From intermodulation components to visual perception and cognition-a review.

Perception results from complex interactions among sensory and cognitive processes across hierarchical levels in the brain. Intermodulation (IM) components, used in frequency tagging neuroimaging designs, have emerged as a promising direct measure of such neural interactions. IMs have initially been used in electroencephalography (EEG) to investigate low-level visual processing. In a more recent trend, IMs in EEG and other neuroimaging methods are being used to shed light on mechanisms of mid- and high-level perceptual processes, including the involvement of cognitive functions such as attention and expectation. Here, we provide an account of various mechanisms that may give rise to IMs in neuroimaging data, and what these IMs may look like. We discuss methodologies that can be implemented for different uses of IMs and we demonstrate how IMs can provide insights into the existence, the degree and the type of neural integration mechanisms at hand. We then review a range of recent studies exploiting IMs in visual perception research, placing an emphasis on high-level vision and the influence of awareness and cognition on visual processing. We conclude by suggesting future directions that can enhance the benefits of IM-methodology in perception research.

Expectation and attention increase the integration of top-down and bottom-up signals in perception through different pathways.

Perception likely results from the interplay between sensory information and top-down signals. In this electroencephalography (EEG) study, we utilised the hierarchical frequency tagging (HFT) method to examine how such integration is modulated by expectation and attention. Using intermodulation (IM) components as a measure of nonlinear signal integration, we show in three different experiments that both expectation and attention enhance integration between top-down and bottom-up signals. Based on a multispectral phase coherence (MSPC) measure, we present two direct physiological measures to demonstrate the distinct yet related mechanisms of expectation and attention, which would not have been possible using other amplitude-based measures. Our results link expectation to the modulation of descending signals and to the integration of top-down and bottom-up information at lower levels of the visual hierarchy. Meanwhile, the results link attention to the modulation of ascending signals and to the integration of information at higher levels of the visual hierarchy. These results are consistent with the predictive coding account of perception.

Neural markers of predictive coding under perceptual uncertainty revealed with Hierarchical Frequency Tagging.

There is a growing understanding that both top-down and bottom-up signals underlie perception. But it is not known how these signals integrate with each other and how this depends on the perceived stimuli's predictability. 'Predictive coding' theories describe this integration in terms of how well top-down predictions fit with bottom-up sensory input. Identifying neural markers for such signal integration is therefore essential for the study of perception and predictive coding theories. To achieve this, we combined EEG methods that preferentially tag different levels in the visual hierarchy. Importantly, we examined intermodulation components as a measure of integration between these signals. Our results link the different signals to core aspects of predictive coding, and suggest that top-down predictions indeed integrate with bottom-up signals in a manner that is modulated by the predictability of the sensory input, providing evidence for predictive coding and opening new avenues to studying such interactions in perception.

Understanding alterations in serotonin connectivity in a rat model of depression within the monoamine-deficiency and the hippocampal-neurogenesis frameworks.

The monoamine-deficiency and the hippocampal-neurogenesis hypotheses of depression propose that alterations in the serotonin system and of hippocampal functionality are critical in the pathogenesis of depression. We measured the alterations in the connectivity level of the raphe nucleus in the chronic mild stress (CMS) rat model of depression using the manganese enhanced MRI method (MEMRI). Manganese ions were injected into the median raphe and their anterograde intracellular propagation was followed. Depression-like behavior was demonstrated using the sucrose preference tests. We show that the raphe's connectivity is differentially altered through chronic stress. In line with the monoamine-deficiency hypothesis, the connectivity of the raphe with the basal ganglia (BG) output nuclei, the hippocampus, the habenula and the entorhinal and insular cortices was reduced in CMS rats, suggesting an overall reduction in raphe excitability. Connectivity reductions were predominantly found in the right hemisphere, strengthening previous evidence pointing at a-symmetric hemispheric involvement in depression. Despite the general reduction in raphe connectivity, enhanced connectivity was found between the raphe and the septum, suggesting that alterations are connection-specific. On the basis of our results - while yet equivocal - we further discuss the possible coupling between the serotonergic and dopaminergic systems and two distinct mechanisms (direct and indirect) in which alterations in raphe connectivity may affect hippocampal dysfunction in chronic stress, thus linking the monoamine-deficiency and the hippocampal-neurogenesis hypotheses.

Maximizing negative correlations in resting-state functional connectivity MRI by time-lag.

This paper aims to better understand the physiological meaning of negative correlations in resting state functional connectivity MRI (r-fcMRI). The correlations between anatomy-based brain regions of 18 healthy humans were calculated and analyzed with and without a correction for global signal and with and without spatial smoothing. In addition, correlations between anatomy-based brain regions of 18 naïve anesthetized rats were calculated and compared to the human data. T-statistics were used to differentiate between positive and negative connections. The application of spatial smoothing and global signal correction increased the number of significant positive connections but their effect on negative connections was complex. Positive connections were mainly observed between cortical structures while most negative connections were observed between cortical and non-cortical structures with almost no negative connections between non-cortical structures. In both human and rats, negative connections were never observed between bilateral homologous regions. The main difference between positive and negative connections in both the human and rat data was that positive connections became less significant with time-lags, while negative connections became more significant with time-lag. This effect was evident in all four types of analyses (with and without global signal correction and spatial smoothing) but was most significant in the analysis with no correction for the global signal. We hypothesize that the valence of r-fcMRI connectivity reflects the relative contributions of cerebral blood volume (CBV) and flow (CBF) to the BOLD signal and that these relative contributions are location-specific. If cerebral circulation is primarily regulated by CBF in one region and by CBV in another, a functional connection between these regions can manifest as an r-fcMRI negative and time-delayed correlation. Similarly, negative correlations could result from spatially inhomogeneous responses of rCBV or rCBF alone. Consequently, neuronal regulation of brain circulation may be deduced from the valence of r-fcMRI connectivity.

The habenula couples the dopaminergic and the serotonergic systems: application to depression in Parkinson's disease.

A high percentage of patients with Parkinson's disease suffer from depression in addition to their motor disabilities. However, the etiology of this depression and its relation to Parkinson's disease are unknown. Within the framework of the monoamine deficiency hypothesis of depression, we propose that the dopaminergic and serotonergic systems are coupled by the lateral habenula, and argue that altered basal ganglia activity leads to lateral habenula hyperactivity, which in turn down-regulates the serotonergic system, resulting in depressive symptoms in patients with Parkinson's disease. We tested this hypothesis using the unilateral 6-hydroxydopamine hemiparkinsonian rat model of Parkinson's disease. Behavior was assessed using the novelty suppressed feeding and forced swim tests, and the effective connectivity of the serotonergic system was estimated by manganese-enhanced magnetic resonance imaging of the raphe nuclei. The results show depression-like behaviors and reduced raphe connectivity with the lateral habenula, dentate gyrus of the hippocampus, thalamus and hypothalamus in the 6-hydroxydopamine rat groups. More importantly, partial restoration of the raphe connectivity and partial normalization of behavior were achieved by dopamine replacement therapy (apomorphine, 10 mg/kg, s.c. daily). Furthermore, nearly complete behavioral normalization was reached after a bilateral electric lesion of the lateral habenula. These findings provide a plausible link between Parkinson's disease and depression and open up avenues for new therapeutic interventions in depression and possibly in Parkinson's disease.

Responses of neurons in the inferior colliculus to binaural disparities: insights from the use of Fisher information and mutual information.

The minimal change in a stimulus property that is detectable by neurons has been often quantified using the receiver operating characteristic (ROC) curve, but recent studies introduced the use of the related Fisher information (FI). Whereas ROC analysis and FI quantify the information available for discriminating between two stimuli, global aspects of the information carried by a neuron are quantified by the mutual information (MI) between stimuli and responses. FI and MI have been shown to be related to each other when FI is large. Here the responses of neurons recorded in the inferior colliculus of anesthetized guinea pigs in response to ensembles of sounds differing in their interaural time differences (ITDs) or binaural correlation (BC) were analyzed. Although the FI is not uniformly large, there are strong relationships between MI and FI. Information-theoretic measures are used to demonstrate the importance of the non-Poisson statistics of these responses. These neurons may reflect the maximization of the MI between stimuli and responses under constraints on the coded stimulus range and the range of firing rates. Remarkably, whereas the maximization of MI, in conjunction with the non-Poisson statistics of the spike trains, is enough to create neurons whose ITD discrimination capabilities are close to the behavioral limits, the same rule does not achieve single-neuron BC discrimination that is as close to behavioral performance.