The role of inhibitory G proteins and regulators of G protein signaling in the in vivo control of heart rate and predisposition to cardiac arrhythmias

Inhibitory heterotrimeric G proteins and the control of heart rate. The activation of cell signaling pathways involving inhibitory heterotrimeric G proteins acts to slow the heart rate via modulation of ion channels. A large number of Regulators of G protein signalings (RGSs) can act as GTPase accelerating proteins to inhibitory G proteins and thus it is important to understand the network of RGS\G-protein interaction. We will review our recent findings on in vivo heart rate control in mice with global genetic deletion of various inhibitory G protein alpha subunits. We will discuss potential central and peripheral contributions to the phenotype and the controversies in the literature

No evidence for inhibitory deficits or altered reward processing in ADHD: data from a new integrated incentive delay go/no-go task

Objective: Cognitive and motivational factors differentially affect individuals with mental health problems such as ADHD. Here we introduce a new task to disentangle the relative contribution of inhibitory control and reward anticipation on task performance in children with ADHD and/or autism spectrum disorders (ASD). Method: Typically developing children, children with ADHD, ASD, or both disorders worked during separate sessions for monetary or social rewards in go/no-go tasks with varying inhibitory load levels. Participants also completed a monetary temporal discounting (TD) task. Results: As predicted, task performance was sensitive to both the effects of anticipated reward amount and inhibitory load. Reward amount had different effects depending on inhibitory load level. TD correlated with inhibitory control in the ADHD group. Conclusion: The integration of the monetary incentive delay and go/no-go paradigms was successful. Surprisingly, there was no evidence of inhibitory control deficits or altered reward anticipation in the clinical groups

Why are we not flooded by involuntary thoughts about the past and future? Testing the cognitive inhibition dependency hypothesis

© The Author(s) 2018In everyday life, involuntary thoughts about future plans and events occur as often as involuntary thoughts about the past. However, compared to involuntary autobiographical memories (IAMs), such episodic involuntary future thoughts (IFTs) have become a focus of study only recently. The aim of the present investigation was to examine why we are not constantly flooded by IFTs and IAMs given that they are often triggered by incidental cues while performing undemanding activities. One possibility is that activated thoughts are suppressed by the inhibitory control mechanism, and therefore depleting inhibitory control should enhance the frequency of both IFTs and IAMs. We report an experiment with a between-subjects design, in which participants in the depleted inhibition condition performed a 60-min high-conflict Stroop task before completing a laboratory vigilance task measuring the frequency of IFTs and IAMs. Participants in the intact inhibition condition performed a version of the Stroop task that did not deplete inhibitory control. To control for physical and mental fatigue resulting from performing the 60-min Stroop tasks in experimental conditions, participants in the control condition completed only the vigilance task. Contrary to predictions, the number of IFTs and IAMs reported during the vigilance task, using the probe-caught method, did not differ across conditions. However, manipulation checks showed that participants’ inhibitory resources were reduced in the depleted inhibition condition, and participants were more tired in the experimental than in the control conditions. These initial findings suggest that neither inhibitory control nor physical and mental fatigue affect the frequency of IFTs and IAMs.Peer reviewedFinal Published versio

The Role of executive function in children\u27s source monitoring with varying retrieval strategies

Previous research on the relationship between executive function and source monitoring in young children has been inconclusive, with studies finding conflicting results about whether working memory and inhibitory control are related to source-monitoring ability. In this study, the role of working memory and inhibitory control in recognition memory and source monitoring with two different retrieval strategies were examined. Children (N = 263) aged 4–8 participated in science activities with two sources. They were later given a recognition and source-monitoring test, and completed measures of working memory and inhibitory control. During the source-monitoring test, half of the participants were asked about sources serially (one after the other) whereas the other half of the children were asked about sources in parallel (considering both sources simultaneously). Results demonstrated that working memory was a predictor of source-monitoring accuracy in both conditions, but inhibitory control was only related to source accuracy in the parallel condition. When age was controlled these relationships were no longer significant, suggesting that a more general cognitive development factor is a stronger predictor of source monitoring than executive function alone. Interestingly, the children aged 4–6 years made more accurate source decisions in the parallel condition than in the serial condition. The older children (aged 7–8) were overall more accurate than the younger children, and their accuracy did not differ as a function of interview condition. Suggestions are provided to guide further research in this area that will clarify the diverse results of previous studies examining whether executive function is a cognitive prerequisite for effective source monitoring

Gain control network conditions in early sensory coding

Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models

Addressing the selective role of distinct prefrontal areas in response suppression: A study with brain tumor patients

The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies

Thalamic inputs to dorsomedial striatum are involved in inhibitory control: evidence from the five-choice serial reaction time task in rats

Rationale Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues. Objectives Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats. Methods The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 μl bilateral; 3 μM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively. Results We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field. Conclusions These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control

Neurocognitive Predictors of Treatment Response to Randomized Treatment in Adults with Tic Disorders

Tourette\u27s disorder (TS) and chronic tic disorder (CTD) are neurodevelopmental disorders characterized by involuntary vocal and motor tics. Consequently, TS/CTD have been conceptualized as disorders of cognitive and motor inhibitory control. However, most neurocognitive studies have found comparable or superior inhibitory capacity among individuals with TS/CTD relative to healthy controls. These findings have led to the hypothesis that individuals with TS/CTD develop increased inhibitory control due to the constant need to inhibit tics. However, the role of cognitive control in TS/CTD is not yet understood, particularly in adults. To examine the role of inhibitory control in TS/CTD, the present study investigated this association by assessing the relationship between inhibitory control and treatment response in a large sample of adults with TS/CTD. As part of a large randomized trial comparing behavior therapy versus supportive psychotherapy for TS/CTD, a battery of tests, including tests of inhibitory control was administered to 122 adults with TS/CTD at baseline. We assessed the association between neuropsychological test performance and change in symptom severity, as well as compared the performance of treatment responders and non-responders as defined by the Clinical Global Impression Scale. Results indicated that change in symptoms, and treatment response were not associated with neuropsychological performance on tests of inhibitory control, intellectual ability, or motor function, regardless of type of treatment. The finding that significant change in symptom severity of TS/CTD patients is not associated with impairment or change in inhibitory control regardless of treatment type suggests that inhibitory control may not be a clinically relevant facet of these disorders in adults

Visual attention deficits in schizophrenia can arise from inhibitory dysfunction in thalamus or cortex

Schizophrenia is associated with diverse cognitive deficits, including disorders of attention-related oculomotor behavior. At the structural level, schizophrenia is associated with abnormal inhibitory control in the circuit linking cortex and thalamus. We developed a spiking neural network model that demonstrates how dysfunctional inhibition can degrade attentive gaze control. Our model revealed that perturbations of two functionally distinct classes of cortical inhibitory neurons, or of the inhibitory thalamic reticular nucleus, disrupted processing vital for sustained attention to a stimulus, leading to distractibility. Because perturbation at each circuit node led to comparable but qualitatively distinct disruptions in attentive tracking or fixation, our findings support the search for new eye movement metrics that may index distinct underlying neural defects. Moreover, because the cortico-thalamic circuit is a common motif across sensory, association, and motor systems, the model and extensions can be broadly applied to study normal function and the neural bases of other cognitive deficits in schizophrenia.R01 MH057414 - NIMH NIH HHS; R01 MH101209 - NIMH NIH HHS; R01 NS024760 - NINDS NIH HHSPublished versio