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Neurotherapeutics : the Journal of the... Jun 2024Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique for modulating cortical activities and improving neural plasticity....
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique for modulating cortical activities and improving neural plasticity. Several studies investigated the effects of rTMS, etc., but the results are inconsistent. This study was designed to examine whether rTMS applied on the left dorsolateral prefrontal cortex (l-DLPFC) showed an effect on improving cognitive deficits in SZ and whether the early efficacy could predict efficacy at subsequent follow-ups. Cognitive ability was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale at baseline, weeks 2, 6, and 24. We found a significant interaction between time (weeks 0, 2, 6, and 24) and intervention on immediate memory and RBANS total scores (p = 0.02 and p = 0.04), indicating that both 10-Hz and 20-Hz rTMS stimulations had a delayed beneficial effect on immediate memory in SZ. Moreover, we found that 20-Hz rTMS stimulation, but not 10-Hz rTMS improved immediate memory at week 6 compared to the sham group (p = 0.029). More importantly, improvements in immediate memory at week 2 were positively correlated with improvements at week 24 (β = 0.461, t = 3.322, p = 0.002). Our study suggests that active rTMS was beneficial for cognitive deficits in patients with SZ. Furthermore, efficacy at week 2 could predict the subsequent efficacy at 24-week follow-up.
PubMed: 38944636
DOI: 10.1016/j.neurot.2024.e00392 -
Biological Psychiatry Jun 2024Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and... (Review)
Review
Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction and the thoughtful regulation of attention, action and emotion. For example, schizophrenia, depression, long-COVID and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often focused in layer III. The dlPFC has extensive top-down projections: e.g. to the posterior association cortices to regulate attention, and the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state, and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors in most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research, and are summarized in this review. For example, the layer III dlPFC circuits generating working memory-related neuronal firing have unusual neurotransmission, depending on NMDAR and nicotinic-α7R actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α2A-AR and mGluR3 signaling, but dysregulated by inflammation and/or chronic stress exposure, contributing to spine loss. Treatments that strengthen dlPFC, via pharmacological (the α2A-AR agonist, guanfacine) or rTMS manipulation, provide a rational basis for therapy.
PubMed: 38944141
DOI: 10.1016/j.biopsych.2024.06.016 -
Brain Structure & Function Jun 2024In this novel large-scale multiplexed immunofluorescence study we comprehensively characterized and compared layer-specific proteomic features within regions of interest...
In this novel large-scale multiplexed immunofluorescence study we comprehensively characterized and compared layer-specific proteomic features within regions of interest of the widely divergent dorsolateral prefrontal cortex (A46) and primary visual cortex (A17) of adult rhesus monkeys. Twenty-eight markers were imaged in rounds of sequential staining, and their spatial distribution precisely quantified within gray matter layers and superficial white matter. Cells were classified as neurons, astrocytes, oligodendrocytes, microglia, or endothelial cells. The distribution of fibers and blood vessels were assessed by quantification of staining intensity across regions of interest. This method revealed multivariate similarities and differences between layers and areas. Protein expression in neurons was the strongest determinant of both laminar and regional differences, whereas protein expression in glia was more important for intra-areal laminar distinctions. Among specific results, we observed a lower glia-to-neuron ratio in A17 than in A46 and the pan-neuronal markers HuD and NeuN were differentially distributed in both brain areas with a lower intensity of NeuN in layers 4 and 5 of A17 compared to A46 and other A17 layers. Astrocytes and oligodendrocytes exhibited distinct marker-specific laminar distributions that differed between regions; notably, there was a high proportion of ALDH1L1-expressing astrocytes and of oligodendrocyte markers in layer 4 of A17. The many nuanced differences in protein expression between layers and regions observed here highlight the need for direct assessment of proteins, in addition to RNA expression, and set the stage for future protein-focused studies of these and other brain regions in normal and pathological conditions.
PubMed: 38943018
DOI: 10.1007/s00429-024-02819-y -
Scientific Reports Jun 2024Sporting experience plays a pivotal role in shaping exercise habits, with a mutually reinforcing relationship that enhances cognitive performance. The acknowledged...
Sporting experience plays a pivotal role in shaping exercise habits, with a mutually reinforcing relationship that enhances cognitive performance. The acknowledged plasticity of cognition driven by sports necessitates a comprehensive examination. Hence, this study delves into the dynamic intricacies of the prefrontal cortex, exploring the impact of orienteering experience on cognitive performance. Our findings contribute empirical evidence regarding the functional activation of specific brain regions bridging the nexus between experiential factors and cognitive capabilities. In this cross-sectional study, a cohort of forty-nine athletes was enrolled to meticulously examine behavioral variances and prefrontal cortex dynamics among orienteering athletes of varying experience levels across diverse non-specialized scenarios. These investigations involved the utilization of functional near-infrared spectroscopy (fNIRS) to detect alterations in oxygenated hemoglobin (HbO2). The high-experience expert group exhibited neurological efficiency, demonstrating significantly diminished brain activation in the dorsolateral prefrontal, left ventral lateral prefrontal, and right orbitofrontal regions compared to the low-experience group. Within the low-experience novice group, superior performance in the spatial memory task was observed compared to the mental rotation task, with consistently lower reaction times across all conditions compared to the high-experience group. Notably, cerebral blood oxygenation activation exhibited a significant reduction in the high-experience expert group compared to the low-experience novice group, irrespective of task type. The dorsolateral prefrontal lobe exhibited activation upon task onset, irrespective of experience level. Correct rates in the spatial memory task were consistently higher than those in the mental rotation task, while brain region activation was significantly greater during the mental rotation task than the spatial memory task." This study elucidates disparities in prefrontal cortex dynamics between highly seasoned experts and neophyte novices, showcasing a cognitive edge within the highly experienced cohort and a spatial memory advantage in the inexperienced group. Our findings contribute to the comprehension of the neural mechanisms that underlie the observed cognitive advantage and provide insights into the forebrain resources mobilized by orienteering experience during spatial cognitive tasks."
Topics: Humans; Prefrontal Cortex; Spectroscopy, Near-Infrared; Cognition; Male; Female; Cross-Sectional Studies; Adult; Young Adult; Athletes; Brain Mapping; Oxyhemoglobins
PubMed: 38942820
DOI: 10.1038/s41598-024-65747-1 -
Neurobiology of Disease Jun 2024Human beings are living longer than ever before and aging is accompanied by an increased incidence of motor deficits, including those associated with the...
Human beings are living longer than ever before and aging is accompanied by an increased incidence of motor deficits, including those associated with the neurodegenerative conditions, Parkinson's disease (PD) and Huntington's disease (HD). However, the biological correlates underlying this epidemiological finding, especially the functional basis at the synapse level, have been elusive. This study reveals that motor skill performance examined via rotarod, beam walking and pole tests is impaired in aged mice. This study, via electrophysiology recordings, further identifies an aging-related reduction in the efficacy of inhibitory synaptic transmission onto dorsolateral striatum (DLS) indirect-pathway medium spiny neurons (iMSNs), i.e., a disinhibition effect on DLS iMSNs. In addition, pharmacologically enhancing the activity of DLS iMSNs by infusing an adenosine A receptor (AR) agonist, which presumably mimics the disinhibition effect, impairs motor skill performance in young mice, simulating the behavior in aged naïve mice. Conversely, pharmacologically suppressing the activity of DLS iMSNs by infusing an AR antagonist, in order to offset the disinhibition effect, restores motor skill performance in aged mice, mimicking the behavior in young naïve mice. In conclusion, this study identifies a functional inhibitory synaptic plasticity in DLS iMSNs that likely contributes to the aging-related motor skill deficits, which would potentially serve as a striatal synaptic basis underlying age being a prominent risk factor for neurodegenerative motor deficits.
PubMed: 38942325
DOI: 10.1016/j.nbd.2024.106582 -
NeuroImage Jun 2024Under resource distribution context, individuals have a strong aversion to unfair treatment not only toward themselves but also toward others. However, there is no clear... (Review)
Review
Under resource distribution context, individuals have a strong aversion to unfair treatment not only toward themselves but also toward others. However, there is no clear consensus regarding the commonality and distinction between these two types of unfairness. Moreover, many neuroimaging studies have investigated how people evaluate and respond to unfairness in the abovementioned two contexts, but the consistency of the results remains to be investigated. To resolve these two issues, we sought to summarize existing findings regarding unfairness to self and others and to further elucidate the neural underpinnings related to distinguishing evaluation and response processes through meta-analyses of previous neuroimaging studies. Our results indicated that both types of unfairness consistently activate the affective and conflict-related anterior insula (AI) and dorsal anterior cingulate cortex/supplementary motor area (dACC/SMA), but the activations related to unfairness to self appeared stronger than those related to others, suggesting that individuals had negative reactions to both unfairness and a greater aversive response toward unfairness to self. During the evaluation process, unfairness to self activated the bilateral AI, dACC, and right dorsolateral prefrontal cortex (DLPFC), regions associated with unfairness aversion, conflict, and cognitive control, indicating reactive, emotional and automatic responses. In contrast, unfairness to others activated areas associated with theory of mind, the inferior parietal lobule and temporoparietal junction (IPL-TPJ), suggesting that making rational judgments from the perspective of others was needed. During the response, unfairness to self activated the affective-related left AI and striatum, whereas unfairness to others activated cognitive control areas, the left DLPFC and the thalamus. This indicated that the former maintained the traits of automaticity and emotionality, whereas the latter necessitated cognitive control. These findings provide a fine-grained description of the common and distinct neurocognitive mechanisms underlying unfairness to self and unfairness to others. Overall, this study not only validates the inequity aversion model but also provides direct evidence of neural mechanisms for neurobiological models of fairness.
PubMed: 38942102
DOI: 10.1016/j.neuroimage.2024.120707 -
Science Advances Jun 2024Functional deficits in basal ganglia (BG) circuits contribute to cognitive and motor dysfunctions in alcohol use disorder. Chronic alcohol exposure alters synaptic...
Functional deficits in basal ganglia (BG) circuits contribute to cognitive and motor dysfunctions in alcohol use disorder. Chronic alcohol exposure alters synaptic function and neuronal excitability in the dorsal striatum, but it remains unclear how it affects BG output that is mediated by the substantia nigra pars reticulata (SNr). Here, we describe a neuronal subpopulation-specific synaptic organization of striatal and subthalamic (STN) inputs to the medial and lateral SNr. Chronic alcohol exposure (CIE) potentiated dorsolateral striatum (DLS) inputs but did not change dorsomedial striatum and STN inputs to the SNr. Chemogenetic inhibition of DLS direct pathway neurons revealed an enhanced role for DLS direct pathway neurons in execution of an instrumental lever-pressing task. Overall, we reveal a subregion-specific organization of striatal and subthalamic inputs onto the medial and lateral SNr and find that potentiated DLS-SNr inputs are accompanied by altered BG control of action execution following CIE.
Topics: Animals; Neuronal Plasticity; Basal Ganglia; Substantia Nigra; Ethanol; Corpus Striatum; Male; Mice; Neurons; Alcoholism; Neural Pathways
PubMed: 38941461
DOI: 10.1126/sciadv.adm6951 -
ELife Jun 2024How human prefrontal and insular regions interact while maximizing rewards and minimizing punishments is unknown. Capitalizing on human intracranial recordings, we...
How human prefrontal and insular regions interact while maximizing rewards and minimizing punishments is unknown. Capitalizing on human intracranial recordings, we demonstrate that the functional specificity toward reward or punishment learning is better disentangled by interactions compared to local representations. Prefrontal and insular cortices display non-selective neural populations to rewards and punishments. Non-selective responses, however, give rise to context-specific interareal interactions. We identify a reward subsystem with redundant interactions between the orbitofrontal and ventromedial prefrontal cortices, with a driving role of the latter. In addition, we find a punishment subsystem with redundant interactions between the insular and dorsolateral cortices, with a driving role of the insula. Finally, switching between reward and punishment learning is mediated by synergistic interactions between the two subsystems. These results provide a unifying explanation of distributed cortical representations and interactions supporting reward and punishment learning.
Topics: Humans; Punishment; Reward; Male; Adult; Female; Prefrontal Cortex; Learning; Young Adult; Insular Cortex; Frontal Lobe
PubMed: 38941238
DOI: 10.7554/eLife.92938 -
Frontiers in Aging Neuroscience 2024At least one-third of the identified risk alleles from Genome-Wide Association Studies (GWAS) of Alzheimer's disease (AD) are involved in lipid metabolism, lipid...
INTRODUCTION
At least one-third of the identified risk alleles from Genome-Wide Association Studies (GWAS) of Alzheimer's disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. In fact, a common genetic variant (ε4) in a cholesterol and phospholipid transporter, Apolipoprotein E (), is the primary genetic risk factor for late-onset AD. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, cerebrospinal fluid, blood, and multiple mouse models of AD.
METHODS
We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of lipidomics and transcriptomics from the Religious Order Study and Rush Memory Aging Project (ROSMAP) using differential analysis and network correlation analysis.
RESULTS
Coordinated differences in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and carriers. Interestingly, these correlations were weakened when adjusting for education. Indeed, the cognitively non-impaired carriers have higher education levels in the ROSMAP cohort, suggesting that this lipid signature may be associated with a resilience phenotype. Network correlation analysis identified multiple differential lipids within a single module that are substrates and products in the Lands Cycle for acyl chain remodeling. In addition, our analyses identified multiple genes in the Lands Cycle acyl chain remodeling pathway, which were associated with cognitive decline independent of amyloid-β (Aβ) load and tau tangle pathologies.
DISCUSSION
Our studies highlight the critical differences in acyl chain remodeling in brain tissue from carriers and individual non-carriers with MCI. A coordinated lipid profile shift in dorsolateral prefrontal cortex from both carriers and MCI suggests differences in lipid metabolism occur early in disease stage and highlights lipid homeostasis as a tractable target for early disease modifying intervention.
PubMed: 38938596
DOI: 10.3389/fnagi.2024.1419253 -
ENeuro Jun 2024Elevated intraocular pressure (IOP) triggers glaucoma by damaging the output neurons of the retina called retinal ganglion cells (RGCs). This leads to the loss of RGC...
Elevated intraocular pressure (IOP) triggers glaucoma by damaging the output neurons of the retina called retinal ganglion cells (RGCs). This leads to the loss of RGC signaling to visual centers of the brain such as the dorsolateral geniculate nucleus (dLGN), which is critical for processing and relaying information to the cortex for conscious vision. In response to altered levels of activity or synaptic input, neurons can homeostatically modulate postsynaptic neurotransmitter receptor numbers, allowing them to scale their synaptic responses to stabilize spike output. While prior work has indicated unaltered glutamate receptor properties in the glaucomatous dLGN, it is unknown whether glaucoma impacts dLGN inhibition. Here, using DBA/2J mice, which develop elevated IOP beginning at 6-7 months of age, we tested whether the strength of inhibitory synapses on dLGN thalamocortical relay neurons is altered in response to the disease state. We found an enhancement of feed-forward disynaptic inhibition arising from local interneurons along with increased amplitude of quantal inhibitory synaptic currents. A combination of immunofluorescence staining for the GABA-α1 receptor subunit, peak-scaled nonstationary fluctuation analysis, and measures of homeostatic synaptic scaling pointed to an approximately 1.4-fold increase in GABA receptors at post-synaptic inhibitory synapses, although several pieces of evidence indicate a non-uniform scaling across inhibitory synapses within individual relay neurons. Together, these results indicate an increase in inhibitory synaptic strength in the glaucomatous dLGN, potentially pointing toward homeostatic compensation for disruptions in network and neuronal function triggered by increased IOP. Elevated eye pressure in glaucoma leads to loss of retinal outputs to the dorsolateral geniculate nucleus (dLGN), which is critical for relaying information to the cortex for conscious vision. Alterations in neuronal activity, as could arise from excitatory synapse loss, can trigger homeostatic adaptations to synaptic function that attempt to maintain activity within a meaningful dynamic range, although whether this occurs uniformly at all synapses within a given neuron or is a non-uniform process is debated. Here, using a mouse model of glaucoma, we show that dLGN inhibitory synapses undergo non-uniform upregulation due to addition of post-synaptic GABA receptors. This is likely to be a neuronal adaptation to glaucomatous pathology in an important sub-cortical visual center.
PubMed: 38937109
DOI: 10.1523/ENEURO.0263-24.2024