Therapeutic potential of glutathione-enhancers in stress-related psychopathologies.

The mammalian brain has high energy demands, which may become higher in response to environmental challenges such as psychogenic stress exposure. Therefore, efficient neutralization of reactive oxygen species that are produced as a by-product of ATP synthesis is crucial for preventing oxidative damage and ensuring normal energy supply and brain function. Glutathione (GSH) is arguably the most important endogenous antioxidant in the brain. In recent years, aberrant GSH levels have been implicated in different psychiatric disorders, including stress-related psychopathologies. In this review, we examine the available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Additionally, we identify several promising compounds that could raise GSH levels in the brain by either increasing the availability of its precursors or the expression of GSH-regulating enzymes through activation of Nuclear factor erythroid-2-related factor 2 (Nrf2). Given the high tolerability and safety profile of these compounds, they may represent attractive new opportunities to complement existing therapeutic manipulations against stress-related psychopathologies.

Encoding of Auditory Temporal Gestalt in the Human Brain.

The perception of an acoustic rhythm is invariant to the absolute temporal intervals constituting a sound sequence. It is unknown where in the brain temporal Gestalt, the percept emerging from the relative temporal proximity between acoustic events, is encoded. Two different relative temporal patterns, each induced by three experimental conditions with different absolute temporal patterns as sensory basis, were presented to participants. A linear support vector machine classifier was trained to differentiate activation patterns in functional magnetic resonance imaging data to the two different percepts. Across the sensory constituents the classifier decoded which percept was perceived. A searchlight analysis localized activation patterns specific to the temporal Gestalt bilaterally to the temporoparietal junction, including the planum temporale and supramarginal gyrus, and unilaterally to the right inferior frontal gyrus (pars opercularis). We show that auditory areas not only process absolute temporal intervals, but also integrate them into percepts of Gestalt and that encoding of these percepts persists in high-level associative areas. The findings complement existing knowledge regarding the processing of absolute temporal patterns to the processing of relative temporal patterns relevant to the sequential binding of perceptual elements into Gestalt.

A Combined Dietary and Cognitive Intervention in 3⁻5-Year-Old Children in Indonesia: A Randomized Controlled Trial.

Early childhood nutritional interventions typically combine nutritional and psychosocial stimulation. Such combined interventions result in long-lasting improvements of cognitive abilities in children who are malnourished. Here, we investigated potential cognitive abilities in normally developing children in Indonesia who were, however, at risk for suboptimal cognitive development due to little psychosocial stimulation in their home environment. In a randomized controlled intervention, children of the experimental group received nutritional supplementation combined with cognitive stimulation. Pre- and post-intervention measurements included cognitive development and functioning, behavior, and mother⁻child interaction. The experimental and control group received nutritional supplementation in the form of a fortified or unfortified milk powder, respectively. Additionally, the children and parents of the experimental group jointly engaged in daily learning activities at home and performed iPad-based tasks designed to foster cognitive abilities. The experimental group compared to the control group displayed a significantly higher increase in intelligence quotient as well as a significantly larger reduction in attentional problems after the intervention. These results indicate that low-level cognitive stimulation in combination with nutritional supplementation during early childhood can be an effective intervention that improves global cognitive functioning in healthy developing children. ClinicalTrials.gov Identifier: NCT02359669.

Treatment in early psychosis with N-acetyl-cysteine for 6months improves low-level auditory processing: Pilot study.

Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.

The function of dopaminergic neural signal transmission in auditory pulse perception: evidence from dopaminergic treatment in Parkinson's patients.

Auditory pulse perception, which is the perception of relatively salient and regularly appearing events in an acoustic sequence, is a necessary function in humans and has been suggested to rely on basal ganglia function. Our study investigated the effect dopamine depletion has on the auditory pulse perception in Parkinson's disease (PD). We examined PD patients and healthy seniors in this study, and all participants performed a pulse perception task and a motor control task. The pulse perception task consisted of a two alternative forced choice task in which subjects had to identify stimuli as metrical or non-metrical. We tested PD patients before and after the administration of l-3,4-dihydroxyphenylalanin (l-DOPA). The healthy control group performed the same tasks twice. PD patients that were dopamine depleted performed the pulse perception task equally well and as fast as did the healthy control group. However, after the administration of l-DOPA, PD patients performed the pulse perception task significantly faster than they did before the pharmacological intervention, which showed that pulse perception can be modulated by dopaminergic stimulation. These findings indicate that pulse perception relies on dopaminergic mechanisms but is not affected by dopamine depletion in the early stages of PD.

Refinement of metre perception--training increases hierarchical metre processing.

Auditory metre perception refers to the ability to extract a temporally regular pulse and an underlying hierarchical structure of perceptual accents from a sequence of tones. Pulse perception is widely present in humans, and can be measured by the temporal expectancy for prospective tones, which listeners generate when presented with a metrical rhythm. We tested whether musical expertise leads to an increased perception and representation of the hierarchical structure of a metrical rhythm. Musicians and musical novices were tested in a mismatch negativity (MMN) paradigm for their sensitivity to perceptual accents on tones of the same pulse level (metre-congruent deviant) and on tones of a lower hierarchical level (metre-incongruent deviant). The difference between these two perceptual accents was more pronounced in the MMNs of the musicians than in those of the non-musicians. That is, musical expertise includes increased sensitivity to metre, specifically to its hierarchical structure. This enhanced higher-order temporal pattern perception makes musicians ideal models for investigating neural correlates of metre perception and, potentially, of related abstract pattern perception. Finally, our data show that small differences in sensitivity to higher-order patterns can be captured by means of an MMN paradigm.

Early electrophysiological correlates of meter and rhythm processing in music perception.

The two main characteristics of temporal structuring in music are meter and rhythm. The present experiment investigated the event-related potentials (ERP) of these two structural elements with a focus on differential effects of attended and unattended processing. The stimulus material consisted of an auditory rhythm presented repetitively to subjects in which metrical and rhythmical changes as well as pitch changes were inserted. Subjects were to detect and categorize either temporal changes (attended condition) or pitch changes (unattended condition). Furthermore, we compared a group of long-term trained subjects (musicians) to non-musicians. As expected, behavioural data revealed that trained subjects performed significantly better than untrained subjects. This effect was mainly due to the better detection of the meter deviants. Rhythm as well as meter changes elicited an early negative deflection compared to standard tones in the attended processing condition, while in the unattended processing condition only the rhythm change elicited this negative deflection. Both effects were found across all experimental subjects with no difference between the two groups. Thus, our data suggest that meter and rhythm perception could differ with respect to the time course of processing and lend credence to the notion of different neurophysiological processes underlying the auditory perception of rhythm and meter in music. Furthermore, the data indicate that non-musicians are as proficient as musicians when it comes to rhythm perception, suggesting that correct rhythm perception is crucial not only for musicians but for every individual.

The neural correlate of speech rhythm as evidenced by metrical speech processing.

The present study investigates the neural correlates of rhythm processing in speech perception. German pseudosentences spoken with an exaggerated (isochronous) or a conversational (nonisochronous) rhythm were compared in an auditory functional magnetic resonance imaging experiment. The subjects had to perform either a rhythm task (explicit rhythm processing) or a prosody task (implicit rhythm processing). The study revealed bilateral activation in the supplementary motor area (SMA), extending into the cingulate gyrus, and in the insulae, extending into the right basal ganglia (neostriatum), as well as activity in the right inferior frontal gyrus (IFG) related to the performance of the rhythm task. A direct contrast between isochronous and nonisochronous sentences revealed differences in lateralization of activation for isochronous processing as a function of the explicit and implicit tasks. Explicit processing revealed activation in the right posterior superior temporal gyrus (pSTG), the right supramarginal gyrus, and the right parietal operculum. Implicit processing showed activation in the left supramarginal gyrus, the left pSTG, and the left parietal operculum. The present results indicate a function of the SMA and the insula beyond motor timing and speak for a role of these brain areas in the perception of acoustically temporal intervals. Secondly, the data speak for a specific task-related function of the right IFG in the processing of accent patterns. Finally, the data sustain the assumption that the right secondary auditory cortex is involved in the explicit perception of auditory suprasegmental cues and, moreover, that activity in the right secondary auditory cortex can be modulated by top-down processing mechanisms.

Segmental processing in the human auditory dorsal stream.

In the present study we investigated the functional organization of sublexical auditory perception with specific respect to auditory spectro-temporal processing in speech and non-speech sounds. Participants discriminated verbal and nonverbal auditory stimuli according to either spectral or temporal acoustic features in the context of a sparse event-related functional magnetic resonance imaging (fMRI) study. Based on recent models of speech processing, we hypothesized that auditory segmental processing, as is required in the discrimination of speech and non-speech sound according to its temporal features, will lead to a specific involvement of a left-hemispheric dorsal processing network comprising the posterior portion of the inferior frontal cortex and the inferior parietal lobe. In agreement with our hypothesis results revealed significant responses in the posterior part of the inferior frontal gyrus and the parietal operculum of the left hemisphere when participants had to discriminate speech and non-speech stimuli based on subtle temporal acoustic features. In contrast, when participants had to discriminate speech and non-speech stimuli on the basis of changes in the frequency content, we observed bilateral activations along the middle temporal gyrus and superior temporal sulcus. The results of the present study demonstrate an involvement of the dorsal pathway in the segmental sublexical analysis of speech sounds as well as in the segmental acoustic analysis of non-speech sounds with analogous spectro-temporal characteristics.

Silent and continuous fMRI scanning differentially modulate activation in an auditory language comprehension task.

Sparse temporal acquisition schemes have been adopted to investigate the neural correlates of human audition using blood-oxygen-level dependent (BOLD) based functional magnetic resonance imaging (fMRI) devoid of ambient confounding acoustic scanner noise. These schemes have previously been extended to clustered-sparse temporal acquisition designs which record several subsequent BOLD contrast images in rapid succession in order to enhance temporal sampling efficiency. In the present study we demonstrate that an event-related task design can effectively be combined with a clustered temporal acquisition technique in an auditory language comprehension task. The same fifteen volunteers performed two separate auditory runs which either applied customary fMRI acquisition (CA) composed of continuous scanner noise or "silent" fMRI built on a clustered temporal acquisition (CTA) protocol. In accord with our hypothesis, the CTA scheme relative to the CA protocol is accompanied by significantly stronger functional responses along the entire superior temporal plane. By contrast, the bilateral insulae engage more strongly during continuous scanning. A post-hoc region-of-interest analysis reveals cortical activation in subportions of the supratemporal plane which varies as a function of acquisition protocol. The middle part of the supratemporal plane shows a rightward asymmetry only for the CTA scheme while the posterior supratemporal plane exposes a significantly stronger leftward asymmetry during the CTA. Our findings implicate that silent fMRI is advantageous when it comes to the exploration of auditory and speech functions residing in the supratemporal plane.