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Despite the distortion of speech signals caused by unavoidable noise in daily life, our ability to comprehend speech in noisy environments is relatively stable. However, the neural mechanisms underlying reliable speech-in-noise comprehension remain to be elucidated. The present study investigated the neural tracking of acoustic and semantic speech information during noisy naturalistic speech comprehension. Participants listened to narrative audios mixed with spectrally matched stationary noise at three signal-to-ratio (SNR) levels (no noise, 3 dB, −3 dB), and 60-channel electroencephalography (EEG) signals were recorded. A temporal response function (TRF) method was employed to derive event-related-like responses to the continuous speech stream at both the acoustic and the semantic levels. Whereas the amplitude envelope of the naturalistic speech was taken as the acoustic feature, word entropy and word surprisal were extracted via the natural language processing method as two semantic features. Theta-band frontocentral TRF responses to the acoustic feature were observed at around 400 ms following speech fluctuation onset over all three SNR levels, and the response latency was more delayed with increasing noise. Delta-band frontal TRF responses to the semantic feature of word entropy were observed at around 200 to 600 ms leading to speech fluctuation onset over all three SNR levels. The response latency became more leading with increasing noise and was correlated with the perceived speech intelligibility. While the following responses to speech acoustics were consistent with previous studies, our study revealed the robustness of leading responses to speech semantics, which suggests a possible predictive mechanism at the semantic level for maintaining reliable speech comprehension in noisy environments.HighlightsLeading responses were observed in the semantic-level neural tracking across all noise levels, with more leading latency for increasing noises.Following responses were observed in the acoustic-level neural tracking, with more delayed latency for increasing noises.Semantic-level neural tracking is correlated with perceived intelligibility.Distinct frequency bands were involved in speech semantic and acoustic processing.

BackgroundCovert visuo-spatial attention is marked by the anticipatory lateralization of neuronal alpha activity in the posterior parietal cortex. Previous applications of transcranial alternating current stimulation (tACS) at the alpha frequency, however, were inconclusive regarding the causal contribution of oscillatory activity during visuo-spatial attention.ObjectiveAttentional shifts of behavior and electroencephalography (EEG) after-effects were assessed in a cued visuo-spatial attention paradigm. We hypothesized that parietal alpha-tACS facilitates attention in the ipsilateral visual hemifield. Furthermore, we assumed that modulations of behavior and neurophysiology are related to individual electric field simulations.MethodsWe applied personalized tACS at alpha and gamma frequencies to elucidate the role of oscillatory neuronal activity for visuo-spatial attention. Personalized tACS montages were algorithmically optimized to target individual left and right parietal regions that were defined by an EEG localizer.ResultsBehavioral performance in the left hemifield was specifically increased by alpha-tACS compared to gamma-tACS targeting the left parietal cortex. This hemisphere-specific effect was observed despite the symmetry of simulated electric fields. In addition, visual event-related potential (ERP) amplitudes showed a reduced lateralization over posterior sites induced by left alpha-tACS. Neuronal sources of this effect were localized in the left premotor cortex. Interestingly, accuracy modulations induced by left parietal alpha-tACS were directly related to electric field magnitudes in the left premotor cortex.ConclusionOverall, results corroborate the notion that alpha lateralization plays a causal role in covert visuo-spatial attention and indicate an increased susceptibility of parietal and premotor brain regions of the left dorsal attention network to subtle tACS-neuromodulation.

When we pay attention to someone, do we focus only on the sound they make, the word they use, or do we form a mental space shared with the speaker we want to pay attention to? Some would argue that the human language is no other than a simple signal, but others claim that human beings understand each other not only by relying on the words that have been said but also formed a shared ground in the specific conversation. This debate was raised early, but the conclusion remains vague. Our study aimed to investigate how attention modulates the neural coupling between the speaker and the listener in a cocktail party paradigm. The temporal response function (TRF) method was employed to reveal how the listener was coupled to the speaker at the neural level. The results showed that the neural coupling between the listener and the attended speaker peaked 5 seconds before speech onset at the delta band over the left frontal region, and was correlated with speech comprehension performance. In contrast, the attentional processing of speech acoustics and semantics occurred primarily at a later stage after speech onset and was not significantly correlated with comprehension performance. These findings suggest that our human brain might have adopted a predictive mechanism to achieve speaker-listener neural coupling for successful speech comprehension.Three key pointsListener’s EEG signals coupled to the speaker’s 5 s before the speech onset, which revealed a “beyond the stimulus” attentional modulation.Speaker-listener attentional coupling is correlated to the listener’s comprehension performance, but the speech-listener’s coupling didn’t.The implementation of temporal response function methods and the neural language methods yielded novel perspectives to the analysis of the inter-brain studies.

BackgroundAnaesthesia and surgery can lead to cognitive decline, especially in the elderly. However, to date, the neurophysiological underpinnings of perioperative cognitive decline remain unknown.MethodsWe included male patients, who were 60 years or older scheduled for elective radical prostatectomy under general anaesthesia. We obtained neuropsychological (NP) tests as well as a visual match-to-sample working memory (WM) task with concomitant 62-channel scalp electroencephalography (EEG) before and after surgery.ResultsA total number of 26 patients completed neuropsychological assessments and EEG pre- and postoperatively. Behavioural performance declined in the neuropsychological assessment after anaesthesia (total recall; t-tests: t25 = -3.25, Bonferroni-corrected p = 0.015 d = -0.902), while WM performance showed a dissociation between match and mis-match accuracy (rmANOVA: match*session F1,25 = 3.866, p = 0.060). Distinct EEG signatures tracked behavioural performance: Better performance in the NP assessment was correlated with an increase of non-oscillatory (aperiodic) activity, reflecting increased cortical activity (cluster permutation tests: total recall r = 0.66, p = 0.029, learning slope r = 0.66, p = 0.015), while WM accuracy was tracked by distinct temporally-structured oscillatory theta/alpha (7 – 9 Hz), low beta (14 – 18 Hz) and high beta/gamma (34 – 38 Hz) activity (cluster permutation tests: matches: p < 0.001, mis-matches: p = 0.022).ConclusionsOscillatory and non-oscillatory (aperiodic) activity in perioperative scalp EEG recordings track distinct features of perioperative cognition. Aperiodic activity provides a novel electrophysiological biomarker to identify patients at risk for developing perioperative neurocognitive decline.

Transcranial alternating current stimulation (tACS), applied to two brain sites with different phase lags, has been shown to modulate stimulation-outlasting functional EEG connectivity between the targeted regions. Given the lack of knowledge on mechanisms of tACS aftereffects, it is difficult to further enhance effect sizes and reduce variability in experiments. In this computational study, we tested if spike-timing-dependent plasticity (STDP) can explain stimulation-outlasting connectivity modulation by dual-site tACS and explored the effects of tACS parameter choices. Two populations of spiking neurons were coupled with synapses subject to STDP, and results were validated via a re-analysis of EEG data. Our simulations showed stimulation-outlasting connectivity changes between in- and anti-phase tACS, dependent on both tACS frequency and synaptic conduction delays. Importantly, both a simple network entraining to a wide range of tACS frequencies as well as a more realistic network that spontaneously oscillated at alpha frequency predicted that the largest effects would occur for short conduction delays between the stimulated regions. This finding agreed with experimental EEG connectivity modulation by 10 Hz tACS, showing a clear negative correlation of tACS effects with estimated conduction delays between regions. In conclusion, STDP can explain connectivity aftereffects of dual-site tACS. However, not all combinations of tACS frequency and application sites are expected to effectively modulate connectivity via STDP. We therefore suggest using appropriate computational models and/or EEG analysis for planning and interpretation of dual-site tACS studies relying on aftereffects.HighlightsNetwork model with STDP explains EEG connectivity change after dual-site tACSEffects are predicted to depend on tACS frequency and conduction delaysEEG data confirm dependence on conduction delays between regionsModel can be used to estimate and maximize experimental effects

Transgenic cFos reporter mice are used to identify and manipulate neurons that store contextual information during fear learning. It is not clear, however, how spatial information acquired over several training days is integrated in the hippocampus. Using a water maze task, we observed that cFos expression patterns in the dentate gyrus are temporally unstable and shift daily. Surprisingly, cFos patterns did not get more stable with increasing spatial memory precision. Despite the fact that cFos was no longer expressed, optogenetic inhibition of neurons that expressed cFos on the first training day affected performance days later. Triggered by training, ΔFosB accumulates and provides a negative feedback mechanism that makes the cFos ensemble in the dentate gyrus dependent on the history of activity. Shifting cFos expression to a different set of granule cells every day may aid the formation of episodic memories.

Optogenetic manipulation of neuronal activity has become an indispensable experimental strategy in neuroscience research. A large repertoire of excitatory and inhibitory tools allows precise activation or inhibition of genetically targetable neuronal populations. However, an optogenetic tool for reliable bidirectional control of neuronal activity allowing both up- and downregulation of the same neurons in a single experiment is still missing. Here we report BiPOLES, an optogenetic tool for potent excitation and inhibition of the same population of neurons with light of two different colors. BiPOLES consists of an inhibitory, blue-light-sensitive anion-conducting channelrhodopsin fused to an excitatory, red-light-sensitive cation-conducting channelrhodopsin in a single, trafficking-optimized tandem protein. BiPOLES enables multiple new applications including potent dual-color spiking and silencing of the same neurons in vivo and dual-color optogenetic control of two independent neuronal populations.

Influential accounts postulate distinct roles of the catecholamine and acetylcholine neuromodulatory systems in cognition and behavior. But previous work found similar effects of these modulators on the response properties of individual cortical neurons. Here, we report a double dissociation between catecholamine and acetylcholine effects at the level of cortex-wide network interactions in humans. A pharmacological boost of catecholamine levels increased cortex-wide interactions during a visual task, but not rest. Conversely, an acetylcholine-boost decreased correlations during rest, but not task. Cortical circuit modeling explained this dissociation by differential changes in two circuit properties: the local excitation-inhibition balance (more strongly altered by catecholamines) and intracortical transmission (more strongly reduced by acetylcholine). The inferred catecholaminergic mechanism also predicted increased behavioral exploration, which we confirmed in human behavior during both a perceptual and value-based choice task. In sum, we identified specific circuit mechanisms for shaping cortex-wide network interactions and behavior by key neuromodulatory systems.

Ageing is characterized by changes in sensory and cognitive abilities. While there is evidence that decline in sensory acuity and enhanced multisensory integration predict cognitive status in healthy older adults, potential mechanistic links between these age-related alterations remain unclear. In the current study, we assessed performance of younger and older healthy adults in a visuotactile delayed match-to-sample task and related indices of multisensory integration to unisensory perceptual thresholds and cognitive assessment data. Additionally, we applied transcranial alternating current stimulation (tACS) to modulate cortical networks found to underlie visuotactile interactions and working-memory matching in our previous work. Analysing response times and signal detection measures, we found older adults to show enhanced multisensory integration and benefit more from successful working memory matching. Both measures predicted cognitive status and correlated positively with each other, suggesting that they likely reflect a common underlying tendency to integrate information. Sensory capability, however, independently predicted cognitive status. tACS with beta frequency (20 Hz) accelerated task performance and this effect was more pronounced in the older group. We conclude that sensory capability and information integration represent independent predictors of cognitive status. Finally, we discuss a potential role of the parietal cortex in mediating augmented integration in older adults.

While human speech comprehension is thought to be an active process that involves top-down predictions, it remains unclear how predictive information is used to prepare for the processing of upcoming speech information. We aimed to identify the neural signatures of the preparatory processing of upcoming speech. Participants selectively attended to one of two competing naturalistic, narrative speech streams, and a temporal response function (TRF) method was applied to derive event-related-like neural responses from electroencephalographic data. The phase responses to the attended speech at the delta band (1–4 Hz) were correlated with the comprehension performance of individual participants, with a latency of − 200–0 ms relative to the onset of speech amplitude envelope fluctuations over the fronto-central and left-lateralized parietal electrodes. The phase responses to the attended speech at the alpha band also correlated with comprehension performance but with a latency of 650–980 ms post-onset over the fronto-central electrodes. Distinct neural signatures were found for the attentional modulation, taking the form of TRF-based amplitude responses at a latency of 240–320 ms post-onset over the left-lateralized fronto-central and occipital electrodes. Our findings reveal how the brain gets prepared to process an upcoming speech in a continuous, naturalistic speech context.

The human brain exhibits rhythms that are characteristic for anatomical areas and presumably involved in perceptual and cognitive processes. Visual deprivation results in behavioral adaptation and cortical reorganization. Whether neuroplasticity-related mechanisms involve altered spectral properties of neural signals and which brain areas are particularly affected, is unknown. We analyzed magnetoencephalography resting state data of congenitally blind and matched sighted individuals. First, using clustering procedures (k-means and Gaussian Mixture Models) we identified brain region-specific spectral clusters. Second, a classifier was employed testing the specificity of the spectral profiles within and the differences between groups. We replicated previously reported findings of area-specific spectral profiles, indicated by high classification performance in the sighted. Additionally, we found high classification performance in the blind, suggesting that area-specific spectral profiles were consistently identified after deprivation-related reorganization. Crucially, in the cross-group classification (sighted vs. blind), several sensory (visual and auditory) and right frontal areas were classified worse compared to the control (within sighted classification) condition. Overall the spectral profiles of these areas showed increased neuronal power in higher frequency bands in the blind compared to the sighted, possibly reflecting acceleration of regionally prevalent brain rhythms. The spectral profiles in areas where group differences were observed correlated with microstructural white matter properties in an extended posterior and bilateral cluster. We provide evidence that visual deprivation-related plasticity particulary alters the spectral profiles of right frontal, visual and auditory brain regions, possibly reflecting increased temporal processing capabilities (auditory, frontal cortices) and changes in the visual inhibitory-excitatory circuits in the blind.

Transcranial electric stimulation (tES) induces electric fields that are subject to a complex interaction with individual anatomical properties, such as the low-conducting human skull, the distribution of cerebrospinal fluid or the sulcal depth, as well as stimulation target location and orientation. This complex interaction might contribute to the heterogenous results that are commonly observed in applications of tES in humans. Targeted tES, on the other hand, might be able to account for some of these individual factors. In the present study, we used the finite-element method (FEM) and head models of twenty-one participants to evaluate the effect of individually targeted tES on simulated intracranial current densities. Head models were based on an automated segmentation algorithm to facilitate processing in experimental sample sizes. We compared a standard stimulation montage to two individually optimized tES montages using an Alternating Direction Method of Multipliers (ADMM) and a Constrained Maximum Intensity (CMI) approach. A right parietal target was defined with three different orientations. Individual current densities showed varying intensity and spatial extent near the lower limit at which physiological efficacy of electric fields can be assumed. Both individually optimized targeting algorithms were able to control the electric field properties, with respect to intensities and/or spatial extent of the electric fields. Still, across head models, intensity in the stimulation target was constrained by individual anatomical properties. Thus, our results underline the importance of targeted tES in enhancing the effectiveness of future tES applications and in elucidating the underlying mechanisms.

The phase of neural oscillatory activity aligns to the predicted onset of upcoming stimulation. Whether such phase alignments represent phase resets of underlying neural oscillations or just rhythmically evoked activity, and whether they can be observed in a rhythm-free visual context, however, remains unclear. Here, we recorded the magnetoencephalogram while participants were engaged in a temporal prediction task judging the visual or tactile reappearance of a uniformly moving stimulus. The prediction conditions were contrasted with a control condition to dissociate phase adjustments of neural oscillations from stimulus-driven activity. We observed stronger delta band inter-trial phase consistency (ITPC) in a network of sensory, parietal and frontal brain areas, but no power increase reflecting stimulus-driven or prediction-related processes. Delta ITPC further correlated with prediction performance in the cerebellum and visual cortex. Our results provide evidence that phase alignments of low-frequency neural oscillations underlie temporal predictions in a non-rhythmic visual and crossmodal context.

BackgroundOscillatory phase has been proposed as a key parameter defining the spatiotemporal structure of neural activity. To enhance our understanding of brain rhythms and improve clinical outcomes in pathological conditions, phase-specific modulation of oscillations by transcranial alternating current stimulation (tACS) emerged as a promising approach. However, the effectiveness of tACS in humans is still critically debated.ObjectiveHere, we investigated the phase-specificity of tACS effects on visually evoked steady state responses (SSRs) in 24 healthy human participants of either sex.MethodsTo this end, we used an intermittent electrical stimulation protocol and assessed the influence of tACS on SSR amplitude in the interval immediately following tACS.ResultsWe observed that the phase shift between flicker and tACS modulates evoked SSR amplitudes. The tACS effect size was dependent on the strength of flicker-evoked oscillatory activity, with larger effects in participants showing weaker locking of neural responses to flicker phase. Neural sources of phase-specific effects were localized in the parieto-occipital cortex within flicker-entrained regions. Importantly, the optimal phase shift between flicker and tACS associated with strongest SSRs was correlated with cortical SSR onset delays over the visual cortex.ConclusionsOverall, our data provide electrophysiological evidence for phase-specific modulations of oscillatory activity by tACS in humans. As the optimal timing of tACS application was dependent on neural conduction times as measured by SSR onset delays, data suggest that the interaction between tACS effect and SSR was cortical in nature. These findings corroborate the physiological efficacy of tACS and highlight its potential for controlled modulations of brain signals.

Complex and variable behavior requires fast changes of functional connectivity in large-scale cortical networks. Here, we report on the cortical dynamics of functional coupling across visual, auditory and parietal areas during a lateralized detection task in the ferret. We hypothesized that fluctuations in coupling, indicative of dynamic variations in the network state, might predict the animals’ performance. While power for hit and miss trials showed significant differences only around stimulus and response onset, phase coupling already differed before stimulus onset. Principal component analysis of directed coupling at the single-trial level during this period revealed subnetworks that most strongly related to behavior. While higher global phase coupling of visual and auditory regions to parietal cortex was predictive of task performance, a second component showed that a reduction in coupling between subnetworks of sensory modalities was also necessary, probably to allow a better detection of the unimodal signals. Furthermore, we observed that long-range coupling became more predominant during the task period compared to the pre-stimulus baseline. Taken together, these results suggest that fluctuations in the network state, particular with respect to long-range connectivity, are key determinants of the animals’ behavior.

Rhythmic neuronal activity in the gamma range is a signature of active cortical processing and its synchronization across distant sites has been proposed as a fundamental mechanism of network communication. While this has been shown within sensory modalities, we tested whether crosstalk between the senses relies on similar mechanisms. In two consecutive experiments, we used a task in which human participants (male and female) matched amplitude changes of concurrent visual, auditory and tactile stimuli. In this task, matching of congruent stimuli was associated with a behavioral benefit compared to matching of incongruent stimuli. In the first experiment, we used source-level analysis of high-density electroencephalography (EEG) and observed that cross-modal matching of congruent inputs was associated with relatively weaker coherence between gamma oscillations in early sensory regions. Next, we used bifocal high-definition transcranial alternating current stimulation (hd-tACS) to manipulate the strength of coupling between sensory cortices. Here, we used a lateralized version of the task in which hd-tACS was applied either ipsilateral or contralateral to the hemisphere receiving sensory stimuli. Ipsilateral gamma, but not alpha stimulation slowed responses to congruent trials whereas responding to incongruent trials was not changed by tACS. We speculate that fast responding to congruent stimuli involves decoupling of sensory gamma oscillations, which was prevented by tACS. These results indicate that synchronization of gamma oscillations promotes direct communication between sensory modalities. The framework of coupled gamma oscillations underlying cortical communication might thus be generalizable from processing within sensory streams to interactions between sensory networks.Significance statementCortical gamma oscillations structure segregated neural activity and were suggested to represent a fundamental mechanism of network communication. While there is ample evidence for the role of long-range gamma synchronization in unisensory processing, its significance in multisensory networks is still unclear. We show that direct interactions between sensory cortices rely on synchronization of gamma band activity. To that end, we carried out two consecutive experiments using state-of-the-art high-density electroencephalography (EEG) and high-definition transcranial alternating current stimulation (hd-tACS). By complementing an observational with an interventional method, we provide novel evidence for the role of synchronized gamma oscillations in multisensory communication.

BACKGROUND: In cortical networks, synchronized oscillatory activity of neuronal populations enables communication, and its disturbance is related to a range of pathologies. Transcranial alternating current stimulation (tACS) has been explored as a flexible, noninvasive tool for the modulation and restoration of synchronized oscillatory signals. While numerous studies have addressed cognitive or behavioural effects of electrical stimulation, the neural changes underlying the effects of tACS and their persistence after stimulation offset have remained unclear. OBJECTIVE: Here, we screened for lasting aftereffects of prolonged tACS on intrinsic network activity and audiovisual processing in the anesthetized ferret brain. METHODS: Electrical stimulation was applied via subcutaneous wire electrodes. Current waveforms were synthesized from two frequencies in the alpha or gamma range, respectively. Flashes and clicks were used for audiovisual stimulation. Electrocorticographic recordings from an extended network including occipital, temporal and parietal cortical areas were obtained before and after tACS. RESULTS: Changes in local synchrony (continuous and spike-triggered power of LFP), synchrony across recording sites (imaginary coherence) and altered dynamics of sensory response-features (peak-to-peak amplitude, extremum latency) following electrical stimulation consistently point to a synchronizing effect of tACS that can outlast stimulation offset by at least 10 min. Gamma-band tACS proved particularly effective. In line with previous reports on cross-frequency interactions, we observed effects on coherence and power of baseline activity at frequencies other than the ones targeted by tACS. These cross-frequency interactions appeared to underlie the strengthening and stabilizing effect on audiovisual responses. CONCLUSION: We demonstrate aftereffects of tACS on synchrony and stimulus processing in an extended cortical network, measured intracranially in a setting that resembles tACS stimulation in humans. The data provide direct evidence for the efficacy of tACS as a tool for sustained modulation of cortical network dynamics.

Dynamic communication and routing play important roles in the human brain in order to facilitate flexibility in task solving and thought processes. Here, we present a network perturbation methodology that allows investigating dynamic switching between different network pathways based on phase offsets between two external oscillatory drivers. We apply this method in a computational model of the human connectome with delay-coupled neural masses. To analyze dynamic switching of pathways, we define four new metrics that measure dynamic network response properties for pairs of stimulated nodes. Evaluating these metrics for all network pathways, we found a broad spectrum of pathways with distinct dynamic properties and switching behaviors. We show that network pathways can have characteristic timescales and thus specific preferences for the phase lag between the regions they connect. Specifically, we identified pairs of network nodes whose connecting paths can either be (1) insensitive to the phase relationship between the node pair, (2) turned on and off via changes in the phase relationship between the node pair, or (3) switched between via changes in the phase relationship between the node pair. Regarding the latter, we found that 33% of node pairs can switch their communication from one pathway to another depending on their phase offsets. This reveals a potential mechanistic role that phase offsets and coupling delays might play for the dynamic information routing via communication pathways in the brain., Author summary A big challenge in elucidating information processing in the brain is to understand the neural mechanisms that dynamically organize the communication between different brain regions in a flexible and task-dependent manner. In this theoretical study, we present an approach to investigate the routing and gating of information flow along different pathways from one region to another. We show that stimulation of the brain at two sites with different frequencies and oscillatory phases can reveal the underlying effective connectivity. This yields new insights into the underlying processes that govern dynamic switches in the communication pathways between remote sites of the brain.

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson’s disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopamine-depleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

Audiovisual integration is facilitated by the context-specific dynamical reconfiguration of cortical intrinsic coupling., Intrinsically generated patterns of coupled neuronal activity are associated with the dynamics of specific brain states. Sensory inputs are extrinsic factors that can perturb these intrinsic coupling modes, creating a complex scenario in which forthcoming stimuli are processed. Studying this intrinsic-extrinsic interplay is necessary to better understand perceptual integration and selection. Here, we show that this interplay leads to a reconfiguration of functional cortical connectivity that acts as a mechanism to facilitate stimulus processing. Using audiovisual stimulation in anesthetized ferrets, we found that this reconfiguration of coupling modes is context specific, depending on long-term modulation by repetitive sensory inputs. These reconfigured coupling modes lead to changes in latencies and power of local field potential responses that support multisensory integration. Our study demonstrates that this interplay extends across multiple time scales and involves different types of intrinsic coupling. These results suggest a previously unknown large-scale mechanism that facilitates multisensory integration.

Intrinsic coupling modes (ICMs) provide a framework for describing the interactions of ongoing brain activity at multiple spatial and temporal scales. Two families of ICMs can be distinguished: phase and envelope ICMs. The principles that shape these ICMs remain partly elusive, in particular their relation to the underlying brain structure. Here we explored structure-function relationships in the ferret brain between ICMs quantified from ongoing brain activity recorded with chronically implanted ECoG arrays and structural connectivity (SC) obtained from high-resolution diffusion MRI tractography. Large-scale computational models as well as simple topological ingredients of SC were used to explore the ability to predict both types of ICMs. Importantly, all investigations were conducted with ICM measures that are sensitive or insensitive to volume conduction effects. The results show that both types of ICMs are strongly related to SC, except when using ICM measures removing zero-lag synchronizations. Computational models are challenged to predict these ICM patterns consistently, and simple predictions from SC topological features can sometimes outperform them. Overall, the results demonstrate that patterns of cortical functional coupling as reflected in both phase and envelope ICMs bear a substantial relation to the underlying structural connectivity of the cerebral cortex.

BackgroundLong-range functional connectivity in the brain is considered fundamental for cognition and is known to be altered in many neuropsychiatric disorders. To modify such coupling independent of sensory input, noninvasive brain stimulation could be of utmost value.ObjectiveFirst, we tested if transcranial alternating current stimulation (tACS) is able to influence functional connectivity in the human brain. Second, we investigated the specificity of effects in frequency and space.MethodsEEG aftereffects of bifocal high-definition tACS were analyzed systematically in sensor and source space. Participants were stimulated transcranially in counterbalanced order (1) in-phase, with identical electric fields in both hemispheres, (2) anti-phase, with phase-reversed electric fields in the two hemispheres, and (3) jittered-phase, generated by subtle frequency shifts continuously changing the phase relation between the two fields.ResultsWhile total power and spatial distribution of the fields were comparable between conditions, global pre-post stimulation changes in EEG connectivity were larger after in-phase stimulation than after anti-phase or jittered-phase stimulation. Those differences in connectivity were restricted to the stimulated frequency band and decayed within the first 120 s after stimulation offset. Source reconstruction localized the maximum effect between the stimulated occipitoparietal areas.ConclusionThe relative phase of bifocal alpha-tACS modulated alpha-band connectivity between the targeted regions. As side effects did not differ between stimulation conditions, we conclude that neural activity was phase-specifically influenced by the electric fields. We thus suggest bifocal high-definition tACS as a tool to manipulate long-range cortico-cortical coupling which outlasts the stimulation period.

Prevalence and temporal dynamics of transient oscillations in the beta frequency band (15-35 Hz), referred to as beta bursts, are correlated with motor performance and tactile perception. Disturbance of these activities is a candidate mechanism for motor impairment in Parkinson’s disease (PD), where the excessively long bursts correlate with symptom severity and are reduced by pharmacological and surgical treatments. To date, characterization of beta bursts in PD has been limited to the local field potentials in the subthalamic nucleus (STN) and cortical EEG. Here, we describe the changes that take place in spiking activity across the cortico-basal ganglia circuit, providing a unique insight into the network dynamics of these transient oscillations. Firstly, we demonstrate that rhythmic subthalamic spiking activity emerges at a fixed phase relationship with respect to cortical beta bursts in PD patients. Using multichannel recordings of ensembles of neurons in the 6-OHDA rat model of PD, we then dissect the beta burst dynamics across the sensorimotor cortex and several basal ganglia structures: striatum (Str), globus pallidus externus (GPe) and STN. Each subcortical structure exhibits enhanced rhythmic activity in the beta band locked to the onset of cortical beta bursts and longer cortical bursts lead to stronger subcortical rhythmicity. Crucially, enhanced subcortical rhythmic activity emerges at a fixed phase relationship with respect to the motor cortex, comparable to the relationship observed in PD patients. Striatal beta bursts terminate prior to the recruitment of those in the STN and GPe, suggesting that while they could play an important role in establishing synchrony in the beta band, they do not extensively contribute to its maintenance in other basal ganglia structures. Critically, changes in cortico-subcortical phase coupling precede the onset of a cortical beta burst, supporting the hypothesis that phase alignment across the cortico-basal ganglia network could recruit these structures into synchronous network oscillations. We provide a powerful approach that not only examines pathophysiology of PD across the motor circuit, but also offer insights that could aid in the design of novel neuromodulation strategies to manipulate the state of the motor system before pathological activities emerge.

We investigated the function of oscillatory alpha-band activity in the neural coding of spatial information during tactile processing. Sighted humans concurrently encode tactile location in skin-based and, after integration with posture, external spatial reference frames, whereas congenitally blind humans preferably use skin-based coding. Accordingly, lateralization of alpha-band activity in parietal regions during attentional orienting in expectance of tactile stimulation reflected external spatial coding in sighted, but skin-based coding in blind humans. Here, we asked whether alpha-band activity plays a similar role in spatial coding for tactile processing, that is, after the stimulus has been received. Sighted and congenitally blind participants were cued to attend to one hand in order to detect rare tactile deviant stimuli at this hand while ignoring tactile deviants at the other hand and tactile standard stimuli at both hands. The reference frames encoded by oscillatory activity during tactile processing were probed by adopting either an uncrossed or crossed hand posture. In sighted participants, attended relative to unattended standard stimuli suppressed the power in the alpha-band over ipsilateral centro-parietal and occipital cortex. Hand crossing attenuated this attentional modulation predominantly over ipsilateral posterior-parietal cortex. In contrast, although contralateral alpha-activity was enhanced for attended versus unattended stimuli in blind participants, no crossing effects were evident in the oscillatory activity of this group. These findings suggest that oscillatory alpha-band activity plays a pivotal role in the neural coding of external spatial information for touch.

BackgroundOnly few aerobic exercise intervention trials specifically targeting cognitive functioning have been performed in MS.Objective and methodsThis randomized controlled trial aimed to determine the effects of aerobic exercise on cognition in relapsing-remitting MS. The primary outcome was verbal memory (Verbal learning and memory test, VLMT). Patients were randomized to an intervention group (IG) program or a waitlist control group (CG). Patients in the IG exercised according to an individually tailored training schedule (with 2-3 sessions per week for 12 weeks). The primary analysis was carried out using the intention-to-treat (ITT) sample with ANCOVA adjusting for baseline scores.Results77 RRMS patients were screened and 68 participants randomized (CG n=34; IG n=34). The sample comprised 68% females, had a mean age of 39 years, a mean disease duration of 6.3 years, and a mean EDSS of 1.8. No significant effects were detected in the ITT analysis for the primary endpoint VLMT or any other cognitive measures. Moreover, no significant treatment effects were observed for quality of life, fatigue, or depressive symptoms.ConclusionThis study failed to demonstrate beneficial effects of aerobic exercise on cognition in RRMS.The trial was prospectively registered at clinicaltrials.gov (NCT02005237).

Congenitally blind individuals have been shown to activate the visual cortex during non-visual tasks. The neuronal mechanisms of such cross-modal activation are not fully understood. Here, we used an auditory working memory training paradigm in congenitally blind and in sighted adults. We hypothesized that the visual cortex gets integrated into auditory working memory networks, after these networks have been challenged by training. The spectral profile of functional networks was investigated which mediate cross-modal reorganization following visual deprivation. A training induced integration of visual cortex into task-related networks in congenitally blind individuals was expected to result in changes in long-range functional connectivity in the theta-, beta- and gamma band (imaginary coherency) between visual cortex and working memory networks. Magnetoencephalographic data were recorded in congenitally blind and sighted individuals during resting state as well as during a voicebased working memory task; the task was performed before and after working memory training with either auditory or tactile stimuli, or a control condition. Auditory working memory training strengthened theta-band (2.5–5 Hz) connectivity in the sighted and beta-band (17.5–22.5 Hz) connectivity in the blind. In sighted participants, theta-band connectivity increased between brain areas typically involved in auditory working memory (inferior frontal, superior temporal, insular cortex). In blind participants, beta-band networks largely emerged during the training, and connectivity increased between brain areas involved in auditory working memory and as predicted, the visual cortex. Our findings highlight long-range connectivity as a key mechanism of functional reorganization following congenital blindness, and provide new insights into the spectral characteristics of functional network connectivity.

The ascending modulatory systems of the brain stem are powerful regulators of global brain state. Disturbances of these systems are implicated in several major neuropsychiatric disorders. Yet, how these systems interact with specific neural computations in the cerebral cortex to shape perception, cognition, and behavior remains poorly understood. Here, we probed into the effect of two such systems, the catecholaminergic (dopaminergic and noradrenergic) and cholinergic systems, on an important aspect of cortical computation: its intrinsic variability. To this end, we combined placebo-controlled pharmacological intervention in humans, recordings of cortical population activity using magnetoencephalography (MEG), and psychophysical measurements of the perception of ambiguous visual input. A low-dose catecholaminergic, but not cholinergic, manipulation altered the rate of spontaneous perceptual fluctuations as well as the temporal structure of “scale-free” population activity of large swaths of the visual and parietal cortices. Computational analyses indicate that both effects were consistent with an increase in excitatory relative to inhibitory activity in the cortical areas underlying visual perceptual inference. We propose that catecholamines regulate the variability of perception and cognition through dynamically changing the cortical excitation–inhibition ratio. The combined readout of fluctuations in perception and cortical activity we established here may prove useful as an efficient and easily accessible marker of altered cortical computation in neuropsychiatric disorders., Author summary The human brain is equipped with a number of modulatory neurotransmitter systems, which have widespread projections and regulate global brain states. Disturbances of these systems are implicated in several neuropsychiatric disorders, but how they modulate specific neural computations to shape perception, cognition, and behavior remains unknown. Here, we combined pharmacological interventions with electrophysiological and behavioral measurements to investigate the impact of two classes of such neuromodulatory systems—catecholamines and acetylcholine—on the variability of the activity of neuronal populations in the cerebral cortex and on cognition in humans. We addressed a prominent hypothesis, which holds that noradrenaline—a catecholamine—boosts the variability of inference and decision-making to promote exploration of alternative options—for example, exploring distinct perceptual interpretations of an ambiguous sensory input. Pharmacologically elevating catecholamine levels, but not acetylcholine levels, altered the temporal structure of intrinsic variability of population activity in two cortical regions and increased the rate of spontaneous perceptual alternations induced by ambiguous visual stimulation, in line with an increase in exploration. Computational modeling revealed that the observed changes can be explained by an increase in the ratio between excitation and inhibition in the circuits processing the stimulus.

Cross-frequency coupling (CFC) has been suggested to constitute a highly flexible mechanism for cortical information gating and processing, giving rise to conscious perception and various higher cognitive functions in humans. In particular, it might provide an elegant tool for information integration across several spatiotemporal scales within nested or coupled neuronal networks. However, it is currently unknown whether low frequency (theta/alpha) or high frequency gamma oscillations orchestrate cross-frequency interactions, raising the question of who is master and who is slave. While correlative evidence suggested that at least two distinct CFC modes exist, namely phase-amplitude-coupling (PAC) and amplitude-envelope-correlations (AEC), it is currently unknown whether they subserve distinct cortical functions. Novel non-invasive brain stimulation tools, such as transcranial alternating current stimulation (tACS), now provide the unique opportunity to selectively entrain the low or high frequency component and study subsequent effects on CFC. Here, we demonstrate the differential modulation of CFC during selective entrainment of alpha or gamma oscillations. Our results reveal that entrainment of the low frequency component increased PAC, where gamma power became preferentially locked to the trough of the alpha oscillation, while gamma-band entrainment reduced alpha power through enhanced AECs. These results provide causal evidence for the functional role of coupled alpha and gamma oscillations for visual processing.

A large amount of studies of the last decades revealed an association between human behaviour and oscillatory activity in the human brain. Alike, abnormalities of oscillatory activity were related with pathological behaviour in many neuropsychiatric disorders, such as in Parkinson's disease (PD) or in schizophrenia (SCZ). As a therapeutic tool, non-invasive brain stimulation (NIBS) has demonstrated the potential to improve behavioural performance in patients suffering from neuropsychiatric disorders. Since evidence accumulates that NIBS might be able to modulate oscillatory activity and related behaviour in a scientific setting, this review focuses on discussing potential interventional strategies to target abnormalities in oscillatory activity in neuropsychiatric disorders. In particular, we will review oscillatory changes described in patients after stroke, with PD or suffering from SCZ. Potential ways of targeting interventionally the underlying pathological oscillations to improve related pathological behaviour will be further discussed.

Background: High frequency oscillations in the gamma range are known to be involved in early stages of auditory information processing in terms of synchronization of brain regions, e.g., in cognitive functions. It has been shown using EEG source localisation, as well as simultaneously recorded EEG-fMRI, that the auditory evoked gamma-band response (aeGBR) is modulated by attention. In addition to auditory cortex activity a dorsal anterior cingulate cortex (dACC) generator could be involved. In the present study we investigated aeGBR magnetic fields using magnetoencephalography (MEG). We aimed to localize the aeGBR sources and its connectivity features in relation to mental effort. Methods: We investigated the aeGBR magnetic fields in 13 healthy participants using a 275-channel CTF-MEG system. The experimental paradigms were two auditory choice reaction tasks with different difficulties and demands for mental effort. We performed source localization with eLORETA and calculated the aeGBR lagged phase synchronization between bilateral auditory cortices and frontal midline structures. Results: The eLORETA analysis revealed sources of the aeGBR within bilateral auditory cortices and in frontal midline structures of the brain including the dACC. Compared to the control condition the dACC source activity was found to be significantly stronger during the performance of the cognitively demanding task. Moreover, this task involved a significantly stronger functional connectivity between auditory cortices and dACC. Conclusion: In accordance with previous EEG and EEG-fMRI investigations, our study confirms an aeGBR generator in the dACC by means of MEG and suggests its involvement in the effortful processing of auditory stimuli.

During the last two decades ferrets (Mustela putorius) have been established as a highly efficient animal model in different fields in neuroscience. Here we asked whether ferrets integrate sensory information according to the same principles established for other species. Since only few methods and protocols are available for behaving ferrets we developed a head-free, body-restrained approach allowing a standardized stimulation position and the utilization of the ferret?s natural response behavior. We established a behavioral paradigm to test audiovisual integration in the ferret. Animals had to detect a brief auditory and/or visual stimulus presented either left or right from their midline. We first determined detection thresholds for auditory amplitude and visual contrast. In a second step, we combined both modalities and compared psychometric fits and the reaction times between all conditions. We employed Maximum Likelihood Estimation (MLE) to model bimodal psychometric curves and to investigate whether ferrets integrate modalities in an optimal manner. Furthermore, to test for a redundant signal effect we pooled the reaction times of all animals to calculate a race model. We observed that bimodal detection thresholds were reduced and reaction times were faster in the bimodal compared to unimodal conditions. The race model and MLE modeling showed that ferrets integrate modalities in a statistically optimal fashion. Taken together, the data indicate that principles of multisensory integration previously demonstrated in other species also apply to crossmodal processing in the ferret.