Neuropsychobiology of fear-induced bradycardia in humans: progress and pitfalls.

In the last century, the paradigm of fear conditioning has greatly evolved in a variety of scientific fields. The techniques, protocols, and analysis methods now most used have undergone a progressive development, theoretical and technological, improving the quality of scientific productions. Fear-induced bradycardia is among these techniques and represents the temporary deceleration of heart beats in response to negative outcomes. However, it has often been used as a secondary measure to assess defensive responding to threat, along other more popular techniques. In this review, we aim at paving the road for its employment as an additional tool in fear conditioning experiments in humans. After an overview of the studies carried out throughout the last century, we describe more recent evidence up to the most contemporary research insights. Lastly, we provide some guidelines concerning the best practices to adopt in human fear conditioning studies which aim to investigate fear-induced bradycardia.

'Nip it in the bud': Low-frequency rTMS of the prefrontal cortex disrupts threat memory consolidation in humans.

It is still unclear how the human brain consolidates aversive (e.g., traumatic) memories and whether this process can be disrupted. We hypothesized that the dorsolateral prefrontal cortex (dlPFC) is crucially involved in threat memory consolidation. To test this, we used low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) within the memory stabilization time window to disrupt the expression of threat memory. We combined a differential threat-conditioning paradigm with LF-rTMS targeting the dlPFC in the critical condition, and occipital cortex stimulation, delayed dlPFC stimulation, and sham stimulation as control conditions. In the critical condition, defensive reactions to threat were reduced immediately after brain stimulation, and 1 h and 24 h later. In stark contrast, no decrease was observed in the control conditions, thus showing both the anatomical and temporal specificity of our intervention. We provide causal evidence that selectively targeting the dlPFC within the early consolidation period prevents the persistence and return of conditioned responses. Furthermore, memory disruption lasted longer than the inhibitory window created by our TMS protocol, which suggests that we influenced dlPFC neural activity and hampered the underlying, time-dependent consolidation process. These results provide important insights for future clinical applications aimed at interfering with the consolidation of aversive, threat-related memories.

Innovation at the Intersection: Emerging Translational Research in Neurology and Psychiatry.

Translational research in neurological and psychiatric diseases is a rapidly advancing field that promises to redefine our approach to these complex conditions [...].

The role of pre-supplementary motor cortex in action control with emotional stimuli: A repetitive transcranial magnetic stimulation study.

Swiftly halting ongoing motor actions is essential to react to unforeseen and potentially perilous circumstances. However, the neural bases subtending the complex interplay between emotions and motor control have been scarcely investigated. Here, we used an emotional stop signal task (SST) to investigate whether specific neural circuits engaged by action suppression are differently modulated by emotional signals with respect to neutral ones. Participants performed an SST before and after the administration of one session of repetitive transcranial magnetic stimulation (rTMS) over the pre-supplementary motor cortex (pre-SMA), the right inferior frontal gyrus (rIFG), and the left primary motor cortex (lM1). Results show that rTMS over the pre-SMA improved the ability to inhibit prepotent action (i.e., better action control) when emotional stimuli were presented. In contrast, action control in a neutral context was fostered by rTMS over the rIFG. No changes were observed after lM1 stimulation. Intriguingly, individuals with higher impulsivity traits exhibited enhanced motor control when facing neutral stimuli following rIFG stimulation. These results further our understanding of the interplay between emotions and motor functions, shedding light on the selective modulation of neural pathways underpinning these processes.

Neurodegeneration in Cognitive Impairment and Mood Disorders for Experimental, Clinical and Translational Neuropsychiatry.

Neurodegeneration poses a significant challenge for the fields of neuroscience and medicine, as it is the underlying cause of the development and advancement of numerous neurodegenerative and psychiatric disorders [...].

The intricate brain-body interaction in psychiatric and neurological diseases.

A harmonic brain-body communication is fundamental to individual wellbeing and is the basis of human cognition and behavior. In the last 2 decades, the interaction between the brain and body functioning has become a central area of study for neurologists and neuroscientists in clinical and non-clinical contexts. Indeed, brain-body axis dysfunctions occur in many psychiatric, neurological and neurodegenerative diseases. This editorial will focus on recent advances and future therapeutic perspectives for studying brain-body interactions in health and diseases.

Neural Correlates and Molecular Mechanisms of Memory and Learning.

Memory and learning are essential cognitive processes that enable us to obtain, retain, and recall information [...].

Targeting Human Glucocorticoid Receptors in Fear Learning: A Multiscale Integrated Approach to Study Functional Connectivity.

Fear extinction is a phenomenon that involves a gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how brain regions communicate during these processes. Stress, a ubiquitous aspect of life, influences fear learning and extinction by changing the activity of the amygdala, prefrontal cortex, and hippocampus, leading to enhanced fear responses and/or impaired extinction. Glucocorticoid receptors (GRs) are key to the stress response and show a dual function in fear regulation: while they enhance the consolidation of fear memories, they also facilitate extinction. Accordingly, GR dysregulation is associated with anxiety and mood disorders. Recent advancements in cognitive neuroscience underscore the need for a comprehensive understanding that integrates perspectives from the molecular, cellular, and systems levels. In particular, neuropharmacology provides valuable insights into neurotransmitter and receptor systems, aiding the investigation of mechanisms underlying fear regulation and potential therapeutic targets. A notable player in this context is cortisol, a key stress hormone, which significantly influences both fear memory reconsolidation and extinction processes. Gaining a thorough understanding of these intricate interactions has implications in terms of addressing psychiatric disorders related to stress. This review sheds light on the complex interactions between cognitive processes, emotions, and their neural bases. In this endeavor, our aim is to reshape the comprehension of fear, stress, and their implications for emotional well-being, ultimately aiding in the development of therapeutic interventions.

Error-related cardiac deceleration: Functional interplay between error-related brain activity and autonomic nervous system in performance monitoring.

Coordinated interactions between the central and autonomic nervous systems are crucial for survival due to the inherent propensity for human behavior to make errors. In our ever-changing environment, when individuals make mistakes, these errors can have life-threatening consequences. In response to errors, specific reactions occur in both brain activity and heart rate to detect and correct errors. Specifically, there are two brain-related indicators of error detection and awareness known as error-related negativity and error positivity. Conversely, error-related cardiac deceleration denotes a momentary slowing of heart rate following an error, signaling an autonomic response. However, what is the connection between the brain and the heart during error processing? In this review, we discuss the functional and neuroanatomical connections between the brain and heart markers of error processing, exploring the experimental conditions in which they covary. Given the current limitations of available data, future research will continue to investigate the neurobiological factors governing the brain-heart interaction, aiming to utilize them as combined markers for assessing cognitive control in healthy and pathological conditions.

Genetic differences associated with dopamine and serotonin release mediate fear-induced bradycardia in the human brain.

Fear-induced bradycardia, a transient heartbeat deceleration following exposure to threat, is a physiological index observable in humans, especially in fear conditioning experiments. While gaining interest in recent years, it is still currently underemployed in neuroscientific research compared to more popular physiological indices. Besides its use in research, it could also constitute a valuable resource in a clinical psychiatry setting, as many disorders are also characterized by altered heart rate responses. However, differences in fear-induced bradycardia may also be subtended by genetic interindividual differences, thus suggesting precaution when recommending its use in the clinical setting. Here, we discussed the first endeavors that aimed at clarifying the genetic underpinnings of heart rate variations, which suggest that individual genetic differences have a role in defining the characteristics of heart rate responses. Given this, translating heart rate measurements in the clinical setting must be implemented with caution. Future endeavors in this field will aim at identifying these differences even further, thus allowing for more precise clinical interventions.

Task-related modulation of motor response to emotional bodies: A TMS motor-evoked potential study.

Exposure to emotional body postures during perceptual decision-making tasks has been linked to transient suppression of motor reactivity, supporting the monitoring of emotionally relevant information. However, it remains unclear whether this effect occurs implicitly, i.e., when emotional information is irrelevant to the task. To investigate this issue, we used single-pulse transcranial magnetic stimulation (TMS) to assess motor excitability while healthy participants were asked to categorize pictures of body expressions as emotional or neutral (emotion recognition task) or as belonging to a male or a female actor (gender recognition task) while receiving TMS over the motor cortex at 100 and 125 ms after picture onset. Results demonstrated that motor-evoked potentials (MEPs) were reduced for emotional body postures relative to neutral postures during the emotion recognition task. Conversely, MEPs increased for emotional body postures relative to neutral postures during the gender recognition task. These findings indicate that motor inhibition, contingent upon observing emotional body postures, is selectively associated with actively monitoring emotional features. In contrast, observing emotional body postures prompts motor facilitation when task-relevant features are non-emotional. These findings contribute to embodied cognition models that link emotion perception and action tendencies.

The Role of Serotonin in Fear Learning and Memory: A Systematic Review of Human Studies.

Fear is characterized by distinct behavioral and physiological responses that are essential for the survival of the human species. Fear conditioning (FC) serves as a valuable model for studying the acquisition, extinction, and expression of fear. The serotonin (5-hydroxytryptamine, 5-HT) system is known to play a significant role in emotional and motivational aspects of human behavior, including fear learning and expression. Accumulating evidence from both animal and human studies suggests that brain regions involved in FC, such as the amygdala, hippocampus, and prefrontal cortex, possess a high density of 5-HT receptors, implicating the crucial involvement of serotonin in aversive learning. Additionally, studies exploring serotonin gene polymorphisms have indicated their potential influence on FC. Therefore, the objective of this work was to review the existing evidence linking 5-HT with fear learning and memory in humans. Through a comprehensive screening of the PubMed and Web of Science databases, 29 relevant studies were included in the final review. These studies investigated the relationship between serotonin and fear learning using drug manipulations or by studying 5-HT-related gene polymorphisms. The results suggest that elevated levels of 5-HT enhance aversive learning, indicating that the modulation of serotonin 5-HT2A receptors regulates the expression of fear responses in humans. Understanding the role of this neurochemical messenger in associative aversive learning can provide insights into psychiatric disorders such as anxiety and post-traumatic stress disorder (PTSD), among others.

Advances in EEG-based functional connectivity approaches to the study of the central nervous system in health and disease.

Functional brain connectivity is closely linked to the complex interactions between brain networks. In the last two decades, measures of functional connectivity based on electroencephalogram (EEG) data have proved to be an important tool for neurologists and clinical and non-clinical neuroscientists. Indeed, EEG-based functional connectivity may reveal the neurophysiological processes and networks underlying human cognition and the pathophysiology of neuropsychiatric disorders. This editorial discusses recent advances and future prospects in the study of EEG-based functional connectivity, with a focus on the main methodological approaches to studying brain networks in health and disease.

Neurophysiological Markers of Premotor-Motor Network Plasticity Predict Motor Performance in Young and Older Adults.

Aging is commonly associated with a decline in motor control and neural plasticity. Tuning cortico-cortical interactions between premotor and motor areas is essential for controlling fine manual movements. However, whether plasticity in premotor-motor circuits predicts hand motor abilities in young and elderly humans remains unclear. Here, we administered transcranial magnetic stimulation (TMS) over the ventral premotor cortex (PMv) and primary motor cortex (M1) using the cortico-cortical paired-associative stimulation (ccPAS) protocol to manipulate the strength of PMv-to-M1 connectivity in 14 young and 14 elderly healthy adults. We assessed changes in motor-evoked potentials (MEPs) during ccPAS as an index of PMv-M1 network plasticity. We tested whether the magnitude of MEP changes might predict interindividual differences in performance in two motor tasks that rely on premotor-motor circuits, i.e., the nine-hole pegboard test and a choice reaction task. Results show lower motor performance and decreased PMv-M1 network plasticity in elderly adults. Critically, the slope of MEP changes during ccPAS accurately predicted performance at the two tasks across age groups, with larger slopes (i.e., MEP increase) predicting better motor performance at baseline in both young and elderly participants. These findings suggest that physiological indices of PMv-M1 plasticity could provide a neurophysiological marker of fine motor control across age-groups.

Comprehensive Drug Resistance Characterization of Pulmonary Tuberculosis in Algeria: Insights on Mycobacterium tuberculosis Strains by Whole-Genome Sequencing.

In this study, we aimed to characterize drug-resistant strains by whole-genome sequencing (WGS), to describe the spreading lineages and the history of transmission. Drug susceptibility testing was performed by 96-well broth microdilution plates. The genomic DNA was extracted and purified; libraries were prepared and run on the Illumina NextSeq500 System. Among 82 isolates, 21 tuberculosis (TB) isolates (25.6%) were drug resistant, including 10 MDR and 4 pre-extensively drug-resistant (XDR)-TB. The mutation Ser315Thr in the katG gene was confirmed in 15 isolates. In rpoB, Ser450Leu and His445Asp mutations were the most common. Asp94Asn and Ala90Val mutations were reported in gyrA. The LAM family, the most TB drug resistant, was widely predominant in the north and the T sublineage in the south of the country. This study provides the first insight on TB drug resistance using WGS in Algeria and clearly describes the first pre-XDR-TB cases and lineage distribution across the country.

Neuropharmacological Modulation of N-methyl-D-aspartate, Noradrenaline and Endocannabinoid Receptors in Fear Extinction Learning: Synaptic Transmission and Plasticity.

Learning to recognize and respond to potential threats is crucial for survival. Pavlovian threat conditioning represents a key paradigm for investigating the neurobiological mechanisms of fear learning. In this review, we address the role of specific neuropharmacological adjuvants that act on neurochemical synaptic transmission, as well as on brain plasticity processes implicated in fear memory. We focus on novel neuropharmacological manipulations targeting glutamatergic, noradrenergic, and endocannabinoid systems, and address how the modulation of these neurobiological systems affects fear extinction learning in humans. We show that the administration of N-methyl-D-aspartate (NMDA) agonists and modulation of the endocannabinoid system by fatty acid amide hydrolase (FAAH) inhibition can boost extinction learning through the stabilization and regulation of the receptor concentration. On the other hand, elevated noradrenaline levels dynamically modulate fear learning, hindering long-term extinction processes. These pharmacological interventions could provide novel targeted treatments and prevention strategies for fear-based and anxiety-related disorders.