A functional polymorphism in the promoter region of the human serotonin transporter gene ( SLC6A4 ) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
Introduction Migraine is a leading cause of years lived with disability and preventive strategies represent a mainstay to reduce health-related disability and improve quality of life of migraine patients. Until a few years ago, migraine prevention was based on drugs developed for other clinical indications and relocated in the migraine therapeutic armamentarium, characterized by unfavorable tolerability profiles. The advent of monoclonal antibodies against Calcitonin Gene-Related Peptide (CGRP) and gepants, CGRP receptor antagonists, has been a turning point in migraine prevention owing to advantageous efficacy, safety and tolerability profiles.Nevertheless, while in an ideal scenario a drug characterized by significant greater efficacy and tolerability compared to existing therapeutic strategies should be adopted as a first-line treatment, cost-effectiveness analyses available for monoclonal antibodies against CGRP pathway tend to limit their administration to more severe migraine phenotypes.Areas covered The present narrative review aims to provide a critical appraisal of phase II and III CGRP-mAbs and gepants trials to analyze their use in clinical practice.Expert opinion Despite monoclonal antibodies against CGRP pathway and gepants can be undoubtedly considered top-of-the-range treatments, there are still issues deserving to be addressed in the coming years as the risk of off-target effects as well as their economic sustainability based on the considerable migraine burden.
Migraine is a common neurological disorder characterized by a primary brain dysfunction subtended by an episodic activation and sensitization of the trigemino-vascular pain pathway. Although migraine attacks are clinically welldefined, the underlying pathophysiology of the more complex migraine scenario is largely unknown. Functional brain changes, that occur because of repeated migraine attacks, may be explained through a maladaptive feedforward allostatic cascade model. The fundamental assumption is that “the brain is a central organ of stress” [1], able to detect stressful or potentially stressful situations and react in form of behavioural and/or physiologic responses. These brain responses, mediated by the autonomic nervous system and neuroendocrine mechanisms, could be either adaptive or maladaptive. In this context, allostasis is the ability to protect the body through adaptation [2]. Contrariwise, the allostatic load and overload, resulting from repeated stress and/or allostasis [3], refers to the wear and tear on the systems that normally support adaptation. Compelling evidence suggests that the brain of migraine patients is significantly different from healthy controls. Some of these differences are related to abnormal cortical activity during painful stimulations, suggesting an “adaptive” response observed in the course of moderate or high noxious trigeminal stimulations. Conversely, other differences relate to abnormality in responses that should be adaptive but become impaired or maladaptive, such as altered brainstem processing. More recently, a decreased functional connectivity was demonstrated within the fronto-parietal network (FPN) in patients with migraine without and with aura in the absence of clinically relevant executive deficits. FPN represents the neural substrate of executive functions and FPN functional abnormalities might be a part of a complex cascade that terminates in a migraine attack. Specifically, FPN functional connectivity changes could underlie a defective executive functioning in which high-demanding conditions cannot be correctly processed and solved by patients with migraine, escalating the brain adaptive response, likely resulting in a risk factor for headache attacks. In conclusion, we believe that in migraine an internal state of dysregulation creates an allostatic load with maladaptive consequences on brain, behaviour, physiological regulation and systemic physiology that progress in a feedforward cascade. Thus, we suggest that migraine should be considered a brain disease and not simply a recurrent acute pain syndrome.
Subjective complaints of cognitive deficits are not necessarily consistent with objective evidence of cognitive impairment in Parkinson's disease (PD). Here we examined the factors associated with the objective-subjective cognitive discrepancy.We consecutively enrolled 90 non-demented patients with PD who completed the Parkinson's Disease Cognitive Functional Rating Scale (subjective cognitive measure) and the Montreal Cognitive Assessment (MoCA; objective cognitive measure). The patients were classified as "Overestimators", "Accurate estimators", and "Underestimators" on the basis of the discrepancy between the objective vs. subjective cognitive measures. To identify the factors distinguishing these groups from each other, we used chi-square tests or one-way analyses of variance, completed by logistic and linear regression analyses.Forty-nine patients (54.45%) were classified as "Accurate estimators", 29 (32.22%) as "Underestimators", and 12 (13.33%) as "Overestimators". Relative to the other groups, the "Underestimators" scored higher on the Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), and Parkinson Anxiety Scale (p < 0.01). Logistic regression confirmed that FSS and BDI scores distinguished the "Underestimators" group from the others (p < 0.05). Linear regression analyses also indicated that FSS and BDI scores positively related to objective-subjective cognitive discrepancy (p < 0.01). "Overestimators" scored lower than other groups on the MoCA's total score and attention and working memory subscores (p < 0.01).In more than 45% of consecutive non-demented patients with PD, we found a 'mismatch' between objective and subjective measures of cognitive functioning. Such discrepancy, which was related to the presence of fatigue and depressive symptoms and frontal executive impairments, should be carefully evaluated in clinical setting.
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