No description available.

Huntington disease (HD) is a progressive, autosomal dominantly inherited, neurodegenerative disease that is characterised by involuntary movements (chorea), cognitive decline and psychiatric manifestations. HD is one of a number of late-onset neurodegenerative diseases caused by expanded glutamine repeats, with a likely similar biochemical basis. It has been suggested that the disease-causing mechanism in Huntington disease (and the other polyglutamine disorders) is the ability of polyglutamine to undergo a conformational change that can lead to the formation of very stable anti-parallel β-sheets; more specifically, amyloid structures. This hypothesis is supported by evidence that polyglutamine forms amyloid-like protein aggregates in vitro, which stain with Congo red (a histological stain for amyloid) and exhibit green birefringence under polarized light. Further support for this hypothesis is provided by evidence of Congo red staining with green birefringence, of purified aggregates from HD brain captured on cellulose acetate filters. This study describes the first finding of amyloid-like inclusion bodies in situ, in HD brain. Inclusions possessing an amyloid-like structure were identified by Congo red staining and polarized-light microscopy in the cortex and striatum of HD brain, but these were absent in both normal control brains and Alzheimer's disease brains. Amyloid-like inclusions were of a similar size to the immunohistochemically-detected neuronal inclusions reported by other investigators, however the frequency of the former was far lower than the latter and the relationship between the two types of inclusion is uncertain. Efforts to purify and characterise the amyloid-forming protein(s) in HD utilised the methodologies used to purify amylin from amyloid plaques in the diabetic pancreas, with a number of refinements. Internal fragments of three different proteins, glial fibrillary acidic protein (GFAP), histone H3 and hypothetical protein FLJ20623 were co-purified with the amyloid component of HD brain based on their increased abundance relative to control brains, and subsequently characterised. The role of these proteins in HD is investigated and discussed. In addition, an ~4285 dalton protein was co-purified with the amyloid component of HD brain; this protein was noticeably absent in control brain and displayed unusual biochemical properties, however an amino-acid sequence could not be determined. Interestingly, a protein of the same approximate size, and displaying similar properties, was purified from poorly soluble protein aggregates formed in polyglutamine-expressing cultured cells. SDS-PAGE and Western analysis of sub-cellular fractions of HD and control brain revealed a novel pattern of proteolysis at the N-terminus of huntingtin in HD relative to control, that is supported by recent literature. Myelin basic protein was demonstrated to co-migrate with an N-terminal huntingtin-positive peptide, with apparent molecular weight of ~20 kDa, using tryptic in-gel digestion and protein sequencing. This N-terminal huntingtin-positive peptide and the ~4285 dalton protein described above were both purified from amyloid-containing fractions and both resisted N-terminal protein sequencing. Due to the aberrant migration of polyglutamine-containing proteins in polyacrylamide gels, a possible identity between these peptides is proposed. Laser capture microscopy and tandem mass spectrometry were investigated as potential methods for the purification and characterisation of amyloid-forming proteins in HD and the further development of these techniques may enable the realisation of these aims in the future. The major contribution of this study has been the finding of amyloid-like inclusions in Huntington disease brain. This finding places HD and by association the other polyglutamine disorders into the category of amyloid diseases, and suggests that strategies to prevent amyloid accumulation, a focus of Alzheimer's Disease research, may be of much wider application to glutamine repeat disorders such as HD or vice versa.

No description available.

Hemineglect and unilateral extinction on double simultaneous stimulation in humans are neuropsychological disorders which sometimes follow a lesion to the cortex, subcortex or basal ganglia of one cerebral hemisphere. The main symptom is that the patient appears to neglect or be unaware of stimuli which impinge in one half of space relative to the patient's body. The side of space neglected is usually the side contralateral to the brain lesion. This thesis comprises a collection of studies on various aspects of these disorders. Experimental subjects were patients in the Neurology and Neurosurgical Wards of Auckland Hospital. All had clearly defined solitary unilateral brain lesions confirmed by Computerized Tomography. Chapter 1 provides a historical review of research in the area, defines concepts, reviews recent human and animal research on hemineglect and extinction, and outlines the different theories which have been proposed in order to explain hemineglect. Chapter 2 describes the methods used in neuropsychological testing, the criteria used in the selection of subjects, the etiologies of the different types of lesions sustained by the patient sample, and the neuropsychological tests used in the various studies. Chapter 3 is a study of the incidence and severity of visual hemineglect in a group of 56 patients with left-hemispheric lesions and 45 patients with right-hemispheric lesions. Five paper and pencil tests designed to measure the presence and severity of visual hemineglect were given to these patients. The incidence of hemineglect in the two groups did not differ significantly (50% and 44% in the left and right brain-damaged groups respectively). However, visual hemineglect was found to be more severe after right- than after left-hemispheric lesions. The two groups were found to differ significantly with respect to the loci of lesions most likely to result in hemineglect. In the right brain-damaged group most patients with hemineglect had posterior lesions, and in the left brain-damaged group most patients with hemineglect had anterior lesions. Possible reasons for this are discussed in terms of the effects the lateralization of language representation might have on the representation of spatial functions. Chapter 4 describes an experiment designed to determine whether patients with unilateral cerebral lesions neglect the contralesional sides of their mental images of the external world. This phenomenon has previously been observed for patients with left-sided visual neglect following right-hemispheric lesions. Twenty control subjects and 16 patients with right- and left-hemispheric lesions were involved in the experiment reported in this chapter. In the 'static' condition they viewed pairs of complex shapes displayed, one shape at a time, on a video-screen controlled by a computer. In the 'dynamic' condition the pairs of shapes apparently moved, one at a time, behind a narrow vertical slit. In both conditions the subject had to decide whether the two shapes of each pair were the same or different. In fact, some were the same, while some differed on the right and others on the left. In the 'dynamic' condition subjects had to construct spatial images from non-spatial external stimuli before they could make a same/different response. Both right and left brain-damaged groups demonstrated a significant neglect of the contralesional sides of their images of the shapes in that they often gave 'same' responses when the shapes actually differed on their contralesional sides. This had implications for normal imagery processes. It appears that at some advanced stage our images are mapped onto our hemispheres in an analogue fashion. That is, objects or parts of objects that we imagine to be on our left are mapped onto our right hemispheres, and those parts we imagine to be on our right are mapped onto our left hemispheres. If one hemisphere is damaged at a site which is essential to this imagery process, the contralateral half of the external stimulus that is being imagined will be degraded or neglected. Chapter 5 is a study of auditory extinction in unilaterally brain-damaged patients. In particular the phenomenon of ipsilateral auditory extinction is investigated in detail. Previous researchers have found ipsilateral auditory extinction for dichotically presented verbal stimuli following lesions only of the posterior left hemisphere. It has been hypothesized that a lesion in this area disconnects a posteriorly routed interhemispheric auditory pathway and that as a consequence, left-ear verbal input is unable to reach the left (speech) hemisphere. In Experiment 1, I tested 53 brain-damaged patients for extinction of digits on a dichotic listening task and found that patients with lesions wholly anterior to the central sulcus in the left hemisphere exhibited ipsilateral extinction as well as patients with posterior left-hemispheric lesions. This finding poses problems for the above hypothesis that relies on a posterior inter-hemispheric pathway, and alternatives to this hypothesis are discussed. In Experiment 2, I tested 16 patients for extinction of dichotically presented non-verbal material (tones) to ascertain whether ipsilateral extinction is restricted to verbal tasks. Ipsilateral extinction was not found on this task for either left or right brain-damaged patients. This suggested not only that ipsilateral auditory extinction is related to the disconnection or disruption of left-ear verbal input from the left (speech) hemisphere, but that the right hemisphere is not essential for the decoding and processing of non-verbal material. That is, I did not find right-ear ipsilateral extinction for non-verbal input in patients with right-hemispheric lesions. Chapter 6 is the study of multimodal hemineglect and extinction in patients with right- and left-hemispheric lesions. Clinical observations suggest that multimodal neglect may be a single disorder with a common underlying cause, and that the number of modalities affected is dependent upon the severity of the underlying deficit. For example, patients with hemiasomatagnosia (body hemineglect) are often observed to exhibit visual hemineglect and tactile extinction as well. I tested 50 patients for contralesional visual hemineglect, auditory extinction, tactile extinction and hemiasomatagnosia and computed phi correlation coefficients for pairs of disorders to see if there was any basis for supposing they were caused by the same underlying deficit. As the proportion of patients with hemineglect varied widely from modality to modality, possibly as a result of varying sensitivities of the tests used to measure the different forms of neglect, I also computed tetrachoric correlation coefficients. This measure corrects for varying proportions on the assumption that a normal distribution underlies each dichotomy. The results were inconclusive as the phi-coefficients were generally low and the tetrachoric coefficients very high. Because of the extreme difference between the two forms of correlation it was not possible to come to any conclusions about the 'true' correlations. It may be that at least some forms of hemineglect and extinction are independent of one another and are often found together in the same patients because the lesions overlap modality-specific areas, rather than because they result from the same underlying cause. Chapters 7 summarizes the studies described in Chapters 3, 4, 5 and 6, and the results are reviewed in the light of some of the more important theories of hemineglect.

Hemineglect and unilateral extinction on double simultaneous stimulation in humans are neuropsychological disorders which sometimes follow a lesion to the cortex, subcortex or basal ganglia of one cerebral hemisphere. The main symptom is that the patient appears to neglect or be unaware of stimuli which impinge in one half of space relative to the patient's body. The side of space neglected is usually the side contralateral to the brain lesion. This thesis comprises a collection of studies on various aspects of these disorders. Experimental subjects were patients in the Neurology and Neurosurgical Wards of Auckland Hospital. All had clearly defined solitary unilateral brain lesions confirmed by Computerized Tomography. Chapter 1 provides a historical review of research in the area, defines concepts, reviews recent human and animal research on hemineglect and extinction, and outlines the different theories which have been proposed in order to explain hemineglect. Chapter 2 describes the methods used in neuropsychological testing, the criteria used in the selection of subjects, the etiologies of the different types of lesions sustained by the patient sample, and the neuropsychological tests used in the various studies. Chapter 3 is a study of the incidence and severity of visual hemineglect in a group of 56 patients with left-hemispheric lesions and 45 patients with right-hemispheric lesions. Five paper and pencil tests designed to measure the presence and severity of visual hemineglect were given to these patients. The incidence of hemineglect in the two groups did not differ significantly (50% and 44% in the left and right brain-damaged groups respectively). However, visual hemineglect was found to be more severe after right- than after left-hemispheric lesions. The two groups were found to differ significantly with respect to the loci of lesions most likely to result in hemineglect. In the right brain-damaged group most patients with hemineglect had posterior lesions, and in the left brain-damaged group most patients with hemineglect had anterior lesions. Possible reasons for this are discussed in terms of the effects the lateralization of language representation might have on the representation of spatial functions. Chapter 4 describes an experiment designed to determine whether patients with unilateral cerebral lesions neglect the contralesional sides of their mental images of the external world. This phenomenon has previously been observed for patients with left-sided visual neglect following right-hemispheric lesions. Twenty control subjects and 16 patients with right- and left-hemispheric lesions were involved in the experiment reported in this chapter. In the 'static' condition they viewed pairs of complex shapes displayed, one shape at a time, on a video-screen controlled by a computer. In the 'dynamic' condition the pairs of shapes apparently moved, one at a time, behind a narrow vertical slit. In both conditions the subject had to decide whether the two shapes of each pair were the same or different. In fact, some were the same, while some differed on the right and others on the left. In the 'dynamic' condition subjects had to construct spatial images from non-spatial external stimuli before they could make a same/different response. Both right and left brain-damaged groups demonstrated a significant neglect of the contralesional sides of their images of the shapes in that they often gave 'same' responses when the shapes actually differed on their contralesional sides. This had implications for normal imagery processes. It appears that at some advanced stage our images are mapped onto our hemispheres in an analogue fashion. That is, objects or parts of objects that we imagine to be on our left are mapped onto our right hemispheres, and those parts we imagine to be on our right are mapped onto our left hemispheres. If one hemisphere is damaged at a site which is essential to this imagery process, the contralateral half of the external stimulus that is being imagined will be degraded or neglected. Chapter 5 is a study of auditory extinction in unilaterally brain-damaged patients. In particular the phenomenon of ipsilateral auditory extinction is investigated in detail. Previous researchers have found ipsilateral auditory extinction for dichotically presented verbal stimuli following lesions only of the posterior left hemisphere. It has been hypothesized that a lesion in this area disconnects a posteriorly routed interhemispheric auditory pathway and that as a consequence, left-ear verbal input is unable to reach the left (speech) hemisphere. In Experiment 1, I tested 53 brain-damaged patients for extinction of digits on a dichotic listening task and found that patients with lesions wholly anterior to the central sulcus in the left hemisphere exhibited ipsilateral extinction as well as patients with posterior left-hemispheric lesions. This finding poses problems for the above hypothesis that relies on a posterior inter-hemispheric pathway, and alternatives to this hypothesis are discussed. In Experiment 2, I tested 16 patients for extinction of dichotically presented non-verbal material (tones) to ascertain whether ipsilateral extinction is restricted to verbal tasks. Ipsilateral extinction was not found on this task for either left or right brain-damaged patients. This suggested not only that ipsilateral auditory extinction is related to the disconnection or disruption of left-ear verbal input from the left (speech) hemisphere, but that the right hemisphere is not essential for the decoding and processing of non-verbal material. That is, I did not find right-ear ipsilateral extinction for non-verbal input in patients with right-hemispheric lesions. Chapter 6 is the study of multimodal hemineglect and extinction in patients with right- and left-hemispheric lesions. Clinical observations suggest that multimodal neglect may be a single disorder with a common underlying cause, and that the number of modalities affected is dependent upon the severity of the underlying deficit. For example, patients with hemiasomatagnosia (body hemineglect) are often observed to exhibit visual hemineglect and tactile extinction as well. I tested 50 patients for contralesional visual hemineglect, auditory extinction, tactile extinction and hemiasomatagnosia and computed phi correlation coefficients for pairs of disorders to see if there was any basis for supposing they were caused by the same underlying deficit. As the proportion of patients with hemineglect varied widely from modality to modality, possibly as a result of varying sensitivities of the tests used to measure the different forms of neglect, I also computed tetrachoric correlation coefficients. This measure corrects for varying proportions on the assumption that a normal distribution underlies each dichotomy. The results were inconclusive as the phi-coefficients were generally low and the tetrachoric coefficients very high. Because of the extreme difference between the two forms of correlation it was not possible to come to any conclusions about the 'true' correlations. It may be that at least some forms of hemineglect and extinction are independent of one another and are often found together in the same patients because the lesions overlap modality-specific areas, rather than because they result from the same underlying cause. Chapters 7 summarizes the studies described in Chapters 3, 4, 5 and 6, and the results are reviewed in the light of some of the more important theories of hemineglect.

Hemineglect and unilateral extinction on double simultaneous stimulation in humans are neuropsychological disorders which sometimes follow a lesion to the cortex, subcortex or basal ganglia of one cerebral hemisphere. The main symptom is that the patient appears to neglect or be unaware of stimuli which impinge in one half of space relative to the patient's body. The side of space neglected is usually the side contralateral to the brain lesion. This thesis comprises a collection of studies on various aspects of these disorders. Experimental subjects were patients in the Neurology and Neurosurgical Wards of Auckland Hospital. All had clearly defined solitary unilateral brain lesions confirmed by Computerized Tomography. Chapter 1 provides a historical review of research in the area, defines concepts, reviews recent human and animal research on hemineglect and extinction, and outlines the different theories which have been proposed in order to explain hemineglect. Chapter 2 describes the methods used in neuropsychological testing, the criteria used in the selection of subjects, the etiologies of the different types of lesions sustained by the patient sample, and the neuropsychological tests used in the various studies. Chapter 3 is a study of the incidence and severity of visual hemineglect in a group of 56 patients with left-hemispheric lesions and 45 patients with right-hemispheric lesions. Five paper and pencil tests designed to measure the presence and severity of visual hemineglect were given to these patients. The incidence of hemineglect in the two groups did not differ significantly (50% and 44% in the left and right brain-damaged groups respectively). However, visual hemineglect was found to be more severe after right- than after left-hemispheric lesions. The two groups were found to differ significantly with respect to the loci of lesions most likely to result in hemineglect. In the right brain-damaged group most patients with hemineglect had posterior lesions, and in the left brain-damaged group most patients with hemineglect had anterior lesions. Possible reasons for this are discussed in terms of the effects the lateralization of language representation might have on the representation of spatial functions. Chapter 4 describes an experiment designed to determine whether patients with unilateral cerebral lesions neglect the contralesional sides of their mental images of the external world. This phenomenon has previously been observed for patients with left-sided visual neglect following right-hemispheric lesions. Twenty control subjects and 16 patients with right- and left-hemispheric lesions were involved in the experiment reported in this chapter. In the 'static' condition they viewed pairs of complex shapes displayed, one shape at a time, on a video-screen controlled by a computer. In the 'dynamic' condition the pairs of shapes apparently moved, one at a time, behind a narrow vertical slit. In both conditions the subject had to decide whether the two shapes of each pair were the same or different. In fact, some were the same, while some differed on the right and others on the left. In the 'dynamic' condition subjects had to construct spatial images from non-spatial external stimuli before they could make a same/different response. Both right and left brain-damaged groups demonstrated a significant neglect of the contralesional sides of their images of the shapes in that they often gave 'same' responses when the shapes actually differed on their contralesional sides. This had implications for normal imagery processes. It appears that at some advanced stage our images are mapped onto our hemispheres in an analogue fashion. That is, objects or parts of objects that we imagine to be on our left are mapped onto our right hemispheres, and those parts we imagine to be on our right are mapped onto our left hemispheres. If one hemisphere is damaged at a site which is essential to this imagery process, the contralateral half of the external stimulus that is being imagined will be degraded or neglected. Chapter 5 is a study of auditory extinction in unilaterally brain-damaged patients. In particular the phenomenon of ipsilateral auditory extinction is investigated in detail. Previous researchers have found ipsilateral auditory extinction for dichotically presented verbal stimuli following lesions only of the posterior left hemisphere. It has been hypothesized that a lesion in this area disconnects a posteriorly routed interhemispheric auditory pathway and that as a consequence, left-ear verbal input is unable to reach the left (speech) hemisphere. In Experiment 1, I tested 53 brain-damaged patients for extinction of digits on a dichotic listening task and found that patients with lesions wholly anterior to the central sulcus in the left hemisphere exhibited ipsilateral extinction as well as patients with posterior left-hemispheric lesions. This finding poses problems for the above hypothesis that relies on a posterior inter-hemispheric pathway, and alternatives to this hypothesis are discussed. In Experiment 2, I tested 16 patients for extinction of dichotically presented non-verbal material (tones) to ascertain whether ipsilateral extinction is restricted to verbal tasks. Ipsilateral extinction was not found on this task for either left or right brain-damaged patients. This suggested not only that ipsilateral auditory extinction is related to the disconnection or disruption of left-ear verbal input from the left (speech) hemisphere, but that the right hemisphere is not essential for the decoding and processing of non-verbal material. That is, I did not find right-ear ipsilateral extinction for non-verbal input in patients with right-hemispheric lesions. Chapter 6 is the study of multimodal hemineglect and extinction in patients with right- and left-hemispheric lesions. Clinical observations suggest that multimodal neglect may be a single disorder with a common underlying cause, and that the number of modalities affected is dependent upon the severity of the underlying deficit. For example, patients with hemiasomatagnosia (body hemineglect) are often observed to exhibit visual hemineglect and tactile extinction as well. I tested 50 patients for contralesional visual hemineglect, auditory extinction, tactile extinction and hemiasomatagnosia and computed phi correlation coefficients for pairs of disorders to see if there was any basis for supposing they were caused by the same underlying deficit. As the proportion of patients with hemineglect varied widely from modality to modality, possibly as a result of varying sensitivities of the tests used to measure the different forms of neglect, I also computed tetrachoric correlation coefficients. This measure corrects for varying proportions on the assumption that a normal distribution underlies each dichotomy. The results were inconclusive as the phi-coefficients were generally low and the tetrachoric coefficients very high. Because of the extreme difference between the two forms of correlation it was not possible to come to any conclusions about the 'true' correlations. It may be that at least some forms of hemineglect and extinction are independent of one another and are often found together in the same patients because the lesions overlap modality-specific areas, rather than because they result from the same underlying cause. Chapters 7 summarizes the studies described in Chapters 3, 4, 5 and 6, and the results are reviewed in the light of some of the more important theories of hemineglect.

Hemineglect and unilateral extinction on double simultaneous stimulation in humans are neuropsychological disorders which sometimes follow a lesion to the cortex, subcortex or basal ganglia of one cerebral hemisphere. The main symptom is that the patient appears to neglect or be unaware of stimuli which impinge in one half of space relative to the patient's body. The side of space neglected is usually the side contralateral to the brain lesion. This thesis comprises a collection of studies on various aspects of these disorders. Experimental subjects were patients in the Neurology and Neurosurgical Wards of Auckland Hospital. All had clearly defined solitary unilateral brain lesions confirmed by Computerized Tomography. Chapter 1 provides a historical review of research in the area, defines concepts, reviews recent human and animal research on hemineglect and extinction, and outlines the different theories which have been proposed in order to explain hemineglect. Chapter 2 describes the methods used in neuropsychological testing, the criteria used in the selection of subjects, the etiologies of the different types of lesions sustained by the patient sample, and the neuropsychological tests used in the various studies. Chapter 3 is a study of the incidence and severity of visual hemineglect in a group of 56 patients with left-hemispheric lesions and 45 patients with right-hemispheric lesions. Five paper and pencil tests designed to measure the presence and severity of visual hemineglect were given to these patients. The incidence of hemineglect in the two groups did not differ significantly (50% and 44% in the left and right brain-damaged groups respectively). However, visual hemineglect was found to be more severe after right- than after left-hemispheric lesions. The two groups were found to differ significantly with respect to the loci of lesions most likely to result in hemineglect. In the right brain-damaged group most patients with hemineglect had posterior lesions, and in the left brain-damaged group most patients with hemineglect had anterior lesions. Possible reasons for this are discussed in terms of the effects the lateralization of language representation might have on the representation of spatial functions. Chapter 4 describes an experiment designed to determine whether patients with unilateral cerebral lesions neglect the contralesional sides of their mental images of the external world. This phenomenon has previously been observed for patients with left-sided visual neglect following right-hemispheric lesions. Twenty control subjects and 16 patients with right- and left-hemispheric lesions were involved in the experiment reported in this chapter. In the 'static' condition they viewed pairs of complex shapes displayed, one shape at a time, on a video-screen controlled by a computer. In the 'dynamic' condition the pairs of shapes apparently moved, one at a time, behind a narrow vertical slit. In both conditions the subject had to decide whether the two shapes of each pair were the same or different. In fact, some were the same, while some differed on the right and others on the left. In the 'dynamic' condition subjects had to construct spatial images from non-spatial external stimuli before they could make a same/different response. Both right and left brain-damaged groups demonstrated a significant neglect of the contralesional sides of their images of the shapes in that they often gave 'same' responses when the shapes actually differed on their contralesional sides. This had implications for normal imagery processes. It appears that at some advanced stage our images are mapped onto our hemispheres in an analogue fashion. That is, objects or parts of objects that we imagine to be on our left are mapped onto our right hemispheres, and those parts we imagine to be on our right are mapped onto our left hemispheres. If one hemisphere is damaged at a site which is essential to this imagery process, the contralateral half of the external stimulus that is being imagined will be degraded or neglected. Chapter 5 is a study of auditory extinction in unilaterally brain-damaged patients. In particular the phenomenon of ipsilateral auditory extinction is investigated in detail. Previous researchers have found ipsilateral auditory extinction for dichotically presented verbal stimuli following lesions only of the posterior left hemisphere. It has been hypothesized that a lesion in this area disconnects a posteriorly routed interhemispheric auditory pathway and that as a consequence, left-ear verbal input is unable to reach the left (speech) hemisphere. In Experiment 1, I tested 53 brain-damaged patients for extinction of digits on a dichotic listening task and found that patients with lesions wholly anterior to the central sulcus in the left hemisphere exhibited ipsilateral extinction as well as patients with posterior left-hemispheric lesions. This finding poses problems for the above hypothesis that relies on a posterior inter-hemispheric pathway, and alternatives to this hypothesis are discussed. In Experiment 2, I tested 16 patients for extinction of dichotically presented non-verbal material (tones) to ascertain whether ipsilateral extinction is restricted to verbal tasks. Ipsilateral extinction was not found on this task for either left or right brain-damaged patients. This suggested not only that ipsilateral auditory extinction is related to the disconnection or disruption of left-ear verbal input from the left (speech) hemisphere, but that the right hemisphere is not essential for the decoding and processing of non-verbal material. That is, I did not find right-ear ipsilateral extinction for non-verbal input in patients with right-hemispheric lesions. Chapter 6 is the study of multimodal hemineglect and extinction in patients with right- and left-hemispheric lesions. Clinical observations suggest that multimodal neglect may be a single disorder with a common underlying cause, and that the number of modalities affected is dependent upon the severity of the underlying deficit. For example, patients with hemiasomatagnosia (body hemineglect) are often observed to exhibit visual hemineglect and tactile extinction as well. I tested 50 patients for contralesional visual hemineglect, auditory extinction, tactile extinction and hemiasomatagnosia and computed phi correlation coefficients for pairs of disorders to see if there was any basis for supposing they were caused by the same underlying deficit. As the proportion of patients with hemineglect varied widely from modality to modality, possibly as a result of varying sensitivities of the tests used to measure the different forms of neglect, I also computed tetrachoric correlation coefficients. This measure corrects for varying proportions on the assumption that a normal distribution underlies each dichotomy. The results were inconclusive as the phi-coefficients were generally low and the tetrachoric coefficients very high. Because of the extreme difference between the two forms of correlation it was not possible to come to any conclusions about the 'true' correlations. It may be that at least some forms of hemineglect and extinction are independent of one another and are often found together in the same patients because the lesions overlap modality-specific areas, rather than because they result from the same underlying cause. Chapters 7 summarizes the studies described in Chapters 3, 4, 5 and 6, and the results are reviewed in the light of some of the more important theories of hemineglect.

Hemineglect and unilateral extinction on double simultaneous stimulation in humans are neuropsychological disorders which sometimes follow a lesion to the cortex, subcortex or basal ganglia of one cerebral hemisphere. The main symptom is that the patient appears to neglect or be unaware of stimuli which impinge in one half of space relative to the patient's body. The side of space neglected is usually the side contralateral to the brain lesion. This thesis comprises a collection of studies on various aspects of these disorders. Experimental subjects were patients in the Neurology and Neurosurgical Wards of Auckland Hospital. All had clearly defined solitary unilateral brain lesions confirmed by Computerized Tomography. Chapter 1 provides a historical review of research in the area, defines concepts, reviews recent human and animal research on hemineglect and extinction, and outlines the different theories which have been proposed in order to explain hemineglect. Chapter 2 describes the methods used in neuropsychological testing, the criteria used in the selection of subjects, the etiologies of the different types of lesions sustained by the patient sample, and the neuropsychological tests used in the various studies. Chapter 3 is a study of the incidence and severity of visual hemineglect in a group of 56 patients with left-hemispheric lesions and 45 patients with right-hemispheric lesions. Five paper and pencil tests designed to measure the presence and severity of visual hemineglect were given to these patients. The incidence of hemineglect in the two groups did not differ significantly (50% and 44% in the left and right brain-damaged groups respectively). However, visual hemineglect was found to be more severe after right- than after left-hemispheric lesions. The two groups were found to differ significantly with respect to the loci of lesions most likely to result in hemineglect. In the right brain-damaged group most patients with hemineglect had posterior lesions, and in the left brain-damaged group most patients with hemineglect had anterior lesions. Possible reasons for this are discussed in terms of the effects the lateralization of language representation might have on the representation of spatial functions. Chapter 4 describes an experiment designed to determine whether patients with unilateral cerebral lesions neglect the contralesional sides of their mental images of the external world. This phenomenon has previously been observed for patients with left-sided visual neglect following right-hemispheric lesions. Twenty control subjects and 16 patients with right- and left-hemispheric lesions were involved in the experiment reported in this chapter. In the 'static' condition they viewed pairs of complex shapes displayed, one shape at a time, on a video-screen controlled by a computer. In the 'dynamic' condition the pairs of shapes apparently moved, one at a time, behind a narrow vertical slit. In both conditions the subject had to decide whether the two shapes of each pair were the same or different. In fact, some were the same, while some differed on the right and others on the left. In the 'dynamic' condition subjects had to construct spatial images from non-spatial external stimuli before they could make a same/different response. Both right and left brain-damaged groups demonstrated a significant neglect of the contralesional sides of their images of the shapes in that they often gave 'same' responses when the shapes actually differed on their contralesional sides. This had implications for normal imagery processes. It appears that at some advanced stage our images are mapped onto our hemispheres in an analogue fashion. That is, objects or parts of objects that we imagine to be on our left are mapped onto our right hemispheres, and those parts we imagine to be on our right are mapped onto our left hemispheres. If one hemisphere is damaged at a site which is essential to this imagery process, the contralateral half of the external stimulus that is being imagined will be degraded or neglected. Chapter 5 is a study of auditory extinction in unilaterally brain-damaged patients. In particular the phenomenon of ipsilateral auditory extinction is investigated in detail. Previous researchers have found ipsilateral auditory extinction for dichotically presented verbal stimuli following lesions only of the posterior left hemisphere. It has been hypothesized that a lesion in this area disconnects a posteriorly routed interhemispheric auditory pathway and that as a consequence, left-ear verbal input is unable to reach the left (speech) hemisphere. In Experiment 1, I tested 53 brain-damaged patients for extinction of digits on a dichotic listening task and found that patients with lesions wholly anterior to the central sulcus in the left hemisphere exhibited ipsilateral extinction as well as patients with posterior left-hemispheric lesions. This finding poses problems for the above hypothesis that relies on a posterior inter-hemispheric pathway, and alternatives to this hypothesis are discussed. In Experiment 2, I tested 16 patients for extinction of dichotically presented non-verbal material (tones) to ascertain whether ipsilateral extinction is restricted to verbal tasks. Ipsilateral extinction was not found on this task for either left or right brain-damaged patients. This suggested not only that ipsilateral auditory extinction is related to the disconnection or disruption of left-ear verbal input from the left (speech) hemisphere, but that the right hemisphere is not essential for the decoding and processing of non-verbal material. That is, I did not find right-ear ipsilateral extinction for non-verbal input in patients with right-hemispheric lesions. Chapter 6 is the study of multimodal hemineglect and extinction in patients with right- and left-hemispheric lesions. Clinical observations suggest that multimodal neglect may be a single disorder with a common underlying cause, and that the number of modalities affected is dependent upon the severity of the underlying deficit. For example, patients with hemiasomatagnosia (body hemineglect) are often observed to exhibit visual hemineglect and tactile extinction as well. I tested 50 patients for contralesional visual hemineglect, auditory extinction, tactile extinction and hemiasomatagnosia and computed phi correlation coefficients for pairs of disorders to see if there was any basis for supposing they were caused by the same underlying deficit. As the proportion of patients with hemineglect varied widely from modality to modality, possibly as a result of varying sensitivities of the tests used to measure the different forms of neglect, I also computed tetrachoric correlation coefficients. This measure corrects for varying proportions on the assumption that a normal distribution underlies each dichotomy. The results were inconclusive as the phi-coefficients were generally low and the tetrachoric coefficients very high. Because of the extreme difference between the two forms of correlation it was not possible to come to any conclusions about the 'true' correlations. It may be that at least some forms of hemineglect and extinction are independent of one another and are often found together in the same patients because the lesions overlap modality-specific areas, rather than because they result from the same underlying cause. Chapters 7 summarizes the studies described in Chapters 3, 4, 5 and 6, and the results are reviewed in the light of some of the more important theories of hemineglect.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.