Temporal lobe epilepsy (TLE) is a common form of intractable epilepsy that can be treated with surgical resection of the epileptogenic medial temporal lobe tissue, specifically the hippocampus. This resection can lead to a variable degree of memory deficit and considerable research has been directed at identifying predictors of these deficits. This thesis explores the relationship between structural predictors and functional predictors in TLE. I looked at fMRI activation asymmetry produced by a scene encoding task as well as volume asymmetry ratios within the hippocampus and the relationship of these predictors to memory performance in patients with TLE. Mediation analysis was performed according to Baron and Kenny (1986) and showed that fMRI activation asymmetry mediated the relationship between volume asymmetry and memory asymmetry in patients with TLE. This suggests that activation asymmetry may be a preferred variable for assessing functional adequacy in the medial temporal region.

Absence or impairment of functional communication is a fundamental deficit in Autism Spectrum Disorder (ASD). The specific factors that contribute to a great variety of speech and language impairments are still unknown but have a neurobiological substratum. We investigated the brain control of speech production mechanism in children with ASD using Magnetoencephalography (MEG). MEG is a neuroimaging modality with high temporal resolution that records neural activation in real time. A group of children with ASD and age- and sex- matched controls performed simple oromotor (open and close mouth) and speech tasks (one-syllable and multi-syllable phoneme production). Atypical and significantly different brain neural activation in motor (BA 6 and BA 4) areas and speech control (BA 47, BA 22) areas were noted in children with ASD compared to typically developing controls. The present thesis provides new evidence contributing to the understanding of speech and language production in individuals with autism.

Absence or impairment of functional communication is a fundamental deficit in Autism Spectrum Disorder (ASD). The specific factors that contribute to a great variety of speech and language impairments are still unknown but have a neurobiological substratum. We investigated the brain control of speech production mechanism in children with ASD using Magnetoencephalography (MEG). MEG is a neuroimaging modality with high temporal resolution that records neural activation in real time. A group of children with ASD and age- and sex- matched controls performed simple oromotor (open and close mouth) and speech tasks (one-syllable and multi-syllable phoneme production). Atypical and significantly different brain neural activation in motor (BA 6 and BA 4) areas and speech control (BA 47, BA 22) areas were noted in children with ASD compared to typically developing controls. The present thesis provides new evidence contributing to the understanding of speech and language production in individuals with autism.

Inhibition, an important cognitive skill relying on frontal lobe function, is often deficient in individuals with autism spectrum disorders (ASD). Spatiotemporal measures of brain activity were acquired using magnetoencephalography during a Go/No-go task with adolescents and adults with ASD and matched controls. During the task, participants responded to Go stimuli and withheld their response to No-go stimuli. Typical inhibitory network development was investigated in study 1. Adolescents displayed a distributed activity pattern, recruiting temporal and parietal regions, in addition to frontal areas, unlike adults. In study 2, inhibition was compared between individuals with and without ASD. Lateralization differences were found: adults with ASD activated the left and control adults recruited the right inferior prefrontal cortex. Adolescents with ASD recruited predominantly frontal regions, unlike their controls. Implications include immature inhibitory networks in typical adolescence and deficits in adolescents with ASD in recruiting distal cortical regions to supplement poor frontal lobe function.

Inhibition, an important cognitive skill relying on frontal lobe function, is often deficient in individuals with autism spectrum disorders (ASD). Spatiotemporal measures of brain activity were acquired using magnetoencephalography during a Go/No-go task with adolescents and adults with ASD and matched controls. During the task, participants responded to Go stimuli and withheld their response to No-go stimuli. Typical inhibitory network development was investigated in study 1. Adolescents displayed a distributed activity pattern, recruiting temporal and parietal regions, in addition to frontal areas, unlike adults. In study 2, inhibition was compared between individuals with and without ASD. Lateralization differences were found: adults with ASD activated the left and control adults recruited the right inferior prefrontal cortex. Adolescents with ASD recruited predominantly frontal regions, unlike their controls. Implications include immature inhibitory networks in typical adolescence and deficits in adolescents with ASD in recruiting distal cortical regions to supplement poor frontal lobe function.

Examination of functional brain anatomy is a crucial step in the process of surgical removal of many brain tumors. Functional magnetic resonance imaging (fMRI) is a promising technology capable of mapping brain function non-invasively. To be successfully applied to presurgical mapping, there are questions of diagnostic accuracy that remain to be addressed. One of the greatest difficulties in implementing fMRI is the need to define an activation threshold for producing functional maps. There is as of yet no consensus on the best approach to this problem, and a priori statistical approaches are generally considered insufficient because they are not specific to individual patient data. Additionally, low signal to noise and sensitivity to magnetic susceptibility effects combine to make the production of activation maps technically demanding. This contributes to a wide range of estimates of reproducibility and validity for fMRI, as the results are sensitive to changes in acquisition and processing strategies. Test-retest fMRI imaging at the individual level, and receiver operator characteristic (ROC) analysis of the results can address both of these concerns simultaneously. In this work, it is shown that the area under the ROC curve (AUC) can be used as an indicator of reproducibility, and that this is dependent on the image thresholds used. Production of AUC profiles can thus be used to optimize the selection of individual thresholds on the basis of detecting stable activation patterns, rather than a priori significance levels. The ROC analysis framework developed provides a powerful tool for simultaneous control of protocol reproducibility and data driven threshold selection, at the individual level. This tool can be used to guide optimal acquisition and processing strategies, and as part of a quality assurance program for implementing presurgical fMRI.

Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. These enzymes are associated with the pathology of neurologic disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS). In particular, AChE and BuChE accumulate in B- amyloid (AB) plaques and tau neurofibrillary tangles in the AD brain. Thus, imaging cholinesterase activity associated with plaques and tangles in the brain has the potential to provide definitive diagnosis of AD during life. This would be advantageous since, at present, confirmation of AD relies on detecting pathology through post-mortem examination of the brain. In a similar respect, BuChE is associated with the characteristic lesions in MS brain and thus, is a promising target for diagnosis and monitoring of pathology in this disease. It is hypothesized that cholinesterase-binding radiopharmaceuticals can be used in SPECT or PET imaging to visualize these enzymes associated with AD and MS pathology in the living brain. Several classes of cholinesterase ligands were synthesized and exhibited potent binding and specificity towards AChE and BuChE using enzyme kinetic analysis. These compounds were rapidly radiolabelled with 123I and purified. Radiolabelled molecules accumulated in vitro in areas known to contain cholinesterase activity in transgenic AD mice and post-mortem human AD brain tissues, using autoradiography. Furthermore, cholinesterase activity associated with AB plaques was visualized in human and transgenic mouse AD brain tissues. An enzyme kinetic approach was employed to determine critical residues in the BuChE active site gorge for ligand binding. In particular, residues pertaining to the peripheral site of the enzyme were identified and found to be involved in the binding of various ligands. These results are crucial for optimizing the enzyme binding properties of cholinesterase imaging agents. Finally, PET imaging of a transgenic mouse model of AD was performed as a vanguard for pre-clinical evaluation of cholinesterase imaging agents. PET imaging identified similar characteristics between this AD mouse model and the human condition. This is a promising approach for evaluation of cholinesterase imaging agents. Radioligands specific for cholinesterases have the potential to provide a noninvasive means for early diagnosis of neurological diseases using brain scanning.

Meaningful semantic context has been shown to improve comprehension of spoken sentences by young and old adults, especially in difficult listening conditions. Whether older adults benefit differently than younger adults is a topic of some controversy. I asked young (14 participants, 18-25) and older adults (20 participants, 60-75) to report entire sentences which contained either a coherent or anomalous global semantic context (e.g. coherent: “Her new skirt was made of denim”, anomalous: “Her good slope was done in carrot”). Sentences were mixed with signal-correlated noise, at 10 signal-to-noise ratios (-6 to +2 dB and clear speech). Percentage scores were converted to rationalized arcsine units and subjected to a repeated-measures ANOVA; slopes from psychometric functions fitted to the transformed data were also analyzed. Cognitive and hearing threshold differences were considered as factors influencing results. Finally, individual variability in the use of context was explored. Comprehension by both groups benefited from meaningful context, without a clear difference in the overall amount of benefit obtained. Cognitive factors did not appear to influence the results, although differences in hearing thresholds likely contributed to the consistent performance decrement for older adults. Individuals varied greatly in their use of context, a possible explanation for inconsistent results in studies comparing context use by young and older people. fMRI was then used to look at neural activity associated with deriving benefit from meaningful context. Whole-brain EPI data were acquired from young (16 participants, 19-26) adults using a sparse imaging design. Participants heard coherent and anomalous sentences in the scanner, and were asked to report what they heard on half of the trials. Individual’s word-report data obtained in the scanner were used to model intelligibility in the analysis and results were compared to an analysis conducted using intelligibility estimates based on group data from another study. In addition to bilateral temporal activity associated with increasing intelligibility, I observe a large left inferior-frontal region in which BOLD signal correlated more strongly with highly intelligible anomalous compared to highly intelligible coherent prose, presumably reflecting challenged semantic integration and supporting Hagoort’s (2005) model of semantic unification. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2008-09-18 23:01:40.979

Brain tumours, even though rare, are one of the deadliest types of cancer. The five year survival rate for the most malignant type of brain tumours is below 5%. Modern medicine provides many options for treating brain cancer such as radiotherapy and chemotherapy. However, one of the most effective ways of fighting the disease is surgical resection. During such a procedure the tumour is partially or completely removed. Unfortunately, even after a complete resection some tumourous tissue is left behind and can grow back or metastasise to a different location in the brain. It has been shown, however, that more aggressive resections lead to longer life expectancy. This does not come without risks. Depending on tumour location, extensive resections can lead to transient or permanent post-operative neurological deficits. Therefore, when planning a procedure, the neurosurgeon needs to find balance between extending patients life and maintaining its quality. Recent developments in Magnetic Resonance Imaging (MRI) fueled by the field of human cognitive neuroscience have led to improved methods of non-invasive imaging of the brain function. Such methods allow the creation of functional brain maps of populations or individual subjects. Adapting this technique to the clinical environment enables the assessment of the risks and to plan surgical procedures. The following work aims at improving the use of functional MRI with a specific clinical goal in mind. The thesis begins with description of etiology, epidemiology and treatment options for brain tumours. This is followed by a description of MRI and related data processing methods, which leads to introduction of a new technique for thresholding statistical maps which improves upon existing solutions by adapting to the nature of the problem at hand. In contrast to methods used in cognitive neuroscience our approach is optimized to work on single subjects and maintain a balance between false positive and false negative errors. This balance is crucial for accurate assessment of the risk of a surgical procedure. Using this method a test-retest reliability study was performed to assess five different behavioural paradigms and scanning parameters. This experiment was performed on healthy controls and was aimed at selecting which paradigms produce reliable results and therefore can be used for presurgical planning. This allowed the creation of a battery of task that was applied to glioma patients. Functional maps created before the surgeries were compared with electrocortical stimulation performed during the surgeries. The final contribution of this work focuses on technical aspects of performing neuroimaging data analysis. A novel data processing framework which provides means for rapid prototyping and easy translation and adaptation of already existing methods taken from cognitive neuroscience field is introduced. The framework enables fully automatic processing of patient data and therefore greatly reduced costs while maintaining quality control. A discussion of future directions and challenges in using functional MRI for presurgical planning concludes the thesis.

The current set of three proposed experiments focused on integrating neurological and behavioral levels of analysis in the context of pathological gambling. A thoroughgoing analysis on previous gambling research was explored and discussed in the first four chapters. Specifically, this analysis outlines: similarities between pathological gambling and other substance addictions, new technological advances (i.e. functional magnetic resonance imaging), verbal behavior in general and its role in pathological gambling specifically, and treatment assessments and interventions. Three experiments were then developed and designed based on the outcomes suggested by the literature review. Experiment I determined the effectiveness of the Gambling Functional Assessment (GFA; Dixon & Johnson, 2007) as a clinically relevant gambling assessment tool. Experiment II also investigated neurological differences between pathological gamblers. Similar to other behavioral and substance addictions, limbic and cortical brain systems are activated during gambling related tasks and activities. However, as gambling pathology increases, brain activation in these regions have been reported to decrease, and it is unclear how pathological gamblers brain activation patterns differ across function maintaining gambling (i.e. attention, escape, sensory, and tangible maintaining functions). Therefore, Experiment II built upon the findings of Experiment I by contrasting brain activation images from the two highest maintaining functions of play, as indicated by the GFA. Concomitantly, Experiment III assessed function based assessment and treatment of pathological gamblers, by comparing brief 30 min exposure to function based or non- function based Acceptance and Commitment Therapy for gamblers. Results from both studies suggested differences in brain activation patterns, yet similarities across subjective closeness to win ratings of the slot machine. Furthermore, brain activation patterns did not change following function based therapy, while subjective ratings in the function based treatment group decreased. Implications for brain-behavior relationships both in a gambling context and in relation to behavior therapy will be discussed.