many studies have shown that excitatory neurons in the basolateral amygdala (BLA) of mice respond to both positive and negative potentiation stimuli. The amygdala is also one of the epileptic hubs, which suggests that it might share a common circuit with epileptic seizures. ¹²¹ Research has shown that conditioned fear is regulated by the transfer of information from the conditioned stimulus (CSti) and unconditioned stimulus (USti) to the amygdala, ¹²² and by the output of the amygdala projecting to the behavioral, autonomic, and endocrine response control systems in the brainstem to regulate the fear response. The transmission of CSti inputs to the amygdala has been extensively studied in recent years. A significant portion of this research has focused on the auditory pathway. Reports indicate that auditory and other sensory inputs to the amygdala primarily end in the lateral amygdala (LA). ¹²³ Nevertheless, the perspective that the amygdala is solely committed to the fear‐conditioning reflex is overly limited. BLA neurons exhibit excitatory responses to CSti that are associated with both unpleasant and rewarding consequences, including auditory, visual, or olfactory stimuli linked with either aversive or rewarding outcomes, such as sweet liquids or food particles. ¹²⁴ , ¹²⁵ This is like the emotional changes caused by the positive and negative feedback on emotions induced by the music mentioned above. Music could trigger epileptic seizures and have various impacts on neurological function, including mood changes, through the auditory neural circuit. These consequences may be linked to its potential anti‐convulsant benefits for epilepsy. Meanwhile, there is extensive evidence indicating that the amygdala–auditory circuit contains both positive and negative emotional memories, such as fear and reward. There may be a shared connection between sound‐triggered emotional memory and epilepsy, and acting on this connection could potentially improve epilepsy treatment. In conclusion, the ways in which music might serve as an adjunctive therapy can be diverse and complicated. Multiple hypotheses are presented with some hints provided from both clinical and laboratory settings. Based on the musical mechanisms, a rhythmic synchronization effect is crucial for Mozart K.448's anti‐convulsant efficacy. Also, music has the potential to relieve cognitive and functional impairment in patients with neurologic disorders by influencing the function of brain regions associated with emotions. Additionally, music may be connected to the dopamine neurotransmitter system, which is implicated in epileptic seizures. However, compared with the efficacy of music therapy, the progress of its mechanism studies falls behind, and more systematic research based on advanced techniques is needed.

6. SUMMARY AND PROSPECT

In summary, music has a reciprocal effect on epilepsy and it serves as an adjunction to the treatment of epilepsy; especially Mozart K.448 and K.545 which can significantly reduce the frequency of epileptic discharges. But at the same time, the incidence of acoustic epilepsy should not be ignored, for some patients, music or acoustic stimuli can also induce seizures. Further individualized and systematic studies are needed to clarify the generalizability and reliability of the effects of music and its optimal parameters.

Multiple concepts have been suggested to elucidate the mechanisms underlying music effect, such as the dopamine theory, auditory and emotional memory circuitry, or the Mozart rhythm effect. Previous investigations have demonstrated that music stimulates several auditory regions in the brain, such as the hypothalamus and striatum. These regions have also been shown to be involved in the treatment of other neurological disorders, including schizophrenia, Parkinson's disease, major depressive disorder, and Alzheimer's disease, suggesting the involvement of these brain regions in the benefits of music effects. However, further research is needed to clarify the mechanisms of music therapy in the treatment of epilepsy, based on advanced neuroscience techniques. And especially why different music would show double‐edged effects on epilepsy should be addressed. Although music therapy is not the primary clinical treatment for epilepsy, its safety and feasibility as an adjunctive therapy may hold promise as a preventive and anti‐convulsant approach in clinical practice. Therefore, we suggest the neurologists and basic researchers can form a joint force to provide a theoretical basis and guidance for its clinical application as an effective adjunctive therapy in treating neurologic diseases.

AUTHOR CONTRIBUTIONS

Shajing Gao and Yiwei Gong: Conceptualization, data curation, formal analysis, writing—original draft, and writing—review & editing. Cenglin Xu and Zhong Chen: Conceptualization, funding acquisition, supervision, and writing—review & editing.

FUNDING INFORMATION

This work was supported by grants from the National Natural Science Foundation of China (No. 82173796 and 82374064) and the Research Project of Zhejiang Chinese Medical University (grant number 2023JKZDZC04).

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

ETHICS STATEMENT

Not applicable.

CONSENT FOR PUBLICATION

All authors approved the final manuscript and the submission to this journal.

Gao S, Gong Y, Xu C, Chen Z. The bidirectional role of music effect in epilepsy: Friend or foe? Epilepsia Open. 2024;9:2112–2127. 10.1002/epi4.13064

DATA AVAILABILITY STATEMENT

No data were used for the research described in the article.