Cerebellum, temporal predictability and the updating of a mental model

, 20130403, published 10 November 2014369 2014 Phil. Trans. R. Soc. B Sonja A. Kotz, Anika Stockert and Michael Schwartze mental modelCerebellum, temporal predictability and the updating of a  

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ResearchCite this article: Kotz SA, Stockert A,

Schwartze M. 2014 Cerebellum, temporal

predictability and the updating of a mental

model. Phil. Trans. R. Soc. B 369: 20130403.

http://dx.doi.org/10.1098/rstb.2013.0403

One contribution of 14 to a Theme Issue

‘Communicative rhythms in brain and

behaviour’.

Subject Areas:cognition

Keywords:cerebellum, lesion, timing, prediction,

forward model, event-related potentials

Author for correspondence:Sonja A. Kotz

e-mail: [email protected]

†These authors have contributed equally to

this work.

& 2014 The Author(s) Published by the Royal Society. All rights reserved.

Cerebellum, temporal predictability andthe updating of a mental model

Sonja A. Kotz1,2,†, Anika Stockert2,3 and Michael Schwartze1,†

1School of Psychological Sciences, University of Manchester, Brunswick Street, Manchester M13 9PL, UK2Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Stephanstrasse1a, 04103 Leipzig, Germany3Language and Aphasia Laboratory, University of Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany

We live in a dynamic and changing environment, which necessitates that we

adapt to and efficiently respond to changes of stimulus form (‘what’) and

stimulus occurrence (‘when’). Consequently, behaviour is optimal when we

can anticipate both the ‘what’ and ‘when’ dimensions of a stimulus. For

example, to perceive a temporally expected stimulus, a listener needs to estab-

lish a fairly precise internal representation of its external temporal structure, a

function ascribed to classical sensorimotor areas such as the cerebellum. Here

we investigated how patients with cerebellar lesions and healthy matched con-

trols exploit temporal regularity during auditory deviance processing. We

expected modulations of the N2b and P3b components of the event-related

potential in response to deviant tones, and also a stronger P3b response

when deviant tones are embedded in temporally regular compared to irregu-

lar tone sequences. We further tested to what degree structural damage to the

cerebellar temporal processing system affects the N2b and P3b responses

associated with voluntary attention to change detection and the predictive

adaptation of a mental model of the environment, respectively. Results

revealed that healthy controls and cerebellar patients display an increased

N2b response to deviant tones independent of temporal context. However,

while healthy controls showed the expected enhanced P3b response to deviant

tones in temporally regular sequences, the P3b response in cerebellar patients

was significantly smaller in these sequences. The current data provide evi-

dence that structural damage to the cerebellum affects the predictive

adaptation to the temporal structure of events and the updating of a mental

model of the environment under voluntary attention.

1. IntroductionThe cerebellum has featured prominently in past and recent attempts to identify

the neural basis of temporal processing and to understand how the brain rep-

resents and uses temporal structure [1–5]. However, this line of research is one

of many contributing to a growing body of evidence that the cerebellum is

engaged in numerous cognitive functions including speech and music [6–9]

and the question arises how specific these functions are. One possible way to

delineate these functions is to have a closer look at cerebello-cortical connections

that may allow specification of their respective contribution to cognition. For

example, some of these connections manifest links between the cerebellum and

other brain areas associated with temporal processing such as the basal ganglia

or the supplementary motor area (SMA) [10–14]. Increasingly more fine-grained

anatomical differentiations corroborate assumptions of divergent, and also

shared, operations in motor (production) and non-motor (perception, cognition)

functions in brain areas such as the cerebellar dentate nucleus and its motor and

non-motor sub-compartments, the caudate/putamen of the basal ganglia or the

subdivisions of the SMA [15–18].

Temporal processing is considered fundamental to neurocognitive oper-

ations underlying motor and non-motor function(s) relevant in domains such

as speech and music to optimize overt and covert behaviour. Importantly, opti-

mal timing implies a form of predictive adaptation to the temporal structure of

events in the environment to circumvent exclusively reactive behaviour. It is

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therefore not surprising that ‘prediction’ is another neurocog-

nitive operation that has been associated with the cerebellum

[19–21]. However, efficient prediction and adaptation in be-

haviour requires adequate internal representations of both

the formal structure (‘what’) and the temporal structure

(‘when’) of events in the environment. In other words, infor-

mation pertaining to the form or identity of events has to be

encoded alongside information that relates to the rhythm or

temporal locus of events [22]. Turning to concrete examples,

we can ask how musicians coordinate their play while creat-

ing music together. Recognizing the absence of sound in a

musical piece marks the start of a pause. Prior information

about the duration of a pause allows the musicians to predic-

tively adapt their behaviour and to resume playing together at

the right point in time. In the absence of an external reference,

such as the arm movement of a conductor, the behavioural

benefit granted by temporal prediction is determined byan indi-

vidual’s ability to exploit regular rhythms and temporal

relations such as estimating a pause’s duration. Similarly, we

can consider how two people communicate with each other.

Here, lengthening of a phrase’s final word or syllable, followed

by a pause, may (among other factors) indicate that one social

partner signals the opportunity for the other partner to take a

turn at talk. The combination of verbal and non-verbal temporal

cues as described above allows the communicative partners to

predictively adapt to each other and to take turns at the correct

point in time to ensure optimized communication flow.

One way to investigate the operations underlying the ability

to use temporal structure in order to optimize behaviour is to

infer function from pathological dysfunction. Here we con-

sidered structural damage to the cerebellum, which should

affect precise event-based perceptual encoding of temporal struc-

ture [23,24]. Thus, structural damage to the cerebellum should

disrupt how one efficiently extracts and uses temporal regularity

to generate predictions about the temporal locus of an upcoming

event and may further lead to suboptimal performance in a

number of cognitive tasks. To explore this potential link between

temporal predictability and optimal performance, we tested how

temporal predictability influences auditory deviance processing

under voluntary attention in patients with cerebellar lesions and

healthy controls. Deviance processing provides a relatively

simple framework, which should make it possible to probe

how patients and healthy controls exploit temporal regularity

and the temporal predictability associated with it in optimal

tone perception.

Broadly speaking, deviance processing refers to a set of

neurocognitive operations associated with change. For example,

how does one perceive a change in tone frequency or duration,

while expecting a particular tone frequency or duration that has

been previously established? Deviance processing is classic

in event-related potential (ERP) research. Different stages of

deviance processing are reflected in early responses associated

with sensory processing and progressively later responses

associated with cognitive operations [25,26]. Critically, deviance

processing makes it possible to test the interaction of formal

and temporal structure by varying formal stimulus properties

(e.g. tone frequency) and temporal regularity (e.g. when a

tone occurs in a tone sequence) in one single experimental

setting. In addition, the impact of temporal regularity on

deviance processing (e.g. optimal detection of deviance) is

linked to a number of well-established ERP components.

Consequently, we set out to test patients with cerebellar

lesions and healthy, age-matched controls using an auditory

oddball paradigm, in which frequent standard and less frequent

deviant tones are presented in either a temporally regular or irre-

gular context. This particular approach is based on previous

work, in which pre-attentive deviance processing as indexed

by the P50, N1, mismatch negativity (MMN), P3a and re-

orienting negativity was contrasted with attentive deviance

processing as indexed by the P50, N1, N2b and P3b ERP

components [24,27]. Statistically indifferent ERP responses

obtained in the pre-attentive context suggest that pre-attentive

deviance processing is relatively robust against the manipu-

lation of temporal regularity [24,27], while amplitude

modulations in the P3 range for attentive deviance processing

may indicate an interaction of formal and temporal stimulus

properties at this processing stage [24]. Considering the active

experimental task (counting of deviant tones) and the centro-

parietal topographical distribution of the effect, this finding

was interpreted as an attention-dependent differentiation of

the P3b component. More specifically, deviant tones presented

in a temporally regular context evoked a larger P3b response

(amplitude enhancement) in comparison with physically identi-

cal deviant tones presented in a temporally irregular context.

Similar findings have been obtained with linguistic stimuli

[28], suggesting that the P3b enhancement in response to devi-

ant stimuli in temporally regular stimulus sequences may

reflect the impact of temporal structure and temporal predict-

ability on deviance processing. The fact that P3b enhancement

is reported for lower level auditory stimuli (tones) as well as

more complex linguistic stimuli suggests that these operations

in deviance processing apply to a number of cognitive functions

including speech and music. As a result, it is important to under-

stand how structural damage to the cerebellar temporal

processing system affects the precise encoding of the temporal

structure of successive events and how this may affect the

efficient adaptation to a dynamic environment.

In this study, participants listened attentively to tone

sequences, and counted deviant tones while their electro-

encephalogram (EEG) was recorded. We focused on two ERP

responses in this context. The fronto-centrally distributed

N2b response is typically associated with the detection of a

deviant event, whereas the predominant theoretical account

for the more centro-parietally distributed P3b links this com-

ponent to the updating of a mental model of the

environment in response to a deviant event [29–31]. The

exact nature of this mental model remains elusive at this

stage. However, the P3b is typically believed to instantiate a

neural signature of a change in this model, conceived as a gen-

eral schema of all available data in the environment and of the

stimulus context, in particular [29,31]. With respect to the odd-

ball paradigm used here this suggests that the model

established by frequent standard tones has to be transformed

(updated) when an infrequent deviant tone is encountered,

reflecting the mediation between the participants’ expectancies

and sensory input [32,33]. We expected that healthy controls

would show an N2b response to deviant tones in both types

of sequences and a further enhanced P3b response to deviant

tones in temporally regular compared with irregular tone

sequences [24] reflecting the beneficial effects of temporal regu-

larity on deviance processing and, in turn, effective updating of

a mental model of the environment. Patients with cerebellar

lesions, who are expected to be less sensitive to temporal regu-

larity owing to increased system noise and uncertainty in the

event-based encoding of temporal structure, should not show

a similarly beneficial effect of temporal regularity. Thus,

11

9

7

5

3

1

L ÍR

–53 –42 –33 –23 –12

Figure 1. Cerebellar lesion distribution. Lesions were manually delineated on normalized T1-weighted magnetic resonance (MR) scans of each patient and super-imposed on a single subject template in Montreal Neurological Institute (MNI) space. MNI coordinates are displayed; the orthogonal view illustrates correspondingaxial planes. The colour bar specifies the number of patients with overlapping lesions in each voxel. Purple shades indicate voxels affected in at least one patient,whereas blue shades reflect maximal lesion overlap (maximum N ¼ 3). The respective lesions are distributed over both cerebellar hemispheres, extending to thevermis, cerebellar peduncles and the midbrain. L/R indicates left and right hemisphere. (Online version in colour.)

Table 1. Patient history. m/f, male or female; edu., education (in years); HI, handedness index according to Edinburgh Handedness Inventory [34]; TSL, timesince lesion (in months); vol., volume (in cc). Lesion aetiology: AVM, arteriovenous malformation; SCA, superior cerebellar artery; PICA, posterior inferiorcerebellar artery; ICH, intracranial haemorrhage. Descriptions of lesion locations refer to the MRI atlas nomenclature of the human cerebellum [35]; MCP, middlecerebellar peduncle; SCP, superior cerebellar peduncle.

no. m/f age HI edu. TSL vol. aetiology lesion location

1 m 25 þ100 8 93 48.00 AVM, ICH bilateral lobule VIIB, crus I/II, vermis (VI –

VIII)

2 m 30 þ100 8 108 30.12 SCA aneurysm, ICH left lobule III – VI, crus I, SCP, MCP

3 m 45 þ100 10 77 4.88 basilar artery aneurysm, SCA

infarction

right lobule III – VI, medial thalamus, vermis

(III – V) SCP, left crus I

4 m 35 þ50 12 120 9.00 cerebellopontine angle tumour

resection

right lobule IV – VIII, X, crus I/II, MCP

5 m 59 þ80 10 28 7.13 PICA infarction right lobule VIIB – IX, crus I/II

6 f 39 þ80 10 35 0.29 PICA infarction right crus II

7 f 59 þ100 8 36 5.67 SCA infarction right lobule IV – VI, crus I

8 f 45 þ100 12 71 7.85 PICA infarction left lobule VIIB – IX, crus II, right crus I/II

9 m 56 þ100 10 36 14.50 PICA infarction left lobule VIIB – IX, crus II

10 f 33 þ100 12 40 8.84 medulloblastoma resection right lobule VIIB – VIIIB, crus II, vermis (IV –

VIIIB), SCP

11 f 50 þ100 10 16 2.43 PICA infarction right lobule VIIIA – IX

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while an N2b response to deviance per se may be comparable

with healthy controls, the P3b responses to deviant tones in

temporally regular and irregular tonal sequences should be

dissimilar, substantiating the idea that temporal predictability

cannot be efficiently applied to optimally update the mental

model. We therefore addressed two core questions in the cur-

rent experiment: (i) Does temporal predictability influence

deviance processing under voluntary attention in a similar

fashion in healthy ageing controls as previously observed in

young healthy participants? (ii) How does structural damage

to the cerebellum affect the potentially optimizing influence

of temporal predictability on deviance processing and the

updating of a mental model as indicated by N2b and P3b?

2. Material and methods(a) ParticipantsEleven patients with cerebellar lesions (figure 1 and table 1) and a

corresponding number of healthy controls participated in the

study. Healthy controls matched the patients in terms of gender

(five women), age (mean 43.3+11.9 years), handedness (all

right handed) and education (10+1.6 years). All participants

gave their informed written consent regarding the experiment

and received a compensatory fee. Patients were recruited through

the database of the Clinic for Cognitive Neurology at the Univer-

sity Hospital of Leipzig. Healthy controls were recruited from

the participant database of the Max Planck Institute for Human

Cognitive and Brain Sciences in Leipzig.

(b) Magnetic resonance imaging and lesion mappingHigh-resolution T1-weighted magnetic resonance (MR) scans were

obtained at 3 T with a Siemens TrioTim (Siemens Healthcare,

Erlangen, Germany) or a Bruker BioSpin (BioSpin GmbH, Rhein-

stetten, Germany) MR system with a 32-channel phased-array

head array coil using an MP-RAGE sequence [36]. The resulting

images were segmented and spatially normalized to the Montreal

Neurological Institute (MNI) space by means of the unified

segmentation approach [37] as implemented in SPM (SPM8,

Wellcome Department of Imaging Neuroscience, London, UK,

http://www.fil.ion.ucl.ac.uk/spm). The MRIcron software pack-

age [38] was used to manually delineate lesions on axial slices of

600 ms

600 versus 660 Hz (ratio 4 : 1)

200–1000 ms (600 ms on average)

(b)

(a)

Figure 2. Visualization of excerpts from the auditory stimulus sequences. Using a variant of the set-up implemented in Schwartze et al. [24], equidurational(300 ms, 10 ms rise and fall) sinusoidal standard (600 Hz, N ¼ 360) and deviant tones (660 Hz, N ¼ 90) are presented in two conditions that differ exclusivelyin their ISI. In the regular condition (a) the ISI are fixed to 600 ms. In the irregular condition (b) the ISI are randomly chosen from a range between 200 and1000 ms.

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the normalized T1-weighted images and to create binary lesion

maps for each patient (average lesion volume 12.61 cc, s.d. 14.16

cc). To visualize overall lesion distribution (figure 1), the lesion

maps were superimposed on a scalp-stripped T1-weighted single

subject template in MNI space (Colin27_T1_seg_MNI.nii, available

at http://brainmap.org/ale/index.html).

(c) Stimulus sequences and experimental taskDuring the EEG recording, stimuli were delivered by Presentation

12.0 (Neurobehavioral Systems). Each oddball sequence (figure 2)

consisted of 450 tones in total, corresponding to 360 standard

(600 Hz, 300 ms, 10 ms rise and fall times) tones and 90 deviant

(660 Hz, 300 ms, 10 ms rise and fall times) tones (4 : 1 ratio). In

the regular condition, the inter-stimulus intervals (ISI) were fixed

to 600 ms, while the ISIs were randomly chosen from a range

between 200 and 1000 ms (600 ms on average) in the irregular con-

dition. Randomization constraints ensured that no more than two

deviants were presented in a row and that the first four tones of

each sequence were standards in order to allow participants to

establish a memory trace for these tones. The type of initial

sequence presented was counterbalanced across participants. A

short excerpt of this sequence was presented to the participants

in order to familiarize them with the different tone types. During

the experiment, participants listened to the tones presented via

loudspeakers and silently counted the number of deviant tones

embedded in a sequence. The counting task was employed in

order to make sure that the participants directed their attention

towards the stimulus sequence. This conforms to a cognitive task

with no motor aspect during the recording interval, in which

any brain potential confound owing to impaired motor control

in the cerebellar patients should be absent or at least minimal.

Participants were not informed about the nature of the temporal

context that tones could occur in. They reported one final count

at the end of each type of sequence to which they had listened.

A short pseudo-randomized sequence consisting of 12 additional

tones (7 standards and 5 deviants) was attached to the irregular

sequence to obtain different correct count values for the two con-

ditions (90 regular versus 95 irregular) in order to prevent

accurate task performance being achieved by simply reporting

the same value twice. These additional tones were disregarded

from all further EEG analyses.

(d) Electroencephalogram recording and analysisThe EEG recordings took place in a dimly lit sound-attenuated

booth. Participants sat in front of a computer screen, which dis-

played a fixation cross throughout the session. The EEG was

recorded at a sampling rate of 500 Hz from 25 Ag/AgCl scalp elec-

trodes mounted in an elastic cap and arranged according to the

standard 10–20 International System. Additional horizontal and

vertical electrooculography was recorded by means of four separ-

ate electrodes. The ground electrode was placed on the sternum

and electrodes placed on the left and right mastoids served as

reference during the recording.

Data pre-processing and ERP analyses were performed using

the EEP 3.2 software package (Max Planck Institute for Human

Cognitive and Brain Sciences, Leipzig, commercially available

as EEProbe, ANT Neuro). Raw data were re-referenced offline

to averaged mastoids. Epochs lasting from 2100 to 450 ms rela-

tive to stimulus onset were averaged for standards and deviants

for each condition per participant and across participants. All

epochs of tones that immediately followed the presentation of a

deviant tone were rejected. Automatic rejection was applied to

artefacts exceeding 30 mV at eye-channels or 40 mV at electrode

CZ. To increase the number of eligible trials for both groups, pro-

totypical artefacts reflecting eye blinks and saccades identified

via electrooculography were used to obtain propagation factors,

which were then used to compensate for similar artefacts in the

remaining trials via a regression algorithm (Electrooculogram

Epoch Classification), implemented in the EEP software.

The ERPs of interest were analysed in four regions of interest

(ROIs) to assess both the typical fronto-central and centro-parietal

scalp distributions of the N2b and P3b components as well as

potential hemispheric differences of component distribution as a

result of cerebellar pathology. These ROIs covered left-anterior

(F7, F3, FT7, FC3), right-anterior (F8, F4, FT8, FC4), left-posterior

(T7, C3, CP5, P3) and right-posterior (T8, C4, CP6, P4) electrode

positions. A 2 � 2 � 2 � 2 � 2 ANOVA with a between-factor

group (patients versus controls) and within-factors temporal struc-

ture (regular versus irregular), formal structure (standard versus

deviant), hemisphere (left versus right) and region (anterior

versus posterior) was conducted using SAS 9.3 (SAS Institute

Inc.) for a 50 ms time-window lasting from 198 to 248 ms (N2b)

and a 130 ms time-window lasting from 298 to 428 ms (P3b) rela-

tive to the stimulus onset, respectively. These time-windows

were selected after visual inspection of the data and included the

peak of each component across groups and conditions. Thus,

N2b was analysed from the transition into a negative-going deflec-

tion until the earliest crossing into positive voltages (which was

found in response to regular deviants in controls; figure 3), while

P3b was analysed from the transition into a positive-going deflec-

tion until the latest transition into a negative-going deflection

(found in response to regular deviants in patients).

3. Results(a) Behavioural resultsBoth controls (regular mean value reported 89.36, s.d. 1.29,

range 87–91; irregular mean 94.55, s.d. 0.82, range 93–96)

and patients (regular mean 88.82, s.d. 2.18, range 86–92; irregu-

lar mean 94.45, s.d. 0.82, range 93–96) performed well in the

counting task, which is also indicated by comparably high

regular standard

irre

gula

rre

gula

rir

regu

lar

regu

lar

regular deviantirregular standardirregular deviant

–8.0 +8.0µV

CZ

CZ

N2 198–248 ms

450 ms

P3

N2

N1

–100 ms

–8 µV

8

P3 298–428 ms

CZ

cont

rols

patie

nts

Figure 3. Group-averaged EEG data for healthy controls and patients. Data recorded from a representative electrode (CZ) are shown on the left side. A 7 Hz low-passfilter was applied offline for graphical display only. Topographical maps on the right side illustrate the distribution of the corresponding N2b and P3b effects, i.e.voltage differences obtained by subtracting responses to standard events from responses to deviant events in each experimental condition. (Online version in colour.)

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percentages of accuracy for controls (regular 99%, s.d. 1.1; irre-

gular 99%, s.d. 0.7) and patients (regular 98%, s.d. 1.4; irregular

99%, s.d. 0.7). One-sampled t-tests were conducted to test for

differences between the values provided by the participants

and the actual number of deviants embedded in each sequence

(90 regular, 95 irregular). The results were non-significant in the

control group (regular: t(10)¼ 21.64, p¼ 0.132; irregular:

t(10)¼ 21.84, p ¼ 0.096) and in the patient group, even

though there was a strong trend in the irregular context (regular:

t(10)¼ 21.80, p¼ 0.103; irregular: t(10)¼ 22.21, p¼ 0.052).

Taken together the behavioural results confirm that both healthy

controls and cerebellar patients paid attention to the task

requirements and executed the task appropriately.

(b) Event-related potential resultsVisual inspection of the averaged group ERP data confirmed

the typical component evolution associated with attentive

deviance processing, and also suggested qualitative com-

ponent differences between the two groups (figures 3 and 4).

While the N2b and P3b responses (components of empirical

interest) to standard tones seemed to be comparable between

both groups independent of temporal context, the responses

to deviant tones seemed to vary as a function of temporal con-

text. The N2b response to deviants embedded in irregular

temporal structure appeared similar across groups, but the

difference between regular and irregular temporal structure

seemed to be more pronounced in the patient than the control

group. The P3b was generally larger for deviants embedded in

regular temporal structure, but was much reduced in the

patient group compared with the control group.

Further, in comparison to controls, the patient group also

appeared to show more pronounced differences between

standards and deviants already in the N1 range, with

highly similar responses for standards embedded in regular

and irregular temporal structure. N1 responses in controls

followed a similar pattern as previously reported for younger

healthy participants [27]. However, complementary statistical

analyses in the N1 range did not confirm any significant

group differences.1

Likewise, the repeated-measures ANOVA of the N2b

time-window did not fully confirm the initial visual inspec-

tion. Results showed a strong trend towards a main effect

of temporal structure (F1,20 ¼ 4.30, p ¼ 0.051), while

there was a significant main effect of formal structure

(F1,20 ¼ 8.63, p , 0.01). There was a significant interaction

of temporal structure � hemisphere (F1,20 ¼ 6.12, p , 0.03),

indicating a global effect of temporal structure over right

(F1,20 ¼ 7.49, p , 0.02) but not left hemisphere electrode

sites (F1,20 ¼ 1.18, p ¼ 0.288). However, the three-way

3.00

2.00

1.00

0

–1.00

–2.00

–3.00

7.00

6.00

5.00

4.00

3.00

2.00

1.00

0

–1.00

–2.00P3b 95% Cl lower upper

N2b 95% Cl lower upper

PAT

_RE

G_D

EV

PAT

_RE

G_S

TA

PAT

_IR

R_D

EV

PAT

_IR

R_S

TA

CO

N_R

EG

_DE

V

CO

N_R

EG

_STA

CO

N_I

RR

_DE

V

CO

N_I

RR

_STA

–1.00

2.00

–0.74 –0.73–0.49 –0.41

2.51

1.31

4.47

0.62

–0.30

0.77

–0.31

0.78

0.05

1.30

Figure 4. Ninety-five percentage confidence intervals for N2b and P3b responses in both participant groups. REG, regular condition; IRR, irregular condition; PAT,patients; CON, controls; STA, standards; DEV, deviants. (Online version in colour.)

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interaction of temporal structure � formal structure �hemisphere approached statistical significance (F1,20 ¼ 4.06,

p ¼ 0.058) in accordance with the initial visual inspection.

Of note is the lack of a significant main effect of group

(F1,20 ¼ 0.54, p ¼ 0.473) or interaction involving the factor

group (all p . 0.20). In order to explore a potential relation

between the extents of structural damage (i.e. lesion

volume) and the electrophysiological response, individual

lesion volumes were correlated with individual mean N2b

amplitudes obtained at electrode CZ for patients in all four

conditions. However, this procedure yielded no significant

result for regular standards (r ¼ 0.06, p ¼ 0.87) or deviants

(r ¼ 0.12, p ¼ 0.72) nor for irregular standards (r ¼ 0.12, p ¼0.73) or deviants (r ¼ 0.22, p ¼ 0.53). Thus, the current findings

verify the presence of a typical N2b response to deviant tones

in both groups independent of temporal context.

Analysis of the P3b time-window revealed significant main

effects of temporal structure (F1,20 ¼ 20.66, p , 0.001), formal

structure (F1,20 ¼ 38.26, p , 0.0001) and region (F1,20¼ 11.71,

p , 0.01) but not of group (F1,20 ¼ 2.04, p ¼ 0.169). However,

there was a significant interaction of group � temporal

structure � formal structure (F1,20 ¼ 7.59, p , 0.02). Informed

by our hypotheses, a subsequent step-down analysis by the

factor formal structure revealed an interaction of group � tem-

poral structure for deviant (F1,20¼ 5.25, p , 0.04) but not for

standard tones (F1,20¼ 0.08, p ¼ 0.785). Further resolution

of the two-way interaction for deviant tones by the factor

temporal structure confirmed that the two groups differed

with regard to their deviance response in the regular tempo-

ral context (F1,20¼ 4.81, p ¼ 0.04) but not in the irregular

context (F1,20 ¼ 1.07, p ¼ 0.312). Patients showed a smaller

P3b response (2.0 mV) relative to healthy controls (4.5 mV).

This difference was confirmed by a paired-samples t-test

(t(10) ¼ 22.78, p ¼ 0.02). To further validate this finding

and to preclude any disproportional influence of individual

patients on the statistical group comparison, identical t-tests

were conducted with individual patient–control pairings

excluded one at a time (N-1 method). However, the result

remained significant in each of these cases (minimum

t ¼ 22.37, p ¼ 0.042). Pursuant to the ANOVA analysis, the

P3b amplitude was correlated with the extent of lesion size.

Similar to the non-significant N2b correlation results, this

P3b correlation was also non-significant for regular standards

(r ¼ 0.15, p ¼ 0.65) and deviants (r ¼ 0.06, p ¼ 0.86), as well

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as for irregular standards (r ¼ 0.21, p ¼ 0.54) and deviants

(r ¼ 0.15, p ¼ 0.66). Thus, independent of lesion size, these

P3b results provide evidence for the significant impact of

cerebellar pathology on the use of temporal predictability

and the updating of a mental model of the environment as

reflected in the P3b. Moreover, the fact that deviance pro-

cessing was most affected in temporally regular, but not

irregular context substantiates initial assumptions that struc-

tural damage to the cerebellum leads to imprecise encoding

and use of temporal structure, and accordingly to the encod-

ing and use of temporal regularity. This, in turn, affects

optimized deviance processing in the case of maximal

temporal predictability as seen in the control group.

4. DiscussionTesting the proposed role of the cerebellum in precise event-

based temporal processing [4,14,39] and attempting to repli-

cate previous findings in healthy young participants [24] in

a healthy aging control cohort, this study investigated the

impact of cerebellar lesions on the interaction of formal struc-

ture (varying stimulus form) and temporal structure (varying

temporal regularity in tone sequences) in auditory deviance

processing. Both cerebellar lesion patients and healthy aging

controls detected deviant tones, as evident in the behavioural

and in the N2b results. However, cerebellar patients showed

a qualitatively different P3b response to deviant tones

embedded in temporally regular sequences as confirmed by

statistically significant group differences. Healthy controls

showed the expected enhanced P3b deviance response to

tones in regular compared with irregular temporal contexts.

These data suggest that healthy aging participants display

optimized deviance processing with full temporal predictabil-

ity under voluntary attention. By contrast, while patients with

cerebellar pathology detect formal stimulus deviance, they are

less capable of using temporal predictability, and presumably,

to exploit this information to optimally update a mental

model of the environment.

The current results substantiate previous findings on how

temporal regularity influences basic neurocognitive operations

linked to deviance processing. In earlier reports, deviance pro-

cessing under voluntary attention was evident in N2b and P3b

responses, but deviance processing in the P3b range varied as a

function of temporal context [24]. While a strong statistical

trend (three-way interaction of temporal structure, formal

structure and hemisphere) in the N2b time-window may indi-

cate that temporal regularity impacts deviance processing at

this earlier processing stage, the current results remain incon-

clusive. Clearly, further research has to confirm whether a

potential interaction of temporal and formal structure in

deviance detection (N2b) is prone to individual differences,

as previous results have not reported a similar trend in compar-

able experimental set-ups (i.e. [24]). Awaiting further evidence,

we can therefore only carefully conclude that patients with cer-

ebellar lesions detect deviance comparably to healthy controls

as evidenced in a similar N2b response to deviant tones

independent of temporal context.

However, we report clear group differences in the P3b

response to deviant tones, which confirms that patients with

cerebellar lesions cannot benefit in a similar way as healthy

controls from temporal predictability. Considering the ‘almost

unquestionable’ [33] agreement of P300 theories on the function

of this component as an index for the interplay of stimulus

expectancies and actual sensory input, it seems appropriate to

interpret this finding as an instance of impaired updating of a

mental model of the environment. This result substantiates

the critical role of the cerebellum in event-based temporal

encoding [4,14,39] and the optimized adaptation to change in

the environment (e.g. [29–31]).

The current findings further suggest that damage to the

cerebellum alters how temporal regularity optimizes the quality

of auditory deviance processing. In this context, deviance

processing under voluntary attention is but one example of a

perceptual process. It remains to be shown to what extent the

current findings generalize to other perceptual (e.g. visual, mul-

tisensory) or even higher-level cognitive (e.g. natural and

emotional speech) processes [14,40,41] and temporally more

complex stimulus qualities such as meter and rhythm in

speech or artistic forms of language such as poetry or rhetorical

speech [40,42].

Importantly, cerebellar lesions diminish the response to

deviants in temporally regular tone sequences, whereas no

such reduction was found in the irregular tone sequences.

While this dissociation of temporal processing as a function

of temporal regularity does not speak against the role of the

cerebellum in event-based encoding of temporal structure

per se, it substantiates assumptions concerning a cerebellar

contribution to perceptual processing in those cases in which

predictive adaptation is possible. However, most likely, the

cerebellar temporal processing system does not perform this

function in isolation, but in concert with other structures impli-

cated in temporal processing, namely the basal ganglia and the

SMA, as part of an integrative temporal processing network.

Importantly, the respective anatomical and functional connec-

tions may provide a means to compensate for dysfunction in

each structure [13,43,44]. While cerebellar lesions may lead to

imprecise encoding of temporal structure, thus reducing the

effect of full temporal predictability, the intact basal ganglia

temporal processing system may partially compensate for

this ‘noisy’ encoding, e.g. by increasing tolerance against tem-

poral variability in the processing of sequences with a regular

beat. However, such mechanisms are most likely highly depen-

dent on the specific temporal characteristics of the input, and

compensation for cerebellar dysfunction may be more difficult

for the timing of the absolute duration of single intervals [45].

We now need to consider what classical functions of the

cerebellum (i.e. motor behaviour) and deviance processing in

perception may have in common. These functions may con-

verge in a common operation such as an, at least, two-fold

response to changes in the environment (e.g. initial deviance

detection in the form of an error response when expecting a

particular tone quality in a tonal sequence, followed by the

updating of a mental or internal model of the environment

via adaptation of the expected tone quality in a tonal sequence

to a new tone quality induced by the change and initial error

response to such change [31,46–48]). Accordingly, precise

encoding and subsequent use of temporal structure to optimize

performance should be critical in both the motor and non-

motor domains when updating of a mental model is required.

This line of thinking may therefore be related to the updating of

a forward model of cerebellar information processing [47,48].

A forward model receives its input in the form of (efference)

copies of motor commands, which are used to predict the

sensory consequences of an ideally executed movement,

backed up by a comparator, which identifies discrepancies

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between the predicted and the actual consequences and signals

a corresponding error signal in order to adjust the accuracy of

the model [49]. Analogously, the mental model of the environ-

ment receives its input in the form of sensory events and may

implement a form of error detection and updating in response

to unpredicted events. While the forward model relies on cer-

ebellar connections to central motor and somatosensory brain

areas, one may speculate that a mental model of expected

events in the environment may rely on connections between

the cerebellum and sensory areas (e.g. the temporal cortices

[50,51]). However, whether implemented at the neural,

motor, or non-motor (sensory, cognitive) level, any efficient

model of the environment needs to be dynamic in nature.

Accordingly, temporal structure should contribute to the con-

tinuous generation of hypotheses about the environment by

the nervous system as indexed by the P3b [52]. In this context,

one of the functional roles of the cerebellum may be the precise

encoding of temporal structure, which subsequently is used

to generate specific temporal predictions [46]. Kahneman &

Tversky [53] remarked: ‘Before an event there are expec-

tations—after an event there may be surprise’. What remains

to be resolved is whether the underlying operations of cerebel-

lar function in temporal processing, prediction, or surprise as

indexed in the P3b response [54] share common ground as

they appear to be intimately tied to each other. Moreover,

whether prediction and surprise represent facets of more

global cerebellar computation(s) serving a predisposition

towards optimal timing and adaptation in motor and non-

motor behaviour alike, remains to be addressed in future

studies beyond lower level auditory processes.

Finally, the current results raise a more fundamental

question about how the component evolution from early to

late ERPs relates to formal and temporal stimulus dimensions

on the one hand, and the operations speculated to underlie

optimization of behaviour on the other. Typically, an ERP sup-

pression effect (i.e. an amplitude reduction) in early ERP

components such as the P50 or N1 is considered to reflect effi-

cient sensory gating or successful temporal prediction, while

ERP enhancement seems to indicate qualitative processing

differences in later components such as the P3b [24,28,55].

Morphologically, this component evolution changes at approxi-

mately 200 ms after stimulus onset. In other words, temporal

predictability seems to lead to suppression of early components

as opposed to an enhancement of late components. While there

are indications of reduced N1 suppression effects in cerebellar

patients [56], no significant effects were observed in the current

set-up. However, the absence of a similar finding does not

necessarily contradict these results or imply intact function, as

differences in the paradigms used may result in qualitative

and quantitative ERP differences, e.g. due to the use of a

motor response.

Of note is that early suppression effects reflect tempo-

ral predictability, while later enhanced effects are driven

by an interaction of temporal and formal structure. We

may therefore consider that a change from suppression to

enhancement may result from the differential engagement of

operations such as successful encoding of temporal properties

and the efficient updating/adaptation of a mental model of

the environment in the quest to optimize behaviour. Further,

while a classical dissociation of exogenous and endogenous

ERP components [57] could support such a differentiation

of operations, this conceptualization of ERP components

seems inappropriate as both so-called ‘pre-attentive responses’

(MMN) and early ‘exogenous’ components are sensitive to

attentional (i.e. cognitive) manipulations (e.g. [58]).

In conclusion, we set out to answer two critical questions

regarding the functional role of the cerebellum in temporal

predictability, deviance detection and the updating of a

mental model of the environment. The present results suggest

that structural damage to the cerebellum, apparently inde-

pendent of the extent (across anterior/posterior dimensions)

or the lateralization (left, right, bilateral) of the lesion, critically

affects temporal predictability and its impact on perceptual

deviance processing involving both an error response and

updating a mental model of the environment to achieve opti-

mal behaviour. Clearly, more studies with (i) larger patient

sample sizes and (ii) temporally more complex stimulus

aspects such as meter and rhythm in speech and music (for rel-

evant neuroimaging evidence see [35,39,59–61]) are needed to

further delineate whether specific sub-compartments of the

cerebellum contribute to these operations in a function-specific

or a domain-general manner.

Ethics statement. The local ethics committee at the University of Leipzigapproved the study.

Acknowledgements. The authors thank Anne-Kathrin Franz, Heike Boetheland Ingmar Brilmayer for their support during data acquisition.

Funding statement. This work was support by a DFG KO 2268/6-1 grantto S.A.K.

Endnote1To validate the impression of potential early group difference in theN1, identical analyses as for the later components were conducted ina 50 ms time-window (88 to 138 ms). This analysis yielded statisticallysignificant main effects of temporal structure (F1,20¼ 13.42, p , 0.01),formal structure (F1,20¼ 8.66, p , 0.01) and region (F1,20¼ 4.45, p ,

0.05), as well as a significant interaction of formal structure � region(F1,20¼ 4.84, p , 0.04). Resolving this interaction by the factor regionyielded significant effects of formal structure in anterior (F1,20¼ 10.32,p , 0.01) and posterior regions (F1,20¼ 5.91, p , 0.03). However, therewas no significant main effect of group (F1,20¼ 1.68, p ¼ 0.209) or anyinteraction involving the factor group (all p . 0.11), and only a non-sig-nificant trend for an interaction of temporal structure � formal structure(F1,20¼ 3.20, p ¼ 0.089).

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