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Summary

Persistent tic disorder (PTD) is a neuropsychiatric disorder characterized by involuntary and stereotypical movements called tics. Despite a multitude of research, questions still remain regarding the full neurological bases of tic generative activity, as well as the degree to which certain cognitive functions are impaired in children with PTD. This dissertation aims to further elucidate the atypical neural dynamics associated with PTD through an EEG perspective. To facilitate the investigation of these neural dynamics, we first evaluate an adapted approach for performing group-level analyses on localized EEG measures at the cortical source level and compares performance to classical methods. We examined three approaches (a voxel approach, a region-of-interest (ROI) approach, and a k-means clustering approach) for detecting group differences in spectral activity in both a simulation analysis and visual attention task. Overall, we found that a voxel-approach produces reduced localization error, reduced spectral attenuation, and more accurate time-frequency detection of spectral effects, posing the method as an effective analysis approach. We then examined the degree to which behavioral performance and neural dynamics are atypical in children with PTD (compared to typically developing children) during an inhibitory control flanker paradigm, using measures of spectral power and effective connectivity. While task accuracy did not differ by diagnosis, children with PTD exhibited attenuated spectral activity in the anterior cingulate cortex (ACC), alongside greater information flow from the ACC to fronto-parietal network hubs relative to controls, while controls showed greater central and posterior connectivity. Correlations with clinical features (e.g., tic impairment) and task performance indicate these atypical activations may be neural adaptations from frequent engagement of inhibitory control pathways. Lastly, utilizing similar measures, we investigated the neural antecedents of tic expression, and the degree to which this activity is differentiable from normal resting state activity using a machine learning approach. Prior to tic occurrence, we observed increased spectral activity in the ACC, as well as changes in information flow in frontal, sensorimotor, and posterior regions, suggesting aberrant communication among multiple cognitive and sensory regions. These measurements were also found to be reliable discriminators between pre-tic activity and tic-free activity, using a Na�ve Bayes classification model. We then discuss future directions for each of the three preceding studies, as well as a potential path for developing more effective treatment protocols in PTD.

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Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and costly mental health condition. Innovation in ADHD prevention requires elucidation of underlying causal processes to highlight precise targets for early interventions that promote resilience. However, although ADHD is sensitive to multiple risk factors, including considerable heritability as well as prenatal/perinatal influences (e.g., low birth weight, prenatal exposure to maternal metabolic conditions), the pathways mediating these associations are relatively unknown. This dissertation consists of three studies that address this important gap in knowledge directly.

Cognitive functioning domains including executive functioning (EF) and reasoning (e.g., cognitive flexibility, fluid reasoning) are biologically plausible pathways from genetic and prenatal/perinatal influences to individual differences in ADHD. However, to date, mediation has primarily been inferred rather than formally evaluated, and no study has concurrently tested parallel or overlapping ADHD risk processes in the same sample. Thus, Study 1 employed multiple mediation to test diverse EF and reasoning dimensions as collective and unique mediators of ADHD symptoms from both birth weight and replicated candidate genes in a sample of youth from multiplex families with ADHD. Extending this novel integration of perinatal and genetic influences, Study 2 used a genome-wide association approach in a large population-based sample to estimate if correlations among birth weight, EF, reasoning, and ADHD symptoms were sensitive to shared genetic influences.

Although exposure to adverse maternal health factors during pregnancy (e.g., inflammation, hyperglycemia) reliably predict child EF deficits, it is unclear which factors most compromise child cognitive development and when exposure to these factors is most consequential. To improve traction specifically on the development of child EF deficits from prenatal/perinatal influences, Study 3 employed a prospective, longitudinal sample of maternal health and child development to evaluate multiple maternal metabolic and pro-inflammatory factors (i.e., C-reactive protein, glycated hemoglobin, blood pressure) simultaneously as predictors of offspring EF and compare their relative temporal influence prior to and across pregnancy.

Collectively, results of the three studies partially support that specific prenatal/perinatal influences uniquely predict particular domains of child cognitive development. Results are discussed in the context of implications for future research and for optimizing prevention strategies to reduce the significant public health burden of ADHD.

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