Brain mediators of negative affect-induced physical symptom reporting in patients with functional somatic syndromes.

Functional somatic syndromes (FSS) include fibromyalgia, irritable bowel syndrome (IBS), and others. In FSS patients, merely viewing negative affective pictures can elicit increased physical symptoms. Our aim was to investigate the neural mechanisms underlying such negative affect-induced physical symptoms in FSS patients. Thirty patients with fibromyalgia and/or IBS and 30 healthy controls (all women) watched neutral, positive and negative affective picture blocks during functional MRI scanning and rated negative affect and physical symptoms after every block. We compared brain-wide activation during negative versus neutral picture viewing in FSS patients versus controls using robust general linear model analysis. Further, we compared neurologic pain signature (NPS), stimulus intensity-independent pain signature (SIIPS) and picture-induced negative emotion signature (PINES) responses to the negative versus neutral affect contrast and investigated whether they mediated between-group differences in affective picture-induced physical symptom reporting. More physical symptoms were reported after viewing negative compared to neutral pictures, and this effect was larger in patients than controls (p = 0.025). Accordingly, patients showed stronger activation in somatosensory regions during negative versus neutral picture viewing. NPS, but not SIIPS nor PINES, responses were higher in patients than controls during negative versus neutral pictures (p = 0.026). These differential NPS responses partially mediated between-group differences in physical symptoms. In conclusion, picture-induced negative affect elicits physical symptoms in FSS patients as a result of activation of somatosensory and nociceptive brain patterns, supporting the idea that affect-driven alterations in processing of somatic signals is a critical mechanism underlying FSS.

Soluble guanylate cyclase stimulator riociguat improves spatial memory in mice via peripheral mechanisms.

Soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signalling is important for healthy memory function and a healthy vascular system. Targeting sGC-cGMP signalling can therefore be a potential strategy to enhance memory processes. sGC can be targeted by using agonists, such as sGC stimulator riociguat. Therefore, this study aimed to target sGC using riociguat to investigate its acute effects on memory function and neuronal plasticity in mice. The effects of riociguat on long-term memory and a biperiden-induced memory deficit model for assessing short-term memory were tested in the object location task, and working memory was tested in the Y-maze continuous alternation task. Pharmacokinetic measurements were performed within brain tissue of mice, and hippocampal plasticity measures were assessed using western blotting. Acute oral administration with a low dose of 0.03 mg/kg riociguat was able to enhance working-, short-, and long-term spatial memory. Under cerebral vasoconstriction higher doses of riociguat were still effective on memory. Pharmacokinetic measurements revealed poor brain penetration of riociguat and its metabolite M-1. Increased activation of VASP was found, while no effects were found on other memory-related hippocampal plasticity measures. Memory enhancing effects of riociguat are most likely regulated by vascular peripheral effects on cGMP signalling. Yet, further research is needed to investigate the possible contribution of hemodynamic or metabolic effects of sGC stimulators on memory performance.

The neurobiological reward system and binge eating: A critical systematic review of neuroimaging studies.

OBJECTIVE: Changes in reward processing are hypothesized to play a role in the onset and maintenance of binge eating (BE). However, despite an increasing number of studies investigating the neurobiological reward system in individuals who binge eat, no comprehensive systematic review exists on this topic. Therefore, this review has the following objectives: (1) identify structural and functional changes in the brain reward system, either during rest or while performing a task; and (2) formulate directions for future research. METHODS: A search was conducted of articles published until March 31, 2022. Neuroimaging studies were eligible if they wanted to study the reward system and included a group of individuals who binge eat together with a comparator group. Their results were summarized in a narrative synthesis. RESULTS: A total of 58 articles were included. At rest, individuals who binge eat displayed a lower striatal dopamine release, a change in the volume of the striatum, frontal cortex, and insula, as well as a lower frontostriatal connectivity. While performing a task, there was a higher activity of the brain reward system when anticipating or receiving food, more model-free reinforcement learning, and more habitual behavior. Most studies only included one patient group, used general reward-related measures, and did not evaluate the impact of comorbidities, illness duration, race, or sex. DISCUSSION: Confirming previous hypotheses, this review finds structural and functional changes in the neurobiological reward system in BE. Future studies should compare disorders, use measures that are specific to BE, and investigate the impact of confounding factors. PUBLIC SIGNIFICANCE STATEMENT: This systematic review finds that individuals who binge eat display structural and functional changes in the brain reward system. These changes could be related to a higher sensitivity to food, relying more on previous experiences when making decisions, and more habitual behavior. Future studies should use a task that is specific to binge eating, look across different patient groups, and investigate the impact of comorbidities, illness duration, race, and sex.

OBJETIVO: Se plantea la hipótesis de que los cambios en el procesamiento de la recompensa desempeñan un papel en el inicio y mantenimiento de los atracones (BE). Sin embargo, a pesar de un número creciente de estudios que investigan el sistema de recompensa neurobiológica en individuos que comen en atracones, no existe una revisión sistemática exhaustiva sobre este tema. Por lo tanto, esta revisión tiene los siguientes objetivos: (1) identificar cambios estructurales y funcionales en el sistema de recompensa cerebral, ya sea en reposo o mientras se realiza una tarea; (2) formular direcciones para futuras investigaciones. MÉTODOS: Se realizó una búsqueda de artículos publicados hasta el 31 de marzo de 2022. Los estudios de neuroimagen eran elegibles si querían estudiar el sistema de recompensa e incluían a un grupo de individuos que comían en atracón junto con un grupo de comparación. Sus resultados se resumieron en una síntesis narrativa. RESULTADOS: Se incluyeron un total de 58 artículos. En reposo, los individuos que comen en atracón mostraron una menor liberación de dopamina estriatal, un cambio en el volumen del cuerpo estriado, la corteza frontal y la ínsula, así como una menor conectividad frontostriatal. Al realizar una tarea, hubo una mayor actividad del sistema de recompensa cerebral al anticipar o recibir alimentos, más aprendizaje de refuerzo sin modelos y un comportamiento más habitual. La mayoría de los estudios sólo incluyeron un grupo de pacientes, utilizaron medidas generales relacionadas con la recompensa y no evaluaron el impacto de las comorbilidades, la duración de la enfermedad, la raza o el sexo. DISCUSIÓN: Confirmando hipótesis anteriores, esta revisión encuentra cambios estructurales y funcionales del sistema de recompensa neurobiológica en BE. Los estudios futuros deben comparar los trastornos, utilizar medidas que sean específicas para el comer en atracones e investigar el impacto de los factores de confusión.

The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms.

Soluble guanylate cyclase (sGC) requires a heme-group bound in order to produce cGMP, a second messenger involved in memory formation, while heme-free sGC is inactive. Two compound classes can increase sGC activity: sGC stimulators acting on heme-bound sGC, and sGC activators acting on heme-free sGC. In this rodent study, we investigated the potential of the novel brain-penetrant sGC stimulator BAY-747 and sGC activator runcaciguat to enhance long-term memory and attenuate short-term memory deficits induced by the NOS-inhibitor L-NAME. Furthermore, hippocampal plasticity mechanisms were investigated. In vivo, oral administration of BAY-747 and runcaciguat to male Wistar rats enhanced memory acquisition in the object location task (OLT), while only BAY-747 reversed L-NAME induced memory impairments in the OLT. Ex vivo, both BAY-747 and runcaciguat enhanced hippocampal GluA1-containing AMPA receptor (AMPAR) trafficking in a chemical LTP model for memory acquisition using acute mouse hippocampal slices. In vivo only runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness.