ABSTRACT
In recent years, electronic cigarettes (e-cigs) have gained popularity as stylish, safe, and effective smoking cessation aids, leading to widespread consumer acceptance. Although previous research has explored the acute effects of combustible cigarettes or nicotine replacement therapy on brain functional activities, studies on e-cigs have been limited. Using fNIRS, we conducted graph theory analysis on the resting-state functional connectivity of 61 male abstinent smokers both before and after vaping e-cigs. And we performed Pearson correlation analysis to investigate the relationship between alterations in network metrics and changes in craving. E-cig use resulted in increased degree centrality, nodal efficiency, and local efficiency within the executive control network (ECN), while causing a decrease in these properties within the default model network (DMN). These alterations were found to be correlated with reductions in craving, indicating a relationship between differing network topologies in the ECN and DMN and decreased craving. These findings suggest that the impact of e-cig usage on network topologies observed in male smokers resembles the effects observed with traditional cigarettes and other forms of nicotine delivery, providing valuable insights into their addictive potential and effectiveness as aids for smoking cessation.
Subject(s)
Craving , Electronic Nicotine Delivery Systems , Executive Function , Spectroscopy, Near-Infrared , Vaping , Humans , Male , Adult , Executive Function/drug effects , Executive Function/physiology , Young Adult , Default Mode Network/physiopathology , Default Mode Network/diagnostic imaging , Brain/physiopathology , Brain/diagnostic imaging , Brain/drug effects , Smoking Cessation , Nerve Net/physiopathology , Nerve Net/diagnostic imaging , Nerve Net/drug effectsABSTRACT
PURPOSE OF REVIEW: Self-awareness can be defined as the capacity of becoming the object of one's own awareness and, increasingly, it has been the target of scientific inquiry. Self-awareness has important clinical implications, and a better understanding of the neurochemical basis of self-awareness may help clarifying causes and developing interventions for different psychopathological conditions. The current article explores the relationship between neurochemistry and self-awareness, with special attention to the effects of psychedelics. RECENT FINDINGS: The functioning of self-related networks, such as the default-mode network and the salience network, and how these are influenced by different neurotransmitters is discussed. The impact of psychedelics on self-awareness is reviewed in relation to specific processes, such as interoception, body ownership, agency, metacognition, emotional regulation and autobiographical memory, within a framework based on predictive coding. Improved outcomes in emotional regulation and autobiographical memory have been observed in association with the use of psychedelics, suggesting higher-order self-awareness changes, which can be modulated by relaxation of priors and improved coping mechanisms linked to cognitive flexibility. Alterations in bodily self-awareness are less consistent, being potentially impacted by doses employed, differences in acute/long-term effects and the presence of clinical conditions. Future studies investigating the effects of different molecules in rebalancing connectivity between resting-state networks may lead to novel therapeutic approaches and the refinement of existing treatments.
Subject(s)
Awareness , Brain , Hallucinogens , Neurotransmitter Agents , Humans , Hallucinogens/pharmacology , Neurotransmitter Agents/metabolism , Brain/drug effects , Brain/metabolism , Awareness/physiology , Awareness/drug effects , Nerve Net/drug effects , Nerve Net/metabolismABSTRACT
Brain activity implies the orchestrated functioning of interconnected brain regions. Typical in vitro models aim to mimic the brain using single human pluripotent stem cell-derived neuronal networks. However, the field is constantly evolving to model brain functions more accurately through the use of new paradigms, e.g., brain-on-a-chip models with compartmentalized structures and integrated sensors. These methods create novel data requiring more complex analysis approaches. The previously introduced circular tripartite network concept models the connectivity between spatially diverse neuronal structures. The model consists of a microfluidic device allowing axonal connectivity between separated neuronal networks with an embedded microelectrode array to record both local and global electrophysiological activity patterns in the closed circuitry. The existing tools are suboptimal for the analysis of the data produced with this model. Here, we introduce advanced tools for synchronization and functional connectivity assessment. We used our custom-designed analysis to assess the interrelations between the kainic acid (KA)-exposed proximal compartment and its nonexposed distal neighbors before and after KA. Novel multilevel circuitry bursting patterns were detected and analyzed in parallel with the inter- and intracompartmental functional connectivity. The effect of KA on the proximal compartment was captured, and the spread of this effect to the nonexposed distal compartments was revealed. KA induced divergent changes in bursting behaviors, which may be explained by distinct baseline activity and varied intra- and intercompartmental connectivity strengths. The circular tripartite network concept combined with our developed analysis advances importantly both face and construct validity in modeling human epilepsy in vitro.
Subject(s)
Kainic Acid , Nerve Net , Kainic Acid/pharmacology , Nerve Net/drug effects , Nerve Net/physiology , Models, Neurological , Animals , Excitatory Amino Acid Agonists/pharmacology , Humans , Neurons/drug effects , Neurons/physiology , Action Potentials/drug effects , Action Potentials/physiology , Lab-On-A-Chip DevicesABSTRACT
A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.
Subject(s)
Brain , Hallucinogens , Nerve Net , Psilocybin , Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult , Brain/cytology , Brain/diagnostic imaging , Brain/drug effects , Brain/physiology , Brain Mapping , Default Mode Network/cytology , Default Mode Network/diagnostic imaging , Default Mode Network/drug effects , Default Mode Network/physiology , Hallucinogens/pharmacology , Hallucinogens/administration & dosage , Healthy Volunteers , Hippocampus/cytology , Hippocampus/diagnostic imaging , Hippocampus/drug effects , Hippocampus/physiology , Magnetic Resonance Imaging , Methylphenidate/pharmacology , Methylphenidate/administration & dosage , Nerve Net/cytology , Nerve Net/diagnostic imaging , Nerve Net/drug effects , Nerve Net/physiology , Psilocybin/pharmacology , Psilocybin/administration & dosage , Space Perception/drug effects , Time Perception/drug effects , EgoABSTRACT
BACKGROUND: Reversible loss of consciousness is the primary therapeutic endpoint of general anesthesia; however, the drug-invariant mechanisms underlying anesthetic-induced unconsciousness are still unclear. This study aimed to investigate the static, dynamic, topological and organizational changes in functional brain network induced by five clinically-used general anesthetics in the rat brain. METHOD: Male Sprague-Dawley rats (n = 57) were randomly allocated to received propofol, isoflurane, ketamine, dexmedetomidine, or combined isoflurane plus dexmedetomidine anesthesia. Resting-state functional magnetic resonance images were acquired under general anesthesia and analyzed for changes in dynamic functional brain networks compared to the awake state. RESULTS: Different general anesthetics induced distinct patterns of functional connectivity inhibition within brain-wide networks, resulting in multi-level network reorganization primarily by impairing the functional connectivity of cortico-subcortical networks as well as by reducing information transmission capacity, intrinsic connectivity, and network architecture stability of subcortical regions. Conversely, functional connectivity and topological properties were preserved within cortico-cortical networks, albeit with fewer dynamic fluctuations under general anesthesia. CONCLUSIONS: Our findings highlighted the effects of different general anesthetics on functional brain network reorganization, which might shed light on the drug-invariant mechanism of anesthetic-induced unconsciousness.
Subject(s)
Anesthetics, General , Brain , Dexmedetomidine , Isoflurane , Ketamine , Magnetic Resonance Imaging , Propofol , Rats, Sprague-Dawley , Animals , Male , Rats , Brain/drug effects , Brain/diagnostic imaging , Brain/physiology , Anesthetics, General/pharmacology , Ketamine/pharmacology , Propofol/pharmacology , Dexmedetomidine/pharmacology , Isoflurane/pharmacology , Nerve Net/drug effects , Nerve Net/diagnostic imaging , Nerve Net/physiology , Neural Pathways/drug effects , Neural Pathways/diagnostic imaging , Neural Pathways/physiologyABSTRACT
The awake mammalian brain is functionally organized in terms of large-scale distributed networks that are constantly interacting. Loss of consciousness might disrupt this temporal organization leaving patients unresponsive. We hypothesize that characterizing brain activity in terms of transient events may provide a signature of consciousness. For this, we analyze temporal dynamics of spatiotemporally overlapping functional networks obtained from fMRI transient activity across different anesthetics and levels of anesthesia. We first show a striking homology in spatial organization of networks between monkeys and humans, indicating cross-species similarities in resting-state fMRI structure. We then track how network organization shifts under different anesthesia conditions in macaque monkeys. While the spatial aspect of the networks is preserved, their temporal dynamics are highly affected by anesthesia. Networks express for longer durations and co-activate in an anesthetic-specific configuration. Additionally, hierarchical brain organization is disrupted with a consciousness-level-signature role of the default mode network. In conclusion, large-scale brain network temporal dynamics capture differences in anesthetic-specific consciousness-level, paving the way towards a clinical translation of these cortical signature.
Subject(s)
Brain , Consciousness , Magnetic Resonance Imaging , Consciousness/drug effects , Consciousness/physiology , Animals , Brain/physiology , Brain/diagnostic imaging , Humans , Anesthesia , Male , Macaca mulatta , Adult , Nerve Net/physiology , Nerve Net/diagnostic imaging , Nerve Net/drug effects , Female , Brain Mapping/methodsABSTRACT
States of consciousness are likely mediated by multiple parallel yet interacting cortico-subcortical recurrent networks. Although the mesocircuit model has implicated the pallidocortical circuit as one such network, this circuit has not been extensively evaluated to identify network-level electrophysiological changes related to loss of consciousness (LOC). We characterize changes in the mesocircuit in awake versus propofol-induced LOC in humans by directly simultaneously recording from sensorimotor cortices (S1/M1) and globus pallidus interna and externa (GPi/GPe) in 12 patients with Parkinson disease undergoing deep brain stimulator implantation. Propofol-induced LOC is associated with increases in local power up to 20 Hz in GPi, 35 Hz in GPe, and 100 Hz in S1/M1. LOC is likewise marked by increased pallidocortical alpha synchrony across all nodes, with increased alpha/low beta Granger causal (GC) flow from GPe to all other nodes. In contrast, LOC is associated with decreased network-wide beta coupling and beta GC from M1 to the rest of the network. Results implicate an important and possibly central role of GPe in mediating LOC-related increases in alpha power, supporting a significant role of the GPe in modulating cortico-subcortical circuits for consciousness. Simultaneous LOC-related suppression of beta synchrony highlights that distinct oscillatory frequencies act independently, conveying unique network activity.
Subject(s)
Alpha Rhythm , Globus Pallidus , Propofol , Unconsciousness , Humans , Propofol/pharmacology , Globus Pallidus/drug effects , Globus Pallidus/physiology , Male , Female , Middle Aged , Unconsciousness/chemically induced , Unconsciousness/physiopathology , Alpha Rhythm/drug effects , Alpha Rhythm/physiology , Aged , Parkinson Disease/physiopathology , Deep Brain Stimulation/methods , Anesthetics, Intravenous/pharmacology , Nerve Net/drug effects , Nerve Net/physiology , ElectroencephalographyABSTRACT
Linked rhythmic behaviors, such as respiration/locomotion or swallowing/chewing, often require coordination for proper function. Despite its prevalence, the cellular mechanisms controlling coordination of the underlying neural networks remain undetermined in most systems. We use the stomatogastric nervous system of the crab Cancer borealis to investigate mechanisms of internetwork coordination, due to its small, well-characterized feeding-related networks (gastric mill [chewing, â¼0.1â Hz]; pyloric [filtering food, â¼1â Hz]). Here, we investigate coordination between these networks during the Gly1-SIFamide neuropeptide modulatory state. Gly1-SIFamide activates a unique triphasic gastric mill rhythm in which the typically pyloric-only LPG neuron generates dual pyloric-plus gastric mill-timed oscillations. Additionally, the pyloric rhythm exhibits shorter cycles during gastric mill rhythm-timed LPG bursts, and longer cycles during IC, or IC plus LG gastric mill neuron bursts. Photoinactivation revealed that LPG is necessary to shorten pyloric cycle period, likely through its rectified electrical coupling to pyloric pacemaker neurons. Hyperpolarizing current injections demonstrated that although LG bursting enables IC bursts, only gastric mill rhythm bursts in IC are necessary to prolong the pyloric cycle period. Surprisingly, LPG photoinactivation also eliminated prolonged pyloric cycles, without changing IC firing frequency or gastric mill burst duration, suggesting that pyloric cycles are prolonged via IC synaptic inhibition of LPG, which indirectly slows the pyloric pacemakers via electrical coupling. Thus, the same dual-network neuron directly conveys excitation from its endogenous bursting and indirectly funnels synaptic inhibition to enable one network to alternately decrease and increase the cycle period of a related network.
Subject(s)
Brachyura , Ganglia, Invertebrate , Neurons , Neuropeptides , Animals , Brachyura/physiology , Neuropeptides/pharmacology , Neuropeptides/metabolism , Neurons/physiology , Neurons/drug effects , Ganglia, Invertebrate/physiology , Ganglia, Invertebrate/drug effects , Action Potentials/physiology , Action Potentials/drug effects , Nerve Net/physiology , Nerve Net/drug effects , Male , Feeding Behavior/physiology , Feeding Behavior/drug effects , Pylorus/physiology , Pylorus/drug effects , PeriodicityABSTRACT
It is crucial to understand how anesthetics disrupt information transmission within the whole-brain network and its hub structure to gain insight into the network-level mechanisms underlying propofol-induced sedation. However, the influence of propofol on functional integration, segregation, and community structure of whole-brain networks were still unclear. We recruited 12 healthy subjects and acquired resting-state functional magnetic resonance imaging data during 5 different propofol-induced effect-site concentrations (CEs): 0, 0.5, 1.0, 1.5, and 2.0 µg/ml. We constructed whole-brain functional networks for each subject under different conditions and identify community structures. Subsequently, we calculated the global and local topological properties of whole-brain network to investigate the alterations in functional integration and segregation with deepening propofol sedation. Additionally, we assessed the alteration of key nodes within the whole-brain community structure at each effect-site concentrations level. We found that global participation was significantly increased at high effect-site concentrations, which was mediated by bilateral postcentral gyrus. Meanwhile, connector hubs appeared and were located in posterior cingulate cortex and precentral gyrus at high effect-site concentrations. Finally, nodal participation coefficients of connector hubs were closely associated to the level of sedation. These findings provide valuable insights into the relationship between increasing propofol dosage and enhanced functional interaction within the whole-brain networks.
Subject(s)
Brain , Hypnotics and Sedatives , Magnetic Resonance Imaging , Propofol , Humans , Propofol/pharmacology , Propofol/administration & dosage , Male , Magnetic Resonance Imaging/methods , Brain/drug effects , Brain/physiology , Brain/diagnostic imaging , Adult , Female , Hypnotics and Sedatives/pharmacology , Young Adult , Nerve Net/drug effects , Nerve Net/diagnostic imaging , Nerve Net/physiology , Anesthetics, Intravenous/pharmacology , Brain Mapping/methodsABSTRACT
Prefrontal cortical (PFC) dysfunction has been linked to disorders exhibiting deficits in cognitive performance, attention, motivation, and impulse control. Neurons of the PFC are susceptible to glutamatergic excitotoxicity, an effect associated with cortical degeneration in frontotemporal disorders (FTDs). PFC susceptibility to environmental toxicant exposure, one possible contributor to sporadic FTD, has not been systematically studied. Here, we tested the ability of a well-known environmental neurotoxicant, methylmercury (MeHg), to induce hyperexcitability in medial prefrontal cortex (mPFC) excitatory pyramidal neurons, using whole cell patch-clamp recording. Acute MeHg exposure (20 µM) produced significant mPFC dysfunction, with a shift in the excitatory to inhibitory (E-I) balance toward increased excitability. Both excitatory postsynaptic current (EPSC) and inhibitory postsynaptic current (IPSC) charges were significantly increased after MeHg exposure. MeHg increased EPSC frequency, but there was no observable effect on IPSC frequency, EPSC amplitude or IPSC amplitude. Neither evoked AMPA receptor- nor NMDA receptor-mediated EPSC amplitudes were affected by MeHg. However, excitatory synapses experienced a significant reduction in paired-pulse depression and probability of release. In addition, MeHg induced temporal synchrony in spontaneous IPSCs, reflecting mPFC inhibitory network dysfunction. MeHg exposure also produced increased intrinsic excitability in mPFC neurons, with an increase in action potential firing rate. The observed effects of MeHg on mPFC reflect key potential mechanisms for neuropsychological symptoms from MeHg poisoning. Therefore, MeHg has a significant effect on mPFC circuits known to contribute to cognitive and emotional function and might contribute to etiology of neurodegenerative diseases, such as FTD.NEW & NOTEWORTHY Prefrontal cortical neurons are highly susceptible to glutamatergic excitotoxicity associated with neuronal degeneration in frontal dementia and to environmental toxicant exposure, one potential contributor to FTD. However, this has not been systematically studied. Our results demonstrate that methylmercury exposure leads to hyperexcitability of prefrontal cortical neurons by shifting excitatory to inhibitory (E-I) balance and raising sensitivity for spiking. Our results provide a mechanism by which environmental neurotoxicants may contribute to pathogenesis of diseases such as FTD.
Subject(s)
Excitatory Postsynaptic Potentials , Methylmercury Compounds , Prefrontal Cortex , Pyramidal Cells , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiopathology , Animals , Methylmercury Compounds/toxicity , Male , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Rats , Rats, Sprague-Dawley , Inhibitory Postsynaptic Potentials/drug effects , Inhibitory Postsynaptic Potentials/physiology , Nerve Net/drug effects , Nerve Net/physiopathologyABSTRACT
BACKGROUND: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity. METHODS: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks. RESULTS: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness. CONCLUSION: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior.
Subject(s)
Central Nervous System Stimulants , Default Mode Network , Magnetic Resonance Imaging , Methylphenidate , Nerve Net , Humans , Methylphenidate/pharmacology , Methylphenidate/administration & dosage , Adult , Male , Magnetic Resonance Imaging/methods , Female , Central Nervous System Stimulants/pharmacology , Central Nervous System Stimulants/administration & dosage , Default Mode Network/drug effects , Default Mode Network/diagnostic imaging , Young Adult , Double-Blind Method , Nerve Net/drug effects , Nerve Net/diagnostic imaging , Nerve Net/physiology , Impulsive Behavior/drug effects , Connectome/methods , Brain/drug effects , Brain/diagnostic imaging , Brain/physiology , Neural Pathways/drug effects , Neural Pathways/physiologyABSTRACT
The extent of changes in functional connectivity (FC) within functional networks as a common feature across hallucinogenic drug classes is under-explored. This work utilized fMRI to assess the dissociative hallucinogens Psilocybin, a classical serotonergic psychedelic, and Salvinorin-A, a kappa-opioid receptor (KOR) agonist, on resting-state FC in nonhuman primates. We highlight overlapping and differing influence of these substances on FC relative to the thalamus, claustrum, prefrontal cortex (PFC), default mode network (DMN), and DMN subcomponents. Analysis was conducted on a within-subject basis. Findings support the cortico-claustro-cortical network model for probing functional effects of hallucinogens regardless of serotonergic potential, with a potential key paradigm centered around the claustrum, PFC, anterior cingulate cortices (ACC), and angular gyrus relationship. Thalamo-cortical networks are implicated but appear dependent on 5-HT2AR activation. Acute desynchronization relative to the DMN for both drugs was also shown. Our findings provide a framework to understand broader mechanisms at which hallucinogens in differing classes may impact subjects regardless of the target receptor.
Subject(s)
Diterpenes, Clerodane , Hallucinogens , Magnetic Resonance Imaging , Psilocybin , Hallucinogens/pharmacology , Diterpenes, Clerodane/pharmacology , Animals , Psilocybin/pharmacology , Male , Magnetic Resonance Imaging/methods , Prefrontal Cortex/drug effects , Brain/drug effects , Brain/metabolism , Macaca mulatta , Default Mode Network/drug effects , Thalamus/drug effects , Thalamus/diagnostic imaging , Thalamus/metabolism , Neural Pathways/drug effects , Nerve Net/drug effects , Nerve Net/diagnostic imagingABSTRACT
Despite widespread use of combination antiretroviral therapy (cART), there remains a subset of individuals who display cognitive impairment broadly known as HIV-associated neurocognitive disorder (HAND). Interestingly, HIV-infected cells continuously release the HIV-1 protein Tat even in the presence of cART. Persistent exposure to Tat is proposed to increase both neuroinflammation and neurotoxicity. In vitro evidence shows that matrix metalloproteinases (MMPs) are among the neuroinflammatory molecules induced by Tat, which are known to disrupt specialized neuronal extracellular matrix structures called perineuronal nets (PNNs). PNNs predominantly surround parvalbumin interneurons and help to buffer these cells from oxidant stress and to independently increase their excitability. In order to better understand the link between short-term exposure to Tat, neuroinflammation, and PNNs, we explored the direct effects of Tat on glial cells and neurons. Herein, we report that in mixed glial cultures, Tat directly increases the expression of proinflammatory molecules, including MMP-9. Moreover, direct injection of Tat protein into mouse hippocampus increases the expression of astrocyte and microglia markers as well as MMP-9. The number of PNNs is decreased following Tat exposure, followed later by decreased numbers of hippocampal parvalbumin-expressing neurons. In older mice, Tat induced significant increases in the gene expression of proinflammatory molecules including markers of gliosis, MMPs and complement system proteins. Taken together, these data support a direct effect of Tat on glial-derived MMP expression subsequently affecting PNNs and neuronal health, with older mice more susceptible to Tat-induced inflammation.
Subject(s)
Neuroglia , tat Gene Products, Human Immunodeficiency Virus , Animals , Mice , tat Gene Products, Human Immunodeficiency Virus/metabolism , Neuroglia/metabolism , Neuroglia/drug effects , Hippocampus/metabolism , Hippocampus/drug effects , Mice, Inbred C57BL , Male , Extracellular Matrix/metabolism , Extracellular Matrix/drug effects , Matrix Metalloproteinase 9/metabolism , Neurons/metabolism , Neurons/drug effects , Neurons/virology , Nerve Net/drug effects , Nerve Net/metabolism , Cells, Cultured , Humans , Parvalbumins/metabolismABSTRACT
Hormonal changes in ovarian hormones like estradiol (E2) during the menstrual cycle affect emotional processes, including emotion recognition, memory, and regulation. So far, the neural underpinnings of the effect of E2 on emotional experience have been investigated using task-based functional magnetic resonance imaging (fMRI) and functional connectivity. In the present study, we examined whether the intrinsic network dynamics at rest (i.e., directed effective connectivity) related to emotion regulation are (1) modulated by E2 levels and (2) linked to behavioral emotion regulation ability. Hence, 29 naturally cycling women participated in two resting-state fMRI scans in their early follicular phase after being administered a placebo or an E2 valerate, respectively. Emotion regulation ability was assessed using a standard emotion regulation task in which participants were asked to down-regulate their emotions in response to negative images. The regions of two functionally predefined neural networks related to emotional down-regulation and reactivity were used to investigate effective connectivity at rest using spectral dynamic causal modelling. We found that E2, compared to placebo, resulted in changes in effective connectivity in both networks. In the regulation network, prefrontal regions showed distinct connectivity in the E2 compared to the placebo condition, while mixed results evolved in the emotional reactivity network. Stepwise regressions revealed that in the E2 condition a connection from the parietal to the prefrontal cortex predicted regulation ability. Our results demonstrate that E2 levels influence effective connectivity in networks underlying emotion regulation and emotional reactivity. Thus, E2 and its potential modification via hormonal administration may play a supporting role in the treatment of mental disorders that show a dysregulation of emotions.
Subject(s)
Emotional Regulation , Emotions , Estradiol , Magnetic Resonance Imaging , Nerve Net , Humans , Female , Emotional Regulation/physiology , Emotional Regulation/drug effects , Estradiol/pharmacology , Estradiol/metabolism , Adult , Young Adult , Emotions/drug effects , Emotions/physiology , Nerve Net/drug effects , Nerve Net/physiology , Nerve Net/diagnostic imaging , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Prefrontal Cortex/metabolism , Prefrontal Cortex/diagnostic imaging , Brain/drug effects , Brain/metabolism , Brain/physiology , Brain/diagnostic imaging , Brain Mapping/methods , Menstrual Cycle/drug effects , Menstrual Cycle/physiology , Neural Pathways/drug effects , Neural Pathways/physiology , Follicular Phase/physiology , Follicular Phase/drug effects , Connectome/methodsABSTRACT
Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.
Subject(s)
Language , Parkinson Disease , Speech , Subthalamic Nucleus , Humans , Parkinson Disease/physiopathology , Parkinson Disease/drug therapy , Subthalamic Nucleus/physiopathology , Subthalamic Nucleus/drug effects , Male , Speech/physiology , Speech/drug effects , Female , Middle Aged , Aged , Magnetic Resonance Imaging , Dopamine/metabolism , Nerve Net/drug effects , Nerve Net/physiopathology , Cognition/drug effects , Dopamine Agents/pharmacology , Dopamine Agents/therapeutic useABSTRACT
New approach methodologies (NAMs) can address information gaps on potential neurotoxicity or developmental neurotoxicity hazard for data-poor chemicals. Two assays have been previously developed using microelectrode arrays (MEA), a technology which measures neural activity. The MEA acute network function assay (AcN) uses dissociated rat cortical cells cultured at postnatal day 0 and evaluates network activity during a 40-minute chemical exposure on day in vitro (DIV)13 or 15. In contrast, the MEA network formation assay (NFA) uses a developmental exposure paradigm spanning DIV0 through DIV12. Measures of network activity over time at DIV5, 7, 9, and 12 in the NFA are reduced to an estimated area under the curve to facilitate concentration-response evaluation. Here, we evaluated the hypothesis that chemicals with effects in the AcN also perturb the NFA by examining quantitative and qualitative concordance between assays. Out of 243 chemicals screened in both assays, we observed 70.3% concordance between the AcN and NFA after eliminating activity inferred to be cytotoxic (selective activity), with the majority of discordance explained by chemicals that altered selective activity in the AcN but not NFA. The NFA detected more active chemicals when evaluating activity associated with cytotoxicity. Median potency values were lower in the NFA compared to the AcN, but within-chemical potency values were not uniformly lower in the NFA than the AcN. Lastly, the AcN and NFA captured unique bioactivity fingerprints; the AcN was more informative for identifying chemicals with a shared mode of action, while the NFA provided information relevant to developmental exposure. Taken together, this analysis provides a rationale for using both approaches for chemical evaluation with consideration of the context of use, such as screening/ prioritization, hazard identification, or to address questions regarding biological mechanism or function.
Subject(s)
Microelectrodes , Nerve Net , Animals , Nerve Net/drug effects , Cells, Cultured , Rats , Neurons/drug effects , Rats, Sprague-Dawley , Toxicity Tests/methods , Cerebral Cortex/drug effects , Biological Assay/methodsABSTRACT
BACKGROUND: The decision to treat children with benign epilepsy with centrotemporal spikes (BECTS) using antiseizure medications (ASM) is controversial. Our goal is to compare the effect of ASM treatment on the alteration of electroencephalographic (EEG) functional connectivity and power across four frequency bands in children with BECTS. METHODS: Children with BECTS with two-year follow-up were retrospectively divided into ASM versus non-ASM groups. The network properties of the EEGs as based on network-based statistic and graph theory were evaluated by the following indices: global efficiency, clustering coefficient, betweenness centrality, and nodal strength in four frequency bands (delta, theta, alpha, and beta). EEG power including absolute power (AP) and relative power (RP) was analyzed in four frequency bands. RESULTS: In children with BECTS with ASM treatment, there was no significant change in EEG connectivity across all bands before and after two years of ASM. In children with BECTS without ASM treatment, there was a significant increase of global efficiency, clustering coefficient, and nodal strength but not the betweenness centrality in the delta band after two years of follow-up. A decrease in AP in the delta and theta bands and a decrease in RP in the theta band were found in the ASM group after two years of treatment. CONCLUSIONS: Our results suggest that ASM may play a role in modulating the development of increasing overall brain connectivity and in downregulating overt synaptic activity, but not intrinsic focal connectivity, in the early years of BECTS. The changes in the EEG power indicate that ASM significantly normalized slow-wave band power.
Subject(s)
Anticonvulsants , Electroencephalography , Epilepsy, Rolandic , Humans , Epilepsy, Rolandic/drug therapy , Epilepsy, Rolandic/physiopathology , Female , Child , Male , Anticonvulsants/pharmacology , Retrospective Studies , Child, Preschool , Follow-Up Studies , Brain Waves/drug effects , Brain Waves/physiology , Nerve Net/drug effects , Nerve Net/physiopathology , Brain/physiopathology , Brain/drug effectsABSTRACT
Depression and obesity are prevalent disorders with significant public health implications. In this study, we used a high-fat diet (HFD)-induced obese mouse model to investigate the mechanism underlying HFD-induced depression-like behaviors. HFD-induced obese mice exhibited depression-like behaviors and a reduction in hippocampus volume, which were reversed by treatment with an indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-MT). Interestingly, no changes in IDO levels were observed post-1-MT treatment, suggesting that other mechanisms may be involved in the anti-depressive effect of 1-MT. We further conducted RNA sequencing analysis to clarify the potential underlying mechanism of the anti-depressive effect of 1-MT in HFD-induced depressive mice and found a significant enrichment of shared differential genes in the extracellular matrix (ECM) organization pathway between the 1-MT-treated and untreated HFD-induced depressive mice. Therefore, we hypothesized that changes in ECM play a crucial role in the anti-depressive effect of 1-MT. To this end, we investigated perineuronal nets (PNNs), which are ECM assemblies that preferentially ensheath parvalbumin (PV)-positive interneurons and are involved in many abnormalities. We found that HFD is associated with excessive accumulation of PV-positive neurons and upregulation of PNNs, affecting synaptic transmission in PV-positive neurons and leading to glutamate-gamma-aminobutyric acid imbalances in the hippocampus. The 1-MT effectively reversed these changes, highlighting a PNN-related mechanism by which 1-MT exerts its anti-depressive effect.