Aging into Perceptual Control: A Dynamic Causal Modeling for fMRI Study of Bistable Perception

Aging is accompanied by stereotyped changes in functional brain activations, for example a cortical shift in activity patterns from posterior to anterior regions is one hallmark revealed by functional magnetic resonance imaging (fMRI) of aging cognition. Whether these neuronal effects of aging could potentially contribute to an amelioration of or resistance to the cognitive symptoms associated with psychopathology remains to be explored. We used a visual illusion paradigm to address whether aging affects the cortical control of perceptual beliefs and biases. Our aim was to understand the effective connectivity associated with volitional control of ambiguous visual stimuli and to test whether greater top-down control of early visual networks emerged with advancing age. Using a bias training paradigm for ambiguous images we found that older participants (n = 16) resisted experimenter-induced visual bias compared to a younger cohort (n = 14) and that this resistance was associated with greater activity in prefrontal and temporal cortices. By applying Dynamic Causal Models for fMRI we uncovered a selective recruitment of top-down connections from the middle temporal to lingual gyrus by the older cohort during the perceptual switch decision following bias training. In contrast, our younger cohort did not exhibit any consistent connectivity effects but instead showed a loss of driving inputs to orbitofrontal sources following training. These findings suggest that perceptual beliefs are more readily controlled by top-down strategies in older adults and introduce age-dependent neural mechanisms that may be important for understanding aberrant belief states associated with psychopathology

Oscillatory and epileptiform activity in human and rodent cortical regions in vitro

Epilepsy is a chronic neurological disorder in which patients have spontaneous recurrent seizures. Approximately 50 million people worldwide live with epilepsy and of those ~30% fail to adequately respond to anti-epileptic drugs (AEDs), indicating a need for further research. In this study oscillatory and epileptiform activity was explored in the rodent piriform cortex (PC) in vitro, an underexplored brain region implicated in the development of epilepsy. PC gamma oscillations have been studied in both anaesthetised and awake rodents in vivo; however, to date they have not been reported in vitro. Extracellular field potential recordings were made in rodent PC brain slices prepared from 70-100g male Wistar rats in vitro. Application of kainic acid and carbachol reliably induced persistent gamma oscillations (30 – 40 Hz) in layer II of the PC. These oscillations were found to be pharmacologically similar to gamma oscillations previously found in other rodent brain regions in vitro, as they were dependent on GABAA receptors, AMPA receptors and gap junctions. Persistent oscillations were also induced and characterised for the first time in human neuronal tissue in vitro. Human brain slices were prepared from excised tissue from various brain regions (primarily temporal) from paediatric patients undergoing surgery to alleviate the symptoms of drug resistant epilepsy. As in the rodent PC, oscillations were induced by application of kainic acid and carbachol, however, these oscillations were found to be within the beta frequency range (12 – 30 Hz). Despite this difference in frequency band, these beta oscillations were pharmacologically similar to gamma oscillations found in the rodent PC. Seizure-like events (SLEs) were induced in brain slices prepared from 70-100g male Wistar rats via application of zero Mg2+ artificial cerebral spinal fluid (0[Mg]2+ aCSF). The properties of these SLEs were found to be similar between brain regions when recordings were performed in layer II of the anterior and posterior PC and lateral entorhinal cortex (LEC) and the stratum pyramidale of CA1. In the majority of recordings SLEs occurred in the PC before the LEC or CA1 and SLEs were displayed in the PC in a higher proportion of slices than the LEC. The sensitivity of these PC slices to 0[Mg]2+ aCSF was assessed at several stages (24 hours and 1 week (early latent), 4 weeks (mid latent) and 3 months+ (chronic period)) following the reduced intensity status epilepticus (SE) protocol for epilepsy induction compared to age-matched controls (AMCs). A decrease in excitability of the slices was observed in slices prepared from AMC animals with age, as the inter-event interval and latency to first SLE was observed to be longer in slices prepared from aged compared to young AMC animals. Slices prepared from SE animals maintained their youthful hyperexcitability with no difference in IEI or latency to first SLE observed in the early latent period compared to the chronic period. The pharmacoresistance (or sensitivity) of these SLEs to single and double AED challenge was evaluated. Differences in efficacy of the AEDs were found between SE and AMC in the mid-latent period; increased efficacy of Na+ channel modulating AEDs were found in slices prepared from SE compared to AMC animals. The proportion of slices that displayed pharmacoresistance of these SLEs to AEDs was found to be higher in slices prepared from young animals (early latent period and AMCs), and was similar to that found clinically in human patients. The pharmacoresistance of the SLEs to AEDs was lower in slices prepared from older animals (mid latent, chronic and AMCs) compared to young animals (early latent and AMCs). This age-dependent reduction in resistance likely reflects normal alterations in neuronal networks with ageing. SLEs induced in young control PC slices could be exploited as a new in vitro model of drug resistant epilepsy. Overall, oscillatory and epileptiform activity in the PC and human cortex in vitro could be further explored as tools to evaluate the efficacy and mechanism of action of newly developed AEDs, as well as to explore the networks involved in drug resistant epilepsy

A model of delta frequency neuronal network activity and theta-gamma interactions in rat sensorimotor cortex in vitro

In recent decades, advances in electrophysiological techniques have enabled understanding of neuronal network activity, with in vitro brain slices providing insights into the mechanisms underlying oscillations at various frequency ranges. Understanding the electrical and neuro-pharmacological properties of brain networks using selective receptor modulators in native tissue allows to compare such properties with those in disease models (e.g. epilepsy and Parkinson’s). In vivo and in vitro studies have implicated M1 in execution of voluntary movements and, from both local network in vitro and whole brain in vivo perspectives. M1 has been shown to generate oscillatory activity at various frequencies, including beta frequency and nested theta and gamma oscillations similar to those of rat hippocampus. In vivo studies also confirmed slow wave oscillations in somatosensory cortex including delta and theta band activity. However, despite these findings, non-thalamic mechanisms underlying cortical delta oscillations remain almost unexplored. Therefore, we determined to explore these oscillations in vitro in M1 and S1. Using a modified sagittal plane slice preparation with aCSF containing neuroprotectants, we have greatly improved brain slice viability, enabling the generation and study of dual rhythms (theta and gamma oscillations) in deep layers (LV) of the in vitro sensorimotor slice (M1 and S1) in the presence of KA and CCh. We found that theta-gamma activity in M1 is led by S1 and that the amplitude of gamma oscillations was (phase-amplitude) coupled to theta phase in both regions. Oscillations were dependent on GABAAR, AMPAR and NMDAR and were augmented by DAR activation. Experiments using cut/reduced slices showed both M1 and S1 could be intrinsic generators of oscillatory activity. Delta oscillations were induced in M1 and S1 by maintaining a neuromodulatory state mimicking deep sleep, characterised by low dopaminergic and low cholinergic tone, achieved using DAR blockade and low CCh. Delta activity depends on GABAAR, GABABR and AMPAR but not NMDAR, and once induced was not reversible. Unlike theta-gamma activity, delta was led by M1, and activity took >20mins to develop in S1 after establishement of peak power in M1. Unlike M1, S1 alone was unable to support delta activity. Dopamine modulates network activity in M1 and it is known that fast-spiking interneurons are the pacemakers of network rhythmogenesis. Recent studies reported that dopamine (DA) controled Itonic in medium spiny, ventrobasal thalamus and nucleus accumbens neurons by modulation of GABARs or cation channels. In the current study, voltage-clamp whole cell recordings were performed in fast spiking interneurons (FS cells) in Layer V of M1. These recordings revealed tonic and phasic GABAAR inhibition and when DA was bath applied, a slow inward current (IDA) was induced. IDA was mediated by non-specific cationic TRPC channels following D2R-like receptor activation. Overall, my studies show the strong interdependence of theta-gamma rhythmogenesis between M1 and S1, dominanace of M1 at delta frequency and the crucial role of dopamine in controlling FS cell activity. Further exploration of these rhythms in models of pathological conditions such as Parkinson`s disease and Epilepsy may provide insights into network changes underlying these disease conditions

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Neural mechanisms for reducing uncertainty in 3D depth perception

In order to navigate and interact within their environment, animals must process and interpret sensory information to generate a representation or ‘percept’ of that environment. However, sensory information is invariably noisy, ambiguous, or incomplete due to the constraints of sensory apparatus, and this leads to uncertainty in perceptual interpretation. To overcome these problems, sensory systems have evolved multiple strategies for reducing perceptual uncertainty in the face of uncertain visual input, thus optimizing goal-oriented behaviours. Two available strategies have been observed even in the simplest of neural systems, and are represented in Bayesian formulations of perceptual inference: sensory integration and prior experience. In this thesis, I present a series of studies that examine these processes and the neural mechanisms underlying them in the primate visual system, by studying depth perception in human observers. Chapters 2 & 3 used functional brain imaging to localize cortical areas involved in integrating multiple visual depth cues, which enhance observers’ ability to judge depth. Specifically, we tested which of two possible computational methods the brain uses to combine depth cues. Based on the results we applied disruption techniques to examine whether these select brain regions are critical for depth cue integration. Chapters 4 & 5 addressed the question of how memory systems operating over different time scales interact to resolve perceptual ambiguity when the retinal signal is compatible with more than one 3D interpretation of the world. Finally, we examined the role of higher cortical regions (parietal cortex) in depth perception and the resolution of ambiguous visual input by testing patients with brain lesions