Dissociable rhythmic mechanisms enhance memory for conscious and nonconscious perceptual contents.

Understanding the neural mechanisms of conscious and unconscious experience is a major goal of fundamental and translational neuroscience. Here, we target the early visual cortex with a protocol of noninvasive, high-resolution alternating current stimulation while participants performed a delayed target-probe discrimination task and reveal dissociable mechanisms of mnemonic processing for conscious and unconscious perceptual contents. Entraining ß-rhythms in bilateral visual areas preferentially enhanced short-term memory for seen information, whereas α-entrainment in the same region preferentially enhanced short-term memory for unseen information. The short-term memory improvements were frequency-specific and long-lasting. The results add a mechanistic foundation to existing theories of consciousness, call for revisions to these theories, and contribute to the development of nonpharmacological therapeutics for improving visual cortical processing.

Synchronizing Brain Rhythms to Improve Cognition.

Impaired cognition is common in many neuropsychiatric disorders and severely compromises quality of life. Synchronous electrophysiological rhythms represent a core mechanism for sculpting communication dynamics among large-scale brain networks that underpin cognition and its breakdown in neuropsychiatric disorders. Here, we review an emerging neuromodulation technology called transcranial alternating current stimulation that has shown remarkable early results in rapidly improving various domains of human cognition by modulating properties of rhythmic network synchronization. Future noninvasive neuromodulation research holds promise for potentially rescuing network activity patterns and improving cognition, setting groundwork for the development of drug-free, circuit-based therapeutics for people with cognitive brain disorders.

Disruption and rescue of interareal theta phase coupling and adaptive behavior.

Rescuing executive functions in people with neurological and neuropsychiatric disorders has been a major goal of psychology and neuroscience for decades. Innovative computer-training regimes for executive functions have made tremendous inroads, yet the positive effects of training have not always translated into improved cognitive functioning and often take many days to emerge. In the present study, we asked whether it was possible to immediately change components of executive function by directly manipulating neural activity using a stimulation technology called high-definition transcranial alternating current stimulation (HD-tACS). Twenty minutes of inphase stimulation over medial frontal cortex (MFC) and right lateral prefrontal cortex (lPFC) synchronized theta (∼6 Hz) rhythms between these regions in a frequency and spatially specific manner and rapidly improved adaptive behavior with effects lasting longer than 40 min. In contrast, antiphase stimulation in the same individuals desynchronized MFC-lPFC theta phase coupling and impaired adaptive behavior. Surprisingly, the exogenously driven impairments in performance could be instantly rescued by reversing the phase angle of alternating current. The results suggest executive functions can be rapidly up- or down-regulated by modulating theta phase coupling of distant frontal cortical areas and can contribute to the development of tools for potentially normalizing executive dysfunction in patient populations.

Binding of transcription factor GabR to DNA requires recognition of DNA shape at a location distinct from its cognate binding site.

Mechanisms for transcription factor recognition of specific DNA base sequences are well characterized and recent studies demonstrate that the shape of these cognate binding sites is also important. Here, we uncover a new mechanism where the transcription factor GabR simultaneously recognizes two cognate binding sites and the shape of a 29 bp DNA sequence that bridges these sites. Small-angle X-ray scattering and multi-angle laser light scattering are consistent with a model where the DNA undergoes a conformational change to bend around GabR during binding. In silico predictions suggest that the bridging DNA sequence is likely to be bendable in one direction and kinetic analysis of mutant DNA sequences with biolayer interferometry, allowed the independent quantification of the relative contribution of DNA base and shape recognition in the GabR-DNA interaction. These indicate that the two cognate binding sites as well as the bendability of the DNA sequence in between these sites are required to form a stable complex. The mechanism of GabR-DNA interaction provides an example where the correct shape of DNA, at a clearly distinct location from the cognate binding site, is required for transcription factor binding and has implications for bioinformatics searches for novel binding sites.

Enhancing long-term memory with stimulation tunes visual attention in one trial.

Scientists have long proposed that memory representations control the mechanisms of attention that focus processing on the task-relevant objects in our visual field. Modern theories specifically propose that we rely on working memory to store the object representations that provide top-down control over attentional selection. Here, we show that the tuning of perceptual attention can be sharply accelerated after 20 min of noninvasive brain stimulation over medial-frontal cortex. Contrary to prevailing theories of attention, these improvements did not appear to be caused by changes in the nature of the working memory representations of the search targets. Instead, improvements in attentional tuning were accompanied by changes in an electrophysiological signal hypothesized to index long-term memory. We found that this pattern of effects was reliably observed when we stimulated medial-frontal cortex, but when we stimulated posterior parietal cortex, we found that stimulation directly affected the perceptual processing of the search array elements, not the memory representations providing top-down control. Our findings appear to challenge dominant theories of attention by demonstrating that changes in the storage of target representations in long-term memory may underlie rapid changes in the efficiency with which humans can find targets in arrays of objects.

Synchronizing theta oscillations with direct-current stimulation strengthens adaptive control in the human brain.

Executive control and flexible adjustment of behavior following errors are essential to adaptive functioning. Loss of adaptive control may be a biomarker of a wide range of neuropsychiatric disorders, particularly in the schizophrenia spectrum. Here, we provide support for the view that oscillatory activity in the frontal cortex underlies adaptive adjustments in cognitive processing following errors. Compared with healthy subjects, patients with schizophrenia exhibited low frequency oscillations with abnormal temporal structure and an absence of synchrony over medial-frontal and lateral-prefrontal cortex following errors. To demonstrate that these abnormal oscillations were the origin of the impaired adaptive control in patients with schizophrenia, we applied noninvasive dc electrical stimulation over the medial-frontal cortex. This noninvasive stimulation descrambled the phase of the low-frequency neural oscillations that synchronize activity across cortical regions. Following stimulation, the behavioral index of adaptive control was improved such that patients were indistinguishable from healthy control subjects. These results provide unique causal evidence for theories of executive control and cortical dysconnectivity in schizophrenia.

The morphology of the enamel-dentine junction in Neanderthal molars: Gross morphology, non-metric traits, and temporal trends.

This study explores the morphological differences between the enamel-dentine junction (EDJ) of maxillary and mandibular molars of Neanderthals (n = 150) and recent modern humans (n = 106), and between an earlier Neanderthal sample (consisting of Pre-Eemian and Eemian Neanderthals dating to before 115 ka) and a later Neanderthal sample (consisting of Post-Eemian Neanderthals dating to after 115 ka). The EDJ was visualised by segmenting microtomographic scans of each molar. A geometric morphometric methodology compared the positioning of the dentine horns, the shape of the marginal ridge between the dentine horns, and the shape of the cervix. We also examined the manifestation of non-metric traits at the EDJ including the crista obliqua, cusp 5, and post-paracone tubercle. Furthermore, we report on additional morphological features including centrally placed dentine horn tips and twinned dentine horns. Our results indicate that EDJ morphology can discriminate with a high degree of reliability between Neanderthals and recent modern humans at every molar position, and discriminate between the earlier and the later Neanderthal samples at every molar position, except for the M3 in shape space. The cervix in isolation can also discriminate between Neanderthals and recent modern humans, except at the M3 in form space, and is effective at discriminating between the earlier and the later Neanderthal samples, except at the M2/M2 in form space. In addition to demonstrating the taxonomic valence of the EDJ, our analysis reveals unique manifestations of dental traits in Neanderthals and expanded levels of trait variation that have implications for trait definitions and scoring.

The relationship of CD34+ dosage and platelet recovery following high dose chemotherapy and autologous CD34+ reinfusion in multiple myeloma.

Autologous hematopoietic stem cell transplantation (ASCT) is an established treatment for multiple myeloma (MM), yet the impact of transplanted CD34+ cell dose remains unresolved, especially in patients over the age of 65 years. Data was collected from 207 consecutive ASCT patients to determine the relationship between CD34+ infusion count and short-term and long-term platelet recovery. For MM patients under the age of 65 years (n=155), CD34+ dosage correlates with time to platelet engraftment (p<0.001) and platelet count at 30 days (p=0.003), but not with long-term platelet counts at 180 or 360 days from the CD34+ reinfusion. For MM patients aged 65 years or older (n=46), CD34+ dosage did not correlate with time to platelet engraftment, but did correlate with both short-term and long-term platelet counts at 30 (p<0.001), 180 (p=0.021), and 360 days (p=0.005). Exploratory regression analysis was done to explore platelet stability following the current minimum CD34+ dosage reinfusion. For MM patients under the age of 65 years, the minimum standard CD34+ dosage of 2×106cells/kg was sufficient for a timing to platelet engraftment of <21 days and short-term platelets count ≥150×109/L at 30 days. Alternatively, for MM patients aged 65 years or older, the CD34+ dosage of 2×106cells/kg was insufficient for platelet counts ≥150×109/L at 30 and only marginally attainable at 360 days suggesting that in elderly MM patients a higher CD34+ dosage may be required for platelet recovery and possibly long-term platelet stability.

Medial-Frontal Stimulation Enhances Learning in Schizophrenia by Restoring Prediction Error Signaling.

Posterror learning, associated with medial-frontal cortical recruitment in healthy subjects, is compromised in neuropsychiatric disorders. Here we report novel evidence for the mechanisms underlying learning dysfunctions in schizophrenia. We show that, by noninvasively passing direct current through human medial-frontal cortex, we could enhance the event-related potential related to learning from mistakes (i.e., the error-related negativity), a putative index of prediction error signaling in the brain. Following this causal manipulation of brain activity, the patients learned a new task at a rate that was indistinguishable from healthy individuals. Moreover, the severity of delusions interacted with the efficacy of the stimulation to improve learning. Our results demonstrate a causal link between disrupted prediction error signaling and inefficient learning in schizophrenia. These findings also demonstrate the feasibility of nonpharmacological interventions to address cognitive deficits in neuropsychiatric disorders. SIGNIFICANCE STATEMENT: When there is a difference between what we expect to happen and what we actually experience, our brains generate a prediction error signal, so that we can map stimuli to responses and predict outcomes accurately. Theories of schizophrenia implicate abnormal prediction error signaling in the cognitive deficits of the disorder. Here, we combine noninvasive brain stimulation with large-scale electrophysiological recordings to establish a causal link between faulty prediction error signaling and learning deficits in schizophrenia. We show that it is possible to improve learning rate, as well as the neural signature of prediction error signaling, in patients to a level quantitatively indistinguishable from that of healthy subjects. The results provide mechanistic insight into schizophrenia pathophysiology and suggest a future therapy for this condition.

Attention's Accelerator.

How do people get attention to operate at peak efficiency in high-pressure situations? We tested the hypothesis that the general mechanism that allows this is the maintenance of multiple target representations in working and long-term memory. We recorded subjects' event-related potentials (ERPs) indexing the working memory and long-term memory representations used to control attention while performing visual search. We found that subjects used both types of memories to control attention when they performed the visual search task with a large reward at stake, or when they were cued to respond as fast as possible. However, under normal circumstances, one type of target memory was sufficient for slower task performance. The use of multiple types of memory representations appears to provide converging top-down control of attention, allowing people to step on the attentional accelerator in a variety of high-pressure situations.

Causal control of medial-frontal cortex governs electrophysiological and behavioral indices of performance monitoring and learning.

Adaptive human behavior depends on the capacity to adjust cognitive processing after an error. Here we show that transcranial direct current stimulation of medial-frontal cortex provides causal control over the electrophysiological responses of the human brain to errors and feedback. Using one direction of current flow, we eliminated performance-monitoring activity, reduced behavioral adjustments after an error, and slowed learning. By reversing the current flow in the same subjects, we enhanced performance-monitoring activity, increased behavioral adjustments after an error, and sped learning. These beneficial effects fundamentally improved cognition for nearly 5 h after 20 min of noninvasive stimulation. The stimulation selectively influenced the potentials indexing error and feedback processing without changing potentials indexing mechanisms of perceptual or response processing. Our findings demonstrate that the functioning of mechanisms of cognitive control and learning can be up- or down-regulated using noninvasive stimulation of medial-frontal cortex in the human brain.

Visualizing Trumps Vision in Training Attention.

Mental imagery can have powerful training effects on behavior, but how this occurs is not well understood. Here we show that even a single instance of mental imagery can improve attentional selection of a target more effectively than actually practicing visual search. By recording subjects' brain activity, we found that these imagery-induced training effects were due to perceptual attention being more effectively focused on targets following imagined training. Next, we examined the downside of this potent training by changing the target after several trials of training attention with imagery and found that imagined search resulted in more potent interference than actual practice following these target changes. Finally, we found that proactive interference from task-irrelevant elements in the visual displays appears to underlie the superiority of imagined training relative to actual practice. Our findings demonstrate that visual attention mechanisms can be effectively trained to select target objects in the absence of visual input, and this results in more effective control of attention than practicing the task itself.

High stakes trigger the use of multiple memories to enhance the control of attention.

We can more precisely tune attention to highly rewarding objects than other objects in our environment, but how our brains do this is unknown. After a few trials of searching for the same object, subjects' electrical brain activity indicated that they handed off the memory representations used to control attention from working memory to long-term memory. However, when a large reward was possible, the neural signature of working memory returned as subjects recruited working memory to supplement the cognitive control afforded by the representations accumulated in long-term memory. The amplitude of this neural signature of working memory predicted the magnitude of the subsequent behavioral reward-based attention effects across tasks and individuals, showing the ubiquity of this cognitive reaction to high-stakes situations.

Oscillatory coupling reveals the dynamic reorganization of large-scale neural networks as cognitive demands change.

Cognitive operations are thought to emerge from dynamic interactions between spatially distinct brain areas. Synchronization of oscillations has been proposed to regulate these interactions, but we do not know whether this large-scale synchronization can respond rapidly to changing cognitive demands. Here we show that, as task demands change during a trial, multiple distinct networks are dynamically formed and reformed via oscillatory synchronization. Distinct frequency-coupled networks were rapidly formed to process reward value, maintain information in visual working memory, and deploy visual attention. Strong single-trial correlations showed that networks formed even before the presentation of imperative stimuli could predict the strength of subsequent networks, as well as the speed and accuracy of behavioral responses seconds later. These frequency-coupled networks better predicted single-trial behavior than either local oscillations or ERPs. Our findings demonstrate the rapid reorganization of networks formed by dynamic activity in response to changing task demands within a trial.

Lesion network guided delta frequency neuromodulation improves cognition in patients with psychosis spectrum disorders: A pilot study.

BACKGROUND: Transcranial electric stimulation (tES) may improve cognition in psychosis spectrum disorders. However, few studies have used novel tES approaches, such as high definition tES (HD-tES) to target specific brain circuits. Recently, the extrastriate visual cortex (V5/MT) has been causally linked to visual hallucinations through lesion network mapping and this may be a promising approach for improving cognition. OBJECTIVE: We aim to determine if causal lesion network guided HD-tES to V5/MT improves cognitive performance as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). METHODS: A single-blind pilot study with a within-subjects crossover design was performed to characterize the effect of cathodal HD-transcranial direct current stimulation (tDCS) and 2 Hz HD-transcranial alternating current stimulation (tACS) on cognition. Enrolled patients received 20 mins of HD-tES twice daily for 5 consecutive days applied bilaterally to V5/MT with a washout between conditions. BACS assessments were performed at baseline, day-5, and 1-month. RESULTS: 6 participants with psychosis spectrum disorder were enrolled. 6 individuals received cathodal HD-tDCS. 4 individuals received 2 Hz HD-tACS. HD-tACS resulted in significant (p < 0.1 baseline to 1-month improvements for Digit Sequencing, Verbal Fluency, and Tower of London. HD-tDCS did not result in significant improvement on any task. CONCLUSIONS: HD-tACS targeting V5/MT may be a promising treatment to improve cognitive abilities in individuals with psychosis. By promoting delta oscillations, tACS may enhance cortico-cortico communications across brain networks to improve verbal working memory, processing speed, and executive function. Large-scale investigations are needed to replicate these results.

Homologous mechanisms of visuospatial working memory maintenance in macaque and human: properties and sources.

Although areas of frontal cortex are thought to be critical for maintaining information in visuospatial working memory, the event-related potential (ERP) index of maintenance is found over posterior cortex in humans. In the present study, we reconcile these seemingly contradictory findings. Here, we show that macaque monkeys and humans exhibit the same posterior ERP signature of working memory maintenance that predicts the precision of the memory-based behavioral responses. In addition, we show that the specific pattern of rhythmic oscillations in the alpha band, recently demonstrated to underlie the human visual working memory ERP component, is also present in monkeys. Next, we concurrently recorded intracranial local field potentials from two prefrontal and another frontal cortical area to determine their contribution to the surface potential indexing maintenance. The local fields in the two prefrontal areas, but not the cortex immediately posterior, exhibited amplitude modulations, timing, and relationships to behavior indicating that they contribute to the generation of the surface ERP component measured from the distal posterior electrodes. Rhythmic neural activity in the theta and gamma bands during maintenance provided converging support for the engagement of the same brain regions. These findings demonstrate that nonhuman primates have homologous electrophysiological signatures of visuospatial working memory to those of humans and that a distributed neural network, including frontal areas, underlies the posterior ERP index of visuospatial working memory maintenance.

Where do we store the memory representations that guide attention?

During the last decade one of the most contentious and heavily studied topics in the attention literature has been the role that working memory representations play in controlling perceptual selection. The hypothesis has been advanced that to have attention select a certain perceptual input from the environment, we only need to represent that item in working memory. Here we summarize the work indicating that the relationship between what representations are maintained in working memory and what perceptual inputs are selected is not so simple. First, it appears that attentional selection is also determined by high-level task goals that mediate the relationship between working memory storage and attentional selection. Second, much of the recent work from our laboratory has focused on the role of long-term memory in controlling attentional selection. We review recent evidence supporting the proposal that working memory representations are critical during the initial configuration of attentional control settings, but that after those settings are established long-term memory representations play an important role in controlling which perceptual inputs are selected by mechanisms of attention.

Toxoplasma gondii, a plea for a thorough investigation of its oncogenic potential.

It is estimated that 30 % of the world's population harbours the parasite Toxoplasma gondii, particularly in the brain. Beyond its implication in potentially severe opportunistic or congenital infections, this persistence has long been considered as without consequence. However, certain data in animals and humans suggest that this carriage may be linked to various neuropsychiatric or neurodegenerative disorders. The hypothesis of a potential cerebral oncogenicity of the parasite is also emerging. In this personal view, we will present the epidemiological arguments in favour of an association between toxoplasmosis and cerebral malignancy, before considering the points that could underlie a potential causal link. More specifically, we will focus on the brain as the preferred location for T. gondii persistence and the propensity of this parasite to interfere with the apoptosis and cell cycle signalling pathways of their host cell.

A meta-analysis suggests that tACS improves cognition in healthy, aging, and psychiatric populations.

Transcranial alternating current stimulation (tACS) has attracted interest as a technique for causal investigations into how rhythmic fluctuations in brain neural activity influence cognition and for promoting cognitive rehabilitation. We conducted a systematic review and meta-analysis of the effects of tACS on cognitive function across 102 published studies, which included 2893 individuals in healthy, aging, and neuropsychiatric populations. A total of 304 effects were extracted from these 102 studies. We found modest to moderate improvements in cognitive function with tACS treatment that were evident in several cognitive domains, including working memory, long-term memory, attention, executive control, and fluid intelligence. Improvements in cognitive function were generally stronger after completion of tACS ("offline" effects) than during tACS treatment ("online" effects). Improvements in cognitive function were greater in studies that used current flow models to optimize or confirm neuromodulation targets by stimulating electric fields generated in the brain by tACS protocols. In studies targeting multiple brain regions concurrently, cognitive function changed bidirectionally (improved or decreased) according to the relative phase, or alignment, of the alternating current in the two brain regions (in phase versus antiphase). We also noted improvements in cognitive function separately in older adults and in individuals with neuropsychiatric illnesses. Overall, our findings contribute to the debate surrounding the effectiveness of tACS for cognitive rehabilitation, quantitatively demonstrate its potential, and indicate further directions for optimal tACS clinical study design.