Hippocampal-orbitofrontal interactions in memory and reality filtering

Le filtre orbitofrontal de la réalité est un mécanisme, indépendant des fonctions médio-temporales (MTL) de la mémoir, filtrant les pensées. ORFi permet de percevoir la réalité et est associé à un marqueur électrophysiologique. Nous émettons l'hypothèse que le cortex orbitofrontal (OFC) filtre les pensées alors qu'elles sont générées dans le MTL. Premièrement, un marqueur électrophysiologique de l'encodage de la mémoire, généré par le MTL, a été identifié (Thézé et al. 2016). Ce marqueur était associé avec une augmentation de cohérence thêta dans le MTL. Il apparaît 35 ms avant le marqueur d'ORFi (Thézé et al. 2017a). Les deux sont associés à une augmentation thêta de cohérence, l'un depuis le MTL, l'autre depuis l'OFC, chacun vers l'autre. Finalement, un groupe de patients dans le spectre des trouble de la schizophrénie ont démontré une réduction significative du marqueur ORFi, dont l'ampleur peut prédire le diagnostic. La cohérence thêta qui augmentait chez les contrôles était absence des patients dans l'OFC et le MTL et, pour ce dernier, corrélait avec les scores d'hallucinations.Orbitofrontal reality filtering (ORFi) is a thought-filtering mechanism, separate from medial temporal lobe (MTL) memory functions. ORFi enables perception of reality and is associated to a known electrophysiological marker. We hypothesized the orbitofrontal cortex (OFC) is filtering thoughts as they are being generated in the MTL. First, an electrophysiological marker of memory encoding generated by the MTL was identified. This marker was associated with increased theta-band coherence in the MTL. It was found this marker sets in about 35 ms before the marker reflecting ORFi. Both were associated with increased theta coherence, the former from the MTL and the latter from the OFC, both were targeted at one another. At last, a group of patients with schizophrenic spectrum disorders (i.e. psychosis) were recorded. They displayed significantly reduced, albeit present, marker of ORFi. The magnitude was predictive of the diagnosis. Theta coherence increase observable in the control group was absent in the patient group from OFC and left HC and, for the latter, correlated with scores of hallucination

Electrophysiological correlates of visual binding errors after bilateral parietal damage

Illusory conjunctions (e.g. the confusion between the shape of one stimulus with the color of another stimulus) are the most dramatic expression of binding failures in vision. Under brief exposure or when attention is diverted illusory conjunctions may be observed in healthy participants, but they only represent a real-life problem for patients with parietal damage. However, it is unclear whether such failures reflect the impairment of early or late stages of visual processing. Here, we examined the time-course of visual processing using evoked potential measures in a patient with bilateral damage to the posterior parietal cortex presenting prominent binding failures. The patient was asked to identify colored letters that were briefly flashed to the left or right hemifield. When only one item was presented she adequately identified color or shape of left and right letters. In contrast, when presentation was bilateral she either identified the correct right shape-color combination and missed the item in the left hemifield (extinction) or combined incorrectly the right shape with the left color (illusory conjunction). Evoked potential analyses revealed a specific electrophysiological signature of illusory conjunctions, starting ∼105ms after stimulus onset over the right frontal cortex. These findings indicate that binding errors reflect failures of early stages of attentional filtering relying on the integrity of the posterior parietal cortex

Rapid memory stabilization by transient theta coherence in the human medial temporal lobe

Presenting stimuli again after presentation of intervening stimuli improves their retention, an effect known as the spacing effect. However, using event-related potentials (ERPs), we had observed that immediate, in comparison to spaced, repetition of pictures induced a positive frontal potential at 200-300 ms. This potential appeared to emanate from the left medial temporal lobe (MTL), a structure critical for memory consolidation. In this study, we tested the behavioral relevance of this signal and explored functional connectivity changes during picture repetition. We obtained high-density electroencephalographic recordings from 14 healthy subjects performing a continuous recognition task where pictures were either repeated immediately or after 9 intervening items. Conventional ERP analysis replicated the positive frontal potential emanating from the left MTL at 250-350 ms in response to immediately repeated stimuli. Connectivity analysis showed that this ERP was associated with increased coherence in the MTL region-left more that right-in the theta-band (3.5-7 Hz) 200-400 ms following immediate, but not spaced, repetition. This increase was stronger in subjects who better recognized immediately repeated stimuli after 30 min. These findings indicate that transient theta-band synchronization between the MTL and the rest of the brain at 200-400 ms reflects a memory stabilizing signal. © 2015 Wiley Periodicals, Inc

The phase of cortical oscillations determines the perceptual fate of visual cues in naturalistic audiovisual speech

When we see our interlocutor, our brain seamlessly extracts visual cues from their face and processes them along with the sound of their voice, making speech an intrinsically multimodal signal. Visual cues are especially important in noisy environments, when the auditory signal is less reliable. Neuronal oscillations might be involved in the cortical processing of audiovisual speech by selecting which sensory channel contributes more to perception. To test this, we designed computer-generated naturalistic audiovisual speech stimuli where one mismatched phoneme-viseme pair in a key word of sentences created bistable perception. Neurophysiological recordings (high-density scalp and intracranial electroencephalography) revealed that the precise phase angle of theta-band oscillations in posterior temporal and occipital cortex of the right hemisphere was crucial to select whether the auditory or the visual speech cue drove perception. We demonstrate that the phase of cortical oscillations acts as an instrument for sensory selection in audiovisual speech processing

Simultaneous Reality Filtering and Encoding of Thoughts: The Substrate for Distinguishing between Memories of Real Events and Imaginations?

Any thought, whether it refers to the present moment or reflects an imagination, is again encoded as a new memory trace. Orbitofrontal reality filtering (ORFi) denotes an on-line mechanism which verifies whether upcoming thoughts relate to ongoing reality or not. Its failure induces reality confusion with confabulations and disorientation. If the result of this process were simultaneously encoded, it would easily explain later distinction between memories relating to a past reality and memories relating to imagination, a faculty called reality monitoring. How the brain makes this distinction is unknown but much research suggests that it depends on processes active when information is encoded. Here we explored the precise timing between ORFi and encoding as well as interactions between the involved brain structures. We used high-density evoked potentials and two runs of a continuous recognition task (CRT) combining the challenges of ORFi and encoding. ORFi was measured by the ability to realize that stimuli appearing in the second run had not appeared in this run yet. Encoding was measured with immediately repeated stimuli, which has been previously shown to induce a signal emanating from the medial temporal lobe (MTL), which has a protective effect on the memory trace. We found that encoding, as measured with this task, sets in at about 210 ms after stimulus presentation, 35 ms before ORFi. Both processes end at about 330 ms. Both were characterized by increased coherence in the theta band in the MTL during encoding and in the orbitofrontal cortex (OFC) during ORFi. The study suggests a complex interaction between OFC and MTL allowing for thoughts to be re-encoded while they undergo ORFi. The combined influence of these two processes at 200-300 ms may leave a memory trace that allows for later effortless reality monitoring in most everyday situations

Resting-state connectivity predicts visuo-motor skill learning

Spontaneous brain activity at rest is highly organized even when the brain is not explicitly engaged in a task. Functional connectivity (FC) in the alpha frequency band (α, 8-12 Hz) during rest is associated with improved performance on various cognitive and motor tasks. In this study we explored how FC is associated with visuo-motor skill learning and offline consolidation. We tested two hypotheses by which resting-state FC might achieve its impact on behavior: preparing the brain for an upcoming task or consolidating training gains. Twenty-four healthy participants were assigned to one of two groups: The experimental group (n = 12) performed a computerized mirror-drawing task. The control group (n = 12) performed a similar task but with concordant cursor direction. High-density 156-channel resting-state EEG was recorded before and after learning. Subjects were tested for offline consolidation 24h later. The Experimental group improved during training and showed offline consolidation. Increased α-FC between the left superior parietal cortex and the rest of the brain before training and decreased α-FC in the same region after training predicted learning. Resting-state FC following training did not predict offline consolidation and none of these effects were present in controls. These findings indicate that resting-state alpha-band FC is primarily implicated in providing optimal neural resources for upcoming tasks

Monitoring therapeutic efficacy of sunitinib using [(18)F]FDG and [(18)F]FMISO PET in an immunocompetent model of luminal B (HER2-positive)-type mammary carcinoma

Clinical studies implying the sunitinib multi-kinase inhibitor have led to disappointing results for breast cancer care but mostly focused on HER2-negative subtypes. Preclinical researches involving this drug mostly concern Triple Negative Breast Cancer (TNBC) murine models. Here, we explored the therapeutic efficacy of sunitinib on a PyMT-derived transplanted model classified as luminal B (HER2-positive) and monitored the response to treatment using both in vivo and ex vivo approaches.[br/]Tumour-induced animals were treated for 9 (n = 7) or 14 (n = 8) days with sunitinib at 40 mg/kg or with vehicle only. Response to therapy was assessed in vivo by monitoring glucose tumour metabolism and hypoxia using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and [(18)F]fluoromisonidazole ([(18)F]FMISO) Positron Emission Tomography (PET). After primary tumour excision, ex vivo digital microscopy was performed on treated and control samples to estimate vascular density (CD31), apoptosis (Tunel), proliferation (Ki-67), Tumour-Associated Macrophage (TAM) infiltration (F4/80), metabolism (GLUT1) and cellular response to hypoxia (HIF1 alpha). The drug impact on the metastasis rate was evaluated by monitoring the PyMT gene expression in the lungs of the treated and control groups.[br/]Concomitant with sunitinib-induced tumour size regression, [(18)F]FDG PET imaging showed a stable glycolysis-related metabolism inside tumours undergoing treatment compared to an increased metabolism in untreated tumours, resulting at treatment end in 1.5 less [(18)F]FDG uptake in treated (n = 4) vs control (n = 3) tumours (p < 0.05). With this small sample, [(18)F]FMISO PET showed a non-significant decrease of hypoxia in treated vs control tumours. The drug triggered a 4.9 fold vascular volume regression (p < 0.05), as well as a 17.7 fold induction of tumour cell apoptosis (p < 0.001). The hypoxia induced factor 1 alpha (HIF1 alpha) expression was twice lower in the treated group than in the control group (p < 0.05). Moreover, the occurrence of lung metastases was not reduced by the drug.[br/][(18)F]FDG and [(18)F]FMISO PET were relevant approaches to study the response to sunitinib in this luminal B (HER2-positive) model. The sunitinib-induced vascular network shrinkage did not significantly increase tumour hypoxia, suggesting that tumour regression was mainly due to the pro-apoptotic properties of the drug. Sunitinib did not inhibit the metastatic process in this PyMT transplanted model

Animated virtual characters to explore audio-visual speech in controlled and naturalistic environments

Natural speech is processed in the brain as a mixture of auditory and visual features. An example of the importance of visual speech is the McGurk effect and related perceptual illusions that result from mismatching auditory and visual syllables. Although the McGurk effect has widely been applied to the exploration of audio-visual speech processing, it relies on isolated syllables, which severely limits the conclusions that can be drawn from the paradigm. In addition, the extreme variability and the quality of the stimuli usually employed prevents comparability across studies. To overcome these limitations, we present an innovative methodology using 3D virtual characters with realistic lip movements synchronized on computer-synthesized speech. We used commercially accessible and affordable tools to facilitate reproducibility and comparability, and the set-up was validated on 24 participants performing a perception task. Within complete and meaningful French sentences, we paired a labiodental fricative viseme (i.e. /v/) with a bilabial occlusive phoneme (i.e. /b/). This audiovisual mismatch is known to induce the illusion of hearing /v/ in a proportion of trials. We tested the rate of the illusion while varying the magnitude of background noise and audiovisual lag. Overall, the effect was observed in 40% of trials. The proportion rose to about 50% with added background noise and up to 66% when controlling for phonetic features. Our results conclusively demonstrate that computer-generated speech stimuli are judicious, and that they can supplement natural speech with higher control over stimulus timing and content