Cerebral Palsy

Mixed Reality (MR) refers to the blending of virtual content into the real world. Using MR, we create contextually meaningful scenarios in which users carry out tasks encountered in the presence of visual and aural distracters. Visual distracters can include subtle ones – people walking; and more abrupt ones – cartons falling. Aural distracters can include gentle ones – fans whirring; and more aggressive ones – automobiles backfiring. The intensity of these distracters can be dynamically controlled by a therapist or software that takes into account the patient’s perceived level of stress. Intensity can also be controlled between experiences. For example, one may increase the stress level in a subsequent session, attempting to improve a person’s tolerance. Assessment of progress includes psychophysical metrics (stress indicators) and the performance of tasks (accuracy and adherence to time constraints). By accurately capturing a patient’s interaction with the environment in the context of simulation events, we can use MR as a tool for assessment and rehabilitation planning for individuals with stress-related injuries. This paper reports on the MR environment we have developed and its efficacy (realized and potential) for the assessment of post-traumatic stress disorder (PTSD) with or without traumatic brain injury (TBI).

Disorders of visual search by coordinated eye and head movements are frequently encountered in patients with brain damage. Homonymous visual field disorders, impaired elementary visual capacities (e.g. acuity, contrast sensitivity, convergent fusion, oculomotor disorders), visual neglect, Balint-Holmes syndrome or dementia (e.g. Alzheimer’s disease) are the most frequent causes of such disorders. Efficient visual search is necessary to select salient stimuli and bring them onto the fovea in order to perform an in-depth analysis. Visual search is not only an indispensible capacity for visual activities in vocational and private life but is also important for many motor and cognitive abilities such as reaching, grasping, standing, spatial perception, route navigation as well as mobility. Despite this importance no comprehensive system exists for the standardized assessment and treatment of visual search disorders in the German-speaking area. In this article, we describe the basic properties of such a system (EYEMOVE). After a short survey of the main causes of visual search disorders following brain damage, the diagnostic facilities, normative data as well as a variety of treatment techniques of this novel system are described. Selected results from on-going clinical studies highlight the practicability and effectiveness of this novel system which contributes to a better management of visual search disorders in neurovisual rehabilitation.

BACKGROUND AND AIM: Angiotensin II acts through two major receptors: AT1-R and AT2-R. It is known that the stimulation of AT1-R mediates vasoconstriction, cell proliferation and fibrosis, aldosterone release and inflammatory response but, although the stimulation of AT2-R is thought to promote vasodilation and anti-inflammatory effects, its real in-vivo functions are still unclear. The aim of this study was to investigate the effects of specific and selective AT2-R stimulation on the pathological events occurring in spontaneously hypertensive stroke-prone rats (SHRSPs). METHODS AND RESULTS: SHRSPs who were fed a high-salt diet underwent long-term treatment with vehicle or compound 21 (C21), a nonpeptide selective AT2-R agonist, at doses of 0.75, 5 and 10 mg/kg per day. The vehicle-treated rats developed brain abnormalities detectable by magnetic resonance imaging after 42.5 +/- 7.5 days, and died 43 +/- 9.5 days after the start of the dietary treatment. The highest C21 dose delayed the occurrence of brain damage (P < 0.001 vs. vehicle-treated SHRSPs) and prolonged survival (P < 0.001) without affecting blood pressure. These beneficial effects of C21 were abolished by the administration of PD123319, an AT2-R antagonist. C21 treatment preserved renal structure by preventing inflammatory cell infiltration, collagen accumulation, and the neo-expression of vimentin; it also prevented the increased plasma renin activity and accumulation of urinary acute-phase proteins observed in the vehicle-treated rats. CONCLUSION: Specific and selective AT2-R stimulation has beneficial effects on the pathological events occurring in SHRSPs. These data indicate a new avenue for the pharmacological treatment of diseases in which modulation of the renin-angiotensin system is required.

Karwinskia humboldtiana fruit (Kh) causes a neurological disorder 3-4 weeks after ingestion, characterized by flaccid, symmetrical, ascending paralysis, similar to the Guillain-Barre syndrome. In this polyneuropathy the lesion (demyelization) in peripheral nerves has been described in several animal species, both in acute and in chronic intoxication. However, no reports exist about the presence of lesions in the Central Nervous System (CNS), in chronic intoxication. We considered it important to evaluate, with histological techniques, the possible presence of lesions in the brain, by using a model of chronic intoxication that reproduces the same stages present in the human intoxication, to better understanding of this pathological process. In our present work we fed the ground Kh fruit to Wistar rats and samples of brain, cerebellum, and pons were embedded in paraffin. Sections were stained with Hematoxylin & Eosin (HE) and special stains for nerve tissue. Histopathological changes were evaluated in the CNS through the different stages of the polyneuropathy and comparison to a control group. With this methodology, we found lesions in the motor pathway. This is the first report about the presence of neuronal damage caused by Kh in the Central Nervous System in chronic intoxication.

Oxidative stress has drawn a lot of attention in the past few decades, since it has been reported to participate in the mechanism of many diseases. Therefore, it seemed to be a good rationale to aim oxidative stress on therapeutic research. Sepsis is a complex systemic syndrome characterized by an imbalance between pro- and anti-inflammatory responses to a pathogen; its pathophysiology is a dynamic process which involves components of the immune system, the coagulation pathway, parenchymal cells, and the endocrine and metabolic pathways. It is well characterized that oxidative stress plays a crucial role in sepsis development, but the relation between central nervous system dysfunction and oxidative stress during sepsis is not well understood. Thus, we here summarize the current knowledge on the role of free radicals in the development of brain dysfunction in sepsis focusing on oxidative damage and the redox control of brain inflammatory pathways.

Synaptic activity can boost neuroprotection through a mechanism that requires synapse-to-nucleus communication and calcium signals in the cell nucleus. Here we show that in hippocampal neurons nuclear calcium is one of the most potent signals in neuronal gene expression. The induction or repression of 185 neuronal activity-regulated genes is dependent upon nuclear calcium signaling. The nuclear calcium-regulated gene pool contains a genomic program that mediates synaptic activity-induced, acquired neuroprotection. The core set of neuroprotective genes consists of 9 principal components, termed Activity-regulated Inhibitor of Death (AID) genes, and includes Atf3, Btg2, GADD45beta, GADD45gamma, Inhibin beta-A, Interferon activated gene 202B, Npas4, Nr4a1, and Serpinb2, which strongly promote survival of cultured hippocampal neurons. Several AID genes provide neuroprotection through a common process that renders mitochondria more resistant to cellular stress and toxic insults. Stereotaxic delivery of AID gene-expressing recombinant adeno-associated viruses to the hippocampus confers protection in vivo against seizure-induced brain damage. Thus, treatments that enhance nuclear calcium signaling or supplement AID genes represent novel therapies to combat neurodegenerative conditions and neuronal cell loss caused by synaptic dysfunction, which may be accompanied by a deregulation of calcium signal initiation and/or propagation to the cell nucleus.

Recent studies have suggested a tightly connected perisylvian neural network associated with spatial neglect. Here we investigated whether structural damage in one part of the network typically is accompanied with functional damage in other, structurally intact areas of this network. By combining normalized fluid-attenuated inversion-recovery (FLAIR) imaging, diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI) we asked whether or not lesions centering on fronto-temporal regions co-occur with abnormal perfusion in structurally intact parietal cortex. With thresholds applied to delineate behaviourally relevant malperfusion of brain tissue, the analysis of normalized time-to-peak (TTP) and maximal signal reduction (MSR) perfusion maps did not reveal significant changes outside the area of structural damage. In particular, we found no abnormal perfusion in the structurally intact inferior parietal lobule (IPL) and/or the temporo-parietal junction (TPJ). The present results obtained in three consecutively admitted neglect patients with fronto-temporal lesions indicate that structural damage in one part of the right perisylvian network associated with spatial neglect does not necessarily require dysfunction by malperfusion in other, structurally intact parts of the network to provoke spatial neglect. The neural tissue in the fronto-temporal cortex appears to have an original role in processes of spatial orienting and exploration.

Increased oxidative damage is a prominent and early feature in Alzheimer disease (AD). We previously crossed AD transgenic (APPsw) model mice with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa-/-APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol (alpha-Toc) supplementation. To investigate the mechanism of the increased Abeta accumulation, we here studied generation, degradation, aggregation and efflux of Abeta in the mice. The clearance of intracerebrally microinjected [125I]Abeta1-40 from brain was decreased in Ttpa-/- mice to be compared with wild-type mice, whereas the generation of Abeta was not increased in Ttpa-/-APPsw mice. The activity of an Abeta-degrading enzyme, neprilysin did not decrease, but the expression level of insulin-degrading enzyme (IDE) was markedly decreased in Ttpa-/- mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa-/- mouse brains compared with wild-type ones, and well-known molecules involved in Abeta transport from brain to blood, low-density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were upregulated in the small vascular fraction of Ttpa-/- mouse brains. Moreover, disappearance of intravenously administered [125I]Abeta1-40 was decreased in Ttpa-/- mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of alpha-Toc impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa-/-APPsw mouse brain and plasma.

The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively-normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses. 5/9 patients with LPA had cerebrospinal fluid biomarkers consistent with Alzheimer (AD) pathology (AD-PPA) and 2/9 patients had progranulin (GRN) mutations (GRN-PPA). The LPA group had tissue loss in a widespread left hemisphere network. Compared with PNFA and SD, the LPA group had more extensive involvement of grey matter in posterior temporal and parietal cortices and and long association white matter tracts. Overlapping but distinct networks were involved in the AD-PPA and GRN-PPA subgroups, with more anterior temporal lobe involvement in GRN-PPA. The importance of these findings are threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.

Due to the heterogeneous nature of most brain injuries, the contributions of gray and white matter involvement to motor deficits and recovery potential remain obscure. We tested the hypothesis that duration of hand motor impairment and recovery of skilled arm and hand motor function depends on the volume of gray and white matter damage of the frontal lobe. Lesions of the primary motor cortex (M1), M1+ lateral premotor cortex (LPMC), M1+ LPMC+ supplementary motor cortex (M2) or multi-focal lesions affecting motor areas and medial prefrontal cortex were evaluated in rhesus monkeys. Fine hand motor function was quantitatively assessed pre-lesion and for 3-12 months post-lesion using two motor tests. White and gray matter lesion volumes were determined using histological and quantitative methods. Regression analyses showed that duration of fine hand motor impairment was strongly correlated (R(2)> 0.8) with the volume of gray and white matter lesions, with white matter lesion volume being the primary predictor of impairment duration. Level of recovery of fine hand motor skill was also well correlated (R(2)> 0.5) with gray and white matter lesion volume. In some monkeys post-lesion skill exceeded pre-lesion skill in one or both motor tasks demonstrating that continued post-injury task practice can improve motor performance after localized loss of frontal motor cortex. These findings will assist in interpreting acute motor deficits, predicting the time course and expected level of functional recovery, and designing therapeutic strategies in patients with localized frontal lobe injury or neurosurgical resection.