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.

Convergent evidence suggests that the perirhinal cortex (PRC) is involved in perception, in addition to long-term memory, by representing higher-order object feature conjunctions. Recent functional magnetic resonance imaging (fMRI) investigations have shown greater PRC activity during the processing of objects with a higher versus lower degree of features in common, but notably, these studies have been limited to examining only two levels of feature overlap. To address this, we scanned neurologically healthy participants with fMRI during a 1-back working memory task for objects that possessed a very low, low, medium or high degree of feature overlap. Somewhat consistent with previous findings, trends towards greater PRC activity for high versus medium feature overlap objects, and for semantically identical compared to semantically different objects were observed. However, other aspects of our data, including diminished PRC activity during medium versus low feature overlap objects, are difficult to interpret and require further investigation.

Convergent evidence suggests that the perirhinal cortex (PRC) is involved in perception, in addition to long-term memory, by representing higher-order object feature conjunctions. Recent functional magnetic resonance imaging (fMRI) investigations have shown greater PRC activity during the processing of objects with a higher versus lower degree of features in common, but notably, these studies have been limited to examining only two levels of feature overlap. To address this, we scanned neurologically healthy participants with fMRI during a 1-back working memory task for objects that possessed a very low, low, medium or high degree of feature overlap. Somewhat consistent with previous findings, trends towards greater PRC activity for high versus medium feature overlap objects, and for semantically identical compared to semantically different objects were observed. However, other aspects of our data, including diminished PRC activity during medium versus low feature overlap objects, are difficult to interpret and require further investigation.

<p>Memories are not veridical representations of the environment. Rather, an individual's goals can influence how the surrounding environment is represented in long-term memory. The present dissertation aims to delineate the influence of reward and punishment motivation on human declarative memory encoding and its underlying neural circuitry. Chapter 1 provides a theoretical framework for investigating motivation's influence on declarative memory. This chapter will review the animal and human literatures on declarative memory encoding, reward and punishment motivation, and motivation's influence on learning and memory. Chapter 2 presents a study examining the behavioral effects of reward and punishment motivation on declarative memory encoding. Chapter 3 presents a study examining the neural circuitry underlying punishment-motivated declarative encoding using functional magnetic resonance imaging (fMRI), and compares these findings to previous studies of reward-motivated declarative encoding. Chapter 4 presents a study examining the influence of reward and punishment motivation on neural sensitivity to and declarative memory for unexpected events encountered during goal pursuit using fMRI. Finally, Chapter 5 synthesizes these results and proposes a model of how and why motivational valence has distinct influences on declarative memory encoding. Results indicated that behaviorally, reward motivation resulted in more enriched representations of the environment compared to punishment motivation. Neurally, these motivational states engaged distinct neuromodulatory systems and medial temporal lobe (MTL) targets during encoding. Specifically, results indicated that reward motivation supports interactions between the ventral tegmental area and the hippocampus, whereas, punishment motivation supports interactions between the amygdala and parahippocampal cortex. Together, these findings suggest that reward and punishment engage distinct systems of encoding and result in the storage of qualitatively different representations of the environment into long-term memory.</p> / Dissertation

Cyclin-dependent kinase-5 (Cdk5) was identified as a serine/threonine kinase that plays an important role in neuronal development. Association with one of the neuronal activators, p35 or p39, is required for Cdk5 to elicit its diverse effects in the nervous system, such as neurite outgrowth. In addition to these, increasing evidence suggests that Cdk5 also plays an important role in cocaine addiction, neurotransmitter release, NMDA receptor phosphorylation. This thesis is divided into three parts which deals with the effects of Cdk5 inhibitor¡Ðroscovitine on the morphine tolerance development, acute inflammatory pain, and pilocarpine-induced seizure respectively. The first part explored the effect of Cdk5 inhibitior¡Ðroscovitine on the morphine antinociceptive tolerance development. Delta FosB activation is involved in morphine tolerance. Cyclin-dependent kinase- 5 (Cdk5) is found to be the downstream target of delta FosB. We examined the effects of the potent selective Cdk5 inhibitor¡Ðroscovitine on the development of antinociceptive tolerance of morphine. Tolerance was induced by continuous infusion of morphine 5 &#x00B5;g/hr intrathecally (i.t.) for 5 days. The effect of co-administration of roscovitine 1 &#x00B5;g/hr i.t. for 5 days was also examined. Roscovitine co-administration enhanced the antinociceptive effect of morphine in morphine tolerant rats. It also shift the morphine antinociceptive dose¡Ðresponse curve to the left during morphine tolerance induction, and reduced the increase in the ED50 of morphine two-fold. Collectively, these findings suggest Cdk5 modulation may be involved in the development of morphine tolerance and its inhibitor will enhance antinociceptive effect. The second part discussed the roscovitine effect on acute inflammatory pain. Formalin injected into the rat hind paw will evoke flinching (consisting of an elevation and shrinking back of the injected paw), a reliable parameter of pain behavior. The nociceptive response to formalin occurs in a biphasic pattern: there isan initial acute period (phase 1), and after a short period of remission, phase 2 begins and consists of a longer period (1 hour) of sustained activity. The initial response was initially attributed to a direct algogenic effect of formalin, whereas phase 2 was associated with the central sensitization. In this study, the Cdk5 inhibitor¡Ðroscovitine was injected intrathecally to elucidate the mechanism of Cdk5 activation during formalin-induced hyperalgesia. The 50 ul of 5% formalin solution was used as the noxious stimulant. The rats were injected with 0, 50, 100, and 200ug roscovitine intrathecally thirty minutes before hind paw formalin injection. Intrathecal 200ug roscovitine injection attenuates the phase I flinch response. And intrathecal 50, 100, and 200ug roscovitine injection suppress phase II flinch response effectively. Roscovitine administration could effectively suppress the formalin-induced flinch behavior. This implies the activation of Cdk5 plays an important role in the sensitization after nociceptive stimulation. The third part focus on the roscovitine effect on the pilocarpine induced seizure. Pilocarpine temporal lobe epilepsy model is widely used. Chronic electroconvulsive therapy could upregulate Cdk5 activity. Cdk5 inhibitor¡Ðroscovitine could suppress NMDA induced long-term potentiation in hippocampal slice. Intracerebroventricular injection of 100£gg roscovitine 30 min before pilocarpine-induced epilepsy could significantly decrease the seizure-induced mortality ( 11% in roscovitine group VS 77% in control group). The escape latency, spatial memory impairment, in the pilocarpine-induced seizure group is significant longer than the roscovitine pretreatment group in the Morris water maze test after one month (p¡Õ0.05). It is concluded Cdk5 may play an important in the pathogenesis of epilepsy. Therefore, Cdk5 inhibition may become another way for the epilepsy treatment.

The purpose of this study was to investigate the association between extracellular basal hippocampal glutamate levels and cognitive function in epileptic patients. We used the zero-flow microdialysis method to measure the extracellular concentrations of glutamate in the epileptogenic and non-epileptogenic hippocampus of 23 awake epileptic patients during the interictal period. All patients underwent extensive neuropsychological testing to assess cognitive functioning prior to probe implantation. Basal glutamate levels in the epileptogenic hippocampus were significantly higher than the non-epileptogenic hippocampus (mean, 11.96 micromolar (µM) versus 2.92 µM, respectively). Elevated basal glutamate levels in the epileptogenic hippocampus correlated with decreased scores on the Verbal Selective Reminding Test (V-SRT) (R[exponent]2 = 0.36, p = 0.0244). When controlling for MRI-detected hippocampal atrophy within epileptogenic regions, elevated basal glutamate levels within atrophic hippocampus correlated with decreased cognitive functioning measured by both the V-SRT (R[exponent]2 = 0.7764, p = 0.0204) and Performance Intelligence Quotient (PIQ) (R[exponent]2 = 0.7324, p = 0.0297), but not within non-atrophic hippocampus (V-SRT: R2 = 0.1013, p = 0.4424; PIQ: R[exponent]2 = 0.2303, p = 0.2288). These data suggest that elevated basal glutamate levels in the epileptogenic hippocampus may be implicated in the pathogenesis of hippocampal atrophy and may contribute to impaired cognitive functioning involving verbal memory and visual-spatial skills in patients with temporal lobe epilepsy.

Time-based prospective memory has been found to be negatively affected by aging, possibly as a result of the declining frontal function that often accompanies aging. In the present study we investigated the role of the frontal lobes in prospective memory. Based upon their scores on a composite measure of frontal function, 32 older adults were characterized as possessing high- or low-frontal function, and were then tested on a time-based laboratory prospective memory task. Overall age effects were also assessed and each of the frontal groups was compared to a group of 32 younger adults. High-frontal functioning participants demonstrated better prospective memory than low-frontal functioning participants, and were not distinguishable from younger adults. The results of this study suggest that it is not aging per se that disrupts prospective memory performance, but it is instead the diminished frontal function seen in a subset of older adults.

Abnormally slow processing of language may be a factor contributing to the poor verbal memory seen in many patients with lesions of the anterior temporal region in the left hemisphere. This possibility was examined by comparing the performance of 12 patients with left temporal-lobe resections (LT), 10 patients with similar lesions in the right hemisphere (RT) and 13 normal control (NC) subjects on a lexical-decision task, a sentence-plausibility-judgement task, and a story-recall task. Stimuli were presented aurally, and, in the latter two tasks, at 5 different speech rates ranging from 125 words per minute (wpm) to 325 wpm. Recall of stories by LT subjects was not abnormally sensitive to the effect of increasing rate, although it was inferior to that by NC subjects at all speeds. LT patients presented aurally but not visually (Frisk and Milner, 1991), suggesting that the left anterior temporal region plays a special role in the processing of speech sounds.

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.