Sensory Drive Modifies Brain Dynamics and the Temporal Integration Window.

Perception is suggested to occur in discrete temporal windows, clocked by cycles of neural oscillations. An important testable prediction of this theory is that individuals' peak frequencies of oscillations should correlate with their ability to segregate the appearance of two successive stimuli. An influential study tested this prediction and showed that individual peak frequency of spontaneously occurring alpha (8-12 Hz) correlated with the temporal segregation threshold between two successive flashes of light [Samaha, J., & Postle, B. R. The speed of alpha-band oscillations predicts the temporal resolution of visual perception. Current Biology, 25, 2985-2990, 2015]. However, these findings were recently challenged [Buergers, S., & Noppeney, U. The role of alpha oscillations in temporal binding within and across the senses. Nature Human Behaviour, 6, 732-742, 2022]. To advance our understanding of the link between oscillations and temporal segregation, we devised a novel experimental approach. Rather than relying entirely on spontaneous brain dynamics, we presented a visual grating before the flash stimuli that is known to induce continuous oscillations in the gamma band (45-65 Hz). By manipulating the contrast of the grating, we found that high contrast induces a stronger gamma response and a shorter temporal segregation threshold, compared to low-contrast trials. In addition, we used a novel tool to characterize sustained oscillations and found that, for half of the participants, both the low- and high-contrast gratings were accompanied by a sustained and phase-locked alpha oscillation. These participants tended to have longer temporal segregation thresholds. Our results suggest that visual stimulus drive, reflected by oscillations in specific bands, is related to the temporal resolution of visual perception.

A Role for Bottom-Up Alpha Oscillations in Temporal Integration.

Neural oscillations in the 8-12 Hz alpha band are thought to represent top-down inhibitory control and to influence temporal resolution: Individuals with faster peak frequencies segregate stimuli appearing closer in time. Recently, this theory has been challenged. Here, we investigate a special case in which alpha does not correlate with temporal resolution: when stimuli are presented amidst strong visual drive. Based on findings regarding alpha rhythmogenesis and wave spatial propagation, we suggest that stimulus-induced, bottom-up alpha oscillations play a role in temporal integration. We propose a theoretical model, informed by visual persistence, lateral inhibition, and network refractory periods, and simulate physiologically plausible scenarios of the interaction between bottom-up alpha and the temporal segregation. Our simulations reveal that different features of oscillations, including frequency, phase, and power, can influence temporal perception and provide a theoretically informed starting point for future empirical studies.

Attentional Sampling between Eye Channels.

Our ability to detect targets in the environment fluctuates in time. When individuals focus attention on a single location, the ongoing temporal structure of performance fluctuates at 8 Hz. When task demands require the distribution of attention over two objects defined by their location, color or motion direction, ongoing performance fluctuates at 4 Hz per object. This suggests that distributing attention entails the division of the sampling process found for focused attention. It is unknown, however, at what stage of the processing hierarchy this sampling occurs, and whether attentional sampling depends on awareness. Here, we show that unaware selection between the two eyes leads to rhythmic sampling. We presented a display with a single central object to both eyes and manipulated the presentation of a reset event (i.e., cue) and a detection target to either both eyes (binocular) or separately to the different eyes (monocular). We assume that presenting a cue to one eye biases the selection process to content presented in that eye. Although participants were unaware of this manipulation, target detection fluctuated at 8 Hz under the binocular condition, and at 4 Hz when the right (and dominant) eye was cued. These results are consistent with recent findings reporting that competition between receptive fields leads to attentional sampling and demonstrate that this competition does not rely on aware processes. Furthermore, attentional sampling occurs at an early site of competition among monocular channels, before they are fused in the primary visual cortex.

Spontaneous activity competes with externally evoked responses in sensory cortex.

The interaction between spontaneous and externally evoked neuronal activity is fundamental for a functional brain. Increasing evidence suggests that bursts of high-power oscillations in the 15- to 30-Hz beta-band represent activation of internally generated events and mask perception of external cues. Yet demonstration of the effect of beta-power modulation on perception in real time is missing, and little is known about the underlying mechanism. Here, we used a closed-loop stimulus-intensity adjustment system based on online burst-occupancy analyses in rats involved in a forepaw vibrotactile detection task. We found that the masking influence of burst occupancy on perception can be counterbalanced in real time by adjusting the vibration amplitude. Offline analysis of firing rates (FRs) and local field potentials across cortical layers and frequency bands confirmed that beta-power in the somatosensory cortex anticorrelated with sensory evoked responses. Mechanistically, bursts in all bands were accompanied by transient synchronization of cell assemblies, but only beta-bursts were followed by a reduction of FR. Our closed loop approach reveals that spontaneous beta-bursts reflect a dynamic state that competes with external stimuli.

Effects of Optogenetic Stimulation of Primary Somatosensory Cortex and Its Projections to Striatum on Vibrotactile Perception in Freely Moving Rats.

Tactile sensation is one of our primary means to collect information about the nearby environment and thus crucial for daily activities and survival. Therefore, it is of high importance to restore sensory feedback after sensory loss. Optogenetic manipulation allows local or pathway-specific write-in of information. However, it remains elusive whether optogenetic stimulation can be interpreted as tactile sensation to guide operant behavior and how it is integrated with tactile stimuli. To address these questions, we employed a vibrotactile detection task combined with optogenetic neuromodulation in freely moving rats. By bidirectionally manipulating the activity of neurons in primary somatosensory cortex (S1), we demonstrated that optical activation as well as inhibition of S1 reduced the detection rate for vibrotactile stimuli. Interestingly, activation of corticostriatal terminals improved the detection of tactile stimuli, while inhibition of corticostriatal terminals did not affect the performance. To manipulate the corticostriatal pathway more specifically, we employed a dual viral system. Activation of corticostriatal cell bodies disturbed the tactile perception while activation of corticostriatal terminals slightly facilitated the detection of vibrotactile stimuli. In the absence of tactile stimuli, both corticostriatal cell bodies as well as terminals caused a reaction. Taken together, our data confirmed the possibility to restore sensation using optogenetics and demonstrated that S1 and its descending projections to striatum play differential roles in the neural processing underlying vibrotactile detection.

Real-time detection of neural oscillation bursts allows behaviourally relevant neurofeedback.

Neural oscillations as important information carrier in the brain, are increasingly interpreted as transient bursts rather than as sustained oscillations. Short (<150 ms) bursts of beta-waves (15-30 Hz) have been documented in humans, monkeys and mice. These events were correlated with memory, movement and perception, and were even suggested as the primary ingredient of all beta-band activity. However, a method to measure these short-lived events in real-time and to investigate their impact on behaviour is missing. Here we present a real-time data analysis system, capable to detect short narrowband bursts, and demonstrate its usefulness to increase the beta-band burst-rate in rats. This neurofeedback training induced changes in overall oscillatory power, and bursts could be decoded from the movement of the rats, thus enabling future investigation of the role of oscillatory bursts.

Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice.

Autism spectrum disorders (ASD) are characterized by social communication deficits, cognitive rigidity, and repetitive stereotyped behaviors. Mesenchymal stem cells (MSC) have a paracrine regenerative effect, and were speculated to be a potential therapy for ASD. The BTBR inbred mouse strain is a commonly used model of ASD as it demonstrates robust behavioral deficits consistent with the diagnostic criteria for ASD. BTBR mice also exhibit decreased brain-derived neurotrophic factor (BDNF) signaling and reduced hippocampal neurogenesis. In the current study, we evaluated the behavioral and molecular effects of intracerebroventricular MSC transplantation in BTBR mice. Transplantation of MSC resulted in a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior. Tissue analysis revealed elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice. This might indicate a possible mechanism underpinning the behavioral improvement. Our study suggests a novel therapeutic approach which may be translatable to ASD patients in the future.

Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism.

Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

Systematic autistic-like behavioral phenotyping of 4 mouse strains using a novel wheel-running assay.

Three core symptoms of autistic spectrum disorders are stereotypic movements, resistance to change in routines and deficits in social interaction. In order to understand their neuronal mechanisms, there is a dire need for behavioral paradigms to assess those symptoms in rodents. Here we present a novel method which is based on positive reward in a customized wheel-running apparatus to assess these symptoms. As a proof of concept, 4 mouse strains were tested in the new behavioral paradigm; 2 control lines (C57BL/6 and ICR) and 2 mouse-models of autism (BTBR T+ tf/J and Nlgn3(tm1Sud)). We found that the C57BL/6, ICR and Nlgn3(tm1Sud) mice showed a significant reduction in stereotypical behavior in the presence of the running wheel, ability to forfeit the running habit when the running-wheel was jammed, and preference of interacting with a social stimulus over the jammed running-wheel. No difference was found between genotypes of the Nlgn3(tm1Sud) mice. On the other hand, the BTBR mice exhibited persistent, elevated levels of stereotypical behavior. In addition, they presented a deficit in their ability to adjust to a changing environment, as manifested in persistence to interact with the wheel even when it was jammed. Lastly, the BTBR mice exhibited no significant preference to interact with the stranger mouse over the jammed running-wheel. These results were validated by a set of commonly used behavioral tests. Overall, our novel behavioral paradigm detects multiple components of autistic-like phenotypes, including cognitive rigidity, stereotypic behavior and social deficiency.