Explore the vast range of titles available.

Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects selected cortical and spinal neuronal populations, leading to progressive paralysis and death. A growing body of evidences suggests that the disease may originate in the cerebral cortex and propagate in a corticofugal manner. In particular, transcranial magnetic stimulation studies revealed that ALS patients present with early cortical hyperexcitability arising from a combination of increased excitability and decreased inhibition. Here, we discuss the possibility that initial cortical circuit dysfunction might act as the main driver of ALS onset and progression, and review recent functional, imaging and transcriptomic studies conducted on ALS patients, along with electrophysiological, pathological and transcriptomic studies on animal and cellular models of the disease, in order to evaluate the potential cellular and molecular origins of cortical hyperexcitability in ALS.

Involuntary movements develop after 1-4% of strokes and they have been reported in patients with ischemic and hemorrhagic strokes affecting the basal ganglia, thalamus, and/or their connections. Hemichorea-hemiballism is the most common movement disorder following a stroke in adults while dystonia is most common in children. Tremor, myoclonus, asterixis, stereotypies, and vascular parkinsonism are other movement disorders seen following stroke. Some of them occur immediately after acute stroke, some can develop later, and others may have delayed onset progressive course. Proposed pathophysiological mechanisms include neuronal plasticity, functional diaschisis, and age-related differences in brain metabolism. There are no guidelines regarding the management of post-stroke movement disorders, mainly because of their heterogeneity.

Light-based gamma entrainment using sensory stimuli (GENUS) shows considerable potential for the treatment of Alzheimer’s disease (AD) in both animal and human models. While the clinical efficacy of GENUS for AD is paramount, its effectiveness will eventually also rely on the barrier to treatment adherence imposed by the discomfort of gazing at luminance flickering (LF) light. Currently, there have been few attempts to improve the comfort of GENUS. Here we investigate if Invisible spectral flicker (ISF), a novel type of light-based 40 Hz GENUS for which the flicker is almost imperceptible, can be used as a more comfortable option. We found that whereas ISF, LF, and chromatic flicker (CF) all produce a 40 Hz steady-state visually evoked potential (SSVEP), ISF scores significantly better on measures of comfort and perceived flicker. We also demonstrate that, while there is a trend towards a lower SSVEP response, reducing the stimulation brightness has no significant effect on the 40 Hz SSVEP or perceived flicker, though it significantly improves comfort. Finally, there is a slight decrease in the 40 Hz SSVEP response when stimulating with ISF from increasingly peripheral angles. This may ease the discomfort of GENUS treatment by freeing patients from gazing directly at the light.

INTRODUCTION Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), which features early olfactory dysfunction and pathology. However, how APOE ε4 interacts with age and sex to affect cellular and network function in vulnerable regions such as the anterior olfactory nucleus (AON) remains unclear. METHODS In vivo recordings in awake transgenic mice were used to assess how APOE ε4, age, and sex interact to influence single‐cell excitability and network activity. RESULTS APOE ε4 reduces excitability in the AON; adult females show higher excitability than males, a difference that is lost with age. Excitability and network activity vary by genotype and sex, while aging consistently increases network power, underscoring their complex interplay in an AD‐vulnerable circuit. DISCUSSION APOE ε4, age, and sex interact to shape excitability and network dynamics in the anterior olfactory nucleus, a region affected early in AD. These actions may underlie early olfactory dysfunction and offer electrophysiological markers for early detection and genotype‐, age‐, and sex‐specific interventions. Highlights This is the first study on the interactive impact of three Alzheimer's disease risk factors on anterior olfactory nucleus neural functions. Apolipoprotein E ε4 reduces neuronal excitability regardless of age and sex. Females show higher excitability than males in the adult group but not in aged group. Age increases excitability in a genotype‐dependent manner. Network oscillations vary by genotype and sex but are consistently enhanced by age.

Cognitive impairment (CI) is a characteristic non-motor feature of Parkinson disease (PD) that poses a severe burden on the patients and caregivers, yet relatively little is known about its pathobiology. Cognitive deficits are evident throughout the course of PD, with around 25% of subtle cognitive decline and mild CI (MCI) at the time of diagnosis and up to 83% of patients developing dementia after 20 years. The heterogeneity of cognitive phenotypes suggests that a common neuropathological process, characterized by progressive degeneration of the dopaminergic striatonigral system and of many other neuronal systems, results not only in structural deficits but also extensive changes of functional neuronal network activities and neurotransmitter dysfunctions. Modern neuroimaging studies revealed multilocular cortical and subcortical atrophies and alterations in intrinsic neuronal connectivities. The decreased functional connectivity (FC) of the default mode network (DMN) in the bilateral prefrontal cortex is affected already before the development of clinical CI and in the absence of structural changes. Longitudinal cognitive decline is associated with frontostriatal and limbic affections, white matter microlesions and changes between multiple functional neuronal networks, including thalamo-insular, frontoparietal and attention networks, the cholinergic forebrain and the noradrenergic system. Superimposed Alzheimer-related (and other concomitant) pathologies due to interactions between α-synuclein, tau-protein and β-amyloid contribute to dementia pathogenesis in both PD and dementia with Lewy bodies (DLB). To further elucidate the interaction of the pathomechanisms responsible for CI in PD, well-designed longitudinal clinico-pathological studies are warranted that are supported by fluid and sophisticated imaging biomarkers as a basis for better early diagnosis and future disease-modifying therapies.

INTRODUCTION It is unclear how early neuronal deficits occur in tauopathies, if these are associated with changes in neuronal network activity, and if they can be alleviated with therapies. METHODS To address this, we performed in vivo two‐photon Ca2+ imaging in tauopathy mice at 6 versus 12 months, compared to controls, and treated the younger animals with a tau antibody. RESULTS Neuronal function was impaired at 6 months but did not deteriorate further at 12 months, presumably because cortical tau burden was comparable at these ages. At 6 months, neurons were mostly hypoactive, with enhanced neuronal synchrony, and had dysregulated responses to stimulus. Ex vivo, electrophysiology revealed altered synaptic transmission and enhanced excitability of motor cortical neurons, which likely explains the altered network activity. Acute tau antibody treatment reduced pathological tau and gliosis and partially restored neuronal function. DISCUSSION Tauopathies are associated with early neuronal deficits that can be attenuated with tau antibody therapy. Highlights Neuronal hypofunction in awake and behaving mice in early stages of tauopathy. Altered network activity disrupted local circuitry engagement in tauopathy mice. Enhanced neuronal excitability and altered synaptic transmission in tauopathy mice. Tau antibody acutely reduced soluble phospho‐tau and improved neuronal function.

The rising prevalence of depression, with its associated suicide risk, demands effective fast-acting treatments. Ketamine has emerged as promising, demonstrating rapid antidepressant effects. While early studies show swift mood improvements, its precise mechanisms remain unclear. This article aims to compile and synthesize the literature on ketamine’s molecular actions. Ketamine primarily works by antagonizing NMDA receptors, reducing GABAergic inhibition, and increasing glutamate release. This enhanced glutamate activates AMPA receptors, triggering crucial downstream cascades, including BDNF-TrkB and mTOR pathways, promoting synaptic proliferation and regeneration. Moreover, neuroimaging studies have demonstrated alterations in brain networks involved in emotional regulation, including the Default Mode Network (DMN), Central Executive Network (CEN), and Salience Network (SN), which are frequently disrupted in depression. Despite the promising findings, the literature reveals significant inaccuracies and gaps in understanding the full scope of ketamine’s therapeutic potential. For instance, ketamine engages with opioid receptors, insinuating a permissive role of the opioid system in amplifying ketamine’s antidepressant effects, albeit ketamine does not operate as a direct opioid agonist. Further exploration is requisite to comprehensively ascertain its safety profile, long-term efficacy, and the impact of genetic determinants, such as BDNF polymorphisms, on treatment responsiveness.

Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in memory loss and cognitive decline. Synaptic dysfunction is an early hallmark of the disease whose effects on whole-brain functional architecture can be identified using resting-state functional MRI (rsfMRI). Insights into mechanisms of early, whole-brain network alterations can help our understanding of the functional impact of AD's pathophysiology. Here, we obtained rsfMRI data in the TgF344-AD rat model at the pre- and early-plaque stages. This model recapitulates the major pathological and behavioral hallmarks of AD. We used co-activation pattern (CAP) analysis to investigate if and how the dynamic organization of intrinsic brain functional networks states, undetectable by earlier methods, is altered at these early stages. We identified and characterized six intrinsic brain states as CAPs, their spatial and temporal features, and the transitions between the different states. At the pre-plaque stage, the TgF344-AD rats showed reduced co-activation of hub regions in the CAPs corresponding to the default mode-like and lateral cortical network. Default mode-like network activity segregated into two distinct brain states, with one state characterized by high co-activation of the basal forebrain. This basal forebrain co-activation was reduced in TgF344-AD animals mainly at the pre-plaque stage. Brain state transition probabilities were altered at the pre-plaque stage between states involving the default mode-like network, lateral cortical network, and basal forebrain regions. Additionally, while the directionality preference in the network-state transitions observed in the wild-type animals at the pre-plaque stage had diminished at the early-plaque stage, TgF344-AD animals continued to show directionality preference at both stages. Our study enhances the understanding of intrinsic brain state dynamics and how they are impacted at the early stages of AD, providing a nuanced characterization of the early, functional impact of the disease's neurodegenerative process.