Investigation of hemispheric asymmetry in reasoning with HD-tDCS and fMRI

Studies on multiple patient groups suggest that reasoning has a hemispheric asymmetry component. Previously, we proposed that neural networks in the left hemisphere are driven toward increasing and maintaining certainty, while right frontal networks prioritize congruence between beliefs and evidence. We tested the predictions of this framework with two high definition transcranial direct current stimulation (HD-tDCS) experiments and one functional magnetic resonance imaging (fMRI) experiment. In both HD-tDCS studies, we aimed to induce (or amplify) hemispheric asymmetry in healthy participants as they completed novel reasoning tasks. Each participant completed three tDCS sessions: a LH-bias session, in which the anode was placed over the left inferior frontal gyrus (IFG; BA45) and the cathode over the right IFG; a RH-bias session, in which the anode was placed over the right IFG and the cathode over the left IFG; and a sham session, which served as a control. In the first HD-tDCS experiment, participants (N=26) completed a probabilistic inference task that required the integration of evidence and one’s prior background knowledge. Consistent with predictions, we found that the intensity of RH-bias stimulation was associated with 1) collecting more evidence, 2) adopting a higher threshold for stopping evidence collection, and 3) making less certain guesses than an ideal Bayesian updater during the evidence presentation. Contrary to predictions, we found that greater LH-bias intensity was associated with more evidence collection, and LH-bias stimulation was associated with greater belief backtracks after encountering conflicting evidence than RH-bias or sham stimulation. The second HD-tDCS experiment followed a similar stimulation protocol but used reasoning problems that were more deeply embedded in real-world contexts in order to create more salient belief-evidence conflicts. During each stimulation session, 24 participants 1) judged whether a criminal suspect was guilty or not guilty based on crime scene evidence, 2) judged whether or not to pass a law based on arguments in favor and in opposition to it, and 3) judged whether a news headline was real or fake. We found that RH-bias stimulation reduced belief polarization after conflict, which was consistent with our predictions. Similarly, when evidence conflicted participants’ strong beliefs, they backtracked on their beliefs more under RH-bias stimulation compared to sham stimulation and, albeit to a lesser extent, compared to LH-bias stimulation. Under RH-bias stimulation, participants were less likely to judge real news headlines as being real, which resulted in poorer discrimination of real vs. fake headlines compared to sham and LH-bias stimulation. Finally, in the fMRI experiment, we examined lateralization in frontal anatomical regions for contrasts that we predicted to be more left-lateralized or more right-lateralized. Participants (N=36) completed a modified version of the state guessing task that was used in the first tDCS experiment. Consistent with predictions, contrasts involving uncertainty and belief advances were generally more left-lateralized and contrasts involving conflicting evidence and belief backtracks were more right-lateralized. We show that HD-tDCS can alter belief updating in healthy individuals in a way that is consistent with the patient literature, but additional experiments are necessary to disentangle the causal relationships between different reasoning biases and neural activity in left and right frontal neural networks

NOVEL GRAPHICAL MODEL AND NEURAL NETWORK FRAMEWORKS FOR AUTOMATED SEIZURE DETECTION, TRACKING, AND LOCALIZATION IN FOCAL EPILEPSY

Epilepsy is a heterogenous neurological disorder characterized by recurring and unprovoked seizures. It is estimated that 60% of epilepsy patients suffer from focal epilepsy, where seizures originate from one or more discrete locations within the brain. After onset, focal seizure activity spreads, involving more regions in the cortex. Diagnosis and therapeutic planning for patients with focal epilepsy crucially depends on being able to detect epileptic activity as it starts and localize its origin. Due to the subtlety of seizure activity and the complex spatio-temporal propagation patterns of seizure activity, detection and localization of seizure by visual inspection is time-consuming and must be done by highly trained neurologists. In this thesis, we detail modeling approaches to identify and capture the spatio-temporal ictal propagation of focal epileptic seizures. Through novel multi-scale frameworks, information fusion between signal paths, and hybrid architectures, models that capture the underlying seizure propagation phenomena are developed. The first half relies on graphical modeling approaches to detect seizures and track their activity through the space of EEG electrodes. A coupled hidden Markov model approach to seizure propagation is described. This model is subsequently improved through the addition of convolutional neural network based likelihood functions, removing the reliance on hand designed feature extraction. Through the inclusion of a hierarchical switching chain and localization variables, the model is revised to capture multi-scale seizure onset and spreading information. In the second half of this thesis, end-to-end neural network architectures for seizure detection and localization are developed. First, combination convolutional and recurrent neural networks are used to identify seizure activity at the level of individual EEG channels. Through novel aggregation, the network is trained to recognize seizure activity, track its evolution, and coarsely localize seizure onset from lower resolution labels. Next, a multi-scale network capable of analyzing the global and electrode level signals is developed for challenging task of end-to-end seizure localization. Onset location maps are defined for each patient and an ensemble of weakly supervised loss functions are used in a multi-task learning framework to train the architecture

The Value of Seizure Semiology in Epilepsy Surgery: Epileptogenic-Zone Localisation in Presurgical Patients using Machine Learning and Semiology Visualisation Tool

Background Eight million individuals have focal drug resistant epilepsy worldwide. If their epileptogenic focus is identified and resected, they may become seizure-free and experience significant improvements in quality of life. However, seizure-freedom occurs in less than half of surgical resections. Seizure semiology - the signs and symptoms during a seizure - along with brain imaging and electroencephalography (EEG) are amongst the mainstays of seizure localisation. Although there have been advances in algorithmic identification of abnormalities on EEG and imaging, semiological analysis has remained more subjective. The primary objective of this research was to investigate the localising value of clinician-identified semiology, and secondarily to improve personalised prognostication for epilepsy surgery. Methods I data mined retrospective hospital records to link semiology to outcomes. I trained machine learning models to predict temporal lobe epilepsy (TLE) and determine the value of semiology compared to a benchmark of hippocampal sclerosis (HS). Due to the hospital dataset being relatively small, we also collected data from a systematic review of the literature to curate an open-access Semio2Brain database. We built the Semiology-to-Brain Visualisation Tool (SVT) on this database and retrospectively validated SVT in two separate groups of randomly selected patients and individuals with frontal lobe epilepsy. Separately, a systematic review of multimodal prognostic features of epilepsy surgery was undertaken. The concept of a semiological connectome was devised and compared to structural connectivity to investigate probabilistic propagation and semiology generation. Results Although a (non-chronological) list of patients’ semiologies did not improve localisation beyond the initial semiology, the list of semiology added value when combined with an imaging feature. The absolute added value of semiology in a support vector classifier in diagnosing TLE, compared to HS, was 25%. Semiology was however unable to predict postsurgical outcomes. To help future prognostic models, a list of essential multimodal prognostic features for epilepsy surgery were extracted from meta-analyses and a structural causal model proposed. Semio2Brain consists of over 13000 semiological datapoints from 4643 patients across 309 studies and uniquely enabled a Bayesian approach to localisation to mitigate TLE publication bias. SVT performed well in a retrospective validation, matching the best expert clinician’s localisation scores and exceeding them for lateralisation, and showed modest value in localisation in individuals with frontal lobe epilepsy (FLE). There was a significant correlation between the number of connecting fibres between brain regions and the seizure semiologies that can arise from these regions. Conclusions Semiology is valuable in localisation, but multimodal concordance is more valuable and highly prognostic. SVT could be suitable for use in multimodal models to predict the seizure focus

Prediction error dependent changes in brain connectivity during associative learning

One of the fundaments of associative learning theories is that surprising events drive learning by signalling the need to update one’s beliefs. It has long been suggested that plasticity of connection strengths between neurons underlies the learning of predictive associations: Neural units encoding associated entities change their connectivity to encode the learned associative strength. Surprisingly, previous imaging studies have focused on correlations between regional brain activity and variables of learning models, but neglected how these variables changes in interregional connectivity. Dynamic Causal Models (DCMs) of neuronal populations and their effective connectivity form a novel technique to investigate such learning dependent changes in connection strengths. In the work presented here, I embedded computational learning models into DCMs to investigate how computational processes are reflected by changes in connectivity. These novel models were then used to explain fMRI data from three associative learning studies. The first study integrated a Rescorla-Wagner model into a DCM using an incidental learning paradigm where auditory cues predicted the presence/absence of visual stimuli. Results showed that even for behaviourally irrelevant probabilistic associations, prediction errors drove the consolidation of connection strengths between the auditory and visual areas. In the second study I combined a Bayesian observer model and a nonlinear DCM, using an fMRI paradigm where auditory cues differentially predicted visual stimuli, to investigate how predictions about sensory stimuli influence motor responses. Here, the degree of striatal prediction error activity controlled the plasticity of visuo-motor connections. In a third study, I used a nonlinear DCM and data from a fear learning study to demonstrate that prediction error activity in the amygdala exerts a modulatory influence on visuo-striatal connections. Though postulated by many models and theories about learning, to our knowledge the work presented in this thesis constitutes the first direct report that prediction errors can modulate connection strength

Effects of Diversity and Neuropsychological Performance in an NFL Cohort

Objective: The aim of this study was to examine the effect of ethnicity on neuropsychological test performance by comparing scores of white and black former NFL athletes on each subtest of the WMS. Participants and Methods: Data was derived from a de-identified database in South Florida consisting of 63 former NFL white (n=28, 44.4%) and black (n=35, 55.6%) athletes (Mage= 50.38; SD= 11.57). Participants completed the following subtests of the WMS: Logical Memory I and II, Verbal Paired Associates I and II, and Visual Reproduction I and II. Results: A One-Way ANOVA yielded significant effect between ethnicity and performance on several subtests from the WMS-IV. Black athletes had significantly lower scores compared to white athletes on Logical Memory II: F(1,61) = 4.667, p= .035, Verbal Paired Associates I: F(1,61) = 4.536, p = .037, Verbal Paired Associates: II F(1,61) = 4.677, p = .034, and Visual Reproduction I: F(1,61) = 6.562, p = .013. Conclusions: Results suggest significant differences exist between white and black athletes on neuropsychological test performance, necessitating the need for proper normative samples for each ethnic group. It is possible the differences found can be explained by the psychometric properties of the assessment and possibility of a non-representative sample for minorities, or simply individual differences. Previous literature has found white individuals to outperform African-Americans on verbal and non-verbal cognitive tasks after controlling for socioeconomic and other demographic variables (Manly & Jacobs, 2002). This highlights the need for future investigators to identify cultural factors and evaluate how ethnicity specifically plays a role on neuropsychological test performance. Notably, differences between ethnic groups can have significant implications when evaluating a sample of former athletes for cognitive impairment, as these results suggest retired NFL minorities may be more impaired compared to retired NFL white athletes

Distinguishing Performance on Tests of Executive Functions Between Those with Depression and Anxiety

Objective: To see if there are differences in executive functions between those diagnosed with Major Depressive Disorder (MDD) and those with Generalized Anxiety Disorder (GAD).Participants and Methods: The data were chosen from a de-identified database at a neuropsychological clinic in South Florida. The sample used was adults diagnosed with MDD (n=75) and GAD (n=71) and who had taken the Halstead Category Test, Trail Making Test, Stroop Test, and the Wisconsin Card Sorting Test. Age (M=32.97, SD=11.75), gender (56.7% female), and race (52.7% White) did not differ between groups. IQ did not differ but education did (MDD=13.41 years, SD=2.45; GAD=15.11 years, SD=2.40), so it was ran as a covariate in the analyses. Six ANCOVAs were run separately with diagnosis being held as the fixed factor and executive function test scores held as dependent variables. Results: The MDD group only performed worse on the Category Test than the GAD group ([1,132]=4.022, p\u3c .05). Even though both WCST scores used were significantly different between the two groups, both analyses failed Levene’s test of Equality of Error Variances, so the data were not interpreted. Conclusions: Due to previous findings that those diagnosed with MDD perform worse on tests of executive function than normal controls (Veiel, 1997), this study wanted to compare executive function performance between those diagnosed with MDD and those with another common psychological disorder. The fact that these two groups only differed on the Category Test shows that there may not be much of a difference in executive function deficits between those with MDD and GAD. That being said, not being able to interpret the scores on the WCST test due to a lack of homogeneity of variance indicates that a larger sample size is needed to compare these two types of patients, as significant differences may be found. The results of this specific study, however, could mean that the Category Test could be used in assisting the diagnosis of a MDD patient