Hypofunctioning of the N-methyl-D-aspartate receptor (NMDA-R) has been prominently implicated in the pathophysiology of schizophrenia (ScZ). The current study tested the effects of ketamine, a dissociative anesthetic and NMDA-R antagonist, on resting-state activity recorded with magnetoencephalography (MEG) in healthy volunteers. In a single-blind cross-over design, each participant (n = 12) received, on 2 different sessions, a subanesthetic dose of S-ketamine (0.006 mg/Kg) and saline injection. MEG-data were analyzed at sensor- and source-level in the beta (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In addition, connectivity analysis at source-level was performed using transfer entropy (TE). Ketamine increased gamma-power while beta-band activity was decreased. Specifically, elevated 30-90 Hz activity was pronounced in subcortical (thalamus and hippocampus) and cortical (frontal and temporal cortex) regions, whilst reductions in beta-band power were localized to the precuneus, cerebellum, anterior cingulate, temporal and visual cortex. TE analysis demonstrated increased information transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the pronounced dysregulation of high-frequency oscillations following the inhibition of NMDA-R in animal models of ScZ as well as with evidence from electroencephalogram-data in ScZ-patients and increased functional connectivity during early illness stages. Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits.
Autism spectrum disorder (ASD) is a common developmental disorder characterized by communication difficulties and impaired social interaction. Recent results suggest altered brain dynamics as a potential cause of symptoms in ASD. Here, we aim to describe potential information-processing consequences of these alterations by measuring active information storage (AIS)—a key quantity in the theory of distributed computation in biological networks. AIS is defined as the mutual information between the past state of a process and its next measurement. It measures the amount of stored information that is used for computation of the next time step of a process. AIS is high for rich but predictable dynamics. We recorded magnetoencephalography (MEG) signals in 10 ASD patients and 14 matched control subjects in a visual task. After a beamformer source analysis, 12 task-relevant sources were obtained. For these sources, stationary baseline activity was analyzed using AIS. Our results showed a decrease of AIS values in the hippocampus of ASD patients in comparison with controls, meaning that brain signals in ASD were either less predictable, reduced in their dynamic richness or both. Our study suggests the usefulness of AIS to detect an abnormal type of dynamics in ASD. The observed changes in AIS are compatible with Bayesian theories of reduced use or precision of priors in ASD.
Motor inhibitory control implemented as response inhibition is an essential cognitive function required to dynamically adapt to rapidly changing environments. Despite of over a decade of research on the neural mechanisms of response inhibition, it remains unclear, how exactly response inhibition is initiated and implemented. Using a multimodal MEG/fMRI approach in 59 subjects our results reliably reveal that response inhibition is initiated by the right inferior frontal gyrus (rIFG) as a form of attention-independent top-down control that involves the modulation of beta-band activity. Furthermore, stopping performance was predicted by beta-band power and beta-band connectivity was directed from rIFG to pre-supplementary motor area (pre-SMA), indicating rIFG's dominance over pre-SMA. Thus, these results strongly support the hypothesis that rIFG initiates stopping, implemented by beta-band oscillations with potential to open up new ways of spatially localized oscillation-based interventions.
Unexpected and thus surprising events are omnipresent and oftentimes require adaptive behavior such as unexpected inhibition or unexpected action. The current theory of unexpected events suggests that such unexpected events just like global stopping recruit a fronto-basal-ganglia network. A global suppressive effect impacting ongoing motor responses and cognition is specifically attributed to the subthalamic nucleus (STN). Previous studies either used separate tasks or presented unexpected, task-unrelated stimuli during response inhibition tasks to relate the neural signature of unexpected events to that of stopping. Here, we aimed to test these predictions using a within task design with identical stimulus material for both unexpected action and unexpected inhibition using functional magnetic resonance imaging (fMRI) for the first time. To this end, 32 healthy human participants of both sexes performed a cue-informed go/nogo task comprising expected and unexpected action and inhibition trials during fMRI. Using conjunction, contrast, and Bayesian analyses, we demonstrate that unexpected action elicited by an unexpected go signal and unexpected inhibition elicited by an unexpected nogo signal recruited the same fronto-basal-ganglia network which is usually assigned to stopping. Furthermore, the stronger the unexpected action-related activity in the STN region was the more detrimental was the effect on response times. The present results thus complement earlier findings and provide direct evidence for the unified theory of unexpected events while ruling out alternative task and novelty effects.
SummaryBoth the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (pre-SMA) are crucial for successful response inhibition. However, the particular functional roles of those two regions have been controversially debated for more than a decade now. It is unclear whether the rIFG directly initiates stopping or serves an attentional function, whereas the stopping is triggered by the pre-SMA. The current multimodal MEG/fMRI study sought to clarify the role and temporal activation order of both regions in response inhibition using a selective stopping task. This task dissociates inhibitory from attentional processes. Our results reliably reveal a temporal precedence of rIFG over pre-SMA. Moreover, connectivity during response inhibition is directed from rIFG to pre-SMA and predicts stopping performance. Response inhibition is implemented via beta-band oscillations. Our findings support the hypothesis that response inhibition is initiated by the rIFG as a form of attention-independent top-down control.
Objective: People with schizophrenia (PSZ) are impaired in the attentional prioritization of non-salient but relevant stimuli over salient but irrelevant distractors during visual working memory (VWM) encoding. Conversely, the guidance of top-down attention by external predictive cues is intact. Yet, it is unknown whether this preserved ability can help PSZ overcome impaired attentional prioritization in the presence of salient distractors. Methods: We employed a visuospatial change-detection task using four Gabor Patches with differing orientations in 69 PSZ and 74 healthy controls (HCS). Two patches flickered to reflect saliency and either a predictive or a non-predictive cue was displayed resulting in four conditions. Results: Across all conditions, PSZ stored significantly less information in VWM than HCS (all p < 0.001). With a non-predictive cue, PSZ stored significantly more salient than non-salient information (t140 = 5.66, p < 0.001, dt = 0.5). With a predictive cue, PSZ stored significantly more non-salient information (t140 = 5.70, p < 0.001, dt = 0.5). Conclusion: Our findings support a bottom-up bias in schizophrenia with performance significantly better for visually salient information in the absence of a predictive cue. These results indicate that bottom-up attentional prioritization is disrupted in schizophrenia, but the top-down utilization of cues is intact. We conclude that additional top-down information significantly improves performance in PSZ when non-salient visual information needs to be encoded in working memory.
Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer, mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 86%). At the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate that in addition to the increased signal-to-noise ratio of a surface-based analysis, macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.
BackgroundCognitive impairments including deficits in working memory are commonly observed in schizophrenia. A bottom-up attentional bias has been suggested for encoding visually salient yet irrelevant information. To date it is not known if this bias persists when additional top-down information in the form of a predictive cue is provided. We were motivated to clarify this issue.Methods40 patients with schizophrenia were measured and matched with 40 healthy control participants. During a change detection task four Gabor patches (two flickering and two non-flickering) with varying orientations were shown and participants had to memorize the orientations of the Gabor patches. A colored fixation cross was displayed before the stimuli either cueing two (predictive cue) or all four (non-predictive cue) Gabor patch locations resulting in a 2 x 2 design of four conditions with the factors salience (flickering vs. non-flickering) and cue (predictive cue vs. non-predictive cue). During retrieval a single Gabor patch was displayed, and participants reported if the orientation was the same or had changed in that location. At the beginning of each block participants were instructed to either encode the flickering or non-flickering patches (targets) whose location could either be cued or uncued. In 80 % of trials, a target was probed during retrieval.ResultsPatients encoded less information than healthy controls in all four conditions. Both healthy controls and patients encoded more visually salient information than non-salient information, and performance was near chance level during non-target trials. Patients encoded significantly more information when a predictive cue was provided before encoding visually non-salient information.DiscussionPatients were able to overcome their bottom-up attentional bias of encoding visually salient irrelevant information when provided with top-down information. These findings are in line with previous reports of a bottom-up attentional bias during working memory encoding in schizophrenia. We propose that this bias can be overcome by providing additional top-down information.
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