Blue-Light Therapy for Seasonal and Non-Seasonal Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To determine the efficacy and safety of blue-light therapy in seasonal and non-seasonal major depressive disorder (MDD), by comparison to active and inactive control conditions. METHODS: We searched Web of Science, EMBASE, Medline, PsycInfo, and Clinicaltrials.gov through January 17, 2022, for randomized controlled trials (RCTs) using search terms for blue/blue-enhanced, light therapy, and depression/seasonal affective disorder. Two independent reviewers extracted data. The primary outcome was the difference in endpoint scores on the Structured Interview Guide for the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH-SAD) or the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) between blue light and comparison conditions. Secondary outcomes were response (≥ 50% improvement from baseline to endpoint on a depression scale) and remission rates (endpoint score in the remission range). RESULTS: Of 582 articles retrieved, we included nine RCTs (n = 347 participants) assessing blue-light therapy. Seven studies had participants with seasonal MDD and two studies included participants with non-seasonal MDD. Four studies compared blue light to an inactive light condition (efficacy studies), and five studies compared it to an active condition (comparison studies). For the primary outcome, a meta-analysis with random-effects models found no evidence for the efficacy of blue-light conditions compared to inactive conditions (mean difference [MD] = 2.43; 95% confidence interval [CI], -1.28 to 6.14, P = 0.20); however, blue-light also showed no differences compared to active conditions (MD = -0.11; 95% CI, -2.38 to 2.16, P = 0.93). There were no significant differences in response and remission rates between blue-light conditions and inactive or active light conditions. Blue-light therapy was overall well-tolerated. CONCLUSIONS: The efficacy of blue-light therapy in the treatment of seasonal and non-seasonal MDD remains unproven. Future trials should be of longer duration, include larger sample sizes, and attempt to better standardize the parameters of light therapy.

Distinct Regional Oscillatory Connectivity Patterns During Auditory Target and Novelty Processing.

Auditory attention allows us to focus on relevant target sounds in the acoustic environment while maintaining the capability to orient to unpredictable (novel) sound changes. An open question is whether orienting to expected vs. unexpected auditory events are governed by anatomically distinct attention pathways, respectively, or by differing communication patterns within a common system. To address this question, we applied a recently developed PeSCAR analysis method to evaluate spectrotemporal functional connectivity patterns across subregions of broader cortical regions of interest (ROIs) to analyze magnetoencephalography data obtained during a cued auditory attention task. Subjects were instructed to detect a predictable harmonic target sound embedded among standard tones in one ear and to ignore the standard tones and occasional unpredictable novel sounds presented in the opposite ear. Phase coherence of estimated source activity was calculated between subregions of superior temporal, frontal, inferior parietal, and superior parietal cortex ROIs. Functional connectivity was stronger in response to target than novel stimuli between left superior temporal and left parietal ROIs and between left frontal and right parietal ROIs, with the largest effects observed in the beta band (15-35 Hz). In contrast, functional connectivity was stronger in response to novel than target stimuli in inter-hemispheric connections between left and right frontal ROIs, observed in early time windows in the alpha band (8-12 Hz). Our findings suggest that auditory processing of expected target vs. unexpected novel sounds involves different spatially, temporally, and spectrally distributed oscillatory connectivity patterns across temporal, parietal, and frontal areas.

Interacting parallel pathways associate sounds with visual identity in auditory cortices.

Spatial and non-spatial information of sound events is presumably processed in parallel auditory cortex (AC) "what" and "where" streams, which are modulated by inputs from the respective visual-cortex subsystems. How these parallel processes are integrated to perceptual objects that remain stable across time and the source agent's movements is unknown. We recorded magneto- and electroencephalography (MEG/EEG) data while subjects viewed animated video clips featuring two audiovisual objects, a black cat and a gray cat. Adaptor-probe events were either linked to the same object (the black cat meowed twice in a row in the same location) or included a visually conveyed identity change (the black and then the gray cat meowed with identical voices in the same location). In addition to effects in visual (including fusiform, middle temporal or MT areas) and frontoparietal association areas, the visually conveyed object-identity change was associated with a release from adaptation of early (50-150ms) activity in posterior ACs, spreading to left anterior ACs at 250-450ms in our combined MEG/EEG source estimates. Repetition of events belonging to the same object resulted in increased theta-band (4-8Hz) synchronization within the "what" and "where" pathways (e.g., between anterior AC and fusiform areas). In contrast, the visually conveyed identity changes resulted in distributed synchronization at higher frequencies (alpha and beta bands, 8-32Hz) across different auditory, visual, and association areas. The results suggest that sound events become initially linked to perceptual objects in posterior AC, followed by modulations of representations in anterior AC. Hierarchical what and where pathways seem to operate in parallel after repeating audiovisual associations, whereas the resetting of such associations engages a distributed network across auditory, visual, and multisensory areas.

Auditory conflict resolution correlates with medial-lateral frontal theta/alpha phase synchrony.

When multiple persons speak simultaneously, it may be difficult for the listener to direct attention to correct sound objects among conflicting ones. This could occur, for example, in an emergency situation in which one hears conflicting instructions and the loudest, instead of the wisest, voice prevails. Here, we used cortically-constrained oscillatory MEG/EEG estimates to examine how different brain regions, including caudal anterior cingulate (cACC) and dorsolateral prefrontal cortices (DLPFC), work together to resolve these kinds of auditory conflicts. During an auditory flanker interference task, subjects were presented with sound patterns consisting of three different voices, from three different directions (45° left, straight ahead, 45° right), sounding out either the letters "A" or "O". They were asked to discriminate which sound was presented centrally and ignore the flanking distracters that were phonetically either congruent (50%) or incongruent (50%) with the target. Our cortical MEG/EEG oscillatory estimates demonstrated a direct relationship between performance and brain activity, showing that efficient conflict resolution, as measured with reduced conflict-induced RT lags, is predicted by theta/alpha phase coupling between cACC and right lateral frontal cortex regions intersecting the right frontal eye fields (FEF) and DLPFC, as well as by increased pre-stimulus gamma (60-110 Hz) power in the left inferior fontal cortex. Notably, cACC connectivity patterns that correlated with behavioral conflict-resolution measures were found during both the pre-stimulus and the pre-response periods. Our data provide evidence that, instead of being only transiently activated upon conflict detection, cACC is involved in sustained engagement of attentional resources required for effective sound object selection performance.

Functional connectivity of dorsal and ventral frontoparietal seed regions during auditory orienting.

Our ability to refocus auditory attention is vital for even the most routine day-to-day activities. Shifts in auditory attention can be initiated "voluntarily," or triggered "involuntarily" by unexpected novel sound events. Here we employed psychophysiological interaction (PPI) analyses of auditory functional MRI data, to compare functional connectivity patterns of distinct frontoparietal cortex regions during cued voluntary vs. novelty-driven involuntary auditory attention shifting. Overall, our frontoparietal seed regions exhibited significant PPI increases with auditory cortex (AC) areas during both cued and novelty-driven orienting. However, significant positive PPI patterns associated with voluntary auditory attention (cue>novel task regressor), but mostly absent in analyses emphasizing involuntary orienting (novel>cue task regressor), were observed with seeds within the frontal eye fields (FEF), superior parietal lobule (SPL), and right supramarginal gyri (SMG). In contrast, significant positive PPIs associated selectively with involuntary orienting were observed between ACs and seeds within the bilateral anterior interior frontal gyri (IFG), left posterior IFG, SMG, and posterior cingulate cortices (PCC). We also found indices of lateralization of different attention networks: PPI increases selective to voluntary attention occurred primarily within right-hemispheric regions, whereas those related to involuntary orienting were more frequent with left-hemisphere seeds. In conclusion, despite certain similarities in PPI patterns across conditions, the more dorsal aspects of right frontoparietal cortex demonstrated wider connectivity during cued/voluntary attention shifting, whereas certain left ventral frontoparietal seeds were more widely connected during novelty-triggered/involuntary orienting. Our findings provide partial support for distinct attention networks for voluntary and involuntary auditory attention.

Lateralized parietotemporal oscillatory phase synchronization during auditory selective attention.

Based on the infamous left-lateralized neglect syndrome, one might hypothesize that the dominating right parietal cortex has a bilateral representation of space, whereas the left parietal cortex represents only the contralateral right hemispace. Whether this principle applies to human auditory attention is not yet fully clear. Here, we explicitly tested the differences in cross-hemispheric functional coupling between the intraparietal sulcus (IPS) and auditory cortex (AC) using combined magnetoencephalography (MEG), EEG, and functional MRI (fMRI). Inter-regional pairwise phase consistency (PPC) was analyzed from data obtained during dichotic auditory selective attention task, where subjects were in 10-s trials cued to attend to sounds presented to one ear and to ignore sounds presented in the opposite ear. Using MEG/EEG/fMRI source modeling, parietotemporal PPC patterns were (a) mapped between all AC locations vs. IPS seeds and (b) analyzed between four anatomically defined AC regions-of-interest (ROI) vs. IPS seeds. Consistent with our hypothesis, stronger cross-hemispheric PPC was observed between the right IPS and left AC for attended right-ear sounds, as compared to PPC between the left IPS and right AC for attended left-ear sounds. In the mapping analyses, these differences emerged at 7-13Hz, i.e., at the theta to alpha frequency bands, and peaked in Heschl's gyrus and lateral posterior non-primary ACs. The ROI analysis revealed similarly lateralized differences also in the beta and lower theta bands. Taken together, our results support the view that the right parietal cortex dominates auditory spatial attention.

Evidence for distinct human auditory cortex regions for sound location versus identity processing.

Neurophysiological animal models suggest that anterior auditory cortex (AC) areas process sound identity information, whereas posterior ACs specialize in sound location processing. In humans, inconsistent neuroimaging results and insufficient causal evidence have challenged the existence of such parallel AC organization. Here we transiently inhibit bilateral anterior or posterior AC areas using MRI-guided paired-pulse transcranial magnetic stimulation (TMS) while subjects listen to Reference/Probe sound pairs and perform either sound location or identity discrimination tasks. The targeting of TMS pulses, delivered 55-145 ms after Probes, is confirmed with individual-level cortical electric-field estimates. Our data show that TMS to posterior AC regions delays reaction times (RT) significantly more during sound location than identity discrimination, whereas TMS to anterior AC regions delays RTs significantly more during sound identity than location discrimination. This double dissociation provides direct causal support for parallel processing of sound identity features in anterior AC and sound location in posterior AC.

Brain networks of novelty-driven involuntary and cued voluntary auditory attention shifting.

In everyday life, we need a capacity to flexibly shift attention between alternative sound sources. However, relatively little work has been done to elucidate the mechanisms of attention shifting in the auditory domain. Here, we used a mixed event-related/sparse-sampling fMRI approach to investigate this essential cognitive function. In each 10-sec trial, subjects were instructed to wait for an auditory "cue" signaling the location where a subsequent "target" sound was likely to be presented. The target was occasionally replaced by an unexpected "novel" sound in the uncued ear, to trigger involuntary attention shifting. To maximize the attention effects, cues, targets, and novels were embedded within dichotic 800-Hz vs. 1500-Hz pure-tone "standard" trains. The sound of clustered fMRI acquisition (starting at t = 7.82 sec) served as a controlled trial-end signal. Our approach revealed notable activation differences between the conditions. Cued voluntary attention shifting activated the superior intra--parietal sulcus (IPS), whereas novelty-triggered involuntary orienting activated the inferior IPS and certain subareas of the precuneus. Clearly more widespread activations were observed during voluntary than involuntary orienting in the premotor cortex, including the frontal eye fields. Moreover, we found -evidence for a frontoinsular-cingular attentional control network, consisting of the anterior insula, inferior frontal cortex, and medial frontal cortices, which were activated during both target discrimination and voluntary attention shifting. Finally, novels and targets activated much wider areas of superior temporal auditory cortices than shifting cues.

Neuronal representations of distance in human auditory cortex.

Neuronal mechanisms of auditory distance perception are poorly understood, largely because contributions of intensity and distance processing are difficult to differentiate. Typically, the received intensity increases when sound sources approach us. However, we can also distinguish between soft-but-nearby and loud-but-distant sounds, indicating that distance processing can also be based on intensity-independent cues. Here, we combined behavioral experiments, fMRI measurements, and computational analyses to identify the neural representation of distance independent of intensity. In a virtual reverberant environment, we simulated sound sources at varying distances (15-100 cm) along the right-side interaural axis. Our acoustic analysis suggested that, of the individual intensity-independent depth cues available for these stimuli, direct-to-reverberant ratio (D/R) is more reliable and robust than interaural level difference (ILD). However, on the basis of our behavioral results, subjects' discrimination performance was more consistent with complex intensity-independent distance representations, combining both available cues, than with representations on the basis of either D/R or ILD individually. fMRI activations to sounds varying in distance (containing all cues, including intensity), compared with activations to sounds varying in intensity only, were significantly increased in the planum temporale and posterior superior temporal gyrus contralateral to the direction of stimulation. This fMRI result suggests that neurons in posterior nonprimary auditory cortices, in or near the areas processing other auditory spatial features, are sensitive to intensity-independent sound properties relevant for auditory distance perception.