Activation of nociceptors causes them to secrete neuropeptides, such as substance P (SP) and calcitonin-gene related peptide (CGRP). By reacting with receptors on blood vessels these peptides contribute to inflammation by evoking vasodilation and increasing vascular permeability that allows proteins and fluid to leave the blood vessels (plasma extravasation, PE). These substances can also lead to the sensitization of nociceptors and the resulting positive feedback thereby prolongs inflammation and pain. Thus, blocking the release of neuropeptides may have important therapeutic value in pain conditions where neuropeptides have been implicated. Therefore, the aim of this study was to define the time course of changes in vascular permeability and to test the ability of novel agents to modulate this response. PE and vasodilation was evoked by stimulating the saphenous nerve or by injecting the chemical irritant capsaicin into the rat hindpaw. Changes in blood flow were evaluated with a laser Doppler and digitized image analysis was used to measure changes in reflectance of the skin due to accumulation of extravasated (EB) dye. Analysis of the change in pixel intensity in the digitized images revealed that the magnitude of PE was dependent on the stimulus pulse number. Moreover, the time course of enhanced vascular permeability produced by electrical stimulation was a transient event compared to a much longer response with capsaicin. It was also demonstrated that sumatriptan, (a 5-HT1B/D receptor agonist) and botulinum neurotoxin type-A were effective treatments for capsaicin and saphenous nerve induced vasodilation and PE. Neither drug interfered with activation of the SP or CGRP receptor, which may suggest that both drugs work by inhibiting neuropeptide release. Therefore, this study has described the time course of vascular permeability evoked by two different stimuli and has demonstrated the ability of two novel agents to attenuate these responses.

Activation of nociceptors causes them to secrete neuropeptides, such as substance P (SP) and calcitonin-gene related peptide (CGRP). By reacting with receptors on blood vessels these peptides contribute to inflammation by evoking vasodilation and increasing vascular permeability that allows proteins and fluid to leave the blood vessels (plasma extravasation, PE). These substances can also lead to the sensitization of nociceptors and the resulting positive feedback thereby prolongs inflammation and pain. Thus, blocking the release of neuropeptides may have important therapeutic value in pain conditions where neuropeptides have been implicated. Therefore, the aim of this study was to define the time course of changes in vascular permeability and to test the ability of novel agents to modulate this response. PE and vasodilation was evoked by stimulating the saphenous nerve or by injecting the chemical irritant capsaicin into the rat hindpaw. Changes in blood flow were evaluated with a laser Doppler and digitized image analysis was used to measure changes in reflectance of the skin due to accumulation of extravasated (EB) dye. Analysis of the change in pixel intensity in the digitized images revealed that the magnitude of PE was dependent on the stimulus pulse number. Moreover, the time course of enhanced vascular permeability produced by electrical stimulation was a transient event compared to a much longer response with capsaicin. It was also demonstrated that sumatriptan, (a 5-HT1B/D receptor agonist) and botulinum neurotoxin type-A were effective treatments for capsaicin and saphenous nerve induced vasodilation and PE. Neither drug interfered with activation of the SP or CGRP receptor, which may suggest that both drugs work by inhibiting neuropeptide release. Therefore, this study has described the time course of vascular permeability evoked by two different stimuli and has demonstrated the ability of two novel agents to attenuate these responses.

Perceptual objects often comprise of a visual and auditory signature, which arrives simultaneously through distinct sensory channels, and multisensory features are linked by virtue of being attributed to a specific object. The binding of familiar auditory and visual signatures can be referred to as semantic audiovisual (AV) integration because it involves higher level representations of naturalistic multisensory objects. While integration of semantically related multisensory features is behaviorally advantageous, multisensory competition, or situations of sensory dominance of one modality at the expense of another, impairs performance. Multisensory facilitation and competition effects on performance are exacerbated with age. Older adults show a significantly larger performance gain from bimodal presentations compared to unimodal ones. In the present thesis project, magnetoencephalography (MEG) recordings of semantically related bimodal and unimodal stimuli captured the spatiotemporal patterns underlying both multisensory facilitation and competition in young and older adults. We first demonstrate that multisensory processes unfold in multiple stages: first, posterior parietal neurons respond preferentially to bimodal stimuli; secondly, regions in superior temporal and posterior cingulate cortices detect the semantic category of the stimuli; and finally, at later processing stages, orbitofrontal regions process crossmodal conflicts when complex sounds and pictures are semantically incongruent. Older adults, in contrast to young, are more efficient at integrating semantically congruent multisensory information across auditory and visual channels. Moreover, in these multisensory facilitation conditions, increased neural activity in medial fronto-parietal brain regions predicts faster motor performance in response to bimodal stimuli in older compared to younger adults. Finally, by examining the variability of the MEG signal, we also showed that an increase in local entropy with age is also behaviourally adaptive in the older group as it significantly correlates with more stable and more accurate performance in older compared to young adults.

Perceptual objects often comprise of a visual and auditory signature, which arrives simultaneously through distinct sensory channels, and multisensory features are linked by virtue of being attributed to a specific object. The binding of familiar auditory and visual signatures can be referred to as semantic audiovisual (AV) integration because it involves higher level representations of naturalistic multisensory objects. While integration of semantically related multisensory features is behaviorally advantageous, multisensory competition, or situations of sensory dominance of one modality at the expense of another, impairs performance. Multisensory facilitation and competition effects on performance are exacerbated with age. Older adults show a significantly larger performance gain from bimodal presentations compared to unimodal ones. In the present thesis project, magnetoencephalography (MEG) recordings of semantically related bimodal and unimodal stimuli captured the spatiotemporal patterns underlying both multisensory facilitation and competition in young and older adults. We first demonstrate that multisensory processes unfold in multiple stages: first, posterior parietal neurons respond preferentially to bimodal stimuli; secondly, regions in superior temporal and posterior cingulate cortices detect the semantic category of the stimuli; and finally, at later processing stages, orbitofrontal regions process crossmodal conflicts when complex sounds and pictures are semantically incongruent. Older adults, in contrast to young, are more efficient at integrating semantically congruent multisensory information across auditory and visual channels. Moreover, in these multisensory facilitation conditions, increased neural activity in medial fronto-parietal brain regions predicts faster motor performance in response to bimodal stimuli in older compared to younger adults. Finally, by examining the variability of the MEG signal, we also showed that an increase in local entropy with age is also behaviourally adaptive in the older group as it significantly correlates with more stable and more accurate performance in older compared to young adults.

This thesis includes four studies designed to improve the ability to predict and assess language representation in healthy children and/or individuals with neurological disorders arising in childhood. In the first study, the role of pathology type on interhemispheric plasticity of language was determined by comparing lateralization in children with developmental, acquired, and tumour pathologies. Findings from 105 consecutive intracarotid sodium amobarbital procedures were retrospectively analyzed, revealing no lateralization differences between pathology groups. In the second study, a novel verb generation paradigm and magnetoencephalography (MEG) were used to determine the spatial-temporal characteristics of language expression in healthy subjects (n = 12) and children with neurological disorders (n = 4). Time-frequency and differential beamformer analyses revealed low-beta event-related desynchronization (ERD) in the left inferior frontal lobe for verb generation. The paradigm was well-tolerated by all subjects. The third study involved assessment of expressive language lateralization in 25 healthy subjects, aged 5-18 years, using two novel MEG paradigms: covert picture naming and verb generation. Novel analyses permitted objective quantification of ERD lateralization on an individual basis. For both tasks, left lateralization of frontal lobe ERD tended to increase with advancing age. Findings suggest that adult-typical left lateralization emerges from an early bilateral language network in normal development. In the fourth study, frontal lobe ERD lateralization for naming and verb generation was characterized in 14 children and adolescents with neurological disorders. Novel analyses permitted objective assessment of individual scans at multiple contrast time windows. In several cases, rapid hemispheric shifts in predominant frontal lobe ERD were observed through the response period. On an individual basis, the assessment protocol showed promise for future use in a presurgical context. These studies serve to advance the understanding of normal paediatric language representation, and improve the ability to predict and assess language lateralization in individuals who have experienced early neurological insults.

This thesis includes four studies designed to improve the ability to predict and assess language representation in healthy children and/or individuals with neurological disorders arising in childhood. In the first study, the role of pathology type on interhemispheric plasticity of language was determined by comparing lateralization in children with developmental, acquired, and tumour pathologies. Findings from 105 consecutive intracarotid sodium amobarbital procedures were retrospectively analyzed, revealing no lateralization differences between pathology groups. In the second study, a novel verb generation paradigm and magnetoencephalography (MEG) were used to determine the spatial-temporal characteristics of language expression in healthy subjects (n = 12) and children with neurological disorders (n = 4). Time-frequency and differential beamformer analyses revealed low-beta event-related desynchronization (ERD) in the left inferior frontal lobe for verb generation. The paradigm was well-tolerated by all subjects. The third study involved assessment of expressive language lateralization in 25 healthy subjects, aged 5-18 years, using two novel MEG paradigms: covert picture naming and verb generation. Novel analyses permitted objective quantification of ERD lateralization on an individual basis. For both tasks, left lateralization of frontal lobe ERD tended to increase with advancing age. Findings suggest that adult-typical left lateralization emerges from an early bilateral language network in normal development. In the fourth study, frontal lobe ERD lateralization for naming and verb generation was characterized in 14 children and adolescents with neurological disorders. Novel analyses permitted objective assessment of individual scans at multiple contrast time windows. In several cases, rapid hemispheric shifts in predominant frontal lobe ERD were observed through the response period. On an individual basis, the assessment protocol showed promise for future use in a presurgical context. These studies serve to advance the understanding of normal paediatric language representation, and improve the ability to predict and assess language lateralization in individuals who have experienced early neurological insults.

Research over the last two decades has revealed that the process of neurogenesis continues in some brain regions throughout adulthood in mammals. The dentate gyrus of the hippocampal formation displays adult neurogenesis and is known to be critical for some forms of learning and memory. Adult neurogenesis has been proposed to play an important role in hippocampal function. Seizures have been found to increase the rate of adult neurogenesis as well as alter the development of newborn neurons. Seizure-induced changes in neurogenesis have been proposed to underlie some of the cognitive impairments seen in epileptic patients. This thesis examines changes in neurogenesis in the dentate gyrus in the kindling model of temporal lobe epilepsy in rats, and explores the potential impact of these changes on hippocampal function. Progenitor cell proliferation and net neurogenesis were found to be increased in kindled rats, but increased proliferation was not sustained and returned to baseline by 8 days. This increase was greater in dorsal than ventral dentate gyrus but did not differ among the blades of the granule cell layer. Kindled seizures were found to enhance the survival of newborn neurons when presented during the second week of their development. These survived for at least 1 month after kindling (6 weeks after their birth). Electrical stimulation at current intensities below afterdischarge threshold failed to alter progenitor cell proliferation, while currents above threshold greatly increased it. There was no relationship found between stimulation current intensity and the rate of cell proliferation. Bilateral kindling of the perforant path failed to alter learning or long-term memory in a water maze test in spite of a large increase in neurogenesis in the dentate gyrus. Unkindled rats with more new neurons showed better learning performance, but had poorer long-term memory in the task. Kindled rats showed a disruption of these relationships. This thesis found that neurogenesis was greatly increased in the kindling epilepsy model, but that performance in a commonly used learning/memory task was unaltered. The impact of kindled seizures on water maze performance is questioned as well as the relevance of enhanced neurogenesis to cognitive impairments in epilepsy.

Research over the last two decades has revealed that the process of neurogenesis continues in some brain regions throughout adulthood in mammals. The dentate gyrus of the hippocampal formation displays adult neurogenesis and is known to be critical for some forms of learning and memory. Adult neurogenesis has been proposed to play an important role in hippocampal function. Seizures have been found to increase the rate of adult neurogenesis as well as alter the development of newborn neurons. Seizure-induced changes in neurogenesis have been proposed to underlie some of the cognitive impairments seen in epileptic patients. This thesis examines changes in neurogenesis in the dentate gyrus in the kindling model of temporal lobe epilepsy in rats, and explores the potential impact of these changes on hippocampal function. Progenitor cell proliferation and net neurogenesis were found to be increased in kindled rats, but increased proliferation was not sustained and returned to baseline by 8 days. This increase was greater in dorsal than ventral dentate gyrus but did not differ among the blades of the granule cell layer. Kindled seizures were found to enhance the survival of newborn neurons when presented during the second week of their development. These survived for at least 1 month after kindling (6 weeks after their birth). Electrical stimulation at current intensities below afterdischarge threshold failed to alter progenitor cell proliferation, while currents above threshold greatly increased it. There was no relationship found between stimulation current intensity and the rate of cell proliferation. Bilateral kindling of the perforant path failed to alter learning or long-term memory in a water maze test in spite of a large increase in neurogenesis in the dentate gyrus. Unkindled rats with more new neurons showed better learning performance, but had poorer long-term memory in the task. Kindled rats showed a disruption of these relationships. This thesis found that neurogenesis was greatly increased in the kindling epilepsy model, but that performance in a commonly used learning/memory task was unaltered. The impact of kindled seizures on water maze performance is questioned as well as the relevance of enhanced neurogenesis to cognitive impairments in epilepsy.

Prior research has shown that the distress associated with social exclusion (i.e., social pain) and physical pain share biological and neural substrates. This social-physical pain overlap has spawned a number of hypotheses regarding how both types of pain might interact. The dissertation research reported here employed diverse methodologies to investigate two questions stemming from these hypotheses: 1) what is the effect of social pain on physical pain sensitivity and 2) what is the effect of physical pain on social pain sensitivity? Pertaining to the first question, Study 1 showed that a socially disconnecting live interaction with a partner led to a decrease in physical pain sensitivity. This result, however, was not replicated in Study 2 using an imagination paradigm to conjure two different types of social exclusion experiences, nor did low levels of social connectedness predict subsequent physical pain levels in a sample of chronic pain patients in Study 3. Pertaining to the second question, pain levels did not predict subsequent reports of social disconnection in the diaries of chronic pain patients in Study 3, nor did participants experiencing capsaicin-induced physical pain report social judgments any different from their pain-free counterparts in Study 4. The reasons for, and meaning of, these findings are discussed in detail. Crucial questions that must be confronted to continue advancement in this area of research and recommendations for future studies are also explored.

Prior research has shown that the distress associated with social exclusion (i.e., social pain) and physical pain share biological and neural substrates. This social-physical pain overlap has spawned a number of hypotheses regarding how both types of pain might interact. The dissertation research reported here employed diverse methodologies to investigate two questions stemming from these hypotheses: 1) what is the effect of social pain on physical pain sensitivity and 2) what is the effect of physical pain on social pain sensitivity? Pertaining to the first question, Study 1 showed that a socially disconnecting live interaction with a partner led to a decrease in physical pain sensitivity. This result, however, was not replicated in Study 2 using an imagination paradigm to conjure two different types of social exclusion experiences, nor did low levels of social connectedness predict subsequent physical pain levels in a sample of chronic pain patients in Study 3. Pertaining to the second question, pain levels did not predict subsequent reports of social disconnection in the diaries of chronic pain patients in Study 3, nor did participants experiencing capsaicin-induced physical pain report social judgments any different from their pain-free counterparts in Study 4. The reasons for, and meaning of, these findings are discussed in detail. Crucial questions that must be confronted to continue advancement in this area of research and recommendations for future studies are also explored.