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BioRxiv : the Preprint Server For... May 2024Astrocytes use Ca signals to regulate multiple aspects of normal and pathological brain function. Astrocytes display context-specific diversity in their functions, and...
Astrocytes use Ca signals to regulate multiple aspects of normal and pathological brain function. Astrocytes display context-specific diversity in their functions, and in their response to noxious stimuli between brain regions. Indeed, astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on their ATP generation and Ca buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca signaling in astrocytes, the extent of this regulation into the rich diversity of astrocytes in different brain regions remains largely unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for proper astrocyte function, however, few insights into possible diverse responses to this noxious stimulus from astrocytes in different brain areas were reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI, which expresses the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two distinct brain regions, the dorsolateral striatum, and the hippocampal dentate gyrus, and we show that Mito-PstI can induce astrocytic mtDNA loss , but with remarkable brain-region-dependent differences on mitochondrial dynamics, spontaneous Ca fluxes and astrocytic as well as microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca signaling in a brain-region-selective manner.
PubMed: 38853966
DOI: 10.1101/2024.05.29.596517 -
BioRxiv : the Preprint Server For... May 2024We currently lack a robust noninvasive method to measure prefrontal excitability in humans. Concurrent TMS and EEG in the prefrontal cortex is usually confounded by...
OBJECTIVE
We currently lack a robust noninvasive method to measure prefrontal excitability in humans. Concurrent TMS and EEG in the prefrontal cortex is usually confounded by artifacts. Here we asked if real-time optimization could reduce artifacts and enhance a TMS-EEG measure of left prefrontal excitability.
METHODS
This closed-loop optimization procedure adjusts left dlPFC TMS coil location, angle, and intensity in real-time based on the EEG response to TMS. Our outcome measure was the left prefrontal early (20-60 ms) and local TMS-evoked potential (EL-TEP).
RESULTS
In 18 healthy participants, this optimization of coil angle and brain target significantly reduced artifacts by 63% and, when combined with an increase in intensity, increased EL-TEP magnitude by 75% compared to a non-optimized approach.
CONCLUSIONS
Real-time optimization of TMS parameters during dlPFC stimulation can enhance the EL-TEP.
SIGNIFICANCE
Enhancing our ability to measure prefrontal excitability is important for monitoring pathological states and treatment response.
PubMed: 38853941
DOI: 10.1101/2024.05.29.596317 -
Journal of Psychopharmacology (Oxford,... Jun 2024A better understanding of the mechanisms underlying cognitive impairment in schizophrenia is imperative, as it causes poor functional outcomes and a lack of effective...
BACKGROUND
A better understanding of the mechanisms underlying cognitive impairment in schizophrenia is imperative, as it causes poor functional outcomes and a lack of effective treatments.
AIMS
This study aimed to investigate the relationships of two proposed main pathophysiology of schizophrenia, altered prefrontal-striatal connectivity and the dopamine system, with cognitive impairment and their interactions.
METHODS
Thirty-three patients with schizophrenia and 27 healthy controls (HCs) who are right-handed and matched for age and sex were recruited. We evaluated their cognition, functional connectivity (FC) between the dorsolateral prefrontal cortex (DLPFC)/middle frontal gyrus (MiFG) and striatum, and the availability of striatal dopamine transporter (DAT) using a cognitive battery investigating attention, memory, and executive function, resting-state functional magnetic resonance imaging with group independent component analysis and single-photon emission computed tomography with 99mTc-TRODAT.
RESULTS
Patients with schizophrenia exhibited poorer cognitive performance, reduced FC between DLPFC/MiFG and the caudate nucleus (CN) or putamen, decreased DAT availability in the left CN, and decreased right-left DAT asymmetry in the CN compared to HCs. In patients with schizophrenia, altered imaging markers are associated with cognitive impairments, especially the relationship between DLPFC/MiFG-putamen FC and attention and between DAT asymmetry in the CN and executive function.
CONCLUSIONS
This study is the first to demonstrate how prefrontal-striatal hypoconnectivity and altered striatal DAT markers are associated with different domains of cognitive impairment in schizophrenia. More research is needed to evaluate their complex relationships and potential therapeutic implications.
Topics: Humans; Male; Female; Schizophrenia; Adult; Cognitive Dysfunction; Magnetic Resonance Imaging; Tomography, Emission-Computed, Single-Photon; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dopamine; Prefrontal Cortex; Dorsolateral Prefrontal Cortex; Case-Control Studies; Middle Aged; Executive Function; Neuropsychological Tests; Young Adult
PubMed: 38853592
DOI: 10.1177/02698811241257877 -
Philosophical Transactions of the Royal... Jul 2024Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether...
Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)-a tract important to induce PAS-LTP-were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Humans; Alzheimer Disease; Male; Aged; Female; Dorsolateral Prefrontal Cortex; Long-Term Potentiation; Neuronal Plasticity; Aged, 80 and over; Middle Aged; Electroencephalography; Magnetic Resonance Imaging; Prefrontal Cortex
PubMed: 38853564
DOI: 10.1098/rstb.2023.0233 -
Neurobiology of Disease Aug 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Topics: Animals; Dyskinesia, Drug-Induced; Levodopa; Oxidopamine; Mice; Male; Mice, Inbred C57BL; Serotonin 5-HT4 Receptor Agonists; Antiparkinson Agents; Corpus Striatum; Receptors, Serotonin, 5-HT4; Parkinsonian Disorders; Pyridines; Neurons; Piperidines; Pyrimidines
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559 -
Psychiatry Research Aug 2024The use of methamphetamine in the United States is increasing, contributing now to the "fourth wave" in the national opioid epidemic crisis. People who suffer from... (Review)
Review
The use of methamphetamine in the United States is increasing, contributing now to the "fourth wave" in the national opioid epidemic crisis. People who suffer from methamphetamine use disorder (MUD) have a higher risk of death. No pharmacological interventions are approved by the FDA and psychosocial interventions are only moderately effective. Transcranial Magnetic Stimulation (TMS) is a relatively novel FDA-cleared intervention for the treatment of Major Depressive Disorder (MDD) and other neuropsychiatric conditions. Several lines of research suggest that TMS could be useful for the treatment of addictive disorders, including MUD. We will review those published clinical trials that show potential effects on craving reduction of TMS when applied over the dorsolateral prefrontal cortex (DLPFC) also highlighting some limitations that affect their generalizability and applicability. We propose the use of the Koob and Volkow's neurocircuitry model of addiction as a frame to explain the brain effects of TMS in patients with MUD. We will finally discuss new venues that could lead to a more individualized and effective treatment of this complex disorder including the use of neuroimaging, the exploration of different areas of the brain such as the frontopolar cortex or the salience network and the use of biomarkers.
Topics: Humans; Transcranial Magnetic Stimulation; Amphetamine-Related Disorders; Methamphetamine; Dorsolateral Prefrontal Cortex; Craving; Behavior, Addictive
PubMed: 38852478
DOI: 10.1016/j.psychres.2024.115995 -
NeuroImage Jun 2024Brain disorders are often associated with changes in brain structure and function, where functional changes may be due to underlying structural variations. Gray matter...
Brain disorders are often associated with changes in brain structure and function, where functional changes may be due to underlying structural variations. Gray matter (GM) volume segmentation from 3D structural MRI offers vital structural information for brain disorders like schizophrenia, as it encompasses essential brain tissues such as neuronal cell bodies, dendrites, and synapses, which are crucial for neural signal processing and transmission; changes in GM volume can thus indicate alterations in these tissues, reflecting underlying pathological conditions. In addition, the use of the ICA algorithm to transform high-dimensional fMRI data into functional network connectivity (FNC) matrices serves as an effective carrier of functional information. In our study, we introduce a new generative deep learning architecture, the conditional efficient vision transformer generative adversarial network (cEViT-GAN), which adeptly generates FNC matrices conditioned on GM to facilitate the exploration of potential connections between brain structure and function. We developed a new, lightweight self-attention mechanism for our ViT-based generator, enhancing the generation of refined attention maps critical for identifying structural biomarkers based on GM. Our approach not only generates high quality FNC matrices with a Pearson correlation of 0.74 compared to real FNC data, but also uses attention map technology to identify potential biomarkers in GM structure that could lead to functional abnormalities in schizophrenia patients. Visualization experiments within our study have highlighted these structural biomarkers, including the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DL-PFC), and cerebellum. In addition, through cross-domain analysis comparing generated and real FNC matrices, we have identified functional connections with the highest correlations to structural information, further validating the structure-function connections. This comprehensive analysis helps to understand the intricate relationship between brain structure and its functional manifestations, providing a more refined insight into the neurobiological research of schizophrenia.
PubMed: 38851549
DOI: 10.1016/j.neuroimage.2024.120674 -
Neuroscience Jun 2024Previous studies on the chess game demonstrated that chess experts strongly rely on the activation of memory chunks to manifest accurate decision-making. Although the...
Previous studies on the chess game demonstrated that chess experts strongly rely on the activation of memory chunks to manifest accurate decision-making. Although the chunk memory might be affected by temporal constraints, it is unclear why the performance of chess experts is not significantly dropped under time pressure. In this study, our objective is to examine the variations in cognitive neural mechanisms between chess experts and novices under time pressure. The underlying cognitive neural mechanism was carefully inspected by accessing the chess game performance between 20 local experienced and 20 inexperienced chess players with 1-minute and 5-minute time constraints. In addition, functional near-infrared spectroscopy (fNIRS) recordings were carried out for each individual from the two groups while playing a 1-minute or 5-minute chess game. It was discovered that under temporal constraints, players exhibited different patterns of functional connectivity in frontal-parietal regions, suggesting that temporal stress can enhance segmentation processes in chess games. In particular, the experienced group exhibited significantly enhanced functional connectivity networks under time pressure including the dorsolateral prefrontal cortex, inferior frontal gyrus, supramarginal gyrus, and postcentral gyrus, which demonstrated the important role of the segmentation process for experienced players under time pressure. Our study found that experienced players were able to enhance recall, reorganize, and integrate chunks to improve chess performance under time pressure.
PubMed: 38851380
DOI: 10.1016/j.neuroscience.2024.05.026 -
Brain and Cognition Aug 2024Children reared in institutional settings experience early deprivation that has lasting implications for multiple aspects of neurocognitive functioning, including...
Children reared in institutional settings experience early deprivation that has lasting implications for multiple aspects of neurocognitive functioning, including executive function (EF). Changes in brain development are thought to contribute to these persistent EF challenges, but little research has used fMRI to investigate EF-related brain activity in children with a history of early deprivation. This study examined behavioral and neural data from a response conflict task in 12-14-year-olds who spent varying lengths of time in institutional care prior to adoption (N = 84; age at adoption - mean: 15.85 months, median: 12 months, range: 4-60 months). In initial analyses, earlier- and later-adopted (EA, LA) youth were compared to a group of children raised in their biological families (non-adopted, NA). NA youth performed significantly more accurately than LA youth, with EA youth falling in between. Imaging data suggested that previously institutionalized (PI) youth activated additional frontoparietal regions, including dorsolateral prefrontal cortex, as compared to NA youth. In addition, EA youth uniquely activated medial prefrontal regions, and LA uniquely activated parietal regions during this task. A separate analysis in a larger group of PI youth examined whether behavioral or brain measures of EF varied with the duration of deprivation experienced. Duration of deprivation was negatively associated with activation of default mode network (DMN) regions. Overall, results suggest that there are lasting effects of deprivation on EF, but that those who are removed from institutional care earlier may be able to recruit additional neural resources as a compensatory mechanism.
Topics: Humans; Executive Function; Female; Male; Child; Adolescent; Magnetic Resonance Imaging; Child, Institutionalized; Adoption; Brain; Psychosocial Deprivation; Child, Preschool
PubMed: 38850899
DOI: 10.1016/j.bandc.2024.106183 -
Psychiatry Research Aug 2024The depression response trajectory after a course of repetitive transcranial magnetic stimulation(rTMS) remains understudied. We searched for blinded randomized... (Meta-Analysis)
Meta-Analysis Review
The depression response trajectory after a course of repetitive transcranial magnetic stimulation(rTMS) remains understudied. We searched for blinded randomized controlled trials(RCTs) that examined conventional rTMS over left dorsolateral prefrontal cortex(DLPFC) for major depressive episodes(MDE). The effect size was calculated as the difference in depression improvement, between active and sham rTMS. We conducted a random-effects dose-response meta-analysis to model the response trajectory from the beginning of rTMS to the post-treatment follow-up phase. The area under curve (AUC) of the first 8-week response trajectory was calculated to compare antidepressant efficacy between different rTMS protocols. We included 40 RCTs(n = 2012). The best-fitting trajectory model exhibited a logarithmic curve(X=17.7, P < 0.001), showing a gradual ascent with tapering off around the 3-4th week mark and maintaining until week 16. The maximum effect size was 6.1(95 %CI: 1.25-10.96) at week 16. The subgroup analyses showed distinct trajectories across different rTMS protocols. Besides, the comparisons of AUC showed that conventional rTMS protocols with more pulse/session group or more total pulses were associated with greater efficacy than those with fewer pulse/session or fewer total pulses, respectively. A course of conventional left DLPFC rTMS could lead to both acute antidepressant effects and sustained after-effects, which were modeled by different rTMS protocols in MDE.
Topics: Humans; Depressive Disorder, Major; Transcranial Magnetic Stimulation; Dorsolateral Prefrontal Cortex; Prefrontal Cortex; Randomized Controlled Trials as Topic
PubMed: 38850891
DOI: 10.1016/j.psychres.2024.115979