Brain (1998), 121, 2381–2395
Abnormal development of biceps brachii phasic
stretch reflex and persistence of short latency
heteronymous reflexes from biceps to triceps
brachii in spastic cerebral palsy
M. C. O’Sullivan, S. Miller, V. Ramesh, E. Conway, K. Gilfillan, S. McDonough and J. A. Eyre
Developmental Neuroscience Group, Department of Child
Health, University of Newcastle upon Tyne, Royal Victoria
Infirmary, Queen Victoria Road, Newcastle upon Tyne
NE1 4LP, UK
Correspondence to: Professor J. A. Eyre, Developmental
Neuroscience Group, Department of Child Health,
University of Newcastle upon Tyne, Royal Victoria
Infirmary, Queen Victoria Road, Newcastle upon Tyne
NE1 4LP, UK
Summary
Co-contraction of antagonist muscles is characteristic
of spasticity arising from perinatal brain damage but
not in spasticity occurring after brain damage in
adulthood. Such co-contraction is a normal feature of
early post-natal motor development. Heteronymous,
monosynaptic Group Ia projections from biceps brachii
to both the antagonist triceps brachii and to other
synergist and non-synergist muscles of the upper limb
occur in the newborn baby and become restricted
during the first 4 years to motor neurons of primarily
synergistic muscles. Longitudinal and cross-sectional
studies have been performed to test the hypothesis
that inappropriate heteronymous excitatory projections
persist in children with perinatal brain damage who
develop spasticity. Subjects with spasticity, from brain
damage acquired in adulthood were also studied to
determine if these projections simply become unmasked
as part of spasticity, independent of the age of occurrence
of the brain damage. Twenty-nine healthy newborn
babies and 29 at high risk for cerebral palsy, 12 of
whom developed spastic quadriparesis, were studied
longitudinally for 4 years. Thirty-eight subjects, aged
8–30 years, with spasticity of perinatal origin (11
hemiplegic, 11 quadriplegic, 16 with Rett syndrome)
and 11 subjects with stroke in adulthood and spastic
hemiplegia were also studied. The results were compared
with those obtained in 372 normal subjects aged from
birth to 55 years. Small taps were delivered to the
tendon of biceps brachii using an electromechanical
tapper. Surface EMG was recorded from biceps and
triceps brachii, pectoralis major and deltoid. In the
longitudinal study, those developing spastic quadriparesis
showed persistent low thresholds for the homonymous
phasic stretch reflex, which had abnormally short
onset latencies. There was persistence of short onset
heteronymous excitatory responses in triceps brachii,
while a normal pattern of restriction of heteronymous
responses to pectoralis major and deltoid occurred. The
same pattern was observed in older subject groups with
spasticity of perinatal origin. In adults with hemiplegia
following stroke the threshold of the homonymous
phasic stretch reflex was low, but it had a normal
onset latency. There was no evidence of abnormal
heteronymous excitatory responses. In conclusion,
exaggerated excitatory responses to primary muscle
afferent input were observed in the homonymous (biceps
brachii) and antagonist (triceps brachii) motor neurons
in subjects with spasticity arising from perinatal brain
damage. They are likely to play an important role in
the predominant co-contraction of agonist/antagonist
muscles during voluntary movement observed in subjects
with spastic cerebral palsy.
Keywords: spasticity; phasic stretch reflex; heteronymous Group Ia afferent; development; human
Abbreviations: solid symbols indicate data from spastic limbs; open symbols indicate data from the limbs in normal subjects
or from non-spastic limbs in subjects with hemiplegia
© Oxford University Press 1998
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M. C. O’Sullivan et al.
Introduction
It is well recognized that the pattern of muscle contraction
observed in spasticity depends upon the age at which brain
damage occurs. Thus, individuals with spastic cerebral palsy
have a predominance of co-contraction of agonist/antagonist
muscle pairs during voluntary limb movements, where
reciprocal patterns of activity would normally be appropriate
(Milner-Brown and Penn, 1979; Berger et al., 1982, 1984;
Hallett and Alvarez, 1983). In contrast, the normal reciprocal
mode of muscle activation during limb movement is preserved
in subjects with spasticity acquired in adulthood (MilnerBrown and Penn, 1979; Crenna et al., 1992; Gowland
et al., 1992).
Healthy newborn babies and young infants also display a
predominant pattern of co-contraction of antagonist muscles
during movements of both the upper and lower limbs (Gatev,
1972; Berger et al., 1984; Forssberg, 1985; Hadders-Algra
et al., 1992). Dense monosynaptic projections of Group Ia
afferents from homonymous muscles to direct antagonists as
well as to synergists have been observed in newborn animals,
which rapidly become restricted during the first few postnatal
days (lamb: Änggård et al., 1961; kitten: Eccles et al.,
1963; rat: Saito, 1979; Seebach and Ziskind-Conhaim, 1994).
Parallel observations have been made in human neonates, in
whom Group Ia afferents of biceps brachii have been shown
to have heteronymous monosynaptic excitatory projections
to many motor neuronal cell groups throughout the cervical
enlargement, including a powerful excitatory projection to
the antagonist triceps brachii. These heteronymous excitatory
projections become restricted and focused during the first 4
postnatal years (O’Sullivan et al., 1991). There is increasing
evidence from studies in animals that the normal development
of α-motor neurons and their segmental synaptic input depend
upon the integrity of descending motor pathways and spinal
afferent input (McCouch et al., 1958; Navarrete and Vrbová,
1984; Lowrie et al., 1987; Goldberger, 1988; Commissiong
et al., 1991; Iles and Pisini, 1992; Dekkers and Navarrete,
1993; Nacimiento et al., 1993; O’Hanlon and Lowrie, 1996).
The predominance of co-contraction observed between
antagonist muscles in individuals with spastic cerebral
palsy, may therefore arise from abnormal persistence of
heteronymous excitatory projections between agonist and
antagonist muscle pairs or failure of the appropriate focusing
of the projections following early lesions to the corticospinal
projection.
The aim in the present study was therefore to determine
if there was evidence for abnormal excitatory Group Ia
heteronymous projections between the muscles of the
shoulder and upper limb, including the agonist/antagonist
muscle pair, biceps and triceps brachii, in subjects with
spasticity (Lance, 1980): (i) from cerebral palsy, either spastic
quadriplegia or spastic hemiplegia, and in subjects with
Rett syndrome (Rett Syndrome Diagnostic Criteria Working
Group, 1988), to enable a comparison between subjects in
whom the site of the brain damage was likely to be different,
but in whom the time of occurrence was perinatal; (ii) in
subjects with spastic hemiplegia arising from perinatal brain
damage, but not in subjects with spastic hemiplegia from
adult onset stroke, to enable a comparison between subjects
who were likely to have a similar site but differing times of
occurrence of the lesion; and (iii) a 4-year longitudinal study
was also performed on 29 infants at low risk and 29 infants
at high risk for developing spastic cerebral palsy to compare
and contrast the development of heteronymous excitatory
projections over the time period in which the heteronymous
excitatory responses become restricted and focused.
Subjects
For all subject groups ethical approval was given by the
Joint Ethical Committee of Newcastle upon Tyne University
and Health Authority. Informed written consent was obtained
from the subjects and/or their parents, where appropriate.
Normal subjects were defined as those who had no past
history of a neurological disorder and who were normal
to neurological examination. Subjects with spasticity were
defined according to Lance (1980), i.e. a velocity dependent
increase in muscle tone, as part of an upper motor neuron
syndrome.
Cross-sectional study
Normal group. This group comprised 372 normal subjects
aged from 32 weeks gestation to 55 years. These subjects
are detailed in O’Sullivan et al. (1991) and do not include
the normal subjects of the present longitudinal study.
Subjects with spasticity arising from differing
cortical pathologies, all of perinatal origin
Cerebral palsy hemiplegia. There were 11 subjects (97
males and 4 females), aged 5–18 years (median 9 years). All
the subjects had unilateral signs of impaired voluntary control
of the limbs from early infancy, increased muscle tone and
spasticity (Lance, 1980), and an extensor plantar response.
In these subjects both the paretic and non-paretic upper limbs
were studied.
Cerebral palsy quadriplegia. This group comprised 11
subjects (7 males and 4 females) aged 5-6 years (median 9
years). All had impaired voluntary control, increased muscle
tone and spasticity (Lance, 1980) involving all four limbs,
and bilateral extensor plantar responses. The left upper limb
was studied.
Rett syndrome. Severely disordered control of movement
associated with profound mental handicap is the hallmark
of Rett syndrome, a neurodevelopmental disorder which
exclusively affects females (Rett Syndrome Diagnostic
Criteria Working Group, 1988). The motor component of the
Abnormal development of the phasic stretch reflex
syndrome is highly characteristic and includes abnormal
control of voluntary movement, particularly of the hand,
disordered muscle tone, and spasticity (Lance, 1980). Sixteen
subjects with Rett syndrome, aged 5–26 years (median 9
years) were studied. Since these subjects had bilateral motor
impairment only the left upper limb was studied. The
homonymous phasic stretch reflex in biceps brachii was
studied in all the subjects and heteronymous responses in
triceps brachii, deltoid and pectoralis major were investigated
in 8 subjects.
Subjects with spastic hemiplegia arising from
lesions occurring perinatally or in adulthood
Cerebral palsy hemiplegia. The subjects in the cerebral
palsy hemiplegic group described above were compared with
the adult onset hemiplegic group described below.
Adult onset hemiplegia. Nine adult subjects (6 males
and 3 females) aged 29–62 years (median 40 years) were
studied. All the subjects had unilateral signs of impaired
voluntary control of the limbs, increased muscle tone and
spasticity (Lance, 1980) following stroke in adulthood. For
all subjects the first ever stroke had occurred .18 months
previously and all had had stable clinical signs for .6
months. In these subjects both the paretic and non-paretic
upper limbs were studied.
Longitudinal study of babies with normal
development and those developing spastic
quadriparesis
Normal subjects. This group comprised 29 healthy,
newborn babies (15 males and 14 females) born at 32-42
weeks gestational age, who had no significant neurological
illnesses during the perinatal period or during the period of
the study. All had normal cerebral ultra-sound scans during
the neonatal period and normal neurological examinations
and developmental assessments (NFER developmental scales;
NFER Nelson Publishing Company Ltd, UK) performed by
a paediatric neurologist (J.A.E) at 18 months and 3 years
of age.
Subjects developing spastic quadriparesis
Twenty-nine subjects (gestational age at birth 28–40 weeks)
were selected who were considered to be at high risk for
cerebral palsy, on account of a history of a significant
neurological illness in the perinatal period and the abnormal
findings on cerebral ultra-sound scans of periventricular
haemorrhage, with ventricular dilatation and/or parenchymal
involvement or periventricular leucomalacia. Two of these
subjects died during the period of the study and 5 were lost
to follow-up. Of the remaining 22 children, 10 had normal
neurodevelopmental assessments at 3 years and these
2383
children’s data were excluded from the present analysis.
Twelve children had neurodevelopmental delay and signs of
spasticity (Lance, 1980) involving all four limbs at 18-month
and 3-year neurodevelopmental assessments. These children
formed the group with spastic quadriparesis and comprised
8 males and 4 females. All the subjects were studied as near
to 40 weeks post-menstrual age as possible and then at ~6
monthly intervals for the first 2 years and at yearly intervals
thereafter. The mean follow-up period was 4 years (range
3.3–6.8 years). Data were obtained on both upper limbs but
only data from the left upper limb are presented in this paper,
since it is representative of data obtained from both limbs.
Methods
Positioning of subjects
Subjects of ,6 months were studied supine. An evacuable
plastic bag filled with polystyrene beads was used to stabilize
the head and trunk in the mid-line anatomical position.
Subjects of .6 months of age were seated either on a parent’s
knee or on a chair, with the head and trunk in the mid-line
anatomical position. The arm rested on a support in a position
of adduction, in ~45° of flexion from full extension, and fully
supinated.
Phasic stretch reflex
The phasic stretch reflex in biceps brachii was elicited with
a hand-held electromechanical tapper (Ling Altec 200, Ling
Altec, UK), delivering a single tap, with force rise and decay
times of 2.5 ms. The stylus of the tapper, a Perspex round
disc (diameter 10 mm for adults, 8 mm for babies) was
applied to the skin overlying the tendon of biceps brachii
within the cubital fossa. The peak force delivered could be
varied over a range of 0.1–1.0 N.
This small tendon tap was chosen as the stimulus to evoke
the homonymous phasic stretch reflex, since it has been
shown to excite almost exclusively Group Ia muscle afferents,
when applied to relaxed muscle. When applied to contracting
muscle the tap excites predominantly Group Ia but also some
Group Ib afferents (Burke et al., 1976a, b; Pierrot-Deseilligny
et al., 1981). In each subject an attempt was first made to
elicit the phasic stretch reflex in relaxed biceps brachii. If no
reflex response was obtained, even at maximum force output,
the phasic stretch reflex was then elicited in the presence of
background muscle activity. Since all young children and
many older subjects with spasticity were unable to maintain
a steady level of contraction of biceps brachii in their spastic
limb(s) all adult subjects held a 250 g weight in their
supinated hand unsupported against gravity. Children over
the age of 2 years held a weight of 100–200 g, as judged
appropriate to their age and stature. The weight was held in
the outstretched supinated hand and resulted in a degree of
contraction in biceps and triceps brachii, pectoralis major
and deltoid muscles.
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M. C. O’Sullivan et al.
any of the muscles, including biceps brachii, the data from
the subject were excluded from further analysis.
Data analysis
Fig. 1 (A) Test. Homonymous phasic stretch reflex in biceps
brachii in a newborn baby and heteronymous excitatory responses
in triceps brachii, deltoid and pectoralis major, evoked when the
stimulus was applied to the tendon of ipsilateral biceps brachii.
(B) Control. No responses are seen when the same stimulus was
applied to the lateral humeral epicondyle on the same side. The
hashed line indicates the onset of stimulation. Stim 5 stimulus; P.
major 5 pectoralis major.
To define the threshold of the homonymous phasic stretch
reflex in biceps brachii the force delivered by the stylus was
increased until a reflex response could be elicited in 50% of
trials. The force was then set at 1.1 times this threshold
value, with the result that a reflex response was obtained in
biceps brachii in all trials. At least 20 phasic stretch reflexes
in biceps brachii were recorded in all subjects.
EMG
EMGs were recorded using skin mounted Ag/AgCl standard
EEG electrodes, 5 mm in diameter with centres separated by
15 mm, from the following muscles: biceps brachii, triceps
brachii, posterior deltoid, and the clavicular fibres of
pectoralis major (referred to throughout as pectoralis major)
(Fig. 1). The recording electrodes were placed in the vertical
anatomical plane over the belly of biceps brachii, the lateral
head of triceps brachii, over the lateral aspect of posterior
deltoid and in the horizontal plane over the clavicular fibres
of pectoralis major. The impedance of the recording electrodes
was measured and maintained at 1–5 kΩ. The EMGs were
amplified and filtered using a –3 dB bandpass of 5–1500 Hz
and passed to a computer for on-line and off-line analysis.
Control for mechanical spread of stimulus
Controls were carried out to determine if responses in
muscles other than biceps brachii could be attributed solely
to mechanical spread of the stimulus through the tissues of
the limb. The same stimulus, at the intensity used to evoke
reflex responses (i.e. 1.1 times the threshold for evoking a
reflex in biceps brachii), was also applied to the skin on
either side of the biceps brachii tendon in the cubital fossa
and to the medial and lateral epicondyles of the humerus
(Fig. 1). If any of these stimuli evoked a reflex response in
The EMGs were analysed off-line using a suite of data
analysis programs (SigAvg, Cambridge Electronics Design
Ltd, Cambridge, UK). The shortest onset latency, obtained
from at least 20 responses, was determined for the
homonymous phasic stretch reflex in biceps brachii and also
for the heteronymous excitatory responses occurring in the
other muscles. Since children with cerebral palsy may have
abnormal growth, the latencies for all subjects were related
to pathway length, estimated as the distance from the spinous
process of the fifth cervical vertebra to a point on the belly
of biceps brachii corresponding, to the midpoint of a line
between the acromion and the lateral epicondyle of the
humerus.
Results
For summary see Table 1.
Threshold of the homonymous phasic stretch
reflex in biceps brachii (Fig. 2)
Normal subjects (cross-sectional and longitudinal
studies)
Homonymous phasic stretch reflexes were evoked in relaxed
biceps brachii in all newborn subjects (Fig. 2A and B). There
was an increase in threshold with age, so that all subjects
over the age of 4 years required muscle contraction to evoke
the reflex (Fig. 2A and B). The threshold of the homonymous
phasic stretch reflex in contracting muscle continued to
increase until the ages of 8–16 years, when adult values were
achieved (Fig. 2D and F).
Subjects with spasticity arising from differing
cortical pathologies of perinatal origin (Fig. 2B,
E and F)
Homonymous phasic stretch reflexes had abnormally low
thresholds in all subjects of the cerebral palsy hemiplegic
(j and u) and quadriplegic (r) groups and in the Rett (★)
group, being elicited in relaxed biceps brachii of all the upper
limbs with spasticity (Figs. 2B, E and F). The threshold was
significantly lower in subjects with spastic involvement of
all four limbs (mean 6 SD: cerebral palsy quadriplegia (r)
2.5 6 0.3 N; Rett syndrome (★) 2.5 6 0.4 N), compared
with subjects in the cerebral palsy hemiplegic group
(mean 6 SD: (j) 4.3 6 0.2 N). The thresholds of the
cerebral palsy hemiplegic group differ significantly from
those of the cerebral palsy quadriplegic group (t 5 –4.93,
P , 0.001) and the Rett syndrome group (t 5 –4.2,
P , 0.001).
Abnormal development of the phasic stretch reflex
2385
Table 1 Summary of results
Subject groups
Quadriparesis
Longitud
X-section
r
Biceps brachii phasic stretch reflex
Threshold
Low
Low
↓↓↓
↓↓↓
Onset
Short
Short
Heteronymous excitatory responses
Triceps brachii Increased
Increased
frequency
frequency
Short onset Short onset
latency
latency
Deltoid
Normal
Normal
Pectoralis major Normal
Normal
Perinatal brain damage
Rett
Hemiparesis
Spastic arm
Non-spastic arm
★
j
u
Brain damage acquired in adulthood
Hemiparesis
Spastic arm Non-spastic arm
m
n
Low
↓↓↓
Short
Low
↓↓↓
Short
Low
↓
Short
Low
↓↓
Normal
Low
↓
Normal
Increased
frequency
Short onset
latency
Normal
Normal
Increased
frequency
Short onset
latency
Normal
Increased
frequency
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
↓↓↓ 5 able to be elicited in relaxed muscle in the majority of subjects; ↓↓ 5 elicited in contracting muscle but below the normal range
for the majority of subjects; ↓ 5 elicited in contracting muscle and below the median value for the majority of subjects; X-section 5
cross-sectional study of subjects with spastic quadriparesis; Longitud 5 longitudinal study of subjects developing spastic quadriparesis.
Fig. 2 Threshold of the homonymous phasic stretch reflex in biceps brachii with age. (A, C and E) Thresholds in relaxed biceps brachii.
(B) The percentage of each subject group requiring concomitant contraction. (D and E) Thresholds of subjects requiring concomitant
contraction. In each graph the dashed lines represent the data of the cross-sectional study of 372 normal subjects and define the median
and 10th-90th centile range. (A) Thresholds of 50 normal subjects in the longitudinal study. (C and D) Thresholds of 11 subjects
developing cerebral palsy in the longitudinal study, in relaxed and contracting muscle, respectively. (E and F) Thresholds of 38 subjects
with spasticity of perinatal origin. Each symbol represents a single subject: cerebral palsy hemiplegia (u and j); cerebral palsy
quadriplegia (r) and Rett (★) and 11 subjects with adult onset hemiplegia (n and m); in relaxed and contracting muscle, respectively.
Open symbols represent the data from the non-paretic side of those with hemiplegia. NR 5 no response.
2386
M. C. O’Sullivan et al.
Subjects with spastic hemiplegia arising from
lesions occurring perinatally or in adulthood
(Fig. 2B, E and F)
Homonymous phasic stretch reflexes could be elicited in
relaxed biceps brachii of the spastic arm in only 2 of the 9
subjects with adult onset hemiplegia (m) compared with all
11 subjects from the cerebral palsy hemiplegic group (j)
(χ2 5 7.73, P , 0.005; Fig. 2B, E and F). Two of the
remaining 7 subjects with adult onset hemiplegia were unable
to perform voluntary contraction of biceps brachii, and thus
no phasic stretch reflex could be evoked. In all 5 remaining
subjects the threshold of the homonymous phasic stretch
reflex in contracting biceps brachii in the spastic upper limb
was below the median value for normal adult subjects and
in 4, below the normal range (Fig. 2E and F).
The thresholds in the non-spastic upper limb were similar
for the adult onset (n) and the cerebral palsy hemiplegic
(u) groups. Although in both groups no response could be
elicited in relaxed biceps brachii, the thresholds of the
homonymous phasic stretch reflex in contracting biceps
brachii were low, with all values in the cerebral palsy
hemiplegic group, and 7 out of 9 values in the adult onset
hemiplegia group being below the median value for normal
subjects, and below the normal range for 5 out of 11 subjects
of the cerebral palsy hemiplegic group and 3 out of 9 subjects
of the adult onset hemiplegic group (Fig. 2F).
Longitudinal study of babies developing spastic
quadriparesis (Fig. 2B and D)
The subjects in the longitudinal study who developed spastic
quadriparesis had persistent low thresholds with increasing
age. The homonymous phasic stretch reflex could still be
elicited in relaxed muscle in 11 out of 12 of these children
when aged over 2 years (Figs. 2B and C). In 2 out of 12
subjects the thresholds increased so that muscle contraction
was required to evoke the reflex at ages 2–4 years, but the
threshold values in contracting muscle were low, having
fallen below the normal range by 4 years of age for both
subjects (Fig. 2D).
Onset latency of the homonymous phasic stretch
reflex in biceps brachii (Fig. 3)
Normal subjects (cross-sectional and longitudinal
studies)
The onset latencies decreased with age for the first 5 postnatal years and subsequently increased in proportion to
increasing arm length (Fig. 3A and C).
Subjects with spasticity arising from differing
cortical pathologies with perinatal origin
(Fig. 3C)
Short onset latencies were observed in the spastic limb; for
32 out of 38 subjects the values were below the normal
median value and 26 subjects had values lying below the
normal range for arm length (mean 6 SD: cerebral palsy
quadriplegia (r) 11.8 6 0.3 ms; Rett syndrome (★)
11.3 6 0.3 ms; cerebral palsy hemiplegic group (j)
11.8 6 0.4 ms; Fig. 3C). The onset latencies in the nonspastic limbs of the subjects with cerebral palsy hemiplegia
were also short with only 3 lying within the normal range
(mean 6 SD: (u) 11.3 6 0.3 ms).
Subjects with spastic hemiplegia arising from
lesions occurring perinatally or in adulthood
In contrast to the short onset latencies observed in both limbs
in subjects with cerebral palsy hemiplegia (j and u), the
onset latencies for both the spastic and non-spastic limbs of
subjects with adult onset hemiplegia (m and n) were within
the normal range (mean 6 SD: spastic limb (m) 13.4 6 0.4
ms; non-spastic limb (n) 14.2 6 0.5ms; Fig. 3C).
Longitudinal study of babies developing spastic
quadriparesis
There was a tendency for short onset latencies even at 40
weeks gestational age, with all 11 out of 12 having onset
latencies at or below the normal median value. The tendency
for short onset latencies became more marked with age, so
that by the age of 4 years, 5 out of 6 of the subjects had
values below the normal range (Fig. 3B).
Probability and relative onset latency of
heteronymous excitatory responses in ipsilateral
muscles of the shoulder and upper limb (Figs 4
and 5)
Normal subjects (cross-sectional and longitudinal
studies)
The probability of occurrence of short latency heteronymous
excitatory responses in triceps brachii, deltoid and pectoralis
major was greatest at birth and decreased over the first 4
years (Fig. 4A–C). Where a heteronymous excitatory response
occurred in triceps brachii, deltoid or pectoralis major, the
onset latency of the homonymous phasic stretch reflex in
biceps brachii was subtracted from the onset latency of the
heteronymous response, to give an onset latency relative to
that of biceps brachii (Fig. 5).
Triceps brachii. For those ,2 years old the relative onset
latencies of heteronymous excitatory responses in triceps
brachii had a median value of 0 ms (Fig. 5A). With increasing
age fewer subjects showed heteronymous responses, and
these occurred with longer relative onset latencies (Fig. 5A
and C). When heteronymous responses occurred in normal
adults the relative onset latency had a median value of 14 ms.
Abnormal development of the phasic stretch reflex
2387
Fig. 3 Onset of the homonymous phasic stretch reflex in relation to the pathway length from C5 spine to the midpoint of biceps brachii.
In each graph the dashed lines represent the data of the cross-sectional study of 372 normal subjects and define the median and 10th–
90th centile range. (A) Data of 50 normal subjects in the longitudinal study. (B) Data of 11 subjects developing spastic quadriparesis in
the longitudinal study, each symbol representing a single subject. (C) Data of 38 subjects with spasticity of perinatal origin: cerebral
palsy hemiplegia (u and j), cerebral palsy quadriplegia (r) and Rett (★) and 11 subjects with adult onset hemiplegia (n and m) Open
symbols represent the data from the non-paretic side of those with hemiplegia. Solid symbols indicate data from spastic limbs.
Fig. 4. Percentage of each subject group with heteronymous excitatory responses observed in: triceps
brachii (A), deltoid (B) and pectoralis major (C). In each graph the dashed lines represent the data of
the cross-sectional study of 372 normal subjects. Open circles represent the normal subjects and filled
circles the subjects in the longitudinal study developing spastic quadriplegia. Other symbols: u and
j 5 cerebral palsy hemiplegia; r 5 cerebral palsy quadriplegia; ★ 5 Rett syndrome and n and m 5
adult onset hemiplegia. Open symbols represent the non-spastic arm of those with hemiplegia.
Deltoid. Heteronymous responses in deltoid for those aged
,2 years had a median relative onset latency of –0.4
ms. With age, these heteronymous responses occurred less
frequently and with longer relative onset latencies, so that
subjects older than 4 years had responses with a median
relative onset latency of 12 ms (Fig. 5D and F).
Pectoralis major. The median relative onset latency of
heteronymous responses for all ages was –1 ms (Fig. 5H
and I).
Subjects with spasticity arising from differing
cortical pathologies with perinatal origin
Triceps brachii. There was an increased probability of
short latency heteronymous excitatory responses occurring
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M. C. O’Sullivan et al.
Fig. 5. Relative onset latencies of heteronymous responses in triceps brachii (A–C), deltoid (D–F) and pectoralis major (G–I). Relative
onset latencies were calculated by subtracting the onset latency of the homonymous phasic stretch reflex in biceps brachii from the onset
latency of each heteronymous response. In each graph the dashed lines represent the data of the cross-sectional study of 372 normal
subjects and define the median and 10th–90th centile range and the horizontal dotted lines represent the relative onset latencies for a
monosynaptic linkage, estimated as in O’Sullivan et al. (1991). (A, D and G) Data from the 50 normal subjects, longitudinal study. (B,
E and H) Data from 11 subjects developing cerebral palsy in the longitudinal study, each symbol representing a single subject. (C, F and
I) Data from 38 subjects with spasticity of perinatal origin: cerebral palsy hemiplegia (u and j); cerebral palsy quadriplegia (r) and
Rett syndrome (★); and 11 subjects with adult onset hemiplegia (n and m). Open symbols represent the data from the non-paretic side
of those with hemiplegia. Solid symbols indicate data from spastic limbs.
in triceps brachii of spastic upper limbs but not of the nonspastic upper limb of the cerebral palsy hemiplegic group
(cerebral palsy quadriplegia (r) 7 out of 11; Rett (★) 7 out
of 8; cerebral palsy hemiplegia spastic upper limb (j) 6 out
of 11, non-spastic upper limb (u) 2 out of 11; Fig. 4A). The
responses had relative onset latencies close to 0ms, except
those occurring in the non-spastic upper limb of the cerebral
palsy hemiplegic subjects (u), where the relative onset
latencies fell within the range observed in normal subjects
(Fig. 5C).
Deltoid and pectoralis major. There was a normal
probability of heteronymous responses occurring in deltoid
for all subject groups (cerebral palsy quadriplegia (r) 2 out
of 11; Rett (★) 2 out of 8; cerebral palsy hemiplegia spastic
upper limb (j) 2 out of 11, non-spastic upper limb (u) 0
out of 11; Fig. 4B) and in pectoralis major for all except the
subjects within the cerebral palsy hemiplegic group (j), who
showed an increased probability of a heteronymous response
in pectoralis major in 2 out of 11 on the spastic side (cerebral
palsy quadriplegia (r) 1 out of 11; Rett syndrome (★) 2 out
of 8; cerebral palsy hemiplegia spastic upper limb (j) 7
out of 11, non-spastic upper limb (u); Fig. 4C). Where
heteronymous responses occurred, the relative onset latencies
were within the range observed in normal subjects (Fig. 5E,
F, H and I).
Subjects with spastic hemiplegia arising from
lesions occurring perinatally or in adulthood
Triceps brachii and pectoralis major. In contrast to
the high probability of heteronymous excitatory responses in
triceps brachii and pectoralis major in the spastic upper limb
Abnormal development of the phasic stretch reflex
of the cerebral palsy hemiplegic group (j), only 1 out of 9
subjects with adult onset spastic hemiplegia (m and n) had
heteronymous excitatory responses in both triceps brachii
and pectoralis major. The responses occurred in both the
spastic and non-spastic upper limbs. (Note: the one subject
with heteronymous responses required muscle contraction to
elicit the phasic stretch reflex in biceps brachii in the spastic
arm.) These responses were consistent with the data obtained
in normal adult subjects (Figs 4A–C and 5C and I).
Deltoid. No heteronymous excitatory responses were
observed in deltoid in subjects with adult-onset spastic
hemiplegia (m and n).
Longitudinal study of babies developing spastic
quadriparesis
Triceps brachii. There was persistence of the
heteronymous excitatory responses in triceps brachii
(Fig. 4A), which, for the majority of subjects, had relative
onset latencies close to 0 ms (Fig. 5B).
Deltoid and pectoralis major. A normal pattern of
development of heteronymous excitatory responses to deltoid
(Figs 4B and 5E) and pectoralis major (Figs 4C and 5F) was
observed.
Discussion
Striking differences in both the homonymous and
heteronymous excitatory reflex responses evoked by a tap to
biceps brachii were observed between subjects whose
spasticity arose from perinatal brain damage and those where
the brain damage occurred in adulthood (for summary see
Table 1). The previously documented abnormalities of the
homonymous phasic stretch reflex, in subjects with spasticity
from brain damage in adulthood, were also demonstrated in
the present study. Thus, abnormally low thresholds were
observed on the paretic (spastic) side (e.g. Magladery et al.,
1952; Futagi and Abe, 1985; Cody et al., 1987) and a
tendency for low thresholds also occurred in the apparently
normal arm (Thilmann et al., 1990). The onset latency of
the homonymous phasic stretch reflex and the probability of
heteronymous excitatory responses in triceps brachii and in
pectoralis major and deltoid were all within the ranges
observed in the normal adult subjects studied.
The three groups of subjects with spasticity arising from
perinatal brain damage and those children developing spastic
quadriplegia studied longitudinally also showed abnormally
low thresholds for the homonymous phasic stretch reflex.
The reduction in threshold was more marked than that
observed in those with adult onset spasticity, since the phasic
stretch reflex could be elicited in relaxed muscle in all
subjects with perinatal brain damage. All four subject groups
with perinatal brain damage showed a consistent pattern of
2389
additional abnormalities comprising shorter onset latencies
for the homonymous phasic stretch reflex and the persistence
of short latency, heteronymous, excitatory responses
particularly in the antagonist triceps brachii.
Do different experimental paradigms account
for the differences between subject groups?
For normal babies and infants, those with spasticity from
perinatal brain damage and two subjects with adult onset
spasticity, the responses were recorded when all the muscles
studied were relaxed. For older normal children and for the
majority of those with spasticity of adult onset, the responses
could only be recorded with muscle contraction in all the
muscles studied. The discrepancy between the paradigms is
likely to militate against, rather than provide an explanation
for, the differences observed between those with spasticity
from perinatal brain damage and those with adult-onset
spasticity. The onset latency of the homonymous phasic
stretch reflex is longer in relaxed muscle in comparison to
contracted muscle, since for the former there is an added
requirement for spatiotemporal summation at motor neurons.
The comparison in the present study therefore between onset
latencies obtained in relaxed muscle (subjects with perinatal
brain damage) and those obtained in contracting muscle
(normal subjects and subjects with adult onset spasticity)
will have concealed an even greater decrease in latency.
Co-contraction of biceps and triceps brachii is likely to
promote rather than inhibit the expression of heteronymous
excitatory projections of Group Ia afferents from biceps to
triceps brachii in comparison to the situation where both are
relaxed. The arguments are: (i) triceps brachii motor neurons
during weak active contraction will have a lower threshold
to a further excitatory input than when they are inactive; (ii)
presynaptic inhibition of homonymous and heteronymous
Group Ia terminals on motor neurons is decreased when a
muscle is contracting and conversely increased to terminals
on motor neurons of relaxed muscles (Iles and Roberts, 1986;
Hultborn et al., 1987; Meunier and Morin, 1989; Nielsen and
Kagamihara, 1993); (iii) during co-contraction of antagonist
muscles reciprocal inhibition has been shown to be reduced
(Nielsen and Kagamihara, 1992); and (iv) the excitation of
Group Ib afferents in contracting biceps brachii is likely to
result in facilitation of the antagonist triceps brachii (Laporte
and Lloyd, 1952; Eccles et al., 1957b). Thus, the high
probability of a heteronymous excitatory response in triceps
brachii observed in subjects with perinatal brain damage,
when both biceps and triceps brachii were relaxed, but not
observed in normal subjects and those with adult onset
spasticity during co-contraction of both muscles, is even
more remarkable. (Note: the two subjects in the adult onset
hemiplegic group, in whom the homonymous phasic stretch
reflex could be evoked in relaxed biceps brachii, did not
display heteronymous excitatory responses.)
2390
M. C. O’Sullivan et al.
Do different anatomical sites of brain damage
account for the differences between subject
groups?
The various anatomical sites for brain damage in the subject
groups is an unlikely explanation for the differences observed
since the four groups of subjects with perinatal brain damage
had differing anatomical sites for the brain damage and yet
their patterns of response were similar. In contrast, the two
groups with hemiplegia, those with perinatal onset and those
with adult onset, are likely to have had similar sites for the
brain damage (i.e. unilateral cerebral cortex or sub-cortical
white matter), and yet showed strikingly different patterns
of responses.
Do biophysical changes in spastic muscle
account for the differences observed between
subjects?
A spastic muscle has increased stiffness (see review by
Pierrot-Deseilligny, 1990) and to achieve the same degree of
muscle stretch, a larger force must be applied than in a
normal subject of the same age. Thus, the biophysical changes
which occur to muscle in spasticity will have concealed an
even greater reduction in threshold of the homonymous phasic
stretch reflex than was apparent. Increased responsiveness of
primary muscle afferents to muscle stretch is unlikely, since
no abnormalities have been observed in direct recordings of
primary afferents following muscle stretch in both adult subhuman primates and humans with spasticity (Meltzer et al.,
1963; Hagbarth et al., 1973). Furthermore, low thresholds
and increased excitability of the H-reflex have been observed
in spasticity both of perinatal origin (e.g. Futagi and Abe,
1985) and that acquired in adulthood (e.g. Taylor et al., 1984).
also reduced (Yanagisawa et al., 1976; Delwaide, 1985) There
does not, however, appear to be a significant reorganization of
the spinal reflex, since the reduction in reciprocal inhibition
has been shown to improve significantly during a purposeful,
dynamic task (Plant and Miller, 1990). Furthermore,
reciprocal inhibition is enhanced from extensors to flexors
in subjects with adult onset spasticity (Ashby and Wiens,
1989). Many other inhibitory spinal reflexes have not been
shown to be abnormal at rest in subjects with adult-onset
spasticity. Thus, significant reductions in Group II inhibition
(Burke and Lance, 1973), recurrent inhibition (Katz and
Pierrot-Deseilligny, 1982) and presynaptic inhibition of Group
Ia afferents (Faist et al., 1994) have not been demonstrated.
Abnormal control of recurrent inhibition (Katz and PierrotDeseilligny, 1982) has been demonstrated during the
performance of motor tasks. These observations suggest that
in adult onset spasticity there is abnormal descending control
of inhibition rather than a local reorganization of spinal
reflexes.
In the present study subjects with perinatal brain damage
were shown to have abnormally low thresholds and short
onset latencies of the homonymous phasic stretch reflex,
combined with a high probability of heteronymous Group Ia
excitatory responses in the antagonist muscle triceps brachii.
These abnormalities were observed with the upper limb at
rest and the degree of abnormality correlated with the severity
of the movement disorder, since the abnormalities were most
marked in subjects with spastic involvement of all four limbs
(cerebral palsy quadriplegic and Rett syndrome groups).
These observations suggest that abnormal excitatory spinal
reflexes and their abnormal descending control contribute
significantly to the spasticity following perinatal brain
damage.
Threshold of the homonymous phasic stretch
reflex
Homonymous phasic stretch reflex in subjects
with perinatally acquired brain damage
The pathophysiology underlying the low threshold for the
homonymous phasic stretch reflex in adult onset spasticity has
been studied extensively (for reviews, see Pierrot-Deseilligny,
1990; Ashby and McCrea, 1987). Changes in the biophysical
properties of motor neurons, which increase the efficacy of
a given synaptic current to produce reflex activation, have
been observed in cats with spasticity following spinal
transection (Gustaffsson et al., 1982). However, limited
studies in human subjects with spasticity from cortical lesions
in adulthood suggest that such changes are not likely to lead
to a marked change in the threshold of the phasic stretch
reflex. For example, the rise time of the composite EPSP
produced in soleus motor neurons by electrical volleys was
the same in normal subjects and patients with spasticity
(Ashby and Somerville, 1981; Mailis and Ashby, 1984).
Studies in subjects with adult onset spasticity have provided
evidence for a reduction in Ib inhibition (Delwaide and Oliver,
1988). Reciprocal Ia inhibition from flexors to extensors is
All the subjects with spasticity in the present study had
measurements made of the conduction delays in the
corticospinal and peripheral motor pathways using magnetic
stimulation of the cortex and of cervical motor roots (Eyre
et al., 1990; Ramesh et al., 1990; Heald et al., 1993). For
those with spastic hemiplegia and spastic quadriplegia, the
motor evoked responses following cortical stimulation had
high thresholds and either normal or abnormally prolonged
onset latencies. The evoked muscle action potentials in biceps
brachii, following magnetic stimulation of the spinal motor
roots, had normal thresholds and onset latencies, thus
excluding disorders of neuromuscular transmission as the
origin of the short onset latencies observed. The combination
of very low thresholds and short onset latencies for the
homonymous phasic stretch reflex in subjects with perinatal
brain damage must therefore result from more effective
synaptic transfer between Group Ia afferents and biceps
brachii motor neurons.
Abnormal development of the phasic stretch reflex
Short onset latency of homonymous phasic
stretch reflex
There is both anatomical and physiological evidence that the
initial component of the homonymous phasic stretch reflex
results from monosynaptic excitation of α-motor neurons by
Group Ia afferents at all ages including the foetus (adult cat:
Eccles et al., 1957a; adult primate: Clough et al., 1968;
foetal/newborn rat: Saito, 1979; Kudo and Yamada, 1987;
kitten: Eccles and Willis, 1965; adult man: Burke et al.,
1984; newborn babies and children: O’Sullivan et al., 1991;
human foetus: Okado and Kojima, 1984; Konstantinidou
et al., 1995). It was an unexpected observation therefore that
subjects with perinatal brain damage had onset latencies for
the homonymous phasic stretch reflex, which were up to 2
ms shorter than the shortest onset latencies in comparable
normal subjects, even when controlled for arm length. The
rise time of the excitatory postsynaptic potential following a
tap to a muscle tendon is prolonged due to temporal dispersion
of the afferent volley and has been estimated in adult subjects
to be up to 11 ms in duration (Burke et al., 1983). Significantly
increased effectiveness of synaptic transfer between Group
Ia afferents and biceps brachii motor neurons following
perinatal brain damage, could therefore result in a reduction
in activation time and abnormal short onset latencies, even
in monosynaptic projections.
Low threshold of homonymous phasic stretch
reflex
The children who were studied longitudinally and developed
spastic quadriparesis did not show the normal increase in
threshold with age (Fig. 2B). The very low thresholds of
the older subjects with spastic cerebral palsy are likely
therefore to have arisen from abnormal development of the
homonymous phasic stretch reflex. Excitability of α-motor
neurons has been shown to decrease with development
(cat: Fulton and Walton, 1986), reflecting increases in the
membrane area of the soma (cat: Conradi, 1976; Mellström
and Skoglund, 1969) and of the dendrites (cat: Conradi, 1976;
rat: Ramirez and Ulfhake, 1991) and increased negativity of
the resting membrane potential (cat: Kellerth et al., 1971;
rat: Ziskind-Conhaim, 1988). Group Ia afferent projections
to α-motor neurons decrease in number and there is a
redistribution of synapses from soma to dendrites with
increasing age (rat: Kudo and Yamada, 1987; cat: Conradi
and Skoglund, 1969; Conradi, 1976; monkey: Bodian, 1966).
There is strong evidence that normal maturation of αmotor neurons and their Group Ia afferent input depends
upon the integrity of both descending motor pathways and
segmental afferent sensory input. Following lesions of
descending motor pathways collateral sprouting and increased
synaptogenesis by segmental afferents occurred only if the
lesion was made in the neonate and not in the adult animal
(monkey: McCouch et al., 1958; cat: Goldberger, 1988; rat;
Commissiong et al., 1991; Nacimiento et al., 1993).
2391
Peripheral nerve injury in the neonatal rat resulted in the
alteration of the geometry of motor neuron dendrites and
arrest of the maturation of the motor neuron somatodendritic
receptive surface (Lowrie et al., 1987; Dekkers and Navarrete,
1993; O’Hanlon and Lowrie, 1993). These anatomical
findings were associated with hyperexcitability of reflex
responses and altered EMG patterns during locomotion
(Navarrete and Vrbová, 1984). Similar lesions performed in
the adult rat led to restoration of normal synaptic input to
the α-motor neuron following a brief recovery period (Lowrie
et al., 1987; Navarrete et al., 1990).
Increased frequency of heteronymous excitatory
responses in the antagonist muscle
In the present study the normal newborn babies of both the
longitudinal and cross sectional groups had a high probability
of heteronymous excitatory responses in triceps brachii and
deltoid, which decreased with age. Direct volume conduction
of the excitatory response in biceps brachii is excluded in
view of the earlier onset latencies of the heteronymous
responses in deltoid and pectoralis major (Fig. 5). However,
it is possible that the heteronymous responses could have
arisen from mechanical transmission of the stimulus through
the arm, presumably exciting spindle afferents of other
muscles, as discussed by Burke et al. (1983). The failure of
a tap of the same stimulus intensity to evoke homonymous
or heteronymous responses, when applied to soft tissue or
bony prominences near to the insertion of biceps brachii,
indicates that if mechanical spread of the small tap did
activate muscle spindles in other muscles, the activity was
subthreshold for direct motor neuronal discharge (O’Sullivan
et al., 1991). In addition, the observations that heteronymous
excitatory responses in triceps brachii persisted in the spastic
arms of children with perinatal brain damage, but decreased
in probability with age, in normal children and in the nonspastic arms of children with spastic hemiplegia, also imply
that the responses could not be attributed solely to mechanical
transmission of the stimulus, since mechanical transmission
was likely to be the same in both situations. It is, therefore,
concluded that the heteronymous responses observed
following a tap to the tendon of biceps brachii were primarily
due to heteronymous projections of Group Ia afferents from
biceps brachii to the motor neuronal pools of the other
muscles studied. However, an additional but subthreshold
homonymous Group Ia afferent input due to mechanical
spread of the stimulus to the target muscle cannot be excluded
(O’Sullivan et al., 1991).
In the normal newborn, it is likely that the onset of
the excitatory responses in all three heteronymous muscles
studied resulted from direct projections of muscle afferents
from biceps brachii, based on the evidence of the onset
latencies of the heteronymous responses relative to that of
the homonymous response in biceps brachii (Fig. 5)
(O’Sullivan et al., 1991). With age the probability of the
2392
M. C. O’Sullivan et al.
responses decreased and the relative onset latency of the
heteronymous responses in triceps brachii and deltoid
increased, suggesting that they were mediated by afferents
with slower conduction velocities and/or the reflex involved
more synapses in the spinal cord. Mao et al. (1984) also
observed a weak excitatory projection between antagonist
muscles in the leg in normal adult subjects, which had
similarly prolonged relative onset latency in comparison to
a possible monosynaptic projection. Heteronymous responses
in pectoralis major in the present study were infrequent, but
their onset latencies were compatible with a direct projection
of Group Ia afferents from biceps brachii to the motor
neurons of pectoralis major at all ages.
In adult animals and man, a wide range of heteronymous
primary muscle afferent projections have been observed,
which predominantly excite synergistic heteronymous
muscles (cat: Eccles et al., 1957a; Mendell and Henneman,
1971; Fritz et al., 1989; monkey: Clough et al., 1968; Hongo
et al., 1984; man: Pierrot-Deseilligny et al., 1981; Mao et al.,
1984; Meunier et al., 1990; Créange et al., 1992; Cavallari
et al., 1992; Meunier et al., 1993; Cavallari and Katz, 1989).
In foetal and newborn animals more numerous monosynaptic
heteronymous Group Ia projections have been observed than
in adult animals and these have been shown to project widely
to include the motor neurons of non-synergists and direct
antagonists (lambs: Änggård et al., 1961; kitten: Eccles et al.,
1963; rat: Saito, 1979; Seebach and Ziskind-Conhaim, 1994).
With increasing age a marked restriction in heteronymous
primary muscle afferent projections has been observed, in
particular to non-synergistic and antagonistic muscles
(rat: Saito, 1979; Seebach and Ziskind-Conhaim, 1994).
The restriction of heteronymous primary muscle afferent
projections to antagonist muscles has been shown in the
developing rat to be associated with a change from
predominant co-contraction to alternating agonist/antagonist
patterns of muscle contraction (Seebach and ZiskindConhaim, 1994). In the developing human infant the change
in the pattern of muscle contraction from co-contraction to
alternating agonist/antagonist contraction also occurs over
the time period that the restriction of heteronymous primary
muscle afferent projections between biceps and triceps brachii
was observed in the present study (Gatev, 1972; Berger et al.,
1984; Forssberg, 1985; Hadders-Algra et al., 1992).
Short latency heteronymous excitatory responses between
antagonist muscles pairs in the lower limb, have also been
reported, suggesting that reciprocal excitatory reflexes may
be a general phenomenon between agonist/antagonist muscle
pairs following perinatal brain damage (Myklebust et al.,
1982; Leonard et al., 1991). The persistence of such
inappropriate heteronymous excitatory Group Ia projections
in the subjects of the present longitudinal study, who
developed spastic cerebral palsy, implies that early damage
to descending motor pathways disturbed the normal restriction
of heteronymous projections between agonist and antagonist
muscles. The mechanisms underlying the normal focusing
of heteronymous excitatory projections remain largely
unexplored, even in animal studies. Exaggerated responses to
primary muscle afferent input in homonymous and antagonist
motor neurons are likely to play an important role in the
predominance of co-contraction of agonist and antagonist
muscles during voluntary movement observed in subjects
with cerebral palsy.
Acknowledgements
We gratefully acknowledge the support of the Wellcome
Trust and the Spastics Society. We thank Mr Séan Kelly for
his expert technical assistance, and all the subjects, including
the parents of the babies and children involved, who so
willingly gave of their time.
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Received March 10, 1998. Revised June 11, 1998.
Accepted June 25, 1998