Visual processing streams: interactions, impairments and implications for rehabilitation

The present thesis is organized in three sections. Section 1 (chapter 2) provides a general overview of the cortical and subcortical brain structures that are involved in visual processing and the way these systems interact. Three visual streams are described: a ventral, occipitotemporal stream for processing information related to specialized recognition of objects and faces; a dorsal, occipitoparietal stream for processing information related to movement, location and motor action; and a subcortical, cortico-amygdalar and thalamo-amygdalar pathway for processing of emotion-related information. Also, some of the most important visual impairments due to brain damage will be discussed. In section 2 (chapters 3 and 4) rehabilitation methods of damage to specific parts of the visual system will be reviewed. Section 3 (chapters 5, 6 and 7) consists of experimental studies that focus on interactions between overt and covert recognition of faces and emotional facial expressions. Finally, chapter 8 provides a summary of main findings of this thesis, which will be discussed in chapter 9.

Gene finding in genetically isolated populations

The struggle to identify susceptibility genes for complex disorders has stimulated geneticists to develop new approaches. One approach that has gained considerable interest is to focus on genetically isolated populations rather than on the general population. There remains much controversy and theoretical debate over the feasibility and advantages of such populations, but recent results speak in favor of the feasibility of this approach, and will be reviewed here

High content screening in neurodegenerative diseases

The functional annotation of genomes, construction of molecular networks and novel drug target identification, are important challenges that need to be addressed as a matter of great urgency(1-4). Multiple complementary 'omics' approaches have provided clues as to the genetic risk factors and pathogenic mechanisms underlying numerous neurodegenerative diseases, but most findings still require functional validation(5). For example, a recent genome wide association study for Parkinson's Disease (PD), identified many new loci as risk factors for the disease, but the underlying causative variant(s) or pathogenic mechanism is not known(6, 7). As each associated region can contain several genes, the functional evaluation of each of the genes on phenotypes associated with the disease, using traditional cell biology techniques would take too long. There is also a need to understand the molecular networks that link genetic mutations to the phenotypes they cause. It is expected that disease phenotypes are the result of multiple interactions that have been disrupted. Reconstruction of these networks using traditional molecular methods would be time consuming. Moreover, network predictions from independent studies of individual components, the reductionism approach, will probably underestimate the network complexity(8). This underestimation could, in part, explain the low success rate of drug approval due to undesirable or toxic side effects. Gaining a network perspective of disease related pathways using HT/HC cellular screening approaches, and identifying key nodes within these pathways, could lead to the identification of targets that are more suited for therapeutic intervention. High-throughput screening (HTS) is an ideal methodology to address these issues(9-12). but traditional methods were one dimensional whole-well cell assays, that used simplistic readouts for complex biological processes. They were unable to simultaneously quantify the many phenotypes observed in neurodegenerative diseases such as axonal transport deficits or alterations in morphology properties(13, 14). This approach could not be used to investigate the dynamic nature of cellular processes or pathogenic events that occur in a subset of cells. To quantify such features one has to move to multi-dimensional phenotypes termed high-content screening (HCS)(4, 15-17). HCS is the cell-based quantification of several processes simultaneously, which provides a more detailed representation of the cellular response to various perturbations compared to HTS. HCS has many advantages over HTS(18, 19), but conducting a high-throughput (HT)-high-content (HC) screen in neuronal models is problematic due to high cost, environmental variation and human error. In order to detect cellular responses on a 'phenomics' scale using HC imaging one has to reduce variation and error, while increasing sensitivity and reproducibility. Herein we describe a method to accurately and reliably conduct shRNA screens using automated cell culturing(20) and HC imaging in neuronal cellular models. We describe how we have used this methodology to identify modulators for one particular protein, DJ1, which when mutated causes autosomal recessive parkinsonism(21). Combining the versatility of HC imaging with HT methods, it is possible to accurately quantify a plethora of phenotypes. This could subsequently be utilized to advance our understanding of the genome, the pathways involved in disease pathogenesis as well as identify potential therapeutic targets

The neuropsychological rehabilitation of visual agnosia and Balint’s syndrome

Visual agnosia and Balint’s syndrome are complex neurological disorders of the higher visual system that can have a remarkable impact on individuals’ lives. Rehabilitation of these individuals is important to enable participation in everyday activities despite the impairment. However, the literature about the rehabilitation of these disorders is virtually silent. Therefore, the aim of this systematic review is to give an overview of available literature describing treatment approaches and their effectiveness with regard to these disorders. The search engines Psychinfo, Amed, and Medline were used, resulting in 22 articles meeting the criteria for inclusion. Only articles describing acquired disorders were considered. These articles revealed that there is some information available on the major subtypes of visual agnosia as well as on Balint’s syndrome which practising clinicians can consult for guidance. With regard to the type of rehabilitation, compensatory strategies have proven to be beneficial in most of the cases. Restorative training on the other hand has produced mixed results. Concluding, although still scarce, a scientific foundation about the rehabilitation of visual agnosia and Balint’s syndrome is evolving. The available approaches give valuable information that can be built upon in the future

Effects of low visual acuity on neuropsychological test scores:A simulation study

Objective: To systematically examine the effect of low visual acuity (LVA) on a number of commonly used neuropsychological tests. Method: In this study, the influence of LVA on a number of commonly used neuropsychological tests was examined in 238 healthy older adults (aged 50–80) without visual or neurological impairment. LVA was simulated using simulation glasses. Results: It was found that a simulated LVA of ∼0.2 (decimal acuity; Snellen 6/30 or 20/100, LogMAR 0.7) had a negative impact on test performance for the Trail Making Test, Complex Figure of Rey (copy score), and Visual Object and Space Perception battery subtest 3, but not for the Mini Mental State Examination and Balloons test. For some tests, the negative impact of LVA increased with age. Conclusions: These results have important implications for the use of neuropsychological tests in the visually impaired population. More specifically, when administering the Trail Making Test, Complex Figure of Rey (copy score), and Visual Object and Space Perception Battery subtest 3 to older people with LVA, low test scores should be interpreted with great caution. Low test scores on the Mini Mental State Examination and Balloons Test are not likely to be caused by LVA and are more likely to reflect actual cognitive impairment. The results contribute to the validity of neuropsychological assessment of older people with visual impairment, leading to more effective and more patient-based rehabilitation