Reliability of Neural Entrainment in the Human Auditory System.

Auditory stimuli are often rhythmic in nature. Brain activity synchronizes with auditory rhythms via neural entrainment, and entrainment seems to be beneficial for auditory perception. However, it is not clear to what extent neural entrainment in the auditory system is reliable over time, which is a necessary prerequisite for targeted intervention. The current study aimed to establish the reliability of neural entrainment over time and to predict individual differences in auditory perception from associated neural activity. Across two different sessions, human listeners (21 females, 17 males) detected silent gaps presented at different phase locations of a 2 Hz frequency-modulated (FM) noise while EEG activity was recorded. As expected, neural activity was entrained by the 2 Hz FM noise. Moreover, gap detection was sinusoidally modulated by the phase of the 2 Hz FM into which the gap fell. Critically, both the strength of neural entrainment as well as the modulation of performance by the stimulus rhythm were highly reliable over sessions. Moreover, gap detection was predictable from pregap neural 2 Hz phase and alpha amplitude. Our results demonstrate that neural entrainment in the auditory system and the resulting behavioral modulation are reliable over time, and both entrained delta and nonentrained alpha oscillatory activity contribute to near-threshold stimulus perception. The latter suggests that improving auditory perception might require simultaneously targeting entrained brain rhythms as well as the alpha rhythm.SIGNIFICANCE STATEMENT Neural activity synchronizes to the rhythms in sounds via neural entrainment, which seems to be important for successful auditory perception. A natural hypothesis is that improving neural entrainment, for example, via brain stimulation, should benefit perception. However, the extent to which neural entrainment is reliable over time, a necessary prerequisite for targeted intervention, has not been established. Using electroencephalogram recordings, we demonstrate that both neural entrainment to FM sounds and stimulus-induced behavioral modulation are reliable over time. Moreover, moment-by-moment fluctuations in perception are best predicted by entrained delta phase and nonentrained alpha amplitude. This work suggests that improving auditory perception might require simultaneously targeting entrained brain rhythms as well as the alpha rhythm.

Individual slow wave events give rise to macroscopic fMRI signatures and drive the strength of the BOLD signal in human resting-state EEG-fMRI recordings.

The slow wave state is a general state of quiescence interrupted by sudden bursts of activity or so-called slow wave events (SWEs). Recently, the relationship between SWEs and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals was assessed in rodent models which revealed cortex-wide BOLD activation. However, it remains unclear which macroscopic signature corresponds to these specific neurophysiological events in the human brain. Therefore, we analyzed simultaneous electroencephalographic (EEG)-fMRI data during human non-REM sleep. SWEs individually detected in the EEG data were used as predictors in event-related fMRI analyses to examine the relationship between SWEs and fMRI signals. For all 10 subjects we identified significant changes in BOLD activity associated with SWEs covering substantial parts of the gray matter. As demonstrated in rodents, we observed a direct relation of a neurophysiological event to specific BOLD activation patterns. We found a correlation between the number of SWEs and the spatial extent of these BOLD activation patterns and discovered that the amplitude of the BOLD response strongly depends on the SWE amplitude. As altered SWE propagation has recently been found in neuropsychiatric diseases, it is critical to reveal the brain's physiological slow wave state networks to potentially establish early imaging biomarkers for various diseases long before disease onset.

Phase-amplitude coupling profiles differ in frontal and auditory cortices of bats.

Neural oscillations are at the core of important computations in the mammalian brain. Interactions between oscillatory activities in different frequency bands, such as delta (1-4 Hz), theta (4-8 Hz) or gamma (>30 Hz), are a powerful mechanism for binding fundamentally distinct spatiotemporal scales of neural processing. Phase-amplitude coupling (PAC) is one such plausible and well-described interaction, but much is yet to be uncovered regarding how PAC dynamics contribute to sensory representations. In particular, although PAC appears to have a major role in audition, the characteristics of coupling profiles in sensory and integration (i.e. frontal) cortical areas remain obscure. Here, we address this question by studying PAC dynamics in the frontal-auditory field (FAF; an auditory area in the bat frontal cortex) and the auditory cortex (AC) of the bat Carollia perspicillata. By means of simultaneous electrophysiological recordings in frontal and auditory cortices examining local-field potentials (LFPs), we show that the amplitude of gamma-band activity couples with the phase of low-frequency LFPs in both structures. Our results demonstrate that the coupling in FAF occurs most prominently in delta/high-gamma frequencies (1-4/75-100 Hz), whereas in the AC the coupling is strongest in the delta-theta/low-gamma (2-8/25-55 Hz) range. We argue that distinct PAC profiles may represent different mechanisms for neuronal processing in frontal and auditory cortices, and might complement oscillatory interactions for sensory processing in the frontal-auditory cortex network.

Transcranial alternating current stimulation modulates spontaneous low frequency fluctuations as measured with fMRI.

Transcranial alternating current stimulation (tACS) is a promising tool for modulating brain oscillations. Combining tACS with functional magnetic resonance imaging (fMRI), we recently showed that tACS applied over the occipital cortex did not exert its strongest effect on regions below the electrodes, but mainly on more distant fronto-parietal regions. Theoretically, this effect could be explained by tACS-induced modulation of functional connectivity between directly stimulated areas and more distant but anatomically and functionally connected regions. In the present study, we aimed to characterize the effect of tACS on low frequency fMRI signal fluctuations. We employed simultaneous fMRI-tACS in 20 subjects during resting state (eyes open with central fixation for ~8min). Subjects received tACS at different frequencies (10, 16, 40Hz) and with different electrode montages (Cz-Oz, P5-P6) previously used in behavioral studies. Electric field simulations showed that tACS over Cz-Oz directly stimulates occipital cortex, while tACS over P5-P6 primarily targets parietal cortices. Group-level simulation-based functional connectivity maps for Cz-Oz and P5-P6 resembled the visual and fronto-parietal control resting-state networks, respectively. The effects of tACS were frequency and partly electrode montage dependent. In regions where frequency-dependent effects of tACS were observed, 10 and 40Hz tACS generally induced opposite effects. Most tACS effects on functional connectivity were observed between, as opposed to within, resting-state networks. The left fronto-parietal control network showed the most extensive frequency-dependent modulation in functional connectivity, mainly with occipito-parietal regions, where 10Hz tACS increased and 40Hz tACS decreased correlation values. Taken together, our results show that tACS modulates local spontaneous low frequency fluctuations and their correlations with more distant regions, which should be taken into account when interpreting tACS effects on brain function.

Transcranial alternating current stimulation affects the BOLD signal in a frequency and task-dependent manner.

Transcranial alternating current stimulation (tACS) has emerged as a promising tool for manipulating ongoing brain oscillations. While previous studies demonstrated frequency-specific effects of tACS on diverse cognitive functions, its effect on neural activity remains poorly understood. Here we asked how tACS modulates regional fMRI blood oxygenation level dependent (BOLD) signal as a function of frequency, current strength, and task condition. TACS was applied over the posterior cortex of healthy human subjects while the BOLD signal was measured during rest or task conditions (visual perception, passive video viewing and motor task). TACS was applied in a blockwise manner at different frequencies (10, 16, 60 and 80 Hz). The strongest tACS effects on BOLD activity were observed with stimulation at alpha (10 Hz) and beta (16 Hz) frequency bands, while effects of tACS at the gamma range were rather modest. Specifically, we found that tACS at 16 Hz induced BOLD activity increase in fronto-parietal areas. Overall, tACS effects varied as a function of frequency and task, and were predominantly seen in regions that were not activated by the task. Also, the modulated regions were poorly predicted by current density modeling studies. Taken together, our results suggest that tACS does not necessarily exert its strongest effects in regions below the electrodes and that region specificity might be achieved with tACS due to varying susceptibility of brain regions to entrain to a given frequency.

Rhythmic gamma stimulation affects bistable perception.

When our brain is confronted with ambiguous visual stimuli, perception spontaneously alternates between different possible interpretations although the physical stimulus remains the same. Both alpha (8-12 Hz) and gamma (>30 Hz) oscillations have been reported to correlate with such spontaneous perceptual reversals. However, whether these oscillations play a causal role in triggering perceptual switches remains unknown. To address this question, we applied transcranial alternating current stimulation (tACS) over the posterior cortex of healthy human participants to boost alpha and gamma oscillations. At the same time, participants were reporting their percepts of an ambiguous structure-from-motion stimulus. We found that tACS in the gamma band (60 Hz) increased the number of spontaneous perceptual reversals, whereas no significant effect was found for tACS in alpha (10 Hz) and higher gamma (80 Hz) frequencies. Our results suggest a mechanistic role of gamma but not alpha oscillations in the resolution of perceptual ambiguity.

Behavioral entrainment to rhythmic auditory stimulation can be modulated by tACS depending on the electrical stimulation field properties.

Synchronization between auditory stimuli and brain rhythms is beneficial for perception. In principle, auditory perception could be improved by facilitating neural entrainment to sounds via brain stimulation. However, high inter-individual variability of brain stimulation effects questions the usefulness of this approach. Here we aimed to modulate auditory perception by modulating neural entrainment to frequency modulated (FM) sounds using transcranial alternating current stimulation (tACS). In addition, we evaluated the advantage of using tACS montages spatially optimized for each individual's anatomy and functional data compared to a standard montage applied to all participants. Across two different sessions, 2 Hz tACS was applied targeting auditory brain regions. Concurrent with tACS, participants listened to FM stimuli with modulation rate matching the tACS frequency but with different phase lags relative to the tACS, and detected silent gaps embedded in the FM sound. We observed that tACS modulated the strength of behavioral entrainment to the FM sound in a phase-lag specific manner. Both the optimal tACS lag and the magnitude of the tACS effect were variable across participants and sessions. Inter-individual variability of tACS effects was best explained by the strength of the inward electric field, depending on the field focality and proximity to the target brain region. Although additional evidence is necessary, our results also provided suggestive insights that spatially optimizing the electrode montage could be a promising tool to reduce inter-individual variability of tACS effects. This work demonstrates that tACS effectively modulates entrainment to sounds depending on the optimality of the electric field. However, the lack of reliability on optimal tACS lags calls for caution when planning tACS experiments based on separate sessions.

Echolocation-related reversal of information flow in a cortical vocalization network.

The mammalian frontal and auditory cortices are important for vocal behavior. Here, using local-field potential recordings, we demonstrate that the timing and spatial patterns of oscillations in the fronto-auditory network of vocalizing bats (Carollia perspicillata) predict the purpose of vocalization: echolocation or communication. Transfer entropy analyses revealed predominant top-down (frontal-to-auditory cortex) information flow during spontaneous activity and pre-vocal periods. The dynamics of information flow depend on the behavioral role of the vocalization and on the timing relative to vocal onset. We observed the emergence of predominant bottom-up (auditory-to-frontal) information transfer during the post-vocal period specific to echolocation pulse emission, leading to self-directed acoustic feedback. Electrical stimulation of frontal areas selectively enhanced responses to sounds in auditory cortex. These results reveal unique changes in information flow across sensory and frontal cortices, potentially driven by the purpose of the vocalization in a highly vocal mammalian model.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

Impairment of emotional expression recognition in schizophrenia: a Cuban familial association study.

It is well established that schizophrenia is associated with difficulties in recognizing facial emotional expressions, but few studies have reported the presence of this deficit among their unaffected relatives. This study attempts to add new evidence of familial association on an emotional expression processing test. The study evaluated the performance of 93 paranoid schizophrenia patients, 110 first-degree relatives of probands from multiplex schizophrenia families, and 109 nonpsychiatric controls on a facial emotional recognition test using a computer morphing technique to present the dynamic expressions. The task entailed the recognition of a set of facial expressions depicting the six basic emotions presented in 21 successive frames of increasing intensity. The findings indicated that schizophrenia patients were consistently impaired for the recognition of the six basic facial expressions. In contrast, their unaffected relatives showed a selective impairment for the recognition of disgust and fearful expressions. Familial association of selective facial emotional expressions processing deficit may further implicate promising new endophenotypes that can advance the understanding of affective deficits in schizophrenia.

Probing the Link Between Perception and Oscillations: Lessons from Transcranial Alternating Current Stimulation.

Brain oscillations are regarded as important for perception as they open and close time windows for neural spiking to enable the effective communication within and across brain regions. In the past, studies on perception primarily relied on the use of electrophysiological techniques for probing a correlative link between brain oscillations and perception. The emergence of noninvasive brain stimulation techniques such as transcranial alternating current stimulation (tACS) provides the possibility to study the causal contribution of specific oscillatory frequencies to perception. Here, we review the studies on visual, auditory, and somatosensory perception that employed tACS to probe the causality of brain oscillations for perception. The current literature is consistent with a causal role of alpha and gamma oscillations in parieto-occipital regions for visual perception and theta and gamma oscillations in auditory cortices for auditory perception. In addition, the sensory gating by alpha oscillations applies not only to the visual but also to the somatosensory domain. We conclude that albeit more refined perceptual paradigms and individualized stimulation practices remain to be systematically adopted, tACS is a promising tool for establishing a causal link between neural oscillations and perception.

Fronto-Temporal Coupling Dynamics During Spontaneous Activity and Auditory Processing in the Bat Carollia perspicillata.

Most mammals rely on the extraction of acoustic information from the environment in order to survive. However, the mechanisms that support sound representation in auditory neural networks involving sensory and association brain areas remain underexplored. In this study, we address the functional connectivity between an auditory region in frontal cortex (the frontal auditory field, FAF) and the auditory cortex (AC) in the bat Carollia perspicillata. The AC is a classic sensory area central for the processing of acoustic information. On the other hand, the FAF belongs to the frontal lobe, a brain region involved in the integration of sensory inputs, modulation of cognitive states, and in the coordination of behavioral outputs. The FAF-AC network was examined in terms of oscillatory coherence (local-field potentials, LFPs), and within an information theoretical framework linking FAF and AC spiking activity. We show that in the absence of acoustic stimulation, simultaneously recorded LFPs from FAF and AC are coherent in low frequencies (1-12 Hz). This "default" coupling was strongest in deep AC layers and was unaltered by acoustic stimulation. However, presenting auditory stimuli did trigger the emergence of coherent auditory-evoked gamma-band activity (>25 Hz) between the FAF and AC. In terms of spiking, our results suggest that FAF and AC engage in distinct coding strategies for representing artificial and natural sounds. Taken together, our findings shed light onto the neuronal coding strategies and functional coupling mechanisms that enable sound representation at the network level in the mammalian brain.

Laminar specificity of oscillatory coherence in the auditory cortex.

Empirical evidence suggests that, in the auditory cortex (AC), the phase relationship between spikes and local-field potentials (LFPs) plays an important role in the processing of auditory stimuli. Nevertheless, unlike the case of other sensory systems, it remains largely unexplored in the auditory modality whether the properties of the cortical columnar microcircuit shape the dynamics of spike-LFP coherence in a layer-specific manner. In this study, we directly tackle this issue by addressing whether spike-LFP and LFP-stimulus phase synchronization are spatially distributed in the AC during sensory processing, by performing laminar recordings in the cortex of awake short-tailed bats (Carollia perspicillata) while animals listened to conspecific distress vocalizations. We show that, in the AC, spike-LFP and LFP-stimulus synchrony depend significantly on cortical depth, and that sensory stimulation alters the spatial and spectral patterns of spike-LFP phase-locking. We argue that such laminar distribution of coherence could have functional implications for the representation of naturalistic auditory stimuli at a cortical level.

Neuronal coding of multiscale temporal features in communication sequences within the bat auditory cortex.

Experimental evidence supports that cortical oscillations represent multiscale temporal modulations existent in natural stimuli, yet little is known about the processing of these multiple timescales at a neuronal level. Here, using extracellular recordings from the auditory cortex (AC) of awake bats (Carollia perspicillata), we show the existence of three neuronal types which represent different levels of the temporal structure of conspecific vocalizations, and therefore constitute direct evidence of multiscale temporal processing of naturalistic stimuli by neurons in the AC. These neuronal subpopulations synchronize differently to local-field potentials, particularly in theta- and high frequency bands, and are informative to a different degree in terms of their spike rate. Interestingly, we also observed that both low and high frequency cortical oscillations can be highly informative about the listened calls. Our results suggest that multiscale neuronal processing allows for the precise and non-redundant representation of natural vocalizations in the AC.

Low-Frequency Spike-Field Coherence Is a Fingerprint of Periodicity Coding in the Auditory Cortex.

The extraction of temporal information from sensory input streams is of paramount importance in the auditory system. In this study, amplitude-modulated sounds were used as stimuli to drive auditory cortex (AC) neurons of the bat species Carollia perspicillata, to assess the interactions between cortical spikes and local-field potentials (LFPs) for the processing of temporal acoustic cues. We observed that neurons in the AC capable of eliciting synchronized spiking to periodic acoustic envelopes were significantly more coherent to theta- and alpha-band LFPs than their non-synchronized counterparts. These differences occurred independently of the modulation rate tested and could not be explained by power or phase modulations of the field potentials. We argue that the coupling between neuronal spiking and the phase of low-frequency LFPs might be important for orchestrating the coding of temporal acoustic structures in the AC.

Reach and grasp deficits following damage to the dorsal pulvinar.

Expansion of the dorsal pulvinar in humans and its anatomical connectivity suggests its involvement in higher-order cognitive and visuomotor functions. We investigated visuomotor performance in a 31 year old patient (M.B.) with a lesion centered on the medial portion of the dorsal pulvinar (left > right) due to an atypical Sarcoidosis manifestation. Unlike lesions with a vascular etiology, the lesion of M.B. did not include primary sensory or motor thalamic nuclei. Thus, this patient gave us the exceedingly rare opportunity to study the contribution of the dorsal pulvinar to visuomotor behavior in a human without confounding losses in primary sensory or motor domains. We investigated reaching, saccade and visual decision making performance. Patient data in each task was compared to at least seven age matched healthy controls. While saccades were hypometric towards both hemifields, the patient did not show any spatial choice bias or perceptual deficits. At the same time, he exhibited reach and grasp difficulties, which shared features with both, parietal and cerebellar damage. In particular, he had problems to form a precision grip and exhibited reach deficits expressed in decreased accuracy, delayed initiation and prolonged movement durations. Reach deficits were similar in foveal and extrafoveal viewing conditions and in both visual hemifields but were stronger with the right hand. These results suggest that dorsal pulvinar function in humans goes beyond its subscribed role in visual cognition and is critical for the programming of voluntary actions with the hands.

Simultaneous Transcranial Alternating Current Stimulation and Functional Magnetic Resonance Imaging.

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations. TACS employs frequency-specific stimulation of the human brain through current applied to the scalp with surface electrodes. Most current knowledge of the technique is based on behavioral studies; thus, combining the method with brain imaging holds potential to better understand the mechanisms of tACS. Because of electrical and susceptibility artifacts, combining tACS with brain imaging can be challenging, however, one brain imaging technique that is well suited to be applied simultaneously with tACS is functional magnetic resonance imaging (fMRI). In our lab, we have successfully combined tACS with simultaneous fMRI measurements to show that tACS effects are state, current, and frequency dependent, and that modulation of brain activity is not limited to the area directly below the electrodes. This article describes a safe and reliable setup for applying tACS simultaneously with visual task fMRI studies, which can lend to understanding oscillatory brain function as well as the effects of tACS on the brain.