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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. [ABSTRACT FROM AUTHOR]

The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimers disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-β sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.

The last decades have witnessed huge efforts devoted to deciphering the pathological mechanisms underlying Alzheimer's Disease (AD) and to testing new drugs, with the recent FDA approval of two anti-amyloid monoclonal antibodies for AD treatment. Beyond these drug-based experimentations, a number of pre-clinical and clinical trials are exploring the benefits of alternative treatments, such as non-invasive stimulation techniques on AD neuropathology and symptoms. Among the different non-invasive brain stimulation approaches, transcranial alternating current stimulation (tACS) is gaining particular attention due to its ability to externally control gamma oscillations. Here, we outline the current knowledge concerning the clinical efficacy, safety, ease-of-use and cost-effectiveness of tACS on early and advanced AD, applied specifically at 40 Hz frequency, and also summarise pre-clinical results on validated models of AD and ongoing patient-centred trials. [ABSTRACT FROM AUTHOR]

Introduction: 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 functionalMRI (rsfMRI). Insights into mechanisms of early, whole-brain network alterations can help our understanding of the functional impact of AD's pathophysiology. Methods: 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 earliermethods, is altered at these early stages. Results: 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 defaultmode-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. Discussion: 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. [ABSTRACT FROM AUTHOR]

IntroductionAlzheimer'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.MethodsHere, 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.ResultsWe 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.DiscussionOur 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.

Abstract Background Imbalanced synaptic transmission appears to be an early driver in Alzheimer’s disease (AD) leading to brain network alterations. Early detection of altered synaptic transmission and insight into mechanisms causing early synaptic alterations would be valuable treatment strategies. This study aimed to investigate how whole-brain networks are influenced at pre- and early-plague stages of AD and if these manifestations are associated with concomitant cellular and synaptic deficits. Methods To this end, we used an established AD rat model (TgF344-AD) and employed resting state functional MRI and quasi-periodic pattern (QPP) analysis, a method to detect recurrent spatiotemporal motifs of brain activity, in parallel with state-of-the-art immunohistochemistry in selected brain regions. Results At the pre-plaque stage, QPPs in TgF344-AD rats showed decreased activity of the basal forebrain (BFB) and the default mode-like network. Histological analyses revealed increased astrocyte abundance restricted to the BFB, in the absence of amyloid plaques, tauopathy, and alterations in a number of cholinergic, gaba-ergic, and glutamatergic synapses. During the early-plaque stage, when mild amyloid-beta (Aβ) accumulation was observed in the cortex and hippocampus, QPPs in the TgF344-AD rats normalized suggesting the activation of compensatory mechanisms during this early disease progression period. Interestingly, astrogliosis observed in the BFB at the pre-plaque stage was absent at the early-plaque stage. Moreover, altered excitatory/inhibitory balance was observed in cortical regions belonging to the default mode-like network. In wild-type rats, at both time points, peak activity in the BFB preceded peak activity in other brain regions—indicating its modulatory role during QPPs. However, this pattern was eliminated in TgF344-AD suggesting that alterations in BFB-directed neuromodulation have a pronounced impact in network function in AD. Conclusions This study demonstrates the value of rsfMRI and advanced network analysis methods to detect early alterations in BFB function in AD, which could aid early diagnosis and intervention in AD. Restoring the global synaptic transmission, possibly by modulating astrogliosis in the BFB, might be a promising therapeutic strategy to restore brain network function and delay the onset of symptoms in AD.

• CaMKII- and GFAP-Gq activation impacted memory, anxiety, and social behaviors. • Novel environment exploration was affected by CaMKII- and GFAP-Gq activation. • CaMKII-Gq modified microglial number, while GFAP-Gq affected microglial morphology. • Neither cell manipulation affected astrocytic number or morphology. Network dysfunction is implicated in numerous diseases and psychiatric disorders, and the hippocampus serves as a common origin for these abnormalities. To test the hypothesis that chronic modulation of neurons and astrocytes induces impairments in cognition, we activated the hM3D(Gq) pathway in CaMKII+ neurons or GFAP+ astrocytes within the ventral hippocampus across 3, 6, and 9 months. CaMKII-hM3Dq activation impaired fear extinction at 3 months and acquisition at 9 months. Both CaMKII-hM3Dq manipulation and aging had differential effects on anxiety and social interaction. GFAP-hM3Dq activation impacted fear memory at 6 and 9 months. GFAP-hM3Dq activation impacted anxiety in the open field only at the earliest time point. CaMKII-hM3Dq activation modified the number of microglia, while GFAP-hM3Dq activation impacted microglial morphological characteristics, but neither affected these measures in astrocytes. Overall, our study elucidates how distinct cell types can modify behavior through network dysfunction, while adding a more direct role for glia in modulating behavior. [ABSTRACT FROM AUTHOR]

Altered or atypical functional connectivity as measured with functional magnetic resonance imaging (fMRI) is a hallmark feature of brain connectopathy in psychiatric, developmental, and neurological disorders. However, the biological underpinnings and etiopathological significance of this phenomenon remain unclear. The recent development of MRI-based techniques for mapping brain function in rodents provides a powerful platform to uncover the determinants of functional (dys)connectivity, whether they are genetic mutations, environmental risk factors, or specific cellular and circuit dysfunctions. Here, we summarize the recent contribution of rodent fMRI toward a deeper understanding of network dysconnectivity in developmental and psychiatric disorders. We highlight substantial correspondences in the spatiotemporal organization of rodent and human fMRI networks, supporting the translational relevance of this approach. We then show how this research platform might help us comprehend the importance of connectional heterogeneity in complex brain disorders and causally relate multiscale pathogenic contributors to functional dysconnectivity patterns. Finally, we explore how perturbational techniques can be used to dissect the fundamental aspects of fMRI coupling and reveal the causal contribution of neuromodulatory systems to macroscale network activity, as well as its altered dynamics in brain diseases. These examples outline how rodent functional imaging is poised to advance our understanding of the bases and determinants of human functional dysconnectivity. [ABSTRACT FROM AUTHOR]

Background: Imbalanced synaptic transmission appears to be an early driver in Alzheimer's disease (AD) leading to brain network alterations. Early detection of altered synaptic transmission and insight into mechanisms causing early synaptic alterations would be valuable treatment strategies. This study aimed to investigate how whole-brain networks are influenced at pre- and early-plague stages of AD and if these manifestations are associated with concomitant cellular and synaptic deficits. Methods: To this end, we used an established AD rat model (TgF344-AD) and employed resting state functional MRI and quasi-periodic pattern (QPP) analysis, a method to detect recurrent spatiotemporal motifs of brain activity, in parallel with state-of-the-art immunohistochemistry in selected brain regions. Results: At the pre-plaque stage, QPPs in TgF344-AD rats showed decreased activity of the basal forebrain (BFB) and the default mode-like network. Histological analyses revealed increased astrocyte abundance restricted to the BFB, in the absence of amyloid plaques, tauopathy, and alterations in a number of cholinergic, gaba-ergic, and glutamatergic synapses. During the early-plaque stage, when mild amyloid-beta (Aβ) accumulation was observed in the cortex and hippocampus, QPPs in the TgF344-AD rats normalized suggesting the activation of compensatory mechanisms during this early disease progression period. Interestingly, astrogliosis observed in the BFB at the pre-plaque stage was absent at the early-plaque stage. Moreover, altered excitatory/inhibitory balance was observed in cortical regions belonging to the default mode-like network. In wild-type rats, at both time points, peak activity in the BFB preceded peak activity in other brain regions—indicating its modulatory role during QPPs. However, this pattern was eliminated in TgF344-AD suggesting that alterations in BFB-directed neuromodulation have a pronounced impact in network function in AD. Conclusions: This study demonstrates the value of rsfMRI and advanced network analysis methods to detect early alterations in BFB function in AD, which could aid early diagnosis and intervention in AD. Restoring the global synaptic transmission, possibly by modulating astrogliosis in the BFB, might be a promising therapeutic strategy to restore brain network function and delay the onset of symptoms in AD. [ABSTRACT FROM AUTHOR]

In 1880 Carl Wernicke gave this plenary lecture at an annual meeting of German physicians and natural scientists. He used principles from his 1874 aphasia monograph to build a neural model of mental illness. He proposed that the brain keeps a record of experiences in distinct areas of the sensory and motor cortices in the form of memory images, which allows for recognition of objects and the planning of motor acts. He conjectured that imperfections, partial defects and complete loss of such memory images lead, respectively, to mild, moderate and severe forms of psychopathology in sensory and motor realms. The lecture is an early presentation of Wernicke's system of psychiatry. Several of his concepts have remained relevant in contemporary neuroscience. [ABSTRACT FROM AUTHOR]

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 Ca 2+ 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., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin‐1β (IL‐1β) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL‐1β. Systemic LPS triggered microglial IL‐1β, astrocytic chemokines, IL‐6, and acute cognitive dysfunction, whereas IL‐1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL‐1β and IL‐6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

Background: Several studies on patients with juvenile myoclonic epilepsy (JME) showed widespread white matter (WM) abnormalities in the brain. The aim of this study was to investigate potential structural abnormalities in JME patients (1) compared to healthy controls, (2) among JME subgroups with or without photoparoxysmal responses (PPR), and (3) in correlation with clinical variables.Methods: A selection of 31 patients with JME (12 PPR positive) and 27 age and gender matched healthy controls (HC) were studied at a tertiary epilepsy center. Fractional anisotropy (FA) was calculated and intergroup differences analyzed using Tract Based Spatial Statistics (TBSS).Results: Compared to HC the JME group showed reduced FA widespread and bilateral in the longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, anterior and posterior thalamic radiation, corona radiata, corpus callosum, cingulate gyrus and external capsule (p < 0.01). Subgroup analysis revealed no significant differences of WM alterations between PPR positive and negative patients and with clinical and epilepsy-related factors.Conclusions: Widespread microstructural abnormalities among patients with JME have been identified.Prior findings of frontal and thalamofrontal microstructural abnormalities have been confirmed. Additionally, microstructural abnormalities were found in widespread extra-frontal regions that may help to validate pathophysiological concepts of JME.

Limitations in access to antipsychotic-naïve patients and in the incisiveness of studies that can be conducted on them, together with the inevitability of subsequent antipsychotic treatment, indicate an enduring role for animal models that can inform on the pathobiology of neuromotor abnormalities in schizophrenia and related psychotic illness. This review focusses particularly on genetically modified mouse models that involve genes associated with risk for schizophrenia and with mechanisms implicated in the neuromotor abnormalities evident in psychotic patients, as well as developmental models that seek to mirror the trajectory, phenomenology and putative pathophysiology of psychotic illness. Such abnormalities are inconsistent and subtle in mice mutant for some schizophrenia risk genes but more evident for others. The phenotype of dopaminergic and glutamatergic mutants indicates the involvement of these mechanisms, informs on the roles of specific receptor subtypes, and implicates the interplay of cortical and subcortical processes. Developmental models suggest a criticality in the timing of early adversity for diversity in the relative emergence of psychological symptoms vis-à-vis neuromotor abnormalities in the overall psychosis phenotype. These findings elaborate current concepts of dysfunction in a neuronal network linking the cerebral cortex, basal ganglia, thalamus and cerebellum. Both findings in model systems and clinical evidence converge in indicating that any distinction between 'psychomotor' and 'neuromotor' abnormality is artificial and arbitrary due to a unitary origin in developmentally determined systems/network dysfunction that underlies the lifetime trajectory of psychotic illness. [ABSTRACT FROM AUTHOR]

Neural network dysfunction may contribute to functional decline and disease progression in neurodegenerative disorders. Diverse lines of evidence suggest that neuronal accumulation of tau promotes network dysfunction and cognitive decline. The A152T-variant of human tau (hTau-A152T) increases the risk of Alzheimer's disease (AD) and several other tauopathies. When overexpressed in neurons of transgenic mice, it causes age-dependent neuronal loss and cognitive decline, as well as non-convulsive epileptic activity, which is also seen in patients with AD. Using intracranial EEG recordings with electrodes implanted over the parietal cortex, we demonstrate that hTau-A152T increases the power of brain oscillations in the 0.5–6 Hz range more than wildtype human tau in transgenic lines with comparable levels of human tau protein in brain, and that genetic ablation of endogenous tau in Mapt −/− mice decreases the power of these oscillations as compared to wildtype controls. Suppression of hTau-A152T production in doxycycline-regulatable transgenic mice reversed their abnormal network activity. Treatment of hTau-A152T mice with the antiepileptic drug levetiracetam also rapidly and persistently reversed their brain dysrhythmia and network hypersynchrony. These findings suggest that both the level and the sequence of tau modulate the power of specific brain oscillations. The potential of EEG spectral changes as a biomarker deserves to be explored in clinical trials of tau-lowering therapeutics. Our results also suggest that levetiracetam treatment is able to counteract tau-dependent neural network dysfunction. Tau reduction and levetiracetam treatment may be of benefit in AD and other conditions associated with brain dysrhythmias and network hypersynchrony. [ABSTRACT FROM AUTHOR]

Background: Several studies on patients with juvenilemyoclonic epilepsy (JME) showed widespread white matter (WM) abnormalities in the brain. The aim of this study was to investigate potential structural abnormalities in JME patients (1) compared to healthy controls, (2) among JME subgroups with or without photoparoxysmal responses (PPR), and (3) in correlation with clinical variables. Methods: A selection of 31 patients with JME (12 PPR positive) and 27 age and gender matched healthy controls (HC) were studied at a tertiary epilepsy center. Fractional anisotropy (FA) was calculated and intergroup differences analyzed using Tract Based Spatial Statistics (TBSS). Results: Compared to HC the JME group showed reduced FA widespread and bilateral in the longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, anterior and posterior thalamic radiation, corona radiata, corpus callosum, cingulate gyrus and external capsule (p < 0.01). Subgroup analysis revealed no significant differences of WM alterations between PPR positive and negative patients and with clinical and epilepsy-related factors. Conclusions: Widespreadmicrostructural abnormalities among patients with JME have been identified.Prior findings of frontal and thalamofrontal microstructural abnormalities have been confirmed. Additionally, microstructural abnormalities were found in widespread extra-frontal regions that may help to validate pathophysiological concepts of JME. [ABSTRACT FROM AUTHOR]

Understanding neural network dysfunction in neurodegenerative disease is imperative to effectively develop network-modulating therapies. In Alzheimer’s disease (AD), cognitive decline associates with deficits in resting-state functional connectivity of diffuse brain networks. The goal of the current study was to test whether specific cognitive impairments in AD spectrum correlate with reduced functional connectivity of distinct brain regions. We recorded resting-state functional connectivity of alpha-band activity in 27 patients with AD spectrum − 22 patients with probable AD (5 logopenic variant primary progressive aphasia, 7 posterior cortical atrophy, and 10 early-onset amnestic/dysexecutive AD) and 5 patients with mild cognitive impairment due to AD. We used magnetoencephalographic imaging (MEGI) to perform an unbiased search for regions where patterns of functional connectivity correlated with disease severity and cognitive performance. Functional connectivity measured the strength of coherence between a given region and the rest of the brain. Decreased neural connectivity of multiple brain regions including the right posterior perisylvian region and left middle frontal cortex correlated with a higher degree of disease severity. Deficits in executive control and episodic memory correlated with reduced functional connectivity of the left frontal cortex, whereas visuospatial impairments correlated with reduced functional connectivity of the left inferior parietal cortex. Our findings indicate that reductions in region-specific alpha-band resting-state functional connectivity are strongly correlated with, and might contribute to, specific cognitive deficits in AD spectrum. In the future, MEGI functional connectivity could be an important biomarker to map and follow defective networks in the early stages of AD.

There are many fearful prejudices and misunderstandings on the method of deep brain stimulation (DBS), especially in its application to neuropsychiatric diseases. Using the example of the treatment of resistant depression this article will discuss the current state of DBS in an attempt to overcome some of the prejudices and to elaborate on its potential development. The DBS is a straightforward method and has been used clinically for more than 12 years to treat some neurological diseases, such as tremor in Parkinson's disease and other movement disorders. More than 100,000 patients have already been treated worldwide using DBS which is a procedure in which electrodes are placed bilaterally in certain brain regions where they can modulate disease-related dysfunctions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is caused by the accumulation of amyloid-β (Aβ), which induces progressive decline in learning, memory, and other cognitive functions. Aβ is a neurotoxic protein that disrupts calcium signaling in neurons and alters synaptic plasticity. These effects lead to loss of synapses, neural network dysfunction, and inactivation of neuronal signaling. However, the precise mechanism by which Aβ causes neurodegeneration is still not clear, despite decades of intensive research. The role of astrocytes in early cognitive decline is a major component of disease pathology that has been poorly understood. Recent research suggests that astrocytes are not simply passive support cells for neurons, but are active participants in neural information processing in the brain. Aβ can disrupt astrocytic calcium signaling and gliotransmitter release, processes that are vital for astrocyte-neuron communication. Therefore, astrocyte dysfunction may contribute to the earliest neuronal deficits in AD. Here we discuss emerging concepts in glial biology and the implications of astrocyte dysfunction on neurodegeneration in AD. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, including Alzheimer’s disease (AD), target specific and functionally connected neuronal networks, raising the possibility that neurodegeneration may spread through abnormal patterns of neural network activity. AD is associated with high levels of amyloid-β (Aβ) peptides in the brain, synaptic depression, aberrant excitatory neuronal activity, and cognitive decline. However, the relationships among these alterations and their underlying mechanisms are poorly understood. In experimental models of AD, high concentrations of pathogenic Aβ assemblies reduce glutamatergic transmission and enhance long-term depression at the synaptic level. At the network level, they cause dysrhythmias, including neuronal synchronization, epileptiform activity, seizures, and postictal suppression. Both synaptic depression and aberrant network synchronization likely interfere with activity-dependent synaptic regulation, which is critical for learning and memory. Abnormal patterns of neuronal activity across functionally connected brain regions may also trigger and perpetuate trans-synaptic mechanisms of neurodegeneration. It remains to be determined if synaptic depression and network dysrhythmias are mechanistically related, which of them is primary or secondary, and whether normalization of one will prevent the other as well as cognitive dysfunction in AD. [ABSTRACT FROM AUTHOR]

While it has long been considered whether the pathobiology of schizophrenia extends beyond its defining symptoms to involve diverse domains of abnormality, in the manner of a systemic disease, studies of neuromotor dysfunction have been confounded by treatment with antipsychotic drugs. This challenge has been illuminated by a new generation of studies on first-episode schizophrenia before initiation of antipsychotic treatment and by opportunities in developing countries to study chronically ill patients who have remained antipsychotic naive due to limitations in provision of psychiatric care. Building from studies in antipsychotic-naive patients, this article reviews 2 domains of neuromotor dysfunction in schizophrenia: neurological signs and involuntary movements. The presence and characteristics of neurological signs in untreated vis-à-vis treated psychosis indicate a vulnerability marker for schizophrenia and implicate disruption to neuronal circuits linking the basal ganglia, cerebral cortex, and cerebellum. The presence and characteristics of involuntary movements in untreated vis-à-vis treated psychosis indicate an intrinsic feature of the disease process and implicate dysfunction in cortical-basal ganglia-cortical circuitry. These neuromotor disorders of schizophrenia join other markers of subtle but pervasive cerebral and extracerebral, systemic dysfunction, and complement current concepts of schizophrenia as a disorder of developmentally determined cortical-basal ganglia-thalamo-cortical/cerebellar network disconnectivity. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin-1β (IL-1β) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL-1β. Systemic LPS triggered microglial IL-1β, astrocytic chemokines, IL-6, and acute cognitive dysfunction, whereas IL-1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL-1β and IL-6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)