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.

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.

This perspective article addresses the potential use of cortical excitability (CE) as an indicator of cognitive health in aging people. Changes in CE may be considered a sign of resilience to cognitive decline in old age. The authors describe research on CE and its link to cognitive function in older adults and emphasize that it is a promising, non-invasive measure of healthy aging. They also address the current challenges in its implementation, the need for standardized measurement protocols and possible future avenues of research. If properly considered, CE could pave the way for early detection of cognitive decline and facilitate targeted interventions to promote cognitive resilience.

Post-traumatic olfactory dysfunction (PTOD) is a common and often persistent sequela of mild traumatic brain injury (mTBI), with limited evidence-based treatment options. We propose that high-frequency rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) may support olfactory recovery via top-down modulation of distributed olfactory, attentional, and reward networks, and we outline key mechanistic and methodological considerations for future studies. We summarize the case of a 70-year-old woman with severe post-traumatic hyposmia persisting for ~5 months, who underwent a 12-week, 10 Hz rTMS course over left DLPFC (36 sessions; 800 pulses/session). Using a structured door diary and repeated ratings across odour categories, she reported stepwise improvement starting around sessions 10–12 (re-emergence of pungent odours) and progressing to broad restoration, including subtle fragrances, by treatment end; no adverse events occurred. While causality cannot be inferred from a single case, this pattern is consistent with a network-level neuromodulatory effect and motivates controlled trials combining standardized olfactory testing with neurophysiology and neuroimaging.

Background/Objectives: Cognitive decline and Alzheimer’s disease (AD) pose a major challenge for the ageing population, with impaired synaptic plasticity playing a central role in their pathophysiology. This article explores the hypothesis that cortico–cortical paired associative stimulation (ccPAS), a non-invasive brain stimulation technique, can restore synaptic function by targeting impaired spike-timing-dependent plasticity (STDP), a key mechanism disrupted in AD. Methods: We reviewed existing studies investigating the effects of ccPAS on neuroplasticity in both ageing and AD populations. Results: Findings suggest age-specific effects, with ccPAS improving motor performance in young adults but showing limited efficacy in older adults, likely due to age-related declines in synaptic plasticity and cortical excitability. In AD, ccPAS studies reveal significant impairments in long-term potentiation (LTP)-like plasticity, while long-term depression (LTD)-like mechanisms appear relatively preserved, emphasising the need for targeted neuromodulation approaches. Conclusions: Despite promising preliminary results, evidence remains limited and largely focused on motor function, with the impact of ccPAS on cognitive domains still underexplored. To bridge this gap, future research should focus on larger and more diverse cohorts to optimise ccPAS protocols for ageing and AD populations and investigate its potential for enhancing cognitive function. By refining stimulation parameters and integrating neuroimageing-based personalisation strategies, ccPAS may represent a novel therapeutic approach for mitigating neuroplasticity deficits in ageing and neurodegenerative conditions.