Timing Patterns in the Extended Basal Ganglia System.

The human brain is a constructive organ. It generates predictions to modulate its functioning and continuously adapts to a dynamic environment. Increasingly, the temporal dimension of motor and non-motor behaviour is recognised as a key component of this predictive bias. Nevertheless, the intricate interplay of the neural mechanisms that encode, decode and evaluate temporal information to give rise to a sense of time and control over sensorimotor timing remains largely elusive. Among several brain systems, the basal ganglia have been consistently linked to interval- and beat-based timing operations. Considering the tight embedding of the basal ganglia into multiple complex neurofunctional networks, it is clear that they have to interact with other proximate and distal brain systems. While the primary target of basal ganglia output is the thalamus, many regions connect to the striatum of the basal ganglia, their main input relay. This establishes widespread connectivity, forming the basis for first- and second-order interactions with other systems implicated in timing such as the cerebellum and supplementary motor areas. However, next to this structural interconnectivity, additional functions need to be considered to better understand their contribution to temporally predictive adaptation. To this end, we develop the concept of interval-based patterning, conceived as a temporally explicit hierarchical sequencing operation that underlies motor and non-motor behaviour as a common interpretation of basal ganglia function.

Uncovering hidden resting state dynamics: A new perspective on auditory verbal hallucinations.

In the absence of sensory stimulation, the brain transits between distinct functional networks. Network dynamics such as transition patterns and the time the brain stays in each network link to cognition and behavior and are subject to much investigation. Auditory verbal hallucinations (AVH), the temporally fluctuating unprovoked experience of hearing voices, are associated with aberrant resting state network activity. However, we lack a clear understanding of how different networks contribute to aberrant activity over time. An accurate characterization of latent network dynamics and their relation to neurocognitive changes necessitates methods that capture the sub-second temporal fluctuations of the networks' functional connectivity signatures. Here, we critically evaluate the assumptions and sensitivity of several approaches commonly used to assess temporal dynamics of brain connectivity states in M/EEG and fMRI research, highlighting methodological constraints and their clinical relevance to AVH. Identifying altered brain connectivity states linked to AVH can facilitate the detection of predictive disease markers and ultimately be valuable for generating individual risk profiles, differential diagnosis, targeted intervention, and treatment strategies.

Emotional salience but not valence impacts anterior cingulate cortex conflict processing.

Stimuli that evoke emotions are salient, draw attentional resources, and facilitate situationally appropriate behavior in complex or conflicting environments. However, negative and positive emotions may motivate different response strategies. For example, a threatening stimulus might evoke avoidant behavior, whereas a positive stimulus may prompt approaching behavior. Therefore, emotional stimuli might either elicit differential behavioral responses when a conflict arises or simply mark salience. The present study used functional magnetic resonance imaging to investigate valence-specific emotion effects on attentional control in conflict processing by employing an adapted flanker task with neutral, negative, and positive stimuli. Slower responses were observed for incongruent than congruent trials. Neural activity in the dorsal anterior cingulate cortex was associated with conflict processing regardless of emotional stimulus quality. These findings confirm that both negative and positive emotional stimuli mark salience in both low (congruent) and high (incongruent) conflict scenarios. Regardless of the conflict level, emotional stimuli deployed greater attentional resources in goal directed behavior.

Expectancy changes the self-monitoring of voice identity.

Self-voice attribution can become difficult when voice characteristics are ambiguous, but functional magnetic resonance imaging (fMRI) investigations of such ambiguity are sparse. We utilized voice-morphing (self-other) to manipulate (un-)certainty in self-voice attribution in a button-press paradigm. This allowed investigating how levels of self-voice certainty alter brain activation in brain regions monitoring voice identity and unexpected changes in voice playback quality. FMRI results confirmed a self-voice suppression effect in the right anterior superior temporal gyrus (aSTG) when self-voice attribution was unambiguous. Although the right inferior frontal gyrus (IFG) was more active during a self-generated compared to a passively heard voice, the putative role of this region in detecting unexpected self-voice changes during the action was demonstrated only when hearing the voice of another speaker and not when attribution was uncertain. Further research on the link between right aSTG and IFG is required and may establish a threshold monitoring voice identity in action. The current results have implications for a better understanding of the altered experience of self-voice feedback in auditory verbal hallucinations.

Timing the "magical number seven": Presentation rate and regularity affect verbal working memory performance.

The informative value of time and temporal structure often remains neglected in cognitive assessments. However, next to information about stimulus identity we can exploit temporal ordering principles, such as regularity, periodicity, or grouping to generate predictions about the timing of future events. Such predictions may improve cognitive performance by optimising adaptation to dynamic stimuli. Here, we investigated the influence of temporal structure on verbal working memory by assessing immediate recall performance for aurally presented digit sequences (forward digit span) as a function of standard (1000 ms stimulus-onset-asynchronies, SOAs), short (700 ms), long (1300 ms) and mixed (700-1300 ms) stimulus timing during the presentation phase. Participant's digit spans were lower for short and mixed SOA presentation relative to standard SOAs. This confirms an impact of temporal structure on the classic "magical number seven," suggesting that working memory performance can in part be regulated through the systematic application of temporal ordering principles.

The role of the cerebellum in adaptation: ALE meta-analyses on sensory feedback error.

It is widely accepted that unexpected sensory consequences of self-action engage the cerebellum. However, we currently lack consensus on where in the cerebellum, we find fine-grained differentiation to unexpected sensory feedback. This may result from methodological diversity in task-based human neuroimaging studies that experimentally alter the quality of self-generated sensory feedback. We gathered existing studies that manipulated sensory feedback using a variety of methodological approaches and performed activation likelihood estimation (ALE) meta-analyses. Only half of these studies reported cerebellar activation with considerable variation in spatial location. Consequently, ALE analyses did not reveal significantly increased likelihood of activation in the cerebellum despite the broad scientific consensus of the cerebellum's involvement. In light of the high degree of methodological variability in published studies, we tested for statistical dependence between methodological factors that varied across the published studies. Experiments that elicited an adaptive response to continuously altered sensory feedback more frequently reported activation in the cerebellum than those experiments that did not induce adaptation. These findings may explain the surprisingly low rate of significant cerebellar activation across brain imaging studies investigating unexpected sensory feedback. Furthermore, limitations of functional magnetic resonance imaging to probe the cerebellum could play a role as climbing fiber activity associated with feedback error processing may not be captured by it. We provide methodological recommendations that may guide future studies.

The Timing of Regular Sequences: Production, Perception, and Covariation.

The temporal structure of behavior provides information that allows the tracking of temporal regularity in the sensory and sensorimotor domains. In turn, temporal regularity allows the generation of predictions about upcoming events and to adjust behavior accordingly. These mechanisms are essential to ensure behavior beyond the level of mere reaction. However, efficient temporal processing is required to establish adequate internal representations of temporal structure. The current study used two simple paradigms, namely, finger-tapping at a regular self-chosen rate (spontaneous motor tempo) and ERPs of the EEG (EEG/ERP) recorded during attentive listening to temporally regular and irregular "oddball" sequences to explore the capacity to encode and use temporal regularity in production and perception. The results show that specific aspects of the ability to time a regular sequence of events in production covary with the ability to time a regular sequence in perception, probably pointing toward the engagement of domain-general mechanisms.

Time-travel to "A review and proposal for a model of sensory predictability in auditory language perception".

Since its inception 60 years ago, the mission of Cortex has been to foster a better understanding of cognition and the relationship between the nervous system, behavior in general, and mental processes in particular. Almost 15 years ago, we submitted "a review and proposal" along these lines to the journal, in which we sought to integrate two components that are not often discussed together, namely the basal ganglia and syntactic language functions (Kotz et al., 2009). One of the main motivations was to find potential explanations for two relatively straightforward earlier empirical observations: (i) electroencephalographic event-related potential responses (EEG/ERPs) known to be sensitive markers of syntactic violations in auditory language processing were found to be absent in persons with focal basal ganglia lesions (Friederici et al., 1999; Frisch et al., 2003; Kotz et al., 2003), and (ii) temporally regular rhythmic tone sequences presented before language stimuli were found to compensate for this effect (Kotz et al., 2005; Kotz & Gunter, 2015; Kotz & Schmidt-Kassow, 2015). The critical question was how to reconcile these specific components, the basal ganglia typically associated with motor behavior and language-related syntactic processes, under one hood to foster a better understanding of how the basal ganglia system contributes to auditory language processing. This core question was the starting point for further own research and trying to solve it, unsurprisingly, led to many more questions and rather few answers. It also changed perspectives and established collaborative efforts, sometimes in unsuspected ways and directions. In light of the journal's anniversary, we therefore want to take this exciting opportunity for some time travel, looking back at our original conception while linking it to more recent considerations, thereby providing some insights that might be useful for future research.

Revisiting alpha resting state dynamics underlying hallucinatory vulnerability: Insights from Hidden semi-Markov Modeling.

BACKGROUND: Resting state (RS) brain activity is inherently non-stationary. Hidden semi-Markov Models (HsMM) can characterize continuous RS data as a sequence of recurring and distinct brain states along with their spatio-temporal dynamics. NEW METHOD: Recent explorations suggest that HsMM state dynamics in the alpha frequency band link to auditory hallucination proneness (HP) in non-clinical individuals. The present study aimed to replicate these findings to elucidate robust neural correlates of hallucinatory vulnerability. Specifically, we aimed to investigate the reproducibility of HsMM states across different data sets and within-data set variants as well as the replicability of the association between alpha brain state dynamics and HP. RESULTS: We found that most brain states are reproducible in different data sets, confirming that the HsMM characterized robust and generalizable EEG RS dynamics on a sub-second timescale. Brain state topographies and temporal dynamics of different within-data set variants showed substantial similarities and were robust against reduced data length and number of electrodes. However, the association with HP was not directly reproducible across data sets. COMPARISON WITH EXISTING METHODS: The HsMM optimally leverages the high temporal resolution of EEG data and overcomes time-domain restrictions of other state allocation methods. CONCLUSION: The results indicate that the sensitivity of brain state dynamics to capture individual variability in HP may depend on the data recording characteristics and individual variability in RS cognition, such as mind wandering. Future studies should consider that the order in which eyes-open and eyes-closed RS data are acquired directly influences an individual's attentional state and generation of spontaneous thoughts, and thereby might mediate the link to hallucinatory vulnerability.

Hallucination Proneness Alters Sensory Feedback Processing in Self-voice Production.

BACKGROUND: Sensory suppression occurs when hearing one's self-generated voice, as opposed to passively listening to one's own voice. Quality changes in sensory feedback to the self-generated voice can increase attentional control. These changes affect the self-other voice distinction and might lead to hearing voices in the absence of an external source (ie, auditory verbal hallucinations). However, it is unclear how changes in sensory feedback processing and attention allocation interact and how this interaction might relate to hallucination proneness (HP). STUDY DESIGN: Participants varying in HP self-generated (via a button-press) and passively listened to their voice that varied in emotional quality and certainty of recognition-100% neutral, 60%-40% neutral-angry, 50%-50% neutral-angry, 40%-60% neutral-angry, 100% angry, during electroencephalography (EEG) recordings. STUDY RESULTS: The N1 auditory evoked potential was more suppressed for self-generated than externally generated voices. Increased HP was associated with (1) an increased N1 response to the self- compared with externally generated voices, (2) a reduced N1 response for angry compared with neutral voices, and (3) a reduced N2 response to unexpected voice quality in sensory feedback (60%-40% neutral-angry) compared with neutral voices. CONCLUSIONS: The current study highlights an association between increased HP and systematic changes in the emotional quality and certainty in sensory feedback processing (N1) and attentional control (N2) in self-voice production in a nonclinical population. Considering that voice hearers also display these changes, these findings support the continuum hypothesis.

Macaque monkeys and humans sample temporal regularities in the acoustic environment.

Many animal species show comparable abilities to detect basic rhythms and produce rhythmic behavior. Yet, the capacities to process complex rhythms and synchronize rhythmic behavior appear to be species-specific: vocal learning animals can, but some primates might not. This discrepancy is of high interest as there is a putative link between rhythm processing and the development of sophisticated sensorimotor behavior in humans. Do our closest ancestors show comparable endogenous dispositions to sample the acoustic environment in the absence of task instructions and training? We recorded EEG from macaque monkeys and humans while they passively listened to isochronous equitone sequences. Individual- and trial-level analyses showed that macaque monkeys' and humans' delta-band neural oscillations encoded and tracked the timing of auditory events. Further, mu- (8-15 Hz) and beta-band (12-20 Hz) oscillations revealed the superimposition of varied accentuation patterns on a subset of trials. These observations suggest convergence in the encoding and dynamic attending of temporal regularities in the acoustic environment, bridging a gap in the phylogenesis of rhythm cognition.

Validation of the Dutch Sensory Gating Inventory (D-SGI): Psychometric properties and a Confirmatory factor analysis.

The Sensory Gating Inventory (SGI) is an established self-report questionnaire that is used to assess the capacity for filtering redundant or irrelevant environmental stimuli. Translation and cross-cultural validation of the SGI are necessary to make this tool available to Dutch speaking populations. This study, therefore, aimed to design and validate a Dutch Sensory Gating Inventory (D-SGI). To this end, a forward-backward translation was performed and 469 native Dutch speakers filled in the questionnaire. A confirmatory factor analysis assessed the psychometric properties of the D-SGI. Additionally, test-retest reliability was measured. Results confirmed satisfactory similarity between the original English SGI and the D-SGI in terms of psychometric properties for the factor structure. Internal consistency and discriminant validity were also satisfactory. Overall test-retest reliability was excellent (ICC = 0.91, p < 0.001, 95% CI [0.87-0.93]). These findings confirm that the D-SGI is a psychometrically sound self-report measure that allows assessing the phenomenological dimensions of sensory gating in Dutch. Moreover, the D-SGI is publicly available. This establishes the D-SGI as a new tool for the assessment of sensory gating dimensions in general- and clinical Dutch speaking populations.

Sensory gating functions of the auditory thalamus: Adaptation and modulations through noise-exposure and high-frequency stimulation in rats.

The medial geniculate body (MGB) of the thalamus is an obligatory relay for auditory processing. A breakdown of adaptive filtering and sensory gating at this level may lead to multiple auditory dysfunctions, while high-frequency stimulation (HFS) of the MGB might mitigate aberrant sensory gating. To further investigate the sensory gating functions of the MGB, this study (i) recorded electrophysiological evoked potentials in response to continuous auditory stimulation, and (ii) assessed the effect of MGB HFS on these responses in noise-exposed and control animals. Pure-tone sequences were presented to assess differential sensory gating functions associated with stimulus pitch, grouping (pairing), and temporal regularity. Evoked potentials were recorded from the MGB and acquired before and after HFS (100 Hz). All animals (unexposed and noise-exposed, pre- and post-HFS) showed gating for pitch and grouping. Unexposed animals also showed gating for temporal regularity not found in noise-exposed animals. Moreover, only noise-exposed animals showed restoration comparable to the typical EP amplitude suppression following MGB HFS. The current findings confirm adaptive thalamic sensory gating based on different sound characteristics and provide evidence that temporal regularity affects MGB auditory signaling.

Functional dissociation of pre-SMA and SMA-proper in temporal processing.

The ability to assess temporal structure is crucial in order to adapt to an ever-changing environment. Increasing evidence suggests that the supplementary motor area (SMA) is involved in both sensory and sensorimotor processing of temporal structure. However, it is not entirely clear whether the structural differentiation of the SMA translates into functional specialization, and how the SMA relates to other systems that engage in temporal processing, namely the cerebellum and cortico-striatal circuits. Anatomically, the SMA comprises at least two subareas, the rostral pre-SMA and the caudal SMA-proper. Each displays a characteristic pattern of connections to motor and non-motor structures. Crucially, these connections establish a potential hub among cerebellar and cortico-striatal systems, possibly forming a dedicated subcortico-cortical temporal processing network. To further explore the functional role of each SMA subarea, we performed a meta-analysis of functional neuroimaging studies by contrasting activations according to whether they linked with either sensory, sensorimotor, sequential, non-sequential, explicit, non-explicit, subsecond, or suprasecond temporal processing. This procedure yielded a set of functional differences, which mirror the rostro-caudal anatomical dimension. Activations associated with sensory, non-sequential, and suprasecond temporal processing tend to locate to the rostral SMA, while the opposite is true for the caudal SMA. These findings confirm a functional dissociation of pre-SMA and SMA-proper in temporal processing.

Cognition through the lens of a body-brain dynamic system.

Continuous interactions between physiological body-brain rhythms influence how individuals act, perceive, and evaluate their environment. Despite increasing interest, the intricate interface between breathing, cardiac, neural rhythms, and cognitive function remains poorly understood. By evaluating current theoretical and empirical implications, we derive an integrative framework of a 'body-brain dynamic system' that combines a hidden hierarchical structure with dynamical state transitions. We propose that body-brain signals can interchangeably drive state- and task-specific coupling mechanisms which influence cognitive functions. The dynamical nature of this framework parallels the intrinsic variability of human behavior, and ultimately aims at better understanding how individuals act in and adapt to a dynamically changing environment.

Hypersensitivity to passive voice hearing in hallucination proneness.

Voices are a complex and rich acoustic signal processed in an extensive cortical brain network. Specialized regions within this network support voice perception and production and may be differentially affected in pathological voice processing. For example, the experience of hallucinating voices has been linked to hyperactivity in temporal and extra-temporal voice areas, possibly extending into regions associated with vocalization. Predominant self-monitoring hypotheses ascribe a primary role of voice production regions to auditory verbal hallucinations (AVH). Alternative postulations view a generalized perceptual salience bias as causal to AVH. These theories are not mutually exclusive as both ascribe the emergence and phenomenology of AVH to unbalanced top-down and bottom-up signal processing. The focus of the current study was to investigate the neurocognitive mechanisms underlying predisposition brain states for emergent hallucinations, detached from the effects of inner speech. Using the temporal voice area (TVA) localizer task, we explored putative hypersalient responses to passively presented sounds in relation to hallucination proneness (HP). Furthermore, to avoid confounds commonly found in in clinical samples, we employed the Launay-Slade Hallucination Scale (LSHS) for the quantification of HP levels in healthy people across an experiential continuum spanning the general population. We report increased activation in the right posterior superior temporal gyrus (pSTG) during the perception of voice features that positively correlates with increased HP scores. In line with prior results, we propose that this right-lateralized pSTG activation might indicate early hypersensitivity to acoustic features coding speaker identity that extends beyond own voice production to perception in healthy participants prone to experience AVH.

The role of the medial geniculate body of the thalamus in the pathophysiology of tinnitus and implications for treatment.

Tinnitus is an auditory sensation in the absence of actual external stimulation. Different clinical interventions are used in tinnitus treatment, but only few patients respond to available options. The lack of successful tinnitus treatment is partly due to the limited knowledge about the mechanisms underlying tinnitus. Recently, the auditory part of the thalamus has gained attention as a central structure in the neuropathophysiology of tinnitus. Increased thalamic spontaneous firing rate, bursting activity and oscillations, alongside an increase of GABAergic tonic inhibition have been shown in the auditory thalamus in animal models of tinnitus. In addition, clinical neuroimaging studies have shown structural and functional thalamic changes with tinnitus. This review provides a systematic overview and discussion of these observations that support a central role of the auditory thalamus in tinnitus. Based on this approach, a neuromodulative treatment option for tinnitus is proposed.

A Protocol to Investigate Deep Brain Stimulation for Refractory Tinnitus: From Rat Model to the Set-Up of a Human Pilot Study.

BACKGROUND: Chronic tinnitus can have an immense impact on quality of life. Despite recent treatment advances, many tinnitus patients remain refractory to them. Preclinical and clinical evidence suggests that deep brain stimulation (DBS) is a promising treatment to suppress tinnitus. In rats, it has been shown in multiple regions of the auditory pathway that DBS can have an alleviating effect on tinnitus. The thalamic medial geniculate body (MGB) takes a key position in the tinnitus network, shows pathophysiological hallmarks of tinnitus, and is readily accessible using stereotaxy. Here, a protocol is described to evaluate the safety and test the therapeutic effects of DBS in the MGB in severe tinnitus sufferers. METHODS: Bilateral DBS of the MGB will be applied in a future study in six patients with severe and refractory tinnitus. A double-blinded, randomized 2 × 2 crossover design (stimulation ON and OFF) will be applied, followed by a period of six months of open-label follow-up. The primary focus is to assess safety and feasibility (acceptability). Secondary outcomes assess a potential treatment effect and include tinnitus severity measured by the Tinnitus Functional Index (TFI), tinnitus loudness and distress, hearing, cognitive and psychological functions, quality of life, and neurophysiological characteristics. DISCUSSION: This protocol carefully balances risks and benefits and takes ethical considerations into account. This study will explore the safety and feasibility of DBS in severe refractory tinnitus, through extensive assessment of clinical and neurophysiological outcome measures. Additionally, important insights into the underlying mechanism of tinnitus and hearing function might be revealed. TRIAL REGISTRATION: ClinicalTrials.gov NCT03976908 (6 June 2019).

Did you get the beat? Late proficient French-German learners extract strong-weak patterns in tonal but not in linguistic sequences.

Event-related potential (ERP) data in French and German have shown that metric violations (i.e. incorrectly stressed words) in a sentence elicit a P600. Furthermore, French speakers find it difficult to discriminate stimuli that vary in word stress position and have been labelled as "stress deaf." In the current study we investigated (i) whether French late learners of German can perceive deviations of a regular strong-weak stress pattern (trochee) in German sentences, and (ii) whether the same subjects differ in their electrophysiological response from German monolinguals in a non-linguistic "subjective rhythmization" paradigm. Irrespective of the native language both groups show similar results in the latter paradigm in which isochronous stimulus trains are subjectively converted into a binary strong-weak grouped percept (trochee). However, we report differences between native and non-native speakers of German in the sentence paradigm. In contrast to German native speakers French late learners of German fail to show a P600 component in response to deviations from a regular trochaic stress pattern, although attention was directed to the metric pattern of the sentences. The current data suggest that French stress deafness selectively affects the perception of a strong-weak pattern in sentences while strong-weak grouping of non-linguistic sequences is not language specific. The results imply that linguistic and non-linguistic grouping do not rely on the same neural mechanisms.

Temporo-cerebellar connectivity underlies timing constraints in audition.

The flexible and efficient adaptation to dynamic, rapid changes in the auditory environment likely involves generating and updating of internal models. Such models arguably exploit connections between the neocortex and the cerebellum, supporting proactive adaptation. Here, we tested whether temporo-cerebellar disconnection is associated with the processing of sound at short timescales. First, we identify lesion-specific deficits for the encoding of short timescale spectro-temporal non-speech and speech properties in patients with left posterior temporal cortex stroke. Second, using lesion-guided probabilistic tractography in healthy participants, we revealed bidirectional temporo-cerebellar connectivity with cerebellar dentate nuclei and crura I/II. These findings support the view that the encoding and modeling of rapidly modulated auditory spectro-temporal properties can rely on a temporo-cerebellar interface. We discuss these findings in view of the conjecture that proactive adaptation to a dynamic environment via internal models is a generalizable principle.