Validation of non-REM sleep stage decoding from resting state fMRI using linear support vector machines.

A growing body of literature suggests that changes in consciousness are reflected in specific connectivity patterns of the brain as obtained from resting state fMRI (rs-fMRI). As simultaneous electroencephalography (EEG) is often unavailable, decoding of potentially confounding sleep patterns from rs-fMRI itself might be useful and improve data interpretation. Linear support vector machine classifiers were trained on combined rs-fMRI/EEG recordings from 25 subjects to separate wakefulness (S0) from non-rapid eye movement (NREM) sleep stages 1 (S1), 2 (S2), slow wave sleep (SW) and all three sleep stages combined (SX). Classifier performance was quantified by a leave-one-subject-out cross-validation (LOSO-CV) and on an independent validation dataset comprising 19 subjects. Results demonstrated excellent performance with areas under the receiver operating characteristics curve (AUCs) close to 1.0 for the discrimination of sleep from wakefulness (S0|SX), S0|S1, S0|S2 and S0|SW, and good to excellent performance for the classification between sleep stages (S1|S2:~0.9; S1|SW:~1.0; S2|SW:~0.8). Application windows of fMRI data from about 70 s were found as minimum to provide reliable classifications. Discrimination patterns pointed to subcortical-cortical connectivity and within-occipital lobe reorganization of connectivity as strongest carriers of discriminative information. In conclusion, we report that functional connectivity analysis allows valid classification of NREM sleep stages.

The role of rapid eye movement sleep for amygdala-related memory processing.

Over the years, rapid eye movement (REM) sleep has been associated with general memory consolidation, specific consolidation of perceptual, procedural, emotional and fear memories, brain maturation and preparation of waking consciousness. More recently, some of these associations (e.g., general and procedural memory consolidation) have been shown to be unlikely, while others (e.g., brain maturation and consciousness) remain inconclusive. In this review, we argue that both behavioral and neurophysiological evidence supports a role of REM sleep for amygdala-related memory processing: the amygdala-hippocampus-medial prefrontal cortex network involved in emotional processing, fear memory and valence consolidation shows strongest activity during REM sleep, in contrast to the hippocampus-medial prefrontal cortex only network which is more active during non-REM sleep. However, more research is needed to fully understand the mechanisms.

Ventromedial prefrontal cortex activity and rapid eye movement sleep are associated with subsequent fear expression in human subjects.

In humans, activity patterns in the ventromedial prefrontal cortex (vmPFC) have been found to be predictive of subsequent fear memory consolidation. Pioneering work in rodents has further shown that vmPFC-amygdala theta synchronization is correlated with fear memory consolidation. We aimed to evaluate whether vmPFC activity during fear conditioning is (1) correlated with fear expression the subsequent day and whether (2) this relationship is mediated by rapid eye movement (REM) sleep. We analyzed data from 17 young healthy subjects undergoing a fear conditioning task, followed by a fear extinction task 24 h later, both recorded with simultaneous skin conductance response (SCR) and functional magnetic resonance imaging measurements, with a polysomnographically recorded night sleep in between. Our results showed a correlation between vmPFC activity during fear conditioning and subsequent REM sleep amount, as well as between REM sleep amount and SCR to the conditioned stimulus 24 h later. Moreover, we observed a significant correlation between vmPFC activity during fear conditioning and SCR responses during extinction, which was no longer significant after controlling for REM sleep amount. vmPFC activity during fear conditioning was further correlated with sleep latency. Interestingly, hippocampus activity during fear conditioning was correlated with stage 2 and stage 4 sleep amount. Our results provide preliminary evidence that the relationship between REM sleep and fear conditioning and extinction observed in rodents can be modeled in healthy human subjects, highlighting an interrelated set of potentially relevant trait markers.

Neuroscience-driven discovery and development of sleep therapeutics.

Until recently, neuroscience has given sleep research and discovery of better treatments of sleep disturbances little attention, despite the fact that disturbed sleep has overwhelming impact on human health. Sleep is a complex phenomenon in which specific psychological, electrophysiological, neurochemical, endocrinological, immunological and genetic factors are involved. The brain as both the generator and main object of sleep is obviously of particular interest, which makes a neuroscience-driven view the most promising approach to evaluate clinical implications and applications of sleep research. Polysomnography as the gold standard of sleep research, complemented by brain imaging, neuroendocrine testing, genomics and other laboratory measures can help to create composite biomarkers that allow maximizing the effects of individualized therapies while minimizing adverse effects. Here we review the current state of the neuroscience of sleep, sleep disorders and sleep therapeutics and will give some leads to promote the discovery and development of sleep medicines that are better than those we have today.

Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese-enhanced MRI.

Manganese-enhanced MRI has recently become a valuable tool for the assessment of in vivo functional cerebral activity in animal models. As a result of the toxicity of manganese at higher dosages, fractionated application schemes have been proposed to reduce the toxic side effects by using lower concentrations per injection. Here, we present data on regional-specific manganese accumulation during a fractionated application scheme over 8 days of 30 mg/kg MnCl2 , as well as on the clearance of manganese chloride over the course of several weeks after the termination of the whole application protocol supplying an accumulative dose of 240 mg/kg MnCl2 . Our data show most rapid accumulation in the superior and inferior colliculi, amygdala, bed nucleus of the stria terminalis, cornu ammonis of the hippocampus and globus pallidus. The data suggest that no ceiling effects occur in any region using the proposed application protocol. Therefore, a comparison of basal neuronal activity differences in different animal groups based on locally specific manganese accumulation is possible using fractionated application. Half-life times of manganese clearance varied between 5 and 7 days, and were longest in the periaqueductal gray, amygdala and entorhinal cortex. As the hippocampal formation shows one of the highest T1 -weighted signal intensities after manganese application, and manganese-induced memory impairment has been suggested, we assessed hippocampus-dependent learning as well as possible manganese-induced atrophy of the hippocampal volume. No interference of manganese application on learning was detected after 4 days of Mn(2+) application or 2 weeks after the application protocol. In addition, no volumetric changes induced by manganese application were found for the hippocampus at any of the measured time points. For longitudinal measurements (i.e. repeated manganese applications), a minimum of at least 8 weeks should be considered using the proposed protocol to allow for sufficient clearance of the paramagnetic ion from cerebral tissue.

The neural correlates of negative prediction error signaling in human fear conditioning.

In a temporal difference (TD) learning approach to classical conditioning, a prediction error (PE) signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative PE signal, which is the initial step towards successful extinction. In order to visualize negative PE signaling during fear conditioning, we employed combined functional magnetic resonance (fMRI) and skin conductance response (SCR) measurements in a conditioning task with visual stimuli and mild electrical shocks. Positive PE signaling was associated with increased activation in the bilateral insula, supplementary motor area, brainstem, and visual cortices. Negative PE signaling was associated with increased activation in the ventromedial and dorsolateral prefrontal cortices, the left lateral orbital gyrus, the middle temporal gyri, angular gyri, and visual cortices. The involvement of the ventromedial prefrontal and orbitofrontal cortex in extinction learning has been well documented, and this study provides evidence for the notion that these regions are already involved in negative PE signaling during fear conditioning.

The neural correlates and temporal sequence of the relationship between shock exposure, disturbed sleep and impaired consolidation of fear extinction.

Consolidation of extinction learning is a primary mechanism disrupted in posttraumatic stress disorder (PTSD), associated with hypoactivity of the ventromedial prefrontal cortex and hippocampus. A role for rapid eye movement (REM) sleep disturbances in this failure to consolidate extinction learning has been proposed. We performed functional magnetic resonance imaging (fMRI) with simultaneous skin conductance response (SCR) measurements in 16 healthy participants during conditioning/extinction and later recall of extinction. The visual stimuli were basic geometric forms and electrical shocks functioned as the unconditioned stimulus. Between the conditioning/extinction and recall sessions, participants received a 90-min sleep window in the sleep laboratory. This daytime sleep was polysomnographically recorded and scored by professionals blind to the study design. Only seven out of 16 participants had REM sleep; participants without REM sleep had a significantly slower decline of both SCR and neural activity of the laterodorsal tegmentum in response to electrical shocks during conditioning. At recall of fear extinction, participants with preceding REM sleep had a reduced SCR and stronger activation of the left ventromedial prefrontal cortex and bilateral lingual gyrus in response to the extinguished stimulus than participants lacking REM sleep. This study indicates that trait-like differences in shock reactivity/habituation (mediated by the brainstem) are predictive of REM sleep disruption, which in turn is associated with impaired consolidation of extinction (mediated by the ventromedial prefrontal cortex). These findings help understand the neurobiological basis and the temporal sequence of the relationship between shock exposure, disturbed sleep and impaired consolidation of extinction, as observed in PTSD.