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The acute effect of music on interictal epileptiform discharges
Epilepsy & Behavior 5 (2004) 662–668 www.elsevier.com/locate/yebeh
The acute effect of music on interictal epileptiform discharges Robert P. Turner* Department of Neurology, Medical University of South Carolina, Charleston, SC, USA Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA Department of Neurological Surgery, Medical University of South Carolina, Charleston, SC, USA Department of Biostatistics, Bioinformatics, and Epidemiology, Medical University of South Carolina, Charleston, USA Received 1 June 2004; accepted 7 July 2004 Available online 19 August 2004
Abstract This study was a prospective, randomized, single-blinded, crossover, placebo-controlled, pilot clinical trial investigating the effect of MozartÕs Sonata for Two Pianos (K448) on the frequency of interictal epileptiform discharges (IEDs) from the EEGs of children with benign childhood epilepsy with centrotemporal spikes, or ‘‘rolandic’’ epilepsy. The goal was to demonstrate decreased frequency of IEDs with exposure to K448. Four subjects were recruited and 4-hour awake EEG recordings performed. IED frequency per minute was averaged over each of three epochs per hour. Mean IED count per epoch, standard deviations, and variance were calculated. Only complete waking epochs were analyzed. Two subjects demonstrated sufficient waking IEDs for statistical analysis, consisting of three epochs of K448-related effects. Significant decreases in IEDs per minute (33.7, 50.6, and 33.9%) were demonstrated comparing baseline with exposure to K448, but not to control music (BeethovenÕs Fu¨r Elise). Ó 2004 Elsevier Inc. All rights reserved. Keywords: Music; Rolandic; Interictal epileptiform discharge; Randomized clinical trial; Mozart; Epilepsy; Centrotemporal
1. Introduction Beginning in the early 1990s, scientifically based studies of the potential beneficial effects of music, in particular Wolfgang Amadeus MozartÕs Sonata for Two Pianos in D Major, K448 (hereafter K448), began to be published in scientific, peer-reviewed journals [1– 8]. The seminal 1993 publication by Rauscher et al. [6] demonstrated transient enhancement of performance on Stanford–Binet spatial–temporal tasks during and after listening to the first movement (Allegro con spirito) of K448. This study exposed 36 college students to 10 minutes each of MozartÕs music, a relaxation tape, and silence. Statistically significant (F(2,35) = 7.08, P = 0.002) improvement in spatial reasoning skills on Stanford–Binet intelligence scale testing was *
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demonstrated in the Mozart-exposed group. This positive effect lasted 10–15 minutes after a 10-minute exposure. During the effect, no interaction or main effects for pulse, as representative of arousal, were present. Thus, arousal as a basis for this effect was excluded. Further studies have subsequently tested the validity and reproducibility of this technique [7,9,10]. Attempts to explain this phenomenon on the basis of either ‘‘arousal effect’’ or ‘‘enjoyment/relaxation effect’’ have been refuted by demonstration of the physiologic effect of MozartÕs music on patients in coma/status epilepticus [11,12] and on rat maze learning [13]. These findings of behavioral, performance, neuropsychological, and neurophysiological changes have been substantiated in a growing body of literature on the effects of listening to MozartÕs music from a variety of disciplines, including studies in EEG coherence and synchrony [14–16], functional MRI [17], AlzheimerÕs
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disease [18], general academic and music learning [19,20,22], and spatial learning in rats [13]. Further studies have also shown that longer exposure to music, as well as music training, results in longer-lasting physiologic effects, as well as anatomic differences in brain architecture between musicians and nonmusicians [21–28]. Other articles have suggested an inability to replicate such effects [29–33]. After publication of the study by Rauscher et al. [6], much public awareness and controversy followed, with production of books, videos, tapes, and CDs purporting that listening to such music would ‘‘make you smarter’’ due to the so-called Mozart effect. Beginning in the mid-1990s, Hughes demonstrated the apparent antiseizure and antiepileptogenic effects of K448, summarized in his excellent articles discussing the effects of K448 on generalized and focal epileptiform patterns [34–36]. His studies documented a statistically significant decrease in interictal epileptiform discharges (spike count and amplitude), as well as decreased clinical and subclinical seizures, in patients exposed to K448, but not to Old Time Pop tunes or music of Philip Glass. He hypothesized that the distinctive aspects of K448 accounted for this phemonemon, e.g., long-term periodicity in the power of the music, as well as the repeated melodic line [34–38]. Hughes concluded that a significant basis for the music effect was that ‘‘the superorganization of the cerebral cortex resonates with the great organization found in Mozart music’’ [35]. Some of MozartÕs compositions, as well as works of similar composers, such as J.S. Bach, Haydn, J.C. Bach, Chopin, and Mendelssohn, appear to ‘‘prime’’ the neurons used in spatial tasks [36]. Further research suggested that the basis for this music effect, not due to relaxation or enjoyment of the music, is explained by the trion model of the cortex [1,4,5,8,10,39–41], based on MountcastleÕs vertical cell column, or minicolumn, model of the neocortex model of the columnar organization of mammalian cortex [42–44]. The trion model suggests three levels of activation (thus, ‘‘trion’’) of the columns of neurons involved in processing music, with this activation leading to priming, or enhanced functioning, of the neurons involved in spatial–temporal tasks. These columns exhibit spatial–temporal firing patterns, and the trion model, as discovered by Shaw, provides an explanation, or mathematical realization, of the functioning of these minicolumns. Ongoing research suggests this as the basis of the effect of MozartÕs music on the brain and brain function. Thus, studies continue to suggest, and expand on, the concept of the neuroanatomic and neurophysiologic basis of the Mozart effect. EEG effects from exposure to music and music training have demonstrated specific areas of activation, but these studies did not address epileptogenesis [8,10,14,15,35,36,45–47]. Recent animal
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studies of environmental enrichment (play area with toys, climbing objects, and auditory stimuli consisting of MozartÕs piano concertos) demonstrated induction of hippocampal plasticity, significantly improving visual–spatial learning [48,49]. Other studies have looked at EEG activity related to music in general, as well as Mozart specifically. Listening to K448 for 10 minutes (vs listening to short story) revealed enhanced synchrony in the right frontal and left temporal–parietal areas, and the changes persisted for 12 minutes [46]. Mozart listening resulted in increased EEG power over the b spectrum in right temporal, left temporal, and right frontal regions [14,15]. Listening to music resulted in bilateral precuneus increased b spectrum power [50]. Music and the brain is a rapidly evolving field of neuroscience research, as demonstrated by the comprehensive publications of proceedings from the 2001 The Biological Foundations of Music and 2003 The Neurosciences and Music [51,52]. The widespread cortical processing of music and complex sound, as well as regional organization of music networks, may explain, at least in part, the variety of neuroanatomic and neurophysiologic effects demonstrated in multiple studies [53–71]. Clinically, it is well known that many factors may provoke or aggravate seizures, including sleep deprivation, stress, alcohol and drug exposure, and trauma. Additionally, many types of stimuli have been reported to provoke or aggravate seizures. This heterogeneous group, called the reflex epilepsies, has been reported by a wide variety of seizure-inducing modalities, including music or other auditory stimuli, visual stimuli, and somatosensory stimuli [72–81]. Even AEDs themselves have been reported to aggravate seizures [82,83]. Musicogenic epilepsy, or seizures triggered by specific types or forms of music, has been described for decades, with a wide variety of types and qualities of music apparently inducing seizures [84–93]. Conversely, we are currently in an era in which various types of neurostimulation have been shown to have antiseizure and antiepileptogenic effects, such as vagal nerve stimulation, low-frequency transcranial magnetic stimulation, and, more recently, deep brain stimulation [94–100]. Thus, if certain stimuli are apparently seizure-inducing, could not such stimuli also, in different form, structure, or modality, have antiseizure and/or antiepileptiform effects, in essence acting as their own form of neurostimulation? Though far from any direct application, such a neurostimulation hypothesis must be subject to the rigors of scientific investigation. Though Hughes demonstrated this apparent antiepileptic/antiepileptiform effect in 23 of 29 selected patients [11,35], this landmark finding has not been subjected to clinical trial methodology. This needed
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step formed the foundation of designing and performing this pilot clinical trial, attempting to bring a novel stimulus for studying epilepsy to the rigors of scientific investigation. If reproducible in a well-designed randomized clinical trial, this finding could represent a significant step toward understanding epileptogenesis, as well as safer and more effective treatments for epilepsy. Due to the frequency of IEDs (interictal epileptiform discharges) in children with benign childhood epilepsy with centrotemporal spikes (BCECTS), or benign rolandic epilepsy of childhood (BREC), this study was conducted in pilot form to investigate potential antiepileptiform (but not antiseizure) effects of K448.
2.3. Data acquisition/procedures
2. Methods
Data acquisition consisted of EEG monitoring using standard ABCN guidelines with BMSI 6000 equipment. Data were stored on a hospital-based secure server, and EEG analysis/spike count was performed. EEGs were read at a sensitivity of 15 lV/mm and only ‘‘rolandic’’ spikes > 50 lV were counted. Music was played on a portable CD player at 60 dB with subjects seated in comfortable recliners. Subjects wore headphones during the first two epochs of each hour (15 minutes of silence, 18 minutes of music exposure), only being permitted to sit quietly in recliner. During the remaining 27 minutes of each hour, children sat and colored or participated in quiet conversation with a parent. For consistency of analysis, only waking epochs were analyzed.
2.1. Research design
2.4. Outcome measure
This study was a prospective, randomized, singleblinded, crossover, placebo-controlled, pilot clinical trial investigating exposure to music, specifically K448, on the frequency of IEDs from the EEGs of children diagnosed with BCECTS. The goal of this study was to demonstrate decreased IEDs on the EEGs of children with BCECTS due to exposure to K448. Such EEGs typically demonstrate abundant IEDs during both waking and sleep. The study was prospective and conducted with IRB approval in the Medical University of South Carolina (MUSC) Outpatient GCRC. Randomization and crossover consisted of either alternating hours of Mozart– Beethoven, or Beethoven–Mozart, with randomization performed by GCRC nursing staff. The study was single-blinded in that those analyzing the EEG following data acquisition (one ABCN board-certified pediatric neurologist and two ABRET-certified EEG technologists) were naı¨ve to order of music exposure. Placebo control consisted of another piece of relaxing piano music, BeethovenÕs Fu¨r Elise, played repetitively during each exposure epoch.
The primary outcome measure, IED frequency per minute, was averaged over each of three periods per hour, over four hours of continuous, awake, EEG monitoring: (1) silence/baseline: 15 minutes; (2) exposure: K448 (first and second movements) or control (placebo) music (BeethovenÕs Fu¨r Elise) (18 minutes); (3) washout period: 27 minutes. Mean IED count per epoch, standard deviations, variance, and correlation data were calculated. Only complete waking epochs (EEG criteria) were analyzed by study design.
2.2. Subjects Four subjects, aged 5–9 years, were selected from EEGs diagnostic of BCECTS (ILAE Criteria) performed in the MUSC Clinical Neurophysiology Laboratory within the year prior to enrollment. Subjects were admitted to the GCRC Outpatient Center at MUSC with prior IRB approval. Each subject completed 4 hours of EEG monitoring. All four subjects, two females and two males, successfully completed the study, with two subjects taking AEDs (carbamazepine, oxcarbazepine), and two on no medications. Results are summarized below.
2.5. Statistical analysis Simple averaging of count data of mean IEDs per minute was performed due to the small number of subjects, as well as the small amount of data available in this pilot study.
3. Results Only two subjects demonstrated sufficient waking IEDs for data collection and statistical analysis, consisting of three epochs of K448-related effects. A significant decrease (33.7, 50.6, and 33.9%) in mean IEDs was demonstrated comparing baseline with exposure, but not with control music. Subject 1 demonstrated frequent right centrotemporal (e.g., ‘‘rolandic’’) IEDs throughout the 4-hour period. Compared with baseline mean IEDs of 4.87, 6.87, 6.07, and 6.47, mean IEDs per minute were 3.22 and 3.00 during exposure to K448 and 7.94 and 4.56 during exposure to control music. Subject 2 demonstrated rare waking IEDs, except during one ‘‘washout’’ period when sleep ensued and abundant ‘‘rolandic’’ spikes were evident. The subject awoke at the beginning of the next
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Fig. 1. Average IEDs per minute during control, exposure, and washout periods.
hour when headphones were replaced and did not return to sleep. Mean IEDs per minute were <0.3. Subject 3 demonstrated no IEDs during the 4-hour awake recording, thus making statistical analysis impossible, despite a previous waking EEG within the past year demonstrating abundant IEDs. Subject 4 also demonstrated IEDs throughout the 4-hour period. A >30% decrease in IEDs, compared with baseline, was demonstrated with exposure to K448 during a single waking epoch. The subject became drowsy during the second exposure to K448, excluding this epoch by study design due to confounding effect of increased IEDs during drowsiness and sleep. Thus, a >25% decrease in IEDs was demonstrated during exposure (red bars) to K448, compared with both silence (blue bars) and control music (white bars). Fig. 1 demonstrates the results for Subject 1. This pilot study demonstrated: (1) the willingness of families and ease of recruitment of study subjects, (2) excellent cooperation of subjects and their parents with study protocol, (3) significant effects in two subjects, and (4) the need for further studies with prolonged recording, to include sleep, to obtain adequate outcome variables (IEDs) for statistical analysis. The major limitation of this study was the small number of subjects and, therefore, lack of generalization of findings.
4. Discussion Though the correlation of IEDs with epilepsy has been the basis of the clinical application of electroencephalography, the significance of altering or eliminating IEDs continues to be debated and investigated [101–107]. In this study, demonstration of decreased IEDs from exposure to K448 suggests an alteration in mechanisms of spike generation. Any correlation with
decreased epileptogenesis and seizure control is not possible from this study design. The mechanism of decreasing IEDs remains unknown. The small database of this pilot study does not allow for either sufficient power analysis or generalization of findings. If validated in further sufficiently powered prospective, randomized clinical trials, this music effect could have substantial impact in understanding epileptogenesis, new treatment strategies for aborting and/or preventing seizures, as well as research focused on finding a cure for epilepsy. Further studies are therefore warranted to investigate the extent and mechanism(s) of action of this music effect on IEDs.
Acknowledgment This study has been supported by GCRC Grant RR01070.
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The acute effect of music on interictal epileptiform discharges Robert P. Turner* Department of Neurology, Medical University of South Carolina, Charleston, SC, USA Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA Department of Neurological Surgery, Medical University of South Carolina, Charleston, SC, USA Department of Biostatistics, Bioinformatics, and Epidemiology, Medical University of South Carolina, Charleston, USA Received 1 June 2004; accepted 7 July 2004 Available online 19 August 2004
Abstract This study was a prospective, randomized, single-blinded, crossover, placebo-controlled, pilot clinical trial investigating the effect of MozartÕs Sonata for Two Pianos (K448) on the frequency of interictal epileptiform discharges (IEDs) from the EEGs of children with benign childhood epilepsy with centrotemporal spikes, or ‘‘rolandic’’ epilepsy. The goal was to demonstrate decreased frequency of IEDs with exposure to K448. Four subjects were recruited and 4-hour awake EEG recordings performed. IED frequency per minute was averaged over each of three epochs per hour. Mean IED count per epoch, standard deviations, and variance were calculated. Only complete waking epochs were analyzed. Two subjects demonstrated sufficient waking IEDs for statistical analysis, consisting of three epochs of K448-related effects. Significant decreases in IEDs per minute (33.7, 50.6, and 33.9%) were demonstrated comparing baseline with exposure to K448, but not to control music (BeethovenÕs Fu¨r Elise). Ó 2004 Elsevier Inc. All rights reserved. Keywords: Music; Rolandic; Interictal epileptiform discharge; Randomized clinical trial; Mozart; Epilepsy; Centrotemporal
1. Introduction Beginning in the early 1990s, scientifically based studies of the potential beneficial effects of music, in particular Wolfgang Amadeus MozartÕs Sonata for Two Pianos in D Major, K448 (hereafter K448), began to be published in scientific, peer-reviewed journals [1– 8]. The seminal 1993 publication by Rauscher et al. [6] demonstrated transient enhancement of performance on Stanford–Binet spatial–temporal tasks during and after listening to the first movement (Allegro con spirito) of K448. This study exposed 36 college students to 10 minutes each of MozartÕs music, a relaxation tape, and silence. Statistically significant (F(2,35) = 7.08, P = 0.002) improvement in spatial reasoning skills on Stanford–Binet intelligence scale testing was *
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demonstrated in the Mozart-exposed group. This positive effect lasted 10–15 minutes after a 10-minute exposure. During the effect, no interaction or main effects for pulse, as representative of arousal, were present. Thus, arousal as a basis for this effect was excluded. Further studies have subsequently tested the validity and reproducibility of this technique [7,9,10]. Attempts to explain this phenomenon on the basis of either ‘‘arousal effect’’ or ‘‘enjoyment/relaxation effect’’ have been refuted by demonstration of the physiologic effect of MozartÕs music on patients in coma/status epilepticus [11,12] and on rat maze learning [13]. These findings of behavioral, performance, neuropsychological, and neurophysiological changes have been substantiated in a growing body of literature on the effects of listening to MozartÕs music from a variety of disciplines, including studies in EEG coherence and synchrony [14–16], functional MRI [17], AlzheimerÕs
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disease [18], general academic and music learning [19,20,22], and spatial learning in rats [13]. Further studies have also shown that longer exposure to music, as well as music training, results in longer-lasting physiologic effects, as well as anatomic differences in brain architecture between musicians and nonmusicians [21–28]. Other articles have suggested an inability to replicate such effects [29–33]. After publication of the study by Rauscher et al. [6], much public awareness and controversy followed, with production of books, videos, tapes, and CDs purporting that listening to such music would ‘‘make you smarter’’ due to the so-called Mozart effect. Beginning in the mid-1990s, Hughes demonstrated the apparent antiseizure and antiepileptogenic effects of K448, summarized in his excellent articles discussing the effects of K448 on generalized and focal epileptiform patterns [34–36]. His studies documented a statistically significant decrease in interictal epileptiform discharges (spike count and amplitude), as well as decreased clinical and subclinical seizures, in patients exposed to K448, but not to Old Time Pop tunes or music of Philip Glass. He hypothesized that the distinctive aspects of K448 accounted for this phemonemon, e.g., long-term periodicity in the power of the music, as well as the repeated melodic line [34–38]. Hughes concluded that a significant basis for the music effect was that ‘‘the superorganization of the cerebral cortex resonates with the great organization found in Mozart music’’ [35]. Some of MozartÕs compositions, as well as works of similar composers, such as J.S. Bach, Haydn, J.C. Bach, Chopin, and Mendelssohn, appear to ‘‘prime’’ the neurons used in spatial tasks [36]. Further research suggested that the basis for this music effect, not due to relaxation or enjoyment of the music, is explained by the trion model of the cortex [1,4,5,8,10,39–41], based on MountcastleÕs vertical cell column, or minicolumn, model of the neocortex model of the columnar organization of mammalian cortex [42–44]. The trion model suggests three levels of activation (thus, ‘‘trion’’) of the columns of neurons involved in processing music, with this activation leading to priming, or enhanced functioning, of the neurons involved in spatial–temporal tasks. These columns exhibit spatial–temporal firing patterns, and the trion model, as discovered by Shaw, provides an explanation, or mathematical realization, of the functioning of these minicolumns. Ongoing research suggests this as the basis of the effect of MozartÕs music on the brain and brain function. Thus, studies continue to suggest, and expand on, the concept of the neuroanatomic and neurophysiologic basis of the Mozart effect. EEG effects from exposure to music and music training have demonstrated specific areas of activation, but these studies did not address epileptogenesis [8,10,14,15,35,36,45–47]. Recent animal
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studies of environmental enrichment (play area with toys, climbing objects, and auditory stimuli consisting of MozartÕs piano concertos) demonstrated induction of hippocampal plasticity, significantly improving visual–spatial learning [48,49]. Other studies have looked at EEG activity related to music in general, as well as Mozart specifically. Listening to K448 for 10 minutes (vs listening to short story) revealed enhanced synchrony in the right frontal and left temporal–parietal areas, and the changes persisted for 12 minutes [46]. Mozart listening resulted in increased EEG power over the b spectrum in right temporal, left temporal, and right frontal regions [14,15]. Listening to music resulted in bilateral precuneus increased b spectrum power [50]. Music and the brain is a rapidly evolving field of neuroscience research, as demonstrated by the comprehensive publications of proceedings from the 2001 The Biological Foundations of Music and 2003 The Neurosciences and Music [51,52]. The widespread cortical processing of music and complex sound, as well as regional organization of music networks, may explain, at least in part, the variety of neuroanatomic and neurophysiologic effects demonstrated in multiple studies [53–71]. Clinically, it is well known that many factors may provoke or aggravate seizures, including sleep deprivation, stress, alcohol and drug exposure, and trauma. Additionally, many types of stimuli have been reported to provoke or aggravate seizures. This heterogeneous group, called the reflex epilepsies, has been reported by a wide variety of seizure-inducing modalities, including music or other auditory stimuli, visual stimuli, and somatosensory stimuli [72–81]. Even AEDs themselves have been reported to aggravate seizures [82,83]. Musicogenic epilepsy, or seizures triggered by specific types or forms of music, has been described for decades, with a wide variety of types and qualities of music apparently inducing seizures [84–93]. Conversely, we are currently in an era in which various types of neurostimulation have been shown to have antiseizure and antiepileptogenic effects, such as vagal nerve stimulation, low-frequency transcranial magnetic stimulation, and, more recently, deep brain stimulation [94–100]. Thus, if certain stimuli are apparently seizure-inducing, could not such stimuli also, in different form, structure, or modality, have antiseizure and/or antiepileptiform effects, in essence acting as their own form of neurostimulation? Though far from any direct application, such a neurostimulation hypothesis must be subject to the rigors of scientific investigation. Though Hughes demonstrated this apparent antiepileptic/antiepileptiform effect in 23 of 29 selected patients [11,35], this landmark finding has not been subjected to clinical trial methodology. This needed
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step formed the foundation of designing and performing this pilot clinical trial, attempting to bring a novel stimulus for studying epilepsy to the rigors of scientific investigation. If reproducible in a well-designed randomized clinical trial, this finding could represent a significant step toward understanding epileptogenesis, as well as safer and more effective treatments for epilepsy. Due to the frequency of IEDs (interictal epileptiform discharges) in children with benign childhood epilepsy with centrotemporal spikes (BCECTS), or benign rolandic epilepsy of childhood (BREC), this study was conducted in pilot form to investigate potential antiepileptiform (but not antiseizure) effects of K448.
2.3. Data acquisition/procedures
2. Methods
Data acquisition consisted of EEG monitoring using standard ABCN guidelines with BMSI 6000 equipment. Data were stored on a hospital-based secure server, and EEG analysis/spike count was performed. EEGs were read at a sensitivity of 15 lV/mm and only ‘‘rolandic’’ spikes > 50 lV were counted. Music was played on a portable CD player at 60 dB with subjects seated in comfortable recliners. Subjects wore headphones during the first two epochs of each hour (15 minutes of silence, 18 minutes of music exposure), only being permitted to sit quietly in recliner. During the remaining 27 minutes of each hour, children sat and colored or participated in quiet conversation with a parent. For consistency of analysis, only waking epochs were analyzed.
2.1. Research design
2.4. Outcome measure
This study was a prospective, randomized, singleblinded, crossover, placebo-controlled, pilot clinical trial investigating exposure to music, specifically K448, on the frequency of IEDs from the EEGs of children diagnosed with BCECTS. The goal of this study was to demonstrate decreased IEDs on the EEGs of children with BCECTS due to exposure to K448. Such EEGs typically demonstrate abundant IEDs during both waking and sleep. The study was prospective and conducted with IRB approval in the Medical University of South Carolina (MUSC) Outpatient GCRC. Randomization and crossover consisted of either alternating hours of Mozart– Beethoven, or Beethoven–Mozart, with randomization performed by GCRC nursing staff. The study was single-blinded in that those analyzing the EEG following data acquisition (one ABCN board-certified pediatric neurologist and two ABRET-certified EEG technologists) were naı¨ve to order of music exposure. Placebo control consisted of another piece of relaxing piano music, BeethovenÕs Fu¨r Elise, played repetitively during each exposure epoch.
The primary outcome measure, IED frequency per minute, was averaged over each of three periods per hour, over four hours of continuous, awake, EEG monitoring: (1) silence/baseline: 15 minutes; (2) exposure: K448 (first and second movements) or control (placebo) music (BeethovenÕs Fu¨r Elise) (18 minutes); (3) washout period: 27 minutes. Mean IED count per epoch, standard deviations, variance, and correlation data were calculated. Only complete waking epochs (EEG criteria) were analyzed by study design.
2.2. Subjects Four subjects, aged 5–9 years, were selected from EEGs diagnostic of BCECTS (ILAE Criteria) performed in the MUSC Clinical Neurophysiology Laboratory within the year prior to enrollment. Subjects were admitted to the GCRC Outpatient Center at MUSC with prior IRB approval. Each subject completed 4 hours of EEG monitoring. All four subjects, two females and two males, successfully completed the study, with two subjects taking AEDs (carbamazepine, oxcarbazepine), and two on no medications. Results are summarized below.
2.5. Statistical analysis Simple averaging of count data of mean IEDs per minute was performed due to the small number of subjects, as well as the small amount of data available in this pilot study.
3. Results Only two subjects demonstrated sufficient waking IEDs for data collection and statistical analysis, consisting of three epochs of K448-related effects. A significant decrease (33.7, 50.6, and 33.9%) in mean IEDs was demonstrated comparing baseline with exposure, but not with control music. Subject 1 demonstrated frequent right centrotemporal (e.g., ‘‘rolandic’’) IEDs throughout the 4-hour period. Compared with baseline mean IEDs of 4.87, 6.87, 6.07, and 6.47, mean IEDs per minute were 3.22 and 3.00 during exposure to K448 and 7.94 and 4.56 during exposure to control music. Subject 2 demonstrated rare waking IEDs, except during one ‘‘washout’’ period when sleep ensued and abundant ‘‘rolandic’’ spikes were evident. The subject awoke at the beginning of the next
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Fig. 1. Average IEDs per minute during control, exposure, and washout periods.
hour when headphones were replaced and did not return to sleep. Mean IEDs per minute were <0.3. Subject 3 demonstrated no IEDs during the 4-hour awake recording, thus making statistical analysis impossible, despite a previous waking EEG within the past year demonstrating abundant IEDs. Subject 4 also demonstrated IEDs throughout the 4-hour period. A >30% decrease in IEDs, compared with baseline, was demonstrated with exposure to K448 during a single waking epoch. The subject became drowsy during the second exposure to K448, excluding this epoch by study design due to confounding effect of increased IEDs during drowsiness and sleep. Thus, a >25% decrease in IEDs was demonstrated during exposure (red bars) to K448, compared with both silence (blue bars) and control music (white bars). Fig. 1 demonstrates the results for Subject 1. This pilot study demonstrated: (1) the willingness of families and ease of recruitment of study subjects, (2) excellent cooperation of subjects and their parents with study protocol, (3) significant effects in two subjects, and (4) the need for further studies with prolonged recording, to include sleep, to obtain adequate outcome variables (IEDs) for statistical analysis. The major limitation of this study was the small number of subjects and, therefore, lack of generalization of findings.
4. Discussion Though the correlation of IEDs with epilepsy has been the basis of the clinical application of electroencephalography, the significance of altering or eliminating IEDs continues to be debated and investigated [101–107]. In this study, demonstration of decreased IEDs from exposure to K448 suggests an alteration in mechanisms of spike generation. Any correlation with
decreased epileptogenesis and seizure control is not possible from this study design. The mechanism of decreasing IEDs remains unknown. The small database of this pilot study does not allow for either sufficient power analysis or generalization of findings. If validated in further sufficiently powered prospective, randomized clinical trials, this music effect could have substantial impact in understanding epileptogenesis, new treatment strategies for aborting and/or preventing seizures, as well as research focused on finding a cure for epilepsy. Further studies are therefore warranted to investigate the extent and mechanism(s) of action of this music effect on IEDs.
Acknowledgment This study has been supported by GCRC Grant RR01070.
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