Leading and following: Noise differently affects semantic and acoustic processing during naturalistic speech comprehension.

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 audio recordings 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 latencies were 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 latencies became more leading with increasing noise and decreasing speech comprehension and 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.

Non-rhythmic temporal prediction involves phase resets of low-frequency delta oscillations.

The phase of neural oscillatory signals 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 evoked activity. 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.

Single particle cryo-EM of the complex between interphotoreceptor retinoid-binding protein and a monoclonal antibody.

Interphotoreceptor retinoid-binding protein (IRBP) is a highly expressed protein secreted by rod and cone photoreceptors that has major roles in photoreceptor homeostasis as well as retinoid and polyunsaturated fatty acid transport between the neural retina and retinal pigment epithelium. Despite two crystal structures reported on fragments of IRBP and decades of research, the overall structure of IRBP and function within the visual cycle remain unsolved. Here, we studied the structure of native bovine IRBP in complex with a monoclonal antibody (mAb5) by cryo-electron microscopy, revealing the tertiary and quaternary structure at sufficient resolution to clearly identify the complex components. Complementary mass spectrometry experiments revealed the structure and locations of N-linked carbohydrate post-translational modifications. This work provides insight into the structure of IRBP, displaying an elongated, flexible three-dimensional architecture not seen among other retinoid-binding proteins. This work is the first step in elucidation of the function of this enigmatic protein.

Working memory training integrates visual cortex into beta-band networks in congenitally blind individuals.

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 voice-based 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.

Frontal and parietal alpha oscillations reflect attentional modulation of cross-modal matching.

Multisensory perception is shaped by both attentional selection of relevant sensory inputs and exploitation of stimulus-driven factors that promote cross-modal binding. Underlying mechanisms of both top-down and bottom-up modulations have been linked to changes in alpha/gamma dynamics in primary sensory cortices and temporoparietal cortex. Accordingly, it has been proposed that alpha oscillations provide pulsed inhibition for gamma activity and thereby dynamically route cortical information flow. In this study, we employed a recently introduced multisensory paradigm incorporating both bottom-up and top-down aspects of cross-modal attention in an EEG study. The same trimodal stimuli were presented in two distinct attentional conditions, focused on visual-tactile or audio-visual components, for which cross-modal congruence of amplitude changes had to be evaluated. Neither top-down nor bottom-up cross-modal attention modulated alpha or gamma power in primary sensory cortices. Instead, we found alpha band effects in bilateral frontal and right parietal cortex. We propose that frontal alpha oscillations reflect the origin of top-down control regulating perceptual gains and that modulations of parietal alpha oscillations relates to intersensory re-orienting. Taken together, we suggest that the idea of selective cortical routing via alpha oscillations can be extended from sensory cortices to the frontoparietal attention network.

Acupuncture analgesia involves modulation of pain-induced gamma oscillations and cortical network connectivity.

Recent studies support the view that cortical sensory, limbic and executive networks and the autonomic nervous system might interact in distinct manners under the influence of acupuncture to modulate pain. We performed a double-blind crossover design study to investigate subjective ratings, EEG and ECG following experimental laser pain under the influence of sham and verum acupuncture in 26 healthy volunteers. We analyzed neuronal oscillations and inter-regional coherence in the gamma band of 128-channel-EEG recordings as well as heart rate variability (HRV) on two experimental days. Pain ratings and pain-induced gamma oscillations together with vagally-mediated power in the high-frequency bandwidth (vmHF) of HRV decreased significantly stronger during verum than sham acupuncture. Gamma oscillations were localized in the prefrontal cortex (PFC), mid-cingulate cortex (MCC), primary somatosensory cortex and insula. Reductions of pain ratings and vmHF-power were significantly correlated with increase of connectivity between the insula and MCC. In contrast, connectivity between left and right PFC and between PFC and insula correlated positively with vmHF-power without a relationship to acupuncture analgesia. Overall, these findings highlight the influence of the insula in integrating activity in limbic-saliency networks with vagally mediated homeostatic control to mediate antinociception under the influence of acupuncture.

Oscillatory brain activity during multisensory attention reflects activation, disinhibition, and cognitive control.

In this study, we used a novel multisensory attention paradigm to investigate attention-modulated cortical oscillations over a wide range of frequencies using magnetencephalography in healthy human participants. By employing a task that required the evaluation of the congruence of audio-visual stimuli, we promoted the formation of widespread cortical networks including early sensory cortices as well as regions associated with cognitive control. We found that attention led to increased high-frequency gamma-band activity and decreased lower frequency theta-, alpha-, and beta-band activity in early sensory cortex areas. Moreover, alpha-band coherence decreased in visual cortex. Frontal cortex was found to exert attentional control through increased low-frequency phase synchronisation. Crossmodal congruence modulated beta-band coherence in mid-cingulate and superior temporal cortex. Together, these results offer an integrative view on the concurrence of oscillations at different frequencies during multisensory attention.

A matter of attention: Crossmodal congruence enhances and impairs performance in a novel trimodal matching paradigm.

A novel crossmodal matching paradigm including vision, audition, and somatosensation was developed in order to investigate the interaction between attention and crossmodal congruence in multisensory integration. To that end, all three modalities were stimulated concurrently while a bimodal focus was defined blockwise. Congruence between stimulus intensity changes in the attended modalities had to be evaluated. We found that crossmodal congruence improved performance if both, the attended modalities and the task-irrelevant distractor were congruent. If the attended modalities were incongruent, the distractor impaired performance due to its congruence relation to one of the attended modalities. Between attentional conditions, magnitudes of crossmodal enhancement or impairment differed. Largest crossmodal effects were seen in visual-tactile matching, intermediate effects for audio-visual and smallest effects for audio-tactile matching. We conclude that differences in crossmodal matching likely reflect characteristics of multisensory neural network architecture. We discuss our results with respect to the timing of perceptual processing and state hypotheses for future physiological studies. Finally, etiological questions are addressed.

Generators and Connectivity of the Early Auditory Evoked Gamma Band Response.

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. 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. 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. 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.

High-frequency stimulation of the subthalamic nucleus counteracts cortical expression of major histocompatibility complex genes in a rat model of Parkinson's disease.

High-frequency stimulation of the subthalamic nucleus (STN-HFS) is widely used as therapeutic intervention in patients suffering from advanced Parkinson's disease. STN-HFS exerts a powerful modulatory effect on cortical motor control by orthodromic modulation of basal ganglia outflow and via antidromic activation of corticofugal fibers. However, STN-HFS-induced changes of the sensorimotor cortex are hitherto unexplored. To address this question at a genomic level, we performed mRNA expression analyses using Affymetrix microarray gene chips and real-time RT-PCR in sensorimotor cortex of parkinsonian and control rats following STN-HFS. Experimental parkinsonism was induced in Brown Norway rats by bilateral nigral injections of 6-hydroxydopamine and was assessed histologically, behaviorally, and electrophysiologically. We applied prolonged (23h) unilateral STN-HFS in awake and freely moving animals, with the non-stimulated hemisphere serving as an internal control for gene expression analyses. Gene enrichment analysis revealed strongest regulation in major histocompatibility complex (MHC) related genes. STN-HFS led to a cortical downregulation of several MHC class II (RT1-Da, Db1, Ba, and Cd74) and MHC class I (RT1CE) encoding genes. The same set of genes showed increased expression levels in a comparison addressing the effect of 6-hydroxydopamine lesioning. Hence, our data suggest the possible association of altered microglial activity and synaptic transmission by STN-HFS within the sensorimotor cortex of 6-hydroxydopamine treated rats.

Beta-band activity in auditory pathways reflects speech localization and recognition in bilateral cochlear implant users.

In normal-hearing listeners, localization of auditory speech involves stimulus processing in the postero-dorsal pathway of the auditory system. In quiet environments, bilateral cochlear implant (CI) users show high speech recognition performance, but localization of auditory speech is poor, especially when discriminating stimuli from the same hemifield. Whether this difficulty relates to the inability of the auditory system to translate binaural electrical cues into neural signals, or to a functional reorganization of auditory cortical pathways following long periods of binaural deprivation is unknown. In this electroencephalography study, we examined the processing of auditory syllables in postlingually deaf adults with bilateral CIs and in normal-hearing adults. Participants were instructed to either recognize ("recognition" task) or localize ("localization" task) the syllables. The analysis focused on event-related potentials and oscillatory brain responses. N1 amplitudes in CI users were larger in the localization compared with recognition task, suggesting an enhanced stimulus processing effort in the localization task. Linear beamforming of oscillatory activity in CI users revealed stronger suppression of beta-band activity after 200 ms in the postero-dorsal auditory pathway for the localization compared with the recognition task. In normal-hearing adults, effects for longer latency event-related potentials were found, but no effects were observed for N1 amplitudes or beta-band responses. Our study suggests that difficulties in speech localization in bilateral CI users are not reflected in a functional reorganization of cortical auditory pathways. New signal processing strategies of cochlear devices preserving unambiguous binaural cues may improve auditory localization performance in bilateral CI users.

The influence of music and music therapy on pain-induced neuronal oscillations measured by magnetencephalography.

Modern forms of music therapy are clinically established for various therapeutic or rehabilitative goals, especially in the treatment of chronic pain. However, little is known about the neuronal mechanisms that underlie pain modulation by music. Therefore, we attempted to characterize the effects of music therapy on pain perception by comparing the effects of 2 different therapeutic concepts, referred to as receptive and entrainment methods, on cortical activity recorded by magnetencephalography in combination with laser heat pain. Listening to preferred music within the receptive method yielded a significant reduction of pain ratings associated with a significant power reduction of delta-band activity in the cingulate gyrus, which suggests that participants displaced their focus of attention away from the pain stimulus. On the other hand, listening to self-composed "pain music" and "healing music" within the entrainment method exerted major effects on gamma-band activity in primary and secondary somatosensory cortices. Pain music, in contrast to healing music, increased pain ratings in parallel with an increase in gamma-band activity in somatosensory brain structures. In conclusion, our data suggest that the 2 music therapy approaches operationalized in this study seem to modulate pain perception through at least 2 different mechanisms, involving changes of activity in the delta and gamma bands at different stages of the pain processing system.

Auditory evoked bursts in mouse visual cortex during isoflurane anesthesia.

General anesthesia is not a uniform state of the brain. Ongoing activity differs between light and deep anesthesia and cortical response properties are modulated in dependence of anesthetic dosage. We investigated how anesthesia level affects cross-modal interactions in primary sensory cortex. To examine this, we continuously measured the effects of visual and auditory stimulation during increasing and decreasing isoflurane level in the mouse visual cortex and the subiculum (from baseline at 0.7 to 2.5 vol % and reverse). Auditory evoked burst activity occurred in visual cortex after a transition during increase of anesthesia level. At the same time, auditory and visual evoked bursts occurred in the subiculum, even though the subiculum was unresponsive to both stimuli previous to the transition. This altered sensory excitability was linked to the presence of burst suppression activity in cortex, and to a regular slow burst suppression rhythm (~0.2 Hz) in the subiculum. The effect disappeared during return to light anesthesia. The results show that pseudo-heteromodal sensory burst responses can appear in brain structures as an effect of an anesthesia induced state change.

Gamma-band activity as a signature for cross-modal priming of auditory object recognition by active haptic exploration.

When visual sensory information is restricted, we often rely on haptic and auditory information to recognize objects. Here we examined how haptic exploration of familiar objects affects neural processing of subsequently presented sounds of objects. Recent studies indicated that oscillatory responses, in particular in the gamma band (30-100 Hz), reflect cross-modal processing, but it is not clear which cortical networks are involved. In this high-density EEG study, we measured gamma-band activity (GBA) in humans performing a haptic-to-auditory priming paradigm. Haptic stimuli served as primes, and sounds of objects as targets. Haptic and auditory stimuli were either semantically congruent or incongruent, and participants were asked to categorize the objects represented by the sounds. Response times were shorter for semantically congruent compared with semantically incongruent inputs. This haptic-to-auditory priming effect was associated with enhanced total power GBA (250-350 ms) for semantically congruent inputs and additional effects of semantic congruency on evoked GBA (50-100 ms). Source reconstruction of total GBA using linear beamforming revealed effects of semantic congruency in the left lateral temporal lobe, possibly reflecting matching of information across modalities. For semantically incongruent inputs, total GBA was enhanced in middle frontal cortices, possibly indicating the processing or detection of conflicting information. Our findings demonstrate that semantic priming by haptic object exploration affects processing of auditory inputs in the lateral temporal lobe and suggest an important role of oscillatory activity for multisensory processing.

Fast propagating waves within the rodent auditory cortex.

Central processing of acoustic signals is assumed to take place in a stereotypical spatial and temporal pattern involving different fields of auditory cortex. So far, cortical propagating waves representing such patterns have mainly been demonstrated by optical imaging, repeatedly in the visual and somatosensory cortex. In this study, the surface of rat auditory cortex was mapped by recording local field potentials (LFPs) in response to a broadband acoustic stimulus. From the peak amplitudes of LFPs, cortical activation maps were constructed over 4 cortical auditory fields. Whereas response onset had same latencies across primary auditory field (A1), anterior auditory field (AAF), and ventral auditory field and longer latencies in posterior auditory field, activation maps revealed a reproducible wavelike pattern of activity propagating for ∼45 ms poststimulus through all cortical fields. The movement observed started with 2 waves within the primary auditory fields A1 and AAF moving from ventral to dorsal followed by a motion from rostral to caudal, passing continuously through higher-order fields. The pattern of propagating waves was well reproducible and showed only minor changes if different anesthetics were used. The results question the classical "hierarchical" model of cortical areas and demonstrate that the different fields process incoming information as a functional unit.

Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions.

PURPOSE: Development of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method. METHODS: Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature. RESULTS: Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations. CONCLUSIONS: The presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days.

Gamma-band activity reflects multisensory matching in working memory.

In real-world situations, the integration of sensory information in working memory (WM) is an important mechanism for the recognition of objects. Studies in single sensory modalities show that object recognition is facilitated if bottom-up inputs match a template held in WM, and that this effect may be linked to enhanced synchronization of neurons in the gamma-band (>30 Hz). Natural objects, however, frequently provide inputs to multiple sensory modalities. In this EEG study, we examined the integration of semantically matching or non-matching visual and auditory inputs using a delayed visual-to-auditory object-matching paradigm. In the event-related potentials (ERPs) triggered by auditory inputs, effects of semantic matching were observed after 120-170 ms at frontal and posterior regions, indicating WM-specific processing across modalities, and after 250-400 ms over medial-central regions, possibly reflecting the contextual integration of sensory inputs. Additionally, total gamma-band activity (GBA) with medial-central topography after 120-180 ms was larger for matching compared to non-matching trials. This demonstrates that multisensory matching in WM is reflected by GBA and that dynamic coupling of neural populations in this frequency range might be a crucial mechanism for integrative multisensory processes.

Spatiotemporal patterns of cortical activity with bilateral cochlear implants in congenital deafness.

Congenital deafness affects developmental processes in the auditory cortex. In this study, local field potentials (LFPs) were mapped at the cortical surface with microelectrodes in response to cochlear implant stimulation. LFPs were compared between hearing controls and congenitally deaf cats (CDCs). Pulsatile electrical stimulation initially evoked cortical activity in the rostral parts of the primary auditory field (A1). This progressed both in the approximate dorsoventral direction (along the isofrequency stripe) and in the rostrocaudal direction. The dorsal branch of the wavefront split into a caudal branch (propagating in A1) and another smaller one propagating rostrally into the AAF (anterior auditory field). After the front reached the caudal border of A1, a "reflection wave" appeared, propagating back rostrally. In total, the waves took approximately 13-15 ms to propagate along A1 and return back. In CDCs, the propagation pattern was significantly disturbed, with a more synchronous activation of distant cortical regions. The maps obtained from contralateral and ipsilateral stimulation overlapped in both groups of animals. Although controls showed differences in the latency-amplitude patterns, cortical waves evoked by contralateral and ipsilateral stimulation were more similar in CDCs. Additionally, in controls, LFPs with contralateral and ipsilateral stimulation were more similar in caudal A1 than in rostral A1. This dichotomy was lost in deaf animals. In conclusion, propagating cortical waves are specific for the contralateral ear, they are affected by auditory deprivation, and the specificity of the cortex for stimulation of the contralateral ear is reduced by deprivation.

The supramolecular assemblies of voltage-dependent anion channels in the native membrane.

Voltage-dependent anion channels (VDACs) are major constituents of the outer mitochondrial membrane (OMM). These primary transporters of nucleotides, ions and metabolites mediate a substantial portion of the OMM molecular traffic. To study the native supramolecular organization of the VDAC, we have isolated, characterized and imaged OMMs from potato tubers. SDS-PAGE and mass spectrometry of OMMs revealed the presence of the VDAC isoforms POM34 and POM36, as well as the translocase of the OMM complex. Tubular two-dimensional crystals of the VDAC spontaneously formed after incubation of OMMs for two to three months at 4 degrees C. Transmission electron microscopy revealed an oblique lattice and unit cells housing six circular depressions arranged in a hexagon. Atomic force microscopy of freshly isolated OMMs demonstrated (i) the existence of monomers to tetramers, hexamers and higher oligomers of the VDAC and (ii) its spatial arrangement within the oligomers in the native membrane. We discuss the importance of the observed oligomerization for modulation of the VDAC function, for the binding of hexokinase and creatine kinase to the OMM and for mitochondria-mediated apoptosis.

Cortical correlates of false expectations during pain intensity judgments--a possible manifestation of placebo/nocebo cognitions.

We investigated the effects of expectation on intensity ratings and somatosensory evoked magnetic fields and electrical potentials following painful infrared laser stimuli in six healthy subjects. The stimulus series contained trials preceded by different auditory cues which either contained valid, invalid or no information about the upcoming laser intensity. High and low intensities occurred equally probable across cue types. High intensity stimuli induced greater pain than low intensity across all cue types. Furthermore, laser intensity significantly interacted with cue validity: high intensity stimuli were perceived less painful and low intensity stimuli more painful following invalid compared to valid cues. The amplitude of the evoked magnetic field localized within the contralateral secondary somatosensory cortex (SII) at about 165 ms after laser stimuli varied also both with stimulus intensity and cue validity. The evoked electric potential peaked at about 300 ms after laser stimuli and yielded a single dipole source within a region encompassing the caudal anterior cingulate cortex and posterior cingulate cortex. Its amplitude also varied with stimulus intensity, but failed to show any cue validity effects. This result suggests a priming of early cortical nociceptive sensitivity by cues signaling pain severity. A possible contribution of the SII cortex to the manifestation of nocebo/placebo cognitions is discussed.