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The computational roles of dopamine and serotonin in Tourette syndrome and obsessive-compulsive disorder
Publication . Conceição, Vasco Manuel Aranha da; Maia, Tiago Vaz
Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) are two comorbid and heterogenous neuropsychiatric disorders that are both characterized by repetitive, stereotyped pathological behaviors, which are generally preceded by intrusive, unwanted sensations, impulses, or thoughts. Disturbances in cortico-basal ganglia-thalamo-cortical (CBGTC) loops and in distinct neuromodulatory systems have long been implicated in both TS and OCD, but a clear mechanistic understanding of how such disturbances relate to the pathophysiology of TS and OCD is far from attained. Such lack of mechanistic understanding partially explains why standard treatments result in a moderate, at best, reduction of symptom severity for most patients with TS and/or OCD.
Motivated by extant pitfalls on the understanding and clinical management of TS and OCD, by the fact that dopaminergic and serotonergic disturbances have long been strongly implicated in TS and OCD, respectively, and by the fact that dopamine antagonists and serotonin reuptake inhibitors (SRIs) are the most efficacious treatments in TS and OCD, respectively, during my PhD, I aimed to assess computationally how dopaminergic and serotonergic disturbances are respectively implicated in TS and OCD. This thesis is therefore divided into three main parts: a comprehensive introduction to TS, OCD, and some of the computational approaches that have been applied to each of these disorders (Chapters 1–3), an overview of our work on TS (Chapters 4–6), and a comprehensive description of our work on OCD and OCD-like [obsessive-compulsive (OC)] manifestations (Chapters 7–8).
Our work on TS is divided in three main subparts, which have been published in three distinct reviews. Briefly, we have shown that, from extant hypothesis on dopaminergic disturbances on TS, the hypothesis that TS involves dopaminergic hyperinnervation—that is, an increased number of dopaminergic terminals—provides an integrated account of all neuroimaging studies that have assessed the functioning of the dopaminergic system in TS, in addition to explaining why all medications with proven efficacy in TS reduce dopaminergic neurotransmission (Chapter 4). We have then shown, using computational models, that increases in striatal phasic and tonic dopamine—predicted under dopaminergic hyperinnervation—likely promote tic learning and expression (Chapter 5). Finally, we have expanded our computational account to explain mechanistically how premonitory urges, the aversive sensations that typically precede and are ceased by tics, may drive tic learning and expression in TS. Simultaneously, we have identified possible neural correlates of such computations, by comprehensively reviewing structural and functional neuroimaging studies on TS. We have specifically implicated the somatosensory cortices in premonitory urges, the insula in both premonitory urges and tic learning, and the motor CBGTC loop in both tic learning and expression (Chapter 6). In doing so, we have provided an integrated, mechanistic account of the two key aspects of TS: tics and premonitory urges.
Our work on OCD is divided in two main subparts, which are yet unpublished. Similar to what we did in TS—where we have comprehensively reviewed all neurochemical studies on the dopaminergic system—I have reviewed neurochemical, and complementary animal-model, studies on the serotonergic system in OCD. Contrary to TS, however, the review on OCD was brief and far from comprehensive (Chapter 7). Such review indicated, nonetheless, that increased pre- and post-treatment serotonin levels were both associated with better treatment-outcome in patients with OCD. More speculatively, but in line with extant literature (including prior work from our lab), such review suggested that there could be a causal association between suboptimal (orbitofrontal) serotonin levels and obsessive-compulsive (OC) manifestations, including those from patients with OCD (Chapter 7), with the suboptimal serotonin levels of (some) patients with OCD possibly being driven by serotonergic hypoinnervation.
While fully testing the latter hypothesis during my PhD would be (nearly) impossible, because it would require us to perform a longitudinal assessment of patients with OCD, we aimed at investigating two related topics: the modulation of state inference—that is, the learning about, and switching between, hidden, or partially observable, states (or contexts)—by serotonin and the association between such inference and OC traits (Chapter 8). We specifically chose to study state inference because (1) patients with OCD present considerable anatomical and functional disturbances in several regions from the limbic CBGTC loop, among which the orbitofrontal cortex (OFC), which is both strongly modulated by serotonin and strongly implicated in state inference, and, more importantly, because (2) impaired (orbitofrontal-serotonin-mediated) state inference seems to explain multiple OC traits.
To study the association between state inference and both serotonin levels and OC traits, we assessed the effects of acutely administering the selective serotonin reuptake inhibitor (SSRI) escitalopram to adults with different severities of OC traits, by conducting a double-blind, placebo-controlled study. In that original study (whose first manuscript is currently under preparation; Chapter 8), we applied a novel reversal-learning task, which we developed, to 50 adult men. In reversal-learning tasks, (stimulus-specific) action-outcome contingencies are changed in a discrete, partially observable, or hidden, fashion throughout the task; thus, subjects need to quickly adapt their behavior according to (hidden-)state changes to attain good performance. Such reasoning makes reversal-learning tasks theoretically ideal to study state inference; however, in practice, there are multiple factors that need to be considered so that such tasks are suitable to analyze state inference. Previously developed reversal-learning tasks did not disentangle, for example, state learning from lower-order state-response learning—which corresponds to classical stimulus-response (S-R) learning when states are uniquely determined by the respective observable stimuli—which is necessary to assess state learning mechanistically. Therefore, we developed our novel reversal-learning task so that it orthogonalized, precisely, those two processes.
To maximize the amount of biologically relevant information that we could extract from the acquired reversal-learning behavioral data, we fitted the data of each individual subject using several CBGTC-inspired reinforcement-learning (RL) models, which we compared using state-of-the-art model-comparison techniques. We specifically implemented two types of RL models: simple S-R learning models (Q-learning models) and extensions of those S-R models that also included higher-order state learning, which we developed for this study (Belief Q-learning models). Bayesian model comparison between the implemented models showed that a single Belief Q-learning model could be confidently selected, indicating that subjects had performed state learning (and state switching) while solving our reversal-learning task, irrespective of their medication status. We then analyzed the biologically relevant variables that we had estimated for each subject using the selected Belief Q-learning model, to inspect the associations between state inference and both serotonin levels and OC traits. We considered that subject-specific escitalopram plasma levels would be associated with the respective increases in (orbitofrontal) serotonin levels and that the subjects’ scores on the Obsessive-Compulsive Inventory – Revised (OCI–R), which is a well-validated neuropsychological questionnaire, would be a proxy for their severity of OC traits (Chapter 8).
Briefly, we showed that, during the first session of our study, state-inference performance was both negatively associated with the severity of OC traits and facilitated by escitalopram (with higher escitalopram levels, which should lead to bigger increases in cortical extracellular serotonin levels, leading to bigger improvements in state learning; Chapter 8). By simultaneously demonstrating the latter two associations, our work provided a new perspective on the possible mechanisms underlying OC traits. Indeed, while OC traits had been previously associated with cognitive inflexibility, OC traits had never been specifically associated with impaired state inference, the process which we had hypothesized to underlie both OC traits and the so-called cognitive inflexibility during reversal-learning and other behavioral tasks.
The latter and several other implications of our empirical work are comprehensively discussed in the last chapter of this thesis (Chapter 9). There, I discuss additionally the possibility that TS and OCD lie within a dopaminergic hyperinnervation/serotonergic hypoinnervation continuum, in which patients with TS and/or OCD may express both these abnormalities to different degrees—a hypothesis that emerged from the review work mentioned above. I do so because such hypothesis, besides broadly consistent with the neuroimaging and pharmacological data from patients with TS and/or OCD, seems to partially explain (and/or be explained by) the comorbidity and genetic relation between TS and OCD (Chapter 9).
C9orf72 expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis
Publication . Miltenberger-Miltenyi, Gabriel; Conceição, Vasco A.; Gromicho, Marta; Pronto Laborinho, Ana Catarina; Pinto, Susana; Andersen, Peter Munch; Carvalho, Mamede
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with short survival, mainly due to respiratory failure. A pathological repeat expansion in the C9orf72 gene is observed in about 10% of the European ALS population and is associated with a worse prognosis. Still, the exact function of this gene is unknown. To understand the role of the C9orf72 expansion in disease prognosis, we tested the impact of this mutation on the respiratory function in ALS.
The roles of phasic and tonic dopamine in tic learning and expression
Publication . Maia, Tiago; Conceição, Vasco A.
Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively.
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PD/BD/105852/2014