Reliving the past requires the integration of multi-modal sensory details into a coherent mental impression of the initial event. In most people, memory for life episodes, or Autobiographical Memory (AM), is rich in sensory-perceptual elements that provide the vivid impression of travelling back in time. Abundant evidence indicates that the hippocampus plays a central role in AM recollection, but much research is still needed to determine which AM attributes engage the hippocampus at retrieval. My work assessed the relationship between hippocampal function and the perceptual richness of memory episodes. I designed a paradigm that captured the complexity of AM, and that manipulated perceptual richness while controlling for other AM confounds, such as recency, rehearsal, personal relevance, and “story” content. Participants studied and recalled perceptually enriched and impoverished laboratory events (film clips and written narratives, respectively) matched for the complexity of their storyline. An AM condition was also included for comparison. I tested healthy individuals and participants with unilateral medial temporal lobe epilepsy (mTLE), a clinical population with well documented hippocampal damage, on this paradigm. Perceptual richness was greatly reduced in people with mTLE, an effect that was most salient in the perceptually enriched conditions (AM and film clips). In a functional MRI version of this paradigm conducted on healthy individuals, I identified neural regions sensitive to the perceptual richness of AM and laboratory events, which included the anterior portion of the right hippocampus and other regions known to play a role in imagery and visual processing. In patients with right-lateralized mTLE, activation in these brain regions was markedly reduced in all memory conditions, which was consistent with the reduced perceptual richness I observed behaviourally. I reveal a clear relationship between hippocampal function and the perceptual richness of episodic memory, suggesting that the hippocampus plays a central role among brain regions that support the integration of multi-modal details into enriched memory experiences. My findings also advance our knowledge of how pathology and the nature of memory representation affect the neural correlates of episodic memory.

The present research examined the hypothesis that omega-3 polyunsaturated fatty acids would increase seizure threshold in rats in vivo, and reduce neuronal excitability in mouse hippocampal slices. Seizure thresholds were measured in rats using the maximal pentylenetetrazol and electrical stimulation seizure tests following α-linolenic acid (ALA) or docosahexaenoic acid administration. ALA raised seizure threshold in the maximal PTZ seizure test, but this effect probably occurred because ALA displaced DHA from liver to the brain. DHA itself was therefore tested in the PTZ and electrical stimulation seizure tests. Direct administration of DHA by subcutaneous injection raised seizure thresholds in the PTZ seizure test, which models tonic-clonic attacks in humans. Dietary enrichment with DHA raised afterdischarge seizure thresholds in the cortex and amygdala, which model simplex and complex partial seizures in humans, although this effect took some time to occur. In vitro, the application of DHA also reduced the incidence of excitatory sharp waves in mouse hippocampal slices. This effect did not appear to be due to either an increase in GABAergic inhibitory tone, nor to a decrease in glutamatergic drive. The fatty acid composition of phospholipids and unesterified fatty acids were measured in the brain following microwave fixation in order to determine whether the effects of DHA on seizure thresholds were due to its de-esterification from the phospholipid membrane. The assay surprisingly revealed that subcutaneous administration of DHA at a dose that raised seizure threshold, increased unesterified arachidonic acid, but not unesterified DHA concentrations during seizures. The results of these studies support the hypothesis that DHA raises seizure threshold in rats, and reduces neuronal excitability in vitro. The effects of DHA on seizure threshold are possibly mediated by the de-esterification of arachidonic acid, which is known to have effects on the voltage-dependent sodium channel.

The lithium/pilocarpine model of epilepsy mimics mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) in humans. Systemic injection of pilocarpine in lithium chloride (LiCL) pretreated adult rats results in an acute episode of severe continuous seizure activity (status epilepticus, SE). SE causes a latent period, whereby the animal appears neurologically normal, with subsequent development of spontaneous recurrent seizures (SRSs). Neuropathological changes that occur during the latent period are believed to contribute to the epileptic condition. The present thesis characterized the development of neuronal death and behavioural alterations in rats after SE induced by the repeated low-dose pilocarpine procedure (RLDP), and investigated the causal relationship between these two processes. Our data demonstrated that the RLDP procedure for the induction of SE results in widespread neurodegeneration and behavioural alterations comparable to the pilocarpine and low-dose pilocarpine (LDP) procedures. However, the advantage to using this protocol was strain-dependent as it reduced mortality in Wistar, but not in Long Evans Hooded (LEH), rats. Stereological analysis of neurons (stained for the neuronal specific marker [NeuN]) at various times (1 hr to 3 months) following SE showed that different brain regions within the hippocampus, amygdala, thalamus and piriform cortex exhibited differential rates of neuronal loss, with the majority of SE-induced neuronal death present by 24 hours. SE resulted in decreased exploratory behavior as assessed in the open field test, increased aggression to handling, increased hyperreactivity as assessed in the touch-response test, and anxiolytic effects as measured in the elevated-plus maze. Furthermore, deficits in search strategies used, as well as impaired spatial learning and memory, contributed to poor Morris water maze (MWM) performance. Partial neuroprotection within the hippocampus (by tat-NR2B9c) had no effect on the number of rats developing SRSs or on behavioural alterations; this argues against a causal relationship between neurodegeneration within this region, genesis of SRSs, and behavioural morbidity.

Reliving the past requires the integration of multi-modal sensory details into a coherent mental impression of the initial event. In most people, memory for life episodes, or Autobiographical Memory (AM), is rich in sensory-perceptual elements that provide the vivid impression of travelling back in time. Abundant evidence indicates that the hippocampus plays a central role in AM recollection, but much research is still needed to determine which AM attributes engage the hippocampus at retrieval. My work assessed the relationship between hippocampal function and the perceptual richness of memory episodes. I designed a paradigm that captured the complexity of AM, and that manipulated perceptual richness while controlling for other AM confounds, such as recency, rehearsal, personal relevance, and “story” content. Participants studied and recalled perceptually enriched and impoverished laboratory events (film clips and written narratives, respectively) matched for the complexity of their storyline. An AM condition was also included for comparison. I tested healthy individuals and participants with unilateral medial temporal lobe epilepsy (mTLE), a clinical population with well documented hippocampal damage, on this paradigm. Perceptual richness was greatly reduced in people with mTLE, an effect that was most salient in the perceptually enriched conditions (AM and film clips). In a functional MRI version of this paradigm conducted on healthy individuals, I identified neural regions sensitive to the perceptual richness of AM and laboratory events, which included the anterior portion of the right hippocampus and other regions known to play a role in imagery and visual processing. In patients with right-lateralized mTLE, activation in these brain regions was markedly reduced in all memory conditions, which was consistent with the reduced perceptual richness I observed behaviourally. I reveal a clear relationship between hippocampal function and the perceptual richness of episodic memory, suggesting that the hippocampus plays a central role among brain regions that support the integration of multi-modal details into enriched memory experiences. My findings also advance our knowledge of how pathology and the nature of memory representation affect the neural correlates of episodic memory.

The goal of this thesis was to understand and quantify to what extent plants are used for the treatment of mental and folk illnesses such as susto and mal aire in the Neotropics and to investigate the anxiolytic and antiepileptic potential of previously unstudied Neotropical members of the genera Piper and Peperomia. Firstly, the literature was reviewed and a regression analysis method was used in order to quantitatively determine which plant families are preferred for the treatment of mental, behavioral and neurological health disorders in the Neotropics. This analysis identified Piperaceae, among others, as an important taxonomic group for the treatment of such disorders. Following that lead, a botanical survey was conducted in Peru, where 47 species of Piperaceae and 21 plants traditionally used for folk illnesses by the Yanesha of Peru, an Amazonian ethnic group, were collected. In order to target potential anxiolytic and antiepileptic plants, two high throughput bioassays were used to evaluate the extracts’ in vitro activity on the γ-aminobutyric acid (GABA) system. Plant extracts in general demonstrated moderate to high affinity to the GABA-BZD receptor. Additionally, extracts demonstrated low to moderate activity in the inhibition of the GABA-T enzyme, with a few plants exhibiting promising activity. Plants selected by the Yanesha showed comparable activity to the other Piperaceae plants with Piper cremii being the most active plant in the GABAA assay, and Drymaria cordata in the GABA-T assay. Finally, four phytochemicals from Piper tuerckheimii, a plant regarded as one of the most effective traditional remedy for the treatment of epilepsy and susto by the Q’eqchi’ Maya of Belize presented, were isolated for the first time.

Masters of Philosophy / In today's society, the misdiagnosis of school-age children with the neurological condition Child Absence Epilepsy (CAE) as having Attention-Deficit/Hyperactivity Disorder (ADHD) has a low profile. This may be because of the lack of popular awareness of CAE. The increasing social salience towards the neuropsychological condition of ADHD places these children at risk of experiencing high psychosocial effects. Many symptoms of CAE are also associated with ADHD. However if the condition is misdiagnosed as ADHD, the child with CAE is often mistreated, both medically and socially until the correct diagnosis is made. There is little research available on the psychosocial effects of the misdiagnosis of epilepsy as ADHD, and none available relating to CAE. This research study uses case study methodology to focus on how children with CAE are psychosocially affected at the time of the misdiagnosis of ADHD and subsequently. It also explores the experiences of their parents. An in-depth interview method was adopted to gather the personal recollections of these effects directly from the ten participants in this study. The participants were found with the assistance of Epilepsy Australia and constituted one adolescent from five different families who had experienced the sequence of events and effects under investigation, and a parent (guardian) who cared for these children during this period. The findings of this research indicate that as a result of labelling, these children were misjudged in their communities, leaving strong psychosocial effects on each of the child participants who had previously been misdiagnosed with ADHD. These effects include low self-esteem, insecurity and fear experienced most often in the company of peers. As a result, when reaching adulthood, most of these participants chose to isolate themselves from social contact whenever possible. The findings offer a basis for further research in the area.

Defining language lateralisation is important to minimise morbidity in patients treated surgically for temporal lobe epilepsy (TLE). Functional magnetic resonance imaging (fMRI) offers a promising, non-invasive, alternative strategy to the Wada test. Here, fMRI has been used to study healthy controls and patients with TLE in order (i) to define language-related activation patterns and their reproducibility; (ii) to compare lateralisation determined by fMRI with that from the Wada test; and (iii) to explore the usefulness of multiple fMRI language paradigms. 18 healthy controls (12 right-handed and 6 left-handed) and 24 pre-operative TLE patients (19 right-handed: 12 left-TLE, 7 right-TLE; 5 left-handed: 2 right-TLE, 3 left-TLE) were studied using fMRI. Four fMRI language paradigms used: phonetic and semantic fluency, and the naming of living and non-living things. The data for all 4 tasks were acquired during a single scanning session on two occasions. All patients also underwent Wada testing. In patients and controls, phonetic and semantic fluency tasks were robustly activating and strongly lateralising. Quantified language-related lateralisation from fMRI verbal fluency data was highly reproducible and concordant with the lateralisation of the Wada test. Both fluency tasks identified patients with atypical language lateralisation, including 4/12 right-handed patients with left-TLE and 4/5 left-handed TLE patients, regardless of the side of epileptic focus. In comparison, the two confrontational naming tasks were not strongly lateralising and did not reliably agree with Wada lateralisation in either 12 right-handed controls or 19 right-handed patients with TLE. However, there was a difference in the pattern of fMRI activation in right-handed pat ients with left-TLE. Left-TLE patients had a more right lateralised network of activation when naming living things relative to non-living things, suggesting that some patients may be at risk of a category specific naming decline for non-living things after left anterior temporal lobectomy. These results demonstrate that non-invasive fMRI measures of languagerelated lateralisation may provide a practical and reliable alternative to invasive testing for pre-surgical language lateralisation in patients with TLE. The high proportion of TLE patients showing atypical language lateralisation suggests considerable plasticity of language representation in the brains of patients with intractable TLE.

Defining language lateralisation is important to minimise morbidity in patients treated surgically for temporal lobe epilepsy (TLE). Functional magnetic resonance imaging (fMRI) offers a promising, non-invasive, alternative strategy to the Wada test. Here, fMRI has been used to study healthy controls and patients with TLE in order (i) to define language-related activation patterns and their reproducibility; (ii) to compare lateralisation determined by fMRI with that from the Wada test; and (iii) to explore the usefulness of multiple fMRI language paradigms. 18 healthy controls (12 right-handed and 6 left-handed) and 24 pre-operative TLE patients (19 right-handed: 12 left-TLE, 7 right-TLE; 5 left-handed: 2 right-TLE, 3 left-TLE) were studied using fMRI. Four fMRI language paradigms used: phonetic and semantic fluency, and the naming of living and non-living things. The data for all 4 tasks were acquired during a single scanning session on two occasions. All patients also underwent Wada testing. In patients and controls, phonetic and semantic fluency tasks were robustly activating and strongly lateralising. Quantified language-related lateralisation from fMRI verbal fluency data was highly reproducible and concordant with the lateralisation of the Wada test. Both fluency tasks identified patients with atypical language lateralisation, including 4/12 right-handed patients with left-TLE and 4/5 left-handed TLE patients, regardless of the side of epileptic focus. In comparison, the two confrontational naming tasks were not strongly lateralising and did not reliably agree with Wada lateralisation in either 12 right-handed controls or 19 right-handed patients with TLE. However, there was a difference in the pattern of fMRI activation in right-handed pat ients with left-TLE. Left-TLE patients had a more right lateralised network of activation when naming living things relative to non-living things, suggesting that some patients may be at risk of a category specific naming decline for non-living things after left anterior temporal lobectomy. These results demonstrate that non-invasive fMRI measures of languagerelated lateralisation may provide a practical and reliable alternative to invasive testing for pre-surgical language lateralisation in patients with TLE. The high proportion of TLE patients showing atypical language lateralisation suggests considerable plasticity of language representation in the brains of patients with intractable TLE.

Masters of Philosophy / In today's society, the misdiagnosis of school-age children with the neurological condition Child Absence Epilepsy (CAE) as having Attention-Deficit/Hyperactivity Disorder (ADHD) has a low profile. This may be because of the lack of popular awareness of CAE. The increasing social salience towards the neuropsychological condition of ADHD places these children at risk of experiencing high psychosocial effects. Many symptoms of CAE are also associated with ADHD. However if the condition is misdiagnosed as ADHD, the child with CAE is often mistreated, both medically and socially until the correct diagnosis is made. There is little research available on the psychosocial effects of the misdiagnosis of epilepsy as ADHD, and none available relating to CAE. This research study uses case study methodology to focus on how children with CAE are psychosocially affected at the time of the misdiagnosis of ADHD and subsequently. It also explores the experiences of their parents. An in-depth interview method was adopted to gather the personal recollections of these effects directly from the ten participants in this study. The participants were found with the assistance of Epilepsy Australia and constituted one adolescent from five different families who had experienced the sequence of events and effects under investigation, and a parent (guardian) who cared for these children during this period. The findings of this research indicate that as a result of labelling, these children were misjudged in their communities, leaving strong psychosocial effects on each of the child participants who had previously been misdiagnosed with ADHD. These effects include low self-esteem, insecurity and fear experienced most often in the company of peers. As a result, when reaching adulthood, most of these participants chose to isolate themselves from social contact whenever possible. The findings offer a basis for further research in the area.

Thesis (Ph.D.)--Duquesne University, 2007. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p. 300-314) and index.