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.

Cross-frequency coupling in cortico-hippocampal networks supports the maintenance of sequential auditory information in short-term memory.

It has been suggested that cross-frequency coupling in cortico-hippocampal networks enables the maintenance of multiple visuo-spatial items in working memory. However, whether this mechanism acts as a global neural code for memory retention across sensory modalities remains to be demonstrated. Intracranial EEG data were recorded while drug-resistant patients with epilepsy performed a delayed matched-to-sample task with tone sequences. We manipulated task difficulty by varying the memory load and the duration of the silent retention period between the to-be-compared sequences. We show that the strength of theta-gamma phase amplitude coupling in the superior temporal sulcus, the inferior frontal gyrus, the inferior temporal gyrus, and the hippocampus (i) supports the short-term retention of auditory sequences; (ii) decodes correct and incorrect memory trials as revealed by machine learning analysis; and (iii) is positively correlated with individual short-term memory performance. Specifically, we show that successful task performance is associated with consistent phase coupling in these regions across participants, with gamma bursts restricted to specific theta phase ranges corresponding to higher levels of neural excitability. These findings highlight the role of cortico-hippocampal activity in auditory short-term memory and expand our knowledge about the role of cross-frequency coupling as a global biological mechanism for information processing, integration, and memory in the human brain.

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.

Distinct brain dynamics and networks for processing short and long auditory time intervals.

Psychophysical studies suggest that time intervals above and below 1.2 s are processed differently in the human brain. However, the neural underpinnings of this dissociation remain unclear. Here, we investigate whether distinct or common brain networks and dynamics support the passive perception of short (below 1.2 s) and long (above 1.2 s) empty time intervals. Twenty participants underwent an EEG recording during an auditory oddball paradigm with .8- and 1.6-s standard time intervals and deviant intervals either shorter (early) or longer (delayed) than the standard interval. We computed the auditory ERPs for each condition at the sensor and source levels. We then performed whole brain cluster-based permutation statistics for the CNV, N1 and P2, components, testing deviants against standards. A CNV was found only for above 1.2 s intervals (delayed deviants), with generators in temporo-parietal, SMA, and motor regions. Deviance detection of above 1.2 s intervals occurred during the N1 period over fronto-central sensors for delayed deviants only, with generators in parietal and motor regions. Deviance detection of below 1.2 s intervals occurred during the P2 period over fronto-central sensors for delayed deviants only, with generators in primary auditory cortex, SMA, IFG, cingulate and parietal cortex. We then identified deviance related changes in directed connectivity using bivariate Granger causality to highlight the networks dynamics associated with interval processing above and below 1.2. These results suggest that distinct brain dynamics and networks support the perception of time intervals above and below 1.2 s.

Auditory cortex and beyond: Deficits in congenital amusia.

Congenital amusia is a neuro-developmental disorder of music perception and production, with the observed deficits contrasting with the sophisticated music processing reported for the general population. Musical deficits within amusia have been hypothesized to arise from altered pitch processing, with impairments in pitch discrimination and, notably, short-term memory. We here review research investigating its behavioral and neural correlates, in particular the impairments at encoding, retention, and recollection of pitch information, as well as how these impairments extend to the processing of pitch cues in speech and emotion. The impairments have been related to altered brain responses in a distributed fronto-temporal network, which can be observed also at rest. Neuroimaging studies revealed changes in connectivity patterns within this network and beyond, shedding light on the brain dynamics underlying auditory cognition. Interestingly, some studies revealed spared implicit pitch processing in congenital amusia, showing the power of implicit cognition in the music domain. Building on these findings, together with audiovisual integration and other beneficial mechanisms, we outline perspectives for training and rehabilitation and the future directions of this research domain.

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.

Tonal structures benefit short-term memory for real music: Evidence from non-musicians and individuals with congenital amusia.

Congenital amusia is a neurodevelopmental disorder of music processing, which includes impaired pitch memory, associated to abnormalities in the right fronto-temporal network. Previous research has shown that tonal structures (as defined by the Western musical system) improve short-term memory performance for short tone sequences (in comparison to atonal versions) in non-musician listeners, but the tonal structures only benefited response times in amusic individuals. We here tested the potential benefit of tonal structures for short-term memory with more complex musical material. Congenital amusics and their matched non-musician controls were required to indicate whether two excerpts were the same or different. Results confirmed impaired performance of amusic individuals in this short-term memory task. However, most importantly, both groups of participants showed better memory performance for tonal material than for atonal material. These results revealed that even amusics' impaired short-term memory for pitch shows classical characteristics of short-term memory, that is the mnemonic benefit of structure in the to-be-memorized material. The findings show that amusic individuals have acquired some implicit knowledge of regularities of their culture, allowing for implicit processing of tonal structures, which benefits to memory even for complex material.

Cross-Frequency Brain Network Dynamics Support Pitch Change Detection.

Processing auditory sequences involves multiple brain networks and is crucial to complex perception associated with music appreciation and speech comprehension. We used time-resolved cortical imaging in a pitch change detection task to detail the underlying nature of human brain network activity, at the rapid time scales of neurophysiology. In response to tone sequence presentation to the participants, we observed slow inter-regional signaling at the pace of tone presentations (2-4 Hz) that was directed from auditory cortex toward both inferior frontal and motor cortices. Symmetrically, motor cortex manifested directed influence onto auditory and inferior frontal cortices via bursts of faster (15-35 Hz) activity. These bursts occurred precisely at the expected latencies of each tone in a sequence. This expression of interdependency between slow/fast neurophysiological activity yielded a form of local cross-frequency phase-amplitude coupling in auditory cortex, which strength varied dynamically and peaked when pitch changes were anticipated. We clarified the mechanistic relevance of these observations in relation to behavior by including a group of individuals afflicted by congenital amusia, as a model of altered function in processing sound sequences. In amusia, we found a depression of inter-regional slow signaling toward motor and inferior frontal cortices, and a chronic overexpression of slow/fast phase-amplitude coupling in auditory cortex. These observations are compatible with a misalignment between the respective neurophysiological mechanisms of stimulus encoding and internal predictive signaling, which was absent in controls. In summary, our study provides a functional and mechanistic account of neurophysiological activity for predictive, sequential timing of auditory inputs.SIGNIFICANCE STATEMENT Auditory sequences are processed by extensive brain networks, involving multiple systems. In particular, fronto-temporal brain connections participate in the encoding of sequential auditory events, but so far, their study was limited to static depictions. This study details the nature of oscillatory brain activity involved in these inter-regional interactions in human participants. It demonstrates how directed, polyrhythmic oscillatory interactions between auditory and motor cortical regions provide a functional account for predictive timing of incoming items in an auditory sequence. In addition, we show the functional relevance of these observations in relation to behavior, with data from both normal hearing participants and a rare cohort of individuals afflicted by congenital amusia, which we considered here as a model of altered function in processing sound sequences.

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.

Distinct sensitivity to spectrotemporal modulation supports brain asymmetry for speech and melody.

Does brain asymmetry for speech and music emerge from acoustical cues or from domain-specific neural networks? We selectively filtered temporal or spectral modulations in sung speech stimuli for which verbal and melodic content was crossed and balanced. Perception of speech decreased only with degradation of temporal information, whereas perception of melodies decreased only with spectral degradation. Functional magnetic resonance imaging data showed that the neural decoding of speech and melodies depends on activity patterns in left and right auditory regions, respectively. This asymmetry is supported by specific sensitivity to spectrotemporal modulation rates within each region. Finally, the effects of degradation on perception were paralleled by their effects on neural classification. Our results suggest a match between acoustical properties of communicative signals and neural specializations adapted to that purpose.

Decoding Task-Related Functional Brain Imaging Data to Identify Developmental Disorders: The Case of Congenital Amusia.

Machine learning classification techniques are frequently applied to structural and resting-state fMRI data to identify brain-based biomarkers for developmental disorders. However, task-related fMRI has rarely been used as a diagnostic tool. Here, we used structural MRI, resting-state connectivity and task-based fMRI data to detect congenital amusia, a pitch-specific developmental disorder. All approaches discriminated amusics from controls in meaningful brain networks at similar levels of accuracy. Interestingly, the classifier outcome was specific to deficit-related neural circuits, as the group classification failed for fMRI data acquired during a verbal task for which amusics were unimpaired. Most importantly, classifier outputs of task-related fMRI data predicted individual behavioral performance on an independent pitch-based task, while this relationship was not observed for structural or resting-state data. These results suggest that task-related imaging data can potentially be used as a powerful diagnostic tool to identify developmental disorders as they allow for the prediction of symptom severity.

Specialized neural dynamics for verbal and tonal memory: fMRI evidence in congenital amusia.

Behavioral and neuropsychological studies have suggested that tonal and verbal short-term memory are supported by specialized neural networks. To date however, neuroimaging investigations have failed to confirm this hypothesis. In this study, we investigated the hypothesis of distinct neural resources for tonal and verbal memory by comparing typical nonmusician listeners to individuals with congenital amusia, who exhibit pitch memory impairments with preserved verbal memory. During fMRI, amusics and matched controls performed delayed-match-to-sample tasks with tones and words and perceptual control tasks with the same stimuli. For tonal maintenance, amusics showed decreased activity in the right auditory cortex, inferior frontal gyrus (IFG) and dorso-lateral-prefrontal cortex (DLPFC). Moreover, they exhibited reduced right-lateralized functional connectivity between the auditory cortex and the IFG during tonal encoding and between the IFG and the DLPFC during tonal maintenance. In contrasts, amusics showed no difference compared with the controls for verbal memory, with activation in the left IFG and left fronto-temporal connectivity. Critically, we observed a group-by-material interaction in right fronto-temporal regions: while amusics recruited these regions less strongly for tonal memory than verbal memory, control participants showed the reversed pattern (tonal > verbal). By benefitting from the rare condition of amusia, our findings suggest specialized cortical systems for tonal and verbal short-term memory in the human brain.

Driving working memory with frequency-tuned noninvasive brain stimulation.

Frequency-tuned noninvasive brain stimulation is a recent approach in cognitive neuroscience that involves matching the frequency of transcranially applied electromagnetic fields to that of specific oscillatory components of the underlying neurophysiology. The objective of this method is to modulate ongoing/intrinsic brain oscillations, which correspond to rhythmic fluctuations of neural excitability, to causally change behavior. We review the impact of frequency-tuned noninvasive brain stimulation on the research field of human working memory. We argue that this is a powerful method to probe and understand the mechanisms of memory functions, targeting specifically task-related oscillatory dynamics, neuronal representations, and brain networks. We report the main behavioral and neurophysiological outcomes published to date, in particular, how functionally relevant oscillatory signatures in signal power and interregional connectivity yield causal changes of working memory abilities. We also present recent developments of the technique that aim to modulate cross-frequency coupling in polyrhythmic neural activity. Overall, the method has led to significant advances in our understanding of the mechanisms of systems neuroscience, and the role of brain oscillations in cognition and behavior. We also emphasize the translational impact of noninvasive brain stimulation techniques in the development of therapeutic approaches.

Selective Entrainment of Theta Oscillations in the Dorsal Stream Causally Enhances Auditory Working Memory Performance.

The implication of the dorsal stream in manipulating auditory information in working memory has been recently established. However, the oscillatory dynamics within this network and its causal relationship with behavior remain undefined. Using simultaneous MEG/EEG, we show that theta oscillations in the dorsal stream predict participants' manipulation abilities during memory retention in a task requiring the comparison of two patterns differing in temporal order. We investigated the causal relationship between brain oscillations and behavior by applying theta-rhythmic TMS combined with EEG over the MEG-identified target (left intraparietal sulcus) during the silent interval between the two stimuli. Rhythmic TMS entrained theta oscillation and boosted participants' accuracy. TMS-induced oscillatory entrainment scaled with behavioral enhancement, and both gains varied with participants' baseline abilities. These effects were not seen for a melody-comparison control task and were not observed for arrhythmic TMS. These data establish theta activity in the dorsal stream as causally related to memory manipulation. VIDEO ABSTRACT.

Discrimination of tonal and atonal music in congenital amusia: The advantage of implicit tasks.

Congenital amusia is a neurodevelopmental disorder of music perception and production, which has been attributed to a major deficit in pitch processing. While most studies and diagnosis tests have used explicit investigation methods, recent studies using implicit investigation approaches have revealed some unimpaired pitch structure processing in congenital amusia. The present study investigated amusic individuals' processing of tonal structures (e.g., musical structures respecting the Western tonal system) via three different questions. Amusic participants and their matched controls judged tonal versions (original musical excerpts) and atonal versions (with manipulated pitch content to remove tonal structures) of 12 musical pieces. For each piece, participants answered three questions that required judgments from different perspectives: an explicit structural one, a personal, emotional one and a more social one (judging the perception of others). Results revealed that amusic individuals' judgments differed between tonal and atonal versions. However, the question type influenced the extent of the revealed structure processing: while amusic individuals were impaired for the question requiring explicit structural judgments, they performed as well as their matched controls for the two other questions. Together with other recent studies, these findings suggest that congenital amusia might be related to a disorder of the conscious access to music processing rather than music processing per se.

Altered intrinsic connectivity of the auditory cortex in congenital amusia.

Congenital amusia, a neurodevelopmental disorder of music perception and production, has been associated with abnormal anatomical and functional connectivity in a right frontotemporal pathway. To investigate whether spontaneous connectivity in brain networks involving the auditory cortex is altered in the amusic brain, we ran a seed-based connectivity analysis, contrasting at-rest functional MRI data of amusic and matched control participants. Our results reveal reduced frontotemporal connectivity in amusia during resting state, as well as an overconnectivity between the auditory cortex and the default mode network (DMN). The findings suggest that the auditory cortex is intrinsically more engaged toward internal processes and less available to external stimuli in amusics compared with controls. Beyond amusia, our findings provide new evidence for the link between cognitive deficits in pathology and abnormalities in the connectivity between sensory areas and the DMN at rest.

Pitch-Responsive Cortical Regions in Congenital Amusia.

Congenital amusia is a lifelong deficit in music perception thought to reflect an underlying impairment in the perception and memory of pitch. The neural basis of amusic impairments is actively debated. Some prior studies have suggested that amusia stems from impaired connectivity between auditory and frontal cortex. However, it remains possible that impairments in pitch coding within auditory cortex also contribute to the disorder, in part because prior studies have not measured responses from the cortical regions most implicated in pitch perception in normal individuals. We addressed this question by measuring fMRI responses in 11 subjects with amusia and 11 age- and education-matched controls to a stimulus contrast that reliably identifies pitch-responsive regions in normal individuals: harmonic tones versus frequency-matched noise. Our findings demonstrate that amusic individuals with a substantial pitch perception deficit exhibit clusters of pitch-responsive voxels that are comparable in extent, selectivity, and anatomical location to those of control participants. We discuss possible explanations for why amusics might be impaired at perceiving pitch relations despite exhibiting normal fMRI responses to pitch in their auditory cortex: (1) individual neurons within the pitch-responsive region might exhibit abnormal tuning or temporal coding not detectable with fMRI, (2) anatomical tracts that link pitch-responsive regions to other brain areas (e.g., frontal cortex) might be altered, and (3) cortical regions outside of pitch-responsive cortex might be abnormal. The ability to identify pitch-responsive regions in individual amusic subjects will make it possible to ask more precise questions about their role in amusia in future work.

Impaired encoding of rapid pitch information underlies perception and memory deficits in congenital amusia.

Recent theories suggest that the basis of neurodevelopmental auditory disorders such as dyslexia or specific language impairment might be a low-level sensory dysfunction. In the present study we test this hypothesis in congenital amusia, a neurodevelopmental disorder characterized by severe deficits in the processing of pitch-based material. We manipulated the temporal characteristics of auditory stimuli and investigated the influence of the time given to encode pitch information on participants' performance in discrimination and short-term memory. Our results show that amusics' performance in such tasks scales with the duration available to encode acoustic information. This suggests that in auditory neuro-developmental disorders, abnormalities in early steps of the auditory processing can underlie the high-level deficits (here musical disabilities). Observing that the slowing down of temporal dynamics improves amusics' pitch abilities allows considering this approach as a potential tool for remediation in developmental auditory disorders.

Impaired short-term memory for pitch in congenital amusia.

Congenital amusia is a neuro-developmental disorder of music perception and production. The hypothesis is that the musical deficits arise from altered pitch processing, with impairments in pitch discrimination (i.e., pitch change detection, pitch direction discrimination and identification) and short-term memory. The present review article focuses on the deficit of short-term memory for pitch. Overall, the data discussed here suggest impairments at each level of processing in short-term memory tasks; starting with the encoding of the pitch information and the creation of the adequate memory trace, the retention of the pitch traces over time as well as the recollection and comparison of the stored information with newly incoming information. These impairments have been related to altered brain responses in a distributed fronto-temporal network, associated with decreased connectivity between these structures, as well as in abnormalities in the connectivity between the two auditory cortices. In contrast, amusic participants׳ short-term memory abilities for verbal material are preserved. These findings show that short-term memory deficits in congenital amusia are specific to pitch, suggesting a pitch-memory system that is, at least partly, separated from verbal memory. This article is part of a Special Issue entitled SI: Auditory working memory.

Altered retrieval of melodic information in congenital amusia: insights from dynamic causal modeling of MEG data.

Congenital amusia is a neuro-developmental disorder that primarily manifests as a difficulty in the perception and memory of pitch-based materials, including music. Recent findings have shown that the amusic brain exhibits altered functioning of a fronto-temporal network during pitch perception and short-term memory. Within this network, during the encoding of melodies, a decreased right backward frontal-to-temporal connectivity was reported in amusia, along with an abnormal connectivity within and between auditory cortices. The present study investigated whether connectivity patterns between these regions were affected during the short-term memory retrieval of melodies. Amusics and controls had to indicate whether sequences of six tones that were presented in pairs were the same or different. When melodies were different only one tone changed in the second melody. Brain responses to the changed tone in "Different" trials and to its equivalent (original) tone in "Same" trials were compared between groups using Dynamic Causal Modeling (DCM). DCM results confirmed that congenital amusia is characterized by an altered effective connectivity within and between the two auditory cortices during sound processing. Furthermore, right temporal-to-frontal message passing was altered in comparison to controls, with notably an increase in "Same" trials. An additional analysis in control participants emphasized that the detection of an unexpected event in the typically functioning brain is supported by right fronto-temporal connections. The results can be interpreted in a predictive coding framework as reflecting an abnormal prediction error sent by temporal auditory regions towards frontal areas in the amusic brain.