A case of polymicrogyria in macaque monkey: impact on anatomy and function of the motor system
- Eric Schmidlin†1Email author,
- Christophe Jouffrais†1, 2,
- Patrick Freund1,
- Patrizia Wannier-Morino1,
- Marie-Laure Beaud1,
- Eric M Rouiller1 and
- Thierry Wannier1
© Schmidlin et al; licensee BioMed Central Ltd. 2009
Received: 10 February 2009
Accepted: 23 December 2009
Published: 23 December 2009
Polymicrogyria is a malformation of the cerebral cortex often resulting in epilepsy or mental retardation. It remains unclear whether this pathology affects the structure and function of the corticospinal (CS) system. The anatomy and histology of the brain of one macaque monkey exhibiting a spontaneous polymicrogyria (PMG monkey) were examined and compared to the brain of normal monkeys. The CS tract was labelled by injecting a neuronal tracer (BDA) unilaterally in a region where low intensity electrical microstimulation elicited contralateral hand movements (presumably the primary motor cortex in the PMG monkey).
The examination of the brain showed a large number of microgyri at macro- and microscopic levels, covering mainly the frontoparietal regions. The layered cortical organization was locally disrupted and the number of SMI-32 stained pyramidal neurons in the cortical layer III of the presumed motor cortex was reduced. We compared the distribution of labelled CS axons in the PMG monkey at spinal cervical level C5. The cumulated length of CS axon arbors in the spinal grey matter was not significantly different in the PMG monkey. In the red nucleus, numerous neurons presented large vesicles. We also assessed its motor performances by comparing its capacity to execute a complex reach and grasp behavioral task. The PMG monkey exhibited an increase of reaction time without any modification of other motor parameters, an observation in line with a normal CS tract organisation.
In spite of substantial cortical malformations in the frontal and parietal lobes, the PMG monkey exhibits surprisingly normal structure and function of the corticospinal system.
Polymicrogyria is a developmental malformation of the cerebral cortex, characterized by multiple small gyri with abnormal cortical lamination . PMG can be unilateral or bilateral and its extent varies from focal PMG in otherwise normal brain to diffuse PMG with multiple other brain abnormalities. The spectrum of clinical manifestations ranges from normal individuals, with only selective impairment of cognitive function  and no or easily controlled epilepsy, to patients with severe encephalopathy and intractable epilepsy . Motor and cognitive deficits such as a delay in development , or congenital contractures  are commonly described in patients suffering from PMG. Microscopically, two histological types of PMG were recognized: a simplified four layered form and an unlayered form . The two types of PMG may coexist in contiguous cortical areas . Recent report provides evidence that PMG areas are functional .
The present report describes a case of spontaneously occurring PMG in a macaque monkey for which tracing of corticospinal projections had been obtained. Moreover, the animal was involved in a study on the mechanisms of bimanual coordination, and its PMG was discovered after sacrifice. The first goal of the present report was to present in more details the general morphological traits of the PMG brain. More specifically, we sought to establish which brain regions and how the laminar pattern of the cerebral cortex have been affected by the PMG. In human patients with a unilateral PMG, the CS tract originating from the affected hemisphere presented an altered structure in DTI and fMRI investigations . The second aim of the present case report in monkeys was to evaluate whether the cortical malformations affected the characteristics of the corticospinal projections. For this purpose, the anterograde tracer Biotinylated Dextran Amine (BDA) was injected unilaterally in the electrophysiologically identified hand representation of the presumed primary motor cortex. Finally, the motor capacity of the PGM macaque was compared with that of a normal macaque monkey, both trained to perform the same motor task, namely a modified version of the so-called "reach and grasp drawer" task .
The PMG monkey described in this study is the only case of cortical malformation ever observed in our laboratory.
1) Cortical structure
When compared to normal monkeys (Mk-IU, Mk-I2 and Mk-IZ), the frequency of sulci measured on coronal sections in the fronto-parietal as well as in the ventro-temporal cortical regions was significantly higher in the PMG monkey (p < 0.05, Mann and Whitney with Bonferroni correction for multiple comparisons). Furthermore, in the PMG monkey, the frequency of sulci in the fronto-parietal cortex was nearly twice as high than that of the ventro-temporal region (Fig. 2F; p < 0.05, Mann-Whitney). No statistically significant difference was observed in the three normal monkeys. These differences do not reflect changes in the volume of the cortex, as at a comparable rostro-caudal position, the measured distance between the corpus callosum and the external part of the lateral fissure is similar among all animals.
In contrast to the few SMI-32 positive neurons detected in layer III of the presumed M1 area of the PMG-monkey, injections of BDA in this cortical region in the left hemisphere stained a large number of fibers in the corpus callosum (Fig. 2G) and several retrogradely labelled neurons were found in the right hemisphere in the frontal lobe. This observation suggests that a significant number of pyramidal neurons in lamina III are present, but do not express the neurofilament recognized by the SMI-32 antibody. As the cortical structure of the PMG brain is also disturbed in the contralateral side, it was not possible to assess the exact areas where projections were terminating and where callosal neurons were stained.
2) The corticospinal (CS) projection
2a) Crossed versus uncrossed CS projections
2b) Density of CS axonal arbors in the grey matter
Quantitative anatomical data for the CS tract tracing.
Volume of BDA
Injected in M1 in μl
Number of BDA
(in days) cumulated
Number of BDA-labelled CS axons at C5 in white matter
% of uncrossed CS axons at C5
Normalized axon arbor length at C5 per section
Normalized number of axonal arbors crossing midline at C5
2c) CS axons crossing the midline at C5
We examined the same material to determine whether BDA-labelled CS axon collaterals crossed the midline in the grey matter (see methods). The number of CS axons crossing the midline at C5 in each monkey was normalized to the total number of labelled CS axons, in the white matter. On average, the PMG monkey exhibited a higher number of midline crossing CS axons, comprised within the range found in normal monkeys (Fig. 6E).
3) Magnocellular part of the red nucleus (RNm)
4) Intracortical microstimulation and manual dexterity data
During the two years of behavioral training and single neuron recording, no deficit in learning and executing the demanding reach and grasp drawer task was detected in the PMG monkey, the pathology being discovered post-mortem.
The extracellular single neuron activities recorded in motor areas of the left hemisphere while the PMG monkey performed the reach and grasp drawer task were similar to those obtained in normal monkeys. Epileptic seizures were never observed.
The present case of brain malformation in a macaque monkey can be diagnosed as a PMG according to previously reported criteria, namely disorganized cortical gyri in excessive number in both hemispheres and local loss of laminar organization in the frontal and parietal cortices . According to the extent of the cortical malformation, the PMG corresponds to a bilateral frontoparietal polymicrogyria (BFPP), sparing most parts of the occipital and the temporal lobes, at both macro- and microscopic levels.
However, in the PMG monkey, the cortical region stereotaxically corresponding to the motor cortex of normal monkey contained large pyramidal neurons in layer V, giving rise to corticospinal projections. Moreover, ICMS in this region elicited movements at current thresholds similar to those reported for the motor cortex of normal monkeys [12, 13].
In contrast to normal monkeys, only few SMI-32 positive layer III pyramidal neurons were present in the motor cortex of the PMG monkey. Despite the loss of SMI-32 staining in layer III in the motor cortical region, interhemispheric connections were seen between the left hemisphere (BDA- injections) and the right hemisphere (BDA labelled fibers in the Corpus Callosum and labelled neurons in the frontal lobe). As interhemispheric projections originate mostly from layer III pyramidal neurons, their presence in Mk-PM indicates that the loss of SMI-32 staining rather corresponds to a phenotypical change of layer III pyramidal neurons than to an absence of such cells.
The small but significant difference in soma size of layer V SMI-32 positive neurons observed between both hemispheres could result from observations made in somatotopically different regions. Due to the cortical disorganization in Mk-PM, it is difficult to ascertain that two regions equivalently located on both hemispheres project to the same level of the spinal cord .
After BDA injections in the ICMS identified hand area in M1, a large number of BDA stained axons were observed in the white matter at cervical levels. Their distribution and density were similar to that of normal monkeys , indicating that the basic structure of the corticospinal tract was preserved in the PMG monkey. This observation contrasts with recent imaging reports showing a decreased density of CS projections in patients suffering from PMG affecting only one hemisphere [9, 16]. PMG is essentially a cortical malformation. Macroscopically, the subcortical structures appear entirely normal (Fig. 2). However, one cannot exclude some minor, microscopical changes in subcortical structures, as indeed found with the large number of vesicles observed in RNm neurones. The soma size of SMI-32 positive neurons in the RNm of the PMG monkey was however in the same range of that reported for normal monkeys . As no motor impairment was observed, we have no direct indication that the histological changes that we observed in some RNm neurons altered the function of the red nucleus.
The absence of epileptic episodes in the PMG monkey contrasts with the study of Chang and colleagues  where all patients showed epileptic seizures or cognitive delays at different levels of severity, but is in line with the study of Teixeira and colleagues , where a majority of 40 patients diagnosed as suffering from PMG presented normal EEG recordings. The difference observed between these two studies in human subjects may be due to the heterogeneity of the localization of the cortical malformation.
The present study reports on a PMG monkey engaged in a sophisticated conditional delayed motor task (requiring 6-12 months training), comprising four conditional behavioral responses instructed by 4 visual cues, with a direct comparison to a normal monkey engaged simultaneously in the same behavioral task. The most striking observation is that the PMG monkey, in spite of considerable malformation of the cerebral cortex (Figs. 1, 2, 3, 4), performs apparently as well as the normal monkey, both in terms of training curve and stabilized motor performance after training. However, the behavioral data derived from the reach and grasp drawer task showed that the PMG monkey (Mk-PM) had significantly longer RTs than the normal monkeys (Fig. 9A). Nevertheless, after initiation of the movement sequence, the time intervals between different movement components of the overall motor response did not show any systematic variation (longer or shorter). Indeed, the first reaching time (interval between movement onset and drawer knob grasping) in the unimanual task was longer in the PMG monkey but the pulling time (opening of the drawer), the second reaching time and the grasping time were slightly shorter (Fig. 9B). This observation of "normal" motor control in the PMG monkey is in line with a generally normal organization of its corticospinal tract (Fig. 6). Furthermore, "normal" motor control in the PMG monkey is also consistent with the electrophysiological data, namely the presence of low (normal) threshold ICMS effects observed in the presumed hand area of the primary motor cortex (Fig. 8). The latter ICMS data are also coherent with a normal density and appearance of large pyramidal neurons in layer V in the presumed motor cortex in the PMG monkey, as seen in SMI-32 staining (Fig. 4).
The significantly prolonged RTs in the PMG monkey may be associated to a deficit of attention. It has been shown that, in a delayed conditional task instructed with visual cue signals and requiring discrimination of a specific stimulus among irrelevant distracters, attention is under the control of top-down inputs from the lateral prefrontal cortex onto visual cortical areas . The authors found a significant increase of RTs in the task after lesion of the lateral prefrontal cortex. In the present case, as the PMG involved the frontal lobe, the lateral prefrontal cortex may be affected, leading to a deficit of attention. Along this line, the disorganization of some cortical layers, and the decrease of the density of SMI-32 positive neurons in layer III (Fig. 4C), suggests that some cortico-cortical interactions may be abnormal in the PMG monkey.
Overall, these data suggest that the PMG pathology may have affected some cortico-cortical connections (crucial for attention), but not the corticospinal projection as indicated by normal motor control in a well trained behavioral task.
The data were derived from eleven young adults (2-9 years old) macaque monkeys (Macaca mulatta or fascicularis, of either sex, weighing from 3.0 to 9.0 kg, see Table 2). Monkeys Mk-IG, Mk-IE, Mk-IRh, Mk-IR, and Mk-IZ were involved in previously published studies [17, 20]. Surgical procedures and animal care were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (ISBN 0-309-05377-3; 1996) and approved by local (Swiss) veterinary authorities. Details on the sacrifice of the animals at the end of the experiments and on histological processing are available in Additional file 1.
The PMG monkey (Mk-PM) and a normal monkey (Mk-IU) were enrolled in a conditional delayed bimanual dexterity task (see additional files 1 and 2 and additional Fig. S1), corresponding to a modified and more complex version of the so-called "reach and grasp drawer task" [10, 21–23]. In order to locate the hand representation of the primary motor cortex (M1), an intracortical microstimulation (ICMS) mapping was performed, as described in detail earlier [13, 24–28].
In the PMG monkey and three normal monkeys, a craniotomy provided access to the cerebral cortex, allowing injections of the tracer BDA at physiologically defined loci in the M1 hand area of one hemisphere. Under propofol anaesthesia (Disoprivan, 3 mg/kg/h, i.v.), the craniotomy was performed in those four monkeys to expose the stereotaxic area corresponding to the motor cortex. In intact monkeys, injections of BDA were placed in the rostral bank of the central sulcus, following the central sulcus going from lateral (hand representation) to medial (leg representation). In the PMG monkey, the BDA injections were performed at side where ICMS elicited hand movements. Based on our previous experience of tracing the CS tract with BDA in monkeys, the survival time after BDA injection was set to three to four weeks .
To compare the frequency of sulci in the brain of the PMG monkey with that of normal monkeys, we counted the number of sulci in the frontoparietal and ventro-temporal lobes in the PMG monkey and in three control monkeys (Mk-IU, Mk-I2 and Mk-IZ), divided by the measured length of the corresponding cortical surface. The measurements were made on 5 coronal sections at 40× magnification, regularly distributed between the rostral end of the Nucleus Caudatus and the rostral end of the Lateral Geniculate Nucleus (LGN). On the rostral sections, where the lateral fissure is not present, the measure was obtained from the region delimited by the Corpus Callosum and the angle between the lateral and the ventral walls of the frontal lobe. A depression of the cortical surface was considered as a sulcus when we could identify a clear invagination of the layer I (Fig. 2A).
Measurement of CS axonal arborization
List of monkeys included in the present study with identification code.
Age at sacrifice (years)
BIM + RT + SF
SCI study +SF
SCI study + RN + SF
Cortex BIM + RT + SF
Cortex + RN
The authors wish to thank the technical assistance of Georgette Fischer, Véronique Moret, Françoise Tinguely, Christiane Marti, Monika Bennefeld and Christine Roulin (histology and behavioral evaluations), Josef Corpataux, Bernard Bapst, Laurent Bossy and Bernard Morandi (animal house keeping), André Gaillard (mechanics), Bernard Aebischer (electronics), Laurent Monney (informatics).
Grant Sponsors: Swiss National Science Foundation, grants No 31-61857.00, 310000-110005 (EMR, 4038043918/2 (PNR-38), 3100A0-104061/1 and 310000-118357/1 (TW); Novartis Foundation; The Swiss National Science Foundation Centre of Competence in Research (NCCR) on "Neural plasticity and repair" and the Christopher Reeves Foundation (Spinal Cord Consortium, Springfield, N.J.).
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