Perception and propagation of activity through the cortical hierarchy is determined by neural variability

The brains of higher organisms are composed of anatomically and functionally distinct regions performing specialised tasks; but regions do not operate in isolation. Orchestration of complex behaviours requires communication between brain regions, but how neural activity dynamics are organised to facilitate reliable transmission is not well understood. We studied this process directly by generating neural activity that propagates between brain regions and drives behaviour, allowing us to assess how populations of neurons in sensory cortex cooperate to transmit information. We achieved this by imaging two hierarchically organised and densely interconnected regions, the primary and secondary somatosensory cortex (S1 and S2) in mice while performing two-photon photostimulation of S1 neurons and assigning behavioural salience to the photostimulation. We found that the probability of perception is determined not only by the strength of the photostimulation signal, but also by the variability of S1 neural activity. Therefore, maximising the signal-to-noise ratio of the stimulus representation in cortex is critical to its continued propagation downstream. Further, we show that propagated, behaviourally salient activity elicits balanced, persistent, and generalised activation of the downstream region. Hence, our work adds to existing understanding of cortical function by identifying how population activity is formatted to ensure robust transmission of information, allowing specialised brain regions to communicate and coordinate behaviour.

Loss of Awareness or Urinary Dysfunction? Investigating Amyloidosis and Urinary Physiology in a Transgenic Mouse

Alzheimer’s disease (AD) is a devastating disorder primarily affecting older adults and is the most common neurodegenerative disease in the US. More than one in three AD patients experience AD-associated urinary dysfunction (ADUD), which directly contributes to their institutionalization. While ADUD has been clinically regarded as a result of poor cognitive control over urinary function, the physiology underlying loss of urinary control remains unknown. We hypothesize that amyloidosis in the CNS results in pathologic changes in urinary structure and function. Tg-APP/PS1DE9 mice were used before plaque deposition (4-6 months) and after plaque accumulation (8-10 months) and compared to WT littermates. Behavioral assays (open field testing and voiding spot assays) were performed to assess cortical function. Pressure-flow cystometry was conducted under urethane anesthesia to assess autonomic control of urinary function without cortical influence. Pharmacomyography of bladder strips was used to determine tissue-level changes in the absence of CNS input. In Tg-APP/PS1DE9 mice, plaque accumulation resulted in significant cystometric changes to voiding phase parameters, but not storage phase parameters. Pharmacologic studies showed decreased sensitivity to adrenergic stimulation without change in muscarinic sensitivity. Behavioral assays demonstrated significant differences between transgenic animals and WT in locomotion and voiding spot sizes. We interpret our data to support AD-related pathology of Aβ accumulation results in a distinct urinary phenotype in our model, analogous to the ADUD observed in AD patients. Establishing and verifying models of ADUD may improve the efficacy of treating ADUD and increase quality of life for patients and their caregivers.

Sex influences the brain functional connectivity correlates of originality

Creative cognition is thought to involve two processes, the creation of new ideas and the selection and retention of suitable new ideas. Neuroimaging studies suggest that the Default Mode Network contributes to the creation of new ideas while left inferior frontal and parieto-temporal cortical networks mediate the selection/retention process. Higher levels of activity in the selection/retention have been shown to be associated with stricter criteria for selection and hence the expression of fewer novel ideas. In this study, we examined the brain functional connectivity correlates of an originality score while 27 males and 27 females performed a low and a high demand visual vigilance task. Brain functional connectivity was estimated from the steady state visual evoked potential event related partial coherence. In the male group, we observed a hypothesized left frontal functional connectivity that was negatively correlated with originality in both tasks. By contrast, in the female group no significant correlation between functional connectivity and originality was observed in either task. We interpret the findings to suggest that males and females engaged different functional networks when performing the vigilance tasks. We conclude with a consideration of the possible risks when data pooling across sex in studies of higher cortical function.

A Review on P300 in Obsessive-Compulsive Disorder

Neuropsychological studies indicate the presence of cognitive changes in patients with obsessive-compulsive disorder (OCD). Indeed, OCD may be included among the dysfunctions of the frontal lobes and their connections with the limbic system, associative cortex, and basal ganglia. P300 is a positive component of the human event-related potential (ERP); it is associated with processes of encoding, identification, and categorization constituting, as a whole, the superior cortical function of information processing. Thus, P300 explores several areas that are implicated in OCD pathophysiology. Our aim is to review all relevant studies on the P300 component of the human ERP in order to recognize any significant central nervous system (CNS) correlate of cognitive dysfunction in OCD. A PubMed-based literature search resulted in 35 articles assessing P300 in OCD and reporting neurophysiological correlates of response inhibition, cortical hyperarousal, and over-focused attention. A decreased P300 amplitude was reported in both adult and pediatric patients, with a trend toward normalization after pharmacological treatment. Source localization studies disclosed an association between P300 abnormalities and the functioning of brain regions involved in the pathophysiology of OCD. Moreover, studies converge on the evidence of neurophysiological dysfunction in the frontal areas with impairment of the normal inhibitory processes in OCD. At least some of these electrophysiological correlates might reflect the obsessive thoughts and compulsions that characterize this disorder. These findings may also support cognitive-behavioral therapy (CBT) approaches on over-focused attention and inflexibility of compulsive behaviors, which should be associated to pharmacological treatment in these patients.

Bilateral Asymmetry in Ocular Counter-Rolling Reflex Is Associated With Individual Motion Sickness Susceptibility

Accumulating evidence suggests that individual variations in vestibular functions are associated with motion sickness (MS) susceptibility. We investigated whether vestibular functions in the reflex and cortical pathways could predict the susceptibility of individuals to MS. MS-susceptible and control adults were recruited according to the Motion Sickness Susceptibility Questionnaire (MSSQ) score. Otolith reflex and cortical functions were assessed using the ocular counter rolling test and the head-tilt subjective visual vertical (HT-SVV) test, respectively. The bilateral asymmetry of each function was compared between the MS-susceptible and the control groups. Although the two tests for otolith functions were conducted using the same stimulation (lateral head tilt), bilateral asymmetry of otolith reflex rather than cortical function was significantly associated with MS susceptibility. Our data suggests that bilateral asymmetry in the otolith reflex pathway is capable of predicting susceptibility to MS to some extent. Our data also suggest that the association between vestibular function and MS susceptibility can vary based on the vehicle types. Future vehicles, such as self-driving cars, will make us aware of other vestibular functions associated with MS susceptibility.

Don’t Forget the Little Brain: A Framework for Incorporating the Cerebellum Into the Understanding of Cognitive Aging

With the rapidly growing population of older adults, an improved understanding of brain and cognitive aging is critical, given the impacts on health, independence, and quality of life. To this point, we have a well-developed literature on the cortical contributions to cognition in advanced age. However, while this work has been foundational for our understanding of brain and behavior in older adults, subcortical contributions, particularly those from the cerebellum, have not been integrated into these models and frameworks. Incorporating the cerebellum into models of cognitive aging is an important step for moving the field forward. There has also been recent interest in this structure in Alzheimer’s Disease, indicating that such work may be beneficial to our understanding of neurodegenerative disease. Here, I provide an updated overview of the cerebellum in advanced age, and propose that it serves as a critical source of scaffolding or reserve for cortical function. Age-related impacts on cerebellar function further impact cortical processing, perhaps resulting in many of the activation patterns commonly seen in aging.

Hierarchical Bayesian Modeling of the Relationship between Task Related Hemodynamic Responses and Neuronal Excitability: a Simultaneous fNIRS/TMS Study

Background: Investigating the relationship between task-related cortical hemodynamic activity and brain excitability is challenging because it requires simultaneous measurement of brain hemodynamic activity while applying non-invasive brain stimulation. There is also considerable inter-/intra-subject variability which both brain excitability and task-related hemodynamic responses are associated with. Here we proposed hierarchical Bayesian modeling to taking into account variability in the data at the individual and group levels, aiming to provide accurate and reliable statistical inferences on this research question. Methods: We performed a study on 16 healthy subjects with simultaneous Paired Associative Stimulation (Inhibitory PAS10, Excitatory PAS25, Sham) and functional Near-Infrared Spectroscopy (fNIRS) targeting the primary motor cortex (M1). PAS was applied to modulate the cortical function and induce plasticity. Before and after each intervention cortical excitability was measured by motor evoked potentials (MEPs), and the motor task-related hemodynamic response was measured using fNIRS. We constructed three models to encode 1) PAS effects on the M1 excitability; 2) PAS effects on the whole-time course of fNIRS hemodynamic responses to finger tapping tasks, and 3) the correlation between PAS effects on M1 excitability and PAS effects on task-related hemodynamic responses. Results: Significant increase of the cortical excitability was found after PAS25, whereas a small reduction of the cortical excitability was shown after PAS10 and no changes after sham. We found PAS effects on finger tapping evoked HbO/HbR within M1, around the peak of the hemodynamic time courses. Both HbO and HbR absolute amplitudes increased after PAS25 and decreased after PAS10. Cortical excitability changes and task-related HbO/HbR changes showed a high probability of being positively correlated, 0.77 and 0.79, respectively. The corresponding Pearson correlations were 0.58 (p<.0001, HbO with MEP) and 0.56 (p<.001, HbR with MEP), respectively. Conclusion: Benefiting from this original Bayesian data analysis, our results showed that PAS modulates task-related cortical hemodynamic responses in addition to M1 excitability. The fact that PAS effects on hemodynamic response were exhibited mainly around the peak of the hemodynamic time course may indicate that the intervention only increases metabolic demanding rather than modulating hemodynamic response function per se. Moreover, the positive correlation between PAS modulations of excitability and hemodynamic brings insights to understand the fundamental properties of cortical function and cortical excitability.

Multi-Domain Touchscreen-Based Cognitive Assessment of C57BL/6J Female Mice Shows Whole-Body Exposure to 56Fe Particle Space Radiation in Maturity Improves Discrimination Learning Yet Impairs Stimulus-Response Rule-Based Habit Learning

Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Most preclinical studies with mature, “astronaut-aged” rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As there are conflicting results on whether the female rodent brain is preferentially injured by or resistant to charged particle exposure, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to fractionated whole-body 56Fe irradiation (3 × 6.7cGy 56Fe over 5 days, 600 MeV/n) would improve performance vs. Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function [e.g., location discrimination reversal (LDR) and extinction, respectively]. In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal stimulus-response rule-based habit learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASA’s risk assessments from being based on a single cognitive domain.