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Ataxia after pontine stroke Insights from pontocerebellar fibers in monkey.

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Ataxia after Pontine Stroke:
Insights from Pontocerebellar
Fibers in Monkey
Jeremy D. Schmahmann, MD,1 Douglas L. Rosene, PhD,2
and Deepak N. Pandya, MD2
the basis pontis to the contralateral middle cerebellar
peduncle. This level of fiber system analysis can be addressed only by an experimental tract tracing study,
and we therefore evaluated the trajectory of the pontocerebellar fibers in rhesus monkey using the isotope autoradiographic technique.
Materials and Methods
Basis pontis lacunes cause contralateral but rarely ipsilateral ataxia. We explored this phenomenon with isotope
tract tracing in the rhesus monkey. Labeled pontocerebellar fibers cross midline and disperse widely in the opposite hemipons before coalescing in the brachium pontis.
This anatomical arrangement suggests that small pontine
strokes spare sufficient decussating pontocerebellar fibers
to prevent ipsilateral dysmetria, and that ipsilateral dysmetria after large pontine stroke represents a disconnection syndrome.
Ann Neurol 2004;55:585–589
Lacunar infarction in the mid- and caudal pons causes
contralateral weakness and incoordination, that is,
ataxic hemiparesis.1– 6 Fisher and Cole2 hypothesized
that the contralateral weakness results from disruption
of corticospinal fibers, whereas contralateral dysmetria
is a consequence of damage to pontine neurons or their
axons.
There is an unresolved conundrum in this clinical
scenario. If the pontine lesion produces contralateral
dysmetria because of damage to pontocerebellar fibers
crossing to the opposite cerebellar hemisphere, then the
same lesion should disrupt pontocerebellar fibers from
the unaffected side that are coursing through the lesion, and there should be dysmetria on the side ipsilateral to the lesion. However, ipsilateral dysmetria is seldom present in ataxic hemiparesis and its related
disorders including dysarthria clumsy hand syndrome
and dysarthria-dysmetria4,7,8 and in our series6 occurred only when the pontine lesion was large and associated with contralateral hemiplegia.
This suggested to us that the explanation may lie in
the course of the pontocerebellar fibers as they traverse
From the 1Department of Neurology, Massachusetts General Hospital and Harvard Medical School; and 2Department of Anatomy
and Neurobiology, Boston University School of Medicine, Boston,
MA.
Received Nov 11, 2003, and in revised form Nov 13. Accepted for
publication Jan 14, 2004.
Published online Mar 22, 2004, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20060
Address correspondence to Dr Schmahmann, Department of Neurology, VBK 915, Massachusetts General Hospital, Fruit Street,
Boston, MA 02114. E-mail: jschmahmann@partners.org
A rhesus monkey was sedated (ketamine hydrochloride,
10mg/kg IM) and placed in a stereotactic head frame compatible with magnetic resonance imaging (MRI). The target
injection site in the dorsolateral pontine region was determined using a 1.5T GE MRI Scanner with threedimensional spoiled gradient echo pulse (SPGR) sequences
in sagittal and axial planes, TR 70, TE 8, FOV 24, NEX 1,
that generated 1.3mm-thick slices with no gap. One week
later, the animal was anesthetized (sodium pentobarbital,
15mg/kg IV) and placed in the stereotactic apparatus, a midline craniotomy was performed and a dural flap reflected one
on side. A 5␮l Hamilton syringe filled with mineral oil was
coupled with polyvinyl chloride tubing to a 30-gauge stainless steel injection cannula that was advanced through the
cerebral hemisphere using a stereotactic manipulator toward
the target coordinates. The tracer consisted of tritiated amino
acids (leucine, lysine, proline, and an algal protein hydrolysate [New England Nuclear, Boston, MA], concentration
100␮Ci/␮l, injected amount 0.40␮l or 40␮Ci). To prevent
backflow of tracer up the needle track after the injection was
completed, we sealed the cannula, cemented it to the skull
using dental acrylic secured with stainless steel screws, and
left it in the brain until after the animal was perfused.
The animal recovered fully from the surgery and injection
procedure, and 7 days later it was anesthetized and perfused
transcardially with formaldehyde (2L, 4.0%). The brain was
blocked in situ in the coronal stereotactic plane, the brainstem was separated at the intercollicular level, and the blocks
were postfixed in 10% formalin for 1 week and embedded in
paraffin. The pons was sectioned at a thickness of 10␮m in
the axial plane perpendicular to the long axis of the brainstem and mounted onto gelatin-subbed slides. Sections were
deparaffinized in xylene, hydrated through graded alcohols to
distilled water, dip-coated in nuclear emulsion (Kodak
NTB-2, diluted 1:1 with distilled water), stored with desiccant in light-tight boxes, and exposed for 16 weeks. The
emulsion was developed in Kodak D19, fixed with Rapid
Fix, and stained with thionin. The slides were dehydrated,
cleared. and cover-slipped with Permount.9
The injection sites and labeled axons in the pons were
viewed under light- and dark-field microscopy using a Nikon
Eclipse E800 microscope. The images were photographed using a Spot Camera and Adobe Photoshop software.
All procedures were approved by the Massachusetts General Hospital Subcommittee on Animal Research and adhered to guidelines of the National Research Council Guide
for the Care and Use of Laboratory Animals, 1996.
Results
The isotope injection was concentrated in the dorsolateral part of the rostral third of the basis pontis in levels
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
585
I to III (Figs 1 and 2A) and involved the lateral and
dorsal parts of the peripeduncular nucleus, the dorsolateral nucleus, and the adjacent regions of the lateral
and the dorsal nuclei (nomenclature of Nyby and
Jansen10 and Schmahmann and Pandya11).
Labeled pontocerebellar fibers emanated from the in-
Fig 1. Dark-field photomicrographs with partial light-field illumination of pontine levels I through V (of nine possible transverse
levels according to Nyby and Jansen10 and Schmahmann and Pandya11). A schematic view of the lateral aspect of the pons (top)
illustrates the levels from which the pontine sections below are derived. The injection site of the radiolabeled amino acids is seen in
the dorsolateral parts of the peripeduncular nucleus and the dorsolateral nucleus of the basis pontis of a rhesus monkey. Pontocerebellar fibers emanate from the injection site and fan out in the contralateral hemipons as they course toward the middle cerebellar
peduncle, and into the posterior lobe of the cerebellum (not shown). Pontine level I is seen in A, II in B, adjacent sections of level
III in C and D, level IV in E, and level V in F. Magnification ⫻0.5; Bar ⫽ 5.0mm.
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Fig 2. Dark-field photomicrographs with partial light-field illumination of pons level 1 to depict the course of the fibers from the
isotope injection site in the rostral pons. A low-power view of the pons is seen in A (magnification ⫻0.5; Bar ⫽ 5.0mm), with
labeled fibers in designated areas shown at higher power in B, C, and D (magnification ⫻4; Bar ⫽0.5 mm).
jection site, situated within the confines of the transversely oriented fiber bundles in the dorsal part of the
peripeduncular nucleus in level I and II, and the dorsal
pontine nucleus in level III. They traversed the paramedian and dorsomedial nuclei and crossed through
the median pontine nucleus in the midline to the opposite hemipons. The course of the fibers then changed
abruptly and spread out in several directions (see Figs
1A–D and 2A,C). One contingent of labeled fibers
continued within the transverse pontocerebellar fibers
in the dorsal part of the peripeduncular nucleus and
the dorsal nucleus. Another coursed ventrally in the
pontocerebellar fibers in the ventral pontine nucleus. A
third group fanned out and coursed through the multiple avenues occupied by the transverse fibers interspersed in the intrapeduncular nucleus. At the lateral
aspect of the hemipons on the side opposite to, but at
the same rostrocaudal level as the injection site, the fibers regrouped to form a concentrated collection
within the white matter (brachium pontis) that descended to pontine levels IV and V before they coursed
in the middle cerebellar peduncle to enter the cerebellar hemisphere opposite the pontine injection.
Discussion
Anatomical studies in the monkey have investigated the
organization of cerebral projections to the basis pontis10 –15 and the projections to cerebellum from the
pontine neurons,16,17 but there is essentially no information currently available concerning the course of the
pontocerebellar fibers within the pons.
Gerrits and Voogd18 placed isotope in the nucleus
reticularis tegmenti pontis, and one illustration in that
report (p. 32) suggests that pontocerebellar fibers travel
through the opposite hemipons in multiple widely dispersed channels. The results of the present investigation demonstrate that pontocerebellar fibers emanating
from the dorsolateral pontine region course horizon-
Schmahmann et al: Pontocerebellar Fibers
587
tally in a focused aggregate toward the midline but fan
out in multiple directions to travel in most of the
transverse pontocerebellar fiber bundles of the contralateral hemipons before regrouping in the brachium
pontis.
This anatomic arrangement characterized by the distribution of pontocerebellar fibers across the entire extent of the opposite side of the basis pontis at approximately the same rostrocaudal level (Fig 3A) provides a
compelling explanation for the clinical observations fol-
Fig 3. Schematic diagram of the motor consequences of basis pontis infarction. A ventral view of the monkey pons is shown with
the median, paramedian, and peduncular pontine nuclei represented. Partial views of coronal sections of human cerebellum are seen
on either side. (A) Normal arrangement, showing the pontine neurons, pontocerebellar fibers, and descending corticofugal pathways
to spinal cord. (B) Anatomical and clinical consequences following a small lesion in the basis pontis (shaded black area). Some
pontine neurons are destroyed (marked by X), and the pontocerebellar fibers emanating from the lesioned neurons are affected (dotted lines). Pontocerebellar fibers arising from neurons in the contralateral hemipons are interrupted by the lesion (dashed lines), as
are the descending corticofugal fibers. (C)Large pontine lesions (shaded black area) destroy many pontine neurons and descending
corticofugal fibers and interrupt most of the pontocerebellar fibers traveling through the lesion from the normal hemipons.
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lowing pontine lacunes. Ataxic hemiparesis of the contralateral extremities results from a focal lesion in the
middle or caudal pons that destroys descending corticofugal fibers as well as adjacent pontine neurons and
their pontocerebellar axons.1,3–7 The hemiparesis certainly results from involvement of the descending corticospinal fibers. Fisher proposed2,3 that dysmetria is a
consequence of damage to the pontine neurons or their
axons (see Fig 3B). Pontine neurons are implicated in
contralateral dysmetria because they are the obligatory
synaptic step in the feedforward limb of the cerebrocerebellar system, but the role of the pontocerebellar
fibers is uncertain because of the difficulty reconciling
involvement of these fibers with the rarity of ipsilateral
dysmetria.
Our study indicates that dysmetria does not usually
manifest on the side ipsilateral to pontine lacunes because sufficient pontocerebellar fibers traversing from
the nonlesioned hemipons are left intact to prevent this
(see Fig 3B). The nonlesioned pons retains the ability
to transmit information to the cerebellum through the
side of the pons on which a small lesion is located, by
virtue of a combination of anatomic features. First,
projections from each cortical area terminate in multiple discrete patches within different rostral-caudal levels of the pons with pontine topography unique to that
cortical area.11,12,15 Second, as shown here, pontocerebellar fibers are transmitted to the opposite hemipons
at approximately the same rostral-caudal level as the
neurons from which they arise, and there is divergence
of the fibers within the transverse plane in the opposite
hemipons. A small lesion is not sufficient to disrupt
this line of communication severely enough to produce
the ipsilateral clinical deficit; a much larger lesion is
required to achieve that end.
In agreement with earlier observations,5,19 in our series6 ipsilateral dysmetria occurred only in the setting of
large hemipontine infarction that produced contralateral
hemiplegia. Dysmetria ipsilateral to the stroke thus results from the complete or near-complete disruption of
pontocerebellar fibers from the intact pons as they attempt to course through the lesion (see Fig 3C). In this
sense, ipsilateral dysmetria represents a disconnection
syndrome, as envisaged by Geschwind for white matter
lesions in the cerebral hemispheres,20 in that the clinical
features result from loss of the fiber pathway connection
between the intact neurons of the pons and their intended target in the contralateral cerebellum.
Our results also provide insights into the pathophysiology of dysmetria contralateral to pontine lacunes. If
disruption of a subset of pontocerebellar fibers from
the nonlesioned side traveling through the stroke is insufficient to produce ipsilateral dysmetria, then it is
reasonable to conclude that damage to the pontine
neurons themselves, rather than their pontocerebellar
fibers, produces the contralateral dysmetria.
This work was supported by the McDonnell-Pew Program in Cognitive Neuroscience, the Aaron J. Berman Neurosurgical Research
Fund, and the Birmingham Foundation (J.D.S.).
C. DeMong and J. MacMore provided invaluable assistance.
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