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Neuroscience Letters 611 (2016) 5967

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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Research paper

Longitudinal study of children with perinatal brain damage in whom


early neurohabilitation was applied: Preliminary report
Thala Harmony , Jess Barrera-Resndiz, Mara Elena Jurez-Coln,
Cristina Carrillo-Prado, M. del Consuelo Pedraza-Aguilar, Aurora Asprn Ramrez,
Manuel Hinojosa-Rodrguez, Thala Fernndez, Josena Ricardo-Garcell
Unidad de Investigacin en Neurodesarrollo, Departamento de Neurobiologa Conductual y Cognitiva, Instituto de Neurobiologa, Universidad Nacional
Autnoma de Mxico, Campus Juriquilla, Mexico

h i g h l i g h t s

It is a longitudinal study of perinatal brain damaged children.


Katonas neurohabilitation procedure was used as treatment.
89% of preterm 34 weeks treated had normal neurodevelopment.
Only 20% of non-treated preterm 34 weeks had normal neurodevelopment.
Application of neurohabilitation to perinatal brain damaged infants is recommended.

a r t i c l e

i n f o

Article history:
Received 31 March 2015
Received in revised form
26 September 2015
Accepted 10 November 2015
Available online 17 November 2015
Keywords:
Perinatal brain damage
Prenatal risk factors
Neurohabilitation
Preterm encephalopathy
Hypoxic ischemic encephalopathy
MRI

a b s t r a c t
Objective: The neurohabilitation treatment has been shown to be a successful method for decreasing the
sequelae of perinatal brain damage (PBD) in Hungarian population. The goal of this pilot trial was to
introduce this procedure by describing the results of its application in infants with PBD as demonstrated
by clinical, developmental and MRI studies. As this procedure has proved to be useful, according the
declaration of Helsinki, no control clinical trial was permitted.
Participants: Infants younger than 2 months of corrected age (CA) with prenatal and/or perinatal risk factors for brain damage. Two groups were considered. One group was treated using the neurohabilitation
method (n = 20), and the other was not treated (n = 13) because treatment was voluntarily discontinued
after the initial evaluation. Evaluations were carried out prior to 2 months of CA and at 68 years of age.
All children showed abnormal clinical and MRI characteristics in the rst study.
Results: The treated group had a higher percentage (90%) of children with normal outcome than did the
non-treated group (38%; OR = 2.37, CI 95% = 1.24.7; p < 0.005). In this latter group, only one out of ve
(20%) children born at or before 34 weeks of gestational age had a normal outcome. In contrast, eight out
of nine treated preterm infants had normal outcomes (8/9 = 89%, OR = 4.45, CI 95% = 0.726; p = 0.017).
Conclusions: This pilot trial conrms previous studies suggesting that Neurohabilitation decreases the
neurological and cognitive sequelae of preterm and at-term infants with PBD.
2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Despite advances in medicine and signicant improvements in
the survival of preterm infants over the last 1020 years, the incidence of births at risk for brain damage has not diminished; in

Corresponding author at: Instituto de Neurobiologa, UNAM Campus Juriquilla,


Quertaro 76230, Mxico. Tel.: +52 442 1926101x113.
E-mail address: thaliah@unam.mx (T. Harmony).
http://dx.doi.org/10.1016/j.neulet.2015.11.013
0304-3940/ 2015 Elsevier Ireland Ltd. All rights reserved.

fact, some evidence suggests that disability rates have increased


[1]. Data in the literature also showed that even preterm children
who survive without apparent motor disability, have a substantial
reduction in the mean intelligence quotient (IQ) and an increased
incidence of cognitive and educational difculties [25].
A revision of the literature related to early interventions programs to study high risk premature infants has shown that when
applied to severe low weight preterm babies scores [6] or infants
with brain lesions [7] did not show any improvement on neurodevelopment. Neurodevelopmental treatment (NDT) is the method

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T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

most frequently used for intervention in children with a developmental disorder [8]. NDT is generally applied later in life, when
there are symptoms and signs of brain injury, therefore as a rehabilitation procedure. The same happened with Vojtas method. On
the other hand, the effectiveness of the NDT approach and other
pediatric therapies is currently an issue generating considerable
professional debate [9]. None of ve studies that evaluated NDT
effects demonstrated a statistically signicant effect of intervention
in motor development [913]. In a report comparing NDT vs. Vojta
methods for the early treatment of cerebral palsy, Vojtas procedure
showed to normalize more infants than NDT method [14].
Although decreasing the number of births at risk for brain
damage should be the priority to decrease the neurological and cognitive sequelae, the early diagnosis and treatment of brain damage
in newborns at risk may also decrease these sequelae. This is the
goal of the therapy known as neurohabilitation, as proposed by
Ferenc Katona [1518] to differentiate this process from rehabilitation. The main difference between the two is that neurohabilitatory
treatment should begin before the lesion sequelae have been established, during the rst 34 months after birth, to try to reduce or
abolish the neurological sequelae that may result from perinatal
brain damage. The results of the application of this therapy to 2189
infants of less than 6 months old with suspected perinatal brain
damage showed, at 18 months of corrected age (CA), that 46% had
a normal outcome, 32% improved relative to their initial symptoms, and 22% had no change or their symptoms had become worse
[15,16]. These results were obtained in Hungary where this technique has been applied for more than 30 years; however, it is not
well known in other countries. The results obtained in Hungary led
us to evaluate this procedure in our group of patients in Mexico. To
our knowledge, this is the rst report describing the longitudinal
results obtained in the application of neurohabilitation to infants
with perinatal brain damage demonstrated by magnetic resonance
images (MRI) as well as by clinical and psychological evaluations.
2. Patients and methods
The Ethics Committee of the Instituto de Neurobiologa of
the Universidad Nacional Autnoma de Mxico approved this
study, which also complies with the Ethical Principles for Medical Research Involving Human Subjects established by the Helsinki
Declaration. Informed written parental consent for participation in
this study was obtained for all subjects.
2.1. Patients
Inclusion criteria: infants during the rst 2 months of corrected
age (CA) with prenatal and/or perinatal history of risk factors for
brain damage. These risk factors are described in Tables 1 and 2 for
each patient. After the infants were discharged from the hospital
where they were born, their parents were invited to participate in
a special project of the Unit for Neurodevelopmental Research at
the National Autonomous University of Mexico in Quertaro. This
Unit currently has a data base with 1138 subjects from 0 to 8 years
old.
Two groups of children were considered: the treated and the
non-treated groups. To build a non-treated group who did not
undergo treatment but who had initiated the protocol with all the
indicated studies, we looked for children between 6 and 8 years
old that voluntarily discontinued the treatment after one month.
We used these criteria for ethical reasons. If it had been shown that
the neurohabilitation procedure is useful to improve development
even in the case of infants with severe brain lesions [1518], it is
against the Helsinki declaration to leave infants without the treatment in order to have a control trial. The parents of 13 children

agreed to return to the unit for re-evaluation. They comprised the


non-treated group, and they did not have any type of treatment. In
this group the clinical observations were only done before 2 months
of corrected age (CA) and at 6-8 years old.
Then, from a pool of 1138 treated children from our data base,
20 were pseudo-randomly selected [19] from those who had followed the treatment and all the evaluations and who were similar
to the non-treated group in terms of age, gender, weight at birth,
Apgar, risk factors and diagnosis. These 20 children formed the
treated group. Exclusion criteria were: infants older than 2 months
of CA, presence of genetic factors associated with brain damage, cardiovascular pathology, brain malformations and/or chromosomal
aberrations.
2.2. Evaluations
The initial evaluations were performed in the two groups and
they included:
(a) Clinical pediatric and neuropediatric examinations [20], (b)
Bayley scales [21] (c) Magnetic resonance imaging (MRI) using 1.0
T Philips equipment, and (d) Katonas evaluations [17,18,22]. These
evaluations were repeated according to a time schedule only in the
treated group. Neuropediatric evaluations were done each month
during the rst year, each 3 months during the second year, and
each 6 months after 3 years old. Bayleys evaluations and MRIs were
done each 4 months during the rst year and each 6 months during
the second and third year. In the fourth year WIPPSI scales were
used and applied each 6 months and later on, WISC was applied
each year. After the fourth year, MRIs were obtained each year
if there was some abnormal nding. When the children reached
68 years of age, the following evaluations were performed: (a)
neuropediatric examination, (b) clinical psychological evaluations
and performance in the WISC-IV test [23], (c) clinical language
evaluations [24], and (d) MRI evaluations. At these ages MRI was
performed using a 3.0 T GE scanner. If in the rst 3 examinations
the child showed normal results, or a borderline IQ, then her/his
outcome was considered normal. The abnormal outcomes were
classied as neurological when the last neuropediatric examination showed abnormal ndings, and as cognitive sequelae when the
clinical psychological evaluation and/or IQ values were abnormal
and/or language delays were observed.
2.3. Katonas procedure (see Ref. [25], data in brief)
Katonas methodology is both diagnostic and therapeutic.
Katonas assessment is performed with some of the maneuvers
used in the therapy itself, where it has to take into account several
evaluation parameters such as: muscle tone (passive and active);
hemi bodies symmetry along the maneuver performance; attention, eye tracking and auditory monitoring; neurological signs
of alarm (thumb in st, scissor gait, strabismus, irritability, axial
hyperextension, among others).
Katona based the neurohabilitation procedure on the elementary neuromotor patterns. These early integrated complex
movements are chains of processes in which the neck, trunk and
extremities perform complex and continual movements in certain repetitive patterns. These motor patterns are characterized
by a high degree of organization, persistence and stereotypy and
can be divided in two groups: (1) complex chains of movements
directed to verticalization of the body and (2) complex movements
directed to locomotion [17,18,25]. These movements are controlled
by the developing subcortical structures and can be activated by
determined positions of the head and the body that triggers the
activation of the vestibular nuclei and their projections to the spinal
cord, the reticular formation, thalamus, cerebellum, basal ganglia
[26]. Nearly all these tracts project to the motor cortex [27]. At the

Table 1
Group without therapy.
GA weeks/gender

Weight at birth
Apgar

Age in years in last exam

Risk factors

Initial clinical
ndings/diagnosis

Outcome nal clinical


ndings
WISC total IQ

First MRI

Final MRI

C1

34/F

2100 gr.
8/9

5.8

2100 gr.
9/9

5.8

LV2
Frontal SAS

Subarachnoid
space
LV

C3

38/M

3600 gr.
8/9

6.3

Oligohydramnios hypoxia

Subarachnoid space,
diffuse white matter
damage

Normal

C4

39/F

3280 gr.
9/9

5.6

Vagina and cervix


infections

Normal,
IQ = 81, low average

Subarachnoid space

LV

C5

27/M

1000 gr.
7/8

6.4

LV

34/M

1725 gr.
7/9

4.9

LV
Subarachnoid space

LV

C7

35/M

2830 gr.
5/6

5.5

Generalized
hypotonia/preterm
encephalopathy
Generalized hypertonia,
Right central VII palsy/
Preterm encephalopathy

Severe incoordination
problems, learning
problems,
IQ = 54,
Cerebral palsy epilepsy,
IQ = 93, average

LV
Subarachnoid space

C6

Right central VII palsy,


Moderate coordination and
ne motor problems

Diffuse white matter


damage, probable
leukomalacia.

Right LV

C8

36/M

2260 gr.
8/9

7.3

Preterm hyaline
membranes, respiratory
distress, icterus,
enterocolitis
Preterm, respiratory
distress, sepsis,
hyperbilirubinemia
Preterm
Pre-eclampsia
Lung hemorrhage
Acute fetal distress
Preterm
hyperbilirubinemia

Generalized
hypotonia/hypoxic
ischemic encephalopathy
Sarnat 2
Hypotonia/Hypoxic
ischemic Encephalopathy
Sarnat 2
Mixed hypotonia and
hypertonia/preterm
encephalopathy

Normal,
IQ = 121
Superior
Moderate coordination
problems,
Adiadochokinesis,
IQ = superior
Normal,
IQ = 86 low average

LV

34/F

Generalized
hypotonia/preterm
encephalopathy
Generalized
hypotonia/preterm
encephalopathy

Subarachnoid
space, LV

C2

Preterm twin II
Premature rupture of
membranes
Preterm twin I
Premature rupture of
membranes

Generalized hypotonia/
Preterm encephalopathy

Normal,
IQ = 82, low average

Right frontal and


cerebellar
arachnoid cysts

C9

39/F

3000 gr.
9/9

Seizures
Hypocalcemia

C10

29/F

1200 gr.
8/9

6.3

Preterm, twin I,
pneumonia, sepsis, anemia

Hypotonia/hypoxic
ischemic encephalopathy
Sarnat 2
Hypotonia
Preterm encephalopathy

Diffuse leukomalacia
Corpus callosum

Normal

C11

40/F

2850 gr.
7/8

Bradycardia

Normal development,
Dyscalculia,
IQ = 80, low average
Cerebral palsy: Right
hemiparesia, attention
decits,
IQ = 78, borderline
Hearing loss,
IQ = 77, borderline

Diffuse white matter


damage, probable
leukomalacia
Corpus callosum
Left LV

Occipital leukomalacia

Normal

C12

40/F

2375 gr.
8/9

Seizures,
hyperbilirubinemia,

Diffuse leukomalacia
Corpus callosum

Corpus callosum

C13

39/M

5.1

Chickenpox during
pregnancy (3rd Trimester)

Corpus callosum
Subarachnoid space

Normal

X=
SD=

35.69
4.13

2375 gr.
8/9
2361/7.46
764/1.71

Generalized hypertonia
Hypoxic ischemic
Encephalopathy Sarnat 2
Generalized hypotonia/
hypoxic ischemic
Encephalopathy Sarnat 3

Generalized hypertonia

Severe neurodevelopmental delay, generalized


hypertonic,
IQ severe mental
retardation
Normal,
IQ = 79, borderline

LV

T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

Id.

61

62

Table 2
Treated group.
Id.

GA weeks/gender Weight
Apgar

Age in years in last


evaluation

Risk factors

Initial clinical ndings/diagnosis

Outcome nal clinical


ndings/total IQ

First MRI

Final MRI

E1

33/F

5.11

Normal,
IQ = 100, average
Normal,
IQ = 75, borderline

39/M

5.11

E4

34/M

E5

30/F

2250 gr.
8/9
1550 gr.
8/9
1350 gr.
8/9

5.2

Hypoglycemia, in utero
growth restriction
Preterm, pre-eclampsia,
acute fetal distress
Preterm

Leucoencephalopathy,
Periventricular
hemorrhage, LV
Diffuse leukomalacia

Normal

E3

Generalized hypotonia/preterm
encephalopathy
Generalized
hypotonia/hypoxic-ischemic
encephalopathy Sarnat 2
Generalized hypotonia

Normal

37/M

Preterm, pre-eclampsia,
respiratory distress
Pre-eclampsia, icterus,
apnea

Leucoencephalopathy

E2

1950 gr.
8/9
1800 gr.
9/9

E6

39/M

3750 gr.
5/8

4.6

Eclampsia

E7

39/F

3950 gr.
5/7

4.6

Seizures, acute fetal


distress, sepsis

E8

36/M

1680 gr.
8/8

E9

30/M

6.2

E10

36/M

1680 gr.
8/8
2000 gr.
7/8

E11

39/F

E12

35/M

3800 gr.
9/10
3775 gr.
3/7

E13

40/F

Preterm pre-eclampsia,
hyperbilirubinemia, sepsis,
apnea
Preterm, twin I, icterus,
sepsis
Preterm pre-eclampsia,
hyperbilirubinemia, sepsis,
apnea
Condylomatosis, maternal
urinary infections
Preterm premature rupture
of membranes,
resuscitation
Seizures, sepsis

E14

30/F

E15

32/F

1400 gr.
6/8

5.6

E16

27/M

800 gr.

5.8

E17

39/F

E18

40/M

2475 gr.
9/9
3100 gr.
7/8

E19

32/M

E20

33/M

6.4

Generalized hypotonia/preterm
encephalopathy
Generalized hypotonia/preterm
encephalopathy
Generalized
hypotonia/hypoxic-ischemic
encephalopathy Sarnat 2
Generalized
hypotonia/hypoxic-ischemic
encephalopathy Sarnat 2
Hypertonia
Hyperbilirubinemic
encephalopathy
Generalized hypotonia/preterm
encephalopathy
Generalized hypotonia/preterm
encephalopathy

Normal
IQ = 113, average
Normal
IQ = 79, borderline
Normal
IQ = 87, low average
Normal
IQ = 84, low average

Leukoencephalopathy
Occipital white matter
hyperintensity, Corpus
callosum
Leucoencephalopathy

Normal
Left temporal arachnoidal
cyst, LV
Normal

LV

Normal
IQ = 81, low average

Subarachnoid space

Normal

Normal
IQ = 116, high average

Leucoencephalopathy

Normal

Normal
IQ = 88, low average
Normal
IQ = 82, low average

Corpus callosum

Normal

Diffuse leukomalacia

Normal

Left LV

LV

Generalized hypotonia/preterm
encephalopathy

Normal
IQ = 86, low average
Normal
IQ = 87, low average

Subarachnoid space

Normal

Hypoxic-ischemic encephalopathy
Sarnat 2
Generalized hypotonia/preterm
encephalopathy

Normal
IQ = 77, borderline
Normal
IQ = 94, average

Leukomalacia

Normal

Leukomalacia,
Subarachnoid space

Left LV

Normal
IQ = 107, average

Leukomalacia

Normal

Preterm, sepsis

Mixed hypertonia and


hypotonia/preterm
encephalopathy
Hypertensive encephalopathy

Icterus, RH incompatibility

Generalized hypertonia

Perinatal asphyxia

Generalized hypertonia

1750 gr.
5/7

9.2

Generalized hypotonia/preterm
encephalopathy

2240 gr.
9/9

6.3

Preterm, respiratory
distress, perinatal
asphyxia, sepsis
Preterm, twin II,
respiratory distress

4700 gr.
6/9
1250 gr.
8/9

2362/7.16
1094/8.42

6.9
5.4

Preterm, twin II,


pre-eclampsia, maternal
urinary infections
Preterm, pre-eclampsia,
acute fetal distress

Generalized hypotonia

Mixed hypertonia and


hypotonia/preterm
encephalopathy

Moderate language decits, Leukomalacia


IQ = 70, borderline

LV
Subarachnoid space
Corpus callosum
Atrophy of the parietal
cortex
Cyst in left
cerebellopontine angle

Normal
IQ = 90, average
Delay language
development, attention
decits,
IQ = 40 very low
Normal
IQ = 82, low average

Corpus Callosum
Subarachnoid space
LV

Cerebral atrophy

Normal

Normal
IQ = 72, borderline

Subarachnoid space
Corpus callosum

LV

T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

35
X=
SD= 3.98

5.9

T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

63

Fig. 1. Main maneuvers for verticalization. (1) Lift trunk with hand drive. (1a) Double lift trunk with hand drive. (2) From lying to sitting. (3) Lift the trunk with back and hip
support. (3a) Lift trunk with back support. (4) Sitting in the air. (5) Front protection to support thighs and chest. (6) Lateral and anterior protections.
Table 3
MRI Initial ndings.
Diagnosis

Control

Diffuse white matter damage


Increased LV volumes
Decreased CC volume
Cerebral atrophy

Treated

6
5
4
0

46
38
31
0

12
4
4
2

60
20
20
10

Table 4A
Outcome of the patients with 34 weeks of GA.

OR

CI(95%)

1.75
2.50
1.77

0.4277.171
0.52211.955
0.3558.881

0.436
0.251
0.483

Table 4B
Outcome of the patients with >34 weeks of GA.

Group

Normal outcome

Abnormal outcome

Total

Group

Normal outcome

Abnormal outcome

Total

Control 34 weeks
Treated 34 weeks

1
8

4
1

5
9

Control > 34 weeks


Treated > 34 weeks

4
10

4
1

8
11

OR = 4.45, CI 95% = 0.726; effect size = 0.68, CI 95% = 0.10.9; p = 0.017.

OR = 4.45, CI 95% = 0.122; effect size = 0.4, CI 95% = 0.07 to 0.7; p = 0.28.

same time, movements generate activation of different receptors,


which send afferent impulses. This constant feedback helps in the
organization of motor control.
A therapeutic program consists of training of a series of neuromotor patterns each day for a certain time. The generation of
these movements repeated several times produce brain engrams
that improve motor development [28]. At the initiation of the
treatment, specialized therapists conducted the Katona evaluations
to obtain a diagnosis and to program the exercises that parents
should learn to apply to their infants at home during the rst
month of therapy. The therapy was intensive and specic for each
infant.
The different positions to generate the specic neuromotor patterns are described in Refs. [22] and [25]. Figs. 15 show the
different maneuvers described in Ref. [25].
During the rst 3 months, parents should go daily with the
therapist in order to learn how to stimulate the infant under the
supervision of the therapist. The therapy consists in the elaboration
of the individual program, a session consists in the repetition, 48

times, of 69 sensoromotor patterns such as lift trunk with hand


drive [25]. One session has a duration of 45 min and sessions should
be repeated 3 or 5 times daily. Parents learn how to correctly perform the exercises since they are going to treat the infant at home.
Therapy must be integrated to the infants schedule and divided
into periods according to patterns of sleeping and wakefulness as
well as feeding and nursing schedules.
Each month, the infant was examined evaluating not only motor
performance but also visual and auditory attention and the ages at
which the infant mastered various developmental milestones.
2.4. Statistics
Almost all comparisons between groups were performed using
Chi-square statistics. Odds ratio (OR) and 95% condence intervals
(CI) were calculated for proportions. Effect size and 95% CI were
calculated following Cummings [29] software. The Students t-test
was used to compare WISC values between groups. As it is known
that the outcome of preterm infants with equal or less GA than

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T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

Fig. 2. Maneuvers to change posture. (7) Rolling over on a blanket. (8) Rolled over with head support. (9) Half roll over. (10) Sitting to four points support. (11) From kneeling
to standing.

Fig. 3. Maneuvers to creeping. (12) Elementary horizontal creeping. (13) Elementary creeping downward on slide. (14) Elementary creeping upward on a slide. (15) Shifting
support in knees (kneeling creeping).

34 weeks (GA 34) is worst than the outcome of infants with GA


greater than 34 weeks (GA > 34), comparisons between treated and
non-treated groups were also done separately for infants GA 34
and GA > 34 weeks.

3. Results
Tables 1 and 2 describe the characteristics of the treated and
non-treated groups. No signicant differences between groups
were observed in the initial ndings and diagnosis. All children

showed abnormal ndings in the rst clinical and MRI examinations, indicating brain damage (see Table 3).
In terms of outcomes, the treated group had a signicantly
higher percentage of children with normal neurodevelopment
(18/20) compared to the non-treated group (5/13 = 38%; Odds
ratio = 2.37, CI 95% = 1.24.7; effect size = 0.5, CI 95% = 0.20.7;
p < 0.005).
In relation to the children with a gestational age (GA) 34
weeks, the results were signicantly different between groups,
with higher percentage of normal outcomes in the treated
than in the non-treated group (OR = 4.45, CI 95% = 0.726; effect

T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

65

Fig. 4. Maneuvers to crawling. (16) Elementary assisted crawling. (17) Modied assisted crawling. (18) Crawling with lateral support. (19) Crawling leg support. (20) Crawling
in an ascending plane. (21) Crawling a downward slide. (22) Crawling on stairs.

Fig. 5. Maneuvers to walking. (23) Elementary walk. (24) Elementary walk on upward slide.

size = 0.68CI 95% = 0.10.9; p = 0.017 ; see Tables 4A and B). Fig. 6
shows the MRI of two patients, one of each group.
However, no signicant differences were observed between the
groups in infants with >34 weeks of GA. Total IQ values are shown in
Tables 1 and 2. In the non-treated group there was one child with
very severe mental retardation who was not able to perform the
WISC test. This child was not taken into account when the mean values of the subtests or the total IQ were compared between groups.
No signicant differences between groups for the total or the IQ
subtests were observed for all the infants and for those subgroups
with GA 34 or GA > 34.

Interestingly, although all the children of both groups had


abnormal ndings in the initial MRI evaluation, in the last MRI
study four of thirteen of the non-treated group (31%) and twelve
of twenty in the treated group (12/20 = 60%) showed a normal MRI (see Fig. 6), the difference between groups was not
signicant (p = 0.15). The children of both groups who nished
the study with normal MRI scans also showed signicant differences in outcome: two of four in the non-treated group
(50%) and twelve of twelve in the treated group (12/12 = 100%;
OR = 2, CI 95% = 0.755.32; effect size = 0.6CI 95% = 0.070.85;
p = 0.05).

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T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

Fig. 6. MRIs of patients E-02 and E-15. Patient E-02. On the upper line, at 2 months CA, lateral ventricles (LV) have an abnormal shape and increased volume, there is increased
volume of subarachnoidal space, and there are small periventricular hemorrhages. On the second line at 5.9 years old, the volumes of the LV are normal and the MRI is normal,
and on the third line the tractographies of the corticospinal tracts (CST) and the corpus callosum (CC) are normal. Patient E-15. The MRI at 2 weeks CA, shows PVL and the
LV with abnormal shapes. On the second line the MRI at 5.6 years old is normal, and the CST and the CC are normal.

4. Discussion
It is well known that premature fetuses and neonates are at
increased risk for brain injury compared to term infants. In a
national study in Norway of the prevalence of sequelae according to GA [1], from 1822 infants that were born before or at 34
weeks of GA, the incidence of cerebral palsy was 17%, of mental
retardation 7.2%, and of sensory disabilities 6.8%. The nding in the
present paper that eight out of nine treated preterm infants born
before or at 34 weeks of GA had normal outcomes at school age,
whereas only one of the similar, non-treated children did, is a very
promising result that suggests the benets of neurohabilitation in
preterm infants. In the patients with GA greater than 34 weeks in
the non-treated group, four out of eight infants had a normal outcome while in the treated group ten out of eleven had a normal
outcome. However, this difference was not signicant. Thus, the
signicant difference observed for the total number of infants in
each group was mainly due to the infants with GA 34.
The improvement in neurodevelopment of the treated group
may be explained by the plastic changes produced by the intensive treatment. The repetition of the maneuvers used to generate
the sensoromotor response facilitates the performance of normal
movements, changing the representations of these movements in
the brain. Numerous references show that learning motor skills,
even in adults, produces a reorganization of the motor system, and
even structural changes have been reported [3033].
In relation to our results although all the children of both groups
had abnormal ndings in the initial MRI evaluation, in the last MRI
study four of thirteen of the non-treated group (31%) and twelve
of twenty in the treated group (60%, p = 0.15) showed normal MRI
(see Fig. 6). The children of both groups who nished the study with
normal MRI scans also showed signicant differences in outcome:
two of four in the non-treated group (50%) and twelve of twelve
in the treated group (100%; p = 0.05). These results may imply that
the myelination of the corpus callosum and of the white matter
surrounding the lateral ventricles not only improves with development but may improve even more with the treatment. Therefore,
our results although preliminary, point to be very promising.
Finally, the drawbacks of this study should be discussed. It is
not a clinical control trial since previous studies have shown the

efcacy of the procedure and therefore, ethical considerations and


the Helsinki Declaration prohibit a control sample with the same
type of evaluations across time as those used for the treated group
but without treatment.
5. Conclusion
Although there are clear limitations of this study, our ndings
support the results obtained in Hungary with the neurohabilitation
procedure and increase our knowledge in relation to the neurological and cognitive sequelae of infants with perinatal brain damage
demonstrated by MRI and clinical examinations. As our results
although preliminary, point to be very promising, we propose that
other groups apply this procedure early in life in those infants at
risk for brain damage to increase our knowledge of this type of therapy. For this reason the accompanying data in brief article describe
the principal maneuvers used in Kalonas neurohabilitation.
Conicts of interest
None.
Funding source
This project was partially supported by projects 122547, 166772
and 218556 from CONACyT.
Financial disclosure
The authors have no nancial relationships relevant to this article to disclose.
Acknowledgements
The authors want to acknowledge all members of the
Unidad de Investigacin en Neurodesarrollo for their participation in this work (in alphabetical order): Teresa Alvarez-Vzquez,
Paulina Alvarez-Garca, Eduardo Arias-Kanemoto, Gloria AvecillaRamrez, Hctor M. Barragn-Campos, Hctor Belmont-Tamayo,

T. Harmony et al. / Neuroscience Letters 611 (2016) 5967

Erika Cruz-Rivero, Antonio Fernndez-Bouzas , Delia FigueroaNavarro, Johanna Flores-Arizmendi, Berta Gonzlez-Frankenberger
, Vernica Guidobono-Radesca, Rosa M. Hernndez-Corona, Claudia Jimnez-Snchez, Alma Janeth Moreno-Aguirre, Juan Jos
Ortiz-Resndiz, Erik Pasay-Alcaraz, Tonatzin Pineda-Martnez,
Sara Elisa Ponce-Rodrguez, Eneida Porras-Kattz, Amaya SobernGarca and Angeles Zavala. Authors also acknowledge the
anonymous reviewer for his/her suggestions, Dr. Dorothy Pless for
the revision of the English version of the manuscript, and Dr. Susana
Szava for the translation to Spanish from Hungarian of Katonas
book Ontogenesis of the human nervous system.
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