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| Gamma amplitude modulation by theta phase is impaired in a mouse model of Alzheimer's disease (AD; amyloid precursor protein 23, APP23 mice). (A) Raw EEG (LFP), band pass filtered signals for theta (4-12 Hz) and gamma (25-100 Hz) oscillations, gamma amplitude envelope (green) and theta phase in APP23 and non-transgenic (non-tg) mice (blue). Representative signals from five animals per genotype are shown. (B) Representative phase-amplitude comodulograms computed for hippocampal LFPs recorded in non-tg and APP23 mice. (C) Phase-amplitude plot computed for hippocampal LFPs recorded in non-tg and APP23 mice (means ? SEM). (D) MI computed for the phase-amplitude distributions shown in (C); * p < 0.05. Adapted from Ittner et al. (2014; Open Access).
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Alzheimer’s disease (AD) and temporal lobe epilepsy (TLE) are the most common forms of neurodegenerative disorders characterized by the loss of cells and progressive irreversible alteration of cognitive functions, such as attention and memory. AD may be an important cause of epilepsy in the elderly. Early diagnosis of diseases is very important for...
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... the AD model (adult APP23 transgenic free-roaming mice), an impairment of cross-frequency gamma amplitude modulation by hippocampal theta rhythm was observed (Ittner et al., 2014; Figure 3). It is important that these changes were observed before the onset of A? plaque pathology. Moreover, it was shown on TgCRND8 mice that a significant proportion of 1-month-old animals exhibited marked alterations in the theta-gamma coupling in the output region of the hippocampus, the subiculum. This uncoupling of rhythms arises before any histopathological abnormalities such as the presence of amyloid plaques ( Goutagny et al., 2013). In addition, it was shown that 1-month-old TgCRND8 mice expressed extremely low levels of A? compared to controls. Goutagny et al. (2013) suggested that in animals (TgCRND8 mice) disturbed theta-gamma CFC in the subiculum may be the earliest detectable AD-related biomarker. This is in contrast with the existing hypothesis, which states that the beginning of hippocampal network alterations and memory deficits in animal models of AD are caused by the overproduction of soluble A? ( Francis et al., 2010;Palop and Mucke, 2010;Scott et al., ...
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Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects a significant percentage of the elderly. EEG has emerged as a promising tool for the timely diagnosis and classification of AD or other dementia types. This paper proposes a novel approach to AD EEG classification using a Dual-Input Convolution Encoder Netw...
Citations
... Among the spectrum of the characteristic frequency bands, gamma (γ) oscillations (30-80 Hz) have been related to higher brain functions (e.g., the attentive processing of information and active maintenance of memory contents) [11][12][13]. Disturbances in γ rhythms have been reported in multiple neuropsychiatric conditions [2,14,15], even prior to symptom onset [16]. Schizophrenia (ScZ) represents a prime example of brain rhythm disruption, with γ oscillations recognized as a core substrate of clinical symptoms and cognitive deficits [17]. ...
Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms.
... Theta oscillations, crucial for working memory, can modulate local highfrequency gamma band synchronization nested within the theta cycle. Impaired theta-gamma cross-frequency coupling is implicated in various cognitive processes, including attention, learning, and memory, as well as disorders like epilepsy and Alzheimer's Disease (Goodman et al., 2018;Kitchigina, 2018;Park et al., 2020), highlighting its pathophysiological relevance in humans. Theta synchronization is also implicated in playing a role in several learning-related network processes (Likhtik et al., 2014;Chen et al., 2021). ...
Introduction
Chemogenetic techniques, specifically the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have become invaluable tools in neuroscience research. Yet, the understanding of how Gq- and Gicoupled DREADDs alter local field potential (LFP) oscillations in vivo remains incomplete.
Methods
This study investigates the in vivo electrophysiological effects of DREADD actuation by deschloroclozapine, on spontaneous firing rate and LFP oscillations recorded from the anterior cingulate cortex in lightly anesthetized male rats.
Results
Unexpectedly, in response to the administration of deschloroclozapine, we observed inhibitory effects with pan-neuronal hM3D(Gq) stimulation, and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons. These results emphasize the need to account for indirect perturbation effects at the local neuronal network level in vivo, particularly when not all neurons express the chemogenetic receptors uniformly. In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic. Moreover, we found that panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity, presenting a potential research tool or therapeutic strategy in several neuropsychiatric models and diseases.
Discussion
These findings help to optimize the use of chemogenetic techniques in neuroscience research and open new possibilities for novel therapeutic strategies.
... Abnormal communication in the prefrontal-hippocampal pathway may be involved in the occurrence of seizures 4-6 and has been suggested as a marker for TLE. 40,41 In addition, the occurrence of epileptiform discharges may disconnect the hippocampal-cortical coupling, thereby impairing the cognitive domains, such as learning and memory, in epilepsy patients. 42 The connection between the hippocampus and prefrontal cortex is essential for memory function. ...
Aims
In this study, the anticonvulsant action of closed‐loop, low‐frequency deep brain stimulation (DBS) was investigated. In addition, the changes in brain rhythms and functional connectivity of the hippocampus and prefrontal cortex were evaluated.
Methods
Epilepsy was induced by pilocarpine in male Wistar rats. After the chronic phase, a tripolar electrode was implanted in the right ventral hippocampus and a monopolar electrode in medial prefrontal cortex (mPFC). Subjects' spontaneous seizure behaviors were observed in continuous video recording, while the local field potentials (LFPs) were recorded simultaneously. In addition, spatial memory was evaluated by the Barnes maze test.
Results
Applying hippocampal DBS, immediately after seizure detection in epileptic animals, reduced their seizure severity and duration, and improved their performance in Barnes maze test. DBS reduced the increment in power of delta, theta, and gamma waves in pre‐ictal, ictal, and post‐ictal periods. Meanwhile, DBS increased the post‐ictal‐to‐pre‐ictal ratio of theta band. DBS decreased delta and increased theta coherences, and also increased the post‐ictal‐to‐pre‐ictal ratio of coherence. In addition, DBS increased the hippocampal‐mPFC coupling in pre‐ictal period and decreased the coupling in the ictal and post‐ictal periods.
Conclusion
Applying closed‐loop, low‐frequency DBS at seizure onset reduced seizure severity and improved memory. In addition, the changes in power, coherence, and coupling of the LFP oscillations in the hippocampus and mPFC demonstrate low‐frequency DBS efficacy as an antiepileptic treatment, returning LFPs to a seemingly non‐seizure state in subjects that received DBS.
... Finally, we likened conditions of low theta input to pathological states characteristic of oscillopathies such as Alzheimer's disease, as these conditions disrupted all aspects of theta-gamma oscillations in our model: theta power, gamma power, and theta-gamma PAC ( Figure 5). However, it should be noted that changes in theta or gamma power in these pathologies are often unclear, and that the most consistent alteration that has been reported in Alzheimer's disease is a reduction of thetagamma PAC (for review, see Kitchigina, 2018). Future work should explore the effects of cellular alterations intrinsic to the hippocampal formation and their impact on theta-gamma oscillations. ...
Neurostimulation of the hippocampal formation has shown promising results for modulating memory but the underlying mechanisms remain unclear. In particular, the effects on hippocampal theta-nested gamma oscillations and theta phase reset, which are both crucial for memory processes, are unknown. Moreover, these effects cannot be investigated using current computational models, which consider theta oscillations with a fixed amplitude and phase velocity. Here, we developed a novel computational model that includes the medial septum, represented as a set of abstract Kuramoto oscillators producing a dynamical theta rhythm with phase reset, and the hippocampal formation, composed of biophysically realistic neurons and able to generate theta-nested gamma oscillations under theta drive. We showed that, for theta inputs just below the threshold to induce self-sustained theta-nested gamma oscillations, a single stimulation pulse could switch the network behavior from non-oscillatory to a state producing sustained oscillations. Next, we demonstrated that, for a weaker theta input, pulse train stimulation at the theta frequency could transiently restore seemingly physiological oscillations. Importantly, the presence of phase reset influenced whether these two effects depended on the phase at which stimulation onset was delivered, which has practical implications for designing neurostimulation protocols that are triggered by the phase of ongoing theta oscillations. This novel model opens new avenues for studying the effects of neurostimulation on the hippocampal formation. Furthermore, our hybrid approach that combines different levels of abstraction could be extended in future work to other neural circuits that produce dynamical brain rhythms.
... PAC refers to the modulation of the amplitude of high-frequency components of electrophysiological signals by the phase of lowfrequency components (Özkurt, 2012). During animal engagement in spatial learning and navigation, research has shown a notable enhancement in theta-gamma PAC power (Kitchigina, 2018). Consequently, the strength of theta-gamma coupling within the hippocampus is typically associated with accurate performance in cognitive tasks. ...
Introduction
In our study, we applied transcranial magneto-acoustic stimulation (TMAS), a technique based on focused ultrasound stimulation within a static magnetic field, in the APP/PS1 mouse model of Alzheimer's disease (AD) to explore the feasibility of TMAS on improving AD related spatial memory deficits and abnormal neural oscillations.
Methods
The mice treated with TMAS once daily for 21 days. We recorded local field potential signals in the hippocampal CA1 region of the mice after TMAS treatment with in-vivo electrophysiology and evaluated the neural rehabilitative effect of TMAS with sharp-wave ripple (SWR), gamma oscillations during SWRs, and phase-amplitude coupling (PAC). The spatial memory function of the mice was examined by the Morris water maze (MWM) task.
Results
We found that TMAS improved the performance of MWM related spatial cognitive functions compared with AD group. Furthermore, our results implied that TMAS alleviated abnormalities in hippocampal SWRs, increased slow gamma power during SWRs, and promoted theta-slow gamma phase-amplitude coupling. These findings suggest that TMAS could have a positive influence on spatial memory through the modulation of neural oscillations.
Discussion
This work emphasizes the potential of TMAS to serve as a non-invasive method for Alzheimer's disease rehabilitation and promote the application of TMAS for the treatment of more neurological and brain aging diseases in the future.
... Second, we focused on θ oscillations since research strongly supports its involvement in WM across neurodegeneration , and social processing van der Velde et al., 2021). However, future works should also target alpha/gamma oscillations and cross-frequency coupling also related to WM and reported impaired in neurodegenerative conditions Kitchigina, 2018). Third, beyond the novel contributions of convergent rsEEG and rsfMRI methodologies across multiple neurodegenerative models, future works should also include active paradigms to better elucidate brain networks directly engaged in social WM modulation. ...
Although social functioning relies on working memory, whether a social-specific mechanism exists remains unclear. This undermines the characterization of neurodegenerative conditions with both working memory and social deficits. We assessed working memory domain-specificity across behavioral, electrophysiological, and neuroimaging dimensions in 245 participants. A novel working memory task involving social and non-social stimuli with three load levels was assessed across controls and different neurodegenerative conditions with recognized impairments in: working memory and social cognition (behavioral-variant frontotemporal dementia); general cognition (Alzheimer's disease); and unspecific patterns (Parkinson's disease). We also examined resting-state theta oscillations and functional connectivity correlates of working memory domain-specificity. Results in controls and all groups together evidenced increased working memory demands for social stimuli associated with frontocinguloparietal theta oscillations and salience network connectivity. Canonical frontal theta oscillations and executive-default mode network anticorrelation indexed non-social stimuli. Behavioral-variant frontotemporal dementia presented generalized working memory deficits related to posterior theta oscillations, with social stimuli linked to salience network connectivity. In Alzheimer's disease, generalized working memory impairments were related to temporoparietal theta oscillations, with non-social stimuli linked to the executive network. Parkinson's disease showed spared working memory performance and canonical brain correlates. Findings support a social-specific working memory and related disease-selective pathophysiological mechanisms.
... The strength of this coupling has been shown to be increased during learning. Moreover, the PAC strength is also directly correlated with an increased chance of correctly performing a cognitive task, suggesting that PAC improves the transfer of information in the brain (Tort et al., 2009(Tort et al., , 2010Fell and Axmacher, 2011;Kitchigina, 2018). In patients with AD-related dementia and mild cognitive impairment (MCI), a decreased theta-gamma PAC was observed when compared with healthy subjects, which worsened as the disease progressed (Goodman et al., 2018). ...
... The PAC between theta and high gamma (60-130 Hz) is thought to be important for sensory processing and memory encoding (Belluscio et al., 2012;Newman et al., 2013;Bieri et al., 2014). Electrophysiological experiments in the hippocampus of healthy rats, and in the non-epileptogenic hippocampus of patients have shown that the strength of the theta-gamma PAC will increase during learning (Tort et al., 2008(Tort et al., , 2009Kitchigina, 2018). It seems that the theta-gamma PAC strength is correlated directly with the increase in correctly performing a cognitive task and that the temporal coordination of neural spikes by theta-gamma PAC improves the transfer of information in the brain (Tort et al., 2009;Fell and Axmacher, 2011;Kitchigina, 2018). ...
... Electrophysiological experiments in the hippocampus of healthy rats, and in the non-epileptogenic hippocampus of patients have shown that the strength of the theta-gamma PAC will increase during learning (Tort et al., 2008(Tort et al., , 2009Kitchigina, 2018). It seems that the theta-gamma PAC strength is correlated directly with the increase in correctly performing a cognitive task and that the temporal coordination of neural spikes by theta-gamma PAC improves the transfer of information in the brain (Tort et al., 2009;Fell and Axmacher, 2011;Kitchigina, 2018). Moreover, increased PAC between low theta oscillations and both low and fast gamma oscillations in the HC during memory retrieval is also correlated with (memory) task performance (Vivekananda et al., 2021). ...
Alzheimer’s disease (AD) is a severe neurodegenerative disorder caused by the accumulation of toxic proteins, amyloid-beta (Aβ) and tau, which eventually leads to dementia. Disease-modifying therapies are still lacking, due to incomplete insights into the neuropathological mechanisms of AD. Synaptic dysfunction is known to occur before cognitive symptoms become apparent and recent studies have demonstrated that imbalanced synaptic signaling drives the progression of AD, suggesting that early synaptic dysfunction could be an interesting therapeutic target. Synaptic dysfunction results in altered oscillatory activity, which can be detected with electroencephalography and electrophysiological recordings. However, the majority of these studies have been performed at advanced stages of AD, when extensive damage and cognitive symptoms are already present. The current study aimed to investigate if the hippocampal oscillatory activity is altered at pre-plaque stages of AD. The rats received stereotactic surgery to implant a laminar electrode in the CA1 layer of the right hippocampus. Electrophysiological recordings during two consecutive days in an open field were performed in 4–5-month-old TgF344-AD rats when increased concentrations of soluble Aβ species were observed in the brain, in the absence of Aβ-plaques. We observed a decreased power of high theta oscillations in TgF344-AD rats compared to wild-type littermates. Sharp wave-ripple (SWR) analysis revealed an increased SWR power and a decreased duration of SWR during quiet wake in TgF344-AD rats. The alterations in properties of SWR and the increased power of fast oscillations are suggestive of neuronal hyperexcitability, as has been demonstrated to occur during presymptomatic stages of AD. In addition, decreased strength of theta-gamma coupling, an important neuronal correlate of memory encoding, was observed in the TgF344-AD rats. Theta-gamma phase amplitude coupling has been associated with memory encoding and the execution of cognitive functions. Studies have demonstrated that mild cognitive impairment patients display decreased coupling strength, similar to what is described here. The current study demonstrates altered hippocampal network activity occurring at pre-plaque stages of AD and provides insights into prodromal network dysfunction in AD. The alterations observed could aid in the detection of AD during presymptomatic stages.
... Other oscillatory disruptions have been observed as well, including disruptions to both gamma and theta band activity (Kitchigina, 2018;Traikapi and Konstantinou, 2021). For example, some studies have observed a loss in both theta and gamma power, whereas other studies have suggested an increase in theta power with a loss of gamma power (Adler et al., 2003;Moretti et al., 2010;Kitchigina, 2018;Traikapi and Konstantinou, 2021). ...
... Other oscillatory disruptions have been observed as well, including disruptions to both gamma and theta band activity (Kitchigina, 2018;Traikapi and Konstantinou, 2021). For example, some studies have observed a loss in both theta and gamma power, whereas other studies have suggested an increase in theta power with a loss of gamma power (Adler et al., 2003;Moretti et al., 2010;Kitchigina, 2018;Traikapi and Konstantinou, 2021). Oscillatory coupling between these two frequencies is also important for learning and memory tasks, and memory transfer (Düzel et al., 2010). ...
The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer’s disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer’s disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer’s disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer’s disease, and what we know from Alzheimer’s disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer’s disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer’s disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer’s disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer’s disease. The synapse will certainly continue to be an important target within Alzheimer’s disease for the foreseeable future.
... Interestingly, recordings of single units and local field potentials in animals have showed a match between neocortical gamma power and hippocampal theta phase, further indicating the entrainment of neocortical neuron ensembles to highfrequency oscillations by low-frequency oscillations [75,76]. In fact, alterations in theta-gamma cross-frequency coupling are now considered a biomarker of neurologic conditions that share GABAergic dysfunction, especially Alzheimer's disease and epilepsy [77,78]. Notwithstanding the potential effect of AEDs on theta spectral power as previously mentioned, this observation raises questions regarding a potential effect of DEPDC5 and NPRL3 mutations on the coupling of theta and gamma activities leading to a failure in the functions they support With this in mind, and accounting for the nature and main features of mTORopathies, it can be hypothesized that although mutations in the GATOR1 genes do not directly affect GABAergic functions at the synaptic level, they likely promote electrophysiological changes within neuron ensembles, including GABAergic circuits, through increased mTORC1 activity, resulting in cortical hyperexcitability driven by hippocampal-neocortical interactions [79]. ...
Background:
Mutations in the GATOR1 complex genes, DEPDC5 and NPRL3, play a major role in the development of lesional and non-lesional focal epilepsy through increased mTORC1 signalling. We aimed to assess the effects of mTORC1 hyperactivation on GABAergic inhibitory circuits, in 3 and 5 individuals carrying DEPDC5 and NPRL3 mutations respectively using a multimodal approach including transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy (MRS), and electroencephalography (EEG).
Results:
Inhibitory functions probed by TMS and MRS showed no effect of mutations on cortical GABAergic receptor-mediated inhibition and GABA concentration, in both cortical and subcortical regions. However, stronger EEG theta oscillations and stronger and more synchronous gamma oscillations were observed in DEPDC5 and NPRL3 mutations carriers.
Conclusions:
These results suggest that DEPDC5 and NPRL3-related epileptic mTORopathies may not directly modulate GABAergic functions but are nonetheless characterized by a stronger neural entrainment that may be reflective of a cortical hyperexcitability mediated by increased mTORC1 signaling.
... Memory disorders occur when a part of this episodic memory circuit gets disrupted. This finding has been supported by a large body of evidence showing structural and functional disconnections between nodes of the large-scale episodic memory network in neurodegenerative diseases 158,159 , posttraumatic amnesia 160 and other forms of memory disorders 161 . For example, the EC is one of the first areas to be affected in the early stages of AD, even before the first symptoms are diagnosed, and plays a key role in the communication between neocortical areas and the hippocampus 162 . ...
... Such alterations in theta and gamma rhythms and their CFC have been observed in AD and temporal lobe epilepsy 161 . A long history of EEG studies in patients with AD has shown an increase in low-frequency delta and theta rhythms, and a decrease in faster alpha and beta rhythms 163 . ...
... Despite the variability and relative scarcity of human studies on this topic, the changes in theta and gamma rhythms, as well as their CFC, have also been thoroughly investigated in animal models of AD. The results in individual theta and gamma rhythms were not quite conclusive in these models or did not mirror the observations in patients 161 , but a reduced thetagamma CFC was consistently observed in several transgenic mouse models of AD 159,[170][171][172] . Only one study has found an opposite trend in a rat model of hyperglycemia, which is a risk factor for AD 173 . ...
Neuroprosthetics is a multidisciplinary field at the interface between neurosciences and biomedical engineering, which aims at replacing or modulating parts of the nervous system that get disrupted in neurological disorders or after injury. Although neuroprostheses have steadily evolved over the past 60 years in the field of sensory and motor disorders, their application to higher-order cognitive functions is still at a relatively preliminary stage. Nevertheless, a recent series of proof-of-concept studies suggest that electrical neuromodulation strategies might also be useful in alleviating some cognitive and memory deficits, in particular in the context of dementia. Here, we review the evolution of neuroprosthetics from sensorimotor to cognitive disorders, highlighting important common principles such as the need for neuroprosthetic systems that enable multisite bidirectional interactions with the nervous system. This state-of-the-art Review highlights the evolution of neuromodulation and neuroprosthetic systems from sensorimotor to cognitive disorders.
