Vermal Lobules VI Research Articles

Distinct cerebellar regions for body motion discrimination.

Visual processing of human movements is critical for adaptive social behavior. Cerebellar activations have been observed during biological motion discrimination in prior neuroimaging studies, and cerebellar lesions may be detrimental for this task. However, whether the cerebellum plays a causal role in biological motion discrimination has never been tested. Here, we addressed this issue in three different experiments by interfering with the posterior cerebellar lobe using transcranial magnetic stimulation (TMS) during a biological discrimination task. In Experiments 1 and 2, we found that TMS delivered at onset of the visual stimuli over the vermis (vermal lobule VI), but not over the left cerebellar hemisphere (left lobule VI/Crus I), interfered with participants’ ability to distinguish biological from scrambled motion compared to stimulation of a control site (vertex). Interestingly, when stimulation was delivered at a later time point (300 ms after stimulus onset), participants performed worse when TMS was delivered over the left cerebellar hemisphere compared to the vermis and the vertex (Experiment 3). Our data show that the posterior cerebellum is causally involved in biological motion discrimination and suggest that different sectors of the posterior cerebellar lobe may contribute to the task at different time points.

Postural Ataxia in Cerebellar Downbeat Nystagmus: Its Relation to Visual, Proprioceptive and Vestibular Signals and Cerebellar Atrophy.

BackgroundThe cerebellum integrates proprioceptive, vestibular and visual signals for postural control. Cerebellar patients with downbeat nystagmus (DBN) complain of unsteadiness of stance and gait as well as blurred vision and oscillopsia.ObjectivesThe aim of this study was to elucidate the differential role of visual input, gaze eccentricity, vestibular and proprioceptive input on the postural stability in a large cohort of cerebellar patients with DBN, in comparison to healthy age-matched control subjects.MethodsOculomotor (nystagmus, smooth pursuit eye movements) and postural (postural sway speed) parameters were recorded and related to each other and volumetric changes of the cerebellum (voxel-based morphometry, SPM).ResultsTwenty-seven patients showed larger postural instability in all experimental conditions. Postural sway increased with nystagmus in the eyes closed condition but not with the eyes open. Romberg’s ratio remained stable and was not different from healthy controls. Postural sway did not change with gaze position or graviceptive input. It increased with attenuated proprioceptive input and on tandem stance in both groups but Romberg’s ratio also did not differ. Cerebellar atrophy (vermal lobule VI, VIII) correlated with the severity of impaired smooth pursuit eye movements of DBN patients.ConclusionsPostural ataxia of cerebellar patients with DBN cannot be explained by impaired visual feedback. Despite oscillopsia visual feedback control on cerebellar postural control seems to be preserved as postural sway was strongest on visual deprivation. The increase in postural ataxia is neither related to modulations of single components characterizing nystagmus nor to deprivation of single sensory (visual, proprioceptive) inputs usually stabilizing stance. Re-weighting of multisensory signals and/or inappropriate cerebellar motor commands might account for this postural ataxia.

Differential Pattern of Cerebellar Atrophy in Tremor-Predominant and Akinetic/Rigidity-Predominant Parkinson's Disease.

Parkinson's disease (PD) is an akinetic-rigid disorder characterized by basal ganglia dysfunction and a possible cerebello-thalamo-cortical circuit involvement. This study aims to investigate the pattern of cerebellar involvement in PD and to assess whether it correlates with clinical parameters. MRI scans were acquired from 50 healthy controls (HC) and 63 patients; 44 were classified as tremor-predominant-PD (PDT) and 19 as akinetic/rigidity-predominant-PD (PDAR). We designed an analysis of covariance including the three groups and contrasted as follows: (1) all 63 PD vs HC, (2) PDT vs HC, (3) PDAR vs HC, and (4) PDT vs PDAR. For a precise evaluation of the cerebellum, we used the SUIT tool for voxel-based morphometry. Applying p=0.001 and extent threshold = 20 voxels, the overall PD group vs HC showed decreased gray matter (GM) in the left lobules VI and crus I. The PDT group showed decreased cerebellar GM when compared with HC at left lobules VI, VIIb, and VIIIa; at right lobules Crus I, VIIb, and VIIIb; and vermal lobules VI and VIIIa. When compared with PDAR, PDT also showed a decrease in the left lobules VIIIa (p<0.001). There were small clusters of both positive and negative correlation between disease duration and PDT group. The PDAR group showed no cerebellar changes. Our findings support the growing evidence of cerebellar involvement in the pathogenesis of the resting tremor.

Altered Cerebellar Activity in Visceral Pain-Related Fear Conditioning in Irritable Bowel Syndrome.

There is evidence to support a role of the cerebellum in emotional learning processes, which are demonstrably altered in patients with chronic pain. We tested if cerebellar activation is altered during visceral pain-related fear conditioning and extinction in irritable bowel syndrome (IBS). Cerebellar blood oxygenation level-dependent (BOLD) data from N=17 IBS patients and N=21 healthy controls, collected as part of a previous fMRI study, was reanalyzed utilizing an advanced normalizing method of the cerebellum. The differential fear conditioning paradigm consisted of acquisition, extinction, and reinstatement phases. During acquisition, two visual conditioned stimuli (CS) were presented either paired (CS+) or unpaired (CS-) with painful rectal distension as unconditioned stimulus (US). In the extinction phase, the CS+ and CS- were presented without US. For reinstatement, unpaired US presentations were followed by unpaired CS+ and CS- presentations. Group differences in cerebellar activation were analyzed for the contrasts CS+>CS- and CS->CS+. During acquisition, IBS patients revealed significantly enhanced cerebellar BOLD responses to pain-predictive (CS+) and safety (CS-) cues compared to controls (p<0.05, family-wise error corrected). Increased activation was found in three main clusters, including the vermis (maximum in vermal lobule VI), intermediate cerebellum (maximum in lobule VIII), and the posterolateral cerebellar hemisphere (maximum in lobule VI). Areas overlapped for the contrasts CS+>CS- and CS->CS+. Group differences were most prominent in the contrast CS->CS+. During extinction and reinstatement, no significant group differences were found. During visceral pain-related fear conditioning, IBS patients showed increased activations in circumscribed areas of the medial, intermediate, and lateral cerebellum. These areas are involved in autonomic, somatosensory, and cognitive functions and likely contribute to the different aspects of pain-related fear. The cerebellum contributes to altered pain-related fear learning in IBS.

Adaptation and aftereffects of split-belt walking in cerebellar lesion patients.

To walk efficiently and stably on different surfaces under various constrained conditions, humans need to adapt their gait pattern substantially. Although the mechanisms behind locomotor adaptation are still not fully understood, the cerebellum is thought to play an important role. In this study we aimed to address the specific localization of cerebellar involvement in split-belt adaptation by comparing performance in patients with stable focal lesions after cerebellar tumor resection and in healthy controls. We observed that changes in symmetry of those parameters that were most closely related to interlimb coordination (such as step length and relative double stance time) were similar between healthy controls and cerebellar patients during and after split-belt walking. In contrast, relative stance times (proportions of stance in the gait cycle) were more asymmetric for the patient group than for the control group during the early phase of the post-split-belt condition. Patients who walked with more asymmetric relative stance times were more likely to demonstrate lesions in vermal lobules VI and Crus II. These results confirm that deficits in gait adaptation vary with ataxia severity and between patients with different types of cerebellar damage.

Mapping motor representations in the human cerebellum

The cerebellum is a major motor structure. However, in humans, its efferent topographical organization remains controversial and indirectly inferred from neuroimaging and animal studies. Even central questions such as 'Can we evoke limb movements by stimulating the cerebellar cortex?' have no clear answer. To address this issue, we electrically stimulated the posterior cerebellum of 20 human patients undergoing surgery for tumours located outside this structure (e.g. pineal gland, quadrigeminal plate). Stimulation, delivered at a 60-Hz frequency for 2 s, evoked focal (single-joint) ipsilateral movements. Different regions were associated with the production of head (vermal lobule VI), face/mouth (hemispheric lobule VI) and lower-limb (hemispheric lobules VIIb-IX) responses. Upper-limb representations were more widely distributed. They intermingled with face/mouth representations in the superior posterior cerebellum (hemispheric lobule VI) and lower-limb representations in the inferior posterior cerebellum (hemispheric lobules VIIb-IX). No intra- or inter-limb somatotopy was found in these areas. Functionally, upper-limb (face/mouth movements) and upper limb-lower limb postural coordinations are major elements of our motor repertoire. Representation of these pairs of segments in common regions might favour the production of integrated motor behaviours. The intermediate region of the posterior cerebellum (hemispheric lobule VII and vermal lobules VII-VIII) was mostly silent. Latency results in conjunction with previous electrophysiological evidence in animals suggest that electrically evoked motor responses were not mediated by a cortical route but rather by brainstem structures. The potential role of this descending efferent pathway for fine motor control is discussed.

Patterned Purkinje cell loss in the ataxic sticky mouse

The ataxic sticky (sti/sti) mouse is a spontaneous autosomal recessive mutant resulting from a disruption in the editing domain of the alanyl-tRNA synthetase (Aars) gene. The sticky phenotype is characterized by a small body size, a characteristic unkempt coat and neurological manifestations including marked tremor and ataxia starting at 6 weeks of age. The present study was undertaken to examine the spatiotemporal features of Purkinje cell degeneration in the sticky mouse. Purkinje cell loss was found to be both progressive and patterned, with vermal lobules VI, IX and X, crus 1 of the hemisphere, and the flocculus and paraflocculus being differentially resistant to degeneration. The pattern of Purkinje cell degeneration in sticky is not random - in general, the sphingosine kinase 1a-immunonegative Purkinje cell subset is preferentially susceptible to early cell death. In addition, zebrin II/aldolase C expression in the sticky cerebellum is profoundly downregulated, whereas the heat-shock protein 25 is both ectopically expressed in some scattered Purkinje cells and downregulated in other Purkinje cells in which it is normally expressed constitutively. Compared with many mouse mutants with patterned Purkinje cell death, in which successive stripes of cell loss are very clear, Purkinje cell loss in sticky shows a less clear-cut pattern between different Purkinje cell subtypes, with the result that preferential survival is less dramatic. This may represent a secondary consequence of the downregulation of zebrin II expression.

Scaling of neural responses to visual and auditory motion in the human cerebellum.

The human cerebellum contains approximately half of all the neurons within the cerebrum, yet most experimental work in human neuroscience over the last century has focused exclusively on the structure and functions of the forebrain. The cerebellum has an undisputed role in a range of motor functions (Thach et al., 1992), but its potential contributions to sensory and cognitive processes are widely debated (Stoodley and Schmahmann, 2009). Here we used functional magnetic resonance imaging to test the hypothesis that the human cerebellum is involved in the acquisition of auditory and visual sensory data. We monitored neural activity within the cerebellum while participants engaged in a task that required them to discriminate the direction of a visual or auditory motion signal in noise. We identified a distinct set of cerebellar regions that were differentially activated for visual stimuli (vermal lobule VI and right-hemispheric lobule X) and auditory stimuli (right-hemispheric lobules VIIIA and VIIIB and hemispheric lobule VI bilaterally). In addition, we identified a region in left crus I in which activity correlated significantly with increases in the perceptual demands of the task (i.e., with decreasing signal strength), for both auditory and visual stimuli. Our results support suggestions of a role for the cerebellum in the processing of auditory and visual motion and suggest that parts of cerebellar cortex are concerned with tracking movements of objects around the animal, rather than with controlling movements of the animal itself (Paulin, 1993).

Gastrointestinal symptoms in ASD, brain structure of identical twins with ASD

Gastrointestinal symptoms in ASD, brain structure of identical twins with ASD

Gaze Pursuit Responses in Nucleus Reticularis Tegmenti Pontis of Head-Unrestrained Macaques

Eye-head gaze pursuit-related activity was recorded in rostral portions of the nucleus reticularis tegmenti pontis (rNRTP) in alert macaques. The head was unrestrained in the horizontal plane, and macaques were trained to pursue a moving target either with their head, with the eyes stationary in the orbits, or with their eyes, with their head voluntarily held stationary in space. Head-pursuit-related modulations in rNRTP activity were observed with some cells exhibiting increases in firing rate with increases in head-pursuit frequency. For many units, this head-pursuit response appeared to saturate at higher frequencies (>0.6 Hz). The response phase re:peak head-pursuit velocity formed a continuum, containing cells that could encode head-pursuit velocity and those encoding head-pursuit acceleration. The latter cells did not exhibit head position-related activity. Sensitivities were calculated with respect to peak head-pursuit velocity and averaged 1.8 spikes/s/deg/s. Of the cells that were tested for both head- and eye-pursuit-related activity, 86% exhibited responses to both head- and eye-pursuit and therefore carried a putative gaze-pursuit signal. For these gaze-pursuit units, the ratio of head to eye response sensitivities averaged approximately 1.4. Pursuit eccentricity seemed to affect head-pursuit response amplitude even in the absence of a head position response per se. The results indicated that rNRTP is a strong candidate for the source of an active head-pursuit signal that projects to the cerebellum, specifically to the target-velocity and gaze-velocity Purkinje cells that have been observed in vermal lobules VI and VII.

Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor

Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4 −/−) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4 −/− brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4 −/− cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4 −/− cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4 −/− cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4 −/− mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4 −/− brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development.

Delayed postnatal settlement of cerebellar Purkinje cells in vermal lobules VI and VII of the mouse

The postnatal development of the ganglionic (Purkinje) layer was studied in the mouse cerebellum from P0 to young adulthood with special emphasis to vermal lobules VI-VII (oculomotor vermis) in the mouse. In order to visualize Purkinje cells (PCs), toluidine blue staining of resin-embedded semithin sections and calbindin immunohistochemistry were utilized. The number of PCs in the whole cerebellum was 199,080+/-2966 at postnatal day eight (P8), 222,000+/-2979 at P20 and nearly the same, 225,800+/-7549 in young adults; i.e., there was an approximately 13.4% increase of PCs between P8 and adults. The number of PC somata aligned into a rostrocaudal stripe along the developing ganglionic layer increased by about 24% in vermal cerebellar lobule III but much more markedly (i.e., by 49%) in VI+VII between P6 and young adulthood. Between P6 and P16, the increase of the number of PCs in the ganglionic layer of lobules VI and VII resulted in the (delayed) completion of PC layer, caused by the (late) alignment of rostrocaudally dispersed PCs, although late postnatal migration of a smaller population of these cells cannot be excluded either. It is concluded that the oculomotor vermis belongs to the latest developing cerebellar cortical structures, which could be the reason for its frequent involvement in developmentally related disturbances and disorders.

Cerebellar neural responses related to actively and passively applied noxious thermal stimulation in human subjects: a parametric fMRI study*1

Cerebellar activation is consistently found during noxious stimulation but little is known about its pain-related specificity. Under natural circumstances noxious stimuli are actively or passively delivered with concomitant tactile sensory stimulation. Using fMRI we therefore studied pain-related cerebellar activation with innocuous and noxious thermal stimuli in a parametric design taking motor execution as confounding factor into account. With respect to psychophysical pain ratings anterior vermal and ipsilateral hemispheric lobule VI activation was parametrically modulated for stimulus intensity in actively but not in passively elicited thermal stimulation. The cerebellum seems to be capable of distinguishing active from passive painful stimuli.

Cerebellar neural responses related to actively and passively applied noxious thermal stimulation in human subjects: a parametric fMRI study

Cerebellar activation is consistently found during noxious stimulation but little is known about its pain-related specificity. Under natural circumstances noxious stimuli are actively or passively delivered with concomitant tactile sensory stimulation. Using fMRI we therefore studied pain-related cerebellar activation with innocuous and noxious thermal stimuli in a parametric design taking motor execution as confounding factor into account. With respect to psychophysical pain ratings anterior vermal and ipsilateral hemispheric lobule VI activation was parametrically modulated for stimulus intensity in actively but not in passively elicited thermal stimulation. The cerebellum seems to be capable of distinguishing active from passive painful stimuli.

Contrasting expression of Kv4.3, an A‐type K+ channel, in migrating Purkinje cells and other post‐migratory cerebellar neurons

Kv4.3, an A-type K+ channel, is the only channel molecule showing anterior-posterior (A-P) compartmentalization in the granular layer of mammalian cerebellum known so far. Kv4.3 mRNA has been detected from the posterior but not anterior granular layer in adult rat cerebellum. To characterize this A-P compartmentalization further, we examined Kv4.3 protein expression in rat cerebellum by immunohistochemistry at the embryonic, early postnatal and adult stages. Specificity of the Kv4.3 antibody was confirmed by both Western blot and immunoprecipitation analysis. In adulthood, Kv4.3 was detected from the somatodendritic domain of posterior granule cells, with a restriction boundary in the vermal lobule VI extending laterally to the hemispheric crus 1 ansiform lobules. At the early postnatal stage, this A-P pattern first appeared on postnatal day 8, when significant numbers of granule cells had migrated into the posterior granular layer and started to express Kv4.3. Similar Kv4.3 expression in the somatodendritic domain of post-migratory neurons in the cerebellum was also observed in basket cells, stellate cells, a subset of GABAergic deep neurons, Lugaro cells and, probably, deep Lugaro cells. However, none of them showed A-P compartmentalization. Strikingly, we found Kv4.3 in several clusters of migrating Purkinje cells with mediolateral compartmentalization. These Purkinje cells no longer expressed Kv4.3 after completing the migration. By contrasting the expression in migrating and post-migratory neurons, our results suggest that Kv4.3 may play an important role in the development of cerebellum, as well as in the mature cerebellum.

Multiple zonal projections of the nucleus reticularis tegmenti pontis to the cerebellar cortex of the rat.

Compartmentalization (alternating labelled and unlabelled stripes) of mossy fibre terminals was found in the cerebellar cortex after iontophoretic injections of biotinylated dextran amine into discrete regions of the nucleus reticularis tegmenti pontis (NRTP). The zonal pattern was only observed when volumes of nuclear tissue ranging from 4.5 x 106 to 17.66 x 106 microm3 were impregnated. Up to nine compartments (i.e. up to five stripes separated by four interstripes) were found in crus I and in vermal lobule VI. Up to seven compartments (four stripes and three interstripes) were found in crus II; up to five compartments (three stripes and two interstripes) were identified in the lobulus simplex, the paraflocculus and vermal lobules IV, V and VII; up to three compartments (two stripes and one interstripe) were identified in the paramedian lobule and, finally, up to two compartments (one stripe and one interstripe) were identified in the copula pyramidis, in the flocculus and in vermal lobules II, III, VIII and IX. The projections of the NRTP are arranged according to a divergent/convergent projection pattern. From single injections in the NRTP, projections were traced to a set of cortical stripes widely distributed over the cerebellar cortex. The set of stripes labelled from different regions of the NRTP partially overlapped but complete overlap was never found. This finding revealed that the topographic combination of the projections of the NRTP to the cerebellar cortex is specific for each region of the NRTP. Finally, the projections to single cortical areas were arranged according to a pattern of compartmentalization that is specific for each cortical area, independent of the site of injection in the NRTP and of the number of stripes evident in the cortex.

Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism

Background: Although limited environmental exploration in autism is an obvious behavioral feature and may be a manifestation of “restricted interests” as described in DSM-IV criteria, there have been no behavioral or neurobiological studies of this important aspect of the disorder. Given consistent reports of cerebellar abnormality in autism, combined with animal research showing a relationship between exploration and the cerebellum, this study aimed to test the possible link between cerebellar abnormality and exploration in autism. Methods: The relationship between visuospatial exploration, stereotyped motor movements, and magnetic resonance imaging measures of the cerebellar vermis, whole brain volume, and frontal lobes in 14 autistic and 14 normal children was investigated. Children were exposed to a large room with several exploration containers and instructed to play. Exploration behavior was videotaped and scored for percentage of time engaged in exploration, number of containers explored, as well as stereotyped movements. Results: Children with autism spent significantly less time in active exploration and explored fewer containers overall than normal children. Measures of decreased exploration were significantly correlated with the magnitude of cerebellar hypoplasia of vermal lobules VI–VII in the autistic children, but no relationship to vermis size was found with normal control children. Further, measures of rates of stereotyped behavior were significantly negatively correlated with area measures of cerebellar vermis lobules VI–VII and positively correlated with frontal lobe volume in the autism sample. Conclusions: Reduced environmental exploration and repetitive behavior may have particularly important developmental consequences for children with autism because it may lead them to miss learning opportunities that fall outside their scope of interest. Our findings represent the first documented link between the restricted range of interests and stereotyped behaviors pathognomonic of autism and particular neuroanatomic sites.

Multiple zonal projections of the basilar pontine nuclei to the cerebellar cortex of the rat.

This study revealed a sagittal zonal pattern of projections to the cerebellar cortex after hydraulic or iontophoretic injections of anterograde tracers (tritiated leucine, wheat germ agglutinin-horseradish peroxidase, or biotinylated dextrane amine) in the basilar pontine nuclei of Wistar rats. The zonal pattern of projection was observed only after injections of small size, whereas large injections labeled diffusely wide areas of the cerebellar cortex, masking the zonal projection because the fusion of contiguous stripes. Diverging projections to discrete sets of sagittal stripes in the two sides of the cerebellar cortex arose from single injections. The stripes of fiber terminals were sharply delimited on both sides by areas, interstripes, either virtually void of labeling or with a much lower density of labeling. Thus, the areas of the cerebellar cortex were parceled in sets of sagittal compartments, stripes and interstripes, by the pontine projections. Up to five compartments (three stripes and two interstripes) were observed in the paraflocculus, in the copula pyramidis, and in vermal lobule IX. Up to nine compartments (five stripes and four interstripes) were found in the crus I, the lobulus simplex, the paramedian lobule, and vermal lobules VI-VIII. Up to seven compartments (four stripes and three interstripes) were found in the crus II. Single injections into the basilar pontine nuclei usually labeled symmetric areas of the cerebellar cortex, which, in some cases, showed similar number of stripes. When this was not the case, the stripes were usually more numerous in the contralateral than in the ipsilateral side. All areas of the cerebellar cortex were projected upon, with zonation patterns from different regions of the basilar pontine nuclei. The projections of the basilar pontine nuclei to the cerebellar cortex were arranged according to a fixed pattern specific for each cortical area, independently of the number of stripes labeled within. The mean width of the stripes visualized in the single cortical areas of different rats was similar, despite the different size of the injections. The length of the stripes ranged widely in the various areas of different rats. The data collected in this study are consistent with the idea that all the mossy afferents to the cerebellar cortex are arranged with a zonal pattern.

Clinical correlates of brain morphometric features of subjects with low-functioning autistic disorder.

Numerous neuropathologic and imaging studies have reported different structural abnormalities in the brains of autistic subjects. However, whether or not the degree of brain abnormality is correlated with the severity of developmental impairment in autistic disorder is still unknown. The midsagittal area of the cerebrum, corpus callosum, midbrain, cerebellar vermis, and vermal lobules VI and VII was measured by means of magnetic resonance imaging in 22 boys with low-functioning autistic disorder and in 11 age-matched normal controls. Morphometric measures were statistically compared between groups and correlated with age and scores on the Psychoeducational Profile-Revised and the Childhood Autism Rating Scale. A significant negative correlation was found between midsagittal area of the cerebrum and age in patients with autistic disorder, and a positive correlation was found between the midsagittal area of the midbrain and some subscales of the Psychoeducational Profile-Revised.

Oculomotor evidence for neocortical systems but not cerebellar dysfunction in autism.

To investigate the functional integrity of cerebellar and frontal systems in autism using oculomotor paradigms. Cerebellar and neocortical systems models of autism have been proposed. Courchesne and colleagues have argued that cognitive deficits such as shifting attention disturbances result from dysfunction of vermal lobules VI and VII. Such a vermal deficit should be associated with dysmetric saccadic eye movements because of the major role these areas play in guiding the motor precision of saccades. In contrast, neocortical models of autism predict intact saccade metrics, but impairments on tasks requiring the higher cognitive control of saccades. A total of 26 rigorously diagnosed nonmentally retarded autistic subjects and 26 matched healthy control subjects were assessed with a visually guided saccade task and two volitional saccade tasks, the oculomotor delayed-response task and the antisaccade task. Metrics and dynamics of the visually guided saccades were normal in autistic subjects, documenting the absence of disturbances in cerebellar vermal lobules VI and VII and in automatic shifts of visual attention. Deficits were demonstrated on both volitional saccade tasks, indicating dysfunction in the circuitry of prefrontal cortex and its connections with the parietal cortex, and associated cognitive impairments in spatial working memory and in the ability to voluntarily suppress context-inappropriate responses. These findings demonstrate intrinsic neocortical, not cerebellar, dysfunction in autism, and parallel deficits in higher order cognitive mechanisms and not in elementary attentional and sensorimotor systems in autism.