# Influence of music therapy on the rehabilitation of children with severe brain damage Auditory Cognitive Neuroscience

Maria L Bringas, Marilyn Zaldivar, Jorge Bosch, Karelia Martinez-Montes, Eduardo Martínez-Montes, Pedro A Rojas, Dora M Chongo, Maria A Ortega, Reynaldo Galvizu, Alba E Perez, et al.

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Maria L Bringas, Marilyn Zaldivar, Jorge Bosch, Karelia Martinez-Montes, Eduardo Martínez-Montes, et al.. Influence of music therapy on the rehabilitation of children with severe brain damage Auditory Cognitive Neuroscience. Frontiers in Human Neuroscience, 2014. hal-02437775

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# Influence of music therapy on the rehabilitation of children with severe brain damage

Maria L Bringas, Marilyn Zaldivar, Jorge Bosch, Karelia Martinez-Montes, Eduardo Martínez-Montes, Pedro A. Rojas, Dora M. Chongo, Maria A. Ortega, Reynaldo Galvizu, Alba E Perez, Lilia M Morales, Carlos Maragoto, Hector Vera and Mirielle Besson

**Journal Name:** Frontiers in Neuroscience

**ISSN:** 1662-453X

**Article type:** Original Research Article

**First received on:** 04 Apr 2014

**Frontiers website link:** www.frontiersin.org
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# Influence of music therapy on the rehabilitation of children with severe brain damage

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Maria L. Bringas¹,⁴*, Marilyn Zaldivar¹, Jorge Bosch², Karelia Martinez-Montes¹, Eduardo Martinez-Montes²,

Pedro A. Rojas², Dora Ma. Chongo¹, Maria A. Ortega¹, Reynaldo Galvizu¹, Alba E. Perez¹, Lilia Morales¹,

Carlos Maragoto¹, Hector Vera¹, Mireille Besson¹, ²,³

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¹Centro Internacional de Restauracion Neurologica CIREN Habana, Cuba

²Centro de Neurociencias de Cuba, Habana, Cuba

³Laboratoire de Neurosciences Cognitives, CNRS and Marseille Université, Fédération 3C, Marseille, France

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⁴Laboratory of Neuroinformation, School of Life Sciences, University of Electronic Sciences and Technology of China,

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Chengdu China

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* Correspondence: Maria L. Bringas, Centro Internacional de Restauracion Neurologica CIREN Habana, Cuba.

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Maria.luisa.bringas@gmail.com

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**Keywords:** rehabilitation, children, ERPs, music therapy, neurological disorders

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**Contributions:** MLB and MB designed and wrote the paper. All authors contributed to data collection and analysis.

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Word count: 8,476

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Number of figures: 2

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## Abstract

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The aim of this experiment was to test for the efficiency of a music therapy (MT) program implemented at the Centro Internacional de Restauracion Neurologica (CIREN), La Habana, Cuba.

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All the children who participated in this study had severe neurological disorders and were involved in an intense neuro-restoration program for 4 to 8 weeks. Children were randomly assigned to the MT group or to a control group. Overall results from questionnaires filled in by the occupational and speech therapists showed that all children improved from Week 1 to Week 4 on three dimensions (motor, social and emotional behaviours). Importantly, improvements on the motor behaviour dimension were larger for children in the experimental MT group than for children in the control group. Moreover, results in the MT group revealed that improvements on musical tests were larger after 8 weeks than after 4 weeks of MT. Finally, although analyses of the Event-Related brain Potentials (ERPs) showed large inter-individual variability, it was nevertheless possible to isolate subgroups of children with similar patterns of results (P250 vs N300 components). Taken together, these results are encouraging in showing that the use of different methodologies can provide complementary information on the efficiency of neuro-restoration and MT programs

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## 1. Introduction

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Music Therapy (MT) defined as the use of music for clinical purposes has been used for a long time (e.g., Van de Wall, 1946) and MT is often recommended as a treatment for infantile autism, for instance (Accordino, et. al. 2006). Until the past ten years, however, empirical support for MT was relatively scarce and not entirely convincing for several reasons. First, support was mainly coming
42 from case studies conducted by music therapists with limited use of controlled research

43 methodologies. Second, when conducting group studies, a number of factors were not controlled. For

44 instance, groups involved in MT were often heterogeneous without control groups matched on age,

45 sex, level of school education, socio-economic status of the family etc... Patients were not randomly

46 assigned to the experimental (MT) or control group. Data were not always analyzed using appropriate

47 statistical tools and the number of participants was often too small to obtain statistically reliable

48 results (Mrazova&Celec, 2010). Finally, and may be most importantly, these first studies were not

49 theoretically-based and the reasons for using MT in clinical settings were not explicitly described.

50 Importantly, these shortcomings have been fully considered and rigorously controlled studies have

51 been conducted in the past ten years to test for the effects of MT in different groups of patients (see

52 Robb et al. 2011; Robb & Carpenter, 2009 for reviews of music-based interventions and Wan et al.

53 2010, for a review of singing therapy). For instance, Särkämo (Särkämo et al., 2008) and

54 collaborators tested a group of 60 stroke patients with acute middle cerebral artery stroke in left or

55 right hemisphere to determine whether music listening improved cognitive recovery and mood.

56 Patients were randomly assigned to music listening (20 patients), audiobook listening (20 patients) or

57 to a control group (20 patients). Brain magnetic activity, Magnetoencephalography (MEG) was

58 recorded and the Mismatch Negativity (MMNm) was analyzed. The MMN is considered as a good

59 index of preattentive auditory processing (Näätänen et al. 1978). The main advantage of the MMN is

60 that it can be recorded under passive listening conditions from many different types of patients

61 without requiring any specific action from their part (Kujala & Naatanen, 2010). Patients typically

62 watch a silent movie while a sequence of sounds is delivered that comprises standard and deviant

63 stimuli. The MMN is computed by subtracting the Event-Related Potentials (ERPs) to the standard

64 stimulus from the ERPs to the deviant stimuli. Results of Särkämo et al. showed that both music and

65 audiobook listening enhanced recovery of auditory sensory memory functions as reflected by

66 enhanced amplitude MMNm compared to the control group. However, only music listening

67 improved cognitive recovery (verbal memory and focused attention) and prevented depression in the

68 6 months following the stroke. In a subsequent study from the same group (Forsblom et al. 2010), the

69 authors tried to disentangle two factors that may have contributed to improved cognitive recovery

70 and mood in the stroke patients tested by Särkämo (Särkämo et al., 2008), namely enhanced neuronal

71 plasticity and stimulation or emotional and psychological factors related to the music listening

72 experience. Using a phenomenological approach based on the analysis of the patients' own

73 narratives, they found that both types of activities were considered as refreshing stimulations and that

74 both evoked thoughts and memories. However, only music listening was considered as favoring

75 relaxation and increased motor activity and as contributing more than audiobook listening to

76 recovery and positive mood changes.

77 Still with stroke patients, Rodriguez-Fornells and collaborators (Grau-Sanchez et al., 2013;

78 Rodriguez-Fornells et al., 2012), tested the hypothesis that by improving auditory-motor coupling

79 (e.g., Bangert et al., 2006; Baumann et al., 2007; Lahav et al. 2007), playing a musical instrument can

80 promote neuroplastic changes in the motor cortex and the restoration of motor abilities. Patients were

81 involved in a Music-Supported-Therapy (MST) program (Schneider, et al. 2007) during 4 weeks (20

82 individual sessions of 30min each) in which they trained on a MIDI-piano for fine movements and on

83 an electronic drum set for gross movements. Improvements in motor abilities were monitored using

84 3D movement analysis and clinical motor tests. The authors also employed different brain imaging

85 methods, functional Magnetic Resonance Imaging (fMRI) coupled with functional connectivity

86 analyses and Trans-Magnetic Stimulation (TMS). Patients involved in MST showed restored

87 activation in different brain regions (primary auditory cortex, precentralgyrus, inferior frontal regions
and supplementary motor area) as well as increased functional connectivity between these different brain regions. Moreover, applying TMS revealed changes in the excitability of the motor cortex and in the organization of sensori-motor cortex accompanied by a reduction of motor deficits. The authors suggested that MST may restore the inherent dynamics of the auditory-motor loops involved in music processing. While these results are highly promising, one caveat is that no patients were involved in another activity as interesting and motivating as MST that would allow controlling for attention and motivation. This is important insofar as neuroplasticity may depend on the motivational value of the activity (Sanes& Donoghue, 2000).

MT has also been used with Alzheimer patients. For instance, Narme (Narme et al., 2012) compared musical (12 patients) vs non-musical (painting: 10 patients or cooking, 5 patients) interventions (2 hours, twice a week) in 27 patients with moderate to severe dementia (Mini-mental state: 3-18/30). The largest improvements in emotional states were found in the music group both immediately and 2 weeks after the interventions. Särkämo and collaborators, (Särkämö et al., 2013) tested a larger number of patients (89) with mild to moderate dementia and involved in singing (n = 30), music listening (n = 29) or in usual care (control group, n = 30) for 10 weeks. Results showed positive changes in the mood and the quality of life of the patients immediately after the musical intervention and 6 months after. Results of neuropsychological assessments also revealed improvements in general cognition, orientation, short-term memory, attention and executive functions after singing and music listening. They concluded that simple musical activities that are easy to implement can have positive long-term cognitive, emotional, and social benefits in mild/moderate dementia. Another example of cost-effective music-based interventions is provided by the results of Janata (2012) showing that playing individually-selected music programs in the rooms of patients with moderate-to-severe dementia, several hours per day each day for 12 weeks reduced the average levels of agitation and depression among the residents.

Music listening was also shown to facilitate motor activities and the initiation of walking in Parkinson patients (McIntosh et al. 1997) as well as to reduce the speech deficits often associated with Parkinson disease (see Wan et al., 2010, for review). More generally, Stahl et al (2013) showed that singing and rhythmic therapies in non-fluent aphasic patients did facilitate the production of formulaic phrases but only standard therapy allowed transfer to the production of unknown phrases (non formulaic language). These results led the authors to conclude that propositional (left perilesional brain regions) and formulaic speech (right corticostriatal areas) may rely on different neural pathways. Similarly, recent results from Schlaug and collaborators (Vines et al. 2011; Wan et al., 2010) showed that combining singing therapy with trans-Direct Current Stimulation (t-DCS), to increase the excitability of the right posterior inferior frontal gyrus known as a key region for the recovery of aphasia, improved the fluency of speech in non fluent aphasic patients. To our knowledge, only a few controlled randomized studies have tested the effects of MT in children. For instance, Kim and collaborators (Kim et al. 2008; Kim et al. 2009) employed a single subject comparison design to investigate social interactions between children with autism and the therapist during improvisational music therapy and toy play. Within these two conditions they measured emotional, motivational and inter-personal responsiveness in the children during joint engagement episodes using video recordings (analyses of facial expressions, eye contacts...). Results indicated more and longer events of joy, 'emotional synchronicity' and 'initiation of engagement' behaviors in improvisational music therapy than in toy play sessions.

In sum, this short review of the literature shows that the number of well-controlled studies, including random assignment of patients to experimental or control groups and large groups of patients is rapidly increasing. Overall, results are positive and encouraging but this may also result from a
134 publication bias with negative results remaining unpublished. Importantly, mechanisms underlying
135 the positive influence of MT in several pathologies as described above are currently investigated
136 using different behavioral and brain imaging methods. Several hypotheses have been proposed. For
137 instance, music listening and performance engage extensive brain networks that are also involved in
138 other perceptual, cognitive and motor activities. Moreover, many results have shown that music
139 training promotes neuroplastic changes in different brain regions (see Münte et al. 2002, for review)
140 including auditory (e.g., Meyer et al. 2007) and motor-related brain areas (e.g., Bangert et al., 2006;
141 Baumann et al., 2007; Lahav et al., 2007), thereby enhancing auditory-motor coupling (Rodriguez-
142 Fornells et al., 2012). It has also been proposed that the preservation of the medial prefrontal cortex
143 may explain why familiar music is still remembered and able to evoke emotions in persons with
144 severe and advanced dementia (Janata, 2012). The short-term positive effects of music on mood and
145 arousal are possibly mediated by the dopaminergic mesolimbic [reward] system and noradrenaline
146 system (Särkämö & Soto, 2012). Finally, results of epidemiological studies have shown that
147 stimulating cognitive activities (and cognitive reserve) in late life have protective effect against
dementia (Verghese et al., 2003) and can slower cognitive decline in dementia (Hall et al., 2009;
148 Treiber et al., 2011). Findings from Alzheimer transgenic mice are interesting in this respect: they
149 showed that enriched environments can protect against cognitive impairment, decreased beta-amyloid
deposition, and increased hippocampal synaptic immunoreactivity (Cracchiolo et al., 2007).
150 Following Mrazova and Celec (2010), “The ultimate goal of mechanistic research is the molecular
151 understanding of music therapy”. While this goal may still require time to be reached, important
152 progress is made in this direction (e.g., Gomez-Pinilla & Hillman, 2013).
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155 The aim of the present research project was to implement an experiment aimed at investigating the
156 influence of MT in children with severe brain damages. These children were patients from the
157 “Centro Internacional de RestauracionNeurologica (CIREN)”, directly dependent from the Ministry
158 of Health of Cuba. This center is well-known for receiving patients (adults and children) from all
159 over the world and, in particular from Latin America (but also Portugal, Spain, United States...). The
160 general procedure is similar for all incoming patients. The first week is dedicated to complete
161 evaluation of the patient by a multi-disciplinary team of neurologists, neuropsychologists,
162 neurophysiologists and clinicians to establish a diagnostic. Based upon this diagnostic, individualized
163 therapies are implemented to fulfill the specific needs of the patients (e.g. motor, cognitive, speech,
164 memory etc...). Typically, patients are involved in these different therapies from 8:30 until 12:00 am
165 and from 2:00 until 5:30 pm every day except Sundays (Saturday from 8:00 to 12:00). Each therapy
166 session lasts for one hour minimum. Importantly, at least one member of the family remains at the
167 CIREN during the entire stay of the patient to take care of him(her) when (s)he is not involved in the
therapies. The neuro-restorative program lasts for a minimum of 4 weeks but may last longer
168 depending upon the patient needs and the family economic situation.
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170 We took advantage of the organization of the neuro-restorative program at the pediatric clinic of the
171 CIREN to implement a protocol based on a Test – Training – Retest procedure. We had three main
172 objectives. First, we aimed at testing whether 10 to 15 min of MT would increase children’s attention
173 and motivation in the subsequent speech and cognitive therapies that they received several times a
174 day. Second, it was of importance to determine whether music therapy improved musical abilities,
175 social behavior (verbal and nonverbal) and the quality of life of the children enrolled in the program
176 and of their parents. To reach the first and second aim, speech and occupational therapists were asked
177 to fill in questionnaires specifically designed for this experiment based on standard questionnaires
178 (see methods) and parents expressed their opinions in interviews. Finally, we aimed at testing the
179 feasibility of recording the Mismatch Negativity (MMN) from these children. As mentioned above,
180 the MMN is recorded under passive listening conditions and is taken to reflect preattentive auditory
181 processing (Kujala & Näätänen, 2010; Näätänen et al., 1978). In this project, we implemented a
182 typical MMN design with sequences of standard syllables intermixed with deviant syllables varying
183 in pitch, duration and Voice Onset Time (VOT, a phonological parameter that allows differentiating
184 "Ba" from "Pa", for instance). Our aim in recording the MMN from a sample of the children included
185 in the present experiment was to gain objective information on the specific acoustic cues (pitch,
186 duration or VOT) that the child would be most sensitive to and thereafter use this cue to orient
187 subsequent speech therapy. For instance, if one child is most sensitive to frequency, this is interesting
188 information for the speech therapist that can then use voice frequency modulations in the speech
189 therapy program. Moreover, it was also of specific interest to examine changes in MMN amplitude
190 and/or latency before and after the restorative program and the MT.

191 **2. Materials and methods**

192 **2.1. Participants**

193 A total of twenty-seven children participated to this project that lasted from January to October 2013.
194 The inclusion criteria were as follows: participation in the neuro-restorative program at CIREN for at
195 at least 4 weeks, age between 3 and 12 years old; Spanish as native language; functional Auditory
196 Brainstem Responses (ABRs) and parents' consent. Out of the 27 children, all from Latin American
197 countries (Argentina, Chile, Mexico and Venezuela), 17 were randomly assigned to the experimental
198 group (7 girls) and 10 to the control group (3 girls). The mean age of the children was not
199 significantly different in the experimental (mean=6.83, SD=3.22) and in the control group
200 (mean=6.80, SD=3.77; U-Mann Whitney test for independent samples: p= 0.44). The socio-
201 economic background of the family was assessed based on the family income as determined from the
202 parent(s) profession (scale from 1 to 4: Working class=1, Low middle class=2, Middle class=3,
203 Upper middle class=4) and was not significantly different between the experimental (mean = 2.66,
204 SD= 1.18) and control groups (mean=2.55, SD=1.13; p=0.71). The level of education of the parents
205 was also assessed based on the number of years of education (including primary school) and was
206 again not significantly different between the experimental (mean= 14.3 years, SD=4.14) and control
207 groups (mean= 13.1 years, SD=4.9; p=0.36).

208 During the first evaluation week, a comprehensive battery of standard psychometric and
209 neuropsychological tests (Progressive Matrices Test (Raven et al.1998), Wechsler intelligence scale
210 children WISC-r (Wechsler, 1974), Brunet-Lezine psychomotor scale (Brunet & Lezine, 1978),
211 Children neuropsychological scale ENI (Rosselli et al. 2001), as well as routine
212 ElectroEncephaloGram (EEG) recordings and neuroimaging (structural anatomy using Magnetic
213 Resonance Imaging (1.5 T MRI) were performed to establish or to confirm neurological diagnosis
214 and to propose individualized neuro-restorative programs. Screening included search for associated
215 epilepsy, mental retardation, ophthalmologic and/or hearing impairments, speech and language
216 disorders as well as oral-motor dysfunctions. Cognitive assessments revealed a high proportion of
217 mental and psychomotor retardation (n=6), apraxia (n=12) and attention (n=16) impairments.
218 Moreover, out of the 27children with brain damage, 19 suffered from Static Lesions of the Central
219 Nervous System (SLCNS; 12 in the experimental group and 7 in the control group) of prenatal and/or
220 perinatal origins that were expressed in cerebral palsy (n=12, with spastic diparesia subtype) or in
221 cognitive and/or language disorders (n=9). Seven children (5 in the experimental group and 2 in the
222 control group) were diagnosed with other disorders including Autistic Spectrum Disorder (ASD,
223 n=2), generalized dystonia (n=1), neurofibromatosis (n=1) and paraplegia due to spinal cord injury
224 (n=2). Finally, 12 children showed abnormal EEG, 6 children had unilateral impairments in the
225 Auditory Brainstem Responses (ABRs) and MRI showed that 22 children had brain structural
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abnormalities (see Table 1). While we are aware that ideally, homogeneous groups of patients should be included in such an experiment, this was not possible considering the heterogeneity of the specific lesions and associated behaviors of the children who were enrolled at CIREN.

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## 2.2. Ethics

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This study was approved by the scientific council of CIREN and received necessary support from the direction of the hospital. The project was conducted in accordance with norms and guidelines for the protection of human subjects. Informed consent from the doctors and therapists of the neuro-pediatric clinic was granted before the start of the project. Parents were informed in details of the procedure (see below) and on the music training program that was described as an interesting and rewarding experience for their children. Parents who agreed with the project signed an informed consent form.

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## 2.3. Occupational and speech therapy questionnaires

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The study comprised three phases: Test – Rehabilitation –ReTest.

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During the evaluation week (Week 1), the occupational and speech therapists met the child and filled a questionnaire build from standard questionnaires (MacArthur-Bates Inventario I and II, (Jackson-Maldonado et al. 2003); Escala Autónoma Asperger-Autismo, (Belinchon et al., 2008); CUMANIN, (Portellano Perez et al. 2000) around three main dimensions: motor behavior, social behavior and emotional behavior. The therapists received specific training to use the quantitative scale (no reaction= 1, relevant reaction= 5 best). Both therapists filled the same questionnaires again at Week 4 (and at Week 8 for the children that remained at CIREN for 8 weeks).

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**Data Analysis:** Data from the questionnaires filled in by the occupational and speech therapists were analyzed first, by computing the means and standard deviation related to the three dimensions. These data were then submitted to non-parametric Sign-tests and to the Kruskal Wallis one way ANOVA to compare results in the Experimental MT group and in the Control group.

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The parent's questionnaire was administered by a specialist in Physical Medicine and Rehabilitation in an interactive interview that took around one hour and that was conducted twice, once at Week 1 (evaluation week) and once at the end of the restoration program (Week 4 or Week 8, depending upon how long the children remained at CIREN). The overall aim was to determine whether the parents observed changes in the behavior of their children (from MT or control groups) and how they evaluated different aspects of the rehabilitation program. Moreover, parents from children included in the MT program were also asked whether they felt that their children was happy to participate in the MT and whether they considered that MT increased the quality of life of their children.

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## 2.4. Music Therapy

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MT was implemented three times a day, three days per week during 4 to 8 weeks for 10 to 15 min. before the speech and cognitive therapies (Total MT=360 min after 4 weeks and 720 minutes after 8 weeks). Musical stimuli were presented to the children in a quiet, dedicated room, using a computer and external speakers. MT involved active music listening: while listening to the different musical excerpts the music therapist played games with the children to orientate their attention toward specific aspects of the music and to favor their active participation (e.g. throwing a ball to other child when changing from one music excerpt to the other, clapping hands/feet/fingers/moving head in rhythm with the music, etc...). Four different sequences of musical excerpts were prerecorded and each was used in different sessions to avoid habituation. Musical pieces with different characteristics
267 (rhythm, melody, intensity and timber) were selected based on a pilot study conducted in the same
268 clinical settings at CIREN (April to July 2012) with a sample of 17 pediatrics patients (the list of
269 musical pieces is available upon request and included excerpts from, Vivaldi, Benny More, Mozart,
270 Piazzola, etc.). Each sequence was built in such a way as to start with quiet music pieces, continue
271 with more dynamic, entraining musical pieces and end with more quiet pieces.

272 Children in the control group were not involved in extra activity equivalent to MT, but they received
273 more of the classic neuro-restoration program. Ideally, it would have been important for children in
274 the control group to participate in an extra activity to control for attention and motivation but this was
275 not possible to implement for practical reasons.

276 **2.5. Evaluation of children in the music therapy group**

277 The level of performance of the children in the experimental group was evaluated by the music
278 therapist by using three different tests. Performance Scale: this scale comprised 5 domains: motor
279 ability, attention, emotion, imitation and communication. At the end of each MT day, the therapist
280 filled a 5 points scale for each child (from 0 -poor level of performance- to 5 -high level of
281 performance). Averaged individual scores were computed weekly (i.e., over 9 MT sessions).
282 Comparisons are reported between Week 1, Week 4 (all children) and Week 8 (for the subset of
283 children who stayed for 8 weeks).

284 Rhythm test (subtest of CUMANIN, (Portellano Perez et al., 2000): children were asked to reproduce
285 a rhythmic sequence played by the therapist by clapping her hands. The number of taps and their
286 grouping increase in difficulty (from level 1 to 7). Rhythmic performance was evaluated using a 5
287 points scale (0 poor and 5 exact reproduction). For data processing, a score equal or superior to 4 was
288 considered as an index of successful rhythmic reproduction.

289 “Musical” test: this test was developed by KMM & MB to evaluate the orientation response,
290 perceptual discrimination and attention. Fifteen music excerpts were presented twice to the children,
291 once in their original version and once in a modified version that included abrupt changes in timber,
292 harmony and melody. This test was presented twice, under implicit and explicit conditions. In the
293 implicit condition, the music therapist watched the child reaction (1: no reaction and 5: child clearly
294 reacted to the changes). In the explicit conditions, children were given the following instructions:
295 “We are going to play a little game. You listen to the music and you raise a finger/arm/foot/leg/move
296 your head… if you hear something surprising” (scores varied from 1: (no reaction to 5: (detect
297 surprising events at the right time).

298 The Rhythm and “musical” tests were administered to each child individually at different time points
299 during the therapy (Week 1, Week 4 and Week 8) and scores corresponding to the three time points
300 were compared using pairwise nonparametric Sign Tests and Kruskal Wallis one-way ANOVA.

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302 **2.6. Electrophysiology experiment**

303 **Stimuli:** Children were presented with a sequence of syllables (Consonant-Vowel structure) with the
304 syllable "Ba" serving as standard stimulus and deviant stimuli in vowel frequency, vowel duration
305 and Voice Onset Time (VOT; the syllable "Pa"). The standard stimulus "Ba" had a fundamental
306 frequency (F0) of 103 Hz, vowel duration of 208 msec and VOT of–70msec for a total duration of
307 the stimulus of 278 msec. For frequency deviant syllables, the F0 of the vowel was increased to 155
308 Hz using Praat (Boersma & Weenink, 2001). For duration deviant syllables, vowel duration was
309 shortened by 75 msec using Adobe Audition, for a total syllabic duration of 203 msec. Finally, for
310 VOT deviant syllables, the VOT was 70 msec. shorter than for the standard syllable for a total
311 duration of 208 msec.
**Procedure:** The EEG was recorded from a subset of 12 children (out of 17) from the experimental MT group (mean age 7.78, SD 3.01; 5 girls) and from 6 children (out of 10) from the control group (mean age 7.47, SD 3.7; 2 girls; see Table 1). Children who required anesthesia for EEG recordings during the first evaluation week were not included in the subgroup because we did not want to repeat the anesthesia at the end of the MT program (Retest session, see below). Thus, EEG was recorded pre and post training without anesthesia. During EEG recordings, children were told to watch a silent movie without paying attention to the sounds that were presented through headphones. Standard syllables and frequency, duration, and VOT deviant syllables were randomly presented within the auditory sequence with a fixed Stimulus Onset Asynchrony of 600 msec. A total of 920 stimuli were presented binaurally and pseudo-randomly (at least one standard stimulus between each deviant stimulus) with 76% standard stimulus and 8% for each type of deviant stimulus. All stimuli were presented within a single block that lasted for 8 min.

**Recordings:** EEG was recorded continuously at a sampling rate of 200 Hz using a MEDICID IV amplifier system (Neuronic, Cuba) from 19 active Ag-Cl electrodes at standard positions of the International 10/20 System (Jasper, 1958): Fp1, Fp2, F7, F8, F3, F4, C3, C4, T5, T6, T3, T4, P3, P4, O1, O2, Fz, Cz, Pz and nose. Data were re-referenced off-line to the algebraic average of the left and right mastoids and filtered with a bandpass of 1-30 Hz (12 dB/oct).

**Data analyses:** EEG data were analyzed using EEGLab(Delorme & Makeig, 2004) and the Neuronic Analysis software (Version 3.0.2.0; www.Neuronicsa.com). EEG recordings were segmented into 600 msec. epochs (from -100 msec. until 495 msec. post-stimulus onset) time-locked with stimulus presentation. Epochs with electric activity exceeding baseline activity by ±100 µV were considered as artifact and were automatically rejected from further processing. The percent of rejected trials was calculated by experimental condition (25% standard, 24% frequency, 22% duration, 25% VOT). The selected EEG artifacts free trials of each child were averaged for the four types of stimuli (standard, frequency, duration and VOT) in the PRE and POST conditions.

## 3. Results

### 3.1. Comparison between Experimental MT group and Control group

Results are reported for the comparisons between Week 1 (before therapies started) and Week 4 (after therapies started). The number of children who remained at CIREN for 8 weeks was too unbalanced (Occupational therapy: MT n=8 and Control n=4) or too small (Speech therapy: MT n= 3 and Control n =3) to conduct further analyses.

**Occupational therapy:** This questionnaire relates to all children involved in the neuro-restoration program (MT: n= 17 and Control = 10). Using pairwise Sign-tests, results showed significant improvements on motor behavior: Week 1 (mean=3.30) and Week 4 (mean=3.76, z=2.69, p=0.007), social behavior: Week 1 (mean=2.64) and Week 4 (mean=3.33, z=3.20, p=0.001) and emotional behavior: Week 1 (mean=3.07) and Week 4 (mean=3.60, z=2.91, p=0.003).

Using the Kruskal Wallis non parametric one way ANOVA, results showed that the main effect of Group was only significant for motor behavior (ChiSq(2) = 3.84, p<.04) with larger improvements from Week 1 to Week 4 in the experimental MT group (0.66) than in the control group (0.35). No significant between-groups differences were found on the other dimensions.

**Speech therapy:** This questionnaire relates to the subset of children who followed speech therapy (MT: n= 9 and Control = 8). For the three main dimensions that were considered, motor behavior, social behavior and emotional behavior, results of pairwise Sign-tests showed that the improvement between Week 1 and Week 4 was significant for motor behavior (z=2.75, p<0.005) but not
356 significant for the other dimensions.

357 Using the Kruskal Wallis non parametric one-way ANOVA, results showed that the main effect of
358 Group was also significant for motor behavior (ChiSq=4.5, p<.03): the improvement between Week1
359 and Week 4 was larger in the MT group (1.0) than in the control group (.69).

360 **Evaluation of the parents' interview:** Complete information was obtained from 18 parents (MT, n=15 and Control, n = 3). Because of the unbalanced number in the two groups, it was not possible to conduct quantitative analyses. Qualitative observations are reported below.

363 In the initial interview, all parents (n=18) reported that their children enjoyed music and were able to pay attention to music. They also believed that music can help their children in their everyday life.
364 Only one question, related to rhythmic movement associated with music, was negatively rated by parents (n=4) of children with spasticity or dystonia. The majority of children had previous experiences with different types of music therapy in their countries and parents generally agreed on the importance of this intervention.
365
366
367
368

369 In the final interviews, the positive aspects noted by parents of children in the MT group (n=15) were
370 related to increased motivation, sociability and auditory attention. In particular, they noted that MT
371 improved motivation so that children more easily engaged in functional games during the speech and
372 occupational therapies, were less angry and less irritable and were more likely to allow facial
373 massages. Related to sociability, parents noted that their children were more understanding and
374 complying with complex requests and that the collaboration with adults was improved. Overall,
375 children seemed more communicative and more relaxed. Finally, related to auditory attention, parents
376 noted that their children listened more carefully to adult' speech, that they tend to apply during
377 speech and occupational therapies the listening strategies learned during MT and that they paid more
378 attention to music outside the MT therapy. Some children spontaneously started singing songs to
379 their parents. May be most importantly, parents noted that their children were very happy to go to the
380 music therapy sessions.

381 The positive aspects noted by the parents of children in the control group (n=3) were mainly related
382 to social behavior (e.g., improved verbal and nonverbal communication, increased contact with other
383 children and adults). Finally, two parents (from one child in MT group and from one child in control
384 group) also mentioned negative aspects related to increased irritability in their children, possibly
385 because children were taking new anti-epileptic medications.

386 **3.2. Evaluation of children in the experimental MT group**

387 **Behaviour:** the music therapist did evaluate the level of performance of the children at Week 1 (n=17), Week 4 (n=17) and at Week 8 (n=9) on five psychological scales related to motor ability, attention, emotional behaviour, imitation and communication. Using pairwise Sign tests, results revealed significant improvements from Week 1 to Week 4 on all dimensions (all p<0.005, ) and from Week 1 to Week 8 (all p<0.04) but only marginally significant improvements from Week 4 to Week 8 (all p<0.08; see Table 2).

393 Using Kruskal Wallis tests, results showed that the main effect of Session was significant for each dimension (p<.001, see Table 2). Moreover, results of post hoc Tukey HSD tests revealed that the improvements from Week 1 to both Week 4 and Week 8 were significant for each dimension (p<.05) but improvements from Week 4 to Week 8 were not significant (p>.05) except for the attention and communication dimensions (p<.05; see Table 2).

398 **Specific music tests:** Three children could not perform either the rhythm reproduction tests or the "musical" test. The rest were tested at Week 1 (n=14), at Week 4 (n=14) and at Week 8 (n=9).
400 **Rhythm reproduction test** (subtest of CUMANIN): Using pairwise Sign-tests, results showed that the improvement was not significant from Week 1 (mean=0.43, Std=1.16, median=0) to Week 4 (mean=1.43; std=2.14, median=0; z=1.22, p>.22) and from Week 1 to Week 8 (mean=2.75, std=1.83, median=2.50; z=1.51, p>.13). However, the improvement was significant from Week 4 to Week 8 (z=2.27, p<.03), that is for the subset of children (n=9) that remained longer.

405 Using the Kruskal Wallis test, results showed that the main effect of Session was significant (ChiSq(2) = 10.13, p<.007). Results of post hoc Tukey HSD tests showed significant improvements from Week 1 (0.43) to Week 8 (2.75, p<.05). However, mean scores in Week 4 (1.43) were in between and not significantly different either from Week 1 or from Week 8 (both p>.05).

409 **Explicit "musical" test:** Using sign tests, results showed increased level of performance from Week 1 (mean score = 23.57, Std = 11.48, median = 19.00) to Week 4 (mean score =34.00; std= 14.28, median=29.50; z=2.60, p<.01), from Week 1 to Week 8 (mean score =46.88, std=12.14, median=47.00; z=2.47, p<.02) and from Week 4 to Week 8 (z=2.47, p<.02).

413 Using the Kruskal Wallis non parametric test, results showed that the main effect of Session was significant (ChiSq(2) = 12.17, p<.003). Results of post hoc Tukey HSD tests showed significant improvements from Week 1 to Week 8 (p<.05). However, mean scores in Week 4 were in between and not significantly different from Week 1 or Week 8 (p>.05).

417 **Implicit "musical" test:** Using pairwise Sign-tests, results showed increased level of performance from Week 1 (mean score=29.43, std=11.61, median=27.50) to Week 4 (mean score=41.21, std=16.33, median=42.50; z=2.77, p<.006), from Week 1 to Week 8 (mean score=54.13, std=13.34, median=53.50; z=2.47, p<.02) and from Week 4 to Week 8 (z=2.47, p<.02).

421 Using the Kruskal Wallis non parametric test, results showed that the main effect of Session was significant (ChiSq(2) = 11.49, p<.004). Results of post hoc Tukey HSD test showed improvements from Week 1 to Week 8 (p<.05). Again, mean scores in Week 4 were in between and not significantly different from Week 1 or Week 8 (p>.05).

425 Finally, results of pairwise Sign-tests showed that implicit mean scores were higher than explicit mean scores at Week 1 (z=3.18; p<.0002), Week 4 (z=3.18; p<.0002) and Week 8 (z=2.47; p<.02). 426 Results of the Kruskal Wallis test also showed that mean scores in the implicit musical test were 427 significantly higher than mean scores in the explicit test (ChiSq(1) = 4.32, p<.04). 428

429 **3.3. Correlation analyses between different instruments**

430 To determine whether results at the different scales and questionnaires employed in our study were 431 correlated, we compared scores at Week 1 and at Week 4 using one-tailed Spearman correlation 432 coefficient. Importantly, results revealed significant correlations between the social behavior subscale 433 of the parent's interview and the subscales of the occupational therapy questionnaire: social behavior 434 (p=0.009), emotional behavior (p=0.04) and motor behavior (p=0.05). Thus, the improvements noted 435 by the parents were in agreement with the ratings of the occupational therapists. Turning to results in 436 the MT group, scores on emotional behavior were significantly correlated in MT performance and 437 speech therapy subscales (r=0.528, p=0.02).

438 **3.4. ERPs data**

439 Close examination of the ERPs data revealed large inter-individual variability which was expected 440 due to the heterogeneity of the various brain lesions and neurological disorders of the children tested 441 in this study. No clear pattern emerged from a quantitative comparison of the experimental and 442 control group. Nevertheless, on the basis of visual inspection of the data, two suggestive patterns
443 emerged, independently of whether children belonged to the experimental or to the control groups:

444 For a group of children, called the “P250 responsive group”, ERPs were more positive between 200 and 300 ms post-stimulus onset (P250 component) after the neuro-restoration and MT programs than before this intervention.

447 For the other group of children, called the “N300 responsive group”, ERPs were more negative between 300 and 400 ms post-stimulus onset (N300 component) after the neuro-restoration and MT programs than before this intervention.

450 Thus, we computed separate averages for these two sub-groups of children both in the experimental and in the control groups.

452 For the P250 responsive group, as can be seen in Figure 1, the ERPs to standard stimuli and VOT deviant stimuli overlap for the experimental and control subgroups before the start of the restoration and MT programs. By contrast, after the programs, the amplitude of the P250 components elicited by standard stimuli and VOT deviant stimuli were clearly larger in the experimental than in the control group. The parietal scalp distribution of this positive component is an indication that this component may belong to the P3 family (P3b) and may reflect increased auditory reactivity after the MT program.

458 For the N300 responsive group, as can be seen on Figure 2, the pattern of results is quite different from the P250 responsive group. Again, there is good overlap of the ERPs to standard stimuli and VOT deviant stimuli in the experimental and control subgroups before the start of the restoration and MT programs. By contrast, after the programs, a negative component peaking around 300 ms (N300) developed after both standard stimuli and VOT deviant stimuli, with larger amplitude in the experimental than in the control group.

465 While these observations are encouraging for further studies, the small number of children included in the subgroups (from 3 to 6), precluded to conduct further analyses

467 **4. Discussion**

468 Overall results of this experiment showed that all children improved from Week 1 to Week 4 on the three dimensions (motor, social and emotional behaviors) that were tested through the occupational and speech therapies questionnaires. Children from the experimental MT group only differed from children in the control group on the motor behavior dimension. Moreover, children in the MT group showed improvements on the five dimensions (attention, emotion, imitation, communication and motor behavior) of the psychological scales with larger improvements from Week 1 to Week 4 than from Week 4 to Week 8. By contrast, overall results of the specific music tests (rhythm reproduction and explicit and implicit “musical” tests) showed significant improvements from Week 1 to Week 8 but not from Week 1 to Week 4. Importantly, in the MT group and for the emotional dimension, scores on the psychological scale were correlated with scores in the speech therapy questionnaire.

478 More generally, results of correlation analyses showed that the improvements noted by the parents were correlated with those reported by the occupational therapist on the social, emotional and motor behavior subscales. Finally, results of parents’ interviews revealed that they considered that MT had a positive influence on their children motivation, sociability and auditory attention. These different aspects are considered in turn in the following discussion.

483 Considering first results from the occupational and speech therapies questionnaires for all children enrolled in the experiment, the finding of significant improvements from Week 1 to Week 4 on the three dimensions that were tested (social, emotional and motor behaviors) shows the positive impact of the neuro-restoration program implemented at the neuro-pediatric clinic of the CIREN. However, one can argue that since the occupational and speech therapists were involved in the rehabilitation, there is a potential bias toward obtaining positive results. While this may be the case, correlation
analyses showed that the improvements noted by the occupational therapist were correlated with those reported by the parents (who tend to be more critical because of their high expectations regarding the outcome of the program) on the social, emotional and motor behavior subscales. Even if results converge in showing improvements on these dimensions, it will be important in future experiment for children to be tested by occupational and speech therapists that are not directly involved in the neuro-restoration program at CIREN.

Results from the occupational and speech therapies questionnaires revealed significant between-groups differences for the motor behavior dimension with larger motor improvements in the MT group than in the control group. The neuro-restoration program includes motor rehabilitation and all children involved in the experiment were receiving this therapy to variable extents depending upon their specific impairments. However, dancing (or moving any part of the body) was encouraged during music therapy and children very much enjoyed this aspect. Thus, MT provided increased motor training possibly linked to an increased motivation to move due to the entraining function of music (e.g., salsa, tango etc...). These two effects may contribute to the further improvement found in the MT group. This interpretation is in line with results of McIntosh et al. (McIntosh et al., 1997) showing that music facilitates initiation of walking in Parkinson patients. Forsblom et al (Forsblom et al., 2010) also showed that the stroke patients tested in their study considered music listening as favoring engagement in motor activity. Based on these results, it would be useful to implement motor rehabilitation programs associated with entraining musical pieces.

Turning to children in the MT experimental group, results also showed improvements on the five dimensions (attention, emotion, imitation, communication and motor behavior) of the psychological scales. Several results in the psychology of music and neuroscience of music literature have shown that music training is associated with increased attentional abilities (Tervaniemi et al., 2009); see Besson et al. (2011) for a review). For instance, recording brain electrical activity and analyzing ERPs, Marie (Marie et al. 2011) reported shorter latency and larger amplitude of ERP components associated to categorization and decision processes (N2/N3 and P3b components, respectively) in adult French musicians compared to nonmusicians in a same-different task on tone and segmental variations in Mandarin Chinese. These results were interpreted as reflecting enhanced auditory cognitive and attentional abilities in musicians. Similarly, Bauman (Baumann et al., 2007) showed that focussed attention on sine wave tones was associated with an early negative component in musicians but not in nonmusicians which again suggested that music training influenced top-down attentional processes. Moreover, Särkämo (Särkämö et al., 2008) also reported enhanced focussed attention in stroke patients after music listening. While fewer studies have been conducted with children, Chobert (Chobert, et al., 2011) reported enhanced preattentive processing of French syllables varying in pitch, duration and VOT in musician than in nonmusician children.

The relationship between music and emotion has been extensively studied and it is common knowledge that different types of music can induce different emotions and mood. Importantly, and as mentioned in the introduction, Forsblom (Forsblom et al., 2010) found that music listening contributed more than audiobook listening to recovery and positive mood changes in stroke patients and Särkärmo (Särkämö et al., 2008) showed that only music listening prevented depression in the 6 months following the stroke. Moreover, Narme (Narme et al., 2012) showed that music interventions were associated with larger improvements in emotional states than painting or cooking interventions. Similarly, Särkämo and collaborators (Särkämö et al., 2013) showed positive changes in the mood and the quality of life of Alzheimer patients immediately after and 6 months after the music intervention and Janata (Janata, 2012) reported reduced level of agitation and depression in Alzheimer patients listening to music programs several hours per day. Finally, our results showed that MT improved imitation and communication possibly because the music therapist encouraged children to reproduce the movements that she performed on-line with the music (e.g., clapping hands
537 in rhythm with the music, rising hands or fingers or moving the head with melodic changes in the
538 musical excerpts, etc...). Children were also encouraged to share with each other's the emotions and
539 movements induced by the music.

540 However, and as discussed above for the results of the occupational and speech therapies
541 questionnaires, the music therapist was at the same time providing the MT interventions and filling
542 up the questionnaires to test for the results of the therapy. Even if the therapist performing the
543 therapy is probably the best person to evaluate changes in children's behavior because she worked
544 with them regularly three days per week, there is a potential bias toward obtaining positive results.
545 However, two sets of results provide evidence that such a bias is not the unique explanatory source.
546 First, correlation analyses showed that for the emotional dimension, scores on the psychological scale
547 were correlated with scores in the speech therapy questionnaire and the two therapists did not discuss
548 results together. Moreover, analyses of the parents' interviews also revealed that they considered that
549 MT had a positive influence on motivation, sociability and auditory attention. Second, results showed
550 larger improvements from Week 1 to Week 4 than from Week 4 to Week 8 which is not expected
551 based on the hypothesis of a positive bias toward "more music therapy better results". Note that the
552 reasons why the effects of MT were smaller during the second month of the intervention are unclear
553 but it may be that children tend to habituate to the music sessions with decreased positive effects of
554 MT with longer therapy. Based on these results, it would be of interest in future experiments to test
555 for the effect of an On-Off music therapy program (e.g., On for 4 weeks, Off for 2 weeks, On for 2
556 weeks...). It would also be important to compare the results obtained by the music therapist
557 performing the therapy and those obtained by another therapist not directly involved in the
558 rehabilitation program.

559 It is interesting to note that in contrast to results showing larger improvements from Week 1 to Week
560 4 than from Week 4 to Week 8 on the several dimensions of the psychological scales, results of the
561 rhythm reproduction test (CUMANIN) showed significant improvements from Week 1 to Week 8
562 but not from Week 1 to Week 4.Thus, a rather long period of training is necessary for the
563 improvement in rhythmic reproduction to be significant. The level of performance of the children in
564 Week 1 was 0.43, a score close to what reported for children with Down syndrome (0.36, SD= 0.50;
565 (Barba Colmenero & Robles Bello, 2012)). In the subset of children who stayed for 8 weeks, the
566 level of performance increased to 2.75 (SD= 1.83) which should not, however, be considered as
567 normal level (2.72, SD = 1.70) (Barba Colmenero & Robles Bello, 2012) because level 4 rather than
568 level 7 was considered as correct reproduction and some of the children were older than in the Barba
569 Colmenero 2012 study. That music therapy improved the reproduction of rhythmic patterns with
570 increasing complexity was expected based on several results showing that musicians are more
571 sensitive to several aspects of the music rhythmic structure than nonmusicians(e.g, Vuust et al.,
572 2006). However, it is important that similar results can be obtained from children with severe
573 neurological impairments as those tested in the present study.

574 Turning to the “musical” test, results were somewhat different depending upon the statistical test that
575 was used to conduct the analyses (Sign-tests vs Kruskal Wallis tests). While results from the Sign-
576 tests revealed significant improvements from Week 1 to Week 4, results of the more conservative
577 Kruskal Wallis tests only showed significant improvements from Week 1 to Week 8. Thus, more
578 than one month of MT seems to be necessary for the children tested here to increase their sensitivity
579 to abrupt changes (i.e., a combination of timber, harmonic and melodic changes) in the musical
580 pieces. Finally, while similar results were obtained in the explicit and implicit music tests, mean
581 scores in the implicit test were higher, as expected, than mean scores in the explicit test.

582 In sum, results of this experiment are encouraging in showing effects of music therapy both on
583 specific music tests (rhythm reproduction and detection of timber, harmonic and melodic changes in
584 the musical pieces) and on more general aspects of the children behavior, in particular motor
behavior. In line with the literature, we used questionnaires to assess the effectiveness of music therapy (Mrazova & Celec, 2010). However, two caveats are in order. First, while the questionnaires that we used were built from questionnaires published in the literature (MacArthur-Bates Inventario I and II, (Jackson-Maldonado et al., 2003); Escala autónoma Asperger-Autismo, (Belinchon et al., 2008), they were not normalized with children without neurological problems. Second, our results are based on the analyses of questionnaires filled by therapists actively involved in the neuro-restoration program or the MT so that these measures may not be objective. Moreover, the use of questionnaires may not be sensitive enough to detect subtle changes in the children's behavior. However, because the group of children involved in this program was very heterogeneous, including children with different types of brain damage and diverse etiologies (see methods and Table 1), it was not possible to find an experimental test that can be performed by all of them. Moreover, the number of children was not sufficiently larger to allow making subgroups of children with similar neurological problems. In an attempt to find an objective measure of the influence of the neuro-restoration and MT programs, we analyzed the ERPs from a subset of children at Week 1 (evaluation week) and at Week 4 (end of the neuro-restoration and MT programs). While the sample of children was too small to compute statistical analyses and to draw firm conclusions from these data, they nevertheless lead to interesting observations. First, while individual averages were highly variables from one child to the other, it was nevertheless possible to note differences between Week 1 and Week 4. Furthermore, in some children it was also possible to detect the type of deviants they were more sensitive to. While these individual differences are difficult to quantify, it is our hope that new methods are developed for analyzing clinical data (e.g., (Aarts et al., 2014) and for allowing the use of electrophysiological measures as biomarkers of the prognosis and the efficacy of the therapeutic intervention. Second, even if the individual data were variable, it was nevertheless possible to identify two sub-groups of children with similar patterns of results (i.e., the P250 responsive group and the N300 responsive group). While the small number of children in these subgroups precluded further analyses, these between-group differences are encouraging us to collect more data in this experimental design. In conclusion, results of this study provided clear indications that MT had a positive influence on motor behavior, possibly because the children in the MT group benefitted from the entraining and motivational effects of music. Moreover, they are encouraging in showing that the use of different methodologies based on the analyses of questionnaires, specific tests and recording of the ERPs provide complementary information on the efficiency of the neuro-restoration and MT programs.

## 5. Acknowledgement

Thanks to all the children and parents who participated in the study. This experimental program was implemented during Prof. Besson was on sabbatical (2012) at the CIREN and CNEURO. We are very grateful to the nurses and physical therapists who devoted a lot of their time to this investigation. Finally, our special thanks to Dr. Lidice Galan for her valuable statistical advices.

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760 **7. Figure legends**

761 **Figure 1.Sub-averages for the “P250 responsive group”**. ERPs elicited by Standard stimuli (left
762 side) and deviant stimuli in Voice Onset Time (VOT) before and after rehabilitation are compared in
763 the Control (blue trace) and Experimental (red trace) groups. After rehabilitation, the amplitude of
764 the parietally-distributed P250 component was larger in the Experimental than in the Control group.
765 Time is in abscissa and the amplitude of the effects is in ordinate in microvolt (µV).

766 **Figure 2.Sub-averages for the “N300 responsive group”**. ERPs elicited by Standard stimuli (left
767 side) and deviant stimuli in Voice Onset Time (VOT) before and after therapy are compared in the
768 Control (blue trace) and Experimental (red trace) groups. After rehabilitation, amplitude of the
769 frontally-distributed N300 component was larger in the Experimental group than in the Control
770 group.
771

8. Tables

772

<table><caption>Table 1. Clinical Characteristic of the Children</caption><thead><tr><th>Patient/gender</th><th>Age</th><th>Nationality</th><th>Type of disease</th><th>Expressed by</th><th>MRI</th><th>EEG/MMN</th><th>ABRs</th></tr></thead><tbody><tr><td colspan="8"><strong>Experimental Group</strong></td></tr><tr><td>D.F./f</td><td>6.85</td><td>Argentina</td><td>SLCNS</td><td>Cognitive Deficit</td><td>Dysplasia in left temporal region</td><td>EA/MMN</td><td>Ok</td></tr><tr><td>A.J./f</td><td>9.93</td><td>Chile</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Cortical atrophies in insular region. Vascular lesion at left occipito- mesial area. Lesion at caudate nucleus</td><td>MMN</td><td>Abn.</td></tr><tr><td>A.E.V. */f</td><td>9.22</td><td>Mexico</td><td>SLCNS</td><td>Cognitive deficits</td><td>Bilateral atrophy of hippocampus.</td><td>Abn/MMN</td><td>Ok</td></tr><tr><td>C.A.P./m</td><td>8.79</td><td>Mexico</td><td>SLCNS</td><td>Spastic Cerebral Palsy</td><td>Cortical heterotopias deforming lateral ventricles at oval centers. Hypoxia signs.</td><td>MMN</td><td>Abn.</td></tr><tr><td>Y.D./m</td><td>5.43</td><td>Venezuela</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Left fronto-parietal sulci absents</td><td>EA/MMN</td><td>Abn.</td></tr><tr><td>A.Y.H./m</td><td>7.67</td><td>Venezuela</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Subcortical lesions adjacent to upper lateral ventricles. Mild bilateral hippocampal atrophy. Pineal gland cyst.</td><td>MMN</td><td>Ok</td></tr><tr><td>B.A.A. */f</td><td>11.6</td><td>Mexico</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Cortical heterotopias deforming lateral ventricles. Right frontal atrophy.</td><td>MMN</td><td>Ok</td></tr><tr><td>D.A. */m</td><td>8</td><td>Mexico</td><td>Neurodevelop ment Disorder</td><td>Non-verbal Learning Disability</td><td>Mild right fronto-temporal atrophy</td><td>EA/MMN</td><td>Ok</td></tr><tr><td>C.G.*/m</td><td>4</td><td>Mexico</td><td>SLCNS</td><td>Language impairment</td><td>Ok</td><td>MMN</td><td>Ok</td></tr><tr><td>A.H.H./m</td><td>3.2</td><td>Venezuela</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Hypoxic lesions in peri- ventricle areas</td><td>MMN</td><td>Ok</td></tr><tr><td>S.C./m</td><td>3.1</td><td>Venezuela</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Subcortical lesions adjacent to lateral ventricles. Mild atrophy left temporal lobe. Hypoplasia Corpus Callosum</td><td>MMN</td><td>Ok</td></tr><tr><td>X.B.L. */f</td><td>7</td><td>Mexico</td><td>SLCNS</td><td>Cognitive deficit</td><td>Ok</td><td>Abn/MMN</td><td>Ok</td></tr><tr><td>A.S.N./f</td><td>6</td><td>Venezuela</td><td>Spinal Cord Lesion</td><td>Paraplegia</td><td>Ok</td><td>No</td><td>Ok</td></tr><tr><td>L.Y.T./f</td><td>11</td><td>Venezuela</td><td>Idiopathic Dystonia</td><td></td><td>Cortical atrophy (temporal lobe). Cavum vergae. Brainstem hypoplasia</td><td>No</td><td>Ok</td></tr><tr><td>M.S./m</td><td>7</td><td>Angola</td><td>Neurofibromat osis</td><td></td><td>Tumor. Frontal atrophy.</td><td>EA</td><td>Abn.</td></tr><tr><td>D.F.*/m</td><td>4.2</td><td>Mexico</td><td>SLCNS</td><td></td><td>Bilateral atrophy hippocampus.</td><td>EA</td><td>Ok</td></tr><tr><td>O.E.T.*/m</td><td>5.8</td><td>Mexico</td><td>ASD</td><td></td><td>Left occipital lesion related to heterotopia area</td><td>EA</td><td>Abn</td></tr><tr><td colspan="8"><strong>Control Group</strong></td></tr><tr><td>D.N.Q./f</td><td>9.48</td><td>Venezuela</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Cortical atrophy. Cavum vergae.</td><td>Ok/MMN</td><td>Ok</td></tr><tr><td>A.J.B./m</td><td>12</td><td>Venezuela</td><td>Spinal Cord Lesion</td><td>Paraplegia</td><td>Ok</td><td>No/MMN</td><td>Ok</td></tr><tr><td>E.C./m</td><td>4.71</td><td>Mexico</td><td>SLCNS</td><td>Cognitive deficits</td><td>Left occipital lesion (heterotopia)</td><td>EA/MMN</td><td>Ok</td></tr><tr><td>S.G.*/f</td><td>3.99</td><td>Mexico</td><td>ADS</td><td>Rett Syndrome</td><td>Mild cortical atrophy more evident at temporal lobes.</td><td>EA/MMN</td><td>Abn</td></tr><tr><td>J.P.M./m</td><td>3.95</td><td>Venezuela</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Periventricular heterotopias</td><td>MMN</td><td>No</td></tr><tr><td>K.P.R.*/f</td><td>9.64</td><td>Mexico</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Ok</td><td>SW/MMN</td><td>Ok</td></tr><tr><td>L.A.C./m</td><td>3</td><td>Venezuela</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Periventricular heterotopias. Corpus Callosum hypoplasia</td><td></td><td>No</td></tr><tr><td>A.A.M.*/m</td><td>4.96</td><td>Mexico</td><td>SLCNS</td><td>Language Disorder</td><td>Diminished cranial diameter. Temporal Operculum atrophy</td><td>EA</td><td>Ok</td></tr><tr><td>E.H.S./m</td><td>12</td><td>Mexico</td><td>SLCNS post surgery</td><td>Cognitive Deficit</td><td>Generalized cortical atrophy. Hypoxic lesion at basal ganglia</td><td>Abn.</td><td>Abn</td></tr><tr><td>J.P.R.*/m</td><td>4.6</td><td>Mexico</td><td>SLCNS</td><td>Cerebral Palsy</td><td>Periventricular heterotopias</td><td>EA</td><td>Ok</td></tr></tbody></table>

773

SLCNS: Static Lesions of the Central Nervous System (when not explicit is by prenatal and/or perinatal causes); ASD: Autistic

774

Spectrum Disorder. ABRs: Auditory Brainstem responses. * = quit after 4 weeks. Sex f=feminine, m=masculine. EEG/MMN:

775

EA indicates Epileptiform abnormalities, SW: predominant slow waves, Abn: abnormal EEG or ABRs.

776
**Table 2.** Results of questionnaires related to five dimensions administered in the MT group. Means, Standard deviations (STD) as well as p-values from the non-parametric Kruskal-Wallis test and from post hoc Tukey HSD tests (correcting for multiple comparisons) are reported to compare scores in Week 1 (17 children), Week 4 (17 children) and Week 8 (9 children).

<table><thead><tr><th rowspan="2">Item</th><th colspan="2">Week 1</th><th colspan="2">Week 4</th><th colspan="2">Week 8</th><th rowspan="2">K-W<br>ChiSq(2)(pval)</th><th rowspan="2">W1<br>vs.<br>W4</th><th rowspan="2">W1<br>vs.<br>W8</th><th rowspan="2">W4<br>vs.<br>W8</th></tr><tr><th>Mean<br>(STD)</th><th>Median</th><th>Mean<br>(STD)</th><th>Median</th><th>Mean<br>(STD)</th><th>Median</th></tr></thead><tbody><tr><td>Motor ability</td><td>1.95<br>(0.39)</td><td>1.79</td><td>3.42<br>(0.80)</td><td>3.38</td><td>4.48<br>(0.52)</td><td>4.63</td><td>30.01 (&lt;4e-07)</td><td>&lt;0.05</td><td>&lt;0.05</td><td><strong>&gt;0.05</strong></td></tr><tr><td>Attention</td><td>1.69<br>(0.48)</td><td>1.83</td><td>3.17<br>(1.10)</td><td>3.17</td><td>4.64<br>(0.55)</td><td>4.88</td><td>26.63 (&lt;2e-06)</td><td>&lt;0.05</td><td>&lt;0.05</td><td>&lt;0.05</td></tr><tr><td>Affection</td><td>2.74<br>(0.75)</td><td>3.20</td><td>3.77<br>(0.70)</td><td>3.88</td><td>4.60<br>(0.64)</td><td>4.99</td><td>21.69 (&lt;2e-05)</td><td>&lt;0.05</td><td>&lt;0.05</td><td><strong>&gt;0.05</strong></td></tr><tr><td>Imitation</td><td>1.45<br>(0.40)</td><td>1.67</td><td>3.73<br>(0.71)</td><td>3.95</td><td>4.58<br>(0.58)</td><td>4.75</td><td>33.81 (&lt;5e-08)</td><td>&lt;0.05</td><td>&lt;0.05</td><td><strong>&gt;0.05</strong></td></tr><tr><td>Communication</td><td>1.58<br>(0.48)</td><td>1.75</td><td>2.85<br>(0.98)</td><td>3.10</td><td>4.45<br>(0.64)</td><td>4.75</td><td>26.94 (&lt;2e-06)</td><td>&lt;0.05</td><td>&lt;0.05</td><td>&lt;0.05</td></tr></tbody></table>
<figure><img src="image_2.png" /><figcaption>Figure 1.TIF</figcaption></figure>
<caption>Figure 2.TIF</caption>

<figure><img src="image_3.png" /><figcaption>VOT Deviant stimuli</figcaption></figure>

<figure><img src="image_4.png" /></figure>