Abstract
Increasing evidence from neuroimaging and clinical studies has demonstrated cerebellar involvement in social cognition components, including the mentalizing process. The aim of this study was to apply transcranial direct current stimulation (tDCS) to modulate cerebellar excitability to investigate the role the cerebellum plays in mental state recognition. Forty-eight healthy subjects were randomly assigned to different groups in which anodal, cathodal, or sham tDCS (2 mA for 20 min) was delivered centering the electrode on the vermis to stimulate the posterior portion of the cerebellum. The ability to attribute mental states to others was tested before and after tDCS using a digital version of the 'Reading the Mind in the Eyes test', which includes visual perceptive and motor stimuli as control conditions. Correct response and reaction times (RTs) were recorded. The results revealed a significant reduction in RTs between the baseline and post-stimulation sessions after cerebellar anodal tDCS only for mental state stimuli (Wilcoxon test p = 0.00055), whereas no significant effect was found in the cathodal or sham conditions or for visual perceptive and motor stimuli. Overall, our study suggests that cerebellar anodal tDCS might selectively improve mental state recognition and constitute an effective strategy to positively modulate the mentalizing process.
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Introduction
Over the last decades, the cerebellum has been recognized as a critical structure not only in motor control but also in cognitive and affective functioning1,2,3,4,5,6. More recently, increasing evidence has extended the role of this brain region in the social cognition domain7,8,9,10,11. Specifically, several neuroimaging studies have shown cerebellar activation in social cognition tasks12,13,14,15 and its functional connections with brain regions belonging to the ‘social brain network’ (i.e., the default mode network)16,17,18,19,20,21.
Clinical studies in patients with cerebellar damage demonstrated specific social cognition difficulties, including impairments in basic emotions and mental state recognition3,11,22,23, suggesting that alterations in specific cerebellar regions could be responsible for the corresponding neurobiological underpinnings22. Very recently, Frosch and colleagues8 described the literature regarding cerebellar contributions to social cognition and adaptive prediction in individuals with and without autism.
The emerging idea is that the cerebellum is a good candidate for the predictive function that allows humans to be more adaptive in social interactions24 thanks to its neuroanatomical connections with the limbic and associative areas25,26,27.
In this view, the cerebellum might act in the social cognitive domain as a modulator and optimizer of the projection brain areas activity, in a very similar way in which it does in the motor and cognitive domains4,7,11,17.
Despite the data reported above, the role played by the cerebellum in social behavior still needs to be better defined. To address this issue, it is crucial to exclude possible confounding effects resulting from to other methodological approaches. For instance, in functional magnetic resonance imaging (fMRI) studies, cerebellar activation during social cognition tasks is often detected together with other brain regions12,17,18,20 making it difficult to test its role in specific aspects of information processing. Moreover, cerebellar damage does not often occur in isolation in patient studies28,29, making conclusions about direct region-specific effects difficult to draw. Finally, the life changes associated with cerebellar disease onset may themselves produce alterations in social behavior, affecting everyday life as well as compliance with pharmacological and rehabilitative treatments30.
In this framework, brain neuromodulation techniques, including transcranial direct current stimulation (tDCS), represent a very advantageous approach to study cerebellar involvement in specific social behavior processes31.
Indeed, tDCS is a noninvasive brain stimulation technique used to pass a direct current through the brain of subjects via surface electrodes fixed to the head. It allows in vivo manipulation of neuronal excitability in humans in a polarity-specific manner and induces functional changes in the cerebral and cerebellar cortices32,33. This increasingly popular neuroscientific technique offers the opportunity to investigate the behavioral consequences of regional reduction or enhancement in neuronal excitability in healthy individuals34,35,36,37,38. Unlike patient studies, the noninvasive stimulation allows us to investigate the role of a specific brain region in behavioral tasks without confounding factors, such as pharmacological treatment, or concomitant damage to other cerebral brain regions39.
While it is most frequently applied to the cerebral cortex, tDCS was recently used to modulate cerebellar excitability37,38. Indeed, in recent years several modeling studies have investigated the distributions, strength and electrode montage-dependent variability in electric fields induced by cerebellar tDCS40,41,42, and freely available pipelines have been presented to optimize the stimulation of cerebellar lobules involved in different cognitive and motor functions43,44. These studies demonstrated that the electric field generated during tDCS when applied over the cerebellum effectively reaches its posterior portion with relatively little functional spread to neighboring regions45 because of the location of the cerebellum in the posterior cranial fossa.
Currently, this noninvasive brain stimulation technique is providing greater insight into the contribution of the cerebellum in cognitive and social-affective domains31,46,47.
Specifically, a recent study explored the effects of cerebellar tDCS on the prediction of social and physical events48, showing specific involvement of the cerebellum in forming expectations related to social events, but not to physical events. Moreover, a previous study by Ferrucci and colleagues49 showed an effect of both anodal and cathodal cerebellar tDCS on the recognition of basic emotions. However, to the best of our knowledge, no studies have used tDCS applied over the cerebellum to investigate its role in the mentalizing process.
A fundamental aspect of social cognition is the capacity to estimate the mental state of other people in order to understand and predict their behavior. This ability is known as the Theory of Mind (ToM)50,51, or mentalizing process, and implies both lower-level processes based on action recognition and “emotional contagion52” and a higher-level conceptual capacity to adopt the perspective of others to infer their mental state53.
Since in mindreading the first contact between agents is the eyes54, a task frequently used in clinical and experimental studies to investigate this ability is the Reading the Mind in the Eyes Test (RMET), which requires subjects to “tune in” to the mental state of the actor’s eye expression at a rapid and automatic level to make the correct choice55.
Indeed, although very recent studies hypothesized that this task is likely to assess lower-level processes such as perceptual emotion recognition rather than genuine theory-of-mind abilities (mentalizing criteria)56,57, the RMET remains the most used test of theory of mind.
Following the original Baron-Cohen’s description55, the RMET involves the first stage of ToM: attribution of a relevant mental state (e.g., compassion), regardless of its content (e.g., compassion for her mother’s loss). This task has been shown to activate a key mentalizing region in the cerebral cortex, the temporoparietal junction58. Interestingly, in line with findings by Hoche and colleagues23, in recent studies, we found impaired performance in RMET in patients with cerebellar pathology and autism3,22,59. A significant correlation has been shown between RMET scores and indices of microstructural alteration in the superior cerebellar peduncles and reduced cerebellar gray matter volumes in patients affecterd by spinocerebellar ataxia type 222.
Thus, we speculated that the structural alterations in posterior portions of the cerebellum (i.e., Crus I/II), which are known to be linked to advanced ToM features18,60, may structurally and functionally affect key mentalizing areas in the cerebral cortex, leading to ToM impairments in individuals with cerebellar pathologies or autism.
In the present study, we combined cerebellar tDCS with an ad hoc digital version of the RMET to further understand cerebellar involvement in the first stage of the mentalizing process.
We started from the idea that the cerebellum acts in the domain of mentalization through its interaction with the brain areas involved in such processes17,18,19,20. Therefore, we used an extracephalic montage in which the active electrode was centered over the cerebellum (median line, 2 cm below the inion) and the reference electrode over the right deltoid muscle to stimulate the posterior cerebellum in line with the modeling study by Parazzini and colleagues45.
This montage avoids confounding effects because an electrode with opposite polarity placed over the scalp could interfere with the activity of brain areas belonging to such networks, not allowing us to isolate the effect of cerebellar stimulation on task performance40,49,61.
Based on the possible excitatory and inhibitory influences of anodal and cathodal tDCS on cerebellar cortical excitability we also hypothesized that anodal and cathodal polarity increases and reduces, respectively, optimization of the mentalizing process. We tested this hypothesis in 48 healthy individuals using a randomized, sham-controlled, double-blind, between-subjects design.
Results
None of the participants reported adverse effects of tDCS as evidenced by an ad hoc questionnaire administered at the end of every experimental session.
No differences between groups were found with respect to age, education, or the Edinburgh Handedness Inventory (EHI)62 as assessed by the Kruskal–Wallis test. A lower proportion of females was assigned to the anodal group [5/16 (36%)] compared to the cathodal group [9/16 (56%)] and to the sham group [12/16 (75%)], as tested by the chi-square test (see Table 1). For each group, no differences between baseline and post-stimulation sessions were detected in any of the VAS scores63 (anxiety, mood and fatigue) (Table 2).
At baseline, the Kruskal–Wallis one-way analysis of variance showed no differences among the three groups for the correct response (MS stimuli: H = 1.39; p = 0.49; V-P stimuli: H = 0.82; p = 0.66; V-M stimuli: H = 3.48; p = 0.17) or RTs in each stimulus type (MS stimuli: H = 2.99; p = 0.22; V-P stimuli: H = 5.84; p = 0.05; V-M stimuli: H = 2.58; p = 0.27).
Moreover, no differences in the number of correct responses were found between baseline and post-stimulation sessions in any group or for any stimuli, as assessed by the Wilcoxon test (see Table 2 for statistical details).
Notably, an improvement in the processing of mental state stimuli was evident after anodal stimulation, as shown by the significant decrease in RTs between the baseline (mean ± standard deviation: 3446 ± 697) and post-stimulation (mean ± standard deviation: 3007 ± 629) sessions for MS stimuli (Wilcoxon test, p = 0.00055).
A reduction in RTs between the baseline (mean ± standard deviation: 3805 ± 649) and post-stimulation (mean ± standard deviation: 3460 ± 631) phases was also evident in the cathodal group but was not significant after Bonferroni correction (Wilcoxon test, p = 0.01). No significant differences in RTs were observed between baseline and post-stimulation sessions for V-P or V-M stimuli in either the anodal or cathodal group. Again, no significant differences were found in RTs of the sham group for any stimulus type. The RMET results are detailed in Table 2 and illustrated in Fig. 1.
Discussion
In recent years, noninvasive brain stimulation has been increasingly used to study cerebellar involvement in motor control and cognitive functions37. However, only a few studies have used this approach to investigate the cerebellar role in social behavior31 focusing on basic emotion recognition by the processing of facial expressions49,64 and on the prediction of social events48. In particular, Ferrucci and colleagues40 used a standard facial emotion recognition task, focusing on basic emotions such as anger, happiness, and sadness, while Oldrati and colleagues48 investigated cerebellar involvement in forming expectations related to the social events.
Unlike the abovementioned studies, we used the RMET as a measure of adult ‘mentalizing’. As described by Baron-Cohen et al.55, this advanced theory of mind test involves matching terms describing complex mental states to pictures showing only the eye region. In particular, to perform the task correctly subjects have to “match the eyes in each picture to examples of eye-region expressions stored in memory and seen in the context of particular mental states to arrive at a judgment of which word the eyes most closely match55”. This task involves only the first stage of attribution of the theory of mind, namely attribution of the relevant mental state, but not inferring the content of that mental state which represents the second level.
The present study extends the current knowledge in this field, since it demonstrates for the first time the causal effect of cerebellar neuromodulation on the first stage of the mentalizing process.
Specifically, we found that the anodal tDCS delivered over the posterior cerebellum enhanced the processes subtending the ability to recognize the mental state of another person as measured by RMET. We observed the same tendency when cathodal polarity was applied, even though it did not reach statistical significance after Bonferroni correction for multiple comparisons.
Interestingly, the effect on mental state processing was not correlated with a general speeding up, given that cerebellar stimulation did not modify the elaboration speed in terms of RTs when the participants processed perceptual or visuo-motor stimuli.
In our task, the subjects had to read and correctly comprehend the single adjectives, abilities in which a role for the cerebellum has been described65. However, previous studies have shown that anodal cerebellar tDCS does not modulate reading ability and language processing performance in healthy individuals66,67.
Moreover, in agreement with previous cerebellar neuromodulation studies49,64, we did not observe any changes in anxiety, mood or fatigue after cerebellar stimulation.
Although we started from the assumption that increased and reduced cerebellar excitability (due to anodal and cathodal stimulation) could increase and reduce, respectively, optimization of the mentalizing process, we found a similar effect for the two polarity types in the present study. This observation agrees with the lack of polarity-specific tDCS-induced changes observed in cognitive/affective tasks47,49.
One possible explanation for the lack of polarity specificity of cerebellar tDCS comes from general physiological mechanisms that have been known for years, by which a functional inhibition/disruption in any excitable tissue can be obtained with both depolarization and hyperpolarization68. For instance, classic neurophysiological experiments demonstrated that axonal conduction can be blocked, even for several hours, by depolarization ("depolarizing" block) and by hyperpolarization ("hyperpolarizing" or "anodal" block), leading to the same decreased excitability of the stimulated tissue68.
This lack of polarity specificity could also be applied to the cerebellum, since both hyperpolarization and depolarization of the Purkinje cells can lead to a block of cerebellar cortex excitability45,69. Furthermore, the effect on cerebellar excitability modulation could be even more complex, considering the cerebellar cortico-nuclear interactions. Specifically, Purkinje cells are well known to inhibit the deep cerebellar nuclei, which in turn have an excitatory action on the cerebral cortex through the cerebello-thalamo-cortical pathway25,70. Therefore, at baseline, the Purkinje cells exert an inhibitory tone on the projection brain areas, namely cerebellar brain inhibition71,72. Accordingly, any changes in Purkinje cell excitability, either positive or negative, might significantly influence the efficiency of information transmission to the projection brain areas73, through the action exerted on the deep cerebellar nuclei. Therefore, in our experiment, blockade of cerebellar cortex excitability might lead to disinhibition of the deep cerebellar nuclei, facilitating the activity of cerebral areas involved in the mentalizing process with which the cerebellum is connected25,27,70. In this way, cerebellar tDCS improves the response efficiency to mental state stimuli.
The cerebellar role in the mentalizing process
Our study should be seen in the context of the increasing interest of the scientific community in the key role of the cerebellum in social behavior7.
A main component of an adaptive social behavior is the ability to infer others’ mental states, in order to anticipate future interactions74. For a long time, the primary neurobiological underpinning of this dynamic ability has been localized in the cerebral cortex, including the brain areas known as the mentalizing network75,76. More recently, the focus has been extended to the cerebellum7 and fMRI studies have shown that specific cerebellar areas are activated during mirroring and mentalizing tasks12,76, leading to a description of new specific cerebro-cerebellar pathways.
More specifically, studies on healthy individuals and clinical populations have identified the posterior cerebellar region (i.e., Crus II) as a key area within the mentalizing network7,18. This cerebellar area was also identified as functionally specialized in social mentalizing and emotional self-experiences, showing a distinct functional connectivity with cortical mentalizing areas during mentalizing tasks involving others’ beliefs and traits7.
Consistent with these findings, in the present study we used an extracephalic montage to target the posterior cerebellum as described in the modeling study by Parazzini and colleagues45, avoiding direct interference with the activity of other brain areas belonging to the mentalizing network and allowing us to isolate the effect of cerebellar stimulation on task performance32,33,40,49,61.
What we observed was that tDCS over the posterior cerebellum induced changes in the first stage of the mental state recognition process as measured by the RMET.
Interestingly, our results not only provide new evidence on the direct link between cerebellar functioning and the mentalizing process but also add new insights into the possible mechanisms that are implemented by the cerebellum to modulate the mentalizing process.
As reported in the introduction, we started with the idea that the cerebellum acts in the social domain in the same way as it does in the sensorimotor domain. Indeed this brain structure performs a predictive action based on forward internal models, signalizing deviations from the attended outcomes to the projection cerebral areas4. This operational mode is implemented by the constant modulation that the cerebellum exerts on brain regions involved in the processing of information related to specific functional domains25.
Accordingly, in the case of the RMET used in the present study, the cerebellum acts to implicitly match the external information, such as the expression of the eyes, with the internal model of eye region expression linked to previous emotional experiences to guarantee an immediate judgment about the mental state of others.
When cerebellar excitability is modulated by tDCS, the required fast and continuous exchange of information between the external stimuli and the internal model is facilitated, thus speeding up the mindreading processes. Our results are also in line with recent studies in patients with cerebellar pathology, in which impairment in mental state recognition measured by the RMET was reported3,23. This impairment has been linked to the absence of cerebellar modulation action on the cerebral cortex projection areas involved in mentalizing. In fact, when cerebellar damage is present, the required fast and continuous exchange of information between the external stimuli and the internal model might be affected, thus interfering with the process speed3,22.
Clinical implications and future directions
The present study describes new possibilities for the application of cerebellar tDCS, not only in patients with cerebellar damage but also in those clinical conditions in which this brain structure is implicated. Indeed, as extensively reported in the literature, the cerebellum has been described as involved in the pathogenesis of psychiatric disorders (i.e., schizophrenia) and neurodevelopmental conditions (i.e., autism spectrum disorders) characterized by social behavior difficulties77,78. Structural and functional cerebellar alterations have been reported in these conditions77,79,80,81. In line with this, knowing more about the cerebellar tDCS-induced changes in mental state recognition ability would aid in developing new therapeutic protocols in these patient populations82.
The primary strength of this approach is that it does not generate discomfort and can be easily combined with cognitive-behavioral therapy in those pathological conditions that present with pharmacological treatment resistance83. All in all, noninvasive cerebellar stimulation may represent a promising strategy for improving residual cerebellar circuit functioning and as a complementary tool for rehabilitation protocols in patients with cerebellar dysfunction84. However, we have to consider that the after-effects of tDCS over the cerebellum are highly variable among individuals. Additionally, the stimulation effects could be different depending on whether a behavior is tested during (on-line effects) or after (off-line effects) the stimulation session.
These aspects highlight the need to better understand the individual factors that determine the efficacy of this technique (e.g., the baseline neural excitability, cognitive capacity, or personality traits) and to test this cerebellar tDCS protocol in a larger and more homogeneous sample.
Before drawing conclusions, we must consider some limitations.
First, we are aware that the small sample size for each group (n = 16) might affect the statistical power of the analyses. Moreover, the nonnormal distribution of our sample and the tDCS effect variability due to the difference in skin impedance among the participants might limit the power of the present conclusion due to the use of nonparametric statistics. Indeed, it is well known that the efficacy of neuromodulation depends not only on the positioning/design of the electrode montage but also on interindividual variability owing to anatomical differences41, as well as neurophysiological ones based on cytoarchitecture85.
To obviate this limitation, we applied the Bonferroni correction for multiple comparisons, after which only the significant effect in the anodal condition survived.
Second, the lack of computational modeling does not allow us to predict the electric field induced in our targeted cerebellar areas by the selected tDCS montage. Therefore, future studies should include a specific computational approach to guarantee more accurate targeting of the region of interest.
Finally, the lack of functional neuroimaging administration does not allow validation of the results of the behavioral task to demonstrate the possible cerebellar tDCS effect on cerebello-cortical mentalizing networks. Therefore, studies employing noninvasive brain stimulation with functional imaging86 data would improve our understanding of the effect of cerebellar stimulation on participating brain networks.
Conclusions
The present study demonstrates that anodal cerebellar tDCS enhances the processes underlying the ability to recognize the mental state of another person and that the cerebellum directly contributes to the first stage of mental state recognition. Our findings reinforce and extend current knowledge on the role of the cerebellum in the mentalizing process, and add new insights into the possible application of cerebellar tDCS in the social cognition domain. In this view, the cerebellum could be considered a promising target of noninvasive neurostimulation in the treatment of various impairments of social cognition reported in both neurological and psychiatric disorders associated with cerebellar dysfunction. We believe that these aspects are crucial in clinical practice, and we are confident that our results have clinical and translational potential in terms of treatment implementation.
Methods
Participants
Forty-eight tDCS-naïve healthy right-handed volunteers with no history of neurological or psychiatric conditions participated in the study (demographic characteristics are reported in Table 1). The sample size for our between-subjects experiment was determined a-priori considering the mean sample size of previous studies reported in a recent meta-analysis on the tDCS effects on non-motor functions47.
Handedness was confirmed using the Edinburgh Handedness Inventory (EHI)62. Before recruitment, a neurological objective examination was performed including a questionnaire to verify the suitability for tDCS administration.
None of the participants reported treatments for neuropsychiatric and brain-related disorders or took medications or illicit drugs that could affect the central nervous system. Their intellectual level as assessed by Raven’s 47 progressive matrices was in the normal range (score below the cut-off value of 18.96)87.
A double-blinded, randomized, placebo-controlled study was conducted, and each participant was randomly assigned to different groups in which anodal, cathodal, or sham tDCS was delivered over the cerebellum. All groups were well-matched with respect to age, education and intellectual level as reported in Table 1.
A digital version of the RMET55 and three self-evaluation ‘Visual Analogue Scale’ (VAS)63 assessments for mood, anxiety and fatigue were administered before and 35 min after the end of the tDCS stimulation over the cerebellum, since previous studies showed that the major effect appeared after this time-delay49,61. The stimulation type was not known to the experimenter responsible for the testing procedures.
All participants signed an informed consent form in accordance with the Declaration of Helsinki, and the experimental procedures were approved by the Ethical Committee of the IRCCS Santa Lucia Foundation of Rome (Prot. CE/PROG.570).
Cerebellar tDCS protocol
The real stimulation was delivered by a DC stimulator (BrainSTIM, EMS s.r.l, Bologna) connected to a pair of saline-soaked sponge electrodes (6 × 7) at 2 mA intensity (current density = 0.06 mA/cm2) for 20 min49. The active electrode was centered over the cerebellum (median line, 2 cm below the inion) and the reference electrode placed over the right deltoid muscle to stimulate the posterior cerebellum as reported in the modeling study by Parazzini and colleagues45.
This extracephalic montage guarantees the highest electric field and current density below the stimulating electrode with only slight spread to other structures (e.g., occipital cortex and brainstem)45. Moreover, it has already been used in previous cerebellar tDCS studies to avoid any confounding effects due to the action of the opposite polarity electrode on other brain areas and was found to be effective in modulating facial emotion recognition processing and other cognitive tasks in a sample of healthy adults40,49,61.
Stimulation was applied with anodal or cathodal polarity, referring to the electrode placed on the cerebellum or in a placebo mode (sham).
In the real condition, the stimulation was ramped down (15 s) after 20 min of 2 mA tDCS. In the sham condition, the ramp up period was followed by 15 s of real stimulation after which the intensity was ramped down to 0 mA (Fig. 2). This procedure allows the participants to feel the characteristic tingling sensations in the vicinity of the electrodes for a brief period of time, thus enhancing the plausibility of the control condition. In the sham group, half of the participants underwent stimulation with the anodic electrode over the cerebellum, and the other half underwent stimulation with the anodic electrode over the right deltoid.
During the stimulation session, the participants were not involved in specific cognitively demanding activities and the investigator was present throughout the experimental session to check for adverse effects or any technical issues. At the end of every tDCS session, participants completed an ad hoc questionnaire to test for possible adverse effects, including headache, nausea, and impaired balance. Details about the tDCS protocol and montage are also reported in Fig. 3.
Behavioral tasks
Reading the Mind in the Eyes Test (RMET)–digital version
The RMET consists of 36 photographs of the eyes of different actors (19 men and 17 women) illustrating an emotionally charged or neutral mental state (MS–stimuli). As in the original version by Baron-Cohen and colleagues55, the subject is required to choose from 4 words (displayed below the photograph) the one that best describes what the person in the photos is thinking or feeling.
In the present study, we used a computerized version of the RMET in which the original photos (MS stimuli) were randomly administered together with two kinds of control stimuli to evaluate visual perception (V-P) (trials = 36) and visual motor (V-M) (trials = 36) factors. All the stimuli were presented on a PC screen (size: 38 cm × 21.6 cm; 17 inches) in Italian 85.
In our experiment, subjects sat comfortably approximately 60 cm in front of the PC monitor and used the C, V, B, and N keys of the keyboard to respond. The left-hand middle and index fingers were positioned on the C and V keys, respectively, and the right-hand index and middle fingers on the B and N keys, respectively.
In the MS trials, 4 adjectives appeared in a four-cell grid placed under each photo, and the subject was required to press the key corresponding to the position in which the chosen adjective appeared. In the V-P trials, the words ‘man’ and ‘woman’ appear in two of the four grid cells placed under each photo, and the subject was required to judge the actor’s gender from the eyes, pressing the key corresponding to the position in which the chosen adjective appeared in the grid. For the V-M trials, a black dot appeared in one of the four grid cells, and the subject was required to press the key corresponding to the position in which the dot appeared.
The three types of stimuli were randomly administered with an intertrial interval of 6 s and were preannounced by a cross appearing in the middle of the screen for 500 ms. Overall, the administration of the digital RMET test takes approximately 10 min.
The subject had to respond as quickly and accurately as possible and did not receive error feedback.
The task was administered before and 35 min after the end of the stimulation session using a PC with Presentation software, and the correct response (accuracy) and reaction time (RT) in milliseconds were recorded. The trial structure and examples of stimuli are reported in Fig. 3.
Visual analogue scale (VAS)
The VAS63 consists of a horizontal line, 100 mm in length, anchored at each end by a word descriptor, and the subject is required to mark the line at the point they felt best represented how they perceived their current state. The VAS score was calculated by measuring the distance from the left-hand end of the line to the point that the subject marked in millimeters.
We used VAS for anxiety (0 mm, no anxiety and 100 mm, the worst anxiety), mood (0 mm, the worst mood and 100 mm, the best mood) and fatigue (0 mm, no fatigue and 100 mm, the highest level of fatigue).
Statistical analysis
The Shapiro–Wilk test was used to assess our sample distribution, which was not normally distributed (see Table 3 for details). Therefore, nonparametric analysis was performed.
The Kruskal–Wallis one-way analysis of variance with group (anodal N = 16, cathodal N = 16, sham N = 16) as the independent variable was used to test differences in age, education, Raven87 and EHI62 scores. The chi-square test (N F/M = 26/22) was used to evaluate the association between group and gender.
To exclude significant differences in the performance among the three groups at baseline, Kruskal–Wallis one-way analysis of variance with group as an independent variable was used to compare the accuracy and RT for each stimulus type (MS, V-P, V-M). Statistical significance was considered at p < 0.05, and direct comparisons between groups were performed by applying the Bonferroni post hoc correction if necessary.
The Wilcoxon test for matched pairs (dependent samples) was used to assess differences in VAS63 scores (anxiety, mood and fatigue) and in accuracy and RT for the different stimuli of the RMET55 before and after tDCS, separately for each group. A p value ≤ 0.005, as corrected for 9 multiple comparisons by the Bonferroni test, was considered significant. Statistical analyses were performed using SPSS for Windows (version 21.0, Armonk, NY: IBM Corp. Released 2012).
Ethics approval
Approval of the experimental protocols was obtained from the local ethical committee of the IRCCS Santa Lucia Foundation of Rome (Prot. CE/PROG.570).
Consent to participate
Written informed consent was obtained from all participants before starting the study.
Data availability
The datasets used and analyzed during the current study available from the corresponding author (Dr. Silvia Clausi) on reasonable request.
References
Argyropoulos, G. P. D. et al. The cerebellar cognitive affective/Schmahmann syndrome: A task force paper. Cerebellum 19, 102–125 (2020).
Clausi, S. et al. The role of the cerebellum in unconscious and conscious processing of emotions: A review. Appl. Sci. 7, (2017).
Clausi, S. et al. The cerebellar predictions for social interactions: theory of mind abilities in patients with degenerative cerebellar atrophy. Front. Cell Neurosci. 12, (2019).
Ito, M. Control of mental activities by internal models in the cerebellum. Nat. Rev. Neurosci. 9, 304–313 (2008).
Schmahmann, J. D. & Caplan, D. Cognition, emotion and the cerebellum. Brain 129, 290–292 (2006).
Tedesco, A. M. et al. The cerebellar cognitive profile. Brain 134, 3672–3686 (2011).
Van Overwalle, F. et al. Consensus paper: Cerebellum and social cognition. Cerebellum 19, 833–868 (2020).
Frosch, I. R., Mittal, V. A. & D’Mello, A. M. Cerebellar contributions to social cognition in ASD: A predictive processing framework. Front. Integr. Neurosci. 16, (2022).
Adamaszek, M. et al. Consensus paper: Cerebellum and emotion. Cerebellum 16, 552–576 (2017).
Klaus, J. & Schutter, D. J. L. G. Functional topography of anger and aggression in the human cerebellum. Neuroimage 226, (2021).
Sokolov, A. A. The cerebellum in social cognition. Front. Cell Neurosci 12, (2018).
Van Overwalle, F., Baetens, K., Mariën, P. & Vandekerckhove, M. Social cognition and the cerebellum: A meta-analysis of over 350 fMRI studies. Neuroimage 86, 554–572 (2014).
Guell, X. & Schmahmann, J. Cerebellar functional anatomy: A didactic summary based on human fMRI evidence. Cerebellum 19, (2020).
Guell, X., Gabrieli, J. D. E. & Schmahmann, J. D. Triple representation of language, working memory, social and emotion processing in the cerebellum: Convergent evidence from task and seed-based resting-state fmri analyses in a single large cohort. Neuroimage 172, 437 (2018).
Heleven, E., Dun, K. & Van Overwalle, F. The posterior cerebellum is involved in constructing social action sequences: An fMRI study. Sci. Rep. 9, (2019).
Olivito, G. et al. Functional changes of mentalizing network in SCA2 patients: Novel insights into understanding the social cerebellum. Cerebellum 19, 235–242 (2020).
Van Overwalle, F., D’aes, T. & Mariën, P. Social cognition and the cerebellum: A meta-analytic connectivity analysis. Hum Brain Mapp. 36, 5137–5154 (2015).
Van Overwalle, F. & Mariën, P. Functional connectivity between the cerebrum and cerebellum in social cognition: A multi-study analysis. Neuroimage 124, 248–255 (2016).
Leggio, M. & Olivito, G. Topography of the cerebellum in relation to social brain regions and emotions. Handb. Clin. Neurol. 154, 71–84 (2018).
Van Overwalle, F., Baetens, K., Mariën, P. & Vandekerckhove, M. Cerebellar areas dedicated to social cognition? A comparison of meta-analytic and connectivity results. Soc. Neurosci. 10, 337–344 (2015).
Mars, R. B. et al. On the relationship between the ‘default mode network’ and the ‘social brain’. Front. Hum. Neurosci. 6, 1–9 (2012).
Clausi, S. et al. The neurobiological underpinning of the social cognition impairments in patients with spinocerebellar ataxia type 2. Cortex 138, 101–112 (2021).
Hoche, F., Guell, X., Sherman, J. C., Vangel, M. G. & Schmahmann, J. D. Cerebellar contribution to social cognition. Cerebellum 15, 732–743 (2016).
Sokolov, A. A., Miall, R. C. & Ivry, R. B. The cerebellum: Adaptive prediction for movement and cognition. Trends Cogn. Sci. 21, 313–332 (2017).
Middleton, F. A. & Strick, P. L. Cerebellar projections to the prefrontal cortex of the primate. J. Neurosci. 21, 700–712 (2001).
Ramnani, N. The primate cortico-cerebellar system: Anatomy and function. Nat. Rev. Neurosci. 7, 511–522 (2006).
Schmahmann, J. D. & Pandya, D. N. The cerebrocerebellar system. Int. Rev. Neurobiol. 41, 31–60 (1997).
Clausi, S. et al. Quantification of gray matter changes in the cerebral cortex after isolated cerebellar damage: A voxel-based morphometry study. Neuroscience 162, 827–835 (2009).
Lupo, M. et al. Cerebello-cortical alterations linked to cognitive and social problems in patients with spastic paraplegia Type 7: A Preliminary Study. Front. Neurol. 11, (2020).
Joyce, M. R. et al. Quality of life changes following the onset of cerebellar ataxia: Symptoms and concerns self-reported by ataxia patients and informants. Cerebellum 21, 592–605 (2022).
Cattaneo, Z. et al. New horizons on non-invasive brain stimulation of the social and affective cerebellum. Cerebellum 21, 482–496 (2022).
Grimaldi, G. et al. Non-invasive cerebellar stimulation-a consensus paper. Cerebellum 13, 121–138 (2014).
Nitsche, M. A. et al. Modulation of cortical excitability by weak direct current stimulation–technical, safety and functional aspects. Suppl. Clin. Neurophysiol. 56, 255–276 (2003).
Grimaldi, G. et al. Cerebellar transcranial direct current stimulation (ctDCS): A novel approach to understanding cerebellar function in health and disease. Neuroscientist 22, 83–97 (2016).
Miterko, L. N. et al. Consensus paper: Experimental neurostimulation of the cerebellum. Cerebellum 18, 1064–1097 (2019).
Rahman, A. et al. Cellular effects of acute direct current stimulation: Somatic and synaptic terminal effects. J. Physiol. 591, 2563–2578 (2013).
Van Dun, K., Bodranghien, F., Manto, M. & Mariën, P. Targeting the cerebellum by noninvasive neurostimulation: A review. Cerebellum 16, 695–741 (2017).
Van Dun, K., Bodranghien, F. C. A. A., Mariën, P. & Manto, M. U. TDCS of the cerebellum: Where do we stand in 2016? Technical issues and critical review of the literature. Front. Hum. Neurosci. 10, (2016).
Grimaldi, G. et al. Non-invasive cerebellar stimulation: A consensus paper. Cerebellum 13, 121–138 (2014).
Ferrucci, R. et al. Modulating human procedural learning by cerebellar transcranial direct current stimulation. Cerebellum 12, 485–492 (2013).
Gomez-Tames, J. et al. Group-level and functional-region analysis of electric-field shape during cerebellar transcranial direct current stimulation with different electrode montages. J. Neural. Eng. 16(3), 036001 (2019).
Klaus, J. & Schutter, D. J. L. G. Electrode montage-dependent intracranial variabilityin electric fields induced by cerebellar transcranial direct current stimulation. Sci. Rep. 11(1), 22183 (2021).
Rezaee, Z., Ruszala, B., & Dutta, A. A computational pipeline to find lobule-specific electric field distribution during non-invasive cerebellar stimulation. IEEE Int. Conf. Rehabil. Robot., 1191–1196 (2019).
Rezaee, Z. & Dutta, A. Cerebellar Lobules Optimal Stimulation (CLOS): A computational Pipeline to optimize cerebellar lobule-specific electric field distribution. Front. Neurosci. 13, 266 (2019).
Parazzini, M. et al. Modelling the electric field and the current density generated by cerebellar transcranial DC stimulation in humans. Clin. Neurophysiol. 125, 577–584 (2014).
Ferrucci, R. & Priori, A. Transcranial cerebellar direct current stimulation (tcDCS): Motor control, cognition, learning and emotions. Neuroimage 85, 918–923 (2014).
Oldrati, V. & Schutter, D. J. L. G. Targeting the human cerebellum with transcranial direct current stimulation to modulate behaviour: A Meta-Analysis. Cerebellum 17, 228–236 (2018).
Oldrati, V. et al. How social is the cerebellum? Exploring the effects of cerebellar transcranial direct current stimulation on the prediction of social and physical events. Brain Struct. Funct. 226, 671–684 (2021).
Ferrucci, R. et al. Cerebellum and processing of negative facial emotions: cerebellar transcranial DC stimulation specifically enhances the emotional recognition of facial anger and sadness. Cogn. Emot. 26, 786–799 (2012).
Brothers, L. & Ring, B. A neuroethological framework for the representation of mind. J. Cogn. Neurosci. 4, 107–118 (1992).
Premack, D. & Woodruff, G. Does the chimpanzee have a theory of mind?. Behav. Brain Sci. 1, 515–526 (1978).
Meltzoff, A. N. & Moore, M. K. Imitation of facial and manual gestures by human neonates. Science 198, 74–78 (1977).
Coricelli, G. Two-levels of mental states attribution: From automaticity to voluntariness. Neuropsychologia 43, 294–300 (2005).
Maurer, D. Infants’ perception of facedness. in Social perception in infants (eds. T, F. & N, F.) 73–100 (Ablex, 1985).
Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y. & Plumb, I. The, “reading the mind in the eyes” test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J. Child Psychol. Psychiatry Allied Discipl. 42, 241–251 (2001).
Oakley, B. F., Brewer, R., Bird, G. & Catmur, C. Theory of mind is not theory of emotion: A cautionary note on the reading the mind in the eyes test. J. Abn. Psychol. 125, 818–823 (2016).
Francois, Q. & Rossetti, Y. What do theory-of-mind tasks actually measure? Theory and practice. Persp. Psychol. Sci. 15, 384–396 (2020).
Platek, S. M., Keenan, J. P., Gallup, G. G. & Mohamed, F. B. Where am I? The neurological correlates of self and other. Cogn. Brain Res. 19, 114–122 (2004).
Clausi, S. et al. The cerebellum is linked to theory of mind alterations in autism. A direct clinical and MRI comparison between individuals with autism and cerebellar neurodegenerative pathologies. Autism Res. 14, 2300–2313 (2021).
Van Overwalle, F., Van de Steen, F. & Mariën, P. Dynamic causal modeling of the effective connectivity between the cerebrum and cerebellum in social mentalizing across five studies. Cogn. Affect. Behav. Neurosci. 19, 211–223 (2019).
Ferrucci, R. et al. Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory. J Cogn. Neurosci. 20, 1687–1697 (2008).
Oldfield, R. C. The assessment and analysis of handedness: The edinburgh inventory. Neuropsychologia 9, 97–113 (1971).
Gift, A. G. Visual analogue scales: Measurement of a subjective phenomena. Nurs. Res. 38, 286–288 (1989).
Schutter, D. J. L. G., Enter, D. & Hoppenbrouwers, S. S. High-frequency repetitive transcranial magnetic stimulation to the cerebellum and implicit processing of happy facial expressions. J. Psychiatry Neurosci. 34, 60–65 (2009).
King, M., Hernandez-Castillo, C. R., Poldrack, R. A., Ivry, R. B. & Diedrichsen, J. Functional boundaries in the human cerebellum revealed by a multi-domain task battery. Nat. Neurosci. 22(8), 1371–1378 (2019).
Boehringer, A., Macher, K., Dukart, J., Villringer, A. & Pleger, B. Cerebellar transcranial direct current stimulation modulates verbal working memory. Brain. Stimul. 6, 649–653 (2013).
Fleur, L. P. B., Schutter, D. J. L. G. & Klaus, J. Cerebellar tDCS does not modulate language processing performance in healthy individuals. Neuropsychologia 169, 108206 (2022).
de Lorente No, R. A study in nerve physiology. Studies from the Rockefeller Institute for Medical Research 1–548 (1947).
Rampersad, S. M., Janssen, A. M. & Lucka, F. Simulating transcranial direct current stimulation with a detailed anisotropic human head model. IEEE Trans. Neural. Syst. Rehabil. Eng. 22, 441–452 (2014).
Kelly, R. M. & Strick, P. L. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. J. Neurosci. 23, 8432–8444 (2003).
Daskalakis, Z. J. et al. Exploring the connectivity between the cerebellum and motor cortex in humans. J. Physiol. 557, 689–700 (2004).
Ugawa, Y. et al. Modulation of motor cortical excitability by electrical stimulation over the cerebellum in man. J. Physiol. 441, 57–72 (1991).
Shah, B., Nguyen, T. T. & Madhavan, S. Polarity independent effects of cerebellar tDCS on short term ankle visuomotor learning. Brain Stimul. 6, 966–968 (2013).
Molenberghs, P., Johnson, H., Henry, J. D. & Mattingley, J. B. Understanding the minds of others: a neuroimaging meta-analysis. Neurosci. Biobehav. Rev. 65, 276–291 (2016).
Van Overwalle, F. Social cognition and the brain: a meta-analysis. Hum. Brain Mapp. 30(3), 829–858 (2009).
Van Overwalle, F. & Baetens, K. Understanding others’ actions and goals by mirror and mentalizing systems: A meta-analysis. Neuroimage 48(3), 564–584 (2009).
Ding, Y. et al. Cerebellar structural and functional abnormalities in first-episode and drug-naive patients with schizophrenia: A meta-analysis. Psy. Res. Neuroima 283, 24–33 (2019).
Fatemi, S. H. et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum 11, 777–807 (2012).
Wang, S.S.-H., Kloth, A. D. & Badura, A. The cerebellum, sensitive periods, and autism. Neuron 83, 518–532 (2014).
Olivito, G. et al. Resting-state functional connectivity changes between dentate nucleus and cortical social brain regions in autism spectrum disorders. Cerebellum 6, 283–292 (2017).
Olivito, G. et al. Lobular patterns of cerebellar resting-state connectivity in adults with autism spectrum disorder. Eur. J. Neurosci. 47, 729–735 (2018).
Stoodley, C. J. et al. Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice. Nat. Neurosci. 20, 1744–1751 (2017).
Antal, A. et al. Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clin. Neurophysiol. 128, 1774–1809 (2017).
Ferrucci, R. et al. Cerebellar transcranial direct current stimulation (tDCS), leaves virtual navigation performance unchanged. Front. Neurosci. 13, (2019).
Zhang, X., Hancock, R. & Santaniello, S. Transcranial direct current stimulation of cerebellum alters spiking precision in cerebellar cortex: A modeling study of cellular responses. PLoS Comput Biol 17(12), e1009609 (2021).
Rice, L. C., D’Mello, A. M. & Stoodley, C. J. Differential behavioral and neural effects of regional cerebellar tDCS. Neuroscience 462, 288–302 (2021).
Raven, J. C. Progressive Matrices. Sets A, Ab, B: Board and Book Form. (1947).
Acknowledgements
The editing support of American Journal Experts is acknowledged.
Funding
This work was supported by the Italian Ministry of Health (Grant Number GR-2013-02354888) to Silvia Clausi and by the Italian Ministry of Education, University and Research (MIUR) (Grant Number RG120172B8343252) to ML.
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Conceptualization, Methodology, Original draft preparation: S.C.; Data curation: S.C., M.L. and G.F.; Statistical analyses: A.M.; Supervision, Reviewing and Editing: M.L. Information is anonymized and the submission does not include images that may identify the person.
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Clausi, S., Lupo, M., Funghi, G. et al. Modulating mental state recognition by anodal tDCS over the cerebellum. Sci Rep 12, 22616 (2022). https://doi.org/10.1038/s41598-022-26914-4
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DOI: https://doi.org/10.1038/s41598-022-26914-4
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