Identifying Abnormal Connectivity in Patients Using Dynamic Causal Modeling of fMRI Responses

Functional imaging studies of brain damaged patients offer a unique opportunity to understand how sensorimotor and cognitive tasks can be carried out when parts of the neural system that support normal performance are no longer available. In addition to knowing which regions a patient activates, we also need to know how these regions interact with one another, and how these inter-regional interactions deviate from normal. Dynamic causal modeling (DCM) offers the opportunity to assess task-dependent interactions within a set of regions. Here we review its use in patients when the question of interest concerns the characterization of abnormal connectivity for a given pathology. We describe the currently available implementations of DCM for fMRI responses, varying from the deterministic bilinear models with one-state equation to the stochastic non-linear models with two-state equations. We also highlight the importance of the new Bayesian model selection and averaging tools that allow different plausible models to be compared at the single subject and group level. These procedures allow inferences to be made at different levels of model selection, from features (model families) to connectivity parameters. Following a critical review of previous DCM studies that investigated abnormal connectivity we propose a systematic procedure that will ensure more flexibility and efficiency when using DCM in patients. Finally, some practical and methodological issues crucial for interpreting or generalizing DCM findings in patients are discussed

Real-time fMRI neurofeedback and smartphone-based interventions to modulate mental functions

Our brains are constantly changing on a molecular level depending on the demands thrown at them by our environments, behavior, and thoughts. This neuronal plasticity allows us to voluntarily influence mental functions. Taking conscious control over mental functions goes potentially back millenia, but it was psychotherapy since the early 20th century which moulded this concept into a concrete form to target specific mental disorders. Mental disorders constitute a large burden on modern societies. Stress-related disorders like anxiety and depression particularly make up a large part of this burden and new ways to treat or prevent them are highly desirable, since traditional approaches are not equally helpful to every person affected. This might be because the infrastructure is not available where the person lives, their schedules and obligations or financial means do not enable them to seek help or they simply do not respond to traditional forms of treatment. Technological advances bring forth new potential approaches to modulate mental functions and allow using additional information to tailor an intervention better to an individual patient. The focus of this dissertation lies on two promising approaches to cognitively intervene and modulate mental functions: real-time functional magnetic resonance imaging neurofeedback (rtfMRInf) on one hand and smartphone-based interventions (SBIs) on the other. To investigate various aspects of both these methods in the context of stress and in relation to personalized interventions, we designed and conducted two experiments with a main rtfMRInf intervention, and also with ambulatory training of mental strategies, which participants accessed on their mobile phones. The four publication this thesis entails, are related to this topic as follows: The first publication focuses on rtfMRInf effects on the physiological stress response, exploring whether neurofeedback could reduce stress-related changes in brain activity and blood pressure. The second publication focuses on rtfMRInf effects on psychological measures related to the stress response, namely on arousal and mood, based on data from self-report by the participants. The third publication focuses on rtfMRInf methodology itself, looking at complex connectivity data between major neural networks. Finally, the fourth publication focuses on personalized prediction of intervention success of an SBI using data from previous training days

Context-specific activations are a hallmark of the neural basis of individual differences in general executive function

Common executive functioning (cEF) is a domain-general factor that captures shared variance in performance across diverse executive function tasks. To investigate the neural mechanisms of individual differences in cEF (e.g., goal maintenance, biasing), we conducted the largest fMRI study of multiple executive tasks to date (N = 546). Group average activation during response inhibition (antisaccade task), working memory updating (keep track task), and mental set shifting (number–letter switch task) overlapped in classic cognitive control regions. However, there were no areas across tasks that were consistently correlated with individual differences in cEF ability. Although similar brain areas are recruited when completing different executive function tasks, activation levels of those areas are not consistently associated with better performance. This pattern is inconsistent with a simple model in which higher cEF is associated with greater or less activation of a set of control regions across different task contexts; however, it is potentially consistent with a model in which individual differences in cEF primarily depend on activation of domain-specific targets of executive function. Brain features that explain commonalities in executive function performance across tasks remain to be discovered

Investigating the neural basis of self-awareness deficits following traumatic brain injury

Self-awareness deficits are a common and disabling consequence of traumatic brain injury (TBI). ‘On-line’ awareness is one facet of self-awareness that can be studied by examining how people monitor their performance and respond to their errors. Performance monitoring, like many of the cognitive functions disrupted after TBI, is believed to depend on the coordinated activity of neural networks. The fronto-parietal control network (FPCN) is one such network that contains a sub-network called the salience network (SN). The SN consists of the dorsal anterior cingulate (dACC) and bilateral insulae cortex and is thought to monitor salient events (e.g. errors). I used advanced structure and function MRI techniques to investigate these networks and test two overarching hypotheses: first, performance monitoring is regulated by regions within the FPCN; and second, dysfunction of the FPCN leads to impaired self-awareness after TBI. My first study demonstrated two distinct frontal networks that respond to different error types. Predictable/internally signalled errors caused SN activation; whereas unpredictable/externally signalled errors caused activation of the ventral attentional network, a network thought to respond to unexpected events. This suggested the presence of parallel performance monitoring systems within the FPCN. My second study established that the ‘driving’ input into the SN originated in right anterior insula and subsequent behavioural adaptation was regulated by enhanced effective connectivity from the dACC to the left anterior insula. In my third study I identified a large group of TBI patients with impaired performance monitoring. These patients had additional metacognitive evidence of impaired self-awareness and demonstrated reduced functional connectivity between the dACC and the remainder of the FPCN at ‘rest’, and abnormally large insulae activation in response to errors. These studies clarified how the brain monitors and responds to salient events; and, provided evidence that self-awareness deficits after TBI are due to FPCN dysfunction, identifying this network as a potential target for future treatments.Open Acces

Reading aloud boosts connectivity through the putamen

Functional neuroimaging and lesion studies have frequently reported thalamic and putamen activation during reading and speech production. However, it is currently unknown how activity in these structures interacts with that in other reading and speech production areas. This study investigates how reading aloud modulates the neuronal interactions between visual recognition and articulatory areas, when both the putamen and thalamus are explicitly included. Using dynamic causal modeling in skilled readers who were reading regularly spelled English words, we compared 27 possible pathways that might connect the ventral anterior occipito-temporal sulcus (aOT) to articulatory areas in the precentral cortex (PrC). We focused on whether the neuronal interactions within these pathways were increased by reading relative to picture naming and other visual and articulatory control conditions. The results provide strong evidence that reading boosts the aOT–PrC pathway via the putamen but not the thalamus. However, the putamen pathway was not exclusive because there was also evidence for another reading pathway that did not involve either the putamen or the thalamus. We conclude that the putamen plays a special role in reading but this is likely to vary with individual reading preferences and strategies

A computational approach to motivated behaviour and apathy

The loss of motivation and goal-directed behaviour is characteristic of apathy. Across a wide range of neuropsychiatric disorders, including Huntington’s disease (HD), apathy is poorly understood, associated with significant morbidity, and is hard to treat. One of the challenges in understanding the neural basis of apathy is moving from phenomenology and behavioural dysfunction to neural circuits in a principled manner. The computational framework offers one such approach. I adopt this framework to better understand motivated behaviour and apathy in four complementary projects. At the heart of many apathy formulations is impaired self-initiation of goal-directed behaviour. An influential computational theory proposes that “opportunity cost”, the amount of reward we stand to lose by not taking actions per unit time, is a key variable in governing the timing of self-initiated behaviour. Using a novel task, I found that free-operant behaviour in healthy participants both in laboratory conditions and in online testing, conforms to predictions of this computational model. Furthermore, in both studies I found that in younger adults sensitivity to opportunity cost predicted behavioural apathy scores. Similar pilot results were found in a cohort of patients with HD. These data suggest that opportunity cost may be an important computational variable relevant for understanding a core feature of apathy – the timing of self-initiated behaviour. In my second project, I used a reinforcement learning paradigm to probe for early dysfunction in a cohort of HD gene carriers approximately 25 years from clinical onset. Based on empirical data and computational models of basal ganglia function I predicted that asymmetry in learning from gains and losses may be an early feature of carrying the HD gene. As predicted, in this task fMRI study, HD gene carriers demonstrated an exaggerated neural response to gains as compared to losses. Gene carriers also differed in the neural response to expected value suggesting that carrying the HD gene is associated with altered processing of valence and value decades from onset. Finally, based on neurocomputational models of basal ganglia pathway function, I tested the hypothesis that apathy in HD would be associated with the involvement of the direct pathway. Support for this hypothesis was found in two related projects. Firstly, using data from a large international HD cohort study, I found that apathy was associated with motor features of the disease thought to represent direct pathway involvement. Secondly, I tested this hypothesis in vivo using resting state fMRI data and a model of basal ganglia connectivity in a large peri-manifest HD cohort. In keeping with my predictions, whilst emerging motor signs were associated with changes in the indirect pathway, apathy scores were associated with connectivity changes in the direct pathway connectivity within my model. For patients with apathy across neuropsychiatry there is an urgent need to understand the neural basis of motivated behaviour in order to develop novel therapies. In this thesis, I have used a computational framework to develop and test a range of hypotheses to advance this understanding. In particular, I have focussed on the computational factors which drive us to self-initiate, their potential neural underpinnings and the relevance of these models for apathy in patients with HD. The data I present supports the hypothesis that opportunity cost and basal ganglia pathway connectivity may be two important components necessary to generate motivated behaviour and contribute to the development of apathy in HD

To Head or to Heed? Beyond the Surface of Selective Action Inhibition: A Review

To head rather than heed to temptations is easier said than done. Since tempting actions are often contextually inappropriate, selective suppression is invoked to inhibit such actions. Thus far, laboratory tasks have not been very successful in highlighting these processes. We suggest that this is for three reasons. First, it is important to dissociate between an early susceptibility to making stimulus-driven impulsive but erroneous actions, and the subsequent selective suppression of these impulses that facilitates the selection of the correct action. Second, studies have focused on mean or median reaction times (RT), which conceals the temporal dynamics of action control. Third, studies have focused on group means, while considering individual differences as a source of error variance. Here, we present an overview of recent behavioral and imaging studies that overcame these limitations by analyzing RT distributions. As will become clear, this approach has revealed variations in inhibitory control over impulsive actions as a function of task instructions, conflict probability, and between-trial adjustments (following conflict or following an error trial) that are hidden if mean RTs are analyzed. Next, we discuss a selection of behavioral as well as imaging studies to illustrate that individual differences are meaningful and help understand selective suppression during action selection within samples of young and healthy individuals, but also within clinical samples of patients diagnosed with attention deficit/hyperactivity disorder or Parkinson's disease

Cognitive Control in Adolescence: Neural Underpinnings and Relation to Self-Report Behaviors

Adolescence is commonly characterized by impulsivity, poor decision-making, and lack of foresight. However, the developmental neural underpinnings of these characteristics are not well established.To test the hypothesis that these adolescent behaviors are linked to under-developed proactive control mechanisms, the present study employed a hybrid block/event-related functional Magnetic Resonance Imaging (fMRI) Stroop paradigm combined with self-report questionnaires in a large sample of adolescents and adults, ranging in age from 14 to 25. Compared to adults, adolescents under-activated a set of brain regions implicated in proactive top-down control across task blocks comprised of difficult and easy trials. Moreover, the magnitude of lateral prefrontal activity in adolescents predicted self-report measures of impulse control, foresight, and resistance to peer pressure. Consistent with reactive compensatory mechanisms to reduced proactive control, older adolescents exhibited elevated transient activity in regions implicated in response-related interference resolution.Collectively, these results suggest that maturation of cognitive control may be partly mediated by earlier development of neural systems supporting reactive control and delayed development of systems supporting proactive control. Importantly, the development of these mechanisms is associated with cognitive control in real-life behaviors