Research ReportThe internal time keeper: Causal evidence for the role of the cerebellum in anticipating regular acoustic events
Introduction
Over the last decades, the dominant view on the functional role of the human cerebellum has refined considerably: While in an early phase of neuroscience research, specifically the coordination and control of voluntary movements was associated to the cerebellum (Holmes, 1939), cumulative findings pointed out the involvement of the cerebellum in a variety of non-motor functions such as mental rotation (Picazio, Oliveri, Koch, Caltagirone, & Petrosini, 2013), sequence learning (Gao et al., 1996), working memory (Stoodley, Valera, & Schmahmann, 2012), attention (Mannarelli et al., 2016), language (Mariën et al., 2013), and emotion (Schmahmann, 2009b). Furthermore, sensory impairments after cerebellum lesions in clinical populations provided further ample evidence that this structure has also influence on sensory perception. However, the broad variety of functions associated to the cerebellum as well as the observation that cerebellar lesions do not cause a complete loss of sensory, cognitive, and motor function but rather subtle impairments (Baumann et al., 2015; Gao et al., 1996) suggest a more overarching modulating cerebellar function. Moreover, the cerebellum receives information from virtually every sensory system and their associative areas (Baillieux, Smet, Paquier, De Deyn, & Mariën, 2008; Ramnani, 2006; Schmahmann, 2009a), indicating a fundamental and domain-general cerebellar involvement.
In an attempt to accommodate the large body of findings gained from lesion and brain imaging studies, the domain-general processing of event-based temporal information in the millisecond range has been proposed as a key function of the cerebellum (Buhusi & Meck, 2005; Ivry, 1996, 1997). According to this view, the cerebellum establishes a precise representation of the temporal relation between salient events, irrespective of the incoming modality (Bareš et al., 2018; Buhusi & Meck, 2009; Ivry, 1996; Kotz, Stockert, & Schwartze, 2014). Via a cortico-ponto-cerebellar pathway, this information is forwarded to cortical areas (Ramnani, 2006) which allows to modulate the activation level of cortical neurons relevant for the processing of the predicted incoming stimulus (Molinari, Restuccia, & Leggio, 2009). Thereby, the pre-alerted neurons can respond optimally to the anticipated stimulus. Accordingly, the cerebellum is often termed as the brains' pace maker or time keeper (Paton & Buonomano, 2018; Tracy, Faro, Mohamed, Pinsk, & Pinus, 2000) and contributes thereby as a computational hub to the interplay between attention, prediction, and preparation (Bareš et al., 2018; Baumann et al., 2015; Courchesne & Allen, 1997).
One viable approach to quantify proper anticipation of a future event and, thus, exploitation of temporal regularity is to assess the (electrophysiological) response to an expected target stimulus, e.g., the P3b. The posterior-peaking P3b, probably one of the most often investigated auditory event related potential (ERP), can be reliably evoked by means of a ‘classic’ oddball paradigm. Here, a target stimulus embedded in a series of more frequently presented and physically differing standard stimuli occurs (Buhusi & Meck, 2005; Polich & Criado, 2006; Polich & Kok, 1995). Typically, this oddball is task relevant in that participants have to count the number of presented targets or to give a feedback via motor-response whenever a target stimulus occurs. In the dominant view, the P3b reflects the completion of the controlled processing of a series of events signaling the time point when the stimulus has been sufficiently processed to be accurately perceived as task relevant (Halgren, Marinkovic, & Chauvel, 1998). Not mutually exclusive, the P3b has also been claimed to reflect the activation of an acquired “sensory-motor template” in that the successful perception of the task-relevant target stimulus is linked to a specific reaction, e.g., counting or motor-response (Asanowicz et al., 2020; Verleger, Jaśkowski, & Wascher, 2005). Furthermore, the P3b has been demonstrated as sensitive for parameters shaping the saliency of the target stimulus (due to e.g., the probability of occurrence, degree of physical deviation from the standard stimulus, etc.) (Duncan-Johnson & Donchin, 1977; Nieuwenhuis, De Geus, & Aston-Jones, 2011; Roth, Ford, Stephen, & Kopell, 1976). In other terms, the more distinct the target and, thus, the better distinguishable from the standard, the stronger the P3b-response. Importantly, there is compelling evidence that the P3b is sensitive to temporal regularities in which the series of (standard and target) acoustic stimuli are presented: target tones embedded in a regular temporal structure evoke stronger P3b-amplitudes compared to when they are presented at random intervals (Otterbein, Abel, Heinemann, Kaiser, & Schmidt-Kassow, 2012; Schwartze, Rothermich, Schmidt-Kassow, & Kotz, 2011). The P3b has therefore been claimed as an objective marker representing the detecting of “when” the acoustic target occurs (Schwartze, Farrugia, & Kotz, 2013). Accordingly, the successful anticipation of the occurring task-relevant target stimulus, due to exploitation of the temporal regularity in that acoustic stimuli occur, increases the P3b-response. To date, there is broad consensus on the involvement of a multitude of cortical and subcortical structures in the generation of the P3b. Typically, the hippocampus and fronto-temporo-parietal cortical areas are associated with the P3b (Halgren et al., 1998; Polich & Criado, 2006). However, others have suggested that also the motor cortex (Ikeda et al., 1999; Ragazzoni et al., 2019) as well as subcortical areas such as the insula (Kiehl et al., 2005), basal ganglia (Rektor et al., 2003), and specific nuclei of the thalamus (Rektor, Kanovsky, Bares, Louvel, & Lamarche, 2001) are associated to the P3b. Thus, while activation of the cerebellum most likely is not directly reflected in changes of the P3b, cerebellar activation can modulate this component via cerebello-thalamo-cortical and cortico-ponto-cerebellar pathways (Palesi et al., 2017).
Finally, in patients with cerebellar lesions the ability of exploiting and detecting acoustic temporal regularities has been shown as being markedly impaired – indexed by systematically reduced P3b-amplitudes – while the mere sensory-related recognition of the standards and targets, as reflected by the N2-ERP, is unaffected (Kotz et al., 2014; Nozaradan, Schwartze, Obermeier, & Kotz, 2017). These findings provided direct indications of the role of the cerebellum in temporal processing, temporal pattern recognition, and, the anticipation of upcoming stimuli. However, studies inferring from cerebral pathologies to the function of the affected structure come with the significant drawback of substantial variability and heterogeneity with regard to 1) the underlying pathology that, most likely, not only causes the function loss of interest but might affect also other cognitive functions which could act as mediators, 2) the size and spatial specificity of the lesion and, 3) the time passed since the damage was acquired or since the onset of the degeneration. These aspects raise the question about whether and to what extend neuroplasticity effects, i.e., the recruitment of other initially task-irrelevant structures took place to compensate for impairments and, in consequence, complicate direct causal evidence drawn from lesion studies.
Non-invasive brain stimulation is able to overcome these limitations due to its high spatial specificity. The most often used technique is the application of weak electrical currents by means of transcranial direct current stimulation (tDCS). Similar as for the application to the neocortex it is proposed that, depending on the stimulation parameter, the application over the cerebellum either leads to an excitatory (anodal tDCS) or inhibitory (cathodal tDCS) effect on cerebellar functions (Galea, Jayaram, Ajagbe, & Celnik, 2009; Oldrati & Schutter, 2018). Previous data compellingly demonstrated the spatial specificity of cerebellum-tDCS without affecting brainstem or cortico-motor activation (Galea et al., 2009; Grimaldi et al., 2015; Parazzini et al., 2014; Rampersad et al., 2014), as well as its safety and feasibility (van Dun, Bodranghien, Mariën, & Manto, 2016). Therefore, cerebellum-tDCS provides an optimal alternative to infer the causal role of the cerebellum in perception and cognition in healthy participants.
Importantly, similar to the neocortex, there is evidence pointing on a functional lateralization in the cerebellum. While executive functions such as divided attention, working memory, and inhibition are located in the left hemisphere (Gottwald, 2004) timing, as reflected by the estimation of a given interval, is a function of the right cerebellar hemisphere (Tracy et al., 2000). Of note, also the processing of specific acoustic features is lateralized. At the cortical level, the processing of spectral information has been allocated to the right auditory cortex while the left homologue is dedicated to temporal information (Poeppel, 2003; Zatorre & Belin, 2001). A similar division of labor has been observed in the cerebellum (Callan, Kawato, Parsons, & Turner, 2007). However, due to the crossing of the afferent fibers from the sensory cortices in the pons, the lateralization in the cerebellum is reversed compared to the (auditory) cortex. Accordingly, in the present work, we applied tDCS over the cerebellums' right hemisphere.
We here compared the P3b in a condition where subjects can exploit temporal regularity and anticipate the occurrence of a target stimulus (regular oddball task) with a condition where stimuli are presented at random intervals, thus, preventing the anticipation of future events (irregular oddball task). We hypothesized that cathodal tDCS over the cerebellum impairs temporal processing and, thereby, the ability to predict the timing of an upcoming task-relevant target stimulus, as reflected by decreased P3b-amplitudes in the regular oddball task. In contrast, anodal tDCS is hypothesized to improve these processes and, thus, increases P3b-amplitudes. Since the irregular oddball task does not allow to exploit any temporal regularity, we expected the tDCS-modulation exclusively in the regular but not in the irregular oddball task. To assess potential sensory effects of cerebellar-tDCS, we furthermore investigated sensory ERPs reflecting (pre-attentive) acoustic processing of stimulus-specific physical features i.e., the P50, the N1 (Näätänen, Kujala, & Winkler, 2010; Näätänen & Picton, 1987), and the N2 (Kotz et al., 2014; Schwartze et al., 2013) hypothesizing that cerebellum-tDCS, irrespective of polarity and task, does not affect these sensory-related ERPs.
Section snippets
Participants
Twenty normally hearing participants in the age range of 20–30 years (11 female, M = 23.15, SD = 2.0) took part in the present experiment. Sample size was determined based on previous studies assessing the effect of cerebellar-tDCS in humans (Ferrucci et al., 2012, 2008). Three particpants were left-handers. None of the participants reported any neurological or psychiatric disease. Prior to the experiment they all gave their informed consent according to the declaration of Helsinki. The present
Behavioral results
Behavioral performance was high in all conditions (>95% correct responses, see Table 2). The RM-ANOVA revealed a significant main effect of the factor task (F(1,15) = 5.273, p = .036, η2 = .26) due to less correct responses in the irregular compared to the regular condition. Neither the main effect of the factor stimulation nor the interaction stimulation × task reached significance (both, p > .10).
Electrophysiological results
The RM-ANOVA on the P3b-amplitude neither revealed a main effect stimulation, nor a main effect
Discussion
In the present study we applied tDCS to investigate the functional relevance of the cerebellum for the processing of temporal regularities within a series of acoustic stimuli. Participants were presented with two auditory oddball paradigms with either regular or irregular temporal contingencies while anodal, cathodal or sham tDCS was applied over the right cerebellar hemisphere. Following evidence from lesion studies we hypothesized that cathodal tDCS will interfere with, while anodal tDCS will
Conclusion
In the present work, we applied tDCS over the right cerebellar hemisphere to investigate the role of the human cerebellum in the perception of timing and the anticipation of future acoustic events. When cathodal tDCS was applied, we found reduced P3b-responses only to target stimuli presented at regular interstimulus intervals, thus, in a condition allowing to exploit temporal regularity. Thereby, our data mirror previous observations in clinical populatios and provide, for the first time,
Data availability
The conditions of our ethics approval do not permit public archiving of the electrophysiological and behavioral data supporting the conclusion of this study. Readers seeking access to the data should contact the corresponding author. Requestors must complete a formal data sharing agreement to obtain the data.
The experimental code used in this study is available at https://osf.io/zmd6x/. No part of the study procedures or analyses was pre-registered prior to the research being conducted.
We
Author contributions
Katharina S. Rufener: planned the study, analyzed the data, wrote the original draft, prepared the artwork. Astrid-Maria Husemann: collected the data, analyzed the data, wrote the original draft. Tino Zaehle: planned the study, wrote the original draft. All authors participated in interpreting the results, writing the manuscript and approved the final version.
Funding
This work was funded by the Deutsche Forschungsgemeinschaft (ZA 626/2-1) and the Leibniz Association (SAS-2015-LIN-LWC).
Open practices
The study in this article earned an Open Materials badge for transparent practices. Readers seeking access to the data should contact the corresponding authors, Katharina S. Rufener. Requestors must complete a formal data sharing agreement to obtain the data. All data necessary and sufficient to replicate all data processing steps and analyses will be shared to requestors who meet these requirements.
Declaration of competing interest
The authors declare no competing financial interests.
Acknowledgment
This research was supported by the Deutsche Forschungsgemeinschaft (ZA 626/2-1) and the Leibniz Association (SAS-2015-LIN-LWC).
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