Internal Representations Are Prioritized by Frontoparietal Theta Connectivity and Suppressed by alpha Oscillation Dynamics: Evidence from Concurrent Transcranial Magnetic Stimulation EEG and Invasive EEG.

Control over internal representations requires the prioritization of relevant information and suppression of irrelevant information. The frontoparietal network exhibits prominent neural oscillations during these distinct cognitive processes. Yet, the causal role of this network-scale activity is unclear. Here, we targeted theta-frequency frontoparietal coherence and dynamic alpha oscillations in the posterior parietal cortex using online rhythmic transcranial magnetic stimulation (TMS) in women and men while they prioritized or suppressed internally maintained working memory (WM) representations. Using concurrent high-density EEG, we provided evidence that we acutely drove the targeted neural oscillation and TMS improved WM capacity only when the evoked activity corresponded with the desired cognitive process. To suppress an internal representation, we increased the amplitude of lateralized alpha oscillations in the posterior parietal cortex contralateral to the irrelevant visual field. For prioritization, we found that TMS to the prefrontal cortex increased theta-frequency connectivity in the prefrontoparietal network contralateral to the relevant visual field. To understand the spatial specificity of these effects, we administered the WM task to participants with implanted electrodes. We found that theta connectivity during prioritization was directed from the lateral prefrontal to the superior posterior parietal cortex. Together, these findings provide causal evidence in support of a model where a frontoparietal theta network prioritizes internally maintained representations and alpha oscillations in the posterior parietal cortex suppress irrelevant representations.

Contrast detection is enhanced by deterministic, high-frequency transcranial alternating current stimulation with triangle and sine waveform.

Stochastic resonance (SR) describes a phenomenon where an additive noise (stochastic carrier-wave) enhances the signal transmission in a nonlinear system. In the nervous system, nonlinear properties are present from the level of single ion channels all the way to perception and appear to support the emergence of SR. For example, SR has been repeatedly demonstrated for visual detection tasks, also by adding noise directly to cortical areas via transcranial random noise stimulation (tRNS). When dealing with nonlinear physical systems, it has been suggested that resonance can be induced not only by adding stochastic signals (i.e., noise) but also by adding a large class of signals that are not stochastic in nature that cause "deterministic amplitude resonance" (DAR). Here, we mathematically show that high-frequency, deterministic, periodic signals can yield resonance-like effects with linear transfer and infinite signal-to-noise ratio at the output. We tested this prediction empirically and investigated whether nonrandom, high-frequency, transcranial alternating current stimulation (tACS) applied to the visual cortex could induce resonance-like effects and enhance the performance of a visual detection task. We demonstrated in 28 participants that applying 80-Hz triangular-waves or sine-waves with tACS reduced the visual contrast detection threshold for optimal brain stimulation intensities. The influence of tACS on contrast sensitivity was equally effective to tRNS-induced modulation, demonstrating that both tACS and tRNS can reduce contrast detection thresholds. Our findings suggest that a resonance-like mechanism can also emerge when deterministic electrical waveforms are applied via tACS.NEW & NOTEWORTHY Our findings extend our understanding of neuromodulation induced by noninvasive electrical stimulation. We provide the first evidence showing acute online benefits of transcranial alternating current stimulation (tACS)triangle and tACSsine targeting the primary visual cortex (V1) on visual contrast detection in accordance with the resonance-like phenomenon. The "deterministic" tACS and "stochastic" high-frequency-transcranial random noise stimulation (tRNS) are equally effective in enhancing visual contrast detection.

Day-to-day individual alpha frequency variability measured by a mobile EEG device relates to anxiety.

The individual alpha frequency (IAF) has previously been identified as a unique neural signature within the 8-12 Hz alpha frequency band. However, the day-to-day variability of this feature is unknown. To investigate this, healthy participants recorded their own brain activity daily at home using the Muse 2 headband, a low-cost consumer-grade mobile electroencephalography (EEG) device. Resting-state recordings of all participants using a high-density (HD) EEG were also collected in lab before and after the at-home data collection period. We found that the IAF extracted from the Muse 2 was comparable to that of location-matched HD-EEG electrodes. No significant difference was found between these IAF values before and after the at-home recording period for the HD-EEG device. Similarly, there was also no statistically significant difference between the beginning and end of the at-home recording period for the Muse 2 headband over 1 month. Despite the group-level stability of IAF, the individual-level day-to-day IAF variability carried mental health-relevant information: Exploratory analyses revealed a relationship between IAF day-to-day variability and trait anxiety. We also noted that the IAF systematically varied across the scalp and although the Muse 2 electrodes do not cover the occipital lobe where alpha oscillations were the strongest, IAFs measured in the temporal lobe and occipital lobe were strongly correlated. Altogether, these results show that mobile EEG devices are useful for studying IAF variability. The relationship between day-to-day variability of region-specific IAF and the dynamics of psychiatric symptoms, particularly anxiety, should be further investigated.

Reward-Based Decision-Making Engages Distinct Modes of Cross-Frequency Coupling.

Prefrontal cortex exerts control over sensory and motor systems via cross-frequency coupling. However, it is unknown whether these signals play a role in reward-based decision-making and whether such dynamic network configuration is altered in a major depressive episode. We recruited men and women with and without depression to perform a streamlined version of the Expenditure of Effort for Reward Task during recording of electroencephalography. Goal-directed behavior was quantified as willingness to exert physical effort to obtain reward, and reward-evaluation was the degree to which the decision to exert effort was modulated by incentive level. We found that the amplitude of frontal-midline theta oscillations was greatest in participants with the greatest reward-evaluation. Furthermore, coupling between frontal theta phase and parieto-occipital gamma amplitude was positively correlated with reward-evaluation. In addition, goal-directed behavior was positively correlated with coupling between frontal delta phase to motor beta amplitude. Finally, we performed a factor analysis to derive 2 symptom dimensions and found that mood symptoms positively tracked with reward-evaluation and motivation symptoms negatively tracked with goal-directed behavior. Altogether, these results provide evidence that 2 aspects of reward-based decision-making are instantiated by different modes of prefrontal top-down control and are modulated in different symptom dimensions of depression.

Causal role of frontal-midline theta in cognitive effort: a pilot study.

Frontal-midline theta (FMT) oscillations are increased in amplitude during cognitive control tasks. Since these tasks often conflate cognitive control and cognitive effort, it remains unknown if FMT amplitude maps onto cognitive control or effort. To address this gap, we utilized the glucose facilitation effect to manipulate cognitive effort without changing cognitive control demands. We performed a single-blind, crossover human study in which we provided participants with a glucose drink (control session: volume-matched water) to reduce cognitive effort and improve performance on a visuospatial working memory task. Following glucose consumption, participants performed the working memory task at multiple time points of a 3-h window to sample across the rise and fall of blood glucose. Using high-density electroencephalography (EEG), we calculated FMT amplitude during the delay period of the working memory task. Source localization analysis revealed that FMT oscillations originated from bilateral prefrontal cortex. We found that glucose increased working memory accuracy during the high working memory load condition but decreased FMT amplitude. The decrease in FMT amplitude coincided with both peak blood glucose elevation and peak performance enhancement for glucose relative to water. Therefore, the positive association between glucose consumption and task performance provided causal evidence that the amplitude of FMT oscillations may correspond to cognitive effort, rather than cognitive control. Due to the COVID-19 pandemic, data collection was terminated prematurely; the preliminary nature of these findings due to small sample size should be contextualized by rigorous experimental design and use of a novel causal perturbation to dissociate cognitive effort and cognitive control.NEW & NOTEWORTHY We investigated whether frontal-midline theta (FMT) oscillations tracked with cognitive control or cognitive effort by simultaneous manipulation of cognitive control demands in a working memory task and causal perturbation of cognitive effort using glucose consumption. Facilitation of performance from glucose consumption corresponded with decreased FMT amplitude, which provided preliminary causal evidence for a relationship between FMT amplitude with cognitive effort.

Addiction history moderates the effect of prefrontal 10-Hz transcranial alternating current stimulation on habitual action selection.

Individuals with substance use disorders (SUDs) transition more quickly from goal-directed to habitual action-selection, but the neural mechanisms underlying this phenomenon remain unclear. Data from animal models suggest that drugs of abuse can modify the neurocircuits that regulate action-selection, enhancing circuits that drive inflexible, habit-based stimulus-response (S-R) action-selection and weakening circuits that drive flexible, goal-directed actions. Here, we tested the effect of bilateral 10-Hz transcranial alternating current stimulation (10Ηz-tACs) of the dorsolateral prefrontal cortex on action-selection in men and women with a SUD history and an age- and sex-matched control group. We tested the hypothesis that true 10Ηz-tACS versus active sham stimulation would reduce perseverative errors after changed response contingencies for well-learned S-R associations, reflecting reduced habit-based action-selection, specifically in the SUD group. We found that 10 Hz-tACS increased perseverative errors in the control group, but in the SUD group, 10 Hz-tACS effects on perseverative errors depended on substance abuse duration: a longer addiction history was associated with a greater reduction of perseverative errors. These results suggest that 10Ηz-tACs altered circuit level dynamics regulating behavioral flexibility, and provide a foundation for future studies to test stimulation site, frequency, and timing specificity. Moreover, these data suggest that chronic substance abuse is associated with altered circuit dynamics that are ameliorated by 10Ηz-tACs. Determining the generalizability of these effects and their duration merits investigation as a direction for novel therapeutic interventions. These findings are timely based on growing interest in transcranial stimulation methods for treating SUDs.NEW & NOTEWORTHY Treating the executive dysfunction associated with addiction is hampered by redundancies in pharmacological regulation of different behavioral control circuits. Thus, nonpharmacological interventions hold promise for addiction treatment. Here, we show that, among people with an addiction history, 10-Hz transcranial alternating current stimulation (10Hz-tACS) of the dorsolateral prefrontal cortex can reduce habitual actions. The fact that 10Hz-tACS can regulate behavioral flexibility suggests its possible utility in reducing harmful habitual actions.

Experimental increase of blood glucose alters resting state EEG measures of excitation-inhibition balance.

NEW FINDINGS: What is the central question of this study? Glucose is the dominant energy source for the brain. However, little is known about how glucose metabolism impacts the coordination of network activity in the brain in healthy adults. What is the main finding and its importance? We demonstrate that both α oscillations and the aperiodic signal components of the resting EEG are modulated by experimentally elevated blood glucose concentrations. Our findings suggest that glucose increases measures associated with excitation-inhibition (E:I) balance, but that the effect on α oscillations might plateau. Understanding the relationship between glucose consumption and E:I balance is crucial to developing our understanding of how metabolism shapes human brain activity. ABSTRACT: Brain network oscillations can be divided broadly into periodic and aperiodic signal components, which are sensitive to state-dependent changes in network coordination and excitation-inhibition (E:I) balance. We sought to address whether the dominant energy source of the brain, glucose, is implicated in the regulation of network activity and excitability. We conducted an experimenter-blind, crossover study of the effect of blood glucose level (BGL) on the resting EEG frequency spectrum. Participants consumed a glucose drink (75 g glucose) or an equivalent volume of water on two separate visits. EEG data were sampled before and ≤3 h after the drink. We found that the experimentally induced changes in BGL exhibited an inverted U-shaped relationship, with changes in the individual α frequency peak, whereas the slope of the aperiodic signal component of the frequency spectrum showed a positive linear association suggestive of greater excitation. In contrast, peak α power, which is typically associated with top-down inhibitory processes, was negatively associated with changes in BGL. Collectively, these results suggest that high BGL alters brain network coordination in the form of α oscillations and measures associated with E:I balance.

Transcranial Alternating Current Stimulation Reduces Network Hypersynchrony and Persistent Vertigo.

OBJECTIVES: Persistent oscillating vertigo that occurs after entrainment to periodic motion is known as Mal de Débarquement Syndrome (MdDS). Down-modulation of this oscillating vertigo is associated with reduction in long-range resting-state functional connectivity between fronto-parieto-occipital regions. In order to determine the association between this oscillating vertigo and hypersynchrony as measured by the auditory steady-state response (ASSR), we investigated the differences in ASSR between individuals with MdDS and healthy controls as well as the change in ASSR in individuals with MdDS before and after treatment with transcranial alternating current stimulation (tACS). MATERIALS AND METHODS: Individuals with treatment refractory MdDS lasting at least six months received single administrations of fronto-parieto-occipital tACS in an "n-of-1" double-blind randomized design: alpha-frequency in-phase, alpha-frequency antiphase, and gamma frequency antiphase control. The treatment protocol that led to the most acute reduction in symptoms and improved balance was administered for 10-12 sessions given over three days (each session 20-min at 2-4 mA). RESULTS: Twenty-four individuals with MdDS participated (mean age 53.0 ± 11.8 years [range: 22-66 years, median: 57.0 years]; mean duration of illness 38.6 ± 53.4 months [range: 6-240 months, median: 18.0 months]). Individuals with MdDS had elevated ASSR compared to healthy controls at baseline (t11 = 5.95, p < 0.001). There was a significant decrease in the 40 Hz-ASSR response between responders compared to nonresponders to tACS (t-test, t15 = -2.26, p = 0.04). Both in-phase and anti-phase alpha tACS lead to symptom improvement but only antiphase alpha-tACS led to a significant decrease of 40 Hz-ASSR (t-test, t12 = -9.6, p < 0.001). CONCLUSIONS: Our findings suggest that tACS has the potential to reduce network-level hypersynchrony and pathological susceptibility to entrainment by sensory input. To the best of our knowledge, this is the first successful demonstration of desynchronization by noninvasive brain stimulation leading to reduced vertigo. Other disease states associated with pathological functional coupling of neuronal networks may similarly benefit from this novel approach.

Exploring the relationship between geomagnetic activity and human heart rate variability.

PURPOSE: Both geomagnetic and solar activity fluctuate over time and have been proposed to affect human physiology. Heart rate variability (HRV) has substantial health implications regarding the ability to adapt to stressors and has been shown to be altered in many cardiovascular and neurological disorders. Intriguingly, previous work found significant, strong correlations between HRV and geomagnetic/solar activity. The purpose of this study to replicate these findings. We simultaneously measured HRV during a 30-day period. METHODS: We recruited 20 healthy participants and measured their HRV for a 30-day period. We also collected geomagnetic and solar activity during this period for investigating their relationship with the HRV data. RESULTS: In agreement with previous work, we found several significant correlations between short-term HRV and geophysical time-series. However, after correction for autocorrelation, which is inherent in time-series, the only significant results were an increase in very low frequency during higher local geomagnetic activity and a geomagnetic anticipatory decrease in heart rate a day before the higher global geomagnetic activity. Both correlations were very low. The loss of most significant effects after this correction suggests that previous findings may be a result of autocorrelation. A further note of caution is required since our and the previous studies in the field do not correct for multiple comparisons given the exploratory analysis strategy. CONCLUSION: We thus conclude that the effects of geomagnetic and solar activity are (if present) most likely of very small effect size and we question the validity of the previous studies given the methodological concerns we have uncovered with our work.

Targeting reduced neural oscillations in patients with schizophrenia by transcranial alternating current stimulation.

Transcranial alternating current stimulation (tACS) modulates endogenous neural oscillations in healthy human participants by the application of a low-amplitude electrical current with a periodic stimulation waveform. Yet, it is unclear if tACS can modulate and restore neural oscillations that are reduced in patients with psychiatric illnesses such as schizophrenia. Here, we asked if tACS modulates network oscillations in schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast tACS with transcranial direct current stimulation (tDCS) and sham stimulation in 22 schizophrenia patients with auditory hallucinations. We used high-density electroencephalography to investigate if a five-day, twice-daily 10Hz-tACS protocol enhances alpha oscillations and modulates network dynamics that are reduced in schizophrenia. We found that 10Hz-tACS enhanced alpha oscillations and modulated functional connectivity in the alpha frequency band. In addition, 10Hz-tACS enhanced the 40Hz auditory steady-state response (ASSR), which is reduced in patients with schizophrenia. Importantly, clinical improvement of auditory hallucinations correlated with enhancement of alpha oscillations and the 40Hz-ASSR. Together, our findings suggest that tACS has potential as a network-level approach to modulate reduced neural oscillations related to clinical symptoms in patients with schizophrenia.

Modulating neural oscillations by transcranial static magnetic field stimulation of the dorsolateral prefrontal cortex: A crossover, double-blind, sham-controlled pilot study.

Transcranial static magnetic field stimulation (tSMS) is a novel non-invasive brain stimulation technique that has been shown to locally increase alpha power in the parietal and occipital cortex. We investigated if tSMS locally increased alpha power in the left or right prefrontal cortex, as the balance of left/right prefrontal alpha power (frontal alpha asymmetry) has been linked to emotional processing and mood disorders. Therefore, altering frontal alpha asymmetry with tSMS may serve as a novel treatment to psychiatric diseases. We performed a crossover, double-blind, sham-controlled pilot study to assess the effects of prefrontal tSMS on neural oscillations. Twenty-four right-handed healthy participants were recruited and received left dorsolateral prefrontal cortex (DLPFC) tSMS, right DLPFC tSMS, and sham tSMS in a randomized order. Electroencephalography data were collected before (2 min eyes-closed, 2 min eyes-open), during (10 min eyes-open), and after (2 min eyes-open) stimulation. In contrast with our hypothesis, neither left nor right tSMS locally increased frontal alpha power. However, alpha power increased in occipital cortex during left DLPFC tSMS. Right DLPFC tSMS increased post-stimulation fronto-parietal theta power, indicating possible relevance to memory and cognition. Left and right DLPFC tSMS increased post-stimulation left hemisphere beta power, indicating possible changes to motor behavior. Left DLPFC tSMS also increased post-stimulation right frontal beta power, demonstrating complex network effects that may be relevant to aggressive behavior. We concluded that DLPFC tSMS modulated the network oscillations in regions distant from the location of stimulation and that tSMS has region specific effects on neural oscillations.

Neuromodulation-dependent effect of gated high-frequency, LFMS-like electric field stimulation in mouse cortical slices.

Low-field magnetic stimulation (LFMS) is a gated high-frequency non-invasive brain stimulation method (500 Hz gated at 2 Hz) with a proposed antidepressant effect. However, it has remained unknown how such stimulation paradigms modulate neuronal network activity and how the induced changes depend on network state. Here we examined the immediate and outlasting effects of the gated high-frequency electric field associated with LFMS on the cortical activity as a function of neuromodulatory tone that defines network state. We used a sham-controlled study design to investigate effects of stimulation (20 min of 0.5 s trains of 500 Hz charge-balanced pulse stimulation patterned at 0.5 Hz) on neural activity in mouse medial prefrontal cortex in vitro. Bath application of cholinergic and noradrenergic agents enabled us to examine the stimulation effects as a function of neuromodulatory tone. The stimulation attenuated the increase in firing rate of layer V cortical neurons during the post-stimulation period in the presence of cholinergic activation. The same stimulation had no significant immediate or outlasting effect in the absence of exogenous neuromodulators or in the presence of noradrenergic activation. These results provide electrophysiological insights into the neuromodulatory-dependent effects of gated high-frequency stimulation. More broadly, our results are the first to provide a mechanistic demonstration of how behavioral states and arousal levels may modify the effects of non-invasive brain stimulation.

Targeting alpha-band oscillations in a cortical model with amplitude-modulated high-frequency transcranial electric stimulation.

Non-invasive brain stimulation to target specific network activity patterns, e.g. transcranial alternating current stimulation (tACS), has become an essential tool to understand the causal role of neuronal oscillations in cognition and behavior. However, conventional sinusoidal tACS limits the ability to record neuronal activity during stimulation and lacks spatial focality. One particularly promising new tACS stimulation paradigm uses amplitude-modulated (AM) high-frequency waveforms (AM-tACS) with a slow signal envelope that may overcome the limitations. Moreover. AM-tACS using high-frequency carrier signals is more tolerable than conventional tACS, e.g. in terms of skin irritation and occurrence of phosphenes, when applied at the same current intensities (e.g. 1-2 mA). Yet, the fundamental mechanism of neuronal target-engagement by AM-tACS waveforms has remained unknown. We used a computational model of cortex to investigate how AM-tACS modulates endogenous oscillations and compared the target engagement mechanism to the case of conventional (unmodulated) low-frequency tACS. Analysis of stimulation amplitude and frequency indicated that cortical oscillations were phase-locked to the envelope of the AM stimulation signal, which thus exhibits the same target engagement mechanism as conventional (unmodulated) low frequency tACS. However, in the computational model substantially higher current intensities were needed for AM-tACS than for low-frequency (unmodulated) tACS waveforms to achieve pronounced phase synchronization. Our analysis of the carrier frequency suggests that there might be a trade-off between the use of high-frequency carriers and the stimulation amplitude required for successful entrainment. Together, our computational simulations support the use of slow-envelope high frequency carrier AM waveforms as a tool for noninvasive modulation of brain oscillations. More empirical data will be needed to identify the optimal stimulation parameters and to evaluate tolerability and safety of both, AM- and conventional tACS.

Non-linear transfer characteristics of stimulation and recording hardware account for spurious low-frequency artifacts during amplitude modulated transcranial alternating current stimulation (AM-tACS).

Amplitude modulated transcranial alternating current stimulation (AM-tACS) has been recently proposed as a possible solution to overcome the pronounced stimulation artifact encountered when recording brain activity during tACS. In theory, AM-tACS does not entail power at its modulating frequency, thus avoiding the problem of spectral overlap between brain signal of interest and stimulation artifact. However, the current study demonstrates how weak non-linear transfer characteristics inherent to stimulation and recording hardware can reintroduce spurious artifacts at the modulation frequency. The input-output transfer functions (TFs) of different stimulation setups were measured. Setups included recordings of signal-generator and stimulator outputs and M/EEG phantom measurements. 6th-degree polynomial regression models were fitted to model the input-output TFs of each setup. The resulting TF models were applied to digitally generated AM-tACS signals to predict the frequency of spurious artifacts in the spectrum. All four setups measured for the study exhibited low-frequency artifacts at the modulation frequency and its harmonics when recording AM-tACS. Fitted TF models showed non-linear contributions significantly different from zero (all p < .05) and successfully predicted the frequency of artifacts observed in AM-signal recordings. Results suggest that even weak non-linearities of stimulation and recording hardware can lead to spurious artifacts at the modulation frequency and its harmonics. These artifacts were substantially larger than alpha-oscillations of a human subject in the MEG. Findings emphasize the need for more linear stimulation devices for AM-tACS and careful analysis procedures, taking into account low-frequency artifacts to avoid confusion with effects of AM-tACS on the brain.

High-density EEG characterization of brain responses to auditory rhythmic stimuli during wakefulness and NREM sleep.

Auditory rhythmic sensory stimulation modulates brain oscillations by increasing phase-locking to the temporal structure of the stimuli and by increasing the power of specific frequency bands, resulting in Auditory Steady State Responses (ASSR). The ASSR is altered in different diseases of the central nervous system such as schizophrenia. However, in order to use the ASSR as biological markers for disease states, it needs to be understood how different vigilance states and underlying brain activity affect the ASSR. Here, we compared the effects of auditory rhythmic stimuli on EEG brain activity during wake and NREM sleep, investigated the influence of the presence of dominant sleep rhythms on the ASSR, and delineated the topographical distribution of these modulations. Participants (14 healthy males, 20-33 years) completed on the same day a 60 min nap session and two 30 min wakefulness sessions (before and after the nap). During these sessions, amplitude modulated (AM) white noise auditory stimuli at different frequencies were applied. High-density EEG was continuously recorded and time-frequency analyses were performed to assess ASSR during wakefulness and NREM periods. Our analysis revealed that depending on the electrode location, stimulation frequency applied and window/frequencies analysed the ASSR was significantly modulated by sleep pressure (before and after sleep), vigilance state (wake vs. NREM sleep), and the presence of slow wave activity and sleep spindles. Furthermore, AM stimuli increased spindle activity during NREM sleep but not during wakefulness. Thus, (1) electrode location, sleep history, vigilance state and ongoing brain activity needs to be carefully considered when investigating ASSR and (2) auditory rhythmic stimuli during sleep might represent a powerful tool to boost sleep spindles.

Ih interacts with somato-dendritic structure to determine frequency response to weak alternating electric field stimulation.

Transcranial current stimulation (tCS) modulates brain dynamics using weak electric fields. Given the pathological changes in brain network oscillations in neurological and psychiatric illnesses, using alternating electric field waveforms that engage rhythmic activity has been proposed as a targeted, network-level treatment approach. Previous studies have investigated the effects of electric fields at the neuronal level. However, the biophysical basis of the cellular response to electric fields has remained limited. Here, we characterized the frequency-dependent response of different compartments in a layer V pyramidal neuron to exogenous electric fields to dissect the relative contributions of voltage-gated ion channels and neuronal morphology. Hyperpolarization-activated cation current (Ih) in the distal dendrites was the primary ionic mechanism shaping the model's response to electric field stimulation and caused subthreshold resonance in the tuft at 20 ± 4 Hz. In contrast, subthreshold Ih-mediated resonance in response to local sinusoidal current injection was present in all model compartments at 11 ± 2 Hz. The frequencies of both resonance responses were modulated by Ih conductance density. We found that the difference in resonance frequency between the two stimulation types can be explained by the fact that exogenous electric fields simultaneously polarize the membrane potentials at the distal ends of the neuron (relative to field direction) in opposite directions. Our results highlight the role of Ih in shaping the cellular response to electric field stimulation and suggest that the common model of tCS as a weak somatic current injection fails to capture the cellular effects of electric field stimulation. NEW & NOTEWORTHY Modulation of cortical oscillation by brain stimulation serves as a tool to understand the causal role of network oscillations in behavior and is a potential treatment modality that engages impaired network oscillations in disorders of the central nervous system. To develop targeted stimulation paradigms, cellular-level effects must be understood. We demonstrate that hyperpolarization-activated cation current (Ih) and cell morphology cooperatively shape the response to applied alternating electric fields.

Unified thalamic model generates multiple distinct oscillations with state-dependent entrainment by stimulation.

The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh) and norepinephrine (NE) and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations) that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed.

Breakdown of local information processing may underlie isoflurane anesthesia effects.

The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source-such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)-as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy-suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.

Interaction of Intrinsic and Synaptic Currents Mediate Network Resonance Driven by Layer V Pyramidal Cells.

Cortical oscillations modulate cellular excitability and facilitate neuronal communication and information processing. Layer 5 pyramidal cells (L5 PYs) drive low-frequency oscillations (<4 Hz) in neocortical networks in vivo. In vitro, individual L5 PYs exhibit subthreshold resonance in the theta band (4-8 Hz). This bandpass filtering of periodic input is mediated by h-current (Ih) and m-current (IM) that selectively suppress low-frequency input. It has remained unclear how these intrinsic properties of cells contribute to the emergent, network oscillation dynamics. To begin to close this gap, we studied the link between cellular and network mechanisms of network resonance driven by L5 PYs. We performed multielectrode array recordings of network activity in slices of medial prefrontal cortex from the Thy1-ChR2-eYFP line and activated the network by temporally patterned optogenetic suprathreshold stimulation. Networks driven by stimulation of L5 PYs exhibited resonance in the theta band. We found that Ih and IM play a role in resonant suprathreshold network response to depolarizing stimuli. The action of Ih in mediating resonance was dependent on synaptic transmission while that of IM was not. These results demonstrate how synergistic interaction of synaptic and intrinsic ion channels contribute to the response of networks driven by L5 PYs.