Journal of Neonatology & Clinical Pediatrics Category: Clinical Type: Research Article
Event-Related Potentials (P300 - MMN) and Neuropsychological Assessment in Duchenne Muscular Dystrophy Patients
- Bumin Nuri Dundar1*, Nihal Olgac Dundar2, Ferah Kizilay3, Ozgur Duman4, Cigil Fettahoglu4, Sibel Ozkaynak5, Senay Haspolat4
- 1 Faculty Of Medicine, Department Of Pediatric Neurology, Izmir Katip Celebi University Ataturk Training And Research Hospital, 35640 Izmir, Turkey
- 2 Faculty Of Medicine, Department Of Pediatric Neurology, Izmir Katip Celebi University Ataturk Training And Research Hospital, Izmir, Turkey
- 3 Faculty Of Medicine, Department Of Neurology, Akdeniz University, Antalya, Turkey
- 4 Faculty Of Medicine, Department Of Pediatric Neurology, Akdeniz University, Antalya, Turkey
- 5 Faculty Of Medicine, Department Of Neurology, Akdeniz University, Antalya, Turkey
*Corresponding Author:Bumin Nuri Dundar
Faculty Of Medicine, Department Of Pediatric Neurology, Izmir Katip Celebi University Ataturk Training And Research Hospital, 35640 Izmir, Turkey
Received Date: Jul 15, 2014 Accepted Date: Oct 06, 2014 Published Date: Oct 20, 2014
Event Related Potentials (ERPs) are related to the basic aspects of brain mechanisms that are responsible for information processing. P300 and Mismatch Negativity (MMN) are well-known endogenous potentials that have been used extensively for the assessment of cognitive functions in different disorders including anemia, multiple sclerosis, stroke, Alzheimer's disease, myotonic dystrophy, and epilepsy [11-16]. Both P300 and MMN are recorded during irregular rare changes introduced during repetitive stimulation. The former is thought to represent a neurophysiologic index of auditory information processing that is dependent of attention, whereas the latter is considered to be the outcome of a pre-attentive system that is independent of attention .
Although studies on the cognitive functions in DMD patients with neuropsychological tests are many, there is only one neurophysiologic evaluation . The aim of this study is to evaluate DMD patients with electrophysiological (MMN and P300) and neuropsychological tests to demonstrate neurocognitive impairment.
MATERIAL AND METHODS
P300: The oddball paradigm was used in the P300 recordings. This paradigm is based on distinguishing a target stimuli repeated randomly and less frequently from the non-target stimuli of frequent repetition, and the subject is asked to count the stimuli or to press a button when he or she encounters the stimuli. Binaural auditory stimuli were presented with earphones. Twenty percent of stimuli was in the rare (target) tones of 2000 Hz (90 dB) whereas the remainders were the frequent (non-target) tones of 1000 Hz (90 dB). The stimulus sequence was random. The recordings were made with Ag/AgCl electrodes. By using the 10-20 system, the reference electrodes were placed over the mastoid regions and the active electrodes over Fz and Cz. All the electrodes had a resistance of 5 kV or less and the frequency limits were set at 0.1-50 Hz. Thirty-two responses recorded by the target stimuli were averaged. Data from the two trials were obtained consecutively and stored. The latency and the amplitude of the N1, P2, N2, and P300 waves were taken into consideration.
MMN: Auditory stimulus sequences consisted of 1000 Hz standard tones and 900 Hz deviant tones (probability of occurrence: p = 0.20) delivered in random order, with the constraint that each deviant tone was preceded by at least three standard tones. All tones had an intensity of 70 dB Sound Pressure Level (SPL) and a duration of 50 ms (5 ms rise/fall). Stimuli were presented monaurally through headphones with a constant (onset to onset) interstimulus interval of 700 ms. A block of 1,000 stimuli was delivered to each ear; the order of the stimulated ear was counterbalanced across participants. The participants were reading the same storybook during the recording session. The MMN, elicited by the deviant stimulus, was calculated by taking the difference between the deviant and standard ERP.
Evaluation of data and statistical analysis
|Patients (N=10)||Controls (N=10)||P|
|Verbal IQ||71.0 ± 13.2
|101.4 ± 16.3
|Performance IQ||75.7 ± 19.1
|107.2 ± 16.4
|Total IQ||72.3 ± 13.9
|103.8 ± 17.6
*CI: 95% Confidence Interval for Mean Lower/Upper.
|Peak||El||Patients (N=10)||Controls (N=10)||P|
|N100||Fz||134.6 ± 39.2
|112.5 ± 22
|Cz||133.1 ± 41.3
|102.4 ± 14.5
|P300||Fz||340.9 ± 32.5
|355.7 ± 30.4
|Cz||338.9 ± 33.5
|346.4 ± 30.9
|MMN||Fz||263.0 ± 39.5
|189.7 ± 30.2
|Cz||256.1 ± 44.1
|199.4 ± 39.1
*CI: 95% Confidence Interval for Mean Lower/Upper.
|Amplitude||El||Patients (N=10)||Controls (N=10)||P|
|N100||Fz||12.9 ± 5.9
|14.3 ± 2.7
|Cz||12.8 ± 5.6
|9.9 ± 3.8
|N1P2||Fz||9.1 ± 4.7
|8.4 ± 6.7
|Cz||11.4 ± 6.9
|13 ± 6.3
|P2N2||Fz||10.4 ± 4
|12.2 ± 4.7
|Cz||10.2 ± 4.6
|11.0 ± 6.0
|N2P3||Fz||15.2 ± 7.1
|17.2 ± 7.4
|Cz||13.0 ± 4.6
|18.0 ± 8.0
|P3N4||Fz||14.5 ± 4.3
|17.1 ± 7.7
|Cz||12.7 ± 4.4
|17.4 ± 10.5
|MMN||Fz||10.8 ± 3.1
|9.7 ± 3.5
|Cz||10.8 ± 3.7
|10.9 ± 4.2
*CI: 95% Confidence Interval for Mean Lower/Upper.
MMN: MMN quantitative parameters were recorded in Fz and Cz electrodes and considered among the groups. The parameters could not be recorded in one patient. In Fz and Cz recordings, MMN amplitude, peak, latency, and duration did not show any significant differences among the groups (p>0.05) (Tables 2 and 3). There was no correlation between MMN quantitative parameters and full-scale IQ, performance IQ, and verbal IQ.
In a meta-analysis of patients reported by Emery and Muntoni, of 721 children studied in 14 reports, the mean IQ was 82, 202 children had an IQ below 70, and 32 had an IQ below 50 . In the present study, the mean full-scale IQ was 72. In addition to the commonly reported delays in motor milestones, another study documented delays in the acquisition of language milestones as well . Several studies compared performance with verbal IQs and most concluded that verbal IQ was more affected; the difference from performance IQ was approximately 5-8 points . In the current study, the researchers found that mean verbal IQ was 71 and mean performance IQ was 75.7. Consequently, the difference was 4.7 points.
Event related potentials are related to the basic aspects of brain mechanisms. P300 represents the outcome of attention dependent systems and information processing. They have been used for a long time for the assessment of cognitive functions. The auditory P300 response has been studied in mentally retarded patients diagnosed with Fragile X syndrome, Down's syndrome, and Alzheimer's disease in Down's syndrome [28,29]. In all these studies, mentally retarded subjects were found, regardless of the etiology of their retardation, to have increased in latency and reduced in amplitude of the P300 response. In the literature, there is only one study that evaluated P300 in DMD patients. Della Coletta et al.,  found poor performance in DMD patients as evaluated by P300 potential compared to the control group, although the difference was not statistically significant. In the present study, the researchers found no statistical difference in mean P300 values between the groups. The brain promoter of the dystrophin gene drives expression primarily in cortical neurons and the hippocampus of the brain . On the other hand, P300 shows electrical activity in the entire brain. Consequently, it is possible to explain why the difference is not significant. Besides, the power for many variables is under eighty percent so it may be due to lack of power and small sample size.
MMN response reflects pre-attentive auditory information processing. Some studies evaluated the MMN test in children with autism, and attention deficit hyperactivity disorder in the literature [30,31]. The magnitudes of MMN were significantly lower than the controls. Holopainen et al.,  showed that in both the mentally retarded and dysphasic groups, the peak amplitude of the frequency MMN was significantly attenuated when compared with the control group, but no significant difference was observed between the mentally retarded and dysphasic groups. In the current study, magnitudes of MMN were similar in the patient and control groups, which reflects no central auditory defects and information processing in this patient group.
To date, neurocognitive functions were not evaluated with MMN and correlations of ERPs through neuropsychological tests were rarely investigated in children with DMD. MMN and P300 are easy, safe, and inexpensive endogenous potentials that may reflect cognitive functions in such patients. Although the patients had low IQ, the researchers did not find any statistical difference in P300 and peak MMN values. The small number of patients may explain these results. However, the peak latencies of MMN were longer in DMD patients. It may be appropriate to do large-scale studies in DMD patient groups with specific genetic defects that cause to mental retardation.
We thank Bulent Ozkan, Ph.D., from Biostatistics & Medical Informatics Department, School of Medicine Izmir Katip Celebi University, for the statistical analysis.
- Emery AE (1989) Clinical and molecular studies in Duchenne muscular dystrophy. Prog Clin Biol Res 306: 15-28.
- Billard C, Gillet P, Signoret JL, Uicaut E, Bertrand P, et al., (1992) Cognitive functions in Duchenne muscular dystrophy: a reappraisal and comparison with spinal muscular atrophy. Neuromuscul Disord 2: 371-378.
- Dubowitz V (1965) Intellectual Impairment in Muscular Dystrophy. Arch Dis Child 40: 296-301.
- Karagan NJ, Richman LC, Sorensen JP (1980) Analysis of verbal disability in Duchenne muscular dystrophy. J Nerv Ment Dis 168: 419-423.
- Dorman C, Hurley AD, D'Avignon J (1988) Language and learning disorders of older boys with Duchenne muscular dystrophy. Dev Med Child Neurol 30: 316-327.
- Leibowitz D, Dubowitz V (1981) Intellect and behaviour in Duchenne muscular dystrophy. Med Child Neurol 23: 577-590.
- Tokarz SA, Duncan NM, Rash SM, Sadeghi A, Dewan AK, et al., (1998) Redefinition of dystrophin isoform distribution in mouse tissue by RT-PCR implies role in nonmuscle manifestations of duchenne muscular dystrophy. Mol Genet Metab 65: 272-281.
- D'Angelo MG, Bresolin N (2006) Cognitive impairment in neuromuscular disorders. Muscle Nerve 34: 16-33.
- Bardoni A, Sironi M, Felisari G, Comi GP, Bresolin N (1999) Absence of brain Dp140 isoform and cognitive impairment in Becker muscular dystrophy. Lancet 353: 897-898.
- Moizard MP, Toutain A, Fournier D, Berret F, Raynaud M, et al., (2000) Severe cognitive impairment in DMD: obvious clinical indication for Dp71 isoform point mutation screening. Eur J Hum Genet 8: 552-556.
- Weiskopf RB, Toy P, Hopf HW, Feiner J, Finlay HE, et al., (2005) Acute isovolemic anemia impairs central processing as determined by P300 latency. Clin Neurophysiol 116: 1028-1032.
- Gil R, Zai L, Neau JP, Jonveaux T, Agbo C, et al., (1993) Event-related auditory evoked potentials and multiple sclerosis. Electroencephalogr Clin Neurophysiol 88: 182-187.
- Korpelainen JT, Kauhanen ML, Tolonen U, Brusin E, Mononen H, et al., (2000) Auditory P300 event related potential in minor ischemic stroke. Acta Neurol Scand 101: 202-208.
- Polich J, Ladish C, Bloom FE (1990) P300 assessment of early Alzheimer's disease. Electroencephalogr Clin Neurophysiol 77: 179-189.
- Kazis A, Kimiskidis V, Georgiadis G, Kapinas K (1996) Cognitive event-related potentials and magnetic resonance imaging in myotonic dystrophy. Neurophysiol Clin 26: 75-84.
- Duman O, Kizilay F, Fettahoglu C, Ozkaynak S, Haspolat S (2008) Electrophysiologic and neuropsychologic evaluation of patients with centrotemporal spikes. Int J Neurosci 118: 995-1008.
- Naatanen R, Gaillard AW, Mäntysalo S (1978) Early selective-attention effect on evoked potential reinterpreted. Acta Psychol (Amst) 42: 313-329.
- Della Coletta MV, Scola RH, Wiemes GR, Fonseca CN, Mäder MJ, et al., (2007) Event-related Potentials (P300) and neuropsychological assessment in boys exhibiting Duchenne muscular dystrophy. Arq Neuropsiquiatr 65: 59-62.
- Wechsler D (1974) WISC-R Manual for the Wechsler Intelligence Scale for Children-Revised. Psychological Corporation, New York, USA.
- Türk Psikologlar Dernegi (1994) WISC-R. Ankara: Türk Psikologlar Dernegi Yayinlari.
- Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, et al., (1989) The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. Am J Hum Genet 45: 498-506.
- Torelli S, Ferlini A, Obici L, Sewry C, Muntoni F (1999) Expression, regulation and localisation of dystrophin isoforms in human foetal skeletal and cardiac muscle. Neuromuscul Disord 9: 541-551.
- Bies RD, Phelps SF, Cortez MD, Roberts R, Caskey CT, et al. (1992) Human and murine dystrophin mRNA transcripts are differentially expressed during skeletal muscle, heart, and brain development. Nucleic Acids Res 20: 1725-1731.
- Górecki DC, Monaco AP, Derry JM, Walker AP, Barnard EA, et al., (1992) Expression of four alternative dystrophin transcripts in brain regions regulated by different promoters. Hum Mol Genet 1: 505-510.
- Emery A, Muntoni F (2003) Duchenne Muscular Dystrophy. 3rd ed. Oxford: Oxford University Press.
- Cyrulnik SE, Fee RJ, De Vivo DC, Goldstein E, Hinton VJ (2007) Delayed developmental language milestones in children with Duchenne's muscular dystrophy. J Pediatr 150: 474-478.
- Bushby KM, Appleton R, Anderson LV, Welch JL, Kelly P, et al., (1995) Deletion status and intellectual impairment in Duchenne muscular dystrophy. Dev Med Child Neurol 37: 260-269.
- St Clair DM, Blackwood DH, Oliver CJ, Dickens P (1987) P3 abnormality in fragile X syndrome. Biol Psychiatry 22: 303-312.
- Muir WJ, Squire I, Blackwood DH, Speight MD, St Clair DM, et al., (1988) Auditory P300 response in the assessment of Alzheimer's disease in Down's syndrome: a 2-year follow-up study. J Ment Defic Res 32 : 455-463.
- Dunn MA, Gomes H, Gravel J (2008) Mismatch negativity in children with autism and typical development. J Autism Dev Disord 38: 52-71.
- Sawada M, Negoro H, Iida J, Kishimoto T (2008) Pervasive developmental disorder with attention deficit hyperactivity disorder-like symptoms and mismatch negativity. Psychiatry Clin Neurosci 62: 479-481.
- Holopainen IE, Korpilahti P, Juottonen K, Lang H, Sillanpaa M (1998) Abnormal frequency mismatch negativity in mentally retarded children and in children with developmental dysphasia. J Child Neurol 13: 178-183.
Citation:Dundar NO, Kizilay F, Duman O, Fettahoglu C, Ozkaynak S, et al. (2014) Event-Related Potentials (P300 - MMN) and Neuropsychological Assessment in Duchenne Muscular Dystrophy Patients. J Neonatol Clin Pediatr 1: 003.
Copyright: © 2014 Bumin Nuri Dundar, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.