Effects of thalamic deep brain stimulation on spontaneous language production

Neuropsychologia 89 (2016) 74–82

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Effects of thalamic deep brain stimulation on spontaneous language production Felicitas Ehlen a, Isabelle Vonberg a, Andrea A. Kühn b, Fabian Klostermann a,n a Charité – University Medicine Berlin, Campus Benjamin Franklin, Department of Neurology, Motor and Cognition Group, Hindenburgdamm 30, 12203 Berlin, Germany b Charité – University Medicine Berlin, Campus Virchow Klinikum, Department of Neurology, Motor Neuroscience Group, Augustenburger Platz 1, 13353 Berlin, Germany

art ic l e i nf o

a b s t r a c t

Article history: Received 25 January 2016 Received in revised form 18 April 2016 Accepted 25 May 2016 Available online 4 June 2016

The thalamus is thought to contribute to language-related processing, but specifications of this notion remain vague. An assessment of potential effects of thalamic deep brain stimulation (DBS) on spontaneous language may help to delineate respective functions. For this purpose, we analyzed spontaneous language samples from thirteen (six female / seven male) patients with essential tremor treated with DBS of the thalamic ventral intermediate nucleus (VIM) in their respective ON vs. OFF conditions. Samples were obtained from semi-structured interviews and examined on multidimensional linguistic levels. In the VIM-DBS ON condition, participants used a significantly higher proportion of paratactic as opposed to hypotactic sentence structures. This increase correlated negatively with the change in the more global cognitive score, which in itself did not change significantly. In conclusion, VIM-DBS appears to induce the use of a simplified syntactic structure. The findings are discussed in relation to concepts of thalamic roles in language-related cognitive behavior. & 2016 Elsevier Ltd. All rights reserved.

Keywords: VIM-DBS Thalamus Spontaneous language Syntax

1. Introduction Deep brain stimulation (DBS) is a therapeutic option successfully used for the treatment of patients with different long-term movement disorders (Martinez-Ramirez et al., 2015). Next to the most common application of DBS of the subthalamic nucleus (STN) in patients with Parkinson's disease (PD), DBS of the thalamic ventral intermediate nucleus (VIM) is mainly applied to treat patients with essential tremor (ET) (Koller et al., 1999; Obwegeser et al., 2000; Pahwa et al., 2006; Sydow et al., 2003; Zhang et al., 2010; for a review see Chopra et al., 2013). In this context it appears noteworthy, that the thalamus is thought to be crucially involved in the integration of both sensorimotor and cognitive processes, thus enabling contextually suitable behaviors (Ahrens et al., 2015; Bradfield et al., 2013; Fama and Sullivan, 2015; Ferguson and Gao, 2015; Funahashi, 2013; Ketz et al., 2015; Abbreviations: ANOVA, analysis of variance; DBS, deep brain stimulation; ET, essential tremor; PANDA, Parkinson Neuropsychometric Dementia Assessment; PD, Parkinson's disease; STN, subthalamic nucleus; VF, verbal fluency; VIM, ventral intermediate nucleus n Corresponding author. E-mail address: [email protected] (F. Klostermann). http://dx.doi.org/10.1016/j.neuropsychologia.2016.05.028 0028-3932/& 2016 Elsevier Ltd. All rights reserved.

Klostermann, et al., 2006, 2009; Marzinzik et al., 2008; Mitchell et al., 2014; Nikulin et al., 2008; Pinault, 2004; Saalmann and Kastner, 2015; Schmahmann and Pandya, 2008). On the level of language processing, such thalamic function has been conceived as the integration, modulation, and monitoring of cortical languagespecific and working memory functions – complemented by the basal ganglia (Crosson, 1985, 1992; Lieberman, 2002; Nadeau and Crosson, 1997; Ullman, 2001, 2004, 2006; Wahl, et al., 2008; for reviews see Barbas et al., 2013; Crosson, 2013; Klostermann et al., 2013; Saur et al., 2008). Particularly ventral, mediodorsal, and intralaminar nuclei (Barbas et al., 2013; Ehlen et al., 2014; Woods et al., 2003) have been proposed as candidate structures for language-relevant functions. Early conceptions of an integrative thalamic function for language performance came from observations of lexical abnormalities under intraoperative thalamic stimulation (e.g., Hugdahl and Wester, 1997; Ojemann, 1985; Ojemann and Ward, 1971; for a review see Hebb and Ojemann, 2012) and particularly from repeatedly observed “thalamic aphasia” in patients with a history of left hemispheric thalamic stroke. These patients typically suffer from anomia, semantic paraphasia, decreased verbal output and fluency, as well as varying degrees of comprehension deficits (e.g., Bogousslavsky et al., 1986; Carrera and Bogousslavsky, 2006;

F. Ehlen et al. / Neuropsychologia 89 (2016) 74–82

Crosson, 1984; Kuljic-Obradovic, 2003; Liebermann et al., 2013; Nolte et al., 2011; Pergola et al., 2013; Raymer et al., 1997; for reviews see Crosson, 2013; De Witte et al., 2011; Schmahmann, 2003; Van der Werf et al., 2000). Respective deficits appear to increase as a function of sentence complexity and were proposed to result from a reduced thalamic ability to relate sentence elements to one another (Crosson, 2013). In a similar sense, semantic paraphasia in patients with thalamic lesions was argued to result from impaired semantic feature binding (Crosson, 2013), i.e., a reduced capacity to integrate cortically stored semantic features to create a complete concept of the respective word (Assaf et al., 2006; Crosson, 2013; Hart et al., 2013; Kraut et al., 2002a, 2002b; Nadeau and Crosson, 1997; Stringaris, et al., 2007). In line with these clinically-motivated findings, an integrative thalamic function was suggested by electrophysiological studies indicating thalamo-cortical co-activity during semantic and syntactic information processing (Hohlefeld et al., 2013; Krugel et al., 2014; Slotnick et al., 2002; Wahl et al., 2008). However, concrete implications for spontaneous language are difficult to assess systematically. Given that VIM-DBS induces functional state changes well defined with respect to their timing and neuroanatomical point of action in the thalamus, the evaluation of its neuromodulatory effects on language processing may provide further insight into respective functions. In this regard it is worth noting that reduced word production in verbal fluency (VF) tasks has regularly been found under active VIM-DBS (Benabid et al., 1996; Ehlen et al., 2014; Fields et al., 2003; Schuurman et al., 2002; Troster et al., 1999, 1998; Woods et al., 2001, 2003). However, effects of VIM-DBS on natural language have – to our knowledge – not yet been examined. This seems surprising because, from a practical perspective, the question of whether the mentioned DBS effects on VF indicate impairments also on the level of communication, relates to important aspects of patients’ everyday social life. In view of the presumed integrational thalamic function outlined above, VIM-DBS was expected to impact on spoken language primarily on the level of complexity, particularly affecting the hierarchical organization of sentences and possibly word composition or class. However, to gain a broader picture of VIM-DBS effects on natural language beyond these levels, a large number of linguistic measures was additionally investigated. We therefore comprehensively assessed spontaneous language samples from semi-structured interviews of patients with VIMDBS in their ON vs. OFF stimulation conditions. The aim of the study was two-fold: conceptually to gain further information about thalamic contributions to biolinguistic functions and clinically to complement the understanding of potential DBS nonmotor side effects.

2. Patients and methods 2.1. Patients Thirteen patients (six female / seven male) diagnosed with ET and treated with VIM-DBS participated in the study, all of whom were right-handed native German-speakers. VIM-DBS had been established for at least one year in all but one patients (who had been treated for six months) and was generally applied bilaterally except for one participant with left-hemispherical DBS only. None of the participants had a previous or current history of brain disease other than ET, including all psychiatric disorders, such as depression, psychosis or apathy (according to the criteria of the German Manual for Psychopathological Diagnosis (AMDP, 2007)). An overview over the participants’ demographic data is provided in Table 1. The examinations were carried out in the ON vs. OFF

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Table 1 An overview of the participants’ baseline characteristics is given as group mean values and standard deviations (SD) including DBS-related parameters. All data relate to the individual ON-stimulation session. A. Participants' Baseline Data Mean 70.15 9.62 15.38 3.50

SD 7 9.24 7 1.71 7 13.57 7 3.19

Amplitude (V) Pulse width (μs) Frequency (Hz) Polarity (mono / bi)

Right Mean 7 SD 3.32 7 1.46 60.00 (median) 152.50 733.27 8/4

Left Mean 7 SD 3.117 1.49 60.00 (median) 162.69 7 48.63 8/5

Position of center of active contacts x (mm) y (mm) z (mm)

14.107 1.32
15.46 7 1.36
1.30 7 1.89

13.91 71.47
15.477 1.32
1.337 1.44

Age (years) School education (years) Disease duration (years) DBS duration (years)

Range 69–75 13–13 11–56 .5–10

B. Stimulation Parameters

An overview of the participants’ baseline characteristics is given as group mean values and standard deviations (SD) including DBS-related parameters. All data relate to the individual ON-stimulation session.

stimulation state within a two-month interval in randomized order. Medication, if applicable, remained unchanged. For the DBS OFF condition, stimulation was switched off at least thirty minutes before beginning the interview (in order to attain a situation that was considered a compromise between informative value and strain for the patients). Examinations in the DBS ON condition were carried out under therapeutic stimulation parameters that had been stable for at least two months prior to the assessment. All participants had been recruited from the Outpatient Clinic for Movement Disorders of the Charité. They gave written informed consent to the study protocol approved by the local ethics committee (protocol number EA2/047/10). 2.2. VIM-DBS implantation Implantation of tetrapolar DBS electrodes (Medtronics, model 3378) into the VIM had been performed by stereotactic surgery based on preoperative MRIs. Electrode localization had been accomplished using atlas coordinates as well as intraoperative micro-electrode recordings and intraoperative macro-electrode stimulation. They were confirmed by post-operative T2w-MRIs within two days after the implantation. All operations were carried out in the Charité University Hospital Berlin in the Department of Neurosurgery by the same neurosurgeon and his team at the Campus Virchow Klinikum. 2.3. Spontaneous language samples Spontaneous language samples were acquired from semistructured interviews conducted by an interviewer trained in psychological interviewing and were digitally recorded (software: Audacity 1.3.13-beta, microphone: the t.bone MB 88U Dual) in a sound-proof chamber within the Charité University at the Campus Virchow Klinikum. Patients were comfortably seated on a chair in an upright position. The microphone (the t.bone MB 88U Dual) was located at a distance of approximately 30 cm from the mouth. The sound quality was checked and adjusted in the beginning of each interview by simultaneously listening to the spoken voice via

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headphones and observing the recording's spectrogram. As a default one out of six predefined open questions was posed per participant and session related to either i. school days, ii. working life, iii. parents, iv. home, v. vacation, or vi. Hobbies – comparable to those used in similar settings (Batens et al., 2014; Hussmann et al., 2012; Illes et al., 1988). Questions were randomized across the participants and balanced between the individual ON and OFF stimulation sessions. Further questions were asked by the interviewer only if the participants indicated to have ended their stream of thought (either by an above-average pause following a completed sentence, or by expressions like “There is nothing more to say.”), and if the respective answer had not yielded a sufficiently long monologue of at least sixty seconds. In this case a consecutive question was formulated either by referring to the participant's current answer or by asking another out of the six questions above. For further analysis, a monologue of at least sixty seconds – preferably not containing any questions by the interviewer – was excerpted from each spontaneous language sample. As starting point of each monologue, we defined the end of the interviewer's question. 2.4. Transcription Interview transcriptions were performed based on the guidelines developed for the Aachener Sprachanalyse (ASPA; Grande et al., 2006; section “Transkription”; cf. Hussmann et al., 2012). Our protocol deviated in the following: 1. Sample length was based on the criteria described above due to the frequent incapacity of patients to hold a monologue for more than one minute; 2. pause duration was denoted in milliseconds in order to refine the traditional pause analysis. 2.5. Neurolinguistic analysis A comprehensive language analysis was performed by determining the following “direct parameters” from the data sets: i. word class (ten types, each with up to seven subtypes; as defined by the German standard dictionary Duden (http://www.duden.de, last access: 03.08.2015); ii. constituents (28 subcategories); ii. further morphosyntactic categorizations of verbs, nouns, pronouns, adjectives/adverbs, iii. word complexity (simple vs. complex, the latter being compounds or derivatives) of full verbs, nouns, adjectives and adverbs; iv. types of clauses (6 subcategories of main clauses; 18 subcategories of subordinate clauses; sentence equivalents); v. number of sentences; vi. types of stylistic devices (for details see appendix I); vii. types of errors (i.e., grammatical, morphological, lexical, phonetic, contextual, stylistic, idiomatic, pragmatic, logic), viii. duration of monologue (in seconds); ix. number of words; x. number of pauses; xi. pause duration; xii. articulation rate (number of syllables per second, excluding pauses greater than 200 ms). So called “empty particles” (e.g., “uh”) were excluded from all word counts. To reduce data complexity, stylistic devices were categorized as either semantic or syntactic, errors were summed up, and the following “indirect parameters” were derived from the other “direct parameters” based on values commonly tested in comparable study designs (Batens et al., 2014; Boxum et al., 2010; Grande et al., 2006; Holtgraves et al., 2010; Hussmann et al., 2012; Pennebaker et al., 2007; Weston et al., 1989; Zanini et al., 2003,, 2009), i.e., i. speed (here defined as number of words / duration of monologue excluding interruptions); ii. type-token-ratio (number of distinct lexemes / total number of words used; higher values are considered to reflect larger lexical diversity (Johnson, 1944; cf. Perkins, 1994); iii. total pause duration; iv. tactic sentence structure, i.e., iv–a. paratactic structure defined as either syndetic or asyndetic coordination of main clauses (all sentences were counted that were

either constituted of more than one main clause and no subordinate clause, or consisted of only one main clause and followed a sentence containing no subordinate clause); iv–b. hypotactic structure defined as subordination of subclauses to main clauses (Müller, 2011) (all sentences containing at least one subordinate clause were counted; sentence consisting of only one main clause that did not follow a purely main clause construction were not included in either category). The different types of word class were analyzed in a descriptive manner and were classified as belonging to either the “open” or the “closed word class”. Open class words are generally defined as words that convey semantic information (Garrett, 1978); the class can be readily extended by acquiring new words (Dürscheid, 2012). Nouns, (full) verbs, and adjectives are generally classified as members of the open class (Fanselow and Staudacher, 1991), while adverbs are treated somewhat ambiguously in the literature (Grande et al., 2006; Keller and Leuninger). Closed class words, on the other hand, convey structural information (Garrett, 1978) and belong to a class that cannot be extended by the speaker because their number is limited in each language. We here defined open class words as the sum of all full verbs, nouns, adjectives and modal adverbs, and closed class words as the sum of modal and auxiliary verbs, all other types of adverbs, pronouns, numerals, articles, prepositions, particles and conjunctions. To gain independence from differences in monologue length, all values except speed (in words/s) were calculated as ratios of the total number of words. 2.6. Additional assessments We used the Parkinson Neuropsychometric Dementia Assessment (PANDA) (Kalbe et al., 2008) to evaluate cognitive functions such as working memory, executive functions, and VF. This score was chosen because the study was performed in a larger context of DBS, so that comparability with PD patients with STN-DBS was intended, and as the PANDA has been reported to detect cognitive impairments more reliably than other short scales (Gasser et al., 2015). In addition to the semantic alternating VF task of the PANDA (naming animals / pieces of furniture), all patients performed 60 s VF tasks under the following three task conditions: semantic nonalternating (naming of vegetables), phonemic non-alternating (words starting with ‘s’), and phonemic non-alternating (words starting with ‘g’ / ‘r’). 2.7. Statistical analysis ON/OFF comparisons were performed for all “indirect parameters” as well as for stylistic devices, errors, articulation rates and word complexity by using two-tailed ttests for univariate parameters (i.e., speed, type-token-ratio, total pause duration, errors) and ANOVAs for repeated measures for multivariate parameters (i.e., tactic sentence structure, stylistic devices, word complexity) with the within-subject factors “stimulation” (two levels: ON/OFF) and “parameter” (number of level according to number of subcategories). Bonferroni corrections were used for all multivariate ANOVAs. Pearson's correlations were performed between change scores (ON minus OFF) of parameters that differed significantly between the two DBS conditions and the change scores of all PANDA subtests (except VF) as well as of the mean VF performance. Additionally, gender-related effects were assessed by using „gender” as an additional between-subject factor.

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3. Results

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Table 3 Baseline Data of Analyzed Monologues.

3.1. Cognitive scores

ON

The mean number of words produced in the VF tasks was significantly lower in the VIM DBS ON vs. OFF condition (ON: 10.56374.085; OFF: 12.417 73.801; p ¼.048). There were no significant ON/OFF difference in the PANDA subtests (see Table 2).

OFF

Mean

SD

Mean

SD

Duration of monologue (s) Number of words Number of errors Number of sentences

94.75 136.62 10.62 12.62

7 7 7 7

86.57 135.38 9.15 11.31

7 7 7 7

Number of clauses, total Main clauses Subordinate clauses

19.54 15.46 3.62

7 8.22 7 7.05 7 3.07

18.85 13.54 4.62

7 8.10 7 5.64 7 4.05

.852 .538 .387

Number of stylistic devices assessed, total Semantic Syntactic

24.54

7 13.47 22.54

7 12.86

.718

14.23 10.31

7 9.04 7 6.21

7 9.80 7 4.67

.811 .629

31.52 66.19 7.93 6.85

p-Value 22.28 59.44 6.57 4.84

.525 .964 .519 .639

3.2. Baseline data of neurolinguistic analysis Baseline data of the analyzed monologues are summarized as absolute values in Table 3. No significant differences were found here. On a descriptive level, although monologues were slightly longer in the ON condition, they contained relatively fewer words (ON: 1.442/s; OFF: 1.564/s), fewer clauses (ON:.206/s; OFF:.218/s), and slightly more errors (ON:.112/s; OFF:.106/s). The total number of stylistic devices (ON:.259/s; OFF:.260/s) was unaltered with a slightly lower proportion of semantic devices (ON: 57.99%; OFF: 59.39%). The relative number of sentences was almost equal in both conditions (ON:.133/s; OFF:.131/s). Concerning clauses, participants showed a higher proportion of main clauses (ON 79.134%; OFF: 71.837%) and a lower proportion of subclauses (ON: 18.504%; OFF: 24.490%) in the DBS ON condition. 3.3. Type-token-ratio, pauses and speed Statistical evaluations of values relative to the number of words produced indicated no significant ON/OFF effects in the type-token-ratio (ON: 0.007 7.004; OFF: 0.007 7 .003; p¼ .995), total pause duration (ON: 0.341 7.347 s/word; OFF: 0.2577 .161 s/word; p ¼.305), or errors (ON: 0.082 7 .056 errors/word; OFF: 0.067 .034 errors/word; p ¼.410). Likewise, no differences in speed (ON: 1.595 7.525 words/s; OFF: 1.657 7.406 words/s; p ¼.571) or articulation rate (OFF: 225.167776.160 syllables/s; ON: 224.8467100.571 syllables/s; p ¼.932) were found. 3.4. Tactic sentence structure The ANOVA testing ON/OFF effects on tactic sentence structure indicated two significant main effects: firstly, stimulation (ON:.047 7.045 structures/word; OFF:.032 7.020 structures/ word; F 1,12 ¼6.018; p ¼.030), i.e., under active stimulation more of the tested sentence structures were used; secondly, tactic sentence structure itself (proportion of paratactic structure:.057 7.043 structures/word; proportion of hypotactic structure:.019 7.047 structures/word; F1,12 ¼ 10.654; p ¼.007), i.e., regardless of the stimulation state, more paratactic than hypotactic sentences were used. Furthermore, a significant interaction between stimulation and the type of tactic sentence structure was found (ON

13.38 9.15

Baseline data related to the analysed monologues from the DBS OFF vs. ON condition are provided for descriptive reasons. Absolute values are given as means and standard deviations (SD) together values relative to the duration of the monologues (i.e. per second), respectively as percentage values for subtypes of clauses and stylistic devices. Average duration of the monologue was longer in the DBS ON condition. Relative to the duration, participants produced fewer words and fewer clauses in the DBS ON condition with relatively more main clauses and fewer subclauses. The relative number of stylistic devices was marginally reduced in the DBS ON condition with a slightly lower proportion of semantic devices. Rates of errors and sentences were almost equal.

paratactic:.073 7.050 structures/word; hypotactic:.017 7.014 structures/word; F1,12 ¼5.635; OFF paratactic:.044 7.024 structures/word; hypotactic:.025 7.012 structures/word; p ¼.035; post hoc ON/OFF comparison of paratactic structure: p ¼.034; hypotactic structure: p ¼ .123) (see Fig. 1).

3.5. Stylistic devices and word complexity The same ANOVA approach showed no significant effects of stimulation (F1,12 ¼1.296; p ¼.277) on the proportions of stylistic devices, and no further significant main effect or interaction. Likewise, the ANOVA testing stimulation effects on word complexity indicated no significant effect of stimulation (F1,12 ¼.056; p ¼.816) but significant differences between the proportions of simple (.3567 .069) and complex (.144 7.053; F1,12 ¼55.889; po .000) words (regardless of the stimulation state). No interaction was found (F 1,12 ¼ 1.462; p ¼.250).

Table 2 Cognitive PANDA Score. ON

PANDA

Total Part I Part II Part III Part IV Part V

OFF

Mean

SD

Mean

SD

p-Value

20.85 3.46 5.38 3.31 4.54 4.15

5.55 1.76 1.50 1.55 1.13 2.58

21.38 3.92 5.08 3.62 4.00 4.77

6.27 1.55 1.38 1.19 1.58 2.20

.785 .387 .527 .584 .222 .487

PANDA Part I: word pair associate learning task with immediate recall; Part II: semantic alternating verbal fluency; Part III: visuospatial task; Part IV: working memory and attention task; Part V: word pair associate learning task with delayed recall.

Fig. 1. Tactic Sentence Structure. The ratio of paratactic sentences (given as structures/word) was significantly increased in the DBS ON condition (p ¼.034, indicated by the asterisk) while the ratio of hypotactic sentences was reduced. Error bars indicate standard errors.

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Fig. 2. Types of Word Class. Usage of words from the ten different word classes (given as ratios of all words) was assessed and words were categorized as belonging to either the open or closed class. The patterns of word class usage were largely equal in the DBS-OFF and ON condition with a propensity towards a higher ratio of words belonging to the closed class used in the ON condition. Note that twelve categories are depicted since modal adverbs and full verbs were categorized as open class words, whereas other adverbs and modal/auxiliary verbs were counted separately as closed class words. Error bars indicate standard errors.

3.6. Word classes The proportions of different types of word classes were almost equal in the DBS-OFF and ON condition. That said, it may be noted that patients used on average more words from the closed class in the ON condition and more adjectives, modal adverbs (both classified as open class), and conjunctions in the OFF condition (see Fig. 2). 3.7. Correlations Although the DBS-related modulations of the PANDA subtests were not significant in themselves, a significant negative correlation between the change scores of paratactic structure and the change score of PANDA subtest V (word pair associate learning task with delayed recall; r ¼
.710; p ¼.007; see Fig. 3) was identified. There was furthermore a trend towards a negative correlation between the change scores of paratactic structure and the mean VF change score (r ¼
.546; p ¼.066). This means that an increase in

Fig. 3. Correlation between change scores of paratactic sentences and cognitive score. The increase in the ratio of paratactic sentences (given as structures/word) correlated negatively with the change in the cognitive PANDA subtest V (i.e., delayed recall given in points; each change score computed as ON minus OFF values). Accordingly, increased paratactic structure in the DBS ON condition was found together with a slight decrease in this cognitive score.

paratactic sentence structure went along with a slight decline in further cognitive performance. No gender-related differences were found.

4. Discussion In the current study, effects of VIM-DBS on spontaneous language production were assessed by means of a comprehensive linguistic assessment comparing the DBS ON vs. OFF condition. As the main stimulation effect, an increase in paratactic structure (i.e., the alignment of main clauses) with a concomitant decrease in the proportion of hypotactic sentence structures (i.e., subordination of subclauses to main clauses) was observable in the ON compared to the OFF condition. At the same time, rates of errors, stylistic devices and word classes as well as speed and lexical diversity were largely unaltered. This rather circumscribed effect of thalamic neuromodulation on sentence complexity appears of interest in light of proposed behavioral and cognitive functions of the thalamus which has even been labeled as the “little brain” (Carrera and Bogousslavsky, 2006). In this regard, a number of studies have outlined integrative thalamic roles in diverse domains, such as executive control, selective attention, response preparedness, cognitive control, and conscious stimulus perception, by consistently demonstrating thalamo-cortical co-processing (Ahrens et al., 2015; Bradfield et al., 2013; Fama and Sullivan, 2015; Ferguson and Gao, 2015; Funahashi, 2013; Ketz et al., 2015; Klostermann et al., 2006, 2009; Marzinzik et al., 2008; Mitchell et al., 2014; Nikulin et al., 2008; Pinault 2004; Saalmann and Kastner, 2015; Schmahmann and Pandya, 2008), as well as for languagerelated functions (Hohlefeld et al., 2013; Krugel et al., 2014; Slotnick et al., 2002; Tiedt et al., 2016, unpublished results). Comparable neurophysiological findings have also been raised in the context of language, both on the level of syntactic and semantic phrase analysis (Wahl et al., 2008). The physiological basis of these integrative functions has been proposed to rely on the particular properties of thalamic relay neurons and thalamo-cortical networks (Sherman, 2005). With respect to language functions, information from domain-specific frontal, temporal, and cerebellar areas are, e.g., thought to be integrated thalamically with prefrontal working memory representations (Barbas et al., 2013).

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Of note, the stimulation induced increase in paratactic sentence structures correlated with a slight deterioration of measures for working memory and memory retrieval functions, as reflected by the results in the delayed recall and VF tasks. Based on these findings and the aforementioned considerations, the construction of comparably complex hypotactic instead of simpler paratactic sentence structures is well compatible with the concept of a thalamic integration of syntactic information with frontal working memory functions as well as with the influential view that the referencing, hierarchization, and integration of distinct clauses are supported by thalamic nuclei (Crosson, 2013). In this regard, syntax-related information has, e.g., been proposed to be processed in the striatum and might reach thalamic nuclei via the direct and indirect subcortical pathways (Ullman, 2001, 2004). That said, comparable basal ganglia functions have been denied by other authors and have instead been described as restricted to the inhibition of lexical alternatives competing for release (Longworth et al., 2005; cf. Copland, 2003; Kotz et al., 2003; Wallesch and Papagno, 1988). The presently increased proportion of paratactic sentence structures under VIM-DBS may thus be interpreted as an interference with the superordinate capacity to hierarchize language information within the syntactic framework of sentences while leaving correctness, speed, the use of different word classes, and even stylistic devices unaffected. This also appears in line with the model on sentence comprehension proposed by Dominey et al. (Dominey and Inui, 2009). The authors predicted a “significant” basal ganglia and thalamic role for the decoding of complex sentence structures. They proposed the analysis of simple sentences to be achieved cortically, whereas syntactically demanding sentences should necessitate supportive subcortical functions to integrate the lexical content stored within the working memory into the growing sentence. The fact that hypotactic sentence structure imposes high demands on the speaker and that an increase in paratactic structure – even without a loss of grammaticality or correctness – can be a marker of cognitive impairment (Kemper et al., 1993), has been suggested by various clinical studies (Caplan and Waters, 1999; Kemper et al., 1993, 2001; Kircher et al., 2005; Miniscalco et al., 2007; Norman et al., 1991; Stojanovik et al., 2002). The present results corroborate this notion and altogether suggest that subtle impairments in executive functions induced by VIM-DBS, rather than language specific effects, underlay the reduction in sentence complexity. Since the above and other models have posited conjunct striatal and thalamic functions for language processing, respective findings on PD – a condition relying on striatal dysfunction – and on its treatment by STN-DBS shall briefly be outlined: In PD patients a compromised ability to process complex sentences involving relative clauses has been shown to correspond to striatal dysfunction (Grossman et al., 2003), interpreted as the result of impaired set-shifting, reduced verbal working memory, and cognitive flexibility (Hochstadt et al., 2006). Stimulation-related effects of STN-DBS on spontaneous language production have, however, been rather inconsistent. Both subtle improvements (Whelan et al., 2005; Zanini et al., 2003) as well as deterioration (Schulz et al., 2012) – especially of grammatical capacities (Phillips et al., 2012) – were found next to unaltered language functions (Batens, et al., 2014; Whelan et al., 2005; Zanini et al., 2009). To directly compare effects of stimulation in either DBS target nucleus, linguistic evaluations of both patient groups may be a focus of future studies. Also the question of whether thalamic DBS interacts with preexisting language deficits in ET patients may be a relevant subject of further studies, considering that mild frontal dysfunctions, including impaired verbal processing and working memory (Lombardi et al., 2001; Troster et al., 2002) have repeatedly been

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reported in ET patients (Benito-Leon et al., 2006; Duane and Vermilion, 2002; Gasparini et al., 2001; Lacritz et al., 2002; Louis et al., 2010; Sahin et al., 2006; for reviews see Benito-Leon and Louis, 2011; Chandran and Pal, 2012; Louis et al., 2010). With respect to the anatomical substrates of the reported language effect, VIM-DBS could reasonably interfere with functions of nearby structures, such as the intralaminar centromedian–parafascicular complex, the inferior thalamic peduncle, or pulvinar nuclei. These nuclei, rather than VIM itself, have been assumed to support the cortex in language processing (Carreiras et al., 2009; Crosson, 1999; Ketteler et al., 2008; Liebermann et al., 2013; Parent and Parent, 2005; Rumsey et al., 1997; Tettamanti et al., 2005; Van der Werf et al., 2000; Vannest et al., 2011; Ye et al., 2011; Zoppelt et al., 2003). With respect to the study design, it may finally be noted that a large number of linguistic parameters were extracted from relatively short language samples to provide an orienting and broad examination of VIM-DBS effects on spontaneous language. Whether the present findings are also representative of longer speech samples might be addressed in future studies.

5. Conclusion VIM-DBS exerted an effect on the syntactic level of spontaneous language that was reflected by an increase in the proportion of paratactic, i.e., main clause dominated, sentence structure. In view of models depicting a subcortical involvement in language processing, the integration of clauses into syntactically complex sentences appears to be supported by thalamic processes. Therefore we presume VIM-DBS to interfere with this function via current spread into neighbouring language-relevant structures. Worthwhile noticing, speed, rates of errors, stylistic devices, word classes, and lexical diversity were largely unaffected. VIM-DBS thus appears to affect syntax rather specifically, leaving lexicality, style and correctness unaltered.

Financial disclosures None of the authors has any conflict of interest with respect to the present work. Fabian Klostermann received honoraria for advisory activities from Archimedes, UCB, and Abbott, and holds grants from the German Research Foundation (Kl 1276/4 and Kl 1276/5). Andrea A. Kühn received honoraria for advisory activities from Medtronic, St. Jude Medical, Boston Scientific, UCB and holds grants from the German Research Foundation (KFO247 and KU 2261/6-1).

Funding sources for study This study was supported by the German Research Foundation (Kl-1276/5 in Clinical Research Group 247).

Acknowledgements We would like to thank Jan Ehlen as well as Andreas Horn and Dirk Lang for their contributions to this study.

Appendix A. Assessed stylistic devices See Tables A1 and A2.

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Table A1 Syntactic stylistic devices.

Figures of addition

Table A2 Semantic stylistic devices.

Category

Subcategory

Correction

Correction

Sub-subcategory

Category

Figures of addition Retraction Polysyndeton Epithet Paraphrase Redundancy, broader sense

Figures of omission

Epiphrasis Parenthesis Enumeration Ellipsis

Praeteritio Archaism Anachronism

Figures of permutation

Backward Forward

Exemplum

Catachresis Tropes

Other

Contradictio in adiecto Oxymoron Current example Historic example Poetic example Metonymy / Synecdoche Mataphor

Irony

Pars pro toto Toto pro pars Euphemism Anthropomorhism other Litotes Sarcasm Cynicism other

Antonomasia Allegory Symbol

Other

Hyperbola Understatement Peripeteia Pejorative Alogism Neologism Direct speech Indirect speech

The tables present a list of all syntactic and semantic stylistic devices that were assessed in the current study. The classification as ‘syntactic’ vs. ‘semantic’ was based on the work by Baumgarten (Baumgarten, 2011). Amongst semantic stylistic devices, figures of omission (i.e. elisions) were not counted, as they are commonly used in spoken German (e.g. “ich lass’” instead of “ich lasse” or “wir ham’” instead of “wir haben”; cf. Grande et al., 2006).

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