Background
Music has been used for healing mental and physical diseases. Rauscher et al. report that brief exposure to Mozart’s Sonata for Two Pianos in D major, K.448 (Mozart K.448), produces a temporal increase in spatial reasoning scores [
1], the so-called “Mozart Effect.” In addition to improvement of cognitive function, subsequent studies reveal positive effects from listening to music for many medical diseases, including hypertension, anxiety, and dementia [
2]–[
4]. For example, Särkämö et al. investigated patients with strokes who listened to their favorite music for two months. Their results show that recovery in the domains of verbal memory and focus attention improved significantly more in the music group than in the control group, even six months after the stroke [
5]. In patients with Parkinson disease, after listening to self-selected music, motor coordination with “Vienna Test System” shows improvement in aiming and line tracking [
6]. This study provides evidence that specific music can improve the precision of arm and finger movement. Relaxing classical music was also used in sleep disorders. 94 students with sleep complaints participated a music study. They listened to relaxing classical music, including some popular pieces from Baroque to Romantic, for 45 minutes every night at bedtime for 3 consecutive weeks, or audiobooks-a CD containing 11 hours of short stories by Hungarian writers such as Frigyes Karinthy, Gyula Krúdy, Géza Gárdonyi, Zsigmond Móricz and Mihály Babits for 45 minutes every night at bedtime for 3 consecutive weeks, or no intervention for 3 weeks. The results show music significantly improves sleep quality according to the Pittsburg sleep quality index and depressive symptoms. However, sleep quality and depressive symptoms did not improve in the audiobook and control group [
7]. Regarding epilepsy, Hughes et al. and our previous study show that epileptiform discharges decrease when listening to Mozart K.448 in patients with epilepsy [
8,
9]. Furthermore, our study also reveals that listening to Mozart K.448 reduces seizure frequencies in children with intractable seizures [
10].
The seizure recurrence rate after the first unprovoked seizure in pediatric patients is highly variable, depending on the follow-up period and patient selection. Age at onset of epilepsy under 1 year, remote symptomatic etiology, developmental delay/mental retardation, abnormal EEG background, frequent epileptiform discharges, and abnormal neuroimaging are all significant predictors of a higher risk for recurrence of epilepsy [
11,
12]. Children with a recurrence have a similar epileptic outcome when compared to children presenting with multiple seizures, regardless whether they were treated after the first unprovoked seizure or not [
13]. This argues in favor of withholding anti-epileptic drug treatment at least until a second seizure has occurred to reduce the potential for adverse effects of drugs, including unpleasant physical effects, adverse cognitive and behavioral changes, and potential teratogenicity [
13,
14]. Until now, there has been no effective method to reduce seizure recurrence after the first unprovoked seizure. In this study, we investigated the effect of Mozart K.448 on the seizure recurrence in children with their first unprovoked seizure who have epileptiform discharges.
Discussion
Mozart K.448 listening is reported to diminish the intensity of tinnitus, improve the paper-folding and cutting tests in patients with mild cognitive impairment, and increase weight gain in preterm infants by reducing resting energy expenditure [
15]–[
17]. Regarding epilepsy, our previous works show that interictal discharges were reduced in most patients with epilepsy when they listened to Mozart K.448 [
9]. In addition, 72.7% of the patients with refractory epilepsy became seizure free or had a very good response by listening to Mozart K.448 [
10]. Our previous report also demonstrates that Mozart K.448 is not the only piece of music to have beneficial effects on children with epilepsy, and that listening to Mozart K.545 with similar lower harmonics can decrease epileptiform discharges in epileptic children as well [
18].
In this current study, we investigated the effect of Mozart K.448 on seizure recurrence after the first unprovoked seizure. The results showed that listening to Mozart K.448 once daily reduced the seizure recurrence rate and epileptiform discharges. The estimated seizure recurrence rate in the control group was 76.8%, while it was 37.2% in music treated patients. The epileptiform discharges also showed an approximate 70-80% reductions after 1, 2, and 6 months of music listening.
Seizure recurrence after the first unprovoked seizure in pediatric patients ranges from 26-71% [
19]. Risk factors for seizure recurrence include a remote symptomatic etiology, an abnormal EEG, a seizure occurring while asleep, a history of prior febrile seizures, and Todd’s paresis [
12]. In a large study, 564 patients, including adults and children who had first unprovoked seizures, have been followed up for 2–4 years. Sixty-seven percent of them had a recurrence within 12 months of the first seizure, and 78% had a recurrence within 36 months [
20]. In the under the age of 16 group, the seizure recurrence rate was 83% by 36 months [
20]. In our study, the seizure recurrence rate was estimated to be 76.8% by 24 months in the control group. An abnormal EEG and an age less than 16 appeared to be risk factors for a higher recurrence rate in our study. However, the seizure recurrence rate did not demonstrate a significant difference in patients with different gender, mentality, seizure type, and etiology. The results were similar to our previous studies which show that gender, mentality, and etiology of epilepsy do not influence the short-term or long-term music effect on epileptiform discharges [
9,
21].
The epileptiform discharges were significantly reduced in EEGs performed 1, 2, and 6 months after initiating music listening in patients without seizure recurrence. However, the epileptiform discharges did not decrease in a duration-dependence manner. EEG improvement after one month of listening to Mozart K.448 may serve as an indicator in determining the long term outcome of music intervention. Although it is not possible to predict how long the patients should be treated, the effectiveness of music listening was demonstrable within one month and continued for at least 6 months. We suggest that listening to music daily for 6 months has a beneficial effect in decreasing seizure recurrence in children with first unprovoked seizures.
Recently, several theories have been introduced regarding the effects of sound on the brain. Poor health is reported to be associated with lower parasympathetic tone in several medical conditions, including epilepsy [
22]. Lotufo et al. report a sympathovagal imbalance in epilepsy, as shown by lower high frequency (HF), the standard deviation of the RR interval (SDNN), and the square root of the mean squared differences of successive RR intervals (RMSSD) values when compared to controls [
23]. One study shows that a two-hour music intervention in cancer patients increases their relaxation scores and parasympathetic activities [
24]. Another study shows that forty-five minutes of music therapy once a week in patients with cerebrovascular disease enhances parasympathetic activities and decreases congestive heart failure events by reducing plasma cytokine and catecholamine levels [
25]. Our previous data also demonstrates that significant increases in HF, RMSSD, the standard deviation of differences between adjacent RR intervals (SDSD), and a decrease in mean beats per minute in heart rate variability analysis occurs while listening to Mozart music in children with epilepsy. At the same time, epileptiform discharges are significantly reduced during and right after listening to Mozart music. The results suggest that Mozart music stimuli induces parasympathetic activation [
26]. It is possible that musical enhancement of parasympathetic tone may account for the beneficial effects on epilepsy.
Neurotransmitter pathways may also be involved in the effect of Mozart K.448 on epilepsy. Musical exposure is known to increase the expression of dopamine levels in the brain [
2]. In recent years, the role of dopamine in the pathophysiology of epilepsy has been well documented. A Positron Emission Tomography study shows that impaired dopamine uptake in the midbrain is hypothesized to contribute to seizures in juvenile myoclonic epilepsy [
27]. In a recent animal study, the authors report that pentylenetetrazole induced seizures decrease the dopamine levels in striatal and hippocampal areas, accompanying the induction and propagation of seizures [
28]. It is possible that listening to music modifies the dopaminergic pathways contributing to the beneficial effects in epilepsy therapy.
There are limitations to this present study. First, the number of participants was somewhat limited and most of the patients were idiopathic in etiology. The statistical power is 0.74, under alpha error 0.05, based on 22 treatment and 24 control subjects with non-recurrence rates 0.63 and 0.23, respectively. Although the power is not sufficient, our findings may provide preliminary evidence that Mozart K.448 listening is beneficial for children with first unprovoked seizures. Second, the lack of control music made it impossible to say that the effects were specific to Mozart K.448 or to a placebo effect. Third, because we did not follow up the EEG in all patients in the control group, it could not be determined whether time duration itself could have caused the decreases in epileptiform discharges, although we had shown that there were significant decreases in epileptiform discharges after listening to Mozart K.448 in treatment group. Fourth, we used per protocol analysis with compliant patients instead of using intention-to-treat analysis, although the result of intention-to-treat is also significant (p = 0.029).
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LCL carried out the study, participated in the evaluation of data, and helped draft the manuscript. MWL, RCW, and HKM conceived the study and participated in the evaluation of data. RCY participated in the design of the study, evaluation of data, and wrote the final version of the manuscript. All authors read and approved the final manuscript.