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Background Over the past decade, the number of experimental and clinical studies using theta-burst-stimulation (TBS) protocols of transcranial magnetic stimulation (TMS) to modulate brain activity has risen substantially. The use of TBS is motivated by the assumption that these protocols can reliably and lastingly modulate cortical excitability despite their short duration and low number of stimuli. However, this assumption, and thus the experimental validity of studies using TBS, is challenged by recent work showing large inter- and intra-subject variability in response to TBS protocols. Objectives To date, the reproducibility of TBS effects in humans has been exclusively assessed with motor evoked potentials (MEPs), which provide an indirect and limited measure of cortical excitability. Here we combined TMS with electroencephalography (TMS-EEG) and report the first comprehensive investigation of (1) direct TMS-evoked cortical responses to intermittent (iTBS) and continuous TBS (cTBS) of the human motor cortex, and (2) reproducibility of both iTBS- and cTBS-induced cortical response modulation against a robust sham control across repeat visits with commonly used cortical responsivity metrics. Results We show that although single pulse TMS generates stable and reproducible cortical responses across visits, the modulatory effects of TBS vary substantially both between and within individuals. Overall, at the group level, most measures of the iTBS and cTBS-induced effects were not significantly different from sham-TBS. Most importantly, none of the significant TBS-induced effects observed in visit-1 were reproduced in visit-2. Conclusions Our findings suggest that the generally accepted mechanisms of TBS-induced neuromodulation, i.e. through changes in cortical excitability, may not be accurate. Future research is needed to determine the mechanisms underlying the established therapeutic effects of TBS in neuropsychiatry and examine reproducibility of TBS-induced neuromodulation through oscillatory response dynamics.

Background Recent evidence suggests that the dorsal medial frontal cortex (dMFC) may make an important contribution to perceptual decision-making, and not only to motor control. Objective/hypothesis By fitting psychometric functions to behavioural data after TMS we tested whether the dMFC is critical specifically for the precision and/or bias of perceptual judgements. Additionally we aimed to disentangle potential roles of the dMFC in dealing with perceptual versus response switching. Methods A subjective visual vertical task (SVV) was used in which participants weight visual (and other, e.g., vestibular) information to establish whether a line is oriented vertically. To ensure a high perceptual demand (putatively necessary to demonstrate a dMFC involvement) SVV lines were presented inside pop-out targets within a visual search array. Distinct features of perceptual performance were analysed before as compared to following theta-burst TMS stimulation of the dMFC, a control site, or no stimulation, in three groups, each of 20 healthy participants. Results dMFC stimulation improved the precision of verticality judgments. Moreover, dMFC stimulation improved accuracy, selectively when response switches occurred with perceptual repeats. Conclusion These findings point to a causal role of the dMFC in establishing the precision of perceptual decision making, demonstrably dissociable from an additional role in motor control in attentionally demanding contexts.

Background Theta burst stimulation (TBS) and quadripulse stimulation (QPS) are known to induce synaptic plasticity in humans. There have been no head-to-head comparisons of the efficacy and variability between TBS and QPS. Objective To compare the efficacy and interindividual variability between the original TBS and QPS protocols. We hypothesized that QPS would be more effective and less variable than TBS. Methods Forty-six healthy subjects participated in this study. Thirty subjects participated in the main comparison experiment, and the other sixteen subjects participated in the experiment to obtain natural variation in motor-evoked potentials. The facilitatory effects were compared between intermittent TBS (iTBS) and QPS5, and the inhibitory effects were compared between continuous TBS (cTBS) and QPS50. The motor-evoked potential amplitudes elicited by transcranial magnetic stimulation over the primary motor cortex were measured before the intervention and every 5 min after the intervention for 1 h. To investigate the interindividual variability, the responder/nonresponder/opposite-responder rates were also analyzed. Results The facilitatory effects of QPS5 were greater than those of iTBS, and the inhibitory effects of QPS50 were much stronger than those of cTBS. The responder rate of QPS was significantly higher than that of TBS. QPS had a smaller number of opposite responders than TBS. Conclusion QPS is more effective and stable for synaptic plasticity induction than TBS.

Background Many studies have attempted to identify the sources of interindividual variability in response to theta-burst stimulation (TBS). However, these studies have been limited by small sample sizes, leading to conflicting results. Objective/Hypothesis This study brought together over 60 TMS researchers to form the ‘Big TMS Data Collaboration’, and create the largest known sample of individual participant TBS data to date. The goal was to enable a more comprehensive evaluation of factors driving TBS response variability. Methods 118 corresponding authors of TMS studies were emailed and asked to provide deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to iTBS and cTBS response variability. Results 430 healthy participants’ TBS data was pooled across 22 studies (mean age = 41.9; range = 17–82; females = 217). Baseline MEP amplitude, age, target muscle, and time of day significantly predicted iTBS-induced plasticity. Baseline MEP amplitude and timepoint after TBS significantly predicted cTBS-induced plasticity. Conclusions This is the largest known study of interindividual variability in TBS. Our findings indicate that a significant portion of variability can be attributed to the methods used to measure the modulatory effects of TBS. We provide specific methodological recommendations in order to control and mitigate these sources of variability.

Background Intermittent theta-burst stimulation (iTBS), a novel repetitive transcranial magnetic stimulation (rTMS) technique, appears to have antidepressant effects when applied over left dorsolateral prefrontal cortex (DLPFC). However, its underlying neurobiological mechanisms are unclear. Proton magnetic resonance spectroscopy (1H-MRS) provides in vivo measurements of cerebral metabolites altered in major depressive disorder (MDD) like N-acetyl-aspartate (NAA) and choline-containing compounds (Cho). We used MRS to analyse effects of iTBS on the associations between the shifts in the NAA and Cho levels during therapy and MDD improvement. Methods In-patients with unipolar MDD (N = 57), in addition to treatment as usual, were randomized to receive 20 iTBS or sham stimulations applied over left DLPFC over four weeks. Single-voxel 1H-MRS of the anterior cingulate cortex (ACC) was performed at baseline and follow-up. Increments of concentrations, as well as MDD improvement, were defined as endpoints. We tested a moderated mediation model of effects using the PROCESS macro (an observed variable ordinary least squares and logistic regression path analysis modeling tool) for SPSS. Results Improvement of depressive symptoms was significantly associated with decrease of Cho/NAA ratio, mediated by NAA. iTBS had a significant moderating effect enhancing the relationship between NAA change and depression improvement. Conclusions Our findings suggest a potential neurochemical pathway and mechanisms of antidepressant action of iTBS, which may moderate the improvement of metabolic markers of neuronal viability. iTBS might increase neuroplasticity, thus facilitating normalization of neuronal circuit function.

Background Despite its potential to revolutionize the treatment of memory dysfunction, the efficacy of direct electrical hippocampal stimulation for memory performance has not yet been well characterized. One of the main challenges to cross-study comparison in this area of research is the diversity of the cognitive tasks used to measure memory performance. Objective We hypothesized that the tasks that differentially engage the hippocampus may be differentially influenced by hippocampal stimulation and the behavioral effects would be related to the underlying hippocampal activity. Methods To investigate this issue, we recorded intracranial EEG from and directly applied stimulation to the hippocampus of 10 epilepsy patients while they performed two different verbal memory tasks – a word pair associative memory task and a single item memory task. Results Hippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. In addition, subjects with poorer baseline cognitive function improved much more with stimulation. iEEG recordings from the hippocampus during non-stimulation encoding blocks revealed that the associative memory task elicited stronger theta oscillations than did item memory and that stronger theta power was related to memory performance. Conclusions We show here for the first time that stimulation-induced associative memory enhancement was linked to increased theta power during retrieval. These results suggest that hippocampal stimulation enhances associative memory but not item memory because it engages more hippocampal theta activity and that, in general, increasing hippocampal theta may provide a neural mechanism for successful memory enhancement.

Background Long-term recognition memory depends both on initial encoding and on subsequent recognition processes. Objective In this study we aimed at improving long-term memory by modulating posterior parietal brain activity during the encoding process. If this area is causally involved in memory encoding, its facilitation should lead to behavioral improvement. Based on the dual-process memory framework, we also expected that the neuromodulation would dissociate subsequent familiarity-based and recollection-based recognition. Methods We investigated the role of the posterior parietal brain oscillations in facial memory formation in three separate experiments using electroencephalography (EEG), functional magnetic resonance imaging (fMRI), and model-driven, multi-electrode transcranial alternating current stimulation (tACS). Results Using fMRI and EEG, we confirmed that the right posterior parietal cortex is an essential node that promotes the encoding of long-term memories. We found that single-trial low theta power in this region predicts subsequent long-term recognition. On this basis, we fine-tuned the spatial and frequency settings of tACS during memory encoding. Model-driven tACS over the right posterior brain area augmented subsequent long-term recognition memory and particularly the familiarity of the observed stimuli. The recollection process, and short-term task performance as control remained unchanged. Control stimulation over the left hemisphere had no behavioral effect. Conclusion We conclude that the right posterior brain area is crucial in long-term memory encoding.

The amplitude envelope of speech carries crucial low-frequency acoustic information that assists linguistic decoding at multiple time scales. Neurophysiological signals are known to track the amplitude envelope of adult-directed speech (ADS), particularly in the theta-band. Acoustic analysis of infant-directed speech (IDS) has revealed significantly greater modulation energy than ADS in an amplitude-modulation (AM) band centered on ∼2 Hz. Accordingly, cortical tracking of IDS by delta-band neural signals may be key to language acquisition. Speech also contains acoustic information within its higher-frequency bands (beta, gamma). Adult EEG and MEG studies reveal an oscillatory hierarchy, whereby low-frequency (delta, theta) neural phase dynamics temporally organize the amplitude of high-frequency signals (phase amplitude coupling, PAC). Whilst consensus is growing around the role of PAC in the matured adult brain, its role in the development of speech processing is unexplored.Here, we examined the presence and maturation of low-frequency (Graphical abstractHighlightsLongitudinal EEG study in which 4, 7- & 11-month infants listened to nursery rhymesWe demonstrate cortical speech tracking via delta & theta neural signals (mTRF)Periodogram (PSD) analysis revealed stimulus related delta & theta PSD peaksDelta and theta driven phase amplitude coupling (PAC) was found at all agesGamma frequency amplitudes displayed stronger PAC to low frequency phases than beta

Reactive control of response inhibition is associated with a right-lateralised cortical network, as well as frontal-midline theta (FM-theta) activity measured at the scalp. However, response inhibition is also governed by proactive control processes, and how such proactive control is reflected in FM-theta activity and associated neural source activity remains unclear. To investigate this, simultaneous recordings of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data was performed while participants performed a cued stop-signal task. The cues (0%, 25% or 66%) indicated the likelihood of an upcoming stop-signal in the following trial. Results indicated that participants adjusted their behaviour proactively, with increasing go-trial reaction times following increasing stop-signal probability, as well as modulations of both go-trial and stop-trial accuracies. Target-locked theta activity was higher in stop-trials than go-trials and modulated by probability. At the single-trial level, cue-locked theta was associated with shorter reaction-times, while target-locked theta was associated with both faster reaction times and higher probability of an unsuccessful stop-trial. This dissociation was also evident at the neural source level, where a joint ICA revealed independent components related to going, stopping and proactive preparation. Overall, the results indicate that FM-theta activity can be dissociated into several mechanisms associated with proactive control, response initiation and response inhibition processes. We propose that FM-theta activity reflects both heightened preparation of the motor control network, as well as stopping-related processes associated with a right lateralized cortical network.

Infants’ socio-cognitive ability develops dramatically during the first year of life. From the perspective of ontogeny, the early development of social behavior allows for parent-child attachment, which in turn enhances survival. Thus, it is theorized that the development of social behavior, driven by social brain networks, forms the core of developmental acquisitions during this period. Further, understanding the maturation within the neural networks during social development is crucial to obtain a better grasp of the development of social developmental disorders. Therefore, we performed a longitudinal study in 854 infants measured at around 5 and 10 months to map the development of functional networks in the brain when infants were processing social and non-social videos. Using EEG, we focused on the frequency bands most commonly connected to social behavior: theta and alpha. We found that alpha networks remained relatively stable over the first year of life and showed no selectivity for social versus non-social stimuli, theta networks, showed strong global reconfigurations. The development of the theta networks progressed from a parietal occipital network in early infancy to a frontoparietal network towards the end of the first year of life. This reconfiguration coincided with selectivity for social versus non-social stimuli, with infants approaching the end of their first year of life showing increased synchronicity of theta communication when watching social videos versus non-social videos. Our findings provide strong evidence for the involvement of a frontoparietal theta network in the development of the social brain.

Growing evidence suggests that both the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) play crucial roles in conflict processing, but how these two structures coordinate their activities remains poorly understood. We simultaneously recorded electroencephalogram from the mPFC and local field potentials from the STN using deep brain stimulation electrodes in 13 Parkinson's disease patients while they performed a Stroop task. Both mPFC and STN showed significant increases in theta activities (2-8 Hz) in incongruent trials compared to the congruent trials. The theta activity in incongruent trials also demonstrated significantly increased phase synchronization between mPFC and STN. Furthermore, the amplitude of gamma oscillation was modulated by the phase of theta activity at the STN in incongruent trials. Such theta-gamma phase-amplitude coupling (PAC) was much stronger for incongruent trials with faster reaction times than those with slower reaction times. Elevated theta-gamma PAC in the STN provides a novel mechanism by which the STN may operationalize its proposed “hold-your-horses” role. The co-occurrence of mPFC-STN theta phase synchronization and STN theta-gamma PAC reflects a neural substrate for fronto-subthalamic communication during conflict processing. More broadly, it may be a general mechanism for neuronal interactions in the cortico-basal ganglia circuits via a combination of long-range, within-frequency phase synchronization and local cross-frequency PAC.

Brain insults like stroke, trauma or infections often lead to blood-brain barrier-dysfunction (BBBd) frequently resulting into epileptogenesis. Affected patients suffer from seizures and cognitive comorbidities that are potentially linked to altered network oscillations. It has been shown that a hippocampal BBBd in rats leads to in vivo seizures and increased power at theta (3–8 Hz), an important type of network oscillations. However, the underlying cellular mechanisms remain poorly understood. At membrane potentials close to the threshold for action potentials (APs) a subpopulation of CA1 pyramidal cells (PCs) displays intrinsic resonant properties due to an interplay of the muscarine-sensitive K+-current (IM) and the persistent Na+-current (INaP). Such resonant neurons are more excitable and generate more APs when stimulated at theta frequencies, being strong candidates for contributing to hippocampal theta oscillations during epileptogenesis. We tested this hypothesis by characterizing changes in intrinsic properties of hippocampal PCs one week after post-stroke epileptogenesis, a model associated with BBBd, using slice electrophysiology and computer modeling. We find a higher proportion of resonant neurons in BBBd compared to sham animals (47 vs. 29%), accompanied by an increase in their excitability. In contrast, BBBd non-resonant neurons showed a reduced excitability, presented with lower impedance and more positive AP threshold. We identify an increase in IM combined with either a reduction in INaP or an increase in ILeak as possible mechanisms underlying the observed changes. Our results support the hypothesis that a higher proportion of more excitable resonant neurons in the hippocampus contributes to increased theta oscillations and an increased likelihood of seizures in a model of post-stroke epileptogenesis.

Graphical abstract, Highlights • Canonical EEG analyses conflate neural oscillations with the aperiodic signal. • From early childhood to adulthood, the aperiodic signal flattens in slope. • Dominant posterior oscillations shift from theta to alpha around 7–8 years old. • Theta oscillations transition from posterior dominant to anterior dominant with age., Intrinsic, unconstrained neural activity exhibits rich spatial, temporal, and spectral organization that undergoes continuous refinement from childhood through adolescence. The goal of this study was to investigate the development of theta (4−8 Hertz) and alpha (8−12 Hertz) oscillations from early childhood to adulthood (years 3–24), as these oscillations play a fundamental role in cognitive function. We analyzed eyes-open, resting-state EEG data from 96 participants to estimate genuine oscillations separately from the aperiodic (1/f) signal. We examined age-related differences in the aperiodic signal (slope and offset), as well as the peak frequency and power of the dominant posterior oscillation. For the aperiodic signal, we found that both the aperiodic slope and offset decreased with age. For the dominant oscillation, we found that peak frequency, but not power, increased with age. Critically, early childhood (ages 3–7) was characterized by a dominance of theta oscillations in posterior electrodes, whereas peak frequency of the dominant oscillation in the alpha range increased between ages 7 and 24. Furthermore, theta oscillations displayed a topographical transition from dominance in posterior electrodes in early childhood to anterior electrodes in adulthood. Our results provide a quantitative description of the development of theta and alpha oscillations.

Control of movements using visual information is crucial for many daily activities, and such visuomotor control has been revealed to be supported by alpha and beta cortical oscillations. However, it has been remained to be unclear how midfrontal theta and occipital gamma oscillations, which are associated with high-level cognitive functions, would be involved in this process to facilitate performance. Here we addressed this fundamental open question in healthy young adults by measuring high-density cortical activity during a precision force-matching task. We manipulated the amount of error by changing visual feedback gain (low, medium, and high visual gains) and analyzed event-related spectral perturbations. Increasing the visual feedback gain resulted in a decrease in force error and variability. There was an increase in theta synchronization in the midfrontal area and also in beta desynchronization in the sensorimotor and posterior parietal areas with higher visual feedback gains. Gamma de/synchronization was not evident during the task. In addition, we found a moderation effect of midfrontal theta on the positive relationship between the beta oscillations and force error. Subsequent simple slope analysis indicated that the effect of beta oscillations on force error was weaker when midfrontal theta was high. Our findings suggest that the midfrontal area signals the increased need of cognitive control to refine behavior by modulating the visuomotor processing at theta frequencies.

Despite decades of research, our understanding of epilepsy, including how seizures are generated and propagate, is incomplete. However, there is growing recognition that epilepsy is more than just the occurrence of seizures, with patients often experiencing comorbid deficits in cognition that are poorly understood. In addition, the available therapies for treatment of epilepsy, from pharmaceutical treatment to surgical resection and seizure prevention devices, often exacerbate deficits in cognitive function. In this review, we discuss the hypothesis that seizure generation and cognitive deficits have a similar pathological source characterized by, but not limited to, deficits in theta oscillations and their influence on interneurons. We present a new framework that describes oscillatory states in epilepsy as alternating between hyper- and hypo-synchrony rather than solely the spontaneous transition to hyper-excitability characterized by the seizures. This framework suggests that as neural oscillations, specifically in the theta range, vary their tempo from a slowed almost adagio tempo during interictal periods to faster, more rhythmic allegretto tempo preictally, they impact the function of interneurons, modulating their ability to control seizures and their role in cognitive processing. This slow wave oscillatory framework may help explain why current therapies that work to reduce hyper-excitability do not completely eliminate seizures and often lead to exacerbated cognitive deficits.

BackgroundMost of our decisions involve a certain degree of risk regarding the outcomes of our choices. People vary in the way they make decisions, resulting in different levels of risk-taking behavior. These differences have been linked to prefrontal theta band activity. However, a direct functional relationship between prefrontal theta band activity and risk-taking has not yet been demonstrated.ObjectiveWe used noninvasive brain stimulation to test the functional relevance of prefrontal oscillatory theta activity for the regulatory control of risk-taking behavior.MethodsIn a within-subject experiment, 31 healthy participants received theta (6.5 Hertz [Hz]), gamma (40 Hz), and sham transcranial alternating current stimulation (tACS) over the left prefrontal cortex (lPFC). During stimulation, participants completed a task assessing their risk-taking behavior as well as response times and sensitivity to value and outcome probabilities. Electroencephalography (EEG) was recorded before and immediately after stimulation to investigate possible long-lasting stimulation effects.ResultsTheta band, but not gamma band or sham, tACS led to a significant reduction in risk-taking behavior, indicating a frequency-specific effect of prefrontal brain stimulation on the modulation of risk-taking behavior. Moreover, theta band stimulation led to increased response times and decreased sensitivity to reward values. EEG data analyses did not show an offline increase in power in the stimulated frequencies after the stimulation protocol.ConclusionThese findings provide direct empirical evidence for the effects of prefrontal theta band stimulation on behavioral risk-taking regulation.

Human visual cortex contains three scene-selective regions in the lateral, medial and ventral cortex, termed the occipital place area (OPA), medial place area (MPA) and parahippocampal place area (PPA). Using functional magnetic resonance imaging (fMRI), all three regions respond more strongly when viewing visual scenes compared with isolated objects or faces. To determine how these regions are functionally and causally connected, we applied transcranial magnetic stimulation to OPA and measured fMRI responses before and after stimulation, using a theta-burst paradigm (TBS). To test for stimulus category-selectivity, we presented a range of visual categories (scenes, buildings, objects, faces). To test for specificity of any effects to TBS of OPA we employed two control conditions: Sham, with no TBS stimulation, and an active TBS-control with TBS to a proximal face-selective cortical region (occipital face area, or OFA). We predicted that TBS to OPA (but not OFA) would lead to decreased responses to scenes and buildings (but not other categories) in other scene-selective cortical regions. Across both ROI and whole-volume analyses, we observed decreased responses to scenes in PPA as a result of TBS. However, these effects were neither category specific, with decreased responses to all stimulus categories, nor limited to scene-selective regions, with decreases also observed in face-selective fusiform face area (FFA). Furthermore, similar effects were observed with TBS to OFA, thus effects were not specific to the stimulation site in the lateral occipital cortex. Whilst these data are suggestive of a causal, but non-specific relationship between lateral occipital and ventral temporal cortex, we discuss several factors that could have underpinned this result, such as the differences between TBS and online TMS, the role of anatomical distance between stimulated regions and how TMS effects are operationalised. Furthermore, our findings highlight the importance of active control conditions in brain stimulation experiments to accurately assess functional and causal connectivity between specific brain regions.

Background: The timing of an event within an oscillatory phase is considered to be one of the key strategies used by the brain to code and process neural information. Whereas existing methods of studying this phenomenon are chiefly based on retrospective analysis of electroencephalography (EEG) data, we now present a method to study it prospectively. New method: We present a system that allows for the delivery of visual stimuli at a specific phase of the cortical theta oscillation by fitting a sine to raw surface EEG data to estimate and predict the phase. One noteworthy feature of the method is that it can minimize potentially confounding effects of previous trials by using only a short sequence of past data. Results: In a trial with 10 human participants we achieved a significant phase locking with an inter-trial phase coherence of 0.39. We demonstrated successful phase locking on synthetic signals with a signal-to-noise ratio of less than − 20 dB. Comparison with existing method(s): We compared the new method to an autoregressive method published in the literature and found the new method was superior in mean phase offset, circular standard deviation, and prediction latency. Conclusions: By fitting sine waves to raw EEG traces, we locked visual stimuli to arbitrary phases within the theta oscillatory cycle of healthy humans.

Working memory (WM) is a keystone of our cognitive abilities. Increasing load has been shown to dampen its performance and affect oscillatory neural activity in different frequency bands. Nevertheless, mixed results regarding fast frequencies activity and a lack of research on WM load modulations of cross-frequency phase-amplitude coupling mechanisms preclude a better understanding of the impact of increased WM load levels on brain activity as well as inter-regional communication and coordination supporting WM processes. Hence, we analyzed the EEG activity of 25 participants while performing a delayed-matching-to-sample (DMS) WM task with three WM load levels. Current density power and distribution at the source level for theta, beta, and gamma frequencies during the task's delay period were compared for each pair of WM load conditions. Results showed maximal increases of theta activity in frontal areas and of fast frequencies' activity in posterior regions with WM load, showing the involvement of frontal theta activity in WM maintenance and the control of attentional resources and visual processing by beta and gamma activity. To study whether WM load modulates communication between cortical areas, posterior beta and gamma amplitudes distribution across frontal theta phase was also analysed for those areas showing the largest significant WM load modulations. Higher beta activity amplitude at bilateral cuneus and right middle occipital gyrus, and higher gamma activity amplitude at bilateral posterior cingulate were observed during frontal theta phase peak in low than high memory load conditions. Moreover, greater fast beta amplitude at the right postcentral gyrus was observed during theta phase trough at right middle frontal gyrus in high than low memory load conditions. These results show that WM load modulates whether interregional communication occurs during theoretically optimal or non-optimal time windows, depending on the demands of frontal control of posterior areas required to perform the task successfully This study was supported by grants from the Spanish Government, Ministerio de Economía y Competitividad (PSI2014-55316-C3-3-R; PSI2017-89389-C2-2-R), with FEDER Funds; the Galician Government, Consellería de Cultura, Educación e Ordenación Universitaria, Axudas para a Consolidación e Estruturación de Unidades de Investigación Competitivas do Sistema Universitario de Galicia: GRC (GI-1807-USC); Ref: ED431-2017/27, with FEDER funds. D. P. was also supported by the Portuguese Foundation for Science and Technology (FCT) through the fellowship SFRH/BPD/120111/2016 SI

Highlight • Theta-related pro-active control is examined in ADHD/ADD. • inter-relation of pro-active control and inhibition-relation activity is modulated in AD(H)D. • Dynamics between pre-trial and within-trials differs between AD(H)D subtypes., Impulsivity and deficits in response inhibition are hallmarks of attention-deficit(-hyperactivity) disorder (AD(H)D), can cause severe problems in daily functioning, and are thus of high clinical relevance. Traditionally, research to elucidate associated neural correlates has intensively, but also quite selectively examined mechanisms during response inhibition in various tasks. Doing so, in-between trial periods or periods prior to the response inhibition process, where no information relevant to inhibitory control is presented, have been neglected. Yet, these periods may nevertheless reveal relevant information. In the present study, using a case-control cross-sectional design, we take a more holistic approach, examining the inter-relation of pre-trial and within-trial periods in a Go/Nogo task with a focus on EEG theta band activity. Applying EEG beamforming methods, we show that the dynamics between pre-trial (pro-active) and within-trial (inhibition-related) control processes significantly differ between AD(H)D subtypes. We show that response inhibition, and differences between AD(H)D subtypes, exhibit distinct patterns of (at least) three factors: (i) strength of pre-trial (pro-active control) theta-band activity, (ii) the inter-relation of pro-active control and inhibition-relation theta band activity and (iii) the functional neuroanatomical region active during theta-related pro-active control processes. This multi-factorial pattern is captured by AD(H)D subtype clinical symptom clusters. The study provides a first hint that novel cognitive-neurophysiological facets of AD(H)D may be relevant to distinguish AD(H)D subtypes.

Transcranial alternating current stimulation (tACS) can non-invasively modulate neuronal activity in the cerebral cortex, in particular at the frequency of the applied stimulation. Such modulation can matter for speech processing, since the latter involves the tracking of slow amplitude fluctuations in speech by cortical activity. tACS with a current signal that follows the envelope of a speech stimulus has indeed been found to influence the cortical tracking and to modulate the comprehension of the speech in background noise. However, how exactly tACS influences the speech-related cortical activity, and how it causes the observed effects on speech comprehension, remains poorly understood. A computational model for cortical speech processing in a biophysically plausible spiking neural network has recently been proposed. Here we extended the model to investigate the effects of different types of stimulation waveforms, similar to those previously applied in experimental studies, on the processing of speech in noise. We assessed in particular how well speech could be decoded from the neural network activity when paired with the exogenous stimulation. We found that, in the absence of current stimulation, the speech-in-noise decoding accuracy was comparable to the comprehension of speech in background noise of human listeners. We further found that current stimulation could alter the speech decoding accuracy by a few percent, comparable to the effects of tACS on speech-in-noise comprehension. Our simulations further allowed us to identify the parameters for the stimulation waveforms that yielded the largest enhancement of speech-in-noise encoding. Our model thereby provides insight into the potential neural mechanisms by which weak alternating current stimulation may influence speech comprehension and allows to screen a large range of stimulation waveforms for their effect on speech processing.

Inhibitory control processes are indispensable for goal-directed behavior. On a neurophysiological level, theta band power has been suggested to be important during inhibitory control as well as proactive control processes. Here we ask whether theta activity in the pre-trial/between-trial time period, reflects proactive control that correlates with theta activity in the upcoming trial. Theoretical considerations also suggest that such a correlation is modulated by the demands on inhibition. To investigate these questions, we conducted an EEG study using a Go/Nogo task in which demands on inhibitory control are varied. We used different EEG beamforming approaches to focus the analysis on the functional neuroanatomical level. We show that theta band activity in the ventromedial prefrontal cortex (vmPFC, BA10) is associated with the proactive control in the pre-trial interval and correlates with theta-related processes in the right inferior frontal gyrus (rIFG, BA45) during response inhibition. In addition, we show that demands on inhibitory control modulate the inter-relation between proactive vmPFC and inhibitory control-related rIFG-theta activity. Such effects were not observed for beta frequency activity. The study is the first to emphasize the relevance of pre-trial (proactive) vmPFC theta-band activity during inhibitory control in humans. It is shown that pre-trial activity, which is often neglected in EEG research, provides valuable information about the neuronal dynamics of cognitive control.

Probabilistic learning is a fundamental cognitive ability that extracts and represents regularities of our environment enabling predictive processing during perception and acquisition of perceptual, motor, cognitive, and social skills. Previous studies show competition between neural networks related to executive function/working memory vs. probabilistic learning. Theta synchronization has been associated with the former while desynchronization with the latter in correlational studies. In the present paper our aim was to test causal relationship between fronto-parietal midline theta synchronization and probabilistic learning with non-invasive transcranial alternating current (tACS) stimulation. We hypothesize that theta synchronization disrupts probabilistic learning performance by modulating the competitive relationship. Twenty-six young adults performed the Alternating Serial Reaction Time (ASRT) task to assess probabilistic learning in two sessions that took place one week apart. Stimulation was applied in a double-blind cross-over within-subject design with an active theta tACS and a sham stimulation in a counter-balanced order between participants. Sinusoidal current was administered with 1 mA peak-to-peak intensity throughout the task (approximately 20 minutes) for the active stimulation and 30 seconds for the sham. We did not find an effect of fronto-parietal midline theta tACS on probabilistic learning comparing performance during active and sham stimulation. To influence probabilistic learning, we suggest applying higher current intensity and stimulation parameters more precisely aligned to endogenous brain activity for future studies.

Highlights • Prolactin levels negatively correlated with prolactinomas’ executive controls. • Prolactin levels mediated the correlation between frontal theta activity and inhibition control ability. • Prolactinomas exhibited decreased frontal theta power in Go/Nogo task. • The frontal theta oscillation was highlighted as the electrophysiological markers of the impaired inhibitory control in prolactinomas., Impairment of cognitive functions has been reported in prolactinomas. However, the electrophysiological mechanisms of response activation and response inhibition in prolactinomas remain unclear. We recorded participants’ scalp electroencephalography (EEG) in a visual Go/Nogo task. Compared to the healthy controls (HCs), the patients demonstrated worse performance and their prolactin (PRL) levels negatively correlated with behavioral results. Meanwhile, patients’ P300 amplitudes in the Go and Nogo conditions were smaller than the HCs. The amplitudes of N200nogo in patients were smaller than the HCs as well. Lower frontal theta power was found in the patients than the HCs in both Go and Nogo conditions, which indicated a deficit in response activation and inhibition. Moreover, the PRL levels mediated the relationship between frontal theta power and behavior performance, implying that lower frontal theta power caused the dysfunction of response control by abnormally high PRL levels. Patients also showed lower occipital alpha power than the HCs, which suggested that the impaired response inhibition may arise from deficient attention control. Taken together, the present study revealed the neurocognitive discrepancies between prolactinomas and the HCs. The frontal theta oscillation was highlighted as the electrophysiological markers of the impaired response control in prolactinomas.

Children that have experienced psychosocial neglect display impairments in self-monitoring and controlling their behavior (cognitive control) and are at broad, transdiagnostic risk for psychopathology. However, the neural underpinnings of such effects remain unclear. Event-related mediofrontal theta oscillations reflect a neural process supporting cognitive control that may relate to transdiagnostic psychopathology risk. Recent work demonstrates reduced mediofrontal theta in rodent models of neglect; however, similar findings have not been reported in humans. Here, 136 children reared in Romanian institutions were randomly assigned to either a high-quality foster care intervention and placed with families or remained in institutions; 72 never-institutionalized children served as a comparison group. The intervention ended at 54 months; event-related mediofrontal theta and psychopathology were assessed at 12- and 16-year follow-up assessments. Institutional rearing (neglect) predicted reduced mediofrontal theta by age 16, which was linked to heightened transdiagnostic risk for psychopathology (P factor); no specific associations with internalizing/externalizing factors were present once transdiagnostic risk was accounted for. Earlier placement into foster care yielded greater mediofrontal activity by age 16. Moreover, foster care placement was associated with the developmental trajectory of mediofrontal theta across the adolescent period (ages 12-16), which was, in turn, associated with greater reductions in transdiagnostic risk across this same period. These data reflect the first experimental evidence that the development of mediofrontal theta is impacted by removal from situations of neglect in humans, and further characterizes the importance of studying developmental change in mediofrontal theta during the adolescent period.

Highlights • A novel, cutting-edge measure for studying active learning in infancy is introduced: theta oscillations. • Theta rhythms are linked to expectation of information, memory, and reward processing, making it an ideal candidate for studying active learning. • Existing evidence and potential applications of theta oscillations in research on infant active learning are discussed., Active learning is a critical component of human development, however, the mechanisms supporting it are not fully understood. Given that early learning experiences may affect both infants' immediate learning success, as well as their motivation to learn, it is particularly important to investigate the mechanisms of active learning in this period, when the foundations of learning habits and curiosity are built. Traditional behavioural approaches of studying infant learning face challenges that emerging tools from neuroscience may help relieve. We introduce one such tool, EEG theta oscillations, and propose this neural marker has great potential for offering novel insights into active learning. Theta activity, recorded prior to or during learning, has been shown to be predictive of learning success. We argue that this involvement in memory formation, combined with theta activity’s tight association with reward processing, makes theta oscillations a uniquely suited tool for the investigation of motivational mechanisms underlying active learning. We outline research questions as well as methodological approaches pertinent to infant learning and suggest how and why theta oscillations may offer complementary insights. As such, we aim to bridge the gap between cognitive and neural approaches, and advance our knowledge of active learning in development more broadly.

Auditory cortical activity entrains to speech rhythms and has been proposed as a mechanism for online speech processing. In particular, neural activity in the theta frequency band (4–8 ​Hz) tracks the onset of syllables which may aid the parsing of a speech stream. Similarly, cortical activity in the delta band (1–4 ​Hz) entrains to the onset of words in natural speech and has been found to encode both syntactic as well as semantic information. Such neural entrainment to speech rhythms is not merely an epiphenomenon of other neural processes, but plays a functional role in speech processing: modulating the neural entrainment through transcranial alternating current stimulation influences the speech-related neural activity and modulates the comprehension of degraded speech. However, the distinct functional contributions of the delta- and of the theta-band entrainment to the modulation of speech comprehension have not yet been investigated. Here we use transcranial alternating current stimulation with waveforms derived from the speech envelope and filtered in the delta and theta frequency bands to alter cortical entrainment in both bands separately. We find that transcranial alternating current stimulation in the theta band but not in the delta band impacts speech comprehension. Moreover, we find that transcranial alternating current stimulation with the theta-band portion of the speech envelope can improve speech-in-noise comprehension beyond sham stimulation. Our results show a distinct contribution of the theta- but not of the delta-band stimulation to the modulation of speech comprehension. In addition, our findings open up a potential avenue of enhancing the comprehension of speech in noise.

Background Imaging studies point to a posture (finger vs. hand) and domain-specific neural basis of gestures. Furthermore, modulation of gestures by theta burst stimulation (TBS) may depend on interhemispheric disinhibition. Objective/Hypothesis In this randomized sham-controlled study, we hypothesized that dual site continuous TBS over left inferior frontal gyrus (IFG-L) and right inferior parietal gyrus (IPL-R) predominantly affects pantomime of finger postures. Furthermore, we predicted that dual cTBS improves imitation of hand gestures if the effect correlates with measures of callosal connectivity. Methods Forty-six healthy subjects participated in this study and were targeted with one train of TBS in different experimental sessions: baseline, sham, single site IFG-L, dual IFG-L/IPL-R, single site IPL-R. Gestures were evaluated by blinded raters using the Test for Upper Limb Apraxia (TULIA) and Postural Imitation Test (PIT). Callosal connectivity was analyzed by diffusion tensor imaging (DTI). Results Dual cTBS significantly improved TULIAtotal (F [3, 28] = 4.118, p = .009), but did not affect TULIApantomime. The beneficial effect was driven by the cTBS over IPL-R, which improved TULIAimitation (p = .038). Furthermore, TULIAimitation significantly correlated with the microstructure (fractional anisotropy) of the splenium (r = 0.420, p = .026), corrected for age and whole brain volume. Conclusions The study suggests that inhibition of IPL-R largely accounted for improved gesturing, possibly through transcallosal facilitation of IPL-L. Therefore, the findings may be relevant for the treatment of apraxic stroke patients. Gesture pantomime and postural gestures escaped the modulation by dual cTBS, suggesting a more widespread and/or variable neural representation.

The healthy maturation of the brain is one of the intriguing topics that need to be investigated to understand human brain and child development. The present study aimed to investigate the development of memory processes both for auditory and visual memory using electroencephalography (EEG)-Brain Dynamics methodologies. Sixteen healthy children between the ages of 6 and 7 years and eighteen healthy young adults (age: 21.32 ± 3.28 years) were included in the study. EEG was recorded from 18 channels during the visual and auditory memory paradigms. Two different subtests of the WISC-IV IQ test were applied to all children. Event-related theta (4-7 Hz), alpha (8-13 Hz) power and phase-locking were analyzed. The young adults had higher memory performance than the children for both auditory and visual paradigms. The children had increased theta phase-locking and left alpha power in response to the remembered objects in comparison to the forgotten objects. The young adults had higher theta and alpha phase-locking than the children over the frontal and central locations (p 0.05), and the children had higher parietal-occipital alpha phase-locking than the young adults. There was an increase in alpha power in children, whereas young adults had decreased post-stimulus alpha power in response to memory paradigms. The present study showed that frontocentral theta and alpha phase-locking had an essential role in brain maturation and successful memory performance. Event-related theta and alpha responses could be one of the important indicators of the mature and healthy brain, and these responses could change depending on the maturation state and age.

Background Remembering to execute delayed intentions (i.e., prospective memory, PM) entails the allocation of internal and external attention. These processes are crucial for rehearsing PM intentions in memory and for monitoring the presence of the PM cue in the environment, respectively. Aim The study took advantage of the excellent spatial and temporal resolution of magnetoencephalography (MEG) to delineate the neural mechanisms of the memory and monitoring processes underlying PM. Method The spatio-temporal dynamic of theta and alpha oscillations were explored in 21 participants in two PM tasks compared to a baseline condition (i.e., a lexical decision task with no PM instruction). The PM tasks varied for the load of internally-directed attention (Retrospective-load task) vs externally-directed attention (Monitoring-load task). Results Increase in theta activity was observed in the Retrospective-load task, and was particularly expressed in the regions of the Default Mode Network, such as in medial temporal regions, precuneus, posterior cingulate cortex and medial prefrontal cortex. Alpha decrease was the most relevant feature of the Monitoring-load task, and it was expressed over bilateral occipital, occipito-parietal and fronto-temporal regions, as well as over left dorsal fronto-parietal regions. Conclusions Theta and alpha oscillations are strictly associated with the direction of attention during the PM tasks. In particular, theta increase is linked to internal attention necessary for maintaining the intention active in working memory, whereas alpha decrease supports the external attention for detecting the PM cue in the environment.

The research on the abnormalities of event-related oscillations in Parkinson's disease (PD) was mostly studied with cognitively normal patients. The present study aims to show the adverse effects of cognitive decline in PD patients via the EEG-Brain Oscillations approach by comparing the electrophysiological responses in two modalities, i.e. auditory, and visual in which PD group show deficit. We conducted a study in which we analyzed event-related theta power and phase-locking during auditory and visual oddball paradigm. Cognitively normal PD (PDCN) patients (N = 15), PD with mild cognitive impairment (PDMCI) patients (N = 22), PD dementia (PDD) patients (N = 11) and healthy controls (HC) (N = 17) were included in the study. Neuropsychological assessments were applied to all participants. There was a gradual decrease in scores of neuropsychological tests (HC, PDCN, PDMCI, PDD, respectively). Most of the neuropsychological test scores of the participants were highly correlated with the theta power and theta phase locking values, especially over frontal-central areas. HC had higher theta phase-locking and power in comparison to PDMCI and PDD. The differentiation between HC and PDCN was specific to frontal-central areas. Theta power and theta phase-locking were decreased overall locations in PDMCI and PDD both during visual and auditory oddball paradigms compared with PDCN. The results indicate that theta responses in PD patients decreased gradually as the cognitive decline increased. We can conclude that complex abnormalities in their neurotransmitter and neuronal signal systems that occur with the progression of the disease could be responsible for these results.