Download Changes in the cardiac autonomic regulation in children with

Indian J Med Res 130, July 2009, pp 44-50
Changes in the cardiac autonomic regulation in children with
attention deficit hyperactivity disorder (ADHD)
Ingrid Tonhajzerova, Igor Ondrejka*, Pavol Adamik*, Radovan Hruby*, Michal Javorka
Zuzana Trunkvalterova, Daniela Mokra & Kamil Javorka
Department of Physiology & *Clinic of Psychiatry, Jessenius Faculty of Medicine, Comenius University &
Martin Faculty Hospital, Martin, Slovak Republic
Received September 7, 2007
Background & objectives: ADHD is one of the most common mental disorders among children. We
hypothesized that ADHD is associated with the impairment of the cardiac autonomic regulation. The
aim of this study was to evaluate the cardiac autonomic regulation in children with ADHD at the rest and
during orthostasis using short-term heart rate variability (HRV) analysis.
Methods: Eighteen children with ADHD admitted to the Department of Children and Adolescent
Psychiatry, Clinic of Psychiatry, University Hospital in Martin, Slovak Republic between January and
September 2006 and 18 matched healthy subjects were recruited. HRV analysis was carried out in three
positions: supine (S1)-orthostasis (O)-supine (S2). Evaluated parameters were: the mean R-R interval,
mean squared successive difference (MSSD), spectral powers in low (LF) and high frequency (HF) bands,
total power (TP), coefficients of component variance (CCV LF, CCV HF), LF/HF ratio.
Results: The mean R-R interval was significantly shorter in ADHD group compared to controls in all
positions (P<0.05, P<0.001). S1: The parameters MSSD, CCV HF, logHFpower were significantly lower
(P<0.05, P<0.05, P<0.01) and ratio LF/HF was significantly higher (P<0.05) in ADHD group compared
to controls. O: The parameters MSSD, CCVHF, logHFpower, logTP were significantly lower in ADHD
group compared to controls (P<0.01, P<0.05, P<0.01, P<0.01). S2: The parameters MSSD and logHFpower
were significantly lower in children with ADHD compared to controls (P<0.05).
Interpretation and conclusions: The children with ADHD had decreased cardiac vagal modulation and
tachycardia in supine positions with altered ability of dynamic activation of the autonomic nervous system
in response to orthostasis indicating changes in the cardiac autonomic regulation. Further studies need
to be done on a larger sample to confirm these findings and to understand the underlying mechanisms.
Key words Attention deficit/hyperactivity disorder (ADHD) - autonomic nervous system - children - heart rate variability -orthostasis
Psychological states and processes are known to
profoundly influence the autonomic nervous control
of the cardiovascular system with likely contribution
to the increased cardiovascular morbidity in patients
with mental disorders1,2. During this decade the
pathomechanisms by which central nervous system
(CNS) modulates changes in autonomic nervous system
(ANS) in various mental disorders as well the potential
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TONHAJZEROVA et al: HEART RATE VARIABILITY & ATTENTION DEFICIT HYPERACTIVITY DISORDER
links between cognitive and emotional processes and
changes in ANS have drawn increasing interest3,4. Integrative theories that link CNS structures to
autonomic function, such as the polyvagal theory5,
have of late emerged. The polyvagal theory has
introduced a new perspective relating autonomic
function to behaviour but it requires understanding
bidirectional communication between the heart and
the CNS6. Porges′ polyvagal theory5,6 posits that
the myelinated vagus, originating in the nucleus
ambiguus, is a dynamic contributor to the processes
of attention, motion, emotion, and social interactions.
Thus, parasympathetic nervous system-linked cardiac
activity has been associated with emotion regulation
capabilities5.
Cardiac function is extremely sensitive to
autonomic influences. The heart rate variability
(HRV), i.e., the amount of the heart rate fluctuations
around the mean heart rate, is validated indicator of
the function of the cardiorespiratory control system. In
other words, analysis of heart rate variability provides
insights into the autonomic control of the heart and
gives important information about cardiac sympathetic
and parasympathetic interaction7,8. Our previous
studies revealed that HRV analysis is noninvasive and
sensitive method for early detection of asymptomatic
changes of cardiovascular neuropathy in various
somatic diseases such as hypertension and diabetes
mellitus9,10 as well as for the evaluation of the effect of
mental load11. Moreover, the interplay of sympathetic
and parasympathetic (vagal) outputs of the central
autonomic network at the sinoatrial node producing
this complex beat-to-beat variability is characteristic
of a healthy, adaptive organism12. Thus, the HRV is
considered as an index of central-peripheral neural
feedback and CNS-ANS integration13. Consequently,
the HRV analysis can be used to study the possible
links between mental disorders and cardiac autonomic
regulation/dysregulation.
Attention deficit/hyperactivity disorder (ADHD) is
one of the most commonly diagnosed mental disorders
among children. ADHD is a developmental disorder
characterized by distractibility, hyperactivity, impulsive
behaviours, and the inability to remain focused on tasks
or activities14. Evidence from neuropsychological,
pharmacological, and brain-imaging studies implicates
dopamine and norepinephrine neurotransmitter systems
in frontostriatal circuit in the pathophysiology of the
disorder15. Although it is generally assumed that the
45
autonomic regulation of the heart is impaired in ADHD,
the information about this dysregulation is limited.
Some authors propose altered heart rate variability in
ADHD children16 or changes in autonomic profiles in
behaviour-disorder in preschool children17. The aim of this study was to find differences in the
autonomic regulation of the heart at the rest and during
orthostasis between children with attention deficit/
hyperactivity disorder and healthy subjects using shortterm heart rate variability analysis.
Material & Methods
The study was approved by the Ethics Committee
of Jessenius Medical Faculty, Comenius University
Martin, Slovak Republic. All children/patients/guardian
were carefully informed about the study protocol and
informed written consent was obtained from them to
participate in the study prior to examination.
A total of 36 subjects – 18 patients with ADHD
(15 boys, 3 girls) aged 8-12 yr (10.8 ± 0.4 yr) and 18
healthy subjects – control group matched for age (10.9
± 0.5 yr) and gender (15 boys, 3 girls) were included.
ADHD group: Children suffering from ADHD were
recruited consecutively from the patients admitted to
the Department of Children and Adolescent Psychiatry,
Clinic of Psychiatry, University Hospital in Martin,
between January and September 2006.
Inclusion criteria were - ADHD diagnosis –
combined type according to Diagnostic & Statistical
Manual of Mental Disorders DSM-IV-TR (Text
Revision)18 without comorbid mental disorders; before
psychopharmacological and other treatment; nonsmokers; moderate physical activity; and no evidence
of hypertension, diabetes mellitus, obesity, underweight
or other diseases.
Control (non-ADHD) group: The control (non-ADHD)
group consisted of healthy pupils of primary school
matched for age and gender. The healthy probands were
carefully selected according to the same inclusion criteria
as ADHD group – non-smokers, not taking drugs and
substances influencing cardiovascular system, moderate
physical activity, no evidence of cardiovascular,
endocrinologic or other diseases. In addition, the children
in control (non-ADHD) group have been never treated
for any mental disorder (Table I).
Procedure: All subjects were examined in a quiet room
with standard temperature (23oC) and minimalisation
of stimuli in the morning between 0800 and 1200
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INDIAN J MED RES, JULY 2009
Table I. The characteristics of patients with ADHD and control
group
ADHD (n=18)
Controls (n=18)
Age (yr)
10.80 ± 0.40
10.90 ± 0.45
SBP (mmHg)
103 ± 2.15
102 ± 2.18
DBP (mmHg)
66 ± 1.58
67 ± 1.29
BMI
17.44 ± 0.36
18.11 ± 0.37
Values are expressed as mean ± SEM
No significant differences in these parameters
SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI,
body mass index
after a normal breakfast. After 10 min of the rest and
stabilization of the heart rate (to exclude possible effects
of stress) the subjects remained in supine position for
the recording of the R-R intervals in three intervals: the
first supine position – orthostasis (change from lying
to standing during 5 sec) – the second supine position
(change of posture from standing to lying during 5 sec).
The time spent in each interval was 5 min.
The heart rate variability analysis: The R-R intervals
were detected using telemetric diagnostic system
VarCor PF6 (Dimea, Olomouc, Czech Republic).
ECG signal was monitored by a chest belt and the RR intervals were transmitted to a personal computer.
Data were filtered automatically by elimination of
artefacts using a recognition algorithm as well as
manually. The spectral analysis of the HRV using fast
Fourier transformation (partially modified by coarsegraining spectral analysis) was used for data processing
(minimum monitoring interval of 5 min to record at
least 300 R-R intervals). The window length used was
256 samples. The following parameters were used for
evaluation:
Time domain analysis: the mean R-R interval
(ms), MSSD (mean squared successive differences
between R-R intervals in ms2) expressing mainly
parasympathetic activity.
Spectral analysis: Spectral power in low frequency
band (LF: 0.04-0.15 Hz) which determined sympathetic
and parasympathetic activity and 0.1 Hz reflected
mainly baroreflex activity; spectral power in
high frequency band (HF: 0.15-0.5 Hz) reflecting
mainly parasympathetic activity (respiratory sinus
arrhythmia), total spectral power (TP), coefficient of
component variance in low (CCV LF) and high (CCV
HF) frequency bands to eliminate differences in the
mean R-R level and their impact on the amplitude of
oscillations19-21. The LF/HF ratio was calculated from
the absolute values of the LF and HF power21.
The cardiac vagal reactivity in response to
orthostasis was evaluated as percentual change of
logarithmical spectral power in high frequency band
(as index of vagal modulation) using mathematical
expression: [(logHF power in standing position - logHF
power in the 1st supine position) / logHF power in the
1st supine position] x 100 (%).
Statistical analysis: Statistical analyses were performed
using the statistical software package SYSTAT 10 for
Windows (SSI, Richmond, CA, USA). Because basal
spectral absolute values differ greatly among individuals,
the spectral powers were then logarithmically
transformed for statistical testing. The non-gaussian/
gaussian distribution was ascertained using Lilliefors
test22. For data with gaussian distribution, two-way
ANOVA with one repeated measures factor was used
for data analysis. Post-hoc univariate F test was used
for between-groups comparison. Mann-Whitney
U test23 was used for between-groups comparison with
non-gaussian distribution. P<0.05 were considered as
significant.
Results
The main effect of active posture change (in
response to orthostasis and clinostasis) on heart rate
variability parameters was significant for the mean
R-R interval (P<0.01), logHF power (P<0.01), logLF
power (P<0.01), logTP power (P<0.01) and CCV HF
(P<0.01). The effect of group (ADHD vs. control)
was significant for the mean R-R interval (P<0.01),
logHF power (P<0.01), logTP (P<0.05) and CCV
HF (P<0.05). No significant interaction between both
main factors (posture vs group) was found (Table II).
Table II. The analysis of variance table of repeated measures
P
P
R-R interval
CCVLF
0.002 group effect
0.640
group effect
0.001 posture effect
0.366
posture effect
0.890 posture x group
0.233
posture x group
CCV HF
logLF power
0.026 group effect
0.114
group effect
0.001 posture effect
0.003
posture effect
0.760 posture x group
0.098
posture x group
logHF power
logTP power
0.001 group effect
0.018
group effect
0.001 posture effect
0.001
posture effect
0.132 posture x group
0.069
posture x group
R-R interval (ms), CCV (%) - coefficients of component variance
in low (LF) and high (HF) bands, logarithmic values (log) of
spectral powers in low (LF) and high (HF) bands, total power
(TP) in ms2
TONHAJZEROVA et al: HEART RATE VARIABILITY & ATTENTION DEFICIT HYPERACTIVITY DISORDER
47
Table III. The parameters of heart rate variability analysis in ADHD and control groups
ADHD (n=18)
Supine 1
697 ± 24
3031 ± 877
2. 89 ± 0. 18
Ortho
546 ± 18
241 ± 68
2. 80 ± 0. 24
Controls (n=18)
Supine 2
733 ± 26
4905 ± 1146
3. 21± 0. 29
Supine 2
R-R
832 ± 27*
MSSD
10467± 2560*
CCV LF
3.16 ± 0.35
P=0.919
CCV HF
3. 82 ± 0.30
1. 65 ± 0.17
4. 82 ± 0. 30
5. 85 ± 0. 56
P=0.108
LF/HF
0. 77 ± 0. 13
3. 95 ± 0. 76
0. 61 ± 0. 16
0. 58 ± 0. 21*
2.55 ± 0. 78
0. 53 ± 0. 18
P=0.137
P=0.523
log LF
5. 96 ± 0. 17
5. 32 ± 0. 20
6. 21 ± 0. 18
6. 14 ± 0. 18
5. 95 ± 0. 18
6. 30 ± 0. 26
P=0.477
P=0.052
P=0.764
log HF
6. 49 ± 0. 21
4. 16 ± 0.27
7. 07 ± 0. 18
7. 25 ± 0. 23**
5. 53 ± 0. 30**
7. 63 ± 0. 21*
7. 03 ± 0. 16
5. 67 ± 0. 19
7. 53 ± 0.15
7. 51 ± 0. 21
6. 65 ± 0. 21**
log TP
7. 77 ± 0.22
P=0.082
P=0.384
Values are expressed as mean ± SEM. R-R intervals (ms), mean squared successive differences between R-R intervals in ms2 (MSSD),
coefficients of component variance (CCV in %) in low (LF) and high (HF) bands, logarithmic values (log) of spectral powers in low (LF)
and high (HF) bands, total power (TP) in ms2. Data in the first supine position (Supine 1), orthostasis (Ortho) and in the following supine
position (Supine 2) are given as arithmetic mean ± SEM. Significant difference between ADHD and control groups are presented in the Table
alongwith data. *P<0.05, **P<0.01
Post-hoc analysis and Mann-Whitney U test
revealed significant changes in the following heart rate
variability parameters (Table III):
The first supine position: The mean R-R interval was
significantly shorter in the ADHD group compared to
controls (P<0.01). The parameters - MSSD, logHF
power, CCV HF – were significantly lower in the ADHD
group compared to controls (P<0.05, P<0.01, P<0.05).
Ratio LF/HF was significantly higher in the ADHD
group compared to controls (P<0.05). No significant
difference was found in logLF power, logTP, CCV LF.
The orthostasis: The mean R-R interval was
significantly shorter in the ADHD group compared to
controls (P<0.001). The parameters - MSSD, logHF
power, logTP, CCV HF – were significantly lower in the
ADHD group compared to controls (P<0.01, P<0.01,
P<0.01, P<0.05). No significant difference was found
in logLF power, CCV LF and LF/HF.
The second supine position: The mean R-R interval
was significantly shorter in the ADHD group compared
to controls (P<0.05). The parameters - MSSD, logHF
power - were significantly lower in the ADHD
group compared to controls (P<0.05). No significant
difference was found in the remaining parameters.
The vagal reactivity: Percentual change in the
high frequency band in response to orthostasis - was
significantly higher in the ADHD group compared to
controls (-36 vs. -23%, P<0.05).
Supine 1
799 ± 25**
5361 ± 1009*
2. 77 ± 0. 25
P=0.693
5. 20 ± 0. 63*
Ortho
658 ± 20**
1328 ± 426**
3. 19 ± 0. 28
P=0.172
3. 03 ± 0. 49*
Discussion
In the last decade, cardiac vagal tone has emerged
as psychophysiological marker of many aspects of
behavioural functioning and emotion regulation in
both children and adults3. Several studies have linked
changes in cardiac vagal modulation to depression1 or
conduct problems in children and adolescents24,25.
This study focuses on the changes in autonomic
regulation of the heart in children with ADHD. Using
short-term heart rate variability analysis autonomic
regulation of the heart was compared between the
groups of ADHD patients and healthy children under
resting conditions and following dynamic activation of
the ANS by orthostatic manoeuvre. This orthoclinostatic
test measures the dynamic loading of the autonomic
nervous system in the progressive increase of the
sympathetic activity and concomitant decrease in the
vagal activity in the standing position and vice-versa
in the diminishing of the sympathetic and in a rise of
the vagal activity in the supine position after lying
back26,27.
The consensus of opinion is that HF respiratory
component of R-R interval variability primarily
reflects respiration-driven vagal modulation of sinus
arrhythmia21. Consequently, other studies found
decreased respiratory sinus arrhythmia in children
with ADHD28. However, some authors reported the
differences in autonomic activity in dependence on
developmental changes25. Crowell et al17 compared
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INDIAN J MED RES, JULY 2009
autonomic profiles of preschool children (aged from 4
to 6 yr) with ADHD and oppositional defiant disorder
(ODD) with controls. Children with ADHD and ODD
were not significantly different in baseline respiratory
sinus arrhythmia, but authors referred to autonomic
deficiency in later age-period (adolescence) related
to emotion dysregulation and lability. In accordance
with other studies related to conduct problems25 our
results of the HRV analysis indicated decreased cardiac
parasympathetic modulation with higher heart rate in
both supine positions, as well as during orthostatic
manoeuvre, in patients with ADHD in middle
childhood.
Moreover, we evaluated the cardiac vagal
reactivity in the high frequency band in response to
orthostasis. Contrary to the law of initial values29, the
vagal reactivity was significantly higher in the ADHD
group compared to controls (-36% vs. -23%). As noted
by other authors, the excessive vagal withdrawal
may be a non specific marker of emotional lability3.
Thus, it is questionable whether our findings of lower
cardiac vagal modulation associated with higher vagal
reactivity are related to the features of the ADHD (i.e.,
emotional lability due to emotional immaturity) or
it is the reflection of subclinical abnormal dynamic
activation of the autonomic nervous system in response
to posture change in children with ADHD.
The mechanisms underlying these changes in
cardiac autonomic regulation in ADHD remain
unknown. Thayer and Lane13 emphasized the neural
correlates of vagal function and the role of brain
in the regulation of the autonomic nervous system.
Some studies have identified functional units within
central nervous system that are involved in autonomic
regulation - the central autonomic network (CAN)30.
Functionally, this network is an integrated component
of an internal regulation system through which
the brain controls visceromotor, neuroendocrinne,
and behavioural responses that are critical for
goal-directed behaviour and adaptability30. The
primary output of the CAN is mediated through the
sympathetic and parasympathetic neurons innervated
the heart; therefore, it is directly linked to the
heart rate variability13. Moreover, the autonomic
imbalance - low parasympathetic activity and
a relative sympathetic dominance indicated by low
heart rate variability - can be a marker for prefrontal
hypoactivity4. In ADHD children, the deficit in
frontal functioning connected to limbic system and
consequent alteration of baroreflex function as well
as the modifications in a network of brain regions
(e.g., prefrontal cortex, anterior cingulate cortex) are
supposed31,32. Therefore, it is not clear whether the
alteration of cardiac regulation in ADHD patients is a
pure consequence of changes and pathomechanisms
in various brain regions related to the modulation in
autonomic activity by the central nervous system or it
can be an early peripheral autonomic marker of latent
asymptomatic and undiagnosed comorbid emotional
and psychosomatic disorders due to accumulation of
various stressors leading to these disorders.
In addition, the study of the relevant transmitter
systems - specially noradrenergic and dopaminergic
systems - will be important for a better understanding
of ADHD and autonomic dysregulation in children
with ADHD, especially linked to effective treatment.
Therefore, in the explanation of autonomic nervous
system changes the genetic, developmental and others
factors should be considered.
Our study included a relatively small homogeneous
group of patients with ADHD-combined type.
Nonetheless, even with this sample size the potentially
important differences in the heart rate variability
between ADHD children and healthy probands were
identified. The findings of this study need to be
indepedently validated in larger groups of patients.
This study addressed mainly the changes in vagal
(parasympathetic) modulation of the heart determined
by the method of short-term heart rate variability (HRV)
analysis, especially at high frequencies (>0.15 Hz)
reflecting respiratory sinus arrhythmia. On other hand,
the spectral activity in the low frequency band (0.040.15 Hz) is determined by activity of both autonomic
- sympathetic and parasympathetic - divisions via
barorereflex mechanism21. Since our study did not reveal
significant difference between groups in parameters
characterizing the low frequency band; conclusions
regarding changes in alone sympathetic branch of
autonomic nervous system in ADHD could not be drawn
from the short-term heart rate variability analysis.
In conclusion, in children with ADHD the
cardiovascular dysregulation (decreased cardiac
vagal modulation, tachycardia, altered ability of
dynamic autonomic nervous system activation during
orthostatic load) was discovered using short-term
heart rate variability analysis. It is known that lower
heart rate variability is associated with increased
risk of cardiovascular morbidity and mortality.
Therefore, further studies are needed to characterize
TONHAJZEROVA et al: HEART RATE VARIABILITY & ATTENTION DEFICIT HYPERACTIVITY DISORDER
and elucidate their mechanisms which may contribute
to understanding of complex and sophisticated brainheart relations.
Acknowledgment
Authors thank Ing. Maria Petraskova for technical assistance.
This study was supported by National Research Grant VEGA
1/4239/07.
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Reprint requests:Dr Ingrid Tonhajzerova, Associate Professor, Department of Physiology, Jessenius Faculty of Medicine
Comenius University, Mala Hora 4, 037 54 Martin, Slovak Republic
e-mail: [email protected]