Current Opinion in Neurology最新文献

Purpose of review: Cortical excitability, defined as the cortex's responsiveness to incoming stimuli, is a fundamental concept in neuroscience and a targetable mechanism for controlling brain dysfunctions such as epilepsy, as well as other neurological and psychiatric disorders. In this review, we delineate the boundaries between physiological and pathological excitability, highlighting recent theoretical, experimental, and translational advances relevant to human brain disorders. Specifically, we describe the dynamic regulation of cortical excitability and propose practical means to monitor its known fluctuations as to guide therapeutic interventions.

Recent findings: From a conceptual standpoint, the last decade of research on cortical excitability has benefited from dynamical systems theory, which studies the behavior of nonlinear systems (here, the cortex) and their resilience to perturbations in different conditions (here, variable excitability). We review how fundamental relationships between excitability and resilience were verified in the brain in a series of recent studies. We also review natural fluctuations in cortical excitability, and how these may open windows of vulnerability for the expression of cortical dysfunctions. We then turn to the practicalities of measuring and monitoring cortical excitability, a latent variable that must be actively probed.

Summary: Practical means for gauging cortical excitability likely have broad applicability. To enable new developments in clinical practice, a principled design of pharmacological and neurostimulation therapies must leverage current understanding of cortical dynamics.

Purpose of review: Immunometabolism is an emerging field of research investigating the ability of immune cells to modulate their metabolic activity for optimal function. While this has been extensively examined in peripheral immune cells like macrophages, only recently have these studies been extended to assess the immunometabolic activity of microglia, the innate immune cells of the brain.

Recent findings: Microglia are highly metabolically flexible and can utilize different nutrients for their diverse functions. Like other immune cells, they undergo metabolic reprogramming on immune stimulation and in inflammatory, neurodegenerative conditions such as Alzheimer's disease (AD). In recent years, researchers have looked at the intricate mechanisms that modulate microglial activity and have uncovered key links between altered metabolism, neuroinflammation, and the involvement of disease-associated risk genes.

Summary: This review highlights the recent studies that have significantly contributed to our understanding of the metabolic dysregulation observed in activated microglia in conditions such as AD, unveiling novel targets for therapeutic intervention.

Purpose of review: Technological innovations and clinical research in SEEG have dramatically increased with its worldwide dissemination. In this review, we summarize the main advances in the field from the last 5 years.

Recent findings: Several large series and meta-analyses have provided consistent data regarding a lower risk of serious complications with SEEG as compared to sub-dural grids, while some studies also suggest a greater diagnostic value. The safety and precision of SEEG partly depends on the type of vascular imaging and method of implantation, with some series suggesting that MR angiography might not provide an optimal delineation of electrode-vessel conflicts and that frameless stereotaxy lacks precision. Noninvasive frame coupled with robot-guided implantation might offer the best precision/invasiveness tradeoff. Small series suggest that SEEG can be safely performed from the age of 16 months, and that adding electrodes during SEEG often prove beneficial. Transhemispheric electrodes targeting the mesial frontal structures, bilaterally, proved safe and informative. Several interictal and ictal biomarkers of the epileptogenic zone have been investigated. Although high-frequency oscillations (HFOs) remain a biomarker of interest, a randomized controlled trial failed to demonstrate its diagnostic value against spikes. Furthermore, other interictal biomarkers proved to better correlate with the epileptogenic zone than HFOs rate, including spike-gamma and spike-ripples. Ictal biomarkers of interest include the so-called chirp and epileptogenic zone fingerprint. Overall, recent data suggest that high-frequency activities are not a mandatory feature of interictal and ictal biomarkers of the epileptogenic zone. Radiofrequency thermocoagulation (RFTC) performed during SEEG investigation have also progressed, with some authors reporting spectacular rates of seizure freedom in patients with localized epileptogenic lesion but also mesial temporal sclerosis. However, a systematic assessment of memory and mental health demonstrated the presence of altered memory and psychiatric complications in a significant proportion of mesial temporal lobe RFTC.

Summary: Progress has been made in the technology and methods used to perform SEEG and RFTC, with the view to increase safety and effectiveness. Several interictal and ictal biomarkers appear promising but still face challenges in their validation and implementation in clinical practice. Future research requires harmonization in the concepts of the seizure onset and epileptogenic zones, and prospective pathology-specific studies.

Purpose of review: Epilepsy disproportionately affects those in low- and middle-income countries (LMICs) where diagnostic and treatment gaps persist.We highlight key recent developments and showcase practical opportunities to improve epilepsy care in resource limited settings.

Recent findings: In LMICs, cultural, socioeconomic and infrastructural factors drive the epilepsy treatment gap. Robust implementation of the WHO Intersectoral Global Action Plan (WHO IGAP) and Mental Health Gap Action Program (mhGAP), for example, will reduce the epilepsy education gap. Engaging traditional healers and other key community leaders should lessen stigma. The Epilepsy Diagnostic Companion, a culture specific tool that helps identify convulsive seizures, can expedite epilepsy diagnosis at primary care level. Novel, robust 3-D printable EEG headsets prototypes that can be deployed in remote rural communities have been piloted with encouraging results. Levetiracetam has been added to the WHO Essential Medicines List (EML), paving way to safer, less teratogenic antiseizure medications (ASMs). Epilepsy surgery programs in carefully selected patients potentially offer cheap, effective and potentially curative treatments, including in LMICs.

Summary: Apps, EEG prototypes, better access to ASMs and implementation of WHO iGAP offer current, tangible opportunities to improve epilepsy care in LMICs. Bidirectional learning must be facilitated to also help hard to reach communities in high-income settings.

Purpose of review: This review focuses on the role of psychological factors in cognitive aging and dementia, an area that has received less attention compared to other modifiable factors (e.g. sleep, physical activity, and so on) or reduction of disease risk.

Recent findings: A range of mental health and psychological aspects, including clinical symptoms, stable personality traits, and more specific constructs or processes (e.g. repetitive negative thinking, purpose in life), are associated with cognitive aging and dementia risk. Psychological factors can either serve as protective or risk elements, influencing brain health through general mechanisms, including stress regulation and impact on several biological systems, as well as modulate brain resistance and cognitive resilience to Alzheimer's disease and age-related brain changes. Protective psychological traits are linked to healthier lifestyle habits, while risk factors are associated with negative behaviors, and may impact cognitive function across the lifespan, suggesting benefits for psychological education from early life.

Summary: The review emphasizes the need for greater focus on optimizing psychological well being, particularly in at-risk populations, and suggests that interventions should be tailored to individuals' values and life purposes. Additionally, further research is needed to explore the neurobiological mechanisms through which psychologically focused interventions may influence cognitive decline and dementia.

Purpose of review: The present review aims to provide an overview of the existing understanding of the role of the gut microbiome in the Alzheimer's disease pathophysiology.

Recent findings: Recent research has highlighted the significant role of the gut microbiome in the pathogenesis of Alzheimer's disease via the gut-brain axis. However, the precise mechanisms by which gut microbiome and its microbial metabolites influence brain function are not clearly understood. Various factors, such as diet, drugs, lifestyle, stress, and microbial infections can provoke an imbalance in the gut microbiome homeostasis, known as dysbiosis. This dysbiosis impacts intestinal and blood-brain barrier permeability, elevating pro-inflammatory cytokines and contributing to neurodegeneration. Moreover, the gut microbiome generates neurotransmitters, amyloids, neurotoxins, and metabolites, which may play a role in systemic inflammation and in the disruption of physiological barriers.

Summary: In the past decade, advancements in microbiome analysis technologies and bioinformatics have significantly enhanced our understanding of the role of the gut microbiome in Alzheimer's disease. The gut microbiome plays a pivotal regulatory role in the progression of Alzheimer's disease, and closely interacts with its pathogenesis, encompassing inflammation, amyloidosis, neurodegeneration, tauopathy, and co-pathologies.

Purpose of review: Gene therapy in epilepsy has undergone a rapid expansion in recent years. This has largely been driven by both advances in our understanding of epilepsy genetics and mechanisms, and also significant advances in gene therapy tools, in particular safe and effective viral vectors. Epilepsy remains an ideal target disease for gene therapy and this review highlights recent developments in this area.

Recent findings: There have been continued advances in the development of antisense oligonucleotide therapies to knock down genes in the treatment of monogenic epilepsies with some now entering clinical trial. However, the greatest recent advances have been in vector gene therapy, which offers a more permanent solution by delivering therapeutic genes directly to the brain as a one-off therapy. In particular, there has been a growth in methods that target focal epilepsy. Such promising approaches close to or in clinical trial include expressing NPY and its Y2 receptor, knocking-down GluK5, a kainate receptor subunit, and the over-expression of Kv1.1, an endogenous potassium channel.In the future, it is likely that we will take advantage of approaches of regulating more precisely network excitability by using methods such as optogenetics, designer receptors exclusively activated by designer drugs (DREADDs), 'inhibitory' glutamate receptors activated by excessive glutamate spill-over, and activity-dependent promoters, which target gene expression to the 'hyperactive' neurons.

Summary: Gene therapies offer a novel approach to the treatment of not just genetic epilepsies but any form of epilepsy and may in the future offer an alternative to drug and surgical therapies, allowing more precise, permanent and targeted treatment with fewer adverse effects.

Purpose of review: Epilepsy surgery is a potentially curative intervention for medically refractory epilepsy. In the last several decades, epilepsy has been studied as a network disorder. How has this disease model influenced surgical interventions?

Recent findings: Surgical outcomes for resection are increasingly being tied to network features, such as node hubness score. These findings imply that measuring network features may augment epileptologist seizure onset zone designation for surgical planning. Network models are also leveraged for neuromodulation, specifically in studies with thalamic targets. Recent findings suggest that the thalamus may function as a reasonable target for neuromodulation because of its role in the seizure propagation networks.

Summary: In this review, we discuss the degree these models of epilepsy are influencing surgery today and barriers for the widespread adoption of network models when planning epilepsy surgery.

Purpose of review: Paroxysmal hemicrania and hemicrania continua are rare primary headache disorders which are distinguished by an absolute response to indomethacin. As a matter of importance, no guidelines have been proposed for alternative therapeutic options in case of indomethacin intolerance. The purpose of this review is to provide an update on the current findings, especially focusing on the past 18 months, in the treatment of both paroxysmal hemicrania and hemicrania continua and to provide proposed management recommendations based on summarized evidence.

Recent findings: Apart from well recognized gastrolesive effects of indomethacin, a substantial number of patients may suffer from neuropsychiatric adverse reactions. Recent studies demonstrated that melatonin, which has been known for its effectiveness for hemicrania continua, is also useful for paroxysmal hemicrania. Promising nonpharmacological treatment option, which is noninvasive vagus nerve stimulation, has been shown to be beneficial for both indomethacin-responsive headache disorders allowing the reduction of indomethacin dosage. Although the data on substitutive medication choice for indomethacin are currently scarce, the most consistent results have been repeatedly achieved with acemethacin, selective COX-2 inhibitors, and anticonvulsants. However, considering the crucial role of pathophysiology, research investigating the efficacy of drugs targeting the trigemino-vascular system activation, as well as controlled trials assessing the efficacy involving the aforementioned therapeutic options are still vague.

Summary: In spite of numerous reports suggesting reliable alternatives to indomethacin, the consensus on pharmacological therapy guidelines for indomethacin-responsive headache disorders has not yet been reached. Further research and agreement from the experts' standpoint are needed for an establishment of reliable treatment recommendations.

Purpose of review: Stroke is the second leading cause of death worldwide, and exposure to particulate air pollution is now recognized as one of the major modifiable risk factors. However, air pollution can vary in terms of physicochemical composition and exposition specificities. Therefore, its relationships with stroke outcomes remain under intense investigation.

Recent findings: This review highlights, alongside particles, that short-term and long-term exposure to nitrogen dioxide (NO 2 ) and ozone is likely to be also linked to stroke-related morbidity and mortality. Moreover, air pollution may increase the risk of transitioning from a healthy status to incident stroke and morbimortality after stroke. Additionally, relationships may vary depending on the air pollution mixture (e.g., particle-related components, pollutant interactions), pollutant sources (e.g., traffic-related or not), stroke etiology (ischemic or hemorrhagic), or exposed individual's characteristics (e.g., age, sex, genetic predisposition, weight status). Nonlinear dose-response functions and short-term effect lags have been reported, but these features need further refinement.

Summary: The relationship between stroke and air pollution is now well established. Nonetheless, future research should further consider the physicochemical properties of air pollutants, multiple exposures, and individual vulnerabilities. Moreover, advanced statistical methods should be more commonly used to better describe the relationship shapes.