Lissencephalic Cortex Research Articles

Acute Neuropixels Recordings in the Marmoset Monkey.

High-density linear probes, such as Neuropixels, provide an unprecedented opportunity to understand how neural populations within specific laminar compartments contribute to behavior. Marmoset monkeys, unlike macaque monkeys, have a lissencephalic (smooth) cortex that enables recording perpendicular to the cortical surface, thus making them an ideal animal model for studying laminar computations. Here we present a method for acute Neuropixels recordings in the common marmoset (Callithrix jacchus). The approach replaces the native dura with an artificial silicon-based dura that grants visual access to the cortical surface, which is helpful in avoiding blood vessels, ensures perpendicular penetrations, and could be used in conjunction with optical imaging or optogenetic techniques. The chamber housing the artificial dura is simple to maintain with minimal risk of infection and could be combined with semichronic microdrives and wireless recording hardware. This technique enables repeated acute penetrations over a period of several months. With occasional removal of tissue growth on the pial surface, recordings can be performed for a year or more. The approach is fully compatible with Neuropixels probes, enabling the recording of hundreds of single neurons distributed throughout the cortical column.

Delay-related activity in marmoset prefrontal cortex.

Persistent delay-period activity in prefrontal cortex (PFC) has long been regarded as a neural signature of working memory (WM). Electrophysiological investigations in macaque PFC have provided much insight into WM mechanisms; however, a barrier to understanding is the fact that a portion of PFC lies buried within the principal sulcus in this species and is inaccessible for laminar electrophysiology or optical imaging. The relatively lissencephalic cortex of the New World common marmoset (Callithrix jacchus) circumvents such limitations. It remains unknown, however, whether marmoset PFC neurons exhibit persistent activity. Here, we addressed this gap by conducting wireless electrophysiological recordings in PFC of marmosets performing a delayed-match-to-location task on a home cage-based touchscreen system. As in macaques, marmoset PFC neurons exhibited sample-, delay-, and response-related activity that was directionally tuned and linked to correct task performance. Models constructed from population activity consistently and accurately predicted stimulus location throughout the delay period, supporting a framework of delay activity in which mnemonic representations are relatively stable in time. Taken together, our findings support the existence of common neural mechanisms underlying WM performance in PFC of macaques and marmosets and thus validate the marmoset as a suitable model animal for investigating the microcircuitry underlying WM.

Magnetic Resonance Imaging of Marmoset Monkeys.

The use of the common marmoset monkey (Callithrix jacchus) for neuroscientific research has grown markedly in the last decade. Magnetic resonance imaging (MRI) has played a significant role in establishing the extent of comparability of marmoset brain architecture with the human brain and brains of other preclinical species (eg, macaques and rodents). As a non-invasive technique, MRI allows for the flexible acquisition of the same sequences across different species in vivo, including imaging of whole-brain functional topologies not possible with more invasive techniques. Being one of the smallest New World primates, the marmoset may be an ideal nonhuman primate species to study with MRI. As primates, marmosets have an elaborated frontal cortex with features analogous to the human brain, while also having a small enough body size to fit into powerful small-bore MRI systems typically employed for rodent imaging; these systems offer superior signal strength and resolution. Further, marmosets have a rich behavioral repertoire uniquely paired with a lissencephalic cortex (like rodents). This smooth cortical surface lends itself well to MRI and also other invasive methodologies. With the advent of transgenic modification techniques, marmosets have gained significant traction as a powerful complement to canonical mammalian modelling species. Marmosets are poised to make major contributions to preclinical investigations of the pathophysiology of human brain disorders as well as more basic mechanistic explorations of the brain. The goal of this article is to provide an overview of the practical aspects of implementing MRI and fMRI in marmosets (both under anesthesia and fully awake) and discuss the development of resources recently made available for marmoset imaging.

Functional Localization of the Frontal Eye Fields in the Common Marmoset Using Microstimulation.

The frontal eye field (FEF) is a critical region for the deployment of overt and covert spatial attention. Although investigations in the macaque continue to provide insight into the neural underpinnings of the FEF, due to its location within a sulcus, the macaque FEF is virtually inaccessible to electrophysiological techniques such as high-density and laminar recordings. With a largely lissencephalic cortex, the common marmoset (Callithrix jacchus) is a promising alternative primate model for studying FEF microcircuitry. Putative homologies have been established with the macaque FEF on the basis of cytoarchitecture and connectivity; however, physiological investigation in awake, behaving marmosets is necessary to physiologically locate this area. Here, we addressed this gap using intracortical microstimulation in a broad range of frontal cortical areas in three adult marmosets (two males, one female). We implanted marmosets with 96-channel Utah arrays and applied microstimulation trains while they freely viewed video clips. We evoked short-latency fixed vector saccades at low currents (<50 μA) in areas 45, 8aV, 8C, and 6DR. We observed a topography of saccade direction and amplitude consistent with findings in macaques and humans: small saccades in ventrolateral FEF and large saccades combined with contralateral neck and shoulder movements encoded in dorsomedial FEF. Our data provide compelling evidence supporting homology between marmoset and macaque FEF and suggest that the marmoset is a useful primate model for investigating FEF microcircuitry and its contributions to oculomotor and cognitive functions.SIGNIFICANCE STATEMENT The frontal eye field (FEF) is a critical cortical region for overt and covert spatial attention. The microcircuitry of this area remains poorly understood because in the macaque, the most commonly used model, it is embedded within a sulcus and is inaccessible to modern electrophysiological and imaging techniques. The common marmoset is a promising alternative primate model due to its lissencephalic cortex and potential for genetic manipulation. However, evidence for homologous cortical areas in this model remains limited and unclear. Here, we applied microstimulation in frontal cortical areas in marmosets to physiologically identify FEF. Our results provide compelling evidence for an FEF in the marmoset and suggest that the marmoset is a useful model for investigating FEF microcircuitry.

Electrical microstimulation evokes saccades in posterior parietal cortex of common marmosets.

The common marmoset (Callithrix jacchus) is a small-bodied New World primate increasing in prominence as a model animal for neuroscience research. The lissencephalic cortex of this primate species provides substantial advantages for the application of electrophysiological techniques such as high-density and laminar recordings, which have the capacity to advance our understanding of local and laminar cortical circuits and their roles in cognitive and motor functions. This is particularly the case with respect to the oculomotor system, as critical cortical areas of this network such as the frontal eye fields (FEF) and lateral intraparietal area (LIP) lie deep within sulci in macaques. Studies of cytoarchitecture and connectivity have established putative homologies between cortical oculomotor fields in marmoset and macaque, but physiological investigations of these areas, particularly in awake marmosets, have yet to be carried out. Here we addressed this gap by probing the function of posterior parietal cortex of the common marmoset with electrical microstimulation. We implanted two animals with 32-channel Utah arrays at the location of the putative area LIP and applied microstimulation while they viewed a video display and made untrained eye movements. Similar to previous studies in macaques, stimulation evoked fixed-vector and goal-directed saccades, staircase saccades, and eyeblinks. These data demonstrate that area LIP of the marmoset plays a role in the regulation of eye movements, provide additional evidence that this area is homologous with that of the macaque, and further establish the marmoset as a valuable model for neurophysiological investigations of oculomotor and cognitive control.NEW & NOTEWORTHY The macaque monkey has been the preeminent model for investigations of oculomotor control, but studies of cortical areas are limited, as many of these areas are buried within sulci in this species. Here we applied electrical microstimulation to the putative area LIP of the lissencephalic cortex of awake marmosets. Similar to the macaque, microstimulation evoked contralateral saccades from this area, supporting the marmoset as a valuable model for studies of oculomotor control.

Task-based fMRI of a free-viewing visuo-saccadic network in the marmoset monkey

Saccadic tasks are often used to index aberrations of cognitive function in patient populations, with several neuropsychiatric and neurologic disorders characterized by saccadic dysfunction. The common marmoset (Callithrix jacchus) has received recent attention as an additional primate model for studying the neural basis of these dysfunctions – marmosets are amenable to a host of genetic manipulation techniques and have a lissencephalic cortex, which is well suited for a variety of recording techniques (e.g., calcium imaging, laminar electrophysiology). Because the marmoset cortex is mostly lissencephalic, however, the locations of frontal saccade-related regions (e.g., frontal eye fields (FEF)) are less readily identified than in Old World macaque monkeys. Further, although high quality histology-based atlases do exist for marmosets, identifying these regions based on histology alone is not always accurate, with the cytoarchitectonic boundaries often inconsonant with functional boundaries. As such, there is a need to map the functional location of these regions directly. Task-based functional magnetic resonance imaging (fMRI) is of utility in this regard, allowing for detection of whole-brain signal changes in response to moving stimuli. Here, we conducted task-based fMRI in marmosets at ultra-high field (9.4 T) during a free-viewing visuo-saccadic task. We also conducted the same task in humans at ultra-high field (7 T) to validate that our simple task was indeed evoking the visuo-saccadic circuitry we expected (as defined by a meta-analysis of fMRI saccade studies). In the marmosets, we found that the task evoked a robust visuo-saccadic topology, with visual cortex (V1, V2, V3, V4) activation extending ventrally to MT, MST, FST and dorsally into V6, 19M, 23V. This topology also included putative cingulate eye field (area 32 and 24d), posterior parietal cortex (with strongest activation in lateral intraparietal area (LIP)), and a frontolateral peak in area 8 aV in marmosets, extending into 45, 46, 8aD, 6DR, 8c, 6 aV, 6DC. Overall, these results support the view that marmosets are a promising preclinical modelling species for studying saccadic dysfunction related to neuropsychiatric or neurodegenerative human brain diseases.

The effects of cerebral curvature on cortical spreading depression

Neuronal activity evokes a localised increase in cerebral blood flow through neurovascular coupling (NVC), a communication system between a group of cells known as a neurovascular unit (NVU). Dysfunctional NVC can lead to pathologies such as cortical spreading depression (CSD), characterised by a slowly propagating wave of neuronal depolarisation and high extracellular potassium (K+) levels. CSD is associated with several neurological disorders such as migraine, stroke, and traumatic brain injury. Insight into the spatial dynamics of CSD in humans is mainly deduced from animal experiments on the smooth lissencephalic brain (in particular murine experiments), however the human cortex is gyrencephalic (highly folded) and is considered likely to exhibit different and more complex patterns of CSD.In this study a large scale numerical NVC model of multiple NVUs is coupled to a vascular tree simulating a two-dimensional cerebral tissue slice. This model is extended with a spatial Gaussian curvature mapping that can simulate the highly folded nature of the human cortex. For a flat surface comparable to a lissencephalic cortex the model can simulate propagating waves of high extracellular K+ travelling radially outwards from a stimulated area at approximately 6.7 mm/min, corresponding well with multiple experimental results. The high K+ concentration induces a corresponding wave of vasoconstriction (with decreased blood flow) then slight vasodilation, achieved through cellular communication within the NVU. The BOLD response decreases below baseline by approximately 10% followed by an increase of 1%.For a surface with spatially varied curvature comparable to a section of gyrencephalic cortex, areas of positive Gaussian curvature inhibit wave propagation due to decreased extracellular diffusion rate. Whereas areas of negative curvature promote propagation. Consequently extracellular K+ is observed travelling as wave segments (as opposed to radial waves) through flat or negatively curved “valleys” corresponding to folds (sulci) in the cortex. If the wave size (defined as the activated area of high K+ concentration) is too small or diffusion rate too low then wave segments can cease propagation. If the diffusion rate is high enough the wave segments can grow from open ends forming loose spiral waves. These results may provide some insight into the differences seen between human and animal experiments.

Alpha Oscillations Modulate Preparatory Activity in Marmoset Area 8Ad.

Cognitive control often requires suppression of prepotent stimulus-driven responses in favor of less potent alternatives. Suppression of prepotent saccades has been shown to require proactive inhibition in the frontoparietal saccade network. Electrophysiological evidence in macaque monkeys has revealed neural correlates of such inhibition in this network; however, the interlaminar instantiation of inhibitory processes remains poorly understood because these areas lie deep within sulci in macaques, rendering them inaccessible to laminar recordings. Here, we addressed this gap by exploiting the mostly lissencephalic cortex of the common marmoset (Callithrix jacchus). We inserted linear electrode arrays into areas 8Ad-the putative marmoset frontal eye field-and the lateral intraparietal area of two male marmosets and recorded neural activity during performance of a task comprised of alternating blocks of trials requiring a saccade either toward a large, high-luminance stimulus or the inhibition of this prepotent response in favor of a saccade toward a small, low-luminance stimulus. We observed prominent task-dependent activity in both alpha/gamma bands of the LFP and discharge rates of single neurons in area 8Ad during a prestimulus task epoch in which the animals had been instructed which of these two tasks to perform but before peripheral stimulus onset. These data are consistent with a model in which rhythmic alpha-band activity in deeper layers inhibits spiking in upper layers to support proactive inhibitory saccade control.SIGNIFICANCE STATEMENT Failures to inhibit automatic saccadic responses are a hallmark of many neuropsychiatric disorders, but how this process is implemented across the cortical layers in the frontoparietal saccade network remains unknown because many of the areas are inaccessible to laminar recordings in macaques. Here, we investigated laminar neural activity in marmoset monkeys, which have a smooth cortex. Monkeys were required either to generate or inhibit a prepotent saccade response. In area 8Ad, the putative frontal eye field in marmosets, rhythmic alpha-band activity (9-14 Hz) was higher in deeper layers and spiking activity was lower in upper layers when the animals were instructed to suppress a saccade toward a peripheral stimulus. Reduced alpha power during task preparation may be the underlying common neural basis of a saccade suppression deficit.

The marmoset as a model system for studying voluntary motor control.

The common marmoset has recently gained interest as an animal model for systems and behavioral neuroscience. This is due in part to the advent of transgenic marmosets, which affords the possibility of combining genetic manipulations with physiological recording and behavioral monitoring to study neural systems. In this review, they will argue that the marmoset provides a unique opportunity to study the neural basis of voluntary motor control from an integrative perspective. First, as an intermediate animal model, the marmoset represents an important bridge in motor system function between other primates, including humans, and rodents. Second, due to the marmoset's small brain size and lissencephalic cortex, novel electrophysiological and optical recording technologies will allow an integrative study of cortical function at multiple spatial scales beyond that afforded by other non-human primate models. Finally, as a primate expressing an ancestral state of corticospinal organization, the marmoset offers the possibility of understanding the integrative function of cortical and spinal interneuron circuitry in isolation of more recent corticomotoneuronal elaborations. If the potential of the marmoset as a model species is to be realized, they will need to learn to work with their natural behavioral repertoire. They have concluded by considering practical aspects of studying motor systems with marmosets. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 273-285, 2017.

Evolutionary origin of Tbr2‐expressing precursor cells and the subventricular zone in the developing cortex

ABSTRACTThe subventricular zone (SVZ) is greatly expanded in primates with gyrencephalic cortices and is thought to be absent from vertebrates with three‐layered, lissencephalic cortices, such as the turtle. Recent work in rodents has shown that Tbr2‐expressing neural precursor cells in the SVZ produce excitatory neurons for each cortical layer in the neocortex. Many excitatory neurons are generated through a two‐step process in which Pax6‐expressing radial glial cells divide in the VZ to produce Tbr2‐expressing intermediate progenitor cells, which divide in the SVZ to produce cortical neurons. We investigated the evolutionary origin of SVZ neural precursor cells in the prenatal cerebral cortex by testing for the presence and distribution of Tbr2‐expressing cells in the prenatal cortex of reptilian and avian species. We found that mitotic Tbr2+ cells are present in the prenatal cortex of lizard, turtle, chicken, and dove. Furthermore, Tbr2+ cells are organized into a distinct SVZ in the dorsal ventricular ridge (DVR) of turtle forebrain and in the cortices of chicken and dove. Our results are consistent with the concept that Tbr2+ neural precursor cells were present in the common ancestor of mammals and reptiles. Our data also suggest that the organizing principle guiding the assembly of Tbr2+ cells into an anatomically distinct SVZ, both developmentally and evolutionarily, may be shared across vertebrates. Finally, our results indicate that Tbr2 expression can be used to test for the presence of a distinct SVZ and to define the boundaries of the SVZ in developing cortices. J. Comp. Neurol. 524:433–447, 2016. © 2015 Wiley Periodicals, Inc.

Functional MRI of visual responses in the awake, behaving marmoset

The visual brain is composed of interconnected subcortical and cortical structures that receive and process image information originating in the retina. The visual system of nonhuman primates, in particular macaques, has been studied in great detail in order to elucidate principles of human sensation and perception. The common marmoset (Callithrix jacchus) is a small New World monkey of growing interest as a primate model for neuroscience. Marmosets have advantages over macaques because of their small size, lissencephalic cortex, and growing potential for viral and genetic manipulations. Previous anatomical studies and electrophysiological recordings in anesthetized marmosets have shown that this species’ cortical visual hierarchy closely resembles that of other primates, including humans. Until now, however, there have been no attempts to systematically study visual responses throughout the marmoset brain using fMRI. Here we show that awake marmosets readily learn to carry out a simple visual task inside the bore of an MRI scanner during functional mapping experiments. Functional scanning at 500μm in-plane resolution in a 30cm horizontal bore at 7T revealed robust positive blood oxygenation level-dependent (BOLD) fMRI responses to visual stimuli throughout visual cortex and associated subcortical areas. Nonvisual sensory areas showed negative contrasts to visual stimuli compared to the fixation dot only baseline. Structured images of objects and faces led to stronger responses than scrambled control images at stages beyond early visual cortex. Our study establishes fMRI mapping of visual responses in awake, behaving marmosets as a straightforward and valuable tool for assessing the functional organization of the primate brain at high resolution.

From genes to folds: a review of cortical gyrification theory.

Cortical gyrification is not a random process. Instead, the folds that develop are synonymous with the functional organization of the cortex, and form patterns that are remarkably consistent across individuals and even some species. How this happens is not well understood. Although many developmental features and evolutionary adaptations have been proposed as the primary cause of gyrencephaly, it is not evident that gyrification is reducible in this way. In recent years, we have greatly increased our understanding of the multiple factors that influence cortical folding, from the action of genes in health and disease to evolutionary adaptations that characterize distinctions between gyrencephalic and lissencephalic cortices. Nonetheless it is unclear how these factors which influence events at a small-scale synthesize to form the consistent and biologically meaningful large-scale features of sulci and gyri. In this article, we review the empirical evidence which suggests that gyrification is the product of a generalized mechanism, namely the differential expansion of the cortex. By considering the implications of this model, we demonstrate that it is possible to link the fundamental biological components of the cortex to its large-scale pattern-specific morphology and functional organization.

A13 Phenotyping neural networks in an ovine model of huntington's disease

A large animal transgenic model of Huntington9s disease (HD) has been recently developed in domestic sheep (Ovis aries L). 1 Sheep are a long-lived species with large brains, complex basal ganglia and convoluted neocortex; compared to standard models in short-lived rodents with lissencephalic cortices, this ovine model may therefore be better-suited for electrophysiological characterisations of early disease stages and for the development of novel treatments. Using a sheep model will also reduce costs relative to non-human primates, and enables large-scale, long-term and multi-site electrophysiological recording during behavioural testing paradigms. 2 Sleep is an essential and ubiquitous brain state that is known to deteriorate in humans suffering from HD. As a first step towards assessing the normal electrophysiological features of sheep, we aimed to characterise sleep architecture using electroencephalography in healthy sheep. In addition we performed some common behavioural manipulations known to modulate sleep architecture. These include sleep deprivation and learning prior to sleep. The method can be expanded to generate sensitive biomarkers of intra-cortical network activity and interactions between brain structures in the behaving animal. If deterioration of these network interactions precedes the appearance of overt symptoms, this could then be targeted for treatments that might delay symptom onset. We also present deep brain recordings (of local field potentials and single neuron spike activity) from an anaesthetised animal as a proof of concept. Sheep disease models offer unique opportunities for long term in vivo electrophysiological testing, with the potential lead to novel therapeutic treatments targeting early stages of HD progression.

The Role of Intermediate Progenitor Cells in the Evolutionary Expansion of the Cerebral Cortex

The vertebrate cerebral cortex varies from the 3-layered dorsal cortex of reptiles to the 6-layered lissencephalic cortex characteristic of rodents and to the 6-layered gyrencephalic cortex typical of carnivores and primates. Distinct developmental mechanisms may have evolved independently to account for the radial expansion that produced the multilayered cortex of mammals and for the tangential expansion of cortical surface area that resulted in gyrencephalic cortex. Recent evidence shows that during the late stages of cortical development, radial glial cells divide asymmetrically in the ventricular zone to generate radial glial cells and intermediate progenitor (IP) cells and that IP cells subsequently divide symmetrically in the subventricular zone to produce multiple neurons. We propose that the evolution of this two-step pattern of neurogenesis played an important role in the amplification of cell numbers underlying the radial and tangential expansion of the cerebral cortex.

Walker-warburg syndrome: diffusion MR imaging

A 5-month-old boy with Walker-Warburg syndrome is reported. On MR imaging a characteristic pontomesencephalic kink was evident. Collicular fusion, hydrocephalus, callosal dysgenesis, cobblestone lissencephaly, small cerebellar cysts, pontine and cerebellar hypoplasia, and bilateral subretinal hemorrhages were noted. ADC (apparent diffusion coefficient) maps of an echoplanar diffusion MR imaging sequence revealed an elevated diffusion pattern throughout the cerebral white matter, manifested with prominently high ADC values, ranging from 1.82 to 2.45 x 10(-3) mm2/s. This corresponded to prominent hypomyelination. On the other hand, ADC values of the lissencephalic cortex were normal, ranging from 0.95 to 0.97 x 10(-3)mm2/s. In addition, ADC values from the hypoplastic cerebellar hemispheres, and from the hypoplastic pons were normal.

PET Studies of Lissencephaly

The functional activity of lissencephalic cortex was studied using FD Glucose positron emission tomography in 8 patients, mean age 7.5 years, at Children’s Hospital of Michigan, Detroit, MI.

Lissencephaly: fetal pattern of glucose metabolism on positron emission tomography?

In classical lissencephaly, the cerebral cortex is four-layered, containing neurons that have failed to complete their migration between 12 and 16 weeks of gestation. The authors studied the functional activity of lissencephalic cortex using 2-deoxy-2[(18)F]fluoro-D-glucose PET (FDG PET) in eight patients (six girls and two boys, mean age 7.5 years) with isolated lissencephaly sequence. The PET scans revealed a remarkably similar and bilaterally symmetric pattern of glucose metabolism in all eight patients. The cerebral cortex of lissencephaly showed two layers that could be differentiated based on metabolic activity. The inner layer, which probably corresponds to the inner cellular layer of lissencephalic cortex, showed 8 to 63% higher glucose utilization rate than the outer layer, which probably represents a composite of the molecular, outer cellular, and cell-sparse layers. Patients with a higher metabolic ratio between the cortical layers (inner/outer) showed greater delay in communication (p = 0.007) and socialization (p = 0.03). These findings are consistent with [(14)C]-2-deoxyglucose autoradiography studies in fetal sheep that have shown that before the development of significant numbers of axons, dendrites, and synapses, glucose metabolism appears to be highest in regions with the highest density of cell bodies, compared to the more mature state when glucose metabolism is highest in areas of greatest dendritic arborization. FDG PET studies of classical lissencephaly provide a different perspective in the analysis of brain gyral anomalies than those with traditional neuroanatomic imaging techniques.

Problèmes posés par les protocoles des médicaments antiépileptiques en phase pré-AMM chez l'enfant

Agyria-pachygyria or lissencephaly type I, a diffuse cortical malformation, provides infantile spasms (IS) which are refractory and persisting after the first decade, an age at which IS have disappeared in the other causes. In order to study the functional postnatal development of the lissencephalic cortex, we measured regional cerebral blood flow (rCBF) using SPECT (Single photon emission computed tomography) and 133Xe in 14 children with lissencephaly, aged from 4 months to 12 years (mean = 40 months) compared to normal children of the same age range and to children with cryptogenic IS aged from 3 months to 3 years (mean = 13 months). rCBF was calculated in frontal (FR) and parieto-temporo-occipital (PTO) cortex as well as the ratio FR/PTO. FR/PTO was higher in lissencephalic patients than in controls (P < 0.001) due to higher FR rCBF (P < 0.001), particularly in patients aged less than 3 years. FR/PTO was also higher in lissencephalic patients than in patients with cryptogenic IS (P < 0.001) also due to higher FR rCBF (P < 0.001). The values of FR/PTO and FR rCBF remained stable during the first years of life and did not exhibit any age- or topography-related changes as they do in controls or in patients with cryptogenic IS. These results suggest that the normal process of postnatal development in the brain is lacking in agyria-pachygyria. That could play a role in determining the persistance of epileptic spasms, the specific seizure type of this malformation.

Brain functional imaging SPECT in agyria-pachygyria

Agyria-pachygyria or lissencephaly type I, a diffuse cortical malformation, provides infantile spasms (IS) which are refractory and persisting after the first decade, an age at which IS have disappeared in the other causes. In order to study the functional postnatal development of the lissencephalic cortex, we measured regional cerebral blood flow (rCBF) using SPECT (Single photon emission computed tomography) and 133Xe in 14 children with lissencephaly, aged from 4 months to 12 years (mean = 40 months) compared to normal children of the same age range and to children with cryptogenic IS aged from 3 months to 3 years (mean = 13 months). rCBF was calculated in frontal (FR) and parieto-temporo-occipital (PTO) cortex as well as the ratio FR/PTO. FR/PTO was higher in lissencephalic patients than in controls (P < 0.001) due to higher FR rCBF (P < 0.001), particularly in patients aged less than 3 years. FR/PTO was also higher in lissencephalic patients than in patients with cryptogenic IS (P < 0.001) also due to higher FR rCBF (P < 0.001). The values of FR/PTO and FR rCBF remained stable during the first years of life and did not exhibit any age- or topography-related changes as they do in controls or in patients with cryptogenic IS. There results suggest that the normal process of postnatal development in the brain is lacking in agyria-pachygyria. That could play a role in determining the persistence of epileptic spasms, the specific seizure type of this malformation.

Neurotransmitter chemistry of lissencephalic cortex induced in ferrets by fetal treatment with methylazoxymethanol acetate.

Treatment of pregnant ferrets with 15 mg/kg of methylazoxymethanol acetate (MAM) at 33 days of fetal gestation results in offspring with cortical hypoplasia and lissencephally. Neurochemical analysis of 5 areas of cortex from 8-week-old offspring of MAM- or vehicle-treated jills indicated an overall enrichment in markers for catecholaminergic (tyrosine hydroxylase, norepinephrine) and cholinergic (choline acetyltransferase, acetylcholine) terminals but minimal change in the concentration of GABAergic markers (glutamate decarboxylase, gamma-aminobutyric acid); however, there did not appear to be a direct, inverse relationship between the concentration of catecholaminergic and cholinergic markers and the degree of hypoplasia in cortical subareas unlike what has been found previously in the rat.