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Developmental plasticity connects visual cortex to motoneurons after stroke.

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BRIEF COMMUNICATIONS
Developmental Plasticity
Connects Visual Cortex to
Motoneurons After Stroke
Anna Basu, BM, BCh, PhD,1 Sara Graziadio, PhD,1
Martin Smith, MB, BS, PhD,2
Gavin J. Clowry, DPhil,1 Giovanni Cioni, MD,3 and
Janet A. Eyre, MB, ChB, DPhil1
We report motor cortical function in the left occipital
cortex of a subject who suffered a left middle cerebral artery stroke early in development. Transcranial
magnetic stimulation of the left occipital cortex
evoked contraction of right hand muscles. Electroencephalogram recorded over the left occipital cortex
showed: 1) coherence with electromyogram from a
right hand muscle; 2) a typical sensorimotor Mu
rhythm at rest that was suppressed during contraction
of right hand muscles. This is the first evidence that
cortical plasticity extends beyond reshaping of primary sensory cortical fields to respecification of the
cortical origin of subcortically projecting pathways.
ANN NEUROL 2010;67:132–136
D
evelopmental mechanisms controlling neocortical
areal specialization are under intense study, because
these processes provide the basis for sensory perception,
movement control, and flexibility in behavioral responses
to the environment. Research has focused on primary sensory areas and reveals that although the prototype map for
the cortex is probably defined by gradients in gene transcription factors,1 changes in the relative activity between
sensory systems, associated for example with congenital
blindness or deafness, result in major alterations in primary sensory domain allocation, cortical field size, and
cortical connectivity.2 Here we present the first evidence
From 1Developmental Neuroscience, Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK; 2Oswestry and Birmingham Children’s Hospital, Birmingham, UK; and 3Division of Child Neurology and Psychiatry, University of Pisa, Pisa, Italy and Department of
Developmental Neuroscience, Stella Maris Scientific Institute, Pisa, Italy.
Address correspondence to Prof Eyre, Developmental Neuroscience,
Sir James Spence Institute of Child Health, Royal Victoria Infirmary,
Queen Victoria Road, Newcastle Upon Tyne, NE1 4LP, United Kingdom. E-mail j.a.eyre@ncl.ac.uk
Received Apr 1, 2009, and in revised form Jul 20. Accepted for publication Jul 31, 2009.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21827
132
© 2010 American Neurological Association
in humans that cortical plasticity extends beyond reshaping of primary sensory cortical fields to respecification of
the cortical origin of subcortically projecting pathways. As
part of a larger study of reorganization of the cortex after
stroke, we observed responses in 1 subject in intrinsic
hand muscles of the paretic (right) hand after transcranial
magnetic stimulation of the contralateral occipital cortex.
Direct coupling between the left occipital cortex and spinal alpha-motor neurons innervating hand muscles on the
right side was demonstrated using corticomuscular coherence. Further evidence of the reorganization of the occipital cortex was provided by the presence of a reactive Mu
rhythm, with oscillatory activity peaking in the 8 –12Hz
and 18 –22Hz ranges. This rhythm is characteristic of the
resting sensorimotor cortex, and its suppression reflects
asynchronous neural activation before movement.3
Material and Methods
Patient
L.J. presented at age 8 months with a severe right hemiparesis,
the signs of which had been evolving for 6 months. A right
homonymous hemianopia was also present. His mother had
been hospitalized for 3 days during the mid trimester of pregnancy for dehydration due to vomiting. He was born at term by
spontaneous vaginal delivery, had remained well after birth, and
had no major illness before presentation. Magnetic resonance
imaging of the brain at 10 months and again at 4 years revealed
extensive cystic encephalomalacia involving the territory of the
left middle cerebral artery with associated ipsilateral ventricular
dilatation and relative sparing of the basal ganglia (Fig 1A).
Neurophysiological Recordings
Transcranial magnetic stimulation was performed twice, at 14
and 48 months of age. At 48 months electroencephalographic
(EEG) studies were also performed, because L.J. could be asked
to perform isometric contraction of either the right or left first
dorsal interosseous (FDI) by holding a toy.
For transcranial magnetic stimulation (TMS), a Magstim
200 (Magstim Company Ltd., Whitland, UK) was used with a
figure of eight coil (SPC-ENG 8618, MagStim) following published methods.4 To ensure accurate coil placement, a flexible,
latex-coated nylon 0.5 ⫻ 0.5cm grid was placed on the scalp
and orientated according to anatomical landmarks based on the
International 10-20 system of EEG electrode placement. TMS
was performed during bilateral contraction of the FDI. The active motor threshold was defined as the lowest intensity required
to elicit motor evoked potentials (MEPs) of ⬎50␮V peak to
peak amplitude in 50% of trials in contracting muscle. The onset latency was defined as when the electromyogram (EMG)
clearly deviated by eye from background activity. The shortest
Basu et al: Developmental Plasticity After Stroke
Power spectral density (PSD) for each EEG channel was
estimated during relaxation and immediately before the onset of
unilateral contraction of right FDI (Fig 2; Welch procedure;
256 milliseconds duration, Hanning window, 45 trials). Relative
PSD values for each electrode x were calculated according to the
following equation:
PSD X ⫽
FIGURE 1: (A) T1-weighted magnetic resonance imaging of
the brain at age 4 years showing left middle cerebral artery territory infarction. (B, C) Topography of corticomuscular coherence (CMC) with the electromyogram (EMG) of
the right (paretic) first dorsal interosseus (FDI) (B) at 17Hz,
which is centered over O1 and (C) at 24Hz, which is significant at O1 and C4. (D) Topography of CMC with the
EMG of the left FDI at 24Hz, which is centered over C4.
(E, F) Transcranial magnetic stimulation (TMS) motor
evoked potentials (MEPs) recorded in the EMG of the right
and left FDIs when L.J. was aged 14 months (upper traces)
and 48 months (lower traces) evoked when the TMS coil
was placed (E) over the occipital cortex (O1) and (F) over
the right motor cortex (C4). Stimulation over C4 (F) led to
the expected motor responses in the contralateral (left)
FDI (individual responses shown in black) and also to MEPs
in the ipsilateral (right/paretic) FDI (responses shown in
blue). This is a pattern previously recognized in the motor
supply to the paretic hand in congenital hemiplegia. (E)
Finally and uniquely, stimulation over O1 produced MEPs
in the paretic (right) FDI (red lines) but no MEPs in the
unaffected (left) FDI (black lines). All evoked responses
were of shorter latency at 48 months than at 14 months,
as expected. (G) CMC spectra recorded at O1, showing
significant coherence with the EMG of the right FDI (red
line) but not the left FDI (black line). (H) CMC spectra
recorded at C4 showing significant coherence with the
EMG of the right (blue line) and left (black line) FDI. The
dashed line indicates the upper 95% confidence limits for
a CMC of zero for both (G) and (H).
onset latency of at least 20 MEPs at 1.2⫻ the active motor
threshold (up to a maximum of 100% of stimulator output)
gave the total motor conduction delay (TMCD). Magnetic stimulation using a 5cm circular coil placed over the spines of C5–7
excited spinal motor roots and the longest onset MEP estimated
the peripheral efferent delay (PED). Subtraction of PED from
TMCD estimated the central motor conduction delay.
EEG and EMG were recorded using Neuroscan Synamps
(Compumedics Neuroscan and Compumedics DWL, Abbotsford, Australia) and Ag/AgCl electrodes (SLE2, type MO835,
SLE Ltd., South Croydon, UK). Data were sampled at 1kHz
and bandpass filtered (⫺3dB; 5–100 Hz for EEG; 5–1,500Hz
for EMG). EEG was recorded using electrodes placed at F4, FZ,
F3, C4, CZ, C3, P4, PZ, P3, O2, OZ, and O1 (Fig 2A–C)
with linked ears referencing. EMG was recorded from right and
left FDIs and rectified.
January, 2010
冘
f
共PSD X C共 f 兲 ⫺ PSD X R共 f 兲兲
冘
f
PSD X R共 f 兲
where f is frequency, c is during contraction, and r is at rest.
Topographical PSD maps were generated to determine the spatial distribution of PSD (Fig 2E).
Corticomuscular coherence (CMC) was calculated 5 (211
trials, 1,024 milliseconds duration, Hanning window, no overlap) during contraction of either right or left FDI. The upper
FIGURE 2: (A–C) Electroencephalogram (EEG) and electromyogram (EMG) recorded with eyes open (A) at rest and
(C) during contraction of the right first dorsal interosseus
(FDI). Arrows point to (B) EEG montage following the International 10-20 system for EEG electrode placement. The
blue solid line arrow in (A) points to electrode C4, which
shows oscillatory activity peaking at around 10Hz and
around 20Hz during rest (Mu rhythm), and the blue dashed
line arrow in (C) shows diminished 10 and 20Hz oscillatory
activity during contraction of the right FDI, indicating suppression of the Mu rhythm over the intact sensorimotor
cortex. The red solid line arrow and dashed line arrow
indicate electrode O1, which also shows a Mu rhythm at
rest and its suppression during contraction of the right FDI
supporting the transformation of the left occipital cortex
into sensorimotor. Red vertical scale bar: EEG ⴝ 200␮V;
EMG ⴝ 2mV. (D) Power spectral density (PSD) of EEG recorded at O1 (red) and C4 (blue); solid lines show the PSD
during rest, demonstrating a typical Mu pattern at both
electrodes with oscillatory activity peaking in the 8 –12Hz
and 18 –22Hz ranges; dashed lines show the PSD immediately before and during contraction of the right FDI, demonstrating suppression of the Mu rhythm at both C4 and
O1. (E) Topography of the suppression of power in the
frequency band 8 –13Hz, showing maximal suppression occurring over O1 and also suppression occurring over C4.
Note: volume conduction leads to the recording of a lowamplitude Mu rhythm, and its apparent suppression during
contraction over the left cortical area, which is infarcted.
133
ANNALS
of Neurology
95% confidence limit for a CMC of zero was used to determine
significance (Fig 1G and H). Topographical maps of CMC values at the frequencies of the maximum peaks of CMC were then
generated (Fig 1B–D).
Results
TMS
At both ages, MEPs were obtained following TMS over 2
scalp sites, C4 and O1. TMS over C4 evoked MEPs in
both left and right FDI with similar onset latencies (Fig
1F; Table). TMS over O1 evoked MEPs in the right FDI
only (Fig 1E; Table).
EEG Mu Rhythm Suppression
A typical Mu rhythm was recorded over C4 and O1 at
rest (Fig 2A and D), and was no longer evident 1–2 seconds before contraction of the right FDI (Fig 2C and D).
Topographical maps of the spatial distribution showed
that suppression was maximal over the left occipital cortex
(O1) and occurred also over the right sensorimotor cortex
(C4; Fig 2E).
CMC
Significant CMC was observed at 2 scalp sites, C4 and
O1. At C4, CMC was significant with the EMG of both
right and left FDIs and peaked at 24Hz for both muscles
(Fig 1C, D, and H). At O1, CMC was significant with
the EMG of the right FDI only and peaked at 17Hz and
24Hz (Fig 1B, C, and G).
Discussion
Our findings corroborate numerous reports of ipsilateral
motor cortex involvement in control of the paretic arm and
hand in subjects with hemiplegic cerebral palsy. Persistence
of fast-conducting ipsilateral corticospinal projections from
the noninfarcted motor cortex, which normally would have
been withdrawn during development,4 and focal cortico-
muscular coherence over the ipsilateral motor cortex have
been demonstrated previously.6 That the contralateral occipital cortex can also control movement of the paretic
hand has not been reported previously in humans or animal models. Three lines of evidence substantiate the development of a functioning motor cortex in the left occipital
cortex with axonal projections to motoneurons. First, focal
TMS of the left occipital cortex evoked MEPs unilaterally
in the right hand. Stimulation of the occipital cortex evokes
phosphenes in normal subjects and paresthesia3 in the congenitally blind,7,8 but MEPs have not been reported, nor
have they been observed previously by ourselves despite extensive studies mapping the origin of the corticospinal tract
in babies, children, and young and elderly adults. TMS excites neural axons by electromagnetic induction, and only
axons in the cortex immediately below the coil are excited.9
Therefore, excitation of brainstem motor pathways is an
unlikely explanation for our findings, because they lie too
far below the scalp to be excited directly and, with the exception of the rubrospinal pathway, which is virtually absent in the human brain,10 innervate the spinal cord and
excite muscles bilaterally.10,11 Second, significant, focal
CMC between EEG recorded over the left occipital cortex
(O1) and EMG recorded over the right FDI indicates a
constant phase relationship between their oscillations and
therefore a direct connection between the occipital cortex
and spinal motoneurons.6,12 Finally, a Mu rhythm recorded focally in the EEG over the left occipital cortex
(O1), was suppressed before and during unilateral contraction of right hand muscles. The Mu rhythm is characteristic of the resting sensorimotor cortex, and its suppression
reflects asynchronous neural activation before movement.3
The primary motor cortex and the occipital cortex
are the principal sources of the major subcortical pathways to the spinal cord (corticospinal pathway) and superior colliculus (corticotectal pathway), respectively. Studies
TABLE: Summary of the Characteristics of the MEPs Evoked by TMS Over C4 and O1
Muscle
Age, mo
PED, ms
Scalp Position
Threshold, %
TMCD, ms
CMCD, ms
Left FDI
14
48
14
10.1
11.5
10.3
48
11.5
C4
C4
C4
O1
C4
O1
100
75
100
100
80
90
20.2
16.1
22.8
21.7
17.8
18.9
10.1
4.6
12.5
11.4
6.4
7.4
Right FDI
MEP ⫽ motor evoked potential; TMS ⫽ transcranial magnetic stimulation; PED ⫽ peripheral efferent delay; Threshold ⫽
active motor threshold; TMCD ⫽ total motor conduction delay; CMCD ⫽ central motor conduction delay; FDI ⫽ first dorsal
interosseous.
134
Volume 67, No. 1
Basu et al: Developmental Plasticity After Stroke
in rodents have shown that initially each pathway innervates both the spinal cord and superior colliculus. Target
specificity is established later by selective withdrawal of
occipital cortical axon collaterals from the spinal cord and
of motor cortical projections to the superior colliculus.13
Such cortical areal specificity is not genetically predetermined; occipital neurons transplanted to the presumptive
motor cortex early in development will ultimately maintain corticospinal connections, withdrawing those to superior colliculus and vice versa for presumptive motor
cortex neurons transplanted to the occipital cortex.14 Occipitospinal axons establish transient synapses with their
spinal targets,15 and are responsive to their retrograde trophic effects, because the projection is retained if fetal tectal tissue is transplanted to the spinal cord before selective
axonal withdrawal begins.16
The development of the corticospinal projection has
been studied most extensively in rodents. The occipital
projection to the spinal cord is most prominent at the end
of the first postnatal week in rodents (roughly equivalent
to 25 weeks gestation in humans).17 Subsequent withdrawal of the occipitospinal collaterals occurs in the second postnatal week and is complete by P18 (roughly
equivalent to the neonatal stage in humans).18 We can
only speculate as to the timing of L.J.’s lesion, which
must by definition be classified as a presumed perinatal
ischemic stroke,19 but the potential timescale from 20
weeks fetal life to 28 days postnatally maps to the developmental period in which occipitospinal projections are
formed and then withdrawn in rodent studies.
We hypothesize that infarction of the left optic radiations isolated the immature left occipital cortex from afferent visual information, as evidenced by the hemianopia.
Concurrently, infarction of the left sensorimotor cortex and
loss of its projections to the spinal cord led to occipitospinal axons establishing a greater number of synapses in the
spinal cord because of reduced activity-dependent competition for synaptic space4 and compensatory homeostatic reinforcement of excitatory input to spinal neurons.20 Increased retrograde signaling from the spinal cord could
then have counteracted any genetically programmed instruction to occipital neurons to withdraw axons projecting
to the spinal cord.21 The remarkable transformation of the
presumptive visual cortex into a motor cortex implies that
retrograde information from the spinal cord may be involved in cortical areal specification, thereby involving the
spinal cord in the development of its own command structure in a manner analogous to thalamocortical afferents
shaping the formation of their cortical processing circuitry.
This would have important implications for brain development and plasticity, and may open up the opportunity for
January, 2010
new rehabilitation strategies targeting retrograde signaling
mechanisms from muscles, nerves, and spinal cord to promote cortical plasticity and reorganization after sensorimotor cortical injury.22
This study was supported by a program grant from the
Wellcome Trust to J.A.E. and G.J.C.
We thank L.J. and his family.
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Contractures and
Hypertrophic Cardiomyopathy
in a Novel FHL1 Mutation
Hans Knoblauch, MD,1 Christian Geier, MD,2
Stephanie Adams, MD,1 Birgit Budde, PhD,3
André Rudolph, MD,4 Ute Zacharias, PhD,1
Jeannette Schulz-Menger, MD,4
Andreas Spuler, MD,5 Rabah Ben Yaou, MD,6
Peter Nürnberg, MD,3 Thomas Voit, MD,6
Gisele Bonne, PhD,6 and Simone Spuler, MD1
We investigated a large German family (n ⫽ 37) with
male members who had contractures, rigid spine syndrome, and hypertrophic cardiomyopathy. Muscle
weakness or atrophy was not prominent in affected
individuals. Muscle biopsy disclosed a myopathic pattern with cytoplasmic bodies. We used microsatellite
markers and found linkage to a locus at Xq26-28, a
region harboring the FHL1 gene. We sequenced FHL1
1
From the Muscle Research Unit, Experimental and Clinical Research
Center, Charité University Medicine Berlin; 2Department of Cardiology, Virchow Klinikum, Charité University Medicine Berlin, Berlin; 3Cologne Center for Genomics, Cologne; 4Department of Cardiology,
HELIOS-Klinikum Berlin; 5Department of Neurosurgery, HELIOSKlinikum Berlin, Berlin, Germany; and 6Institut de Myologie, University
Marie et Pierre Curie, Paris, France.
Address correspondence to Dr Spuler, Muscle Research Unit, Experimental and Clinical Research Center, Charité University Medicine Berlin, Lindenberger Weg 80, 13125 Berlin, Germany. E-mail:
simone.spuler@charite.de
Received May 21, 2009, and in revised form Jul 24. Accepted for
publication Aug 11, 2009.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21839
Additional Supporting Information may be found in the online version
of this article.
136
and identified a new missense mutation within the
third LIM domain that replaces a highly conserved
cysteine by an arginine (c.625T⬎C; p.C209R). Our
finding expands the phenotypic spectrum of the recently identified FHL1-associated myopathies and widens the differential diagnosis of Emery–Dreifuss–like
syndromes.
ANN NEUROL 2010;67:136 –140
L
“
IM domains,” named after their initial discovery in
the proteins Lin11, Isl-1, and Mec-3, are protein
structural domains composed of two contiguous zinc finger domains separated by a two-amino acid residue hydrophobic linker. Recently, mutations in the gene encoding the “four-and-a-half” LIM-domain protein (FHL1)
have been identified resulting in human reducing body
myopathy, scapuloperoneal myopathy, and postural muscular atrophy with generalized muscle hypertrophy.1–3
FHL1 proteins are a small family of LIM-only proteins
that are highly expressed in skeletal muscle and heart.
LIM domains feature cysteine-rich tandem-zinc fingers
that are involved in protein-protein interaction.4 FHL1 is
involved in mechanical sensing within the sarcomere and
also in transcriptional regulation. Three splice variants of
FHL1 (FHL1a, FHL1b, and FHL1c [identical to
KyoT2]) exist, all of which contain the N-terminal twoand-a-half LIM domains; however, LIM domains 3 and 4
are absent in FHL1c. Most known protein-binding partners of FHL1 bind to the second LIM domain, such as
Raf1, MEK2, or ERK2. FHL1 mutations leading to the
severe phenotypes of reducing body myopathy are also localized in the second LIM domain. We describe here a
novel mutation within the third LIM domain of FHL1.
Our finding expands the known clinical phenotypes to
include an Emery–Dreifuss–like syndrome.
Subjects and Methods
Index patients of a large German family presented with contractures of the Achilles tendon and cardiac left ventricular hypertrophy. We examined 35 members of this family. Twenty-eight
underwent cardiac magnetic resonance imaging, all had electrocardiograms done, and 31 were included in the genetic analysis.
Three patients underwent a muscle biopsy. Our internal review
board approved the studies, and written, informed consent was
obtained. Two members of this family were reported earlier but
died before this investigation.5
Results
Clinical Examination, Genetic Studies, and
Muscle Pathology
The pedigree is shown in Figure A. The clinical findings
are summarized in the Table. Nine male patients, 14 to
60 years old, presented with contractures at the ankle or
knee, or both, and rigid spine syndrome, as shown in FigVolume 67, No. 1
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