John F. Stein

Is the Cerebellum a Smith Predictor

The motor system may use internal predictive models of the motor apparatus to achieve better control than would be possible by negative feedback. Several theories have proposed that the cerebellum may form these predictive representations. In this article, we review these theories and try to unify them by reference to an engineering control model known as a Smith Predictor. We suggest that the cerebellum forms two types of internal model. One model is a forward predictive model of the motor apparatus (e.g., limb and muscle), providing a rapid prediction of the sensory consequences of each movement. The second model is of the time delays in the control loop (due to receptor and effector delays, axonal conductances, and cognitive processing delays). This model delays a copy of the rapid prediction so that it can be compared in temporal register with actual sensory feedback from the movement. The result of this comparison is used both to correct for errors in performance and as a training signal to learn the first model. We discuss evidence that the cerebellum could form both of these models and suggest that the cerebellum may hold at least two separate Smith Predictors. One, in the lateral cerebellum, would predict the movement outcome in visual, egocentric, or peripersonal coordinates. Another, in the intermediate cerebellum, would predict the consequences in motor coordinates. Generalization of the Smith Predictor theory is discussed in light of cerebellar involvement in nonmotor control systems, including autonomic functions and cognition.

Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers

BACKGROUND Developmental dyslexia is a specific disorder of reading and spelling that affects 3-9% of school-age children and adults. Contrary to the view that it results solely from deficits in processes specific to linguistic analysis, current research has shown that deficits in more basic auditory or visual skills may contribute to the reading difficulties of dyslexic individuals. These might also have a crucial role in the development of normal reading skills. Evidence for visual deficits in dyslexia is usually found only with dynamic and not static stimuli, implicating the magnocellular pathway or dorsal visual stream as the cellular locus responsible. Studies of such a dissociation between the processing of dynamic and static auditory stimuli have not been reported previously. RESULTS We show that dyslexic individuals are less sensitive both to particular rates of auditory frequency modulation (2 Hz and 40 Hz but not 240 Hz) and to dynamic visual-motion stimuli. There were high correlations, for both dyslexic and normal readers, between their sensitivity to the dynamic auditory and visual stimuli. Nonword reading, a measure of phonological awareness believed crucial to reading development, was also found to be related to these sensory measures. CONCLUSIONS These results further implicate neuronal mechanisms that are specialised for detecting stimulus timing and change as being dysfunctional in many dyslexic individuals. The dissociation observed in the performance of dyslexic individuals on different auditory tasks suggests a sub-modality division similar to that already described in the visual system. These dynamic tests may provide a non-linguistic means of identifying children at risk of reading failure.

Contrast sensitivity and coherent motion detection measured at photopic luminance levels in dyslexics and controls

Development dyslexics perform differently from controls on a number of low level visual tasks. We carried out three experiments to explore some of these differences. Dyslexics have been found to have reduced luminance contrast sensitivity at mesopic luminance levels. We failed to replicate this finding at photopic luminance levels. We also compared the (photopic) coherent motion detection thresholds of groups of child and adult dyslexics with those of age matched controls. Dyslexics were significantly less sensitive to motion. The results are discussed in relation to a recent suggestion that developmental dyslexia may be associated with a magnocellular visual deficit.

LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia

Left–right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.

Differences in eye movements and reading problems in dyslexic and normal children.

It has been suggested that eye movement abnormalities seen in dyslexics are attributable to their language problems. In order to investigate this claim, we studied eye movements in dyslexic children, during several non-reading tasks. Dyslexic children were compared to normal and backward readers on measures of fixation, vergence amplitude, saccade and smooth pursuit. The results were compared to the childrens phonological ability. Dyslexic children (n = 26) had significantly worse eye movement stability during fixation of small targets than normal children (n = 39). Vergence amplitudes were lower for dyslexics than for controls. A qualitative assessment of saccadic eye movements revealed that dyslexics exhibit fixation instability at the end of saccades. Assessment of smooth pursuit revealed poor smooth pursuit in the dyslexic group, particularly when pursuing a target moving from left to right. Dyslexic children also performed significantly worse than normal children on a test of phonological awareness (Pig Latin). Eye movement results were studied in the light of the findings on phonological awareness: dyslexics with small vergence amplitudes also always have poor phonemic awareness. However, poor fixation control is found in dyslexics with or without poor phonological ability. The backward reading children performed similar to the dyslexics on all tests, suggesting that the deficiencies observed in this study are not specific to children with dyslexia. The problems experienced by the children (revealed by a questionnaire) are in agreement with those measured in terms of eye movement recordings and phonemic awareness. Sex, handedness, IQ or the presence of attention deficit disorder (ADD) did not appear to influence the childrens performances on any of the eye movement tasks. The presence of oculomotor abnormalities in a non-reading task strongly suggests that the underlying deficit in the control of eye movements seen in dyslexics is not caused by language problems alone.

A 77-Kilobase Region of Chromosome 6p22.2 Is Associated with Dyslexia in Families From the United Kingdom and From the United States

Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of approximately 12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.

Paradoxical movement in Parkinson's disease

Patients with Parkinsons disease, although impaired, can sometimes move effectively under visual guidance. The stimuli that often elicit such paradoxical movement are similar to those that relay visual information to the cerebellum. We suggest that many instances of paradoxical movement may be explained by the fact that the pathways relaying those visual stimuli can bypass the damaged basal ganglia and allow an intact cerebellar circuit to be used for visuomotor control.

Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation.

Parkinsons disease is treated pharmacologically with dopamine replacement medication and, more recently, by stimulating basal-ganglia nuclei such as the subthalamic nucleus (STN). Depth recordings after this procedure have revealed excessive activity at frequencies between 8 and 35 Hz (Brown et al., 2001; Kuhn et al., 2004; Priori et al., 2004) that are reduced by dopamine therapy in tandem with improvements in bradykinesia/rigidity, but not tremor (Kuhn et al., 2006). It has also been shown that improvements in motor symptoms after dopamine correlate with single unit activity in the beta range (Weinberger et al., 2006). We recorded local field potentials (LFPs) from the subthalamic nucleus of patients with Parkinsons disease (PD) after surgery to implant deep brain stimulating electrodes while they were on and off dopaminergic medication. As well as replicating Kuhn et al., using the same patients we were able to extend Weinberger et al. to show that LFP beta oscillatory activity correlated with the degree of improvement in bradykinesia/rigidity, but not tremor, after dopamine medication. We also found that the power of beta oscillatory activity uniquely predicted improvements in bradykinesia/rigidity, but again not tremor, after stimulation of the STN in a regression analysis. However improvements after STN stimulation related inversely to beta power, possibly reflecting the accuracy of the electrode placement and/or the limits of STN stimulation in patients with the greatest levels of beta oscillatory activity.

Globus pallidus internus deep brain stimulation for dystonic conditions: A prospective audit

In the current era of functional surgery for movement disorders, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favoured target in the treatment of patients with dystonia. The results of 25 consecutive patients with medically intractable dystonia (12 with generalised dystonia, 7 with spasmodic torticollis, and 6 with other types of dystonia) treated with GPi stimulation are reported. Although comparisons were limited by differences in their respective neurological rating scales, chronic DBS benefited all groups, resulting in clear and progressive improvements in their condition. This study clearly demonstrates that DBS of the GPi provides amelioration of intractable dystonia.

Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey

We have studied the effects of stimulating the pedunculopontine nuclei through a fully implanted macroelectrode with a s.c. implantable pulse generator whose parameters can be programmed telemetrically, in a macaque before and after inducing Parkinsonian akinesia with MPTP. Our results show that in the normal monkey high frequency stimulation of the pedunculopontine nuclei reduces motor activity while low frequency stimulation increases it significantly over baseline. After making the monkey Parkinsonian with MPTP, unilateral low frequency stimulation of the pedunculopontine nuclei led to significant increases in activity. These results suggest that pedunculopontine nuclei stimulation could be clinically effective in treating advanced Parkinsons disease and other akinetic disorders.