Information-based rhythmic transcranial magnetic stimulation to accelerate learning during auditory working memory training: a proof-of-concept study.

Introduction: Rhythmic transcranial magnetic stimulation (rhTMS) has been shown to enhance auditory working memory manipulation, specifically by boosting theta oscillatory power in the dorsal auditory pathway during task performance. It remains unclear whether these enhancements (i) persist beyond the period of stimulation, (ii) if they can accelerate learning and (iii) if they would accumulate over several days of stimulation. In the present study, we investigated the lasting behavioral and electrophysiological effects of applying rhTMS over the left intraparietal sulcus (IPS) throughout the course of seven sessions of cognitive training on an auditory working memory task. Methods: A limited sample of 14 neurologically healthy participants took part in the training protocol with an auditory working memory task while being stimulated with either theta (5 Hz) rhTMS or sham TMS. Electroencephalography (EEG) was recorded before, throughout five training sessions and after the end of training to assess to effects of rhTMS on behavioral performance and on oscillatory entrainment of the dorsal auditory network. Results: We show that this combined approach enhances theta oscillatory activity within the fronto-parietal network and causes improvements in auditoryworking memory performance. We show that compared to individuals who received sham stimulation, cognitive training can be accelerated when combined with optimized rhTMS, and that task performance benefits can outlast the training period by ∼ 3 days. Furthermore, we show that there is increased theta oscillatory power within the recruited dorsal auditory network during training, and that sustained EEG changes can be observed ∼ 3 days following stimulation. Discussion: The present study, while underpowered for definitive statistical analyses, serves to improve our understanding of the causal dynamic interactions supporting auditory working memory. Our results constitute an important proof of concept for the potential translational impact of non-invasive brain stimulation protocols and provide preliminary data for developing optimized rhTMS and training protocols that could be implemented in clinical populations.

Using rare genetic mutations to revisit structural brain asymmetry.

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

Spectrotemporal cues and attention jointly modulate fMRI network topology for sentence and melody perception.

Speech and music are two fundamental modes of human communication. Lateralisation of key processes underlying their perception has been related both to the distinct sensitivity to low-level spectrotemporal acoustic features and to top-down attention. However, the interplay between bottom-up and top-down processes needs to be clarified. In the present study, we investigated the contribution of acoustics and attention to melodies or sentences to lateralisation in fMRI functional network topology. We used sung speech stimuli selectively filtered in temporal or spectral modulation domains with crossed and balanced verbal and melodic content. Perception of speech decreased with degradation of temporal information, whereas perception of melodies decreased with spectral degradation. Applying graph theoretical metrics on fMRI connectivity matrices, we found that local clustering, reflecting functional specialisation, linearly increased when spectral or temporal cues crucial for the task goal were incrementally degraded. These effects occurred in a bilateral fronto-temporo-parietal network for processing temporally degraded sentences and in right auditory regions for processing spectrally degraded melodies. In contrast, global topology remained stable across conditions. These findings suggest that lateralisation for speech and music partially depends on an interplay of acoustic cues and task goals under increased attentional demands.

Attention-Driven Modulation of Auditory Cortex Activity during Selective Listening in a Multispeaker Setting.

Real-world listening settings often consist of multiple concurrent sound streams. To limit perceptual interference during selective listening, the auditory system segregates and filters the relevant sensory input. Previous work provided evidence that the auditory cortex is critically involved in this process and selectively gates attended input toward subsequent processing stages. We studied at which level of auditory cortex processing this filtering of attended information occurs using functional magnetic resonance imaging (fMRI) and a naturalistic selective listening task. Forty-five human listeners (of either sex) attended to one of two continuous speech streams, presented either concurrently or in isolation. Functional data were analyzed using an inter-subject analysis to assess stimulus-specific components of ongoing auditory cortex activity. Our results suggest that stimulus-related activity in the primary auditory cortex and the adjacent planum temporale are hardly affected by attention, whereas brain responses at higher stages of the auditory cortex processing hierarchy become progressively more selective for the attended input. Consistent with these findings, a complementary analysis of stimulus-driven functional connectivity further demonstrated that information on the to-be-ignored speech stream is shared between the primary auditory cortex and the planum temporale but largely fails to reach higher processing stages. Our findings suggest that the neural processing of ignored speech cannot be effectively suppressed at the level of early cortical processing of acoustic features but is gradually attenuated once the competing speech streams are fully segregated.

Auditory and reward structures reflect the pleasure of musical expectancies during naturalistic listening.

Enjoying music consistently engages key structures of the neural auditory and reward systems such as the right superior temporal gyrus (R STG) and ventral striatum (VS). Expectations seem to play a central role in this effect, as preferences reliably vary according to listeners' uncertainty about the musical future and surprise about the musical past. Accordingly, VS activity reflects the pleasure of musical surprise, and exhibits stronger correlations with R STG activity as pleasure grows. Yet the reward value of musical surprise - and thus the reason for these surprises engaging the reward system - remains an open question. Recent models of predictive neural processing and learning suggest that forming, testing, and updating hypotheses about one's environment may be intrinsically rewarding, and that the constantly evolving structure of musical patterns could provide ample opportunity for this procedure. Consistent with these accounts, our group previously found that listeners tend to prefer melodic excerpts taken from real music when it either validates their uncertain melodic predictions (i.e., is high in uncertainty and low in surprise) or when it challenges their highly confident ones (i.e., is low in uncertainty and high in surprise). An independent research group (Cheung et al., 2019) replicated these results with musical chord sequences, and identified their fMRI correlates in the STG, amygdala, and hippocampus but not the VS, raising new questions about the neural mechanisms of musical pleasure that the present study seeks to address. Here, we assessed concurrent liking ratings and hemodynamic fMRI signals as 24 participants listened to 50 naturalistic, real-world musical excerpts that varied across wide spectra of computationally modeled uncertainty and surprise. As in previous studies, liking ratings exhibited an interaction between uncertainty and surprise, with the strongest preferences for high uncertainty/low surprise and low uncertainty/high surprise. FMRI results also replicated previous findings, with music liking effects in the R STG and VS. Furthermore, we identify interactions between uncertainty and surprise on the one hand, and liking and surprise on the other, in VS activity. Altogether, these results provide important support for the hypothesized role of the VS in deriving pleasure from learning about musical structure.

Using cortico-cerebellar structural patterns to classify early- and late-trained musicians.

A body of current evidence suggests that there is a sensitive period for musical training: people who begin training before the age of seven show better performance on tests of musical skill, and also show differences in brain structure-especially in motor cortical and cerebellar regions-compared with those who start later. We used support vector machine models-a subtype of supervised machine learning-to investigate distributed patterns of structural differences between early-trained (ET) and late-trained (LT) musicians and to better understand the age boundaries of the sensitive period for early musicianship. After selecting regions of interest from the cerebellum and cortical sensorimotor regions, we applied recursive feature elimination with cross-validation to produce a model which optimally and accurately classified ET and LT musicians. This model identified a combination of 17 regions, including 9 cerebellar and 8 sensorimotor regions, and maintained a high accuracy and sensitivity (true positives, i.e., ET musicians) without sacrificing specificity (true negatives, i.e., LT musicians). Critically, this model-which defined ET musicians as those who began their training before the age of 7-outperformed all other models in which age of start was earlier or later (between ages 5-10). Our model's ability to accurately classify ET and LT musicians provides additional evidence that musical training before age 7 affects cortico-cerebellar structure in adulthood, and is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioral maturation.

Using rare genetic mutations to revisit structural brain asymmetry.

Asymmetry between the left and right brain is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variant studies, which typically exert small effects on brain phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We quantitatively dissected the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior mapping highlights the consequences of genetically controlled brain lateralization on human-defining cognitive traits.

Development and validation of an fMRI-informed EEG model of reward-related ventral striatum activation.

Reward processing is essential for our mental-health and well-being. In the current study, we developed and validated a scalable, fMRI-informed EEG model for monitoring reward processing related to activation in the ventral-striatum (VS), a significant node in the brain's reward system. To develop this EEG-based model of VS-related activation, we collected simultaneous EEG/fMRI data from 17 healthy individuals while listening to individually-tailored pleasurable music - a highly rewarding stimulus known to engage the VS. Using these cross-modal data, we constructed a generic regression model for predicting the concurrently acquired Blood-Oxygen-Level-Dependent (BOLD) signal from the VS using spectro-temporal features from the EEG signal (termed hereby VS-related-Electrical Finger Print; VS-EFP). The performance of the extracted model was examined using a series of tests that were applied on the original dataset and, importantly, an external validation dataset collected from a different group of 14 healthy individuals who underwent the same EEG/FMRI procedure. Our results showed that the VS-EFP model, as measured by simultaneous EEG, predicted BOLD activation in the VS and additional functionally relevant regions to a greater extent than an EFP model derived from a different anatomical region. The developed VS-EFP was also modulated by musical pleasure and predictive of the VS-BOLD during a monetary reward task, further indicating its functional relevance. These findings provide compelling evidence for the feasibility of using EEG alone to model neural activation related to the VS, paving the way for future use of this scalable neural probing approach in neural monitoring and self-guided neuromodulation.

Training allows switching from limited-capacity manipulations to large-capacity perceptual processing.

In contrast to perceptual tasks, which enable concurrent processing of many stimuli, working memory (WM) tasks have a very small capacity, limiting cognitive skills. Training on WM tasks often yields substantial improvement, suggesting that training might increase the general WM capacity. To understand the underlying processes, we trained a test group with a newly designed tone manipulation WM task and a control group with a challenging perceptual task of pitch pattern discrimination. Functional magnetic resonance imaging (fMRI) scans confirmed that pretraining, manipulation was associated with a dorsal fronto-parietal WM network, while pitch comparison was associated with activation of ventral auditory regions. Training induced improvement in each group, which was limited to the trained task. Analyzing the behavior of the group trained with tone manipulation revealed that participants learned to replace active manipulation with a perceptual verification of the position of a single salient tone in the sequence presented as a tentative reply. Posttraining fMRI scans revealed modifications in ventral activation of both groups. Successful WMtrained participants learned to utilize auditory regions for the trained task. These observations suggest that the huge task-specific enhancement of WM capacity stems from a task-specific switch to perceptual routines, implemented in perceptual regions.

Music engagement is negatively correlated with depressive symptoms during the COVID-19 pandemic via reward-related mechanisms.

The COVID-19 pandemic has deeply affected the mental health of millions of people. We assessed which of many leisure activities correlated with positive mental health outputs, with particular attention to music, which has been reported to be important for coping with the psychological burden of the pandemic. Questionnaire data from about 1000 individuals primarily from Italy, Spain, and the United States during May-June 2020 show that people picked music activities (listening to, playing, singing, etc.) most often as the leisure experiences that helped them the most to cope with psychological distress related with the pandemic. During the pandemic, hours of engagement in music and food-related activities were associated with lower depressive symptoms. The negative correlation between music and depression was mediated by individual differences in sensitivity to reward, whereas the correlation between food-related activities and improved mental health outputs was explained by differences in emotion suppression strategies. Our results, while correlational, suggest that engaging in music activities could be related to improved well-being with the underlying mechanism being related to reward, consistent with neuroscience findings. Our data have practical significance in pointing to effective strategies to cope with mental health issues beyond those related to the COVID-19 pandemic.

The role of opioid transmission in music-induced pleasure.

Studies conducted in rodents indicate a crucial role of the opioid circuit in mediating objective hedonic reactions to primary rewards. However, it remains unclear whether opioid transmission is also essential to experience pleasure with more abstract rewards, such as music. We addressed this question using a double-blind within-subject pharmacological design in which opioid levels were up- and downregulated by administering an opioid agonist (oxycodone) and antagonist (naltrexone), respectively, before healthy participants (n = 21) listened to music. Participants also performed a monetary incentive delay (MID) task to control for the effectiveness of the treatment and the specificity of the effects. Our results revealed that the pharmacological intervention did not modulate subjective reports of pleasure, nor the occurrence of chills. On the contrary, psychophysiological (objective) measures of emotional arousal, such as skin conductance responses (SCRs), were bidirectionally modulated in both the music and MID tasks. This modulation specifically occurred during reward consumption, with greater pleasure-related SCR following oxycodone than naltrexone. These findings indicate that opioid transmission does not modulate subjective evaluations but rather affects objective reward-related psychophysiological responses. These findings raise new caveats about the role of the opioidergic system in the modulation of pleasure for more abstract or cognitive forms of rewarding experiences, such as music.

Music and Brain Circuitry: Strategies for Strengthening Evidence-Based Research for Music-Based Interventions.

The neuroscience of music and music-based interventions (MBIs) is a fascinating but challenging research field. While music is a ubiquitous component of every human society, MBIs may encompass listening to music, performing music, music-based movement, undergoing music education and training, or receiving treatment from music therapists. Unraveling the brain circuits activated and influenced by MBIs may help us gain better understanding of the therapeutic and educational values of MBIs by gathering strong research evidence. However, the complexity and variety of MBIs impose unique research challenges. This article reviews the recent endeavor led by the National Institutes of Health to support evidence-based research of MBIs and their impact on health and diseases. It also highlights fundamental challenges and strategies of MBI research with emphases on the utilization of animal models, human brain imaging and stimulation technologies, behavior and motion capturing tools, and computational approaches. It concludes with suggestions of basic requirements when studying MBIs and promising future directions to further strengthen evidence-based research on MBIs in connections with brain circuitry.SIGNIFICANCE STATEMENT Music and music-based interventions (MBI) engage a wide range of brain circuits and hold promising therapeutic potentials for a variety of health conditions. Comparative studies using animal models have helped in uncovering brain circuit activities involved in rhythm perception, while human imaging, brain stimulation, and motion capture technologies have enabled neural circuit analysis underlying the effects of MBIs on motor, affective/reward, and cognitive function. Combining computational analysis, such as prediction method, with mechanistic studies in animal models and humans may unravel the complexity of MBIs and their effects on health and disease.

Going down to go up: understanding human auditory cognition by investigating cortical-subcortical interactions.

Human auditory cognition spans everything from detecting a creaking door in the night to enjoying beautiful music. Neurofunctional models of these processes tend to focus on cortical networks, but how do subcortical circuits contribute to auditory cognition? Answering this question will lead to a richer understanding of how we process the complex auditory world.

Supramodality of neural entrainment: Rhythmic visual stimulation causally enhances auditory working memory performance.

The frontoparietal network is involved in multiple tasks, such as visual mental rotation, working memory, or arithmetic. Whether those different cognitive processes are supported by the same supramodal network or distinct, but overlapping, functional systems is unresolved. We investigate whether frontoparietal activity can be selectively entrained by rhythmic sensory stimulations (visual rotation) and whether this entrainment can causally modulate task performance in another modality (auditory working memory). We show that rhythmic visual presentations of rotating shapes, known to activate the dorsal pathway, increase frontoparietal connectivity at stimulation frequency as measured with MEG/EEG. We then show that frontoparietal theta oscillations predict auditory working memory performance. Last, we demonstrate that theta rhythmic visual stimulation applied during auditory memory causally enhances performance, and both the rotating properties of the stimulus and its flickering frequency drive the effect. This study provides causal evidence of the supramodal role of the frontoparietal network in human cognition.

Hemispheric asymmetries for music and speech: Spectrotemporal modulations and top-down influences.

Hemispheric asymmetries in auditory cognition have been recognized for a long time, but their neural basis is still debated. Here I focus on specialization for processing of speech and music, the two most important auditory communication systems that humans possess. A great deal of evidence from lesion studies and functional imaging suggests that aspects of music linked to the processing of pitch patterns depend more on right than left auditory networks. A complementary specialization for temporal resolution has been suggested for left auditory networks. These diverse findings can be integrated within the context of the spectrotemporal modulation framework, which has been developed as a way to characterize efficient neuronal encoding of complex sounds. Recent studies show that degradation of spectral modulation impairs melody perception but not speech content, whereas degradation of temporal modulation has the opposite effect. Neural responses in the right and left auditory cortex in those studies are linked to processing of spectral and temporal modulations, respectively. These findings provide a unifying model to understand asymmetries in terms of sensitivity to acoustical features of communication sounds in humans. However, this explanation does not account for evidence that asymmetries can shift as a function of learning, attention, or other top-down factors. Therefore, it seems likely that asymmetries arise both from bottom-up specialization for acoustical modulations and top-down influences coming from hierarchically higher components of the system. Such interactions can be understood in terms of predictive coding mechanisms for perception.

Early musical training shapes cortico-cerebellar structural covariation.

Adult abilities in complex cognitive domains such as music appear to depend critically on the age at which training or experience begins, and relevant experience has greater long-term effects during periods of peak maturational change. Previous work has shown that early trained musicians (ET; < age 7) out-perform later-trained musicians (LT; > age 7) on tests of musical skill, and also have larger volumes of the ventral premotor cortex (vPMC) and smaller volumes of the cerebellum. These cortico-cerebellar networks mature and function in relation to one another, suggesting that early training may promote coordinated developmental plasticity. To test this hypothesis, we examined structural covariation between cerebellar volume and cortical thickness (CT) in sensorimotor regions in ET and LT musicians and non-musicians (NMs). Results show that ETs have smaller volumes in cerebellar lobules connected to sensorimotor cortices, while both musician groups had greater cortical thickness in right pre-supplementary motor area (SMA) and right PMC compared to NMs. Importantly, early musical training had a specific effect on structural covariance between the cerebellum and cortex: NMs showed negative correlations between left lobule VI and right pre-SMA and PMC, but this relationship was reduced in ET musicians. ETs instead showed a significant negative correlation between vermal IV and right pre-SMA and dPMC. Together, these results suggest that early musical training has differential impacts on the maturation of cortico-cerebellar networks important for optimizing sensorimotor performance. This conclusion is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioral maturation.

Modulating Cortical Instrument Representations During Auditory Stream Segregation and Integration With Polyphonic Music.

Numerous neuroimaging studies demonstrated that the auditory cortex tracks ongoing speech and that, in multi-speaker environments, tracking of the attended speaker is enhanced compared to the other irrelevant speakers. In contrast to speech, multi-instrument music can be appreciated by attending not only on its individual entities (i.e., segregation) but also on multiple instruments simultaneously (i.e., integration). We investigated the neural correlates of these two modes of music listening using electroencephalography (EEG) and sound envelope tracking. To this end, we presented uniquely composed music pieces played by two instruments, a bassoon and a cello, in combination with a previously validated music auditory scene analysis behavioral paradigm (Disbergen et al., 2018). Similar to results obtained through selective listening tasks for speech, relevant instruments could be reconstructed better than irrelevant ones during the segregation task. A delay-specific analysis showed higher reconstruction for the relevant instrument during a middle-latency window for both the bassoon and cello and during a late window for the bassoon. During the integration task, we did not observe significant attentional modulation when reconstructing the overall music envelope. Subsequent analyses indicated that this null result might be due to the heterogeneous strategies listeners employ during the integration task. Overall, our results suggest that subsequent to a common processing stage, top-down modulations consistently enhance the relevant instrument's representation during an instrument segregation task, whereas such an enhancement is not observed during an instrument integration task. These findings extend previous results from speech tracking to the tracking of multi-instrument music and, furthermore, inform current theories on polyphonic music perception.

Dopamine modulations of reward-driven music memory consolidation.

Music listening provides one of the most significant abstract rewards for humans because hearing music activates the dopaminergic mesolimbic system. Given the strong link between reward, dopamine, and memory, we aimed here to investigate the hypothesis that dopamine-dependent musical reward can drive memory improvements. Twenty-nine healthy participants of both sexes provided reward ratings of unfamiliar musical excerpts that had to be remembered following a consolidation period under three separate conditions: after the ingestion of a dopaminergic antagonist, a dopaminergic precursor, or a placebo. Linear mixed modeling of the intervention data showed that the effect of reward on memory-i.e., the greater the reward experienced while listening to the musical excerpts, the better the memory recollection performance-was modulated by both dopaminergic signaling and individual differences in reward processing. Greater pleasure was consistently associated with better memory outcomes in participants with high sensitivity to musical reward, but this effect was lost when dopaminergic signaling was disrupted in participants with average or low musical hedonia. Our work highlights the flexibility of the human dopaminergic system, which can enhance memory formation not only through explicit and/or primary reinforcers but also via abstract and aesthetic rewards such as music.

Engagement in Music-Related Activities During the COVID-19 Pandemic as a Mirror of Individual Differences in Musical Reward and Coping Strategies.

The COVID-19 pandemic and the measures taken to mitigate its impact (e.g., confinement orders) have affected people's lives in profound ways that would have been unimagable only months before the pandemic began. Media reports from the height of the pandemic's initial international surge frequently highlighted that many people were engaging in music-related activities (from singing and dancing to playing music from balconies and attending virtual concerts) to help them cope with the strain of the pandemic. Our first goal in this study was to investigate changes in music-related habits due to the pandemic. We also investigated whether engagement in distinct music-related activities (singing, listening, dancing, etc.) was associated with individual differences in musical reward, music perception, musical training, or emotional regulation strategies. To do so, we collected detailed (~1 h-long) surveys during the initial peak of shelter-in-place order implementation (May-June 2020) from over a thousand individuals across different Countries in which the pandemic was especially devastating at that time: the USA, Spain, and Italy. Our findings indicate that, on average, people spent more time in music-related activities while under confinement than they had before the pandemic. Notably, this change in behavior was dependent on individual differences in music reward sensitivity, and in emotional regulation strategies. Finally, the type of musical activity with which individuals engaged was further associated with the degree to which they used music as a way to regulate stress, to address the lack of social interaction (especially the individuals more concerned about the risk of contracting the virus), or to cheer themselves up (especially those who were more worried about the pandemic consequences). Identifying which music-related activities have been particularly sought for by the population as a means for coping with such heightened uncertainty and stress, and understanding the individual differences that underlie said propensities are crucial to implementing personalized music-based interventions that aim to reduce stress, anxiety, and depression symptoms.