NEUROTRANSMITTERS AND RESTING STATE NETWORKS: CLINICAL IMPLICATION FOR MAJOR PSYCHIATRIC DISORDER

Alterations in brain intrinsic activity \u2013 as organized in resting-state networks (RSNs) such as sensorimotor network (SMN), salience network (SN) and default-mode network (DMN) \u2013 and in neurotransmitters signaling \u2013 such as dopamine (DA) and serotonin (5-HT) \u2013 have been independently detected in psychiatric disorders like bipolar disorder and schizophrenia. Thus, the aim of this work was to investigate the relationship between such neurotransmitters and RSNs in healthy, by reviewing the relevant work on this topic and performing complementary analyses, in order to better understand their physiological link as well as their alterations in psychiatric disorders. According to the reviewed data, neurotransmitters nuclei diffusively project to subcortical and cortical regions of RSNs. In particular, the dopaminergic substantia nigra (SNc)-related nigrostriatal pathway is structurally and functionally connected with core regions of the SMN, while the ventral tegmental area (VTA)-related mesocorticolimbic pathway with core regions of the SN. The serotonergic raphe nuclei (RNi) connections involve regions of the SMN and DMN. Coherently, changes in neurotransmitters activity impact the functional configuration and level of activity of RSNs, as measured by functional connectivity (FC) and amplitude of low-frequency fluctuations/temporal variability of BOLD signal. Specifically, DA signaling is associated with increase in FC and activity in the SMN (hypothetically via the SNc-related nigrostriatal pathway) and SN (hypothetically via the VTA-related mesocorticolimbic pathway), as well as concurrent decrease in FC and activity in the DMN. By contrast, 5-HT signaling (via the RNi-related pathways) is associated with decrease in SMN activity along with increase in DMN activity. Complementally, our empirical data showed a positive correlation between SNc-related FC and SMN activity, while a negative correlation between RNi-related FC and SMN activity (along with tilting of networks balance toward the DMN). According to these data, we hypothesize that the activity of neurotransmitters-related neurons synchronize the low-frequency oscillations within different RSNs regions, thus affecting the baseline level of RSNs activity and their balancing. In our model, DA signaling favors the predominance of SMN-SN activity, while 5-HT signaling favors the predominance of DMN activity, manifesting in distinct behavioral patterns. In turn, alterations in neurotransmitters signaling (or its disconnection) may favor a correspondent functional reorganization of RSNs, manifesting in distinct psychopathological states. The here suggested model carries important implications for psychiatric disorders, providing novel and well testable hypotheses especially on bipolar disorder and schizophrenia

Psychological and Neural Dynamics of Trust

Trust is a key feature of social interactions and central to interpersonal cooperation. Acts of trust are not only pivotal aspects of interpersonal cooperation and group cohesion, they also have important consequences for individual health and life expectancy. However, which social qualities of others foster trust, how individuals learn whom to trust, and how the brain integrates this information for optimal behavioral updating is yet unexplored. Here, I will outline two lines of research. On one hand, I will show the psychological and neural predictors of trust in different social contexts. On the other, pharmacological modulations of the neural brain structures involved in trust will be presented. In the first two behavioral experiments, I show that honesty functions as an antecedent of trustworthiness impressions and that an honest reputation is associated with higher trust during a future social interaction. Next, I delineate the neural signatures of these honesty-based trustworthiness impressions. Notably, similar to the behavioral effects of honesty on future trust decisions, I found that honesty-encoding brain regions predicted those future trust decisions, providing evidence of honesty-related brain regions that entail neural signal predictive of trusting behavior. Furthermore, an honest reputation also modulated neural responses to feedback information. Such neural modulation likely biases information integration during social learning. Consequently, I show in a further behavioral study that an honest reputation seems to indeed impair learning due to an honesty-dependent asymmetry in information weighting. Finally, I demonstrate how the pharmacological modulation of brain dynamics impacts trusting behaviors leaving trustworthiness impressions unchanged. On the one hand, these findings shed light on how honesty not only increases trust in others but also hampers learning processes for optimal behavioral adaptation. On the other, they provide the first pharmacological evidence of how impression-based trust can be changed without impacting those very first trustworthiness impressions. I finally propose accounts that might explain the observed behavioral and neural patterns and outline potential directions for new studies

Cortical motor network modulation: Common mechanisms parallel efficient motor integration in implicit motor learning in healthy subjects and subthalamic neurostimulation in Parkinson’s disease

On the one hand, the neuronal circuitry and connectivity of the large-scale motor network play an important role in many human cognitive functions, i. e. in implicit motor learning. On the other hand, alterations in connectivity of the motor network are also a hallmark in the pathophysiology of a variety of psychological and neurological diseases, such as Parkinson’s disease. Here, we set out to study the motor network activity (more exactly the cortical and spinal aspects of it) under two different aspects: in healthy controls during implicit motor learning and in Parkinson’s disease patients in the conditions ‘stimulation off’ and ‘stimulation on’. To this end, 12 healthy controls and 20 Parkinson’s disease patients performed externally paced right finger movements with simultaneous recordings of a 64-channel EEG and EMG of the forearm muscles. The healthy controls performed the serial reaction time task. Parkinson’s disease patients conducted the baseline of this task with only random trials in the two conditions ‘stimulation off’ and ‘stimulation on ‘. Cortical and muscular activity was analyzed by time-frequency movement-related spectral perturbations and by power spectral density and corticospinal synchronization was assessed by time-frequency cross-spectra coherence. Clinically, Parkinson’s disease patients improved significantly with deep brain stimulation, assessed by the Unified Parkinson’s Disease Rating Scale III score, the reaction time and the error ratio. Deep brain stimulation lead to an increased cortical beta-band movement-related desynchronization, which was topographically spread over a wider cortical area. Besides, in ‘stimulation off’ after finger tap we found a premature beta-band rebound of the corticomuscular coherence to the extensor digitorum over the primary sensorimotor cortex, which was suppressed with stimulation on. The healthy controls presented with significantly reduced reaction times in the ‘sequence blocks’ compared to ‘random blocks’. In ‘sequence blocks’, power spectral density increased mainly over the right posterior parietal cortex but also over a larger left-hemispheric cortical area in alpha and low beta band. Alpha and beta band movement-related desynchronization presented most pronounced over the bilateral prefrontal, fronto-central and central channels. The movement-related desynchronization was significantly modulated over the course of implicit motor learning. The present findings reveal the impressive modulation of the motor network activity including cortical activations and corticospinal synchronizations introduced by deep brain stimulation therapy of the subthalamic nucleus in Parkinson’s disease

Imaging Cognitive Impairment and Impulse Control Disorders in Parkinson's Disease

Dementia and mild forms of cognitive impairment as well as neuropsychiatric symptoms (i. e., impulse control disorders) are frequent and disabling non-motor symptoms of Parkinson's disease (PD). The identification of changes in neuroimaging studies for the early diagnosis and monitoring of the cognitive and neuropsychiatric symptoms associated with Parkinson's disease, as well as their pathophysiological understanding, are critical for the development of an optimal therapeutic approach. In the current literature review, we present an update on the latest structural and functional neuroimaging findings, including high magnetic field resonance and radionuclide imaging, assessing cognitive dysfunction and impulse control disorders in PD

Mecanismos fisiopatólogicos del Trastorno de control de Impulsos en la enfermedad de Parkinson

276 p.La presente tesis se ha centrado en el estudio de los mecanismos fisiopatológicos del trastorno de control de impulsos (TCI) en pacientes con enfermedad de Parkinson (EP). El TCI es una complicación relevante ya que es frecuente y grave en muchas ocasiones, comportando una elevada disrupción de la vida del paciente y su entorno que puede llevar hasta al suicidio en los casos más graves. A pesar de las importantes repercusiones, sus mecanismos fisiopatológicos son desconocidos, habiéndose descrito resultados contradictorios a múltiples niveles de estudio, pero especialmente en los estudios de imagen. Esta tesis se ha realizado no sólo con el ánimo de comprender los mecanismos por los que ocurre, sino también con el objetivo de ampliar las herramientas de detección de los sujetos que serán más sensibles al desarrollo de esta complicación tras el inicio de la terapia de reposición dopaminérgica. Por este motivo, se ha realizado en estos pacientes una aproximación multimodal de neuroimagen desde diversas técnicas, con el objetivo de entender la interacción entre el impacto de la degeneración dopaminérgica y elreemplazo terapéutico en aspectos críticos del comportamiento humano, contribuyendo a delinear los posibles correlatos neurales relacionados con esta complicación en los pacientes con EP. El hecho de investigar y profundizar en los circuitos cerebrales que se encuentran alterados en este tipo de pacientes, podría abrir una puerta a la hora de tratar esta complicación una vez establecida, quizá fundamentando las bases de la terapia con ECP con electrodos direccionales y otros tratamientos focalizados en áreas pertenecientes al circuito límbico. Este trabajo también contribuiría al descubrimiento de biomarcadores de neuroimagen que pudiesen identificar pacientes con EP susceptibles de desarrollar un TCI, con el objetivo de su prevención evitando terapias con agonistas dopaminérgicos en dichos casos. Esta tesis se divide en tres subapartados en las que en (i) el primero estudiamos el patrón de denervación dopaminérgica de estos pacientes así como su asociación con el metabolismo cerebral y con diferentes características clínicas y cognitivas. Esto ha dado lugar a un artículo ya publicado en Eur J Nucl Med Mol Imaging. (ii) En segundo lugar se ha investigado la conectividad funcional dinámica en la Resonancia Magnética funcional en reposo en estos pacientes así como las propiedades topológicas de la misma mediante un análisis de teoría de grafos. Este artículo está actualmente en revisión por la revista Parkinsonism and related disorders journal. (iii) Por último en estos pacientes se ha estudiado la activación cerebral, el curso temporal de la misma y la mediación de la conectividad funcional mientras estos pacientes se enfrentaban en la Resonancia Magnética funcional al Juego de Azar de Iowa, una tarea de toma de decisiones y de control inhibitorio.Resumiendo los resultados: el estudio de la denervación dopaminérgica estriatal, muestra en estos pacientes una denervación dopaminérgica en el estriado ventral característica, paralela a la gravedad de su sintomatología y en asociación directa con una disminución de metabolismo cerebral en áreas pertenecientes al sistema mesocorticolimbico en reposo. Además se ha estudiado por primera vez la dinámica de la conectividad funcional también en reposo, en la que se aprecia que las alteraciones de estos pacientes exceden una disfunción en regiones cerebrales localizadas y se extienden a nivel de la comunicación entre redes, presentando una tendencia a mostrar un aumento de la conectividad funcional a nivel local en áreas concretas que intervienen en la evaluación del estímulo a expensas de una tendencia a reducir la conectividad a larga distancia. Este aumento del mantenimiento en este patrón de conectividad concreto, se asocia en estos pacientes tanto al aumento de impulsividad como a la mayor búsqueda de novedad como rasgo de personalidad del sujeto. De la misma manera, el estudio de las propiedades topológicas de estas alteraciones en la conectividad de estos pacientes, nos muestra una elevada eficiencia local en la comunicación entre estas áreas. Estos resultados nos muestran patrones específicos de estos pacientes en reposo, tanto a nivel molecular como de Resonancia Magnética funcional, que se hacen más patentes conforme se acentúa la gravedad del TCI, los cuales podrían plantearse como biomarcadores de imagen de pacientes expuestos al desarrollo de esta complicación. Por último, al enfrentar a estos sujetos a una tarea de toma de decisiones y control inhibitorio, se aprecia una mayor activación de las áreas implicadas tanto en procesos de recompensa como de inhibición. Esto puede traducir la disfunción regional evidenciada previamente en el estudio metabólico desde la otra cara de la moneda, en la que se apreciaría un aumento de activación como reflejo de un posible mecanismo compensatorio para controlar las elecciones de riesgo. Además en estos pacientes se constata una respuesta de activación más precoz, que podría ser el reflejo de la predicción inicial de errores y la asignación de relevancia que precede a la toma de decisiones. Hay que destacar, que en esta tesis se enfatiza el estriado ventral como estructura clave que lleva a la disfunción de otras áreas pertenecientes al circuito mesocorticolímbico en paralelo a un aumento del desarrollo y gravedad del TCI en pacientes con EP. Además, se describe por primera vez la implicación del núcleo subtalámico derecho en una tarea de impulsividad cognitiva y la exclusividad de esta implicación en pacientes con EP y TCI, lo cual podría tener relevancia clínica en el marco terapeútico de la modulación conductual mediante estimulación cerebral profunda del núcleo subtalámico

Biomarkers for Dementia, Fatigue, and Depression in Parkinson's Disease

Parkinson's disease is a common multisystem neurodegenerative disorder characterized by typical motor and non-motor symptoms. There is an urgent need for biomarkers for assessment of disease severity, complications and prognosis. In addition, biomarkers reporting the underlying pathophysiology assist in understanding the disease and developing neuroprotective therapies. Ultimately, biomarkers could be used to develop a more efficient personalized approach for clinical trials and treatment strategies. With the goal to improve quality of life in Parkinson's disease it is essential to understand and objectively monitor non-motor symptoms. This narrative review provides an overview of recent developments of biomarkers (biofluid samples and imaging) for three common neuropsychological syndromes in Parkinson's disease: dementia, fatigue, and depression

Towards a healthier cannabis? Examining neurobehavioural interactions between THC and CBD in mice

Abstract Cannabis is the most widely used illicit drug in the world, however over the past decade there has been increasing interest in its utility as a potential therapeutic. Despite the reported beneficial effects of cannabis constituent Δ9-tetrahydrocannabinol (THC), its psychoactivity has curtailed its therapeutic use. There has been increasing interest in combining non-psychoactive cannabis constituent cannabidiol (CBD with THC to inhibit THC’s adverse effects, leading to generation of medications which contain ~1:1 CBD to THC dose ratios which are currently used for the treatment of spasticity in multiple sclerosis and pain relief. However there is a limited evidence base regarding to what extent CBD might modulate the pharmacological effects of THC at equal doses. The scientific examination of pharmacological interactions between these chemicals is therefore of major medical and public health significance. This thesis examines whether an equivalent dose of CBD is able to ameliorate the neuropharmacological effects of THC in mice following acute and repeated dosing in adulthood and adolescence, using doses relevant to human consumption. We report that CBD acutely inhibited some (but not all) of the neurobehavioural measures taken, suggesting potential benefits of CBD in reducing the unwanted effects of THC. However, the unexpected activation of mesolimbic circuitry when THC and CBD were combined suggests enthusiasm should be tempered until these effects are better understood. Adolescent mice exposed to a modest THC dose equivalent to most recreational and medicinal users did not display long-term behavioural deficits, and hence no reversal of negative outcomes by CBD could be measured. CBD alone produced no behavioural changes following acute or repeated exposure in adult mice, although adolescent CBD exposure reduced depression-like behaviour in adult mice, an intriguing effect warranting further study