Transient susceptibility to interference at event boundaries impacts long-term memory of naturalistic episodes.

During ongoing narratives, event boundaries trigger processes relevant for subsequent memory. Previous work has shown that novel, unrelated input presented at an event boundary can retroactively interfere with short-term retention of the preceding event. This interference was attributed to a perturbation of offset-related processes taking place within seconds after encoding and supporting the binding of elements into a coherent event memory. However, the temporal specificity of this memory interference and whether its impact extends to longer retention delays has not been addressed. Here, participants viewed either individual or pairs of short narrative movie clips. Susceptibility to interference at event boundaries was probed by presenting the second clip either immediately after the first, or with a 2s encoding delay. In free and cued recall, after 20 min and 24 h, only memory for movie clips that were immediately followed by a second clip was reduced compared to clips shown in isolation. Intact offset-related processes (as indexed by successful recall of the first movie) did not negatively affect encoding of the subsequent clip. Together, these results indicate that the 2s time-window immediately after an event is relevant for successful consolidation and long-term retention of memory.

Inconsistencies in atlas-based volumetric measures of the human nucleus basalis of Meynert: A need for high-resolution alternatives.

The nucleus basalis of Meynert (nbM) is the major source of cortical acetylcholine (ACh) and has been related to cognitive processes and to neurological disorders. However, spatially delineating the human nbM in MRI studies remains challenging. Due to the absence of a functional localiser for the human nbM, studies to date have localised it using nearby neuroanatomical landmarks or using probabilistic atlases. To understand the feasibility of MRI of the nbM we set our four goals; our first goal was to review current human nbM region-of-interest (ROI) selection protocols used in MRI studies, which we found have reported highly variable nbM volume estimates. Our next goal was to quantify and discuss the limitations of existing atlas-based volumetry of nbM. We found that the identified ROI volume depends heavily on the atlas used and on the probabilistic threshold set. In addition, we found large disparities even for data/studies using the same atlas and threshold. To test whether spatial resolution contributes to volume variability, as our third goal, we developed a novel nbM mask based on the normalized BigBrain dataset. We found that as long as the spatial resolution of the target data was 1.3 mm isotropic or above, our novel nbM mask offered realistic and stable volume estimates. Finally, as our last goal we tried to discern nbM using publicly available and novel high resolution structural MRI ex vivo MRI datasets. We find that, using an optimised 9.4T quantitative T2⁎ ex vivo dataset, the nbM can be visualised using MRI. We conclude caution is needed when applying the current methods of mapping nbM, especially for high resolution MRI data. Direct imaging of the nbM appears feasible and would eliminate the problems we identify, although further development is required to allow such imaging using standard (f)MRI scanning.

Spatiotemporal patterns of sleep spindle activity in human anterior thalamus and cortex.

Sleep spindles (8 - 16 Hz) are transient electrophysiological events during non-rapid eye movement sleep. While sleep spindles are routinely observed in the cortex using scalp electroencephalography (EEG), recordings of their thalamic counterparts have not been widely studied in humans. Based on a few existing studies, it has been hypothesized that spindles occur as largely local phenomena. We investigated intra-thalamic and thalamocortical spindle co-occurrence, which may underlie thalamocortical communication. We obtained scalp EEG and thalamic recordings from 7 patients that received bilateral deep brain stimulation (DBS) electrodes to the anterior thalamus for the treatment of drug resistant focal epilepsy. Spindles were categorized into subtypes based on their main frequency (i.e., slow (10±2 Hz) or fast (14±2 Hz)) and their level of thalamic involvement (spanning one channel, or spreading uni- or bilaterally within the thalamus). For the first time, we contrasted observed spindle patterns with permuted data to estimate random spindle co-occurrence. We found that multichannel spindle patterns were systematically coordinated at the thalamic and thalamocortical level. Importantly, distinct topographical patterns of thalamocortical spindle overlap were associated with slow and fast subtypes of spindles. These observations provide further evidence for coordinated spindle activity in thalamocortical networks.

Empirically constrained network models for contrast-dependent modulation of gamma rhythm in V1.

Gamma oscillations are thought to play a key role in neuronal network function and neuronal communication, yet the underlying generating mechanisms have not been fully elucidated to date. At least partly, this may be due to the fact that even in simple network models of interconnected inhibitory (I) and excitatory (E) neurons, many parameters remain unknown and are set based on practical considerations or by convention. Here, we mitigate this problem by requiring PING (Pyramidal Interneuron Network Gamma) models to simultaneously satisfy a broad set of criteria for realistic behaviour based on empirical data spanning both the single unit (spikes) and local population (LFP) levels while unknown parameters are varied. By doing so, we were able to constrain the parameter ranges and select empirically valid models. The derived model constraints implied weak rather than strong PING as the generating mechanism for gamma, connectivity between E and I neurons within specific bounds, and variations of the external input to E but not I neurons. Constrained models showed valid behaviours, including gamma frequency increases with contrast and power saturation or decay at high contrasts. Using an empirically-validated model we studied the route to gamma instability at high contrasts. This involved increased heterogeneity of E neurons with increasing input triggering a breakdown of I neuron pacemaker function. Further, we illustrate the model's capacity to resolve disputes in the literature concerning gamma oscillation properties and GABA conductance proxies. We propose that the models derived in our study will be useful for other modelling studies, and that our approach to the empirical constraining of PING models can be expanded when richer empirical datasets become available. As local gamma networks are the building blocks of larger networks that aim to understand complex cognition through their interactions, there is considerable value in improving our models of these building blocks.

Transcranial alternating current stimulation at theta frequency to left parietal cortex impairs associative, but not perceptual, memory encoding.

Neural oscillations in the theta range (4-8 Hz) are thought to underlie associative memory function in the hippocampal-cortical network. While there is ample evidence supporting a role of theta oscillations in animal and human memory, most evidence is correlational. Non-invasive brain stimulation (NIBS) can be employed to modulate cortical oscillatory activity to influence brain activity, and possibly modulate deeper brain regions, such as hippocampus, through strong and reliable cortico-hippocampal functional connections. We applied focal transcranial alternating current stimulation (tACS) at 6 Hz over left parietal cortex to modulate brain activity in the putative cortico-hippocampal network to influence associative memory encoding. After encoding and brain stimulation, participants completed an associative memory and a perceptual recognition task. Results showed that theta tACS significantly decreased associative memory performance but did not affect perceptual memory performance. These results show that parietal theta tACS modulates associative processing separately from perceptual processing, and further substantiate the hypothesis that theta oscillations are implicated in the cortico-hippocampal network and associative encoding.

Microsaccade-rhythmic modulation of neural synchronization and coding within and across cortical areas V1 and V2.

Primates sample their visual environment actively through saccades and microsaccades (MSs). Saccadic eye movements not only modulate neural spike rates but might also affect temporal correlations (synchrony) among neurons. Neural synchrony plays a role in neural coding and modulates information transfer between cortical areas. The question arises of how eye movements shape neural synchrony within and across cortical areas and how it affects visual processing. Through local field recordings in macaque early visual cortex while monitoring eye position and through neural network simulations, we find 2 distinct synchrony regimes in early visual cortex that are embedded in a 3- to 4-Hz MS-related rhythm during visual fixation. In the period shortly after an MS ("transient period"), synchrony was high within and between cortical areas. In the subsequent period ("sustained period"), overall synchrony dropped and became selective to stimulus properties. Only mutually connected neurons with similar stimulus responses exhibited sustained narrow-band gamma synchrony (25-80 Hz), both within and across cortical areas. Recordings in macaque V1 and V2 matched the model predictions. Furthermore, our modeling provides predictions on how (micro)saccade-modulated gamma synchrony in V1 shapes V2 receptive fields (RFs). We suggest that the rhythmic alternation between synchronization regimes represents a basic repeating sampling strategy of the visual system.

Number-related Brain Potentials Are Differentially Affected by Mapping Novel Symbols on Small versus Large Quantities in a Number Learning Task.

The nature of the mapping process that imbues number symbols with their numerical meaning-known as the "symbol-grounding process"-remains poorly understood and the topic of much debate. The aim of this study was to enhance insight into how the nonsymbolic-symbolic number mapping process and its neurocognitive correlates might differ between small (1-4; subitizing range) and larger (6-9) numerical ranges. Hereto, 22 young adults performed a learning task in which novel symbols acquired numerical meaning by mapping them onto nonsymbolic magnitudes presented as dot arrays (range 1-9). Learning-dependent changes in accuracy and RT provided evidence for successful novel symbol quantity mapping in the subitizing (1-4) range only. Corroborating these behavioral results, the number processing related P2p component was only modulated by the learning/mapping of symbols representing small numbers 1-4. The symbolic N1 amplitude increased with learning independent of symbolic numerical range but dependent on the set size of the preceding dot array; it only occurred when mapping on one to four item dot arrays that allow for quick retrieval of a numeric value, on the basis of which, with learning, one could predict the upcoming symbol causing perceptual expectancy violation when observing a different symbol. These combined results suggest that exact nonsymbolic-symbolic mapping is only successful for small quantities 1-4 from which one can readily extract cardinality. Furthermore, we suggest that the P2p reflects the processing stage of first access to or retrieval of numeric codes and might in future studies be used as a neural correlate of nonsymbolic-symbolic mapping/symbol learning.

Hippocampal-striatal functional connectivity supports processing of temporal expectations from associative memory.

The hippocampus and dorsal striatum are both associated with temporal processing, but they are thought to play distinct roles. The hippocampus has been reported to contribute to storing temporal structure of events in memory, whereas the striatum contributes to temporal motor preparation and reward anticipation. Here, we asked whether the striatum cooperates with the hippocampus in processing the temporal context of memorized visual associations. In our task, participants were trained to implicitly form temporal expectations for one of two possible time intervals associated to specific cue-target associations, and subsequently were scanned using ultra-high-field 7T functional magnetic resonance imaging. During scanning, learned temporal expectations could be violated when the pairs were presented at either the associated or not-associated time intervals. When temporal expectations were met during testing trials, activity in left and right hippocampal subfields and right putamen decreased, compared to when temporal expectations were not met. Further, psycho-physiological interactions showed that functional connectivity between left hippocampal subfields and caudate decreased when temporal expectations were not met. Our results indicate that the hippocampus and striatum cooperate to process implicit temporal expectation from mnemonic associations. Our findings provide further support for a hippocampal-striatal network in temporal associative processing.

The Attentional Blink is Related to the Microsaccade Rate Signature.

The reduced detectability of a target T2 following discrimination of a preceding target T1 in the attentional blink (AB) paradigm is classically interpreted as a consequence of reduced attention to T2 due to attentional allocation to T1. Here, we investigated whether AB was related to changes in microsaccade rate (MSR). We found a pronounced MSR signature following T1 onset, characterized by MSR suppression from 200 to 328 ms and enhancement from 380 to 568 ms. Across participants, the magnitude of the MSR suppression correlated with the AB effect such that low T2 detectability corresponded to reduced MSR. However, in the same task, T1 error trials coincided with the presence of microsaccades. We discuss this apparent paradox in terms of known neurophysiological correlates of MS whereby cortical excitability is suppressed both during the microsaccade and MSR suppression, in accordance to poor T1 performance with microsaccade occurrence and poor T2 performance with microsaccade absence. Our data suggest a novel low-level mechanism contributing to AB characterized by reduced MSR, thought to cause suppressed visual cortex excitability. This opens the question of whether attention mediates T2 performance suppression independently from MSR, and if not, how attention interacts with MSR to produce the T2 performance suppression.

Diminished Alpha Lateralization During Working Memory but Not During Attentional Cueing in Older Adults.

Aging has been associated with declined performance in tasks that rely on working memory (WM). Because attention and WM are tightly coupled, declined performance on a WM task in older adults could be due to deficits in attention, memory capacity, or both. We used alpha (8-14 Hz) power modulations as an index to assess how changes in attention and memory capacity contribute to decreased WM performance in older adults. We recorded the magnetoencephalogram in healthy older (60-76 years) and younger adults (18-28 years) while they performed a lateralized WM task. At matched difficulty, older adults showed significantly lower memory spans than younger adults. Alpha lateralization during retention was nearly absent in older adults due to a bilateral reduction of alpha power. By contrast, in younger adults alpha power was reduced only contralateral to the attended hemifield. Surprisingly, during the cue interval, both groups showed equal alpha lateralization. The preserved alpha lateralization during attentional cueing, and lack thereof during retention, suggests that reduced WM performance in older adults is due to deficits in WM-related processes, not deficits in attentional orienting, and that a compensatory mechanism in aging permits significant residual WM performance in the absence of alpha lateralization.

The impact of ultra-high field MRI on cognitive and computational neuroimaging.

The ability to measure functional brain responses non-invasively with ultra high field MRI (7 T and above) represents a unique opportunity in advancing our understanding of the human brain. Compared to lower fields (3 T and below), ultra high field MRI has an increased sensitivity, which can be used to acquire functional images with greater spatial resolution, and greater specificity of the blood oxygen level dependent (BOLD) signal to the underlying neuronal responses. Together, increased resolution and specificity enable investigating brain functions at a submillimeter scale, which so far could only be done with invasive techniques. At this mesoscopic spatial scale, perception, cognition and behavior can be probed at the level of fundamental units of neural computations, such as cortical columns, cortical layers, and subcortical nuclei. This represents a unique and distinctive advantage that differentiates ultra high from lower field imaging and that can foster a tighter link between fMRI and computational modeling of neural networks. So far, functional brain mapping at submillimeter scale has focused on the processing of sensory information and on well-known systems for which extensive information is available from invasive recordings in animals. It remains an open challenge to extend this methodology to uniquely human functions and, more generally, to systems for which animal models may be problematic. To succeed, the possibility to acquire high-resolution functional data with large spatial coverage, the availability of computational models of neural processing as well as accurate biophysical modeling of neurovascular coupling at mesoscopic scale all appear necessary.

Learned interval time facilitates associate memory retrieval.

The extent to which time is represented in memory remains underinvestigated. We designed a time paired associate task (TPAT) in which participants implicitly learned cue-time-target associations between cue-target pairs and specific cue-target intervals. During subsequent memory testing, participants showed increased accuracy of identifying matching cue-target pairs if the time interval during testing matched the implicitly learned interval. A control experiment showed that participants had no explicit knowledge about the cue-time associations. We suggest that "elapsed time" can act as a temporal mnemonic associate that can facilitate retrieval of events associated in memory.

Stimulus repetition modulates gamma-band synchronization in primate visual cortex.

When a sensory stimulus repeats, neuronal firing rate and functional MRI blood oxygen level-dependent responses typically decline, yet perception and behavioral performance either stay constant or improve. An additional aspect of neuronal activity is neuronal synchronization, which can enhance the impact of neurons onto their postsynaptic targets independent of neuronal firing rates. We show that stimulus repetition leads to profound changes of neuronal gamma-band (∼40-90 Hz) synchronization. Electrocorticographic recordings in two awake macaque monkeys demonstrated that repeated presentations of a visual grating stimulus resulted in a steady increase of visually induced gamma-band activity in area V1, gamma-band synchronization between areas V1 and V4, and gamma-band activity in area V4. Microelectrode recordings in area V4 of two additional monkeys under the same stimulation conditions allowed a direct comparison of firing rates and gamma-band synchronization strengths for multiunit activity (MUA), as well as for isolated single units, sorted into putative pyramidal cells and putative interneurons. MUA and putative interneurons showed repetition-related decreases in firing rate, yet increases in gamma-band synchronization. Putative pyramidal cells showed no repetition-related firing rate change, but a decrease in gamma-band synchronization for weakly stimulus-driven units and constant gamma-band synchronization for strongly driven units. We propose that the repetition-related changes in gamma-band synchronization maintain the interareal stimulus signaling and sharpen the stimulus representation by gamma-synchronized pyramidal cell spikes.

Input-dependent frequency modulation of cortical gamma oscillations shapes spatial synchronization and enables phase coding.

Fine-scale temporal organization of cortical activity in the gamma range (∼25-80Hz) may play a significant role in information processing, for example by neural grouping ('binding') and phase coding. Recent experimental studies have shown that the precise frequency of gamma oscillations varies with input drive (e.g. visual contrast) and that it can differ among nearby cortical locations. This has challenged theories assuming widespread gamma synchronization at a fixed common frequency. In the present study, we investigated which principles govern gamma synchronization in the presence of input-dependent frequency modulations and whether they are detrimental for meaningful input-dependent gamma-mediated temporal organization. To this aim, we constructed a biophysically realistic excitatory-inhibitory network able to express different oscillation frequencies at nearby spatial locations. Similarly to cortical networks, the model was topographically organized with spatially local connectivity and spatially-varying input drive. We analyzed gamma synchronization with respect to phase-locking, phase-relations and frequency differences, and quantified the stimulus-related information represented by gamma phase and frequency. By stepwise simplification of our models, we found that the gamma-mediated temporal organization could be reduced to basic synchronization principles of weakly coupled oscillators, where input drive determines the intrinsic (natural) frequency of oscillators. The gamma phase-locking, the precise phase relation and the emergent (measurable) frequencies were determined by two principal factors: the detuning (intrinsic frequency difference, i.e. local input difference) and the coupling strength. In addition to frequency coding, gamma phase contained complementary stimulus information. Crucially, the phase code reflected input differences, but not the absolute input level. This property of relative input-to-phase conversion, contrasting with latency codes or slower oscillation phase codes, may resolve conflicting experimental observations on gamma phase coding. Our modeling results offer clear testable experimental predictions. We conclude that input-dependency of gamma frequencies could be essential rather than detrimental for meaningful gamma-mediated temporal organization of cortical activity.

Visual cortical gamma-band activity during free viewing of natural images.

Gamma-band activity in visual cortex has been implicated in several cognitive operations, like perceptual grouping and attentional selection. So far, it has been studied primarily under well-controlled visual fixation conditions and using well-controlled stimuli, like isolated bars or patches of grating. If gamma-band activity is to subserve its purported functions outside of the laboratory, it should be present during natural viewing conditions. We recorded neuronal activity with a 252-channel electrocorticographic (ECoG) grid covering large parts of the left hemisphere of 2 macaque monkeys, while they freely viewed natural images. We found that natural viewing led to pronounced gamma-band activity in the visual cortex. In area V1, gamma-band activity during natural viewing showed a clear spectral peak indicative of oscillatory activity between 50 and 80 Hz and was highly significant for each of 65 natural images. Across the ECoG grid, gamma-band activity during natural viewing was present over most of the recorded visual cortex and absent over most remaining cortex. After saccades, the gamma peak frequency slid down to 30-40 Hz at around 80 ms postsaccade, after which the sustained 50- to 80-Hz gamma-band activity resumed. We propose that gamma-band activity plays an important role during natural viewing.

Perceived temporal asynchrony between sinusoidally modulated luminance and depth.

Simultaneously presented visual events lead to temporally asynchronous percepts. This has led some researchers to conclude that the asynchronous experience is a manifestation of differences in neural processing time for different visual attributes. Others, however, have suggested that the asynchronous experience is due to differences in temporal markers for changes of different visual attributes. Here, two sets of bars were presented, one to each eye. Either the bars were moving or their luminance was gradually changing. Bars moved horizontally in counterphase at low frequencies along short trajectories and were presented stereoscopically, such that the horizontal movements were perceived as back-and-forth motion on a sagittal plane, or monocularly to a dominant eye, preserving a perception of the horizontal movements on a frontal plane. In a control condition, bars were stationary and their luminance was modulated. The changes in stimulus speed or luminance occurred sinusoidally. When asked to adjust the phase of one stimulus to the other to achieve synchronous perception, participants showed a constant phase offset at the lowest frequencies used. Given the absence of abrupt transitions and the presence of similar gradual turning points in our stimuli to control for attentional effects, it can be concluded that asynchronous percepts in multimodal stimuli may at least in part be a manifestation of difference in neural processing time of visual attributes rather than solely a difference in the temporal markers (transitions versus turning points).

Molecular correlates of cortical network modulation by long-term sensory experience in the adult rat barrel cortex.

Modulation of cortical network connectivity is crucial for an adaptive response to experience. In the rat barrel cortex, long-term sensory stimulation induces cortical network modifications and neuronal response changes of which the molecular basis is unknown. Here, we show that long-term somatosensory stimulation by enriched environment up-regulates cortical expression of neuropeptide mRNAs and down-regulates immediate-early gene (IEG) mRNAs specifically in the barrel cortex, and not in other brain regions. The present data suggest a central role of neuropeptides in the fine-tuning of sensory cortical circuits by long-term experience.

MicroRNA-137 regulates a glucocorticoid receptor-dependent signalling network: implications for the etiology of schizophrenia.

BACKGROUND: Schizophrenia is a highly heritable neurodevelopmental disorder. A genetic variant of microRNA-137 (miR-137) has yielded significant genome-wide association with schizophrenia, suggesting that this miRNA plays a key role in its etiology. Therefore, a molecular network of interacting miR-137 targets may provide insights into the biological processes underlying schizophrenia. METHODS: We first used bioinformatics tools to obtain and analyze predicted human and mouse miR-137 targets. We then determined miR-137 levels in rat barrel cortex after environmental enrichment (EE), a neuronal plasticity model that induces upregulation of several predicted miR-137 targets. Subsequently, expression changes of these predicted targets were examined through loss of miR-137 function experiments in rat cortical neurons. Finally, we conducted bioinformatics and literature analyses to examine the targets that were upregulated upon miR-137 downregulation. RESULTS: Predicted human and mouse miR-137 targets were enriched in neuronal processes, such as axon guidance, neuritogenesis and neurotransmission. The miR-137 levels were significantly downregulated after EE, and we identified 5 novel miR-137 targets through loss of miR-137 function experiments. These targets fit into a glucocorticoid receptor-dependent signalling network that also includes 3 known miR-137 targets with genome-wide significant association with schizophrenia. LIMITATIONS: The bioinformatics analyses involved predicted human and mouse miR-137 targets owing to lack of information on predicted rat miR-137 targets, whereas follow-up experiments were performed with rats. Furthermore, indirect effects in the loss of miR-137 function experiments cannot be excluded. CONCLUSION: We have identified a miR-137-regulated protein network that contributes to our understanding of the molecular basis of schizophrenia and provides clues for future research into psychopharmacological treatments for schizophrenia.

Impaired processing of 3D motion-defined faces in mild cognitive impairment and healthy aging: an fMRI study.

Mild cognitive impairment (MCI), which shows high risk for conversion to Alzheimer's disease (AD), is accompanied by progressive visual deteriorations that so far are poorly understood. Here, we compared dorsal and ventral visual stream functional magnetic resonance imaging (fMRI) activity among amnestic MCI, healthy elderly, and young participants during structure-from-motion (SFM) face categorization performance. Task performance varied with stimulus depth and duration levels and differences among groups were highly correlated with face-related fMRI activation patterns. Young participants showed larger activation to faces than scrambled faces (face sensitivity) in the right fusiform face area (FFA) and right occipital face area (OFA) whereas in elderly, this difference was reduced. Surprisingly, in MCI, scrambled faces elicited larger activation in right FFA/OFA than faces. The latter observation may be related to the additional finding of elevated depth sensitivity in left FFA/OFA of MCI, suggesting that an increased representation of low-level stimulus aspects may impair face perception in MCI. Discriminant function analysis using face and depth sensitivity indices in FFA/OFA classified MCI and healthy elderly with 88.2% accuracy, marking a fundamental distinction between groups. Potentially related findings include altered activation patterns in dorsal-ventral stream integration regions and attention-related networks of MCI patients. Our results highlight aberrant visual and additional potentially compensatory processes that identify dispositions of (preclinical) AD.

Learning of new sound categories shapes neural response patterns in human auditory cortex.

The formation of new sound categories is fundamental to everyday goal-directed behavior. Categorization requires the abstraction of discrete classes from continuous physical features as required by context and task. Electrophysiology in animals has shown that learning to categorize novel sounds alters their spatiotemporal neural representation at the level of early auditory cortex. However, functional magnetic resonance imaging (fMRI) studies so far did not yield insight into the effects of category learning on sound representations in human auditory cortex. This may be due to the use of overlearned speech-like categories and fMRI subtraction paradigms, leading to insufficient sensitivity to distinguish the responses to learning-induced, novel sound categories. Here, we used fMRI pattern analysis to investigate changes in human auditory cortical response patterns induced by category learning. We created complex novel sound categories and analyzed distributed activation patterns during passive listening to a sound continuum before and after category learning. We show that only after training, sound categories could be successfully decoded from early auditory areas and that learning-induced pattern changes were specific to the category-distinctive sound feature (i.e., pitch). Notably, the similarity between fMRI response patterns for the sound continuum mirrored the sigmoid shape of the behavioral category identification function. Our results indicate that perceptual representations of novel sound categories emerge from neural changes at early levels of the human auditory processing hierarchy.