Altering stimulus timing via fast rhythmic sensory stimulation induces STDP-like recall performance in human episodic memory.

Episodic memory provides humans with the ability to mentally travel back to the past,1 where experiences typically involve associations between multimodal information. Forming a memory of the association is thought to be dependent on modification of synaptic connectivity.2,3 Animal studies suggest that the strength of synaptic modification depends on spike timing between pre- and post-synaptic neurons on the order of tens of milliseconds, which is termed "spike-timing-dependent plasticity" (STDP).4 Evidence found in human in vitro studies suggests different temporal scales in long-term potentiation (LTP) and depression (LTD), compared with the critical time window of STDP in animals.5,6 In the healthy human brain, STDP-like effects have been shown in the motor cortex, visual perception, and face identity recognition.7,8,9,10,11,12,13 However, evidence in human episodic memory is lacking. We investigated this using rhythmic sensory stimulation to drive visual and auditory cortices at 37.5 Hz with four phase offsets. Visual relative to auditory cued recall accuracy was significantly enhanced in the 90° condition when the visual stimulus led at the shortest delay (6.67 ms). This pattern was reversed in the 270° condition when the auditory stimulus led at the shortest delay. Within cue modality, recall was enhanced when a stimulus of the corresponding modality led the shortest delay (6.67 ms) compared with the longest delay (20 ms). Our findings provide evidence for STDP in human episodic memory, which builds an important bridge from in vitro studies in animals to human memory behavior.

Interaction between Theta Phase and Spike Timing-Dependent Plasticity Simulates Theta-Induced Memory Effects.

Rodent studies suggest that spike timing relative to hippocampal theta activity determines whether potentiation or depression of synapses arise. Such changes also depend on spike timing between presynaptic and postsynaptic neurons, known as spike timing-dependent plasticity (STDP). STDP, together with theta phase-dependent learning, has inspired several computational models of learning and memory. However, evidence to elucidate how these mechanisms directly link to human episodic memory is lacking. In a computational model, we modulate long-term potentiation (LTP) and long-term depression (LTD) of STDP, by opposing phases of a simulated theta rhythm. We fit parameters to a hippocampal cell culture study in which LTP and LTD were observed to occur in opposing phases of a theta rhythm. Further, we modulated two inputs by cosine waves with 0° and asynchronous phase offsets and replicate key findings in human episodic memory. Learning advantage was found for the in-phase condition, compared with the out-of-phase conditions, and was specific to theta-modulated inputs. Importantly, simulations with and without each mechanism suggest that both STDP and theta phase-dependent plasticity are necessary to replicate the findings. Together, the results indicate a role for circuit-level mechanisms, which bridge the gap between slice preparation studies and human memory.

Isolating Action Prediction from Action Integration in the Perception of Social Interactions.

Previous research suggests that predictive mechanisms are essential in perceiving social interactions. However, these studies did not isolate action prediction (a priori expectations about how partners in an interaction react to one another) from action integration (a posteriori processing of both partner's actions). This study investigated action prediction during social interactions while controlling for integration confounds. Twenty participants viewed 3D animations depicting an action-reaction interaction between two actors. At the start of each action-reaction interaction, one actor performs a social action. Immediately after, instead of presenting the other actor's reaction, a black screen covers the animation for a short time (occlusion duration) until a still frame depicting a precise moment of the reaction is shown (reaction frame). The moment shown in the reaction frame is either temporally aligned with the occlusion duration or deviates by 150 ms or 300 ms. Fifty percent of the action-reaction trials were semantically congruent, and the remaining were incongruent, e.g., one actor offers to shake hands, and the other reciprocally shakes their hand (congruent action-reaction) versus one actor offers to shake hands, and the other leans down (incongruent action-reaction). Participants made fast congruency judgments. We hypothesized that judging the congruency of action-reaction sequences is aided by temporal predictions. The findings supported this hypothesis; linear speed-accuracy scores showed that congruency judgments were facilitated by a temporally aligned occlusion duration, and reaction frames compared to 300 ms deviations, thus suggesting that observers internally simulate the temporal unfolding of an observed social interction. Furthermore, we explored the link between participants with higher autistic traits and their sensitivity to temporal deviations. Overall, the study offers new evidence of prediction mechanisms underpinning the perception of social interactions in isolation from action integration confounds.

Fronto-medial theta coordinates posterior maintenance of working memory content.

How does the human brain manage multiple bits of information to guide goal-directed behavior? Successful working memory (WM) functioning has consistently been linked to oscillatory power in the theta frequency band (4-8 Hz) over fronto-medial cortex (fronto-medial theta [FMT]). Specifically, FMT is thought to reflect the mechanism of an executive sub-system that coordinates maintenance of memory contents in posterior regions. However, direct evidence for the role of FMT in controlling specific WM content is lacking. Here, we collected high-density electroencephalography (EEG) data while participants engaged in WM-dependent tasks and then used multivariate decoding methods to examine WM content during the maintenance period. Engagement of WM was accompanied by a focal increase in FMT. Importantly, decoding of WM content was driven by posterior sites, which, in turn, showed increased functional theta coupling with fronto-medial channels. Finally, we observed a significant slowing of FMT frequency with increasing WM load, consistent with the hypothesized broadening of a theta "duty cycle" to accommodate additional WM items. Together, these findings demonstrate that frontal theta orchestrates posterior maintenance of WM content. Moreover, the observed frequency slowing elucidates the function of FMT oscillations by specifically supporting phase-coding accounts of WM.

Cognitive performance in idiopathic intracranial hypertension and relevance of intracranial pressure.

Cognitive impairments have been reported in idiopathic intracranial hypertension; however, evidence supporting these deficits is scarce and contributing factors have not been defined. Using a case-control prospective study, we identified multiple domains of deficiency in a cohort of 66 female adult idiopathic intracranial hypertension patients. We identified significantly impaired attention networks (executive function) and sustained attention compared to a body mass index and age matched control group of 25 healthy female participants. We aimed to investigate how cognitive function changed over time and demonstrated that deficits were not permanent. Participants exhibited improvement in several domains including executive function, sustained attention and verbal short-term memory over 12-month follow-up. Improved cognition over time was associated with reduction in intracranial pressure but not body weight. We then evaluated cognition before and after a lumbar puncture with acute reduction in intracranial pressure and noted significant improvement in sustained attention to response task performance. The impact of comorbidities (headache, depression, adiposity and obstructive sleep apnoea) was also explored. We observed that body mass index and the obesity associated cytokine interleukin-6 (serum and cerebrospinal fluid) were not associated with cognitive performance. Headache severity during cognitive testing, co-morbid depression and markers of obstructive sleep apnoea were adversely associated with cognitive performance. Dysregulation of the cortisol generating enzyme 11ß hydroxysteroid dehydrogenase type 1 has been observed in idiopathic intracranial hypertension. Elevated cortisol has been associated with impaired cognition. Here, we utilized liquid chromatography-tandem mass spectrometry for multi-steroid profiling in serum and cerebrospinal fluid in idiopathic intracranial hypertension patients. We noted that reduction in the serum cortisol:cortisone ratio in those undergoing bariatric surgery at 12 months was associated with improving verbal working memory. The clinical relevance of cognitive deficits was noted in their significant association with impaired reliability to perform visual field tests, the cornerstone of monitoring vision in idiopathic intracranial hypertension. Our findings propose that cognitive impairment should be accepted as a clinical manifestation of idiopathic intracranial hypertension and impairs the ability to perform visual field testing reliably. Importantly, cognitive deficits can improve over time and with reduction of intracranial pressure. Treating comorbid depression, obstructive sleep apnoea and headache could improve cognitive performance in idiopathic intracranial hypertension.

Using fast visual rhythmic stimulation to control inter-hemispheric phase offsets in visual areas.

Spike timing dependent plasticity (STDP) is believed to be important for neural communication and plasticity in human episodic memory, but causal evidence is lacking due to technical challenges. Rhythmic sensory stimulation that has been used to investigate causal relations between oscillations and cognition may be able to address this question. The challenge, however, is that the frequency corresponding to the critical time window for STDP is gamma (~40 Hz), yet the application of rhythmic sensory stimulation has been limited primarily to lower frequencies (<30 Hz). It remains unknown whether this method can be applied to precisely control the activation time delay between distant groups of neurons at a millisecond scale. To answer this question and examine the role of STDP in human episodic memory, we simulated the STDP function by controlling the activation time delay between the left and right visual cortices during memory encoding. This was achieved by presenting flickering (37.5 Hz) movie pairs in the left and right visual fields with a phase lag of either 0, 90, 180 or 270°. Participants were asked to memorize the two movies within each pair and the association was later tested. Behavioral results revealed no significant difference in memory performance across conditions with different degrees of gamma phase synchrony. Yet importantly, our study showed for the first time, that oscillatory activity can be driven with a precision of 6.67 ms delay between neuronal groups. Our method hereby provides an approach to investigate relations between precise neuronal timing and cognitive functions.

No evidence for a common self-bias across cognitive domains.

It is generally acknowledged that humans have an egocentric bias; processing self-related stimuli in a specialised, preferential manner. The self-bias has been studied within cognitive domains such as memory, attention and perception; but never across cognitive domains in order to assess whether self-biases are a product of a common bias, or independent. This has relevance for conditions such as Autism Spectrum Disorder: certain self-biases are reduced in those with autism, but the pattern of results is not consistent across different cognitive domains. Self-bias was measured across the attentional and perceptual domains on two well-established tasks: the attentional blink (attention) and shape-label matching (perception) tasks. Processing of each participant's own name was compared to processing of the name of another individual very familiar to the participant (to control for familiarity), and the name of an unfamiliar other. In the attentional domain, the attentional blink for the participant's own name was reduced compared to that for the name of a familiar or unfamiliar other. In the perceptual domain, participants showed stronger associations between their own name and a geometric shape than between the other classes of names and associated shapes. Thus, strong evidence of a self-bias, independent of familiarity, was found on both tasks. However, across two experiments, the magnitude of the self-bias on the attentional blink and shape-label matching tasks was not correlated, supporting the idea that self-biases across cognitive domains are distinct. Furthermore, in contrast with extant models, neither type of self-bias was predicted by autistic traits.

Conscious perception of natural images is constrained by category-related visual features.

Conscious perception is crucial for adaptive behaviour yet access to consciousness varies for different types of objects. The visual system comprises regions with widely distributed category information and exemplar-level representations that cluster according to category. Does this categorical organisation in the brain provide insight into object-specific access to consciousness? We address this question using the Attentional Blink approach with visual objects as targets. We find large differences across categories in the attentional blink. We then employ activation patterns extracted from a deep convolutional neural network to reveal that these differences depend on mid- to high-level, rather than low-level, visual features. We further show that these visual features can be used to explain variance in performance across trials. Taken together, our results suggest that the specific organisation of the higher-tier visual system underlies important functions relevant for conscious perception of differing natural images.

Single-Trial Phase Entrainment of Theta Oscillations in Sensory Regions Predicts Human Associative Memory Performance.

Episodic memories are rich in sensory information and often contain integrated information from different sensory modalities. For instance, we can store memories of a recent concert with visual and auditory impressions being integrated in one episode. Theta oscillations have recently been implicated in playing a causal role synchronizing and effectively binding the different modalities together in memory. However, an open question is whether momentary fluctuations in theta synchronization predict the likelihood of associative memory formation for multisensory events. To address this question we entrained the visual and auditory cortex at theta frequency (4 Hz) and in a synchronous or asynchronous manner by modulating the luminance and volume of movies and sounds at 4 Hz, with a phase offset at 0° or 180°. EEG activity from human subjects (both sexes) was recorded while they memorized the association between a movie and a sound. Associative memory performance was significantly enhanced in the 0° compared with the 180° condition. Source-level analysis demonstrated that the physical stimuli effectively entrained their respective cortical areas with a corresponding phase offset. The findings suggested a successful replication of a previous study (Clouter et al., 2017). Importantly, the strength of entrainment during encoding correlated with the efficacy of associative memory such that small phase differences between visual and auditory cortex predicted a high likelihood of correct retrieval in a later recall test. These findings suggest that theta oscillations serve a specific function in the episodic memory system: binding the contents of different modalities into coherent memory episodes.SIGNIFICANCE STATEMENT How multisensory experiences are bound to form a coherent episodic memory representation is one of the fundamental questions in human episodic memory research. Evidence from animal literature suggests that the relative timing between an input and theta oscillations in the hippocampus is crucial for memory formation. We precisely controlled the timing between visual and auditory stimuli and the neural oscillations at 4 Hz using a multisensory entrainment paradigm. Human associative memory formation depends on coincident timing between sensory streams processed by the corresponding brain regions. We provide evidence for a significant role of relative timing of neural theta activity in human episodic memory on a single-trial level, which reveals a crucial mechanism underlying human episodic memory.

Theta Phase Synchronization Is the Glue that Binds Human Associative Memory.

Episodic memories are information-rich, often multisensory events that rely on binding different elements [1]. The elements that will constitute a memory episode are processed in specialized but distinct brain modules. The binding of these elements is most likely mediated by fast-acting long-term potentiation (LTP), which relies on the precise timing of neural activity [2]. Theta oscillations in the hippocampus orchestrate such timing as demonstrated by animal studies in vitro [3, 4] and in vivo [5, 6], suggesting a causal role of theta activity for the formation of complex memory episodes, but direct evidence from humans is missing. Here, we show that human episodic memory formation depends on phase synchrony between different sensory cortices at the theta frequency. By modulating the luminance of visual stimuli and the amplitude of auditory stimuli, we directly manipulated the degree of phase synchrony between visual and auditory cortices. Memory for sound-movie associations was significantly better when the stimuli were presented in phase compared to out of phase. This effect was specific to theta (4 Hz) and did not occur in slower (1.7 Hz) or faster (10.5 Hz) frequencies. These findings provide the first direct evidence that episodic memory formation in humans relies on a theta-specific synchronization mechanism.

Competitive interactions affect working memory performance for both simultaneous and sequential stimulus presentation.

Competition between simultaneously presented visual stimuli lengthens reaction time and reduces both the BOLD response and neural firing. In contrast, conditions of sequential presentation have been assumed to be free from competition. Here we manipulated the spatial proximity of stimuli (Near versus Far conditions) to examine the effects of simultaneous and sequential competition on different measures of working memory (WM) for colour. With simultaneous presentation, the measure of WM precision was significantly lower for Near items, and participants reported the colour of the wrong item more often. These effects were preserved when the second stimulus immediately followed the first, disappeared when they were separated by 500 ms, and were partly recovered (evident for our measure of mis-binding but not WM precision) when the task was altered to encourage participants to maintain the sequentially presented items together in WM. Our results show, for the first time, that competition affects the measure of WM precision, and challenge the assumption that sequential presentation removes competition.

Transcranial direct current stimulation can enhance working memory in Huntington's disease.

Transcranial direct current stimulation (tDCS) combined with a cognitive task can enhance targeted aspects of cognitive functioning in clinical populations. The movement disorder Huntington's disease (HD) is associated with progressive cognitive impairment. Deficits in working memory (WM) can be apparent early in the disease and impact functional capacity. We investigated whether tDCS combined with cognitive training could improve WM in patients with HD, and if baseline clinical or cognitive measures may predict efficacy. Twenty participants with HD completed this crossover trial, undergoing 1.5mA anodal tDCS over left dorsolateral prefrontal cortex and sham stimulation on separate visits. Participants and assessor were blinded to condition order, which was randomised across participants. All participants completed baseline clinical and cognitive assessments. Pre- and post-stimulation tasks included digit reordering, computerised n-back tests and a Stroop task. During 15min of tDCS/sham stimulation, participants practiced 1- and 2-back WM tasks. Participants exhibited an increase in WM span on the digit re-ordering span task from pre- to post-stimulation after tDCS, but not after sham stimulation. Gains in WM were positively related to motor symptom ratings and negatively associated with verbal fluency scores. Patients with more severe motor symptoms showed greatest improvement, suggesting that motor symptom ratings may help identify patients who are most likely to benefit from tDCS. CONCLUSIONS: Dorsolateral prefrontal tDCS appears well tolerated in HD and enhances WM span compared to sham stimulation. Our findings strongly encourage further investigation of the extent to which tDCS combined with cognitive training could enhance everyday function in HD. ClinicalTrials.gov; NCT02216474 Brain stimulation in Movement Disorders; https://clinicaltrials.gov/ct2/show/NCT02216474.

Alpha, beta: The rhythm of the attentional blink.

Extant theories of the attentional blink propose that the most critical factor in determining second target accuracy is the time that elapses between the first and second targets. We report that this conclusion has overlooked an equally important determinant, namely, the frequency of the entraining stream in which these targets are embedded. Specifically, we show in two experiments that the signature of the attentional blink-second target accuracy that increases with intertarget lag-is significantly larger for entraining streams that are in the alpha-beta frequency range, relative to streams that are slower (theta) or faster (gamma). This finding ties the attentional blink critically, for the first time, to these two prominent oscillation frequencies that are known to be involved in the control of human attention and consciousness.

Multisensory integration: how sound alters sight.

What we hear can rapidly alter what we see. A new study provides evidence for a mechanism in which 10 Hz oscillations in the visual system define the time window for integrating auditory and visual information.

Electrophysiological measurement of the effect of inter-stimulus competition on early cortical stages of human vision.

Competition between inputs in early visual cortex has been established as a key determinant in perception through decades of animal single cell and human fMRI research. We developed a novel ERP paradigm allowing this competition to be studied in humans, affording an opportunity to gain further insight into how competition is reflected at the neural level. Checkerboard stimuli were presented to elicit C1 (indexing processing in V1), C2 (hypothesized to reflect V1 after extrastriate feedback), and P1 (extrastriate) components. Stimuli were presented in three randomized conditions: single stimulus, near proximity pairs and far proximity pairs. Importantly, near stimuli (0.16° visual angle apart) were positioned to compete in primary visual cortex, whereas far stimuli (2° apart) were positioned to compete in extrastriate visual areas. As predicted, the degree and spatial range of competition increased from the C1 component to the C2 and P1 components. Specifically, competitive interactions in C1 amplitude were modest and present only for near-proximity pairs, whereas substantial competition was present for the P1, even for far-proximity pairs. To our knowledge, this is the first study to measure how competition unfolds over time in human visual cortex. Importantly, this method provides an empirical means of measuring competitive interactions at specific stages of visual processing, rendering it possible to rigorously test predictions about the effects of competition on perception, attention, and working memory.

Neural Mechanisms Underlying Visual Short-Term Memory Gain for Temporally Distinct Objects.

Recent research has shown that visual short-term memory (VSTM) can substantially be improved when the to-be-remembered objects are split in 2 half-arrays (i.e., sequenced) or the entire array is shown twice (i.e., repeated), rather than presented simultaneously. Here we investigate the hypothesis that sequencing and repeating displays overcomes attentional "bottlenecks" during simultaneous encoding. Using functional magnetic resonance imaging, we show that sequencing and repeating displays increased brain activation in extrastriate and primary visual areas, relative to simultaneous displays (Study 1). Passively viewing identical stimuli did not increase visual activation (Study 2), ruling out a physical confound. Importantly, areas of the frontoparietal attention network showed increased activation in repetition but not in sequential trials. This dissociation suggests that repeating a display increases attentional control by allowing attention to be reallocated in a second encoding episode. In contrast, sequencing the array poses fewer demands on control, with competition from nonattended objects being reduced by the half-arrays. This idea was corroborated by a third study in which we found optimal VSTM for sequential displays minimizing attentional demands. Importantly these results provide support within the same experimental paradigm for the role of stimulus-driven and top-down attentional control aspects of biased competition theory in setting constraints on VSTM.

Fragile visual short-term memory is an object-based and location-specific store.

Fragile visual short-term memory (FM) is a recently discovered form of visual short-term memory. Evidence suggests that it provides rich and high-capacity storage, like iconic memory, yet it exists, without interference, almost as long as visual working memory. In the present study, we sought to unveil the functional underpinnings of this memory storage. We found that FM is only completely erased when the new visual scene appears at the same location and consists of the same objects as the to-be-recalled information. This result has two important implications: First, it shows that FM is an object- and location-specific store, and second, it suggests that FM might be used in everyday life when the presentation of visual information is appropriately designed.

Frontal and parietal theta burst TMS impairs working memory for visual-spatial conjunctions.

In tasks that selectively probe visual or spatial working memory (WM) frontal and posterior cortical areas show a segregation, with dorsal areas preferentially involved in spatial (e.g. location) WM and ventral areas in visual (e.g. object identity) WM. In a previous fMRI study [1], we showed that right parietal cortex (PC) was more active during WM for orientation, whereas left inferior frontal gyrus (IFG) was more active during colour WM. During WM for colour-orientation conjunctions, activity in these areas was intermediate to the level of activity for the single task preferred and non-preferred information. To examine whether these specialised areas play a critical role in coordinating visual and spatial WM to perform a conjunction task, we used theta burst transcranial magnetic stimulation (TMS) to induce a functional deficit. Compared to sham stimulation, TMS to right PC or left IFG selectively impaired WM for conjunctions but not single features. This is consistent with findings from visual search paradigms, in which frontal and parietal TMS selectively affects search for conjunctions compared to single features, and with combined TMS and functional imaging work suggesting that parietal and frontal regions are functionally coupled in tasks requiring integration of visual and spatial information. Our results thus elucidate mechanisms by which the brain coordinates spatially segregated processing streams and have implications beyond the field of working memory.

Alpha entrainment is responsible for the attentional blink phenomenon.

The attentional blink phenomenon is the reduced ability to report a second target (T2) after identifying a first target (T1) in a rapid serial visual presentation (RSVP) of stimuli (e.g., letters), which are presented at approximately 10 items per second. Several explanations have been proposed, which focus primarily on cognitive aspects, such as attentional filter-, capacity limitation- and retrieval failure-processes. Here, we focus on the hypothesis that an entrainment of alpha oscillations (with a frequency of about 10Hz) is a critical factor for the attentional blink phenomenon. Our hypothesis is based on the fact that item presentation rate in the RSVP typically lies in the alpha frequency range and is motivated by theories assuming an inhibitory function for alpha. We predict that entrainment--during the time window of T2 presentation--is larger for attentional blink (AB) items (when T2 cannot be reported) than for NoAB trials (when T2 cannot be reported). The results support our hypothesis and show that alpha entrainment as measured by the amplitude of the alpha evoked response and the extent of alpha phase concentration is larger for AB than for NoAB trials. Together with the lack of differences in alpha power these findings demonstrate that the differences between AB and NoAB trials--during presentation onset of T2--are due to an entrainment of alpha phase and not due to an amplitude modulation. Thus, we conclude that alpha entrainment may be considered the critical factor underlying the attentional blink phenomenon.