No description available.

<p>Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by pathological features that include the selective loss of dopaminergic (DA) neurons in the substantia nigra (SN) region of the midbrain and the presence of intraneuronal Lewy body and Lewy neurite inclusions primarily comprised of fibrillar forms of the pre-synaptic protein alpha-synuclein (aSyn).  aSyn aggregation has been implicated as a critical event in PD pathogenesis, and mutant forms of aSyn are associated with familial, early-onset forms of the disease. PD presents clinically as a movement disorder through appearance of its cardinal motor symptoms of bradykinesia, rigidity, postural instability, and resting tremor. However, upon manifestation of these clinical symptoms, over 50% of the DA nigral neurons have been lost, suggesting that PD neuropathology likely begins 10-15 years prior to the clinical onset. Current PD treatment is focused on symptomatic therapy through dopamine replacement strategies, and there are currently no medications available to prevent or slow disease progression. </p> <p>A major hurdle to developing disease-modifying therapies for PD is a lack of knowledge of the molecular phenomena responsible for the death of DA neurons in the SN. Multiple cellular pathways that are dysregulated in PD include protein clearance systems and oxidative stress responses. Changes in these systems by environmental or genetic perturbations cause increased aSyn aggregation, which in turn leads to increased oxidative and proteasomal stress, thereby generating a vicious cycle culminating in the death of nigral DA neurons. Therefore, strategies to activate these protective pathways have the potential to reduce aSyn aggregation and halt neurodegeneration. One such mechanism is through the activation of the stress-induced transcription factor, Nfe2L1. Nfe2L1 is a cap ‘n’ collar basic leucine zipper (CNC-bZIP) transcription factor that forms heterodimers with small Maf proteins. In turn, the heterodimers bind to antioxidant response element (ARE) sequences in the promoter regions of cytoprotective genes, such as genes encoding proteasome subunits and proteins involved in the glutathione synthesis pathway. In the studies summarized in Chapter 2, we have characterized a pre-clinical <em>in vivo</em> model of PD involving aSyn overexpression in rat SN and used this model to investigate whether Nfe2L1 co-expression could alleviate aSyn neurotoxicity by reducing cytosolic aSyn levels via proteasome activation. Using unbiased stereology to determine nigral DA neuron cell counts, we found that Nfe2L1 may have a protective effect against aSyn-mediated nigral DA neurodegeneration. Surprisingly, we observed no increase in proteasome subunit expression through quantitative PCR or immunoblotting. However, by using a single-neuron analysis approach, we observed a significant increase in PSMC1 subunit expression, suggesting that Nfe2L1 expression could indeed lead to an upregulation of proteasome subunits and an increase in proteasome function. Future experiments will be aimed at determining whether Nfe2L1 expression results in an increase in proteasome activity, an enhancement of aSyn degradation, and a decrease in the burden of proteinase K-resistant (Lewy-like) aSyn aggregates in rat SN. </p> <p>The ability to detect PD in the pre-symptomatic stage is necessary for the development of novel therapies to enable treatment prior to irreversible neuronal loss. Biomarkers with high sensitivity and specificity are critical for early PD detection. aSyn levels have been measured in human biofluids, such as blood and CSF, as a potential biomarker for PD diagnosis and for monitoring disease progression. aSyn can undergo a number of post-translational modifications (PTMs), and a particular form of the protein phosphorylated at serine 129 (pS129-aSyn) is enriched in Lewy bodies, making it an attractive candidate for biomarker studies. Although there are several antibodies targeting pS129, little is known about the influence of PTMs close to pS129 on the antibodies’ affinity for the pS129 epitope, or how these neighboring PTMs could affect assays developed to quantify pS129-aSyn in biofluids. In the studies summarized in Chapter 3, we characterized the impact of PTMs near pS129 on the affinity of currently available pS129-aSyn antibodies for their target antigen using biolayer interferometry (BLI). BLI analysis of the D1R1R pS129-aSyn antibody (Cell Signaling Technology) revealed that tyrosine phosphorylation or nitration at Y133 greatly reduced antibody affinity. In contrast, the MJF-R13 pS129-aSyn antibody (Abcam) was found to have reduced affinity for peptide targets nitrated or phosphorylated on Y125 or phosphorylated on Y133. </p> <p>While aSyn is typically investigated as it relates to PD and other neurodegenerative disorders, recently reported evidence suggests that aSyn downregulation could be linked to an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD).  ASD is a complex neurodevelopmental disorder that presents with characteristic behavioral symptoms of social and communication impairments and restricted, repetitive behaviors. Diagnosis of ASD is based on the presentation of these behavioral symptoms, typically appearing at ~12 months of age, yet individuals don’t receive a diagnosis until the age of five. Early identification and early treatment are regarded as two of the most important factors for improving patient outcomes. SNCA gene deletions and loss-of-function duplications have been found in individuals with intellectual disability, developmental delay, and/or ASD, leading to the idea that reduced aSyn expression may be a biomarker for early ASD diagnosis and may play a role in ASD neuronal dysfunction. In the studies summarized in Chapter 4, we evaluated salivary aSyn as a potential biomarker for early ASD diagnosis and examined SNCA-/- iPSC-derived cortical neurons for indications of ASD-related neuronal anomalies. Our preliminary results suggest that salivary aSyn is reduced in individuals with neurodevelopmental disorders such as ASD and Fragile X Syndrome (FXS), a result consistent with findings of reduced aSyn in serum and plasma from ASD individuals. Furthermore, SNCA-/- iPSC-derived cortical neurons depleted of aSyn expression had increased soma size, a characteristic of iPSC-derived cortical neurons with ASD-associated mutations in the genes encoding MECP2 and TSC1/2 These results suggest that SNCA gene disruptions play a role in ASD-related neuronal anomalies and dysfunction. </p> <p>Overall, the results presented in this thesis support a role for targeting aSyn protein expression in neurodegenerative and neurodevelopmental disorders, and they underscore the importance of designing aSyn biomarker immunoassays that faithfully report on each of these syndromes. Our data suggesting that Nfe2L1 could protect against nigral neurodegeneration by stimulating proteasome-mediated aSyn clearance imply that strategies to increase Nfe2L1-dependent transcriptional activity (e.g., using small molecule activators or gene therapy) could ameliorate pathological aspects of PD. The results presented here also highlight the need for sensitive and specific biomarker assays targeting multiple aSyn proteoforms, and they suggest that aSyn could be a viable biomarker for early ASD diagnosis. Finally, our findings provide the first evidence that aSyn down-regulation contributes to neuronal anomalies associated with ASD, in turn suggesting that strategies to increase cytosolic aSyn by preventing its degradation or through gene therapy could potentially mitigate ASD neuronal dysfunction. </p>

<p>  </p> <p>Approximately 30% of patients with epilepsy do not achieve adequate seizure control through current anti-seizure drugs (ASD) and treatment methods. Therefore, a critical need exists to efficiently screen ASDs to enhance our ability to tailor treatment protocols and improve patient outcomes. The zebrafish pentylenetetrazol (PTZ) seizure model has become an increasingly popular screening paradigm for novel ASDs. Here, we present an optimized PTZ assay to improve reliability and reproducibility based on work in our laboratory. This optimized assay improves robustness in our screening of anti-seizure drugs (topiramate, lamotrigine, carbamazepine and GS967). These findings show that electroencephalogram (EEG) and calcium sensitive GFP from fusion protein (GCaMP) assays largely correlate with the behavioral findings, helping us connect physiological and behavioral responses to ASDs. Genetic epilepsy syndromes, like voltage gated sodium channel <em>SCN2A</em> and <em>SCN8A</em> pathogenic variants, are often poorly controlled by current medications. Our optimized assay relied on a fast and precise zebrafish seizure model using mRNA overexpression of h<em>SCN2A</em> and h<em>SCN8A</em> variants including: hSCN2A R1882Q and R853Q and hSCN8A R1872Q. All three pathogenic variants increased seizure activity, and the ASDs significantly decreased this seizure activity. This mRNA overexpression assay can be used to quickly evaluate seizure activity induced by pathogenic variants in voltage gated sodium channel genes and test ASDs to determine efficacy. In a separate study, we tested if the addition of the human <em>SCN2A </em>sodium channel could potentially rescue the loss of the zebrafish scn1Lab gene. Our GCaMP assay data indicates that this loss was successfully rescued. Cumulatively, these findings can be used to improve the screening of novel ASDs and treatments for patients with refractory epilepsy.</p>

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.

<p dir="ltr">Migraine is a condition that has affected many for generations and yet remains poorly understood. Mutations to the Na_v1.1 voltage gated sodium channels have been implicated in various diseases such as Familial Hemiplegic Migraine 3 (FHM3), epilepsy, and autism spectrum disorder (ASD). Various proteins have been found to modify the function of these channels. Fibroblast growth factor homologous factors (FHFs) have been found to regulate the activity of some voltage-gated sodium channels (Na_vs). More work is needed to determine which FHFs affect which Na_vs. Here I looked at FHF2A and FHF2B in Nav1.1 as well as an FHM3-causing mutation to this channel, F1774S. I found that FHF2A, but not 2B, induced long-term inactivation (LTI) in the wild-type (WT) Nav1.1 and that FHF2A induced LTI in the F1774S mutant channel to a greater extent. Several changes in channel function caused by the mutation were attenuated with the addition of FHF2A, including persistent currents, leading to a possible rescue in the mutant phenotype. By contrast, the P1894L mutation, which has been found to cause ASD, greatly attenuated LTI and other impacts of FHF2A on Nav1.1. The inflammatory cytokine IL-6 was also investigated as a possible modulator of the Na_v1.1 channel. There does not appear to be any direct interaction between this cytokine and the channel. Overall, my data shows for the first time that FHF2A, but FHF2B or IL-6, might be a significant modulator of Nav1.1 and can differentially modulate disease mutations.</p>

<p dir="ltr"><b>ABSTRACT</b></p><p dir="ltr"><b>Background</b></p><p dir="ltr">Alcohol use disorder (AUD) poses negative health and social consequences, and is costly to affected individuals, loved ones, and society (Whiteford et al., 2013). It is a chronic neuropsychiatric disorder, associated with impaired decision making and altered functional connectivity patterns in the brain. Many studies have shown changes in the brain and behaviors after sustained abstinence using within-participant design or between-participant design comparing participants in recovery versus healthy controls (Muller & Meyerhoff, 2021; Wilcox et al., 2019). The purpose of this study was to investigate brain differences between participants in recovery and participants who are actively drinking. Specifically, this study evaluated within- and between-network resting-state functional connectivity (rsFC) strengths in the context of the triple network model, which focuses on three key networks for complex perceptual, emotional and behavior processing as well as introspection, theory of mind and self-awareness; the salience network (SN), the central executive network (CEN), and the default mode network (DMN) (Menon, 2019). Moreover, this study assessed the relationship between impulsive choices in temporal decision-making and changes in resting-state functional connectivity patterns in these networks.</p><p dir="ltr"><b>Methods</b></p><p dir="ltr">This study included two groups: the Recovery Group and the Drinking Group. The Recovery Group included participants who were starting recovery (within one year), met AUD diagnosis criteria or showed lifetime heavy drinking behaviors during a 12-month period, received treatment for substance use disorder for alcohol and/or illicit drugs, and showed ongoing intentions and efforts to maintain recovery (n=18, 6 females, mean age=32.4±7.4, 17 White, mean years of education=14.5±3.1, average days of abstinence prior to interview days=78.2±45.7). The Drinking Group included participants who were currently drinking that met diagnosis criteria for AUD or showed heavy drinking behaviors (n=49, 24 females, mean age=31.7±6.4, 29 White, mean years of education=13.6±2.3). Participants underwent an initial screen day where structured interviews were conducted to evaluate the number of lifetime AUD criteria and prior drinking patterns. On the study day, participants completed computer tasks and questionnaires prior to their functional Magnetic Resonance Imaging (fMRI) sessions. Participants in the Recovery Group received a virtual reality (VR) intervention targeting future self-continuity where they interacted with avatars that are versions of themselves (present self and future selves in recovery and relapsed) prior to MRI sessions. All participants completed baseline Delay Discounting (DD) to measure intertemporal choice preferences prior to the fMRI sessions and prior to the VR intervention for the Recovery Group.</p><p dir="ltr"><b>Results</b></p><p dir="ltr">This study did not find any significant differences in within- and between-network rsFC strength of regions of interest of this study within the triple networks between participants in recovery and those who were actively drinking. The study found that participants in recovery showed a greater preference for delayed rewards (measured by DD task) compared to participants who are actively drinking. Additionally, measures of self-reported impulsivity and impulsive decision-making were associated with resting state functional connectivity (rsFC) strength between regions within the Salience Network (SN), and between the SN and Central Executive Network (CEN). Specifically, baseline delayed reward preference was positively associated with the rsFC between two SN hubs: left dorsal anterior insula (dAIC) and dorsal anterior cingulate cortex (dACC). The rsFC between the left dACC (SN) and dorsolateral prefrontal cortex (dlPFC; CEN) negatively associated with subscales (including negative urgency, lack of perseverance, and lack of premeditation) of self-reported impulsivity measured by the Urgency-Premeditation-Perseverance-Sensation Seeking-Positive Urgency (UPPS-P) impulsive behavior scale. Together, these results suggested that there was an emerging pattern where enhanced the rsFC strength in these regions associated with higher impulsive tendencies. The exploratory analysis showed that the rsFC strength between the right precuneus and ventromedial prefrontal cortex (vmPFC) was related to abstinence length in participants in recovery.</p><p dir="ltr"><b>Conclusions</b></p><p dir="ltr">These findings indicated that participants in recovery exhibited higher delayed reward preference compared to participants who were actively drinking, alongside a significant relationship between measures of impulsivity and the rsFC within the SN and between the SN and CEN. These results highlighted the importance of the SN and its dynamic interaction with the CEN in self-reported impulsivity and impulsive decision making in addiction. Additionally, this study found that within-network functional connectivity strength in the DMN was related to abstinence length, suggesting that repairment in the rsFC strength within DMN might be integral to the process of addiction recovery.</p><p><br></p>