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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.

The integration of sensory signals from different modalities requires flexible interaction of remote brain areas. One candidate mechanism to establish communication in the brain is transient synchronization of oscillatory neural signals. Although there is abundant evidence for the involvement of cortical oscillations in brain functions based on the analysis of local power, assessment of the phase dynamics among spatially distributed neuronal populations and their relevance for behavior is still sparse. In the present study, we investigated the interaction between remote brain areas by analyzing high-density electroencephalogram (EEG) data obtained from human participants engaged in a visuotactile pattern matching task. We deployed an approach for purely data-driven clustering of neuronal phase coupling in source space, which allowed imaging of large-scale functional networks in space, time and frequency without defining a priori constraints. Based on the phase coupling results, we further explored how brain areas interacted across frequencies by computing phase-amplitude coupling. Several networks of interacting sources were identified with our approach, synchronizing their activity within and across the theta (~5 Hz), alpha (~10 Hz), and beta (~ 20 Hz) frequency bands and involving multiple brain areas that have previously been associated with attention and motor control. We demonstrate the functional relevance of these networks by showing that phase delays – in contrast to spectral power – were predictive of task performance. The data-driven analysis approach employed in the current study allowed an unbiased examination of functional brain networks based on EEG source level connectivity data. Showcased for multisensory processing, our results provide evidence that large-scale neuronal coupling is vital to long-range communication in the human brain and relevant for the behavioral outcome in a cognitive task.

Propylene glycol, also denoted as 1.2 propanediol (C3H8O2), often serves as a solvent for dilution of olfactory stimuli. It is supposed to serve as a neutral substance and has been used in many behavioral and electrophysiological studies to dilute pure olfactory stimuli. However, the effect of propylene glycol on perception and on neuronal responses has hitherto never been studied. In this study we tested by means of a threshold test, whether a nasal propylene glycol stimulation is recognizable by humans. Participants were able to recognize propylene glycol at a threshold of 42% concentration and reported a slight cooling effect. In addition to the threshold test, we recorded electroencephalography (EEG) during nasal propylene glycol stimulation to study the neuronal processing of the stimulus. We used a flow olfactometer and stimulated 15 volunteers with three different concentrations of propylene glycol (40 trials each) and water as a control condition (40 trials). To evaluate the neuronal response, we analyzed the event-related potentials (ERPs) and power modulations. The task of the volunteers was to identify a change (olfactory, thermal, or tactile) in the continuous air flow generated by the flow olfactometer. The analysis of the ERPs showed that propylene glycol generates a clear P2 component, which was also visible in the frequency domain as an evoked power response in the theta-band. The source analysis of the P2 revealed a widespread involvement of brain regions, including the postcentral gyrus, the insula and adjacent operculum, the thalamus, and the cerebellum. Thus, it is possible that trigeminal stimulation can at least partly account for sensations and brain responses elicited by propylene glycol. Based on these results, we conclude that the use of high propylene glycol concentrations to dilute fragrances complicates the interpretation of presumed purely olfactory effects.

The classification of repeating stimuli as either old or new is a general mechanism of everyday perception. However, the cortical mechanisms underlying this process are not fully understood. In general, mnemonic processes are thought to rely on changes in oscillatory brain activity across several frequencies as well as their interaction. Lower frequencies, mainly theta-band (3–7 Hz) and alpha-band (8–14 Hz) activity, are attributed to executive control and resource management, respectively; whereas recent studies revealed higher frequencies, e.g. gamma-band (> 25 Hz) activity, to reflect the activation of cortical object representations. Furthermore, low-frequency phase to high-frequency amplitude coupling (PAC) was recently found to coordinate the involved mnemonic networks. To further unravel the processes behind memorization of repeatedly presented stimuli, we applied a continuous item recognition task with up to five presentations per item (mean time between repetitions ~ 10 s) while recording high-density EEG. We examined spectral amplitude modulations as well as PAC. We observed theta amplitudes reaching a peak at second presentation, a reduction of alpha suppression after second presentation, decreased response time, as well as reduced theta–gamma PAC (3 to 7 to − 30 to 45 Hz) at frontal sites after third presentation. We conclude a shift from an explicit- to an implicit-like mnemonic processing, occurring around third presentation, with theta power to signify encoding of repetition-based episodic information and PAC as a neural correlate of the coordination of local neural networks.

Coherent percepts emerge from the accurate combination of inputs from the different sensory systems. There is an ongoing debate about the neurophysiological mechanisms of crossmodal interactions in the brain, and it has been proposed that transient synchronization of neurons might be of central importance. Oscillatory activity in lower frequency ranges (< 30 Hz) has been implicated in mediating long-range communication as typically studied in multisensory research. In the current study, we recorded high-density electroencephalograms while human participants were engaged in a visuotactile pattern matching paradigm and analyzed oscillatory power in the theta- (4-7 Hz), alpha- (8-13 Hz) and beta-bands (13-30 Hz). Employing the same physical stimuli, separate tasks of the experiment either required the detection of predefined targets in visual and tactile modalities or the explicit evaluation of crossmodal stimulus congruence. Analysis of the behavioral data showed benefits for congruent visuotactile stimulus combinations. Differences in oscillatory dynamics related to crossmodal congruence within the two tasks were observed in the beta-band for crossmodal target detection, as well as in the theta-band for congruence evaluation. Contrasting ongoing activity preceding visuotactile stimulation between the two tasks revealed differences in the alpha- and beta-bands. Source reconstruction of between-task differences showed prominent involvement of premotor cortex, supplementary motor area, somatosensory association cortex and the supramarginal gyrus. These areas not only exhibited more involvement in the pre-stimulus interval for target detection compared to congruence evaluation, but were also crucially involved in post-stimulus differences related to crossmodal stimulus congruence within the detection task. These results add to the increasing evidence that low frequency oscillations are functionally relevant for integration in distributed brain networks, as demonstrated for crossmodal interactions in visuotactile pattern matching in the current study.

Working memory (WM) maintenance of sensory information has been associated with enhanced cross-frequency coupling between the phase of low frequencies and the amplitude of high frequencies, particularly in medial temporal lobe (MTL) regions. It has been suggested that these WM maintenance processes are controlled by areas of the prefrontal cortex (PFC) via frontotemporal phase synchronisation in low frequency bands. Here, we investigated whether enhanced cognitive control during audiovisual WM as compared to visual WM alone is associated with increased low-frequency phase synchronisation between sensory areas maintaining WM content and areas from PFC. Using magnetoencephalography, we recorded neural oscillatory activity from healthy human participants engaged in an audiovisual delayed-match-to-sample task. We observed that regions from MTL, which showed enhanced theta-beta phase-amplitude coupling (PAC) during the WM delay window, exhibited stronger phase synchronisation within the theta-band (4–7 Hz) to areas from lateral PFC during audiovisual WM as compared to visual WM alone. Moreover, MTL areas also showed enhanced phase synchronisation to temporooccipital areas in the beta-band (20–32 Hz). Our results provide further evidence that a combination of long-range phase synchronisation and local PAC might constitute a mechanism for neuronal communication between distant brain regions and across frequencies during WM maintenance.

It has been suggested that cross-frequency phase-amplitude coupling (PAC), particularly in temporal brain structures, serves as a neural mechanism for coordinated working memory storage. In this magnetoencephalography study, we show that during visual working memory maintenance, temporal cortex regions, which exhibit enhanced PAC, interact with prefrontal cortex via enhanced low-frequency phase synchronization. Healthy human participants were engaged in a visual delayed match-to-sample task with pictures of natural objects. During the delay period, we observed increased spectral power of beta (20–28 Hz) and gamma (40–94 Hz) bands as well as decreased power of theta/alpha band (7–9 Hz) oscillations in visual sensory areas. Enhanced PAC between the phases of theta/alpha and the amplitudes of beta oscillations was found in the left inferior temporal cortex (IT), an area known to be involved in visual object memory. Furthermore, the IT was functionally connected to the prefrontal cortex by increased low-frequency phase synchronization within the theta/alpha band. Together, these results point to a mechanism in which the combination of PAC and long-range phase synchronization subserves enhanced large-scale brain communication. They suggest that distant brain regions might coordinate their activity in the low-frequency range to engage local stimulus-related processing in higher frequencies via the combination of long-range, within-frequency phase synchronization and local cross-frequency PAC.SIGNIFICANCE STATEMENTWorking memory maintenance, like other cognitive functions, requires the coordinated engagement of brain areas in local and large-scale networks. However, the mechanisms by which spatially distributed brain regions share and combine information remain primarily unknown. We show that the combination of long-range, low-frequency phase synchronization and local cross-frequency phase-amplitude coupling might serve as a mechanism to coordinate memory processes across distant brain areas. In this study, low-frequency phase synchronization between prefrontal and temporal cortex co-occurred with local cross-frequency phase-amplitude coupling to higher frequencies in the latter. By such means, ongoing working memory storage taking place in higher frequencies in temporal regions might be effectively coordinated by distant frontal brain regions through synchronized activity in the low-frequency range.

Recent findings indicate that phase-amplitude coupling between neuronal oscillations in the theta- (3-6 Hz) and the gamma-band (30-100 Hz) plays a functional role in memory processes. Here, using electroencephalography, we provide further evidence for coupling between prefrontal theta and parietal gamma during successful memory retrieval in the human brain. In a pictorial recognition task, the coupling between prefrontal theta phase and parietal gamma amplitude was quantified using the modulation index, 100-1500 ms after stimulus onset. Results show an increased coupling for remembered, as opposed to forgotten and new stimuli (i.e. a "recognition effect" and an "old/new effect"). Phase-amplitude coupling between the prefrontal theta phase and posterior gamma amplitudes is hypothesized to reflect long range communication between prefrontal control processes and the activation of posterior object representations accompanying mnemonic processing.

The role of induced gamma-band responses (iGBRs) in the human electroencephalogram (EEG) is a controversial topic. On the one hand, iGBRs have been associated with neuronal activity reflecting the (re-)activation of cortical object representations. On the other hand, it was shown that miniature saccades (MSs) lead to high-frequency artifacts in the EEG that can mimic cortical iGBRs. We recorded EEG and eye movements simultaneously while participants were engaged in a combined repetition priming and object recognition experiment. MS rates were mainly modulated by object familiarity in a time window from 100 to 300 ms after stimulus onset. In contrast, artifact-corrected iGBRs were sensitive to object repetition and object familiarity in a prolonged time window. EEG source analyses revealed that stimulus repetitions modulated iGBRs in temporal and occipital cortex regions while familiarity was associated with activity in parieto-occipital regions. These results are in line with neuroimaging studies employing functional magnetic resonance imaging or magnetoencephalography. We conclude that MSs reflect early mechanisms of visual perception while iGBRs mirror the activation of cortical networks representing a perceived object.

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.

We used an identical repetition priming paradigm in functional MRI (fMRI) and magnetoencephalography (MEG) to investigate brain networks modulated by stimulus repetition and familiarity. In particular, pictures of familiar or unfamiliar objects were presented sequentially, with stimulus repetitions occurring within few trials. The results of both studies indicated close agreement between the pattern found in fMRI-BOLD (blood oxygenation level dependent) responses and in source localizations of induced gamma-band activity derived from MEG. In both studies, the brain regions that were significantly associated with repetition suppression in response to familiar visual objects encompassed bilaterally the medial and lateral occipital cortex, inferior occipitotemporal regions including the left fusiform cortex, as well as parietal areas. Modulations by stimulus familiarity occurred mainly within this network. Overall, we found noticeable correspondences between the results of fMRI-BOLD signals and MEG gamma-band activity, suggesting that both methods can be used in analogous ways to study the neural basis of repetition priming and object recognition.

The effect of cognitive intervention on brain metabolism in Alzheimer's disease (AD) is largely unexplored. Therefore, we aimed to investigate clinical cognitive parameters and 18FDG PET to test for effects of a cognitive intervention in patients with amnestic mild cognitive impairment (aMCI) or mild AD. Patients with aMCI (n = 24) or mild AD (n = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches to determine longitudinal changes, group-by-time interactions, and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left superior temporal- and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD.

Factors influencing crossmodal interactions are manifold and operate in a stimulus-driven, bottom-up fashion, as well as via top-down control. Here, we evaluate the interplay of stimulus congruence and attention in a visual-tactile task. To this end, we used a matching paradigm requiring the identification of spatial patterns that were concurrently presented visually on a computer screen and haptically to the fingertips by means of a Braille stimulator. Stimulation in our paradigm was always bimodal with only the allocation of attention being manipulated between conditions. In separate blocks of the experiment, participants were instructed to (a) focus on a single modality to detect a specific target pattern, (b) pay attention to both modalities to detect a specific target pattern, or (c) to explicitly evaluate if the patterns in both modalities were congruent or not. For visual as well as tactile targets, congruent stimulus pairs led to quicker and more accurate detection compared to incongruent stimulation. This congruence facilitation effect was more prominent under divided attention. Incongruent stimulation led to behavioral decrements under divided attention as compared to selectively attending a single sensory channel. Additionally, when participants were asked to evaluate congruence explicitly, congruent stimulation was associated with better performance than incongruent stimulation. Our results extend previous findings from audiovisual studies, showing that stimulus congruence also resulted in behavioral improvements in visuotactile pattern matching. The interplay of stimulus processing and attentional control seems to be organized in a highly flexible fashion, with the integration of signals depending on both bottom-up and top-down factors, rather than occurring in an ‘all-or-nothing’ manner.

We used a combined repetition/conceptual priming task to investigate attenuations of induced gamma-band activity (iGBA) due to prior experience. We hypothesized that distinguishable iGBA suppression effects can be related to the processing of (a) perceptual aspects, and (b) conceptual aspects of cortical object representations. Participants were asked to perform a semantic classification task with pictures of real world objects and their semantically corresponding words, using a design that isolated distinct levels of the neural suppression effect. By means of volumetric source analysis we located stimulus domain-specific iGBA repetition suppression effects (60–90 Hz) in temporal, parietal, and occipital areas of the human cortex. In contrast, domain-unspecific iGBA repetition suppression, corresponding to conceptual priming, was restricted to left temporal brain regions. We propose that the selective involvement of left temporal areas points to the activation of conceptual representations, whereas more posterior temporal, parietal, and occipital areas probably reflect perceptual aspects of higher-order visual object processing.

Recent studies have shown that patients with Alzheimer's disease (AD) and its possible prodromal stage mild cognitive impairment benefit from cognitive interventions. Few studies so far have used an active control condition and determined effects in different stages of disease. We evaluated a newly developed 6-month group-based multicomponent cognitive intervention in a randomized controlled pilot study on subjects with amnestic mild cognitive impairment (aMCI) and mild AD patients. Forty-three subjects with aMCI and mild AD were recruited. Primary outcome measures were change in global cognitive function as determined by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini Mental Status Examination (MMSE). Secondary outcomes were specific cognitive and psychopathological ratings. Thirty-nine patients were randomized to intervention groups (IGs: 12 aMCI, 8 AD) and active control groups (CGs: 12 aMCI, 7 AD). At the end of the study, we found significant improvements in the IG(MCI) compared to the CG(MCI) in the ADAS-cog (p = 0.02) and for the secondary endpoint Montgomery Asberg Depression Rating Scale (MADRS) (p < 0.01) Effects on the MMSE score showed a non-significant trend (p = 0.07). In AD patients, we found no significant effect of intervention on the primary outcome measures. In conclusion, these results suggest that participation in a 6-month cognitive intervention can improve cognitive and non-cognitive functions in aMCI subjects. In contrast, AD patients showed no significant benefit from intervention. The findings in this small sample support the use of the intervention in larger scales studies with an extended follow-up period to determine long-term effects.

Diffusion tensor imaging (DTI) demonstrates decline of fractional anisotropy (FA) as a marker of fiber tract integrity in Alzheimer's disease (AD). We aimed to assess the longitudinal course of white matter microstruc- tural changes in AD and healthy elderly control (HC) subjects and to evaluate the effects of treatment with the cholinesterase inhibitor galantamine on white matter microstructure in AD patients. We enrolled 28 AD patients and 11 healthy elderly control subjects (HC). AD patients were randomly assigned to 6-month double-blind galanta- mine treatment or placebo, with a 6-month open-label extension phase. DTI was performed at baseline, as well as at 6 and 12-month follow-up in AD patients. The HC subjects underwent DTI at baseline and 12-month follow- up without treatment. We measured FA in regions of interest covering the posterior cingulate and corpus callo- sum. At 6-month follow-up, the AD group showed signif- icant FA decline in the left posterior cingulate. FA decline was significantly preserved in the posterior body of the corpus callosum in AD group with treatment compared to placebo. At 12-month follow-up, the AD patients showed no differences in FA decline between initial treatment and placebo groups after the 6-month open-label extension phase. A significant FA decline occurred in the left pos- terior cingulate across the AD and HC groups without between-group differences. DTI demonstrated FA decline in intracortically projecting fiber tracts in aging and AD over 1 year. Galantamine had limited impact on regional FA decline, which was not preserved after additional 6-month open-label treatment.

The effect of cognitive intervention on brain metabolism in AD is largely unexplored. Therefore, we aimed to investigate cognitive parameters and 18FDG PET to test for effects of a cognitive intervention in patients with aMCI or mild AD. Patients with aMCI (N = 24) or mild AD (N = 15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches to determine longitudinal changes, group-by-time interactions and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left anterior temporal pole and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD.

We report evidence that multivariate analyses of deformation-based morphometry and diffusion tensor imaging (DTI) data can be used to discriminate between healthy participants and patients with Alzheimer's disease (AD) with comparable diagnostic accuracy. In contrast to other studies on MRI-based biomarkers which usually only focus on a single modality, we derived deformation maps from high-dimensional normalization of T1-weighted images, as well as mean diffusivity maps and fractional anisotropy maps from DTI of the same group of 21 patients with AD and 20 healthy controls. Using an automated multivariate analysis of the entire brain volume, widespread decreased white matter integrity and atrophy effects were found in cortical and subcortical regions of AD patients. Mean diffusivity maps and deformation maps were equally effective in discriminating between AD patients and controls (AUC =0.88 vs. AUC=0.85) while fractional anisotropy maps performed slightly inferior. Combining the maps from different modalities in a logistic regression model resulted in a classification accuracy of AUC=0.86 after leave-one-out cross-validation. It remains to be shown if this automated multivariate analysis of DTI-measures can improve early diagnosis of AD in predementia stages.

During language comprehension, readers or listeners routinely infer information that has not been stated literally in a given text or utterance in order to construct a coherent mental representation (situation model). We used a verification task in a behavioral study and in an event-related functional magnetic resonance imaging (fMRI) experiment to investigate the inference construction process. After having read sentences that mention the outcome of an event explicitly, implicitly, or not at all, participants verified the plausibility of short statements with respect to the context of the just read sentence. The results of the behavioral study established the verification task as a valid method for studying inferences. In the fMRI study, the dorsomedial prefrontal cortex was the most prominent area that was involved in the processing of inference statements. Regions in the left and right temporal lobes were associated with comparison processes that are based on the propositional representations of context sentence and test statements. The results are discussed with respect to levels of representations and the memory systems that underlie the verification process in the different sentence conditions.