Abnormalities Of Sensorimotor Integration Research Articles

Changes in brainstem excitatory and inhibitory pathways in dry eye syndrome

BackgroundWe hypothesized that there may be changes in sensory integration pathways in patients with dry eye. To confront this issue, we analyzed blink reflex (BR), prepulse modulation (PPM) of BR, and excitability recovery of BR to paired stimuli in 17 experimental subjects with dry eye syndrome. MethodWe included 17 experimental subjects, 8 with primary and 9 with secondary, dry eye syndrome. We also examined a control group of 14 age and gender matched control subjects. After clinical evaluation, we recorded BR, PPM of BR (at 50 and 100 ms intervals) and BR percentage recovery to paired stimulation (at 300 and 500 ms intervals). ResultsNone of the patients had any spasm activity. Experimental subjects had significantly larger R2 and R2c AUCs, significantly greater excitability recovery at 300 ms interval and significantly reduced R2 and R2c prepulse inhibition, in comparison to control subjects. Experimental subjects with primary dry eye syndrome had higher number of spontaneous blinks than experimental subjects with secondary dry eye syndrome (54.0 ± 10.3 for primary dry eye and 43.5 ± 13.3 secondary dry eye). ConclusionOur results are compatible with increased excitability and abnormalities in sensorimotor integration in blink reflex circuits of patients with dry eye. This suggests the development of adaptive changes in brainstem synaptic activity, aimed at facilitation of blinking in the context of increased sensory input from corneal irritation.

Loss of egli-1, the Caenorhabditis elegans Orthologue of a Downstream Target of SMN, Leads to Abnormalities in Sensorimotor Integration.

The connectome of Caenorhabditis elegans has been extensively studied and fully mapped, allowing researchers to more confidently conclude on the impact of any change in neuronal circuits based on behavioral data. One of the more complex sensorimotor circuits in nematodes is the one that regulates the integration of feeding status with the subsequent behavioral responses that allow animals to adapt to environmental conditions. Here, we have characterized a Caenorhabditis elegans knockout model of the egli-1 gene (previously known as tag-175). This is an orthologue of the stasimon/tmem41b gene, a downstream target of SMN, the depleted protein in spinal muscular atrophy (SMA), which partially recapitulates the SMA phenotype in fly and zebrafish models when mutated. Surprisingly, egli-1 mutants reveal no deficits in motor function. Instead, they show functional impairment of a specific neuronal circuit, leading to defects in the integration of sensorial information related to food abundance, with consequences at the level of locomotion adaptation, egg laying, and the response to aversive chemical stimuli. This work has demonstrated for the first time the relevance of egli-1 in the nervous system, as well as revealed a function for this gene, which had remained elusive so far.

How psychogenic is dystonia? views from past to present

In the last few centuries, there has been a constant sway between organic and psychogenic explanations for dystonia. In the current study, we investigate this history, assuming the perspective of a spectrum from organic to psychogenic, between which ideas were moving. We have focussed on (i) primary generalized dystonia, (ii) cervical dystonia, (iii) writer's cramp and (iv) fixed dystonia related to complex regional pain syndrome. We have studied medical texts published since the 19th century and their references. Jean-Martin Charcot advocated the concept of hysteria, disorders in which, besides predisposition, environmental factors were involved in their pathogenesis. Sigmund Freud introduced psychoanalysis as an explanatory therapy for psychic disorders. Previous theories, together with the lack of an organic substrate for dystonia, made a strong case for psychogenic explanations. Consequently, many dystonia patients were told that they suffered from psychological conflicts and were treated for them. However, after the description of new hereditary cases in the 1950s, the limited efficacy of psychotherapy in torsion dystonia, the effects of surgical treatments and the lesion studies in the 1960s, more physicians became convinced of the organic nature. The culminating point was the discovery of the DYT1 gene in 1997. In the meantime, experts had already convinced the neurological community that cervical dystonia and writer's cramp were focal dystonias, i.e. minor forms of generalized dystonia, and therefore organic disorders. In contrast, the pathophysiology of fixed dystonia related to complex regional pain syndrome remained controversial. Knowledge of this history, which played on the border between neurology and psychiatry, is instructive and reflects the difficulty in discriminating between them. Today, new insights from functional imaging and neurophysiological studies again challenge the interpretation of these disorders, while the border between psychogenic and organic has become more blurred. Abnormalities of sensorimotor integration and cortical excitability that are currently supposed to be the underlying cause of dystonia bring us back to Sherringtonian physiology. We suggest that this may lead to a common explanation of the four afflictions of which we have traced the history.

Characterization of an immunodeficient mouse model of mucopolysaccharidosis type I suitable for preclinical testing of human stem cell and gene therapy

Mucopolysaccharidosis type I (MPS-I or Hurler syndrome) is an inherited deficiency of the lysosomal glycosaminoglycan (GAG)-degrading enzyme α- l-iduronidase (IDUA) in which GAG accumulation causes progressive multi-system dysfunction and death. Early allogeneic hematopoietic stem cell transplantation (HSCT) ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects its most devastating features including mental retardation and skeletal deformities. To test novel therapies, we characterized an immunodeficient MPS-I mouse model less likely to develop immune reactions to transplanted human or gene-corrected cells or secreted IDUA. In the liver, spleen, heart, lung, kidney and brain of NOD/SCID/MPS-I mice IDUA was undetectable, and reduced to half in heterozygotes. MPS-I mice developed marked GAG accumulation (3–38-fold) in these organs. Neuropathological examination showed GM 3 ganglioside accumulation in the striatum, cerebral peduncles, cerebellum and ventral brainstem of MPS-I mice. Urinary GAG excretion (6.5-fold higher in MPS-I mice) provided a non-invasive and reliable method suitable for serially following the biochemical efficacy of therapeutic interventions. We identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and motor skills development. This Rotarod test revealed marked abnormalities in sensorimotor integration involving the cerebellum, striatum, proprioceptive pathways, motor cortex, and in acquisition of motor coordination. NOD/SCID/MPS-I mice exhibit many of the clinical, skeletal, pathological and behavioral abnormalities of human MPS-I, and provide an extremely suitable animal model for assessing the systemic and neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy.

Characterization of an Immunodeficient Mucopolysaccharidosis Type I (MPS-I) Mouse Model Suitable for Preclinical Testing of Human Stem Cell and Gene Therapy.

Mucopolysaccharidosis type I (MPS-I; Hurler syndrome) is an inborn metabolic disorder due to lack of the lysosomal glycosaminoglycan (GAG)-degrading enzyme alpha-L-iduronidase (IDUA). The resulting GAG accumulation causes progressive multi-system dysfunction and death in the first decade. We recently identified structural abnormalities in the accumulated GAGs that lead to defective heparin-binding cytokine signaling in MPS-I (Pan C et al, Blood 2005 in press: DOI 10.1182/blood-2005-02-0657), which may constitute a mechanism responsible for the diverse clinical manifestations of MPS-I and related mucopolysaccharidoses. Allogeneic hematopoietic stem cell transplantation (HSCT), if performed early in the disease, ameliorates many clinical features and extends life. However, HSCT is not available to all patients, and also does not adequately correct some of the most devastating features of MPS-I including mental retardation and skeletal deformities. Therefore, novel cellular, enzyme replacement and gene therapy approaches need to be developed for MPS-I. Such therapeutic strategies will best be tested in an immunodeficient host which is less likely to develop immune reactions to transplanted human or gene-corrected cells or their secreted IDUA enzyme. We have bred and characterized a homozygous immunodeficient MPS-I mouse (developed as a heterozygous MPS-I mouse on a NOD/SCID background by Jackson Labs) that is well suited for examining the efficacy of such therapeutic approaches. The phenotype of homozygous NOD/SCID/MPS-I mice closely mimicked the clinical features of human MPS-I including coarsening of facial features, skeletal deformities and diverse behavioral abnormalities. IDUA enzyme was completely undetectable in the liver, spleen, heart, lung, kidney and brain of homozygous animals (P<0.001) and was reduced to approximately 50% in heterozygous animals. Homozygous animals developed marked GAG accumulation (3 to 25 fold) in the same organs (P=0.03 to P<0.0001). Neuropathological examination showed accumulation of GM3 gangliosides in the cerebral peduncles, cerebellum and ventral brainstem of homozygous mice. Importantly, measurement of urinary GAG excretion (5-fold higher in homozygous animals; P<0.003) provided a non-invasive and reliable method that can be used to serially follow the biochemical efficacy of therapeutic interventions. We also identified and validated using rigorous biostatistical methods, a highly reproducible method for evaluating sensorimotor function and learning in this mouse model. This Rotarod Test revealed marked abnormalities in sensorimotor integration involving the cerebellum, niagro-striatal and proprioceptive pathways and motor cortex, as well as in learning. We believe that NOD/SCID/MPS-I mice will provide an extremely suitable animal model for assessing the systemic as well as neurological effects of human stem cell transplantation and gene therapeutic approaches, using the above techniques to measure efficacy. We have started using this model to assess the effect of intra-cerebroventricular implantation of human stem cells on the biochemical, pathological and behavioral abnormalities identified. Similar strategies may be invaluable for developing and studying animal models of other MPSs and related diseases.

Abnormalities of sensorimotor integration in focal dystonia: a transcranial magnetic stimulation study.

It has been postulated that sensorimotor integration is abnormal in dystonia. We investigated changes in motor cortical excitability induced by peripheral stimulation in patients with focal hand dystonia (12 patients with hand cramps) and with cervical dystonia (nine with spasmodic torticollis) compared with 16 age-matched normal controls. Motor evoked potentials (MEP) to focal (figure-of-eight coil) transcranial magnetic stimulation of the hand area were recorded from the right abductor pollicis brevis (APB), first dorsal interosseus (FDI), flexor carpi radialis and extensor carpi radialis muscles. Changes of test MEP size following conditioning stimulation of the right median nerve (or of the index finger) at conditioning-test (C-T) intervals of 50, 200, 600 and 1000 ms were analysed. Peripheral stimulation significantly reduced test MEP size in the APB and FDI muscles of normal control and spasmodic torticollis patients. The inhibitory effect was larger upon median nerve stimulation and reached a maximum at the C-T interval of 200 ms. On the contrary, hand cramp patients showed a significant facilitation of test MEP size. This study suggests that MEP suppression following peripheral stimulation is defective in patients with focal hand dystonia. Central processing of sensory input is abnormal in dystonia and may contribute to increased motor cortical excitability.

Kinematic properties of upper limb trajectories in idiopathic torsion dystonia.

The kinematic properties of upper limb trajectories of simple reaching movements have been analysed in patients with idiopathic torsion dystonia (ITD). The velocity profiles differed from those of neurologically healthy subjects by being less symmetric. In several patients movement execution was slow due to a longer deceleration time. This phenomenon was even more conspicuous in the absence of visual feedback from the limb and was accompanied by a significant decrease in the final accuracy. These findings show that patients with ITD have deficits in central motor mechanisms beyond abnormal muscle activation patterns. Similarities between kinematic properties of patients with ITD and patients with Parkinson's disease including the deterioration of motor performance in ITD in the absence of visual feedback from the limb, suggest the existence of abnormalities in sensorimotor integration in both diseases.