Neurocognitive processes in instrumental learning, response reversal, decision-making and psychopathy.

This thesis investigates the neurocognitive systems involved in emotional processing, learning, and decision-making and considers the implications of dysfunction in these systems for psychopathy. The introductory chapter reviews the anatomy and function of the orbitofrontal cortex and amygdala and discusses why impairment in these regions may contribute to psychopathy. Chapter 2 introduces an investigation of the impact of emotional material on operant behaviour that showed that individuals with psychopathy do not display appropriate emotional modulation of attention. The subsequent three chapters investigate the performance of individuals with psychopathy on forms of instrumental learning that are dissociable at both the cognitive and neural levels. Chapter 3 investigates stimulus-reinforcement learning, a form of learning thought to rely on intact amygdala functioning, and found impaired performance in individuals with psychopathy. Chapter 4 presents findings of impaired reversal learning and decision making, which are indicative of orbitofrontal cortex dysfunction. Chapter 5 presents an investigation of conditional learning, which is a form of instrumental learning that is not dependent on the amygdala. As predicted by theories that emphasize amygdala and orbitofrontal cortex dysfunction in psychopathy, both groups performed similarly on the acquisition component of the conditional learning task, but individuals with psychopathy showed impairment on the second phase of the task when correct performance depended on reversing some of the acquired responses. Chapter 6 presents a case study that tests the analogy drawn between patients with lesions involving the orbitofrontal cortex and those with developmental psychopathy. The results show that the two disorders are characterized by sharply contrasting neurocognitive deficits. Chapter 7 reveals a functional Magnetic Resonance Imaging (fMRI) study addressing the basic question of whether discrete regions within the ventrolateral and orbitofrontal cortices are involved in signalling the need for response change and encoding the value of a reinforcer. The concluding chapter summarizes the results of the thesis and outlines future avenues of research that may arise from the work presented

Ventricular volume expansion in presymptomatic genetic frontotemporal dementia

Objective: To characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. Methods: Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers. Results: A total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings. Conclusions: Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD

Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

Objectives The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers. Methods The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales. Results The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills. Conclusion Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group