Neurophysiological Effects Research Articles

Effects of propofol on presynaptic synapsin phosphorylation in the mouse brain in vivo

The commonly used general anesthetic propofol can enhance the γ-aminobutyric acid-mediated inhibitory synaptic transmission and depress the glutamatergic excitatory synaptic transmission to achieve general anesthesia and other outcomes. In addition to the actions at postsynaptic sites, the modulation of presynaptic activity by propofol is thought to contribute to neurophysiological effects of the anesthetic, although potential targets of propofol within presynaptic nerve terminals are incompletely studied at present. In this study, we explored the possible linkage of propofol to synapsins, a family of neuron-specific phosphoproteins which are the most abundant proteins on presynaptic vesicles, in the adult mouse brain in vivo. We found that an intraperitoneal injection of propofol at a dose that caused loss of righting reflex increased basal levels of synapsin phosphorylation at the major representative phosphorylation sites (serine 9, serine 62/67, and serine 603) in the prefrontal cortex (PFC) of male and female mice. Propofol also elevated synapsin phosphorylation at these sites in the striatum and S9 and S62/67 phosphorylation in the hippocampus, while propofol had no effect on tyrosine hydroxylase phosphorylation in striatal nerve terminals. Total synapsin protein expression in the PFC, hippocampus, and striatum was not altered by propofol. These results reveal that synapsin could be a novel substrate of propofol in the presynaptic neurotransmitter release machinery. Propofol possesses the ability to upregulate synapsin phosphorylation in broad mouse brain regions.

Model-based analysis of subthreshold mechanisms of spinal cord stimulation for pain

Objective. Spinal cord stimulation (SCS) is a common treatment for chronic pain. For decades, SCS maximized overlap between stimulation-induced paresthesias and the patient’s painful areas. Recently developed SCS paradigms relieve pain at sub-perceptible amplitudes, yet little is known about the neural response to these new waveforms or their analgesic mechanisms of action. Therefore, in this study, we investigated the neural response to multiple forms of paresthesia-free SCS. Approach. We used computational modeling to investigate the neurophysiological effects and the plausibility of commonly proposed mechanisms of three paresthesia-free SCS paradigms: burst, 1 kHz, and 10 kHz SCS. Specifically, in C- and Aβ-fibers, we investigated the effects of different SCS waveforms on spike timing and activation thresholds, as well as how stochastic ion channel gating affects the response of dorsal column axons. Finally, we characterized membrane polarization of superficial dorsal horn neurons. Main results. We found that none of the SCS waveforms activate nor modulate spike timing in C-fibers. Spike timing was modulated in Aβ-fibers only at suprathreshold amplitudes. Ion channel stochasticity had little effect on Aβ-fiber activation thresholds but produced heterogeneous spike timings at suprathreshold amplitudes. Finally, local cells were preferentially polarized in their axon terminals, and the magnitude of this polarization was dependent on cellular morphology and position relative to the stimulation electrodes. Significance. Overall, the mechanisms of action of subparesthetic SCS remain unclear. Our results suggest that no SCS waveforms directly activate C-fibers, and modulation of spike timing is unlikely at subthreshold amplitudes. We conclude that potential subthreshold neuromodulatory effects of SCS on local cells are likely to be presynaptic in nature, as axons are preferentially depolarized during SCS.

Lasting enhancements in neural efficiency by multi-session transcranial direct current stimulation during working memory training

The neural basis for long-term behavioral improvements resulting from multi-session transcranial direct current stimulation (tDCS) combined with working memory training (WMT) remains unclear. In this study, we used task-related electroencephalography (EEG) measures to investigate the lasting neurophysiological effects of anodal high-definition (HD)-tDCS applied over the left dorsolateral prefrontal cortex (dlPFC) during a challenging WMT. Thirty-four healthy young adults were randomized to sham or active tDCS groups and underwent ten 30-minute training sessions over ten consecutive days, preceded by a pre-test and followed by post-tests performed one day and three weeks after the last session, respectively, by performing high-load WM tasks along with EEG recording. Multi-session HD-tDCS significantly enhanced the behavioral benefits of WMT. Compared to the sham group, the active group showed facilitated increases in theta, alpha, beta, and gamma task-related oscillations at the end of training and significantly increased P300 response 3 weeks post-training. Our findings suggest that applying anodal tDCS over the left dlPFC during multi-session WMT can enhance the behavioral benefits of WMT and facilitate sustained improvements in WM-related neural efficiency.

The use of theta burst stimulation in patients with schizophrenia - A systematic review.

Transcranial magnetic stimulation (TMS) can offer therapeutic benefits and provide value in neurophysiological research. One of the newer TMS paradigms is theta burst stimulation (TBS) which can be delivered in two patterns: continuous (cTBS - inducing LTD-like effects) and intermittent (iTBS - inducing LTP-like effects). This review paper aims to explore studies that have utilized TBS protocols over different areas of the cortex to study the neurophysiological functions and treatment of patients with schizophrenia. PubMed was searched using the following keywords "schizophrenia", "schizoaffective", or "psychosis", and "theta burst stimulation". Out of the 90 articles which were found, thirty met review inclusion criteria. The inclusion criteria included studying the reported effect (clinical, physiological, or both) of at least one session of TBS on human subjects, and abstracts (at minimum) must have been in English. The main target areas included prefrontal cortex (12 studies - 10 dorsolateral prefrontal cortex (DLPFC), 2 dorsomedial prefrontal cortex (DMPFC)) vermal cerebellum (5), and temporo-parietal cortex (8). Other target areas included inferior parietal lobe (2), and motor cortex (3). TBS neurophysiological effect was explored in 5 studies using functional magnetic resonance image (fMRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), electromyography (EMG) and positron emission topography (PET) scan. Overall, TBS can offer great therapeutic potential as it is well-tolerated, feasible, and has few, if any, adverse effects. TBS may be targeted to treat specific symptomatology, as an augmenting intervention to pharmacotherapy, or even improving patient's insight into their diagnosis.

Temporal and spectral analyses of EEG microstate reveals neural effects of transcranial photobiomodulation on the resting brain.

The quantification of electroencephalography (EEG) microstates is an effective method for analyzing synchronous neural firing and assessing the temporal dynamics of the resting state of the human brain. Transcranial photobiomodulation (tPBM) is a safe and effective modality to improve human cognition. However, it is unclear how prefrontal tPBM neuromodulates EEG microstates both temporally and spectrally. 64-channel EEG was recorded from 45 healthy subjects in both 8-min active and sham tPBM sessions, using a 1064-nm laser applied to the right forehead of the subjects. After EEG data preprocessing, time-domain EEG microstate analysis was performed to obtain four microstate classes for both tPBM and sham sessions throughout the pre-, during-, and post-stimulation periods, followed by extraction of the respective microstate parameters. Moreover, frequency-domain analysis was performed by combining multivariate empirical mode decomposition with the Hilbert-Huang transform. Statistical analyses revealed that tPBM resulted in (1) a significant increase in the occurrence of microstates A and D and a significant decrease in the contribution of microstate C, (2) a substantial increase in the transition probabilities between microstates A and D, and (3) a substantial increase in the alpha power of microstate D. These findings confirm the neurophysiological effects of tPBM on EEG microstates of the resting brain, particularly in class D, which represents brain activation across the frontal and parietal regions. This study helps to better understand tPBM-induced dynamic alterations in EEG microstates that may be linked to the tPBM mechanism of action for the enhancement of human cognition.

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent manner.

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4 g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males > females). Ex vivo electrophysiology recordings of NAcSh medium spiny neurons (MSN) in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh MSN excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5 and memantine, robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males and were not estrous cycle dependent. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain from ethanol consumption. Furthermore, these findings also highlight a specific sex-dependent sensitivity in females to acetic acid-NMDAR interactions. This may underlie their more rapid advancement to alcohol use disorder and increased risk of alcohol related neurodegeneration compared to males.

Neurophysiological effects of frequency, length, phonological neighborhood density, and iconicity on sign recognition.

Current theories on lexical recognition are mostly based on studies from spoken languages or their written forms. Much less is known about the process of lexical recognition in sign languages. This study aims to examine the neural correlates of sign recognition by investigating the effects of lexical frequency, length, phonological neighborhood density, and iconicity during Chinese Sign Language comprehension. Twenty-two deaf signers viewed a set of sign videos that varied in the 4 lexical properties and decided if they referred to animals, while event-related potential responses were recorded. Data were analyzed through linear mixed-effects models with the lexical variables treated as continuous measures. The results showed that frequency modulated ERP amplitude as early as around 200 ms and in the late N400 time frame. Sign length invoked effects throughout the process, starting from 200 ms and pertaining to the last epoch. Neighborhood density effects were also observed early around 200 ms and later on the N400 and late positive complex (LPC). Iconicity produced robust effects on the N400 and LPC amplitude. Lexical frequency, length, and neighborhood density influence the neural dynamics of sign recognition in a similar way as to spoken words. Iconicity can confer a processing advantage due to closer form-meaning mappings. The results indicate that lexical recognition engages some mechanisms that are universal across the signed and spoken modality, but it can also be regulated by modality-specific properties such as the prevalent iconicity in sign languages.

The effects of distraction on younger drivers: A neurophysiological perspective

Distracted driving remains a significant cause of traffic accidents globally, including in Australia. However, many younger drivers still admit to using a phone while driving. A simulated driving study investigated the neurophysiological effects of visual, auditory, and higher-order cognitive (i.e., requiring the use of executive functions) distraction on young drivers. In total, 24 young adults aged 18–25 years completed four 8 min simulated driving sessions while concurrently engaging in various distractor tasks. Neurophysiological arousal was measured via EEG. Additionally, subjective workload and objective driving performance were assessed. Frontal beta and gamma power exhibited their highest levels during tasks involving higher-order cognitive and visual demands. The higher-order cognitive condition was rated as the most mentally demanding. In comparison, the visual condition had the most significant impact on both the standard deviation of speed and standard deviation of lateral positioning. This study has significant implications for all road users, particularly those aged 18–25 years, and it reinforces the importance of not using a phone while driving.

Sonic Influence on Initially Neutral Brands: Using EEG to Unveil the Secrets of Audio Evaluative Conditioning.

The present study addresses the question of whether explicit, survey-type measures of attitude differ in sensitivity when compared to implicit, non-conscious measures of attitude in the context of attitude changes in response to evaluative conditioning (EC). In the frame of a pre-test, participants rated 300 brand names on a Likert-type scale, the results of which were then used to create personalised lists of neutral brands. After this initial online component, the participants were exposed to one, five, and ten rounds of EC (during three separate sessions), during which half of the brands were paired with pleasant audio excerpts (positive EC) and the remainder were paired with unpleasant audio excerpts (negative EC). Following each conditioning round, the participants rated the brand names again, whilst changes in the brain's electrical activity in response to the brands were recorded via electroencephalography (EEG). After having rated the brand names, the participants also completed two implicit association tests (IAT; one for each of the neutral conditions). The results revealed that self-reported, explicit responses of brand names remained unchanged despite having been conditioned. Similarly, the IAT did not reveal any declines in reaction time. In contrast, the EEG data appeared to not only be sensitive to initial brand ratings, but also the conditioning effects of initially neutral brands. Respective neurophysiological effects were found at frontal electrode locations AF3 and AF4 for a 1 s-long time window starting at 400 ms after stimulus onset. Furthermore, the EEG revealed that changes in brand attitude are more susceptible to the effects of negative conditioning than positive conditioning. Given the rather small sample size, any generalizability seems vague, but the present results provide scientific evidence that EEG could indeed be a valuable additional method to investigate EC effects. The results of this study support the notion of utilising a multidimensional approach, inclusive of neuroscience, to understanding consumer attitudes instead of solely relying on self-report measures. In the end, the brain knows more than it admits to consciousness and language, which is why objective methods should always be included in any study.

Low dose of levetiracetam counteracts amyloid β-induced alterations of hippocampal gamma oscillations by restoring fast-spiking interneuron activity

Alzheimer's disease (AD) is characterized at an early stage by memory alterations that worsen during the development of the disease. Several clinical trials in phase 3 have failed despite being able to counteract classical AD-related alterations, possibly because of the lack of recovery of the regular neuronal network activity essential for memory including low gamma oscillations (γ-Osc). Nowadays, Levetiracetam (LEV), an SV2A modulator approved for epilepsy, is being used in trials with AD patients without further support for neurophysiological relevant effects on restoring the normal function of hippocampal neuronal network activity. Using concomitant recordings of local field potential γ-Osc and patch-clamp recordings of fast-spiking interneurons (FS-IN) on hippocampal slices of WT and AppNL-G-F AD animals, we found that LEV restores the power and rhythmicity of γ-Osc previously reduced by acute application of amyloid-β on WT hippocampal slices, this effect is accompanied by the recovery of the synchronicity in the firing of FS-IN. In addition, we found that LEV counteracts the hippocampal γ-Osc alterations in the early prodromal stage of the disease in AppNL-G-F mice by recovering the rhythmicity of γ-Osc and the synchronicity in the firing of FS-IN. Altogether the results show that the precise modulation of neuronal circuits with LEV is a promising strategy to counteract early-stage alterations in hippocampal activity by modulating FS-IN in a memory-relevant neuronal network state like γ-Osc.

Volatile anesthetics inhibit presynaptic cGMP signaling to depress presynaptic excitability in rat hippocampal neurons

Volatile anesthetics alter presynaptic function through effects on Ca2+ influx and neurotransmitter release. These actions are proposed to play important roles in their pleiotropic neurophysiological effects including immobility, unconsciousness and amnesia. Nitric oxide and cyclic guanosine monophosphate (NO/cGMP) signaling has been implicated in presynaptic mechanisms, and disruption of NO/cGMP signaling has been shown to alter sensitivity to volatile anesthetics in vivo. We investigated volatile anesthetic actions NO/cGMP signaling in relation to presynaptic function in cultured rat hippocampal neurons using pharmacological tools and genetically encoded biosensors and sequestering probes of cGMP levels. Using the fluorescent cGMP biosensor cGull, we found that electrical stimulation-evoked NMDA-type glutamate receptor-independent presynaptic cGMP transients were inhibited 33.2% by isoflurane (0.51 mM) and 26.4% by sevoflurane (0.57 mM) (p < 0.0001) compared to control stimulation without anesthetic. Stimulation-evoked cGMP transients were blocked by the nonselective inhibitor of nitric oxide synthase N-ω-nitro-l-arginine, but not by the selective neuronal nitric oxide synthase inhibitor N5-(1-imino-3-butenyl)-l-ornithine. Isoflurane and sevoflurane inhibition of stimulation-evoked increases in presynaptic Ca2+ concentration, measured with synaptophysin-GCaMP6f, and of synaptic vesicle exocytosis, measured with synaptophysin-pHlourin, was attenuated in neurons expressing the cGMP scavenger protein sponge (inhibition of exocytosis reduced by 54% for isoflurane and by 53% for sevoflurane). The anesthetic-induced reduction in presynaptic excitability was partially occluded by inhibition of HCN channels, a cGMP-modulated excitatory ion channel that can facilitate glutamate release. We propose that volatile anesthetics depress presynaptic cGMP signaling and downstream effectors like HCN channels that are essential to presynaptic function and excitability. These findings identify novel mechanisms by which volatile anesthetics depress synaptic transmission via second messenger signaling involving the NO/cGMP pathway in hippocampal neurons.

Can upper cervical manual therapy affect the blink reflex in subjects with migraine and neck pain?

ABSTRACT Background Neck pain is a common complaint among migraineurs possibly due to the anatomic connections between cervical and trigeminal afferents in the trigeminocervical complex (TCC). Manual therapy (MT) is used in the management of headache disorders, with demonstrable neurophysiological effects. The blink reflex (BR) is one method of analyzing neurophysiological effects in headache patients. The purpose of this study was to investigate the effect of upper cervical spine MT on BR in subjects with migraine and neck pain. Methods & Materials Twenty subjects were assigned to a medication plus MT (MedMT) group (n = 10) and medication plus sham MT (sham MT) group (n = 10). After random assignment, all patients underwent testing for the BR (R1, R2, R2c responses). Then, subjects in group MedMT and group sham MT received either 4 sessions of MT or sham MT to the upper cervical spine. After completion of the intervention, BR testing was repeated. Results There were no significant differences in both side R1 latency between group MT and group sham MT (P > 0.050). For both sides, R2 latencies were significantly prolonged in MedMT group compared with sham MT group (P < 0.050). Subjects in MedMT group showed significant prolongation in right and left R2c latency compared with sham MT group (P < 0.050). Discussion The present study demonstrated that upper cervical MT affected trigeminal nociceptive neurotransmission in subjects with migraine and neck pain as reflected by changes in the BR. The increase in BR late response latencies of BR indicates an inhibitory effect of upper cervical spine MT on the TCC in these subjects. Trial Registration: The trial design was registered at the Iranian Registry of Clinical Trials (IRCT ID: IRCT20160621028567N2, url: https://www.irct.ir/) before the first patient was enrolled.

Acetylcholine modulates the temporal dynamics of human theta oscillations during memory

The cholinergic system is essential for memory. While degradation of cholinergic pathways characterizes memory-related disorders such as Alzheimer’s disease, the neurophysiological mechanisms linking the cholinergic system to human memory remain unknown. Here, combining intracranial brain recordings with pharmacological manipulation, we describe the neurophysiological effects of a cholinergic blocker, scopolamine, on the human hippocampal formation during episodic memory. We found that the memory impairment caused by scopolamine was coupled to disruptions of both the amplitude and phase alignment of theta oscillations (2–10 Hz) during encoding. Across individuals, the severity of theta phase disruption correlated with the magnitude of memory impairment. Further, cholinergic blockade disrupted connectivity within the hippocampal formation. Our results indicate that cholinergic circuits support memory by coordinating the temporal dynamics of theta oscillations across the hippocampal formation. These findings expand our mechanistic understanding of the neurophysiology of human memory and offer insights into potential treatments for memory-related disorders.

Hearing, seeing, and feeling speech: the neurophysiological correlates of trimodal speech perception.

To perceive speech, our brains process information from different sensory modalities. Previous electroencephalography (EEG) research has established that audio-visual information provides an advantage compared to auditory-only information during early auditory processing. In addition, behavioral research showed that auditory speech perception is not only enhanced by visual information but also by tactile information, transmitted by puffs of air arriving at the skin and aligned with speech. The current EEG study aimed to investigate whether the behavioral benefits of bimodal audio-aerotactile and trimodal audio-visual-aerotactile speech presentation are reflected in cortical auditory event-related neurophysiological responses. To examine the influence of multimodal information on speech perception, 20 listeners conducted a two-alternative forced-choice syllable identification task at three different signal-to-noise levels. Behavioral results showed increased syllable identification accuracy when auditory information was complemented with visual information, but did not show the same effect for the addition of tactile information. Similarly, EEG results showed an amplitude suppression for the auditory N1 and P2 event-related potentials for the audio-visual and audio-visual-aerotactile modalities compared to auditory and audio-aerotactile presentations of the syllable/pa/. No statistically significant difference was present between audio-aerotactile and auditory-only modalities. Current findings are consistent with past EEG research showing a visually induced amplitude suppression during early auditory processing. In addition, the significant neurophysiological effect of audio-visual but not audio-aerotactile presentation is in line with the large benefit of visual information but comparatively much smaller effect of aerotactile information on auditory speech perception previously identified in behavioral research.

Time-locked acute alpha-frequency stimulation of subthalamic nuclei during the evaluation of emotional stimuli and its effect on power modulation.

Deep brain stimulation (DBS) studies in Parkinson's Disease (PD) targeting the subthalamic nucleus (STN) have characterized its spectral properties across cognitive processes. In emotional evaluation tasks, specific alpha frequency (8-12 Hz) event-related de-synchronization (ERD) (reduced power) has been demonstrated. The time-locked stimulation of STN relative to stimuli onset has shown subjective positive valence shifts with 10 Hz but not with 130 Hz. However, neurophysiological effects of stimulation on power modulation have not been investigated. We aim to investigate effects of acute stimulation of the right STN on concurrent power modulation in the contralateral STN and frontal scalp EEG. From our previous study, we had a strong a priori hypothesis that negative imagery without stimulation would be associated with alpha ERD; negative imagery with 130 Hz stimulation would be also associated with alpha ERD given the lack of its effect on subjective valence ratings; negative imagery with 10 Hz stimulation was to be associated with enhanced alpha power given the shift in behavioral valence ratings. Twenty-four subjects with STN DBS underwent emotional picture-viewing tasks comprising neutral and negative pictures. In a subset of these subjects, the negative images were associated with time-locked acute stimulation at either 10 or 130 Hz. Power of signals was estimated relative to the baseline and subjected to non-parametric statistical testing. As hypothesized, in 130 Hz stimulation condition, we show a decrease in alpha power to negative vs. neutral images irrespective of stimulation. In contrast, this alpha power decrease was no longer evident in the negative 10 Hz stimulation condition consistent with a predicted increase in alpha power. Greater beta power in the 10 Hz stimulation condition along with correlations between beta power across the 10 Hz stimulation and unstimulated conditions suggest physiological and cognitive generalization effects. Acute alpha-specific frequency stimulation presumably was associated with a loss of this expected decrease or desynchronization in alpha power to negative images suggesting the capacity to facilitate the synchronization of alpha and enhance power. Acute time-locked stimulation has the potential to provide causal insights into the spectral frequencies and temporal dynamics of emotional processing.

Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice.

Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity. The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted. Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities. The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.

Modulatory dynamics mark the transition between anesthetic states of unconsciousness

Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, is characterized by slow-delta oscillations (0.3 to 4 Hz) and alpha oscillations (8 to 14 Hz) that are readily visible in the electroencephalogram. At higher doses, these slow-delta-alpha (SDA) oscillations transition into burst suppression. This is a marker of a state of profound brain inactivation during which isoelectric (flatline) periods alternate with periods of the SDA patterns present at lower doses. While the SDA and burst suppression patterns have been analyzed separately, the transition from one to the other has not. Using state-space methods, we characterize the dynamic evolution of brain activity from SDA to burst suppression and back during unconsciousness maintained with propofol or sevoflurane in volunteer subjects and surgical patients. We uncover two dynamical processes that continuously modulate the SDA oscillations: alpha-wave amplitude and slow-wave frequency modulation. We present an alpha modulation index and a slow modulation index which characterize how these processes track the transition from SDA oscillations to burst suppression and back to SDA oscillations as a function of increasing and decreasing anesthetic doses, respectively. Our biophysical model reveals that these dynamics track the combined evolution of the neurophysiological and metabolic effects of a GABAergic anesthetic on brain circuits. Our characterization of the modulatory dynamics mediated by GABAergic anesthetics offers insights into the mechanisms of these agents and strategies for monitoring and precisely controlling the level of unconsciousness in patients under general anesthesia.

Neurophysiological mechanisms of deep brain stimulation across spatiotemporal resolutions.

Deep brain stimulation is a neuromodulatory treatment for managing the symptoms of Parkinson's disease and other neurological and psychiatric disorders. Electrodes are chronically implanted in disease-relevant brain regions and pulsatile electrical stimulation delivery is intended to restore neurocircuit function. However, the widespread interest in the application and expansion of this clinical therapy has preceded an overarching understanding of the neurocircuit alterations invoked by deep brain stimulation. Over the years, various forms of neurophysiological evidence have emerged which demonstrate changes to brain activity across spatiotemporal resolutions; from single-neuron, to local field potential, to brain-wide cortical network effects. Though fruitful, such studies have often led to debate about a singular putative mechanism. In this Update we aim to produce an integrative account of complementary instead of mutually exclusive neurophysiological effects to derive a generalizable concept of the mechanisms of deep brain stimulation. In particular, we offer a critical review of the most common historical competing theories, an updated discussion on recent literature from animal and human neurophysiological studies, and a synthesis of synaptic and network effects of DBS across scales of observation, including micro-, meso-, and macroscale circuit alterations.

Interindividual differences in posterior fossa morphometry affect cerebellar tDCS-induced electric field strength

ObjectiveClinical, behavioural, and neurophysiological effects of cerebellar transcranial direct current stimulation (tDCS) are highly variable and difficult to predict. We aimed to examine associations between cerebellar tDCS-induced electric field strength, morphometric posterior fossa parameters, and skin-cerebellum distance. As a secondary objective, field characteristics were compared between cephalic and extracephalic electrode configurations. MethodsElectric field simulations of midline cerebellar tDCS (7 × 5 cm electrodes, current intensities of 2 mA) were performed on MRI-based head models from 37 healthy adults using buccinator, frontopolar, and lower neck reference electrodes. Average field strengths were determined in eight regions of interest (ROIs) covering the anterior and posterior vermis and cerebellar hemispheres. Besides skin-cerebellum distance, various angles were measured between posterior fossa structures. Multivariable linear regression models were used to identify predictors of field strength in different ROIs. ResultsSkin-cerebellum distance and “pons angle” were independently associated with field strength in the anterior and posterior vermis. “Cerebellar angle” and skin-cerebellum distance affected field strength in anterior and posterior regions of the right cerebellar hemisphere. Field strengths in all examined cerebellar areas were highest in the frontopolar and lowest in the lower neck montage, while the opposite was found for field focality. The lower neck montage induced considerably less spreading toward anterior cerebellar regions compared with the buccinator and frontopolar montages, which resulted in a more evenly distributed field within the cerebellum. ConclusionIn addition to skin-cerebellum distance, interindividual differences in posterior fossa morphometry, specifically pons and cerebellar angle, explain part of the variability in cerebellar tDCS-induced electric field strength. Furthermore, when targeting the midline cerebellum with tDCS, an extracephalic reference electrode is associated with lower field strengths and higher field focality than cephalic montages. SignificanceThis study identifies two novel subject-specific anatomical factors that partly determine cerebellar tDCS-induced electric field strength and reveals differences in field characteristics between electrode montages.

Non-Invasive Brain Stimulation and Sex/Polypeptide Hormones in Reciprocal Interactions: A Systematic Review.

A better understanding of interindividual differences and the development of targeted therapies is one of the major challenges of modern medicine. The sex of a person plays a crucial role in this regard. This systematic review aimed to summarise and analyse available evidence on the mutual interactions between non-invasive brain stimulation and sex/polypeptide hormones. The PubMed database was searched from its inception to 31 March 2023, for (i) studies that investigated the impact of sex and/or polypeptide hormones on the effects induced by non-invasive brain stimulation, or (ii) studies that investigated non-invasive brain stimulation in the modulation of sex and/or polypeptide hormones. Eighteen studies (319 healthy and 96 disabled participants) were included. Most studies focused on female sex hormone levels during the menstrual cycle. The later follicular phase is associated with a weak between hemispheric and intracortical inhibition, strong intracortical facilitation, and high stimulation-induced neural and behavioural changes. The opposite effects are observed during the luteal phase. In addition, the participant's sex, presence and/or absence of real ovulation and increase in oestradiol level by chorionic gonadotropin injection influence the stimulation-induced neurophysiological and behavioural effects. In Parkinson's disease and consciousness disorders, the repetitive application of non-invasive brain stimulation increases oestradiol and dehydroepiandrosterone levels and reduces disability. To date, male hormones have not been sufficiently included in these studies. Here, we show that the sex and/or polypeptide hormones and non-invasive brain stimulation methods are in reciprocal interactions. This may be used to create a more effective and individualised approach for healthy individuals and individuals with disabilities.