Timing and other cognitive processes demanding cognitive control become interlinked when there is an increase in the level of difficulty or effort required. Both functions are interrelated and share neuroanatomical bases. A previous meta-analysis of neuroimaging studies found that people with schizophrenia had significantly lower activation, relative to normal controls, of most right hemisphere regions of the time circuit. This finding suggests that a pattern of disconnectivity of this circuit, particularly in the supplementary motor area, is a trait of this mental disease. We hypothesize that a dysfunctional temporal/cognitive control network underlies both cognitive and psychiatric symptoms of schizophrenia and that timing dysfunction is at the root of the cognitive deficits observed. The goal of our study was to look, in schizophrenia patients, for brain structures activated both by execution of cognitive tasks requiring increased effort and by performance of time perception tasks. We conducted a signed differential mapping (SDM) meta-analysis of functional neuroimaging studies in schizophrenia patients assessing the brain response to increasing levels of cognitive difficulty. Then, we performed a multimodal meta-analysis to identify common brain regions in the findings of that SDM meta-analysis and our previously-published activation likelihood estimate (ALE) meta-analysis of neuroimaging of time perception in schizophrenia patients. The current study supports the hypothesis that there exists an overlap between neural structures engaged by both timing tasks and non-temporal cognitive tasks of escalating difficulty in schizophrenia. The implication is that a deficit in timing can be considered as a trait marker of the schizophrenia cognitive profile.

Slow waves, the hallmark feature of deep nonrapid eye movement sleep, do potentially drive restorative effects of sleep on brain and body functions. Sleep modulation techniques to elucidate the functional role of slow waves thus have gained large interest. Auditory slow wave stimulation is a promising tool; however, directly comparing auditory stimulation approaches within a night and analyzing induced dynamic brain and cardiovascular effects are yet missing. Here, we tested various auditory stimulation approaches in a windowed, 10 s ON (stimulations) followed by 10 s OFF (no stimulations), within-night stimulation design and compared them to a SHAM control condition. We report the results of three studies and a total of 51 included nights and found a large and global increase in slow-wave activity (SWA) in the stimulation window compared to SHAM. Furthermore, slow-wave dynamics were most pronouncedly increased at the start of the stimulation and declined across the stimulation window. Beyond the changes in brain oscillations, we observed, for some conditions, a significant increase in the mean interval between two heartbeats within a stimulation window, indicating a slowing of the heart rate, and increased heart rate variability derived parasympathetic activity. Those cardiovascular changes were positively correlated with the change in SWA, and thus, our findings provide insight into the potential of auditory slow wave enhancement to modulate cardiovascular restorative conditions during sleep. However, future studies need to investigate whether the potentially increased restorative capacity through slow-wave enhancements translates into a more rested cardiovascular system on a subsequent day.

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The brain's state of arousal influences cognitive functioning and mental well-being. It is controlled by several neuromodulatory nuclei in the brainstem and, particularly, by the locus coeruleus (LC). The LC is the main source of noradrenaline (NA) in the central nervous system where it exerts powerful effects on neural processing and autonomic function. Here, we investigate whether human participants can gain volitional control of their brain's arousal state using a new neurofeedback approach which exploits the mechanism that the eye's pupil diameter provides an indirect readout of arousal if light conditions are controlled. We show that pupil-based neurofeedback training is essential for learning how to self-regulate pupil size. Once acquired, pupil self-regulation significantly modulates neuromodulatory brainstem centers involved in arousal control and particularly the LC-NA system when carefully measured with functional magnetic resonance imaging. Further, it modulates heart rate, a cardiovascular marker of autonomic function, and it has a significant effect on behavior and specific psychophysiological responses during an oddball task, an attention task that has been shown to be evoke stimulus-dependent LC-NA activity. Considering the modulatory effects of the LC-NA system and other arousal-regulating centers on cognitive functioning and various behaviors including stress-related responses, pupil-based neurofeedback has a tremendous potential to be translated to behavioral and clinical applications across various domains.

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