Brain circuitry of compulsivity.

Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.Dr. Soriano-Mas is funded by a ׳Miguel Servet׳ contract from the Carlos III Health Institute (CP10/00604). Dr. Goudriaan is supported by a VIDI Innovative Research Grant (Grant no. 91713354) funded by the Dutch Scientific Research Association (NWO-ZonMW). Dr. Alonso was funded by the Instituto de Salut Carlos III-FISPI14/00413. Dr. Nakamae received Grant support from MEXT KAKENHI (Nos. 24791223 and 26461753).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2015.12.00

Neurochemical modulation of affective and behavioural control: Models and applications for psychiatry

Impairments in emotional reactivity and behavioural flexibility are pervasive across disparate psychiatric conditions as traditionally defined. Here, I provide new evidence on how these processes are altered by neuromodulators in humans, with a primary focus on serotonin (5- HT; 5-hydroxytryptamine). Emotional reactions prepare the body for action. Some emotion is primitive, implicit, and critical for surviving threats, yet can inappropriately persist in times of safety. Other emotions are more complex, self-conscious and important in maintaining harmonious interpersonal relationships. At the same time, learned behaviours that are adaptive in the first instance, may become irrelevant or even disadvantageous as circumstances change. In Chapters 3 through 6, I report on experiments in healthy human volunteers that employed the dietary technique acute tryptophan depletion (ATD). ATD temporarily lowers serotonin synthesis and release by depleting its biosynthetic precursor tryptophan. Chapter 3 is a study of self-reported social emotion. ATD enhanced emotion in response to social injustice non-specifically; however, consideration of personality traits revealed that highly empathic participants reported more guilt under ATD, whereas individuals high in trait psychopathy demonstrated more annoyance. Chapter 4, in contrast, considers evolutionarily ancient automatic emotional reactions to threats. This was assayed instead by an objective measure, the skin conductance response (SCR). Here, ATD conversely attenuated the retention of Pavlovian conditioned emotional memory to threat. Traits again influenced this response: individuals more intolerant of uncertainty displayed the greatest attenuation of emotional reactions. Chapter 5 both extends the studies on emotion and bridges to the remaining empirical work by investigating reversal learning, an index of cognitive flexibility, in two experiments. Individuals again underwent Pavlovian (stimulus-outcome) threat conditioning, whereby one stimulus predicted threat, and another was safe. These contingencies then swapped (reversed). In a separate experiment, participants underwent instrumental (stimulus-response-outcome) conditioning on a deterministic schedule (the correct option was always correct), followed by reversal of the contingencies. ATD impaired both Pavlovian and instrumental reversal learning. Chapters 6 through 8 instead examine instrumental reversal learning that was probabilistic (the correct option was correct most but not all of the time), rather than deterministic. Chapter 6 expands on previous ATD studies of probabilistic reversal learning (PRL) in the literature, which had not found effects on choice behaviour. Despite nearly tripling the sample size, behaviour here assessed by conventional methods was unaffected, replicating previously published null results. Applying reinforcement learning (RL) models, however, revealed ATD elevated a basic perseverative tendency, referred to as “stimulus stickiness”; behaviour was more stimulus-bound and insensitive to the outcome of actions, consistent with the deterministic instrumental reversal impairment following ATD. Chapters 7 and 8 apply RL models as well, to existing datasets on PRL for comparison. Chapter 7 shows that healthy volunteers under lysergic acid diethylamide (LSD), which acts both at serotonin but also dopamine receptors, showed enhanced learning from positive feedback in particular, which was related to perseveration. Chapter 8 applies computational methods to PRL in clinical populations. RL modelling revealed a computational signature that dissociated PRL in stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD): Individuals with SUD showed heightened stimulus stickiness, as occurred following ATD in healthy volunteers, whereas the OCD group (under serotonergic medication) demonstrated lower stimulus stickiness than healthy controls. Dopaminergic agents remediated a reward learning deficit in SUD, among other measures. The general discussion considers these various findings in terms of theories of central serotonin function, in relation to the animal literature, and its relevance to mental disorder. These results, collectively, advance knowledge of neurochemical and computational mechanisms underlying psychiatric conditions trans-diagnostically, with implications for revised psychiatric classifications in line with the Research Domain Criteria (RDoC).Gates Cambridge Trust Wellcome Trus

Amygdala subnuclei response and connectivity during emotional processing

The involvement of the human amygdala in emotion-related processing has been studied using functional magnetic resonance imaging (fMRI) for many years. However, despite the amygdala being comprised of several subnuclei, most studies investigated the role of the entire amygdala in processing of emotions. Here we combined a novel anatomical tracing protocol with event-related high-resolution fMRI acquisition to study the responsiveness of the amygdala subnuclei to negative emotional stimuli and to examine intra-amygdala functional connectivity. The greatest sensitivity to the negative emotional stimuli was observed in the centromedial amygdala, where the hemodynamic response amplitude elicited by the negative emotional stimuli was greater and peaked later than for neutral stimuli. Connectivity patterns converge with extant findings in animals, such that the centromedial amygdala was more connected with the nuclei of the basal amygdala than with the lateral amygdala. Current findings provide evidence of functional specialization within the human amygdala

Psychobiological mechanisms of endogenous pain modulation by pain relief as reward

Pain is much more than a sensory experience. Pain has strong emotional and motivational components that fulfill crucial functions for survival and well-being, because they drive behavior to avoid and escape from pain. This motivation is also reflected in the opposite and rewarding nature of the pleasure of pain relief. Both endogenous modulation of the perception of pain and pain relief are thought to promote the motivational drive and with that behavior that serves homeostatic needs. In contrast to pain and despite this crucial role of pain relief as reward, the psychobiological mechanisms underlying pain relief perception as well as related learning remain poorly understood. The aim of this dissertation was to deepen our understanding of psychological and neurobiological mechanisms of pain relief in healthy humans and possible alterations of these mechanisms in patients suffering from chronic pain. In a first experimental study, the role of the neurotransmitters dopamine and endogenous opioids in pain modulation and reinforcement learning were investigated using a probabilistic relief seeking task in healthy volunteers. The results showed that the informational value of pain and pain relief was endogenously enhanced in states of active decision making compared to passive states. This endogenous pain modulation scaled with perceived uncertainty of expected outcomes. Dopamine increased endogenous pain and pain relief modulation, while no evidence for the involvement of endogenous opioids was found. Successful reinforcement learning as found in the placebo condition was impaired by dopamine and endogenous opioids. The same probabilistic relief seeking task was used in a second study to investigate neural correlates of learning driven by pain and pain relief using functional magnetic resonance imaging in patients with chronic pain and healthy controls. This study replicated the effects of endogenous pain modulation by its informational value, while no alterations in patients with chronic pain were found compared to healthy controls. This result suggests that motivationally driven enhancement of pain relief perception is a robust phenomenon that appears to be spared by maladaptive changes during pain chronification. However, compared to healthy controls patients with fibromyalgia showed a stronger bias towards relief related cues during learning, but a weaker association of activation in the pregenual anterior cingulate cortex with relief prediction errors. These findings suggest that although the informational content of pain relief seems to be preserved in patients with chronic pain, subtle differences in the underlying mechanisms may reflect altered reward processing in chronic pain, which have been discussed before. In sum, the results highlight the important role of motivation and prospective control of behavior for endogenous modulation of pain and pain relief and provide insights in underlying psychobiological mechanisms in healthy states and in chronic pain

Beyond happiness: Building a science of discrete positive emotions.

While trait positive emotionality and state positive-valence affect have long been the subject of intense study, the importance of differentiating among several "discrete" positive emotions has only recently begun to receive serious attention. In this article, we synthesize existing literature on positive emotion differentiation, proposing that the positive emotions are best described as branches of a "family tree" emerging from a common ancestor mediating adaptive management of fitness-critical resources (e.g., food). Examples are presented of research indicating the importance of differentiating several positive emotion constructs. We then offer a new theoretical framework, built upon a foundation of phylogenetic, neuroscience, and behavioral evidence, that accounts for core features as well as mechanisms for differentiation. We propose several directions for future research suggested by this framework and develop implications for the application of positive emotion research to translational issues in clinical psychology and the science of behavior change. (PsycINFO Database Recor

The effects of losartan and diazepam on emotional processing

Given the prevalence and substantial economic costs of anxiety disorders, and the shortcomings of current treatments, there is dire need for research that helps inform the development of new treatments and medications. The aim of this thesis was to further our understanding of the effects of two medications relevant to anxiety, losartan and diazepam, to help inform the use of existing treatments and lead to more effective ones. Research has indicated that the angiotensin receptor antagonist losartan may potentially be a promising candidate to enhance the efficacy of exposure-based therapies. It however remains to be fully clarified how losartan affects some of the mechanisms relevant to exposure success. In the first study, a single dose of losartan was shown to increase activation in the paracingulate gyrus, insular cortex, lingual gyrus, and fusiform gyrus in healthy, high trait anxious volunteers, which possibly reflects modulation of higher-order visual processing. There was however no evidence found for an effect of losartan on neural responses in the hippocampus during non-emotional memory encoding. Losartan was also shown to increase positive attentional bias, which was reflected in attention being more firmly held by positive stimuli compared to neutral stimuli. Given that both greater reactivity in higher-order visual regions and positive valence training have been shown to be relevant for therapy success, these results may provide further support that losartan might potentially have synergistic effects with exposure therapy, but this remains to be tested directly. The most common pharmacological treatments for anxiety disorders include selective serotonin reuptake inhibitors and benzodiazepines, but both groups of medications have limitations. A better understanding of how existing medications exert their anxiolytic effects may help guide development of new medications. As benzodiazepines are not effective in treating depression, researching their effects provide a means of teasing apart antidepressant and anxiolytic effects. A comprehensive understanding of the cognitive neuropsychological mechanisms behind their anxiolytic effects is still lacking. In the second study, a 7-day treatment of diazepam was shown to lower connectivity between the amygdala and the pre- and post-central gyrus during cognitive reappraisal, and between limbic regions and the precuneous cortex in response to aversive pictures in healthy volunteers. The treatment also led to a decrease in activation in the right vlPFC during reappraisal, and to an increase in activation in the left vlPFC and right ACC in response to positive stimuli, without any subjective changes in mood and state anxiety. Diazepam may thus potentially be exerting its short-term anxiolytic effects by modulating activity within these brain areas. Taken together, these findings provide valuable insights into potential mechanisms through which diazepam and losartan may exert their therapeutic effects. A better understanding of these mechanisms can hopefully help inform the development of future anxiolytics and combination treatments

Cognición y representación interna de entornos dinámicos en el cerebro de los mamíferos

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, leída el 07/05/2021El tiempo es una de las dimensiones fundamentales de la realidad. Paradójicamente, los fenómenos temporales del mundo natural contienen ingentes cantidades de información redundante, y a pesar de ello, codificar internamente el tiempo en el cerebro es imprescindible para anticiparse a peligros en ambientes dinámicos. No obstante, dedicar grandes cantidades de recursos cognitivos a procesar las características espacio-temporales de entornos complejos debería ser incompatible con la supervivencia, que requiere respuestas rápidas. Aun así, los animales son capaces de tomar decisiones en intervalos de tiempo muy estrechos. ¿Cómo consigue hacer esto el cerebro? Como respuesta al balance entre complejidad y velocidad, la hipótesis de la compactación del tiempo propone que el cerebro no codifica el tiempo explícitamente, sino que lo integra en el espacio. En teoría, la compactación del tiempo simplifica las representaciones internas del entorno, reduciendo significativamente la carga de trabajo dedicada a la planificación y la toma de decisiones. La compactación del tiempo proporciona un marco operativo que pretende explicar cómo las situaciones dinámicas, percibidas o producidas, se representan cognitivamente en forma de predicciones espaciales o representaciones internas compactas (CIR), que pueden almacenarse en la memoria y recuperarse más adelante para generar respuestas. Aunque la compactación del tiempo ya ha sido implementada en robots, hasta ahora no se había comprobado su existencia como mecanismo biológico y cognitivo en el cerebro...Time is one of the most prominent dimensions that organize reality. Paradoxically, there are loads of redundant information contained within the temporal features of the natural world, and yet internal coding of time in the brain seems to be crucial for anticipating time-changing, dynamic hazards. Allocating such significant brain resources to process spatiotemporal aspects of complex environments should apparently be incompatible with survival, which requires fast and accurate responses. Nonetheless, animals make decisions under pressure and in narrow time windows. How does the brain achieve this? An effort to resolve the complexity-velocity trade-off led to a hypothesis called time compaction, which states the brain does not encode time explicitly but embeds it into space. Theoretically, time compaction can significantly simplify internal representations of the environment and hence ease the brain workload devoted to planning and decision-making. Time compaction also provides an operational framework that aims to explain how perceived and produced dynamic situations are cognitively represented, in the form of spatial predictions or compact internal representations (CIRs) that can be stored in memory and be used later on to guide behaviour and generate action. Although successfully implemented in robots, time compaction still lacked assessment of its biological soundness as an actual cognitive mechanism in the brain...Fac. de Ciencias BiológicasTRUEunpu