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Impact of deep brain stimulation of the subthalamic nucleus on natural language in patients with Parkinson's disease


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Background: In addition to the typical motor symptoms, a majority of patients suffering from Parkinson’s disease experience language impairments. Deep Brain Stimulation of the subthalamic nucleus robustly reduces motor dysfunction, but its impact on language skills remains ambiguous. Method: To elucidate the impact of subthalamic deep brain stimulation on natural language production, we systematically analyzed language samples from fourteen individuals (three female / eleven male, average age 66.43 ± 7.53 years) with Parkinson’s disease in the active (ON) versus inactive (OFF) stimulation condition. Significant ON-OFF differences were considered as stimulation effects. To localize their neuroanatomical origin within the subthalamic nucleus, they were correlated with the volume of tissue activated by therapeutic stimulation. Results: Word and clause production speed increased significantly under active stimulation. These enhancements correlated with the volume of tissue activated within the associative part of the subthalamic nucleus, but not with that within the dorsolateral motor part, which again correlated with motor improvement. Language error rates were lower in the ON vs. OFF condition, but did not correlate with electrode localization. No significant changes in further semantic or syntactic language features were detected in the current study. Conclusion: The findings point towards a facilitation of executive language functions occurring rather independently from motor improvement. Given the presumed origin of this stimulation effect within the associative part of the subthalamic nucleus, this could be due to co-stimulation of the prefrontal-subthalamic circuit.
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Impact of deep brain stimulation of the
subthalamic nucleus on natural language in
patients with Parkinson’s disease
Felicitas EhlenID
*, Bassam Al-FatlyID
, Andrea A. Ku¨hn
, Fabian Klostermann
1Department of Neurology, Humboldt-Universita
¨t zu Berlin and Berlin Institute of Health, Charite
¨tsmedizin Berlin, Berlin, Germany, 2Department of Psychiatry and Psychotherapy, Ju¨disches
Krankenhaus Berlin, Berlin, Germany, 3Berlin School of Mind and Brain, Humboldt-Universita
¨t zu Berlin,
Berlin, Germany, 4Neurocure Cluster of Excellence, Humboldt-Universita
¨t zu Berlin and Berlin Institute of
Health, Charite
¨tsmedizin Berlin, Berlin, Germany, 5Bernstein Center for Computational
Neuroscience, Humboldt-Universita
¨t zu Berlin and Berlin Institute of Health, Charite
Berlin, Berlin, Germany, 6Deutsches Zentrum fu¨r Neurodegenerative Erkrankungen, Berlin, Germany
In addition to the typical motor symptoms, a majority of patients suffering from Parkinson’s
disease experience language impairments. Deep Brain Stimulation of the subthalamic
nucleus robustly reduces motor dysfunction, but its impact on language skills remains
To elucidate the impact of subthalamic deep brain stimulation on natural language produc-
tion, we systematically analyzed language samples from fourteen individuals (three female /
eleven male, average age 66.43 ±7.53 years) with Parkinson’s disease in the active (ON)
versus inactive (OFF) stimulation condition. Significant ON-OFF differences were consid-
ered as stimulation effects. To localize their neuroanatomical origin within the subthalamic
nucleus, they were correlated with the volume of tissue activated by therapeutic stimulation.
Word and clause production speed increased significantly under active stimulation. These
enhancements correlated with the volume of tissue activated within the associative part of
the subthalamic nucleus, but not with that within the dorsolateral motor part, which again
correlated with motor improvement. Language error rates were lower in the ON vs. OFF
condition, but did not correlate with electrode localization. No significant changes in further
semantic or syntactic language features were detected in the current study.
The findings point towards a facilitation of executive language functions occurring rather
independently from motor improvement. Given the presumed origin of this stimulation effect
PLOS ONE | December 29, 2020 1 / 19
Citation: Ehlen F, Al-Fatly B, Ku¨hn AA, Klostermann
F (2020) Impact of deep brain stimulation of the
subthalamic nucleus on natural language in
patients with Parkinson’s disease. PLoS ONE
15(12): e0244148.
Editor: Allan Siegel, University of Medicine &
Dentistry of NJ - New Jersey Medical School,
Received: September 12, 2020
Accepted: December 3, 2020
Published: December 29, 2020
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
process; therefore, we enable the publication of
all of the content of peer review and author
responses alongside final, published articles. The
editorial history of this article is available here:
Copyright: ©2020 Ehlen et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: Our data are stored in
the public repository G-Node GIN (doi: 10.12751/g-
within the associative part of the subthalamic nucleus, this could be due to co-stimulation of
the prefrontal-subthalamic circuit.
Apart from disabling motor symptoms, Parkinson’s disease (PD) can lead to wide-ranging
non-motor symptoms [1]. These involve cognitive processes [2] which typically also affect
functions relevant to language such as memory, set shifting, flexibility, planning, and the inte-
gration of semantic networks [35]. The majority of PD patients thus develop language symp-
toms including impaired fluency [69] (for reviews see [10]) with an increase in speech
hesitations [11], and slower speech initiation [12]. On the syntax level, symptoms may com-
prise global impairments in sentence generation [13,14] (cf. [12]), decreased syntactic com-
plexity [11] (cf. [12]), and a specific decline in verbs [1517]. Moreover, an abnormally low
informational content [14,18] and impaired pragmatic language production have been
described [18,19]. Finally, comprehension deficits regarding complex sentences (e.g., [12,20
25]) and motor speech dysfunction [12,26] can add to disease-related communication
Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is a well-established thera-
peutic option for patients suffering from complex PD motor symptoms despite optimized
drug treatment [27] (for a review see [28]). One proposed mechanism of action is a modula-
tion of excessive beta frequency synchronization within the cortico-basal circuits [2931]. The
STN is embedded in the inhibitory “indirect” loop [32], while also being monosynaptically
connected with frontal motor and prefrontal cognitive areas [33,34] via the excitatory “hyper-
direct” pathway [35]. In this central position, the nucleus is expected to enable a protraction of
premature answers [34,36] and a modulation [37] of inputs from cortical projection regions.
Further, cross-modal signal integration is a postulated STN function, given marked overlap at
the border zones [34,38,39] of its dorsolateral motor, ventromedial associative, and rostral
limbic sections [32]. Cognitive STN functions, including language processing, have accord-
ingly been suggested to mainly involve inhibitory response control [5,17,33,4042], response
selection [4,43], and action sequencing [44]. However, although STN DBS applied to the dor-
solateral section exerts strong prokinetic motor effects, its impacts on cognition are ambiguous
with the majority of studies suggesting a DBS-related acceleration of cognitive speed [36,40,
41,4547], at the expense of premature responses leading to reduced accuracy [40,41,45,48,
Specifically regarding effects of STN DBS on natural language production, only a few stud-
ies have been conducted and delivered equivocal results: [5054] whereas reduced hesitations,
paraphasias, and errors together with improved lexical retrieval were interpreted as a func-
tional recovery [55], other studies showed vastly unaltered language functions [53,56] or com-
promised grammatical capacities [52].
Since this heterogeneity could relate to differences between language tasks as well as the
impact of variable stimulation fields [57], the current study aims to analyze a comprehensive
range of linguistic parameters in spontaneous language samples from persons with PD with
respect to the volume of tissue activated (VAT) by STN DBS. Under the premise of mainly par-
allel effects on motor and language functions, we hypothesized that STN DBS should primarily
counteract excessive inhibition, resulting in enhanced fluency, sentence generation, and infor-
mative content. At the same time, an increase in language errors could be expected to result
from DBS-induced disinhibition.
STN DBS effects on language
PLOS ONE | December 29, 2020 2 / 19
Funding: This study was supported by the German
Research Foundation (Kl-1276/5 in Clinical
Research Group 247) and the Open Access
Publication Fund of Charite
´– Universita¨tsmedizin
Berlin. Author BA has received a Doctoral Research
Grant from the German Academic Exchange
Service - DAAD. AAK has received honoraria for
advisory activities from Medtronic, Boston
Scientific, Abbott, Ipsen and Teva. FK has received
honoraria for advisory activities from CSL Behring
and Theranexus. The funders had no role in study
design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing interests: The authors have read the
journal’s policy and have the following competing
interests: AAK has received honoraria for advisory
activities from Medtronic, Boston Scientific, Abbott,
Ipsen and Teva. FK has received honoraria for
advisory activities from CSL Behring and
Theranexus. This does not alter our adherence to
PLOS ONE policies on sharing data and materials.
There are no patents, products in development or
marketed products associated with this research to
Participants and methods
Fourteen individuals (three female, average age 66.43 ±7.53 years, average disease duration
13.79 ±4.63 years, average DBS treatment duration of 3.14 ±1.95 years) treated with bilateral,
constant voltage-driven STN DBS participated in the study. All participants met the UK Brain
Bank Criteria for PD and were right-handed native German-speakers. The individual STN
DBS settings had been optimized with respect to clinical parameters during a one week stay on
our specialized ward for DBS patients following the implantation and during regular (i.e. quar-
terly) consultations in our specialized outpatients’ department. Compatible with other clinical
cohorts (e.g., [58]), most of our participants were treated with monopolar stimulation as it
requires lower stimulation intensity. Bipolar stimulation had been chosen if an individual
developed adverse effects arising from the comparably large volume of tissue activated by
monopolar stimulation [59]. An overview of individual demographic, disease and DBS-related
data is provided in Table 1.
Exclusion criteria were a previous or current history of brain disease other than PD, includ-
ing all psychiatric disorders such as depression, psychosis, or apathy as well as dementia
(assessed by the Parkinson Neuropsychometric Dementia Assessment; PANDA [60]) or unin-
telligible speech irrespective of the stimulation condition.
To obtain data for ON-OFF comparisons, all participants were examined in two separate
sessions, i.e. in the STN DBS ON and STN DBS OFF condition at an interval of two months
and systematically alternating order. Examinations in the ON condition were carried out
under therapeutic stimulation parameters that had been stable for at least two months prior to
the assessment. For the OFF condition, stimulation was switched off at least thirty minutes
before the examination. The individually optimized antiparkinsonian medication remained
stable and the timing of the assessments was planned individually to ensure the best clinical
“medication-ON” state (starting time at about 11 a.m. for most participants; the last medica-
tion intake was protocolled.
All participants were recruited from the outpatient clinic for movement disorders of the
´University Hospital Berlin. They gave written informed consent to the study protocol
approved by the ethics committee of the Charite
´–Universita¨tsmedizin Berlin (protocol num-
ber EA2/047/10). The research was conducted in accordance with current guidelines and the
Declaration of Helsinki.
STN DBS implantation
Implantation of tetrapolar, cylindrical DBS electrodes (Medtronics, model 3387; contact
height: 1.5 mm, diameter: 1.27 mm) into the STN had been performed by stereotactic surgery
based on preoperative MRIs using atlas coordinates, intraoperative microelectrode recordings,
and macroelectrode stimulation. Correct localizations had been confirmed by post-operative
MRIs. All operations had been carried out by the same neurosurgical team at the Charite
versity Hospital.
Electrode localization and calculation of volume of tissue activated
Electrode localization and calculation of VAT was performed in all participants except case 8
due to missing postoperative imaging. DBS leads were localized with Lead-DBS open access
MATLAB software (, version 2 [61]). To estimate of the VAT, Lead-DBS
incorporates pre-existing models (first proposed by [6265]) as well as tractography algo-
rithms in order to transition to the global volume of modulation [61]. The localization process
STN DBS effects on language
PLOS ONE | December 29, 2020 3 / 19
has been described in detail in earlier studies [65,66] and shall briefly be outlined: postopera-
tive images (CT or MRI) were co-registered to the preoperative MRI using either Advanced
Normalization Tools (ANTs; [67]) for postoperative CT scans
or the Statistical Parametric Mapping (SPM12) toolbox (
software/spm12/) for postoperative MRI scans. Brain-shift correction was implemented in a
further step to adjust for any bias caused by possible operation-related pneumocephalus.
ANTs normalization pipeline was applied to warp preoperative and postoperative acquisitions
to MNI (ICBM 2009b NLIN asymmetric) space. DBS electrodes were automatically recon-
structed in MNI space, followed by manual refinement if needed (electrode localization in the
xyz-space is provided in the S1 Table). Next, the VAT was modelled around each clinically
Table 1. Overview of demographic, disease and DBS-related data.
Pt. Age (ys) Sex Body Side of
School (ys) Hoehn &Yahr Disease Dur. (ys) DBS Dur. (ys)
1 55 M Right 10 2.5 10 2
2 62 M Right 10 2 15 6
3 61 F Left 10 3 18 2
4 67 M right 10 3 16 5
5 77 M right 12 4 19 2
6 75 M right 11 3 15 4
7 72 M left 12 2 15 3
8 55 F right 10 2 15 7
9 62 F right 8 3 22 8
10 70 M right 10 2 11 4
11 74 M right 8 2.5 14 2
12 73 M right 8 2 4 0.5
13 58 M left 13 2 10 4
14 69 M left 10 2 9 0.5
Pt. Voltage (V) Impulse Width (μs) Frequency (Hz) Impedance (O) Polarity
left right Left right left right Left right Left right
1 3.4 2.9 90 60 90 90 818 1145 Bi Mo
2 2.6 3.8 90 60 90 90 1035 1010 Bi Mo
3 2.2 3 60 90 90 90 604 594 Mo Mo
4 3.9 2.4 90 90 160 160 812 962 Mo Mo
5 3.7 3.8 60 60 130 130 500 956 Mo Mo
6 3.8 3.8 60 60 90 90 500 459 Mo Mo
7 2.9 2.9 60 60 130 130 766 766 Mo Mo
8 3.5 4.4 60 60 80 80 459 283 Mo Mo
9 1.7 1.3 60 60 130 130 577 441 Mo Mo
10 2.7 2.7 60 60 130 130 712 712 Mo Mo
11 3.5 2.1 60 60 130 130 848 523 Bi Mo
12 2.2 1 60 60 130 130 1083 2365 Mo Mo
13 2.1 2 60 60 130 130 550 523 Mo Mo
14 0.5 0.5 60 60 130 130 2457 2084 Mo Mo
The table provides an overview of the participants included in the language analysis (n = 14) regarding demographic, disease, and DBS related data; bi: bipolar; dur.:
duration; f: female; H&Y: Hoehn & Yahr Stage (DBS ON); m: male; mo: monopolar; Pt.: participant code
STN DBS effects on language
PLOS ONE | December 29, 2020 4 / 19
used active contact. Therefore, each participant’s clinical stimulation parameters were used to
calculate a volume conductor model of the DBS electrode and surrounding tissue (in analogy
to the procedure described in [65]). For this purpose, a tetrahedral volume mesh based on the
surface meshes of DBS electrodes and subcortical nuclei was generated using the Iso2Mesh
toolbox included in Lead-DBS. Regions that were neither filled with conductive/insulating
electrode material nor with gray matter were assigned to white matter. Gray matter nuclei
were defined by the DISTAL atlas [68]. Conductivities of 0.14 S/m and 0.33 S/m were assigned
to the white and grey matter, respectively (cf. [69]). We used values of 108 S/m for the plati-
num/iridium contacts and 10–16 S/m for the insulated parts of the electrodes. A simulation of
the potential distribution resulting from the DBS followed based on the volume conductor
model. As boundary condition we used the voltage applied to the active electrode contacts. For
monopolar DBS, the surface of the volume network represented the anode. By derivation of a
finite element method solution (toolbox simbio/FieldTrip incorporated in lead dbs software),
the gradient of the potential distribution was determined, resulting in a piecewise continuous
gradient. The extent and shape of the activated tissue volume were defined by setting the gradi-
ent as a threshold value above the frequently used value of 0.2 V/mm (cf. [38,65,70,71]).
Next, each participant’s bilateral VATs were overlapped with the motor and associative area of
the STN as provided by the DISTAL atlas [68] (see Fig 1). For each STN segment, the size of
the overlap cluster was normalized by taking its ratio to total VAT size. To assess whether the
results are dependent on the 0.2 V/mm threshold, we performed a control analysis that did not
include a heuristic/arbitrary threshold, but instead used the full electric field (see S1 Fig).
Motor and neurocognitive assessment
We used the motor section (i.e., part III) of the Unified Parkinson’s Disease Rating Scale
(UPDRS; minimum score = 0; maximum score = 108; higher scores indicate stronger symptom
severity) to assess motor symptom severity and the PANDA [60] (minimum score = 0; maxi-
mum score = 30; higher scores indicate stronger symptom severity) to evaluate cognitive func-
tions such as working memory, executive functions, and verbal fluency. As a part of the
UPDRS motor score, speech intelligibility was scored on the given scale (i.e., 0, 1, 2, 3, or 4
points indicate no, slight, mild, moderate, or severe speech problems, respectively [73]).
Fig 1. Localization of DBS electrodes within the STN. A: DBS electrodes localizations from thirteen participants in relation to the
STN. Electrodes have been reconstructed in MNI space. Red contacts represent clinically active contacts. B: Spatial distribution of active
contacts in relation to different STN segments (from DISTAL atlas). All 26 active contacts (red spheres) are projected cumulatively onto
the left hemisphere (right contacts have been flipped). Subcortical structures including STN segments were defined from DISTAL
subcortical atlas implemented in Lead-DBS [68]. Backdrop is from the high resolution 100 micron postmortem MRI in Edlow et al. [72].
Please note that due to missing post-operative MRI the data from participant no. 8 did not enter the localization analysis. GPe: globus
pallidus externus, GPi: globus pallidus internus, RN: red nucleus, STN: subthalamic nucleus.
STN DBS effects on language
PLOS ONE | December 29, 2020 5 / 19
Linguistic analysis
Spontaneous language samples. Participants were comfortably seated in a sound-proof
chamber. Semi-structured interviews were carried out by an interviewer trained in psychologi-
cal interviewing. To obtain spontaneous language samples of at least 60 seconds, one out of six
predefined open questions was posed in a randomized order per participant and session (i.e.,
related to i. school days, ii. working life, iii. parents, iv. origin, v. vacation, or vi. hobbies; cf.
[54,56,74]). If the answer did not yield a sufficiently long monologue, the interviewer formu-
lated further questions by either relating to the current answer or by choosing a different ques-
tion out of the six above. All interviews were digitally recorded (software: Audacity
1.3.13-beta, microphone: the t.bone MB 88U Dual). For further analysis, a monologue of
about sixty seconds was excerpted from each language sample. The end of the interviewer’s
question was defined as starting point of each monologue.
Transcription. Interview transcriptions were conducted according to the guidelines
developed for the “Aachener Sprachanalyse” [75] using the computer software ‘Praat’ (version
Linguistic analysis, parameters. With the aim to control for global comparability
between monologues recorded in both conditions, we first assessed monologue duration (in
seconds; excluding interruptions by the interviewer) and the articulation rate (syllables / s,
excluding pauses >200 ms). Next, to explore typical language difficulties described for PD
patients, we analysed i. the word production rate (words / s), ii. the total duration of linguistic
pauses (i.e., pauses corresponding to the grammatical structure), iii. the total duration of non-
linguistic pauses (i.e., pauses interrupting the natural flow of speech), iv. the language error
rate (ratio language errors / total number of words), v. the clause production rate (clauses / s),
and vi. sentence complexity (ratio complex / simple sentences; i.e., sentences including either at
least one subordinate clause or more than one main clause vs. sentences including only one
main clause). To estimate flexibility of word use, we additionally analysed vii. the rate of open
class words (i.e. words conveying semantic information [76] including full verbs, nouns, adjec-
tives, and modal adverbs which altogether can be extended by acquiring new words [77]) and
viii. the type-token ratio (i.e., the proportion of distinct lexemes).
The above parameters have generally been established in similar study designs [51,53,55,
74,75,7882]. To additionally evaluate semantic and syntactic measures not represented by
the above parameters, we performed an analysis of stylistic devices. A detailed list of all
assessed stylistic devices is provided in the S2 Table. In summary, the production rate of
semantic stylistic devices and syntactic stylistic devices was each expressed as the sum value of
the subcategories of semantic figures (i.e., ‘addition’, ‘omission’, ‘transposition’, ‘permutation’,
other’) and syntactic figures (i.e., ‘addition’, ‘omission’, ‘transposition’, ‘other’), respectively, per
Detailed data is publicly available at
Linguistic analysis, procedure. To obtain the above described parameters, the mono-
logues were subjected to manual linguistic analysis including the assessment of: number of
words; number and duration of linguistic and non-linguistic pauses; number and type of lan-
guage errors (i.e., grammatical, lexical, phonetic, contextual, stylistic, idiomatic, pragmatic,
logic); number and type of word classes (as defined by the German standard dictionary Duden
[83]); number and type of constituents (28 subcategories); morphosyntactic categorizations of
verbs, nouns, pronouns, adjectives/adverbs including word complexity; number and type of
clauses (i.e., 6 subcategories of main clauses; 18 subcategories of subordinate clauses; sentence
equivalents); number of sentences, and number and type of semantic and syntactic stylistic
STN DBS effects on language
PLOS ONE | December 29, 2020 6 / 19
Statistical analysis
The UPDRS motor score, PANDA score, and the interval between last medication intake and
assessment onset were compared in the ON vs. OFF condition using two-tailed paired sample
t-tests. The UPDRS speech item was compared using the Wilcoxon signed-rank test.
Regarding the linguistic analyses, we first compared monologue duration and articulation
rate in the ON vs. OFF condition using two-tailed paired sample t-tests. Next, the above
described linguistic parameters i. word production rate, ii. the total duration of linguistic
pauses, iii. the total duration of non-linguistic pauses, iv. language error rate, v. clause produc-
tion rate, vi. sentence complexity, vii. rate of open class words, and viii. type-token ratio were
compared in the ON vs. OFF condition using two-tailed paired sample t-tests (except for sen-
tence complexity where the Wilcoxon signed-rank tests was applicable). To determine the false
discovery rate of these eight ON-OFF comparisons, we applied the Benjamini–Hochberg pro-
cedure setting αto 0.05 (i.e., critical value ((i/m)0.05); with i=p-value rank; m= number
of comparisons; [84]).
Production rates of semantic and syntactic stylistic devices were assessed using two separate
repeated measures ANOVAs (each with the within-subjects factor ‘stimulation’ with two lev-
els). The first contained all categories of semantic figures (i.e., ‘addition’, ‘omission’, ‘transposi-
tion’, ‘permutation’, ‘other’; each expressed as sum value of their subcategories per second), the
second contained all categories of syntactic figures (i.e., ‘addition’, ‘omission’, ‘transposition’,
other’; each expressed as sum value of their subcategories per second).
To identify relationships between stimulation fields and changes in linguistic parameters,
we calculated ON-OFF difference values for each significantly changed linguistic parameter
and performed linear Spearman correlations with the ratio of the VAT overlap with the motor
and the associative area of the STN. Since electrodes were switched on and off bilaterally rather
than separately, overlap ratios were averaged for left and right hemispheric VATs.
The same significant ON-OFF difference values were furthermore related to ON-OFF dif-
ference values of the UPDRS motor score and the PANDA score using linear regression
Effect sizes of ON-OFF differences were estimated using Cohen’s d(>0.2: small; >0.5:
medium; >0.8: large effect size [85]) for t-tests and partial η
(>0.10: small; >0.25: medium;
>0.40: large effect size [86]) for pairwise comparisons resulting from the ANOVAs for stylistic
devices. All statistical analyses were performed in IBM SPSS Statistics (version 25).
The UPDRS motor score was significantly lower in the STN DBS ON vs. OFF condition (ON:
19.571 ±7.871 points; OFF: 38.000 ±13.156 points; p<0.001; Cohen’s d: 1.700). The PANDA
score did not change significantly (ON: 23.643 ±3.225 points; OFF: 22.500 ±3.653 points;
p= 0.345; Cohen’s d: -0.332). Speech was generally well intelligible in both stimulation condi-
tions (ON median: 1 point; OFF median: 1 point; p= 0.656; z<0.001). The interval between
the last medication intake and the beginning of the language assessment did not differ signifi-
cantly between the OFF vs. ON condition (ON: 1.64 ±1.434 hours; OFF: 2.286 ±1.369 hours;
p= 0.089; Cohen’s d: 0.459).
With respect to general comparability of the monologues, no significant ON-OFF differ-
ences were found regarding monologue duration (ON: 65.841 ±9.438 s; OFF: 65.376 ±16.913
s; p= 0.922; Cohen’s d: -0.034) or articulation rate (ON: 5.102 ±0.954 syllables / s; OFF:
4.730 ±0.673 syllables / s; p= 0.251; Cohen’s d: -0.450).
As presented in Table 2, statistical analysis of ON-OFF differences indicated a significantly
higher word production rate and clause production rate in the ON vs. OFF condition and a
STN DBS effects on language
PLOS ONE | December 29, 2020 7 / 19
lower language error rate in the DBS ON condition. No significant differences were indicated
regarding the rate of open class words, the type-token ratio,sentence complexity, and the total
duration of linguistic or non-linguistic pauses.
Regarding stylistic devices, ANOVAs showed a generally higher production rate of semantic
stylistic devices in the ON condition, which failed to reach the level of significance (ON:
.249 ±0.078 devices / s; OFF: .158 ±0.077 devices / s; p= 0.061; Cohen’s d: -1.180) and despite
very large standard deviations indicated a significant increase in figures of permutation (ON:
0.053 ±0.045 figures / s; OFF: 0.017 ±0.019 figures / s; p= 0.016 (after Bonferroni correction);
partial η
= 0.489). An increase in syntactic stylistic devices did not reach the level of signifi-
cance (ON: 0.196 ±0.096 devices / s; OFF: 0.144 ±0.082; devices / s; p= 0.063; Cohen’s d:
-0.585) with none of the single syntactic figures changing significantly.
Electrode localizations within the STN as illustrated in Fig 1 (collapsed for the left and right
STN) indicated 20 out of a total of 26 electrodes to be located within the dorsolateral motor
area and six within the ventromedial associative area.
The observed increase in the clause production rate in the ON vs. OFF condition was
strongly and significantly positively correlated with VAT overlap with the associative area of
the STN (r= 0.779, p<0.001; see Fig 2A top). This correlation was on a slightly weaker, yet
significant level also present for the word production rate (r= 0.498, p= 0.047; see Fig 2A bot-
tom). Furthermore, improvement in the UPDRS motor score in the ON condition was posi-
tively correlated with the average ratio of VAT overlap with the motor area of the STN
(r= 0.592, p= 0.026; see Fig 2B). On the contrary, no significant correlation was indicated
between the increase in the clause (r= 0.051, p= 0.420) or word (r= -0.152, p= 0.312) produc-
tion rates and the ratio of overlap with the motor area or between the improvement in the
UPDRS motor score and the overlap with the associative area of the STN (r= -0.306,
p= 0.158).
We identified no significant correlation between the observed reduction in the language
error rate in the ON vs. OFF condition with VAT overlap with the associative (r= -0.08,
p= 0.406) or the motor area of the STN (r= 0.400, p= 0.085).
We found no significant relationship between ON-OFF difference values of the UPDRS
motor score and clause (r
= 0.121; p= 0.224) or word (r
= 0.103; p= 0.264) production rates
or language error rates (r
= 0.005; p= 0.815) and no significant relationship between differ-
ence values of the PANDA score and clause (r
= 0.030; p= 0.553) or word (r
= 0.005;
p= 0.806) production rates or language error rates (r
= 0.055; p= 0.419).
Table 2. Linguistic parameters in the STN DBS ON and OFF condition.
Mean SD Mean SD p-value Cohen´s dBH
Word production rate (Words / s) 2.049 0.43 1.727 0.469 0.004-0.718 0.007
Clause production rate (Clauses / s) 0.306 0.09 0.223 0.091 0.007-0.926 0.014
Language error rate (Language errors / total number of words) 0.095 0.05 0.142 0.057 0.0180.897 0.021
Rate of open class words (Open class words / total number of words) 0.404 0.05 0.377 0.076 0.148 -0.434 0.029
Type-token ratio (Distinct lexemes / all lexemes) 0.621 0.05 0.611 0.068 0.546 -0.171 0.043
Sentence complexity (Complex / simple sentences) 0.744 1039 0.583 0.55 0.861 -0.193 0.05
Total duration of non-linguistic pauses (s) 6.518 3.149 10.020 6.221 0.049 0.710 0.025
Total duration of linguistic pauses (s) 16.076 7.942 16.273 9.330 0.946 0.023 0.050
Paired t-tests were applied to investigate ON-OFF differences (except for ‘sentence complexity’ where the Wilcoxon signed-rank test was applied). ON-OFF differences
were considered as significant if the p-value was below the Benjamini-Hochberg critical value (BH); according values are marked with an asterisk.
STN DBS effects on language
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Fig 2. Correlations between VAT overlap with associative vs. motor STN and language vs. motor changes. A: VAT overlap (light orange area)
with the associative area (green area) of the STN is depicted on the left; scatter diagrams on the right indicate correlations between VAT overlap with
the associative STN and the increase in clause (right, bottom) and word (right, center) production. B: VAT overlap (light orange area) with the motor
area (blue area) of the STN depicted on the left and the scatter diagram on the right indicate a correlation between VAT overlap with the motor STN
and UPDRS improvement.
STN DBS effects on language
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The present study showed a significant increase in clause and word production rates as well as
a decrease in the language error rate with subthalamic DBS in PD patients. Interestingly, we
found a strong positive correlation between the increase in clause production and VAT overlap
with the associative area of the STN. The same but weaker correlation was found for word pro-
duction. Conversely, no significant relationship was found between the two parameters and
the ratio of VAT overlap with the STN motor area. We identified no significant correlation
between language error rates and the VAT overlap with the associative or motor area of the
STN. Despite large effect sizes, changes in the use of stylistic devices and the total duration of
non-linguistic pauses did not reach the level of significance. No significant ON-OFF differ-
ences were detectable for sentence complexity, the use of open class words or diverse lexemes,
or the total duration of linguistic pauses, each showing rather low effect sizes. In the following,
these results shall be discussed in detail.
The main finding of increased clause and word production rates seems compatible with the
idea that the STN accelerates cognitive speed [40,41,4547] and particularly modulates lan-
guage on the level of response selection [4,43] and inhibitory control [5,17]. The current
results thus appear to reflect a procedural acceleration of functions typically impaired in PD
patients, i.e., sentence production [13,14] and fluency [69]. Importantly, this enhancement
seemed vastly unrelated to the DBS-induced motor improvement, which correlated with the
VAT overlap with the dorsolateral STN.
Thus, DBS appears to unfold differential effects on motor and cognitive functions if elec-
trodes are placed in the hypothesized overlap zone between the motor and associative portion
of the STN, as was mostly the case in the present cohort (see Fig 1). This resembles a dissocia-
tion between STN DBS effects on motor vs. non-motor functions described for cognitive
switching [87], executive functions [36], and impulsiveness [88], which was attributed to a rel-
atively ventral electrode position ([87] but cf. [88]) or a specific recruitment of fibers of the
hyperdirect pathway [36,88]. The present results furthermore seem consistent with an earlier
finding of enhanced verbal fluency performance induced by relatively antero-medial STN DBS
in the largely overlapping cohort [89]. They, however, extend this finding to the clinically
more meaningful production of natural language. By argumentum e contrario, it is further of
note that reduced verbal output was reported for tissue stimulation dorsally [90] or laterally
[91] to the actual target area and that stimulation directly within the associative STN portion
led to lexical and syntactic decline in a previous small-sample study [78]. This underscores the
importance of electrode placement within the anterior part of the dorsolateral STN to obtain
motor improvement by stimulation of the motor section, while also exerting acceleratory
effects on language, probably by co-activation of the associative section closely connected to
prefrontal cortical areas. In this framework it is of interest that experimental low frequency
stimulation of the ventral STN at 5 Hz improved response control in a Stroop task [92] and
dorsolateral stimulation at 4 Hz appeared to normalize the response latency in an interval tim-
ing task [33], which deteriorated at 10 Hz stimulation [93]. The authors therefore proposed a
functional coupling between the prefrontal cortex and the STN in the delta/theta frequency
range, which could be involved in cognitive control processes, including cue processing,
response inhibition, working memory recruitment, and attention [33,92]. Having said that,
improved cognitive parameters also indicated a possible activation of fronto-subthalamic con-
nections when stimulated at 10 Hz [94]. Overall, these results are compatible with the idea of a
relevant role of the prefrontal subthalamic signaling pathway, which can be disturbed or com-
pensated by co-stimulation of the associative part of the STN or its connective fibers, depend-
ing on stimulation parameters, localization and the cognitive requirements of the task type.
STN DBS effects on language
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Given the typical increase of commission errors under STN DBS [40,41,45,48,49,88,95
97], the current finding of reduced language errors may seem surprising. First, it should be
noted that our cumulative parameter comprised diverse linguistic errors that were distributed
heterogeneously among the participants (see S3 Table). Nevertheless, the result suggests differ-
ential effects of STN DBS on accuracy in the context of naturalistic language production com-
pared to specific cognitive tasks: while stimulation appears to have positive effects on language
accuracy if cognitive load is not manipulated, increased error rates in challenging tasks (e.g.,
[36,41,96,97]) were interpreted as interference of STN DBS with inhibitory control functions,
e.g., if increased speed, decision making, or the need for no-go strategies imposed a significant
cognitive stress on the individual. Recent studies have demonstrated a relationship between
corresponding errors and the connectivity strength between subthalamic VAT and prefrontal
areas (including the supplementary motor area, the ventromedial prefrontal cortex, and the
inferior frontal gyrus; [36,88]) Furthermore—consistent with the hypothesis of the physiologi-
cal "stopping" function of STN—seemingly beneficial effects of preoperatively strong frontos-
triatal network connectivity on low impulsiveness and disinhibition could be reversed by STN
DBS [88]. Future studies could further explore DBS effects on language accuracy by employing
tasks to assess the effects of increased cognitive demands on different types of language errors.
Ultimately, we could not identify a correlation between the reduction of language errors
and the VAT overlap with the cognitive or motor part of the STN. This could be due to their
heterogeneity and possibly to a complex involvement of co-stimulated structures, beyond
those investigated here. It seems therefore important to consider further sources of differential
STN DBS effects. Against the background of a relevant density increase of interneurons from
anterodorsolateral to posteroventromedial, Le
´vesque and Parent (2005) proposed their specific
involvement in the processing of associative information such as motivation, anticipation,
planning and integration within the ventromedial STN [98]. Additionally, two different types
of glutamatergic principal neurons prevail in the dorsolateral vs. ventromedial STN, suggesting
differential functions for sensorimotor vs. associative information processing [98]. Thus, the
increase in word and clause production observed here seems to occur along the gradual transi-
tion of cell composition from dorsolateral to ventromedial, so that distinct stimulation effects
on interneurons and different types of principal neurons could be considered. Worth men-
tioning in this context is a tractographic study using local field potential recordings of dorso-
lateral and further ventral STN stimulation sites, which showed gradual connectivity changes
in dorso-ventral direction, e.g., with respect to the additional motor cortex [29]. A recent diffu-
sion tensor imaging tractography study underscored the involvement of white mater tracts
connecting the stimulated STN tissue with the tegmentum, supplementary, premotor and pri-
mary motor cortex as well as the contralateral cerebellar hemisphere [99]. As is known from
neurostimulation models in non-human animals, complex stimulation-related and neuroana-
tomical factors modulate the susceptibility of neighboring cell bodies and passing axons for
co-stimulation [100]. Thus, given the small size of the STN and its close vicinity to various
gray matter areas and white matter tracts [101], unintended co-stimulation particularly of the
hypothalamus, substantia nigra, and the medial forebrain bundle is believed to causes cogni-
tive and behavioral side effects [102,103]. At the same time, more than 50% of VAT outside
the STN was associated with good clinical outcomes, possibly by therapeutic co-stimulation of
axonal tissue confining the STN dorsally, laterally and posteriorly [57]. Regarding language
functions, a recent study in ten individual described a correlation between postoperatively
improved semantic fluency and VAT outside the STN together with improved motor func-
tions and VAT overlap with the motor STN [104]. Against this background, we would wel-
come an extension of the functional neuroanatomical basis of DBS effects on language by
including tractography or functional connectivity measures in future studies.
STN DBS effects on language
PLOS ONE | December 29, 2020 11 / 19
Important to note in this context, although the associative STN is closely connected with corti-
cal regions putatively supporting language production (i.e. monosynaptic connections with the
prefrontal cortex [33,34] and supplementary motor area [44]), the specific involvement of the
STN in the language system is far from conclusive: whereas the above cortical areas [105107] as
well as thalamic and striatal areas [107,108] have been proposed to interact with the “traditional”
perisylvian language areas, functional network analyses provided no evidence of a corresponding
engagement of the STN [107109]. Other network studies, however, suggested an indirect
involvement of the STN in language functions by means of word selection, motor planning, initia-
tion, response inhibition, and action monitoring within the cortical-subcortical network [42,110].
In the present study, faster language production was accompanied by a decrease exclusively
in so-called non-linguistic pauses, i.e., hesitations, which typically interrupt the speech flow in
PD patients [11]. Although this result did not reach the corrected level of significance, it points
in the same direction as two previous studies, which reported an improved ratio of speech to
non-speech pauses [55,111] (but cf. [53]) and could thus indicate an amelioration of underly-
ing word access and selection difficulties (cf. [112]). Importantly, the available data, although
limited by the rather small sample size, seem to speak against a relevant effect of the articula-
tion rate (at syllable level), which did not change significantly.
Our study did not indicate specific effects of STN DBS on the use of diverse lexemes or so-
called open class words. Corresponding results could have been interpreted as an amelioration
of reduced informative content described among PD patients [14,18] and DBS-induced
increases in noun and verb use have indeed been reported in an earlier study [56]. However,
with regard to low effect sizes, the results should be interpreted with caution, as they may be
due to the rather small sample size and do not necessarily indicate the absence of stimulation
effects. Similarly, we found no significant DBS-related effects on sentence complexity, which
can be reduced in PD patients [11] (but cf. [12]). However, as indicated by a very small effect
size, also this result may be skewed by the small sample size and may not necessarily indicate
the absence of stimulation effects.
Our findings regarding stylistic devices remained suggestive only: despite considerable
effect sizes, ON-OFF differences did not reach the level of significance and high standard devi-
ations limit the interpretability. However, there was an increase of so-called permutations
including analogies, metaphors, ironies, and exaggerations, which require cognitive transfer
between concrete expressions and their substitutes and could therefore relate to a DBS-
induced thought flexibilization. Future studies investigating longer speech samples and a larger
cohort may specifically tackle this question.
Limitations of the study
The current study aimed to explore effects of therapeutic DBS on language parameters. It did
not include experimental conditions, such as separated DBS testing per hemisphere or low-fre-
quency stimulation, because we considered the testing to be an excessive strain for the partici-
pants and since we were interested in potential effects, as they occur in the clinical real-word
scenario. Additionally, we focused on VAT overlap with STN subregions whose neuroanatom-
ical segregation is known in detail, leaving aside complex effects due to potential co-stimula-
tion of structures adjacent to the STN or through recruitment of the white matter tracts.
Furthermore, by including a pre-operative condition, future studies could assess the possibility
of active stimulation counteracting adverse effects of DBS implantation on language perfor-
mance (cf. [113]). Also an inclusion of cognitive speed measures could be considered to verify
the here proposed relation between cognitive and linguistic speed enhancements. Moreover, a
possible bias towards participants who particularly profited from STN DBS in our cohort
STN DBS effects on language
PLOS ONE | December 29, 2020 12 / 19
cannot be excluded, given an earlier report on language benefits exclusively in patients with a
left hemispheric disease dominance [56].
In conclusion, therapeutic bilateral DBS of the STN accelerated clause and word production
during natural language in PD patients. The magnitude of this increase was associated with the
VAT within the associative STN, rostral to the dorsolateral motor section of the nucleus. The
observed enhancements seem best compatible with the idea of STN DBS releasing executive
procedures from excessive inhibition. Unexpectedly, this effect did not occur at the expense of
language accuracy. Interestingly, corresponding accelerations appeared independent from
prokinetic DBS effects, which correlated with a more prominent stimulation within the STN
motor region. In sum, subtle variations in electrode localization may exert differential effects
on motor and language functions, which warrant future efforts to expand on approaches for
individualized and symptom-specific neuromodulation.
Supporting information
S1 Fig. Correlations between electric field overlap with associative vs. motor STN and lan-
guage vs. motor changes. Spearman correlations between the intersection of the electric field
with each STN subregion (combined for both hemispheres) and changes in UPDRS, word and
clause production rates, and error rate indicated A) a positive correlation between the
improvement in the UPDRS and the electric field overlap with the motor STN, but not with
the associative STN (top left), B) an association between the increase in the word production
rate and the electric field overlap with the associative STN (on the level of trend), but not the
motor STN (bottom left), and C) a positive correlation between the increase in the clause pro-
duction rate and the electric field overlap with the associative STN, but not with the motor
STN (bottom right). D) changes in error rates were neither significantly related to the electric
field overlap with the associative, nor to the motor STN (top right).
S1 Table. Electrode localization in the XYZ-space. Overview of the localization of active elec-
trodes in the xyz-space; due to missing post-operative MRI the data from participant no. 8 did
not enter the localization analysis. Electrode localizations of all 26 active electrodes from the
thirteen participants are depicted in Fig 1. Pt.: participant code.
S2 Table. Stylistic devices. Overview of all semantic (A) and syntactic (B) stylistic devices ana-
lyzed, including the overall type and subcategories.
S3 Table. Language errors. Distribution of language error rates (number of errors per total
word count) across categories and participants.
We would like to thank all participants of this study.
Author Contributions
Conceptualization: Felicitas Ehlen, Fabian Klostermann.
STN DBS effects on language
PLOS ONE | December 29, 2020 13 / 19
Data curation: Felicitas Ehlen.
Formal analysis: Felicitas Ehlen, Bassam Al-Fatly.
Funding acquisition: Fabian Klostermann.
Investigation: Felicitas Ehlen.
Methodology: Felicitas Ehlen, Fabian Klostermann.
Project administration: Fabian Klostermann.
Resources: Andrea A. Ku¨hn, Fabian Klostermann.
Supervision: Andrea A. Ku¨hn, Fabian Klostermann.
Validation: Andrea A. Ku¨hn, Fabian Klostermann.
Writing – original draft: Felicitas Ehlen.
Writing – review & editing: Bassam Al-Fatly, Andrea A. Ku¨hn, Fabian Klostermann.
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... Findings from studies of spontaneous discourse post-DBS further hint at a relationship between DBS cognitive changes and speech/language outcomes. Recent studies reported that STN-DBS ON-stimulation state was associated with higher word and clause production rates, a measure of language formulation speed (Ehlen et al., 2020); increased proportion of open class words, a measure of word retrieval (Ehlen et al., 2020;Tiedt et al., 2021); and shorter pause durations at non-linguistic boundaries indicating more efficient language planning (Ehlen et al., 2020;Klostermann et al., 2008). However, these improvements may be offset by an increased proportion of language production errors in STN-DBS ON-stimulation (Ehlen et al., 2020) and by reductions in lexical complexity reported in VIM-DBS ON-stimulation state (Tiedt et al., 2021). ...
... Findings from studies of spontaneous discourse post-DBS further hint at a relationship between DBS cognitive changes and speech/language outcomes. Recent studies reported that STN-DBS ON-stimulation state was associated with higher word and clause production rates, a measure of language formulation speed (Ehlen et al., 2020); increased proportion of open class words, a measure of word retrieval (Ehlen et al., 2020;Tiedt et al., 2021); and shorter pause durations at non-linguistic boundaries indicating more efficient language planning (Ehlen et al., 2020;Klostermann et al., 2008). However, these improvements may be offset by an increased proportion of language production errors in STN-DBS ON-stimulation (Ehlen et al., 2020) and by reductions in lexical complexity reported in VIM-DBS ON-stimulation state (Tiedt et al., 2021). ...
... Findings from studies of spontaneous discourse post-DBS further hint at a relationship between DBS cognitive changes and speech/language outcomes. Recent studies reported that STN-DBS ON-stimulation state was associated with higher word and clause production rates, a measure of language formulation speed (Ehlen et al., 2020); increased proportion of open class words, a measure of word retrieval (Ehlen et al., 2020;Tiedt et al., 2021); and shorter pause durations at non-linguistic boundaries indicating more efficient language planning (Ehlen et al., 2020;Klostermann et al., 2008). However, these improvements may be offset by an increased proportion of language production errors in STN-DBS ON-stimulation (Ehlen et al., 2020) and by reductions in lexical complexity reported in VIM-DBS ON-stimulation state (Tiedt et al., 2021). ...
Communication difficulties are a ubiquitous symptom of Parkinson's disease and include changes to both motor speech and language systems. Communication challenges are a significant driver of lower quality of life. They are associated with decreased communication participation, social withdrawal, and increased risks for social isolation and stigmatization in persons with Parkinson's disease. Recent theoretical advances and experimental evidence underscore the intersection of cognition and motor processes in speech production and their impact on spoken language. This chapter overviews a growing evidence base demonstrating that cognitive impairments interact with motor changes in Parkinson's disease to negatively affect communication abilities in myriad ways, at all stages of the disease, both in the absence and presence of dementia. The chapter highlights common PD interventions (pharmacological, surgical, and non-pharmacological) and how cognitive influences on speech production outcomes are considered in each.
... Parkinson's disease (PD) is a complex neurological disease whose main clinical manifestations include tremor, bradykinesia, stiffness in the muscle, and damage of fine motor skill. Additional symptoms include depression, constipation, insomnia and other non-motor symptoms [1][2][3]. The severity of these symptoms increases with the progression of PD [4], greatly affecting the lives of patients. ...
... I Ctx and I Str represent the influence of cortical (into STN) and striatal (into GPe) inputs to the STN-GPe system, modulated by the synaptic weights b 1 ⩾0 and b 2 ⩾0. S S and S G are the activation functions of the STN and GPe neural populations, respectively, which are functions of synaptic input, as given by (2). The sigmoid forms adopted for S S and S G approximate a population of neurons with heterogeneous activation functions [38], i.e. ...
The presence of pathological basal ganglia oscillations in the beta (12–35 Hz) frequency band is associated with Parkinson’s disease (PD). Suppressing the abnormal beta rhythm can effectively alleviate prominent PD movement disorders such as bradykinesia and rigidity. Brain stimulations, such as deep brain stimulation or transcranial stimulation, are effective therapeutic methods in managing the beta rhythm. However, electrostimulation using the current open-loop paradigm for stimulation is not optimal, especially when the controlled system experiences a substantial unknown disturbance. In this work we propose an adaptive radial basis function (ARBF) neural network strategy to achieve closed-loop brain stimulation based on real-time observed neural oscillation feedback. The underlying system is assumed to be an unknown nonlinear system, and the closed-loop strategy adaptively modulates the stimulation signal to cope with the abnormal neuronal discharge fluctuations, so as to eliminate the beta rhythm of the STN-GPe network. The proposed ARBF neural network closed-loop scheme is tested in a neural mass model composed of the subthalamic nucleus and external globus pallidus. It is shown that the performance of the ARBF controller is robust, including when internal synaptic connections within the basal ganglia network are enhanced to endogenously impact pathological conditions, and also when pathological oscillations are induced by exogenous cortical inputs. Simulation results demonstrate the effectiveness of the proposed closed-loop neuromodulation pattern based on an ARBF neural network. This work may help to develop DBS control systems with adaptive optimization and less network complexity.
... Inconsistent phonation effects during STN-DBS were found for males but not females (5). STN-DBS restricted articulatory space at the initiation of phonation (6), altered the pattern of pausing in spontaneous speech (7), increased production rates for words and clauses (8) and single syllables (9). Speech quality received lower ratings during STN-DBS (10). ...
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Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for Parkinson's disease (PD) but can have an adverse effect on speech. In normal speakers and in those with spinocerebellar ataxia, an inverse relationship between regional cerebral blood flow (rCBF) in the left inferior frontal (IFG) region and the right caudate (CAU) is associated with speech rate. This pattern was examined to determine if it was present in PD, and if so, whether it was altered by STN-DBS. Methods: Positron Emission Tomography (PET) measured rCBF during speech in individuals with PD not treated with STN-DBS ( n = 7), and those treated with bilateral STN-DBS ( n = 7). Previously reported results from non-PD control subjects ( n = 16) were reported for comparison. The possible relationships between speech rate during scanning and data from the left and right IFG and CAU head regions were investigated using a step-wise multiple linear regression to identify brain regions that interacted to predict speech rate. Results: The multiple linear regression analysis replicated previously reported predictive coefficients for speech rate involving the left IFG and right CAU regions. However, the relationships between these predictive coefficients and speech rates were abnormal in both PD groups. In PD who had not received STN-DBS, the right CAU coefficient decreased normally with increasing speech rate but the left IFG coefficient abnormally decreased. With STN-DBS, this pattern was partially normalized with the addition of a left IFG coefficient that increased with speech rate, as in normal controls, but the abnormal left IFG decreasing coefficient observed in PD remained. The magnitudes of both cortical predictive coefficients but not the CAU coefficient were exaggerated with STN-DBS. Conclusions: STN-DBS partially corrects the abnormal relationships between rCBF and speech rate found in PD by introducing a left IFG subregion that increases with speech rate, but the conflicting left IFG subregion response remained. Conflicting IFG responses may account for some of the speech problems observed after STN-DBS. Cortical and subcortical regions may be differentially affected by STN-DBS.
Deep Brain Stimulation (DBS) is a therapy for various neurological movement disorders. It acts predominantly on motor symptoms, but may unfold a number of mostly subtle cognitive effects. In this regard, reports on particular language-related DBS sequels are comparably frequent, but difficult to overlook, given the heterogeneity of targeted structures in the brain, treated diseases, assessment methods and results reported. Accordingly, available knowledge was organized with respect to important aspects, such as the main DBS loci and surgical versus neuromodulatory therapy actions. Current views of biolinguistic underpinnings of the reviewed data, their clinical relevance and potential implications are discussed.
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The Subthalamic Nucleus (STh) is an oval-shaped diencephalic structure located ventrally to the thalamus, playing a fundamental role in the circuitry of the basal ganglia. In addition to being involved in the pathophysiology of several neurodegenerative disorders, such as Huntington’s and Parkinson’s disease, the STh is one of the target nuclei for deep brain stimulation. However, most of the anatomical evidence available derives from non-human primate studies. In this review, we will present the topographical and morphological organization of the nucleus and its connections to structurally and functionally related regions of the basal ganglia circuitry. We will also highlight the importance of additional research in humans focused on validating STh connectivity, cytoarchitectural organization, and its functional subdivision.
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We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.
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Essential tremor is the most prevalent movement disorder and is often refractory to medical treatment. Deep brain stimulation offers a therapeutic approach that can efficiently control tremor symptoms. Several deep brain stimulation targets (ventral intermediate nucleus, zona incerta, posterior subthalamic area) have been discussed for tremor treatment. Effective deep brain stimulation therapy for tremor critically involves optimal targeting to modulate the tremor network. This could potentially become more robust and precise by using state-of-the-art brain connectivity measurements. In the current study, we used two normative brain connectomes (structural and functional) to show the pattern of effective deep brain stimulation electrode connectivity in 36 patients with essential tremor. Our structural and functional connectivity models were significantly predictive of postoperative tremor improvement in out-of-sample data (P < 0.001 for both structural and functional leave-one-out cross-validation). Additionally, we segregated the somatotopic brain network based on head and hand tremor scores. These resulted in segregations that mapped onto the well-known somatotopic maps of both motor cortex and cerebellum. Crucially, this shows that slightly distinct networks need to be modulated to ameliorate head versus hand tremor and that those networks could be identified based on somatotopic zones in motor cortex and cerebellum. Finally, we propose a multi-modal connectomic deep brain stimulation sweet spot that may serve as a reference to enhance clinical care, in the future. This spot resided in the posterior subthalamic area, encroaching on the inferior borders of ventral intermediate nucleus and sensory thalamus. Our results underscore the importance of integrating brain connectivity in optimizing deep brain stimulation targeting for essential tremor.
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BACKGROUND Although deep brain stimulation (DBS) of the dorsolateral subthalamic nucleus (STN) is a well-established surgical treatment for patients with Parkinson disease (PD), there is still controversy about the relationship between the functional segregation of the STN and clinical outcomes. OBJECTIVE To correlate motor and neuropsychological (NPS) outcomes with the overlap between the volume of activated tissue (VAT) and the tractography-defined regions within the STN. METHODS Retrospective study evaluating 13 patients with PD treated with STN-DBS. With the aid of tractography, the STN was segmented into 4 regions: smaSTN (supplementary motor area STN), m1STN (primary motor area STN), mSTN (the sum of the m1STN and the smaSTN segments), and nmSTN (non-motor STN). We computed the overlap coefficients between these STN regions and the patient-specific VAT. The VAT outside of the STN was also calculated. These coefficients were then correlated with motor (Unified Parkinson's Disease Rating Scale, UPDRS III) and NPS outcomes. RESULTS Stimulation of the mSTN segment was significantly correlated with UPDRS III and bradykinesia improvement. Stimulation of the smaSTN segment, but not the m1STN one, had a positive correlation with bradykinesia improvement. Stimulation of the nmSTN segment was negatively correlated with the improvement in rigidity. Stimulation outside of the STN was correlated with some beneficial NPS effects. CONCLUSION Stimulation of the tractography-defined motor STN, mainly the smaSTN segment, is positively correlated with motor outcomes, whereas stimulation of the nmSTN is correlated with poor motor outcomes. Further validation of these results might help individualize and optimize targets prior to STN-DBS.
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Comprehending and producing sentences is a complex endeavor requiring the coordinated activity of multiple brain regions. We examined three issues related to the brain networks underlying sentence comprehension and production in healthy individuals: First, which regions are recruited for sentence comprehension and sentence production? Second, are there differences for auditory sentence comprehension vs. visual sentence comprehension? Third, which regions are specifically recruited for the comprehension of syntactically complex sentences? Results from activation likelihood estimation (ALE) analyses (from 45 studies) implicated a sentence comprehension network occupying bilateral frontal and temporal lobe regions. Regions implicated in production (from 15 studies) overlapped with the set of regions associated with sentence comprehension in the left hemisphere, but did not include inferior frontal cortex, and did not extend to the right hemisphere. Modality differences between auditory and visual sentence comprehension were found principally in the temporal lobes. Results from the analysis of complex syntax (from 37 studies) showed engagement of left inferior frontal and posterior temporal regions, as well as the right insula. The involvement of the right hemisphere in the comprehension of these structures has potentially important implications for language treatment and recovery in individuals with agrammatic aphasia following left hemisphere brain damage.
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Deep brain stimulation (DBS) represents one of the major clinical breakthroughs in the age of translational neuroscience. In 1987, Benabid and colleagues demonstrated that high-frequency stimulation can mimic the effects of ablative neurosurgery in Parkinson’s disease (PD), while offering two key advantages to previous procedures: adjustability and reversibility. Deep brain stimulation is now an established therapeutic approach that robustly alleviates symptoms in patients with movement disorders, such as Parkinson’s disease, essential tremor, and dystonia, who present with inadequate or adverse responses to medication. Currently, stimulation electrodes are implanted in specific target regions of the basal ganglia–thalamic circuit and stimulation pulses are delivered chronically. To achieve optimal therapeutic effect, stimulation frequency, amplitude, and pulse width must be adjusted on a patient-specific basis by a movement disorders specialist. The finding that pathological neural activity can be sampled directly from the target region using the DBS electrode has inspired a novel DBS paradigm: closed-loop adaptive DBS (aDBS). The goal of this strategy is to identify pathological and physiologically normal patterns of neuronal activity that can be used to adapt stimulation parameters to the concurrent therapeutic demand. This review will give detailed insight into potential biomarkers and discuss next-generation strategies, implementing advances in artificial intelligence, to further elevate the therapeutic potential of DBS by capitalizing on its modifiable nature. Development of intelligent aDBS, with an ability to deliver highly personalized treatment regimens and to create symptom-specific therapeutic strategies in real-time, could allow for significant further improvements in the quality of life for movement disorders patients with DBS that ultimately could outperform traditional drug treatment.
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Background The majority of Parkinson's disease patients with deep brain stimulation (DBS) use a monopolar configuration, which presents challenges for EEG and MRI studies. The literature reports algorithms to convert monopolar to bipolar settings. Purpose/Hypothesis To assess brain responses of Parkinson's disease patients implanted with DBS during fMRI studies using their clinical and presumed equivalent settings using a published conversion recipe. Study Type Prospective. Subjects Thirteen DBS patients. Field Strength/Sequence 1.5T and 3T, fMRI using gradient echo‐planar imaging. Assessment Patients underwent 30/30sec ON/OFF DBS fMRI scans using monopolar and bipolar settings. To convert to a bipolar setting, the negative contact used for the monopolar configuration remained constant and the adjacent dorsal contact was rendered positive, while increasing the voltage by 30%. fMRI activation/deactivation maps and motor Unified Parkinson's Disease Rating Scale (UPDRS‐III) scores were compared for patients in both configurations. Statistical Tests T‐tests were used to compare UPDRS scores and volumes of tissue activated (VTA) diameters in monopolar and bipolar configurations. Results The patterns of fMRI activation in the monopolar and bipolar configurations were generally different. The thalamus, pallidum, and visual cortices exhibited higher activation using the patient's clinical settings than the presumed equivalent settings. VTA diameters were lower (7 mm vs. 6.3 mm, P = 0.047) and UPDRS scores were generally higher in the bipolar (33.2 ± 16) than in the monopolar configuration (28.3 ± 17.4), without reaching statistical significance (P > 0.05). Data Conclusion Monopolar and bipolar configurations result in different patterns of brain activation while using a previously published monopolar–bipolar conversion algorithm. Clinical benefits may be achieved with varying patterns of brain responses. Blind conversion from one to the other should be avoided for purposes of understanding the mechanisms of DBS. Level of Evidence: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.
Umfassende und verständliche Einführung in die Syntax Im ersten Teil des Buches werden die wichtigsten Kenntnisse zur Analyse syntaktischer Strukturen vermittelt und die syntaktischen Regularitäten des Deutschen vorgestellt. Im zweiten Teil stehen syntaktische Theorien im Mittelpunkt: Stellungsfeldermodell, Valenztheorie, Generative Grammatik, Optimalitätstheorie, Funktionale Grammatik. Übungsaufgaben mit Lösungsvorschlägen, kommentierte Literaturhinweise und ein Glossar der relevanten Fachtermini runden das Buch ab. »Insgesamt besticht das Buch durch die Vielfalt der erörterten (Themen-)Bereiche, die Konzentration auf das Wesentliche und die kritische, aber dennoch abgewogene Bewertung vor allem unterschiedlicher Ansätze.« Gerhard Helbig
These authors contributed equally to this work. Subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease treats motor symptoms and improves quality of life, but can be complicated by adverse neuropsychiatric side-effects, including impulsivity. Several clinically important questions remain unclear: can 'at-risk' patients be identified prior to DBS; do neuropsychiatric symptoms relate to the distribution of the stimulation field; and which brain networks are responsible for the evolution of these symptoms? Using a comprehensive neuropsychiatric battery and a virtual casino to assess impulsive behaviour in a naturalistic fashion, 55 patients with Parkinson's disease (19 females, mean age 62, mean Hoehn and Yahr stage 2.6) were assessed prior to STN-DBS and 3 months postoperatively. Reward evaluation and response inhibition networks were reconstructed with probabilistic tractography using the participant-specific subthalamic volume of activated tissue as a seed. We found that greater connectivity of the stimulation site with these frontostriatal networks was related to greater postoperative impulsiveness and disinhibition as assessed by the neuropsychiatric instruments. Larger bet sizes in the virtual casino postoperatively were associated with greater connectivity of the stimulation site with right and left orbitofrontal cortex, right ventromedial prefrontal cortex and left ventral striatum. For all assessments, the baseline connectivity of reward evaluation and response inhibition networks prior to STN-DBS was not associated with postoperative impulsivity; rather, these relationships were only observed when the stimulation field was incorporated. This suggests that the site and distribution of stimulation is a more important determinant of postoperative neuropsychiatric outcomes than preoperative brain structure and that stimulation acts to mediate impulsivity through differential recruitment of frontostriatal networks. Notably, a distinction could be made amongst participants with clinically-significant, harmful changes in mood and behaviour attributable to DBS, based upon an analysis of connectivity and its relationship with gambling behaviour. Additional analyses suggested that this distinction may be mediated by the differential involvement of fibres connecting ventromedial subthalamic nucleus and orbitofrontal cortex. These findings identify a mechanistic substrate of neuropsychiatric impairment after STN-DBS and suggest that tractography could be used to predict the incidence of adverse neuropsychiatric effects. Clinically, these results highlight the importance of accurate electrode placement and careful stimulation titration in the prevention of neuropsychiatric side-effects after STN-DBS. Abbreviations: DBS = deep brain stimulation; ICB = impulse control behaviour; IFG = inferior frontal gyrus; OFC = orbitofron-tal cortex; SMA = supplementary motor area; STN = subthalamic nucleus; VAT = volume of activated tissue; vmPFC = ventro-medial prefrontal cortex; VTA = ventral tegmental area
Purpose: To depict the specific brain networks that are modulated by deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson’s disease (PD), using diffusion tensor imaging-based fibre tractography (DTI-FT). Materials and methods: Nine patients who received bilateral STN-DBS for PD were included. Electrodes were localized by co-registering preoperative magnetic resonance imaging and postoperative computed tomography. The volume of tissue activated (VTA) was estimated as an isotropic, spherical electric field distribution centred at each effective electrode contact’s centroid coordinates, taking into account individual stimulation parameters (i.e. voltage, impedance). Brain connectivity analysis was undertaken using a deterministic DTI-FT method, seeded from a single region of interest corresponding to the VTA. The labelling of the reconstructed white matter fibre tracts relied on their path and (sub)cortical termination territories. Results: Six months after surgery, we observed a statistically significant reduction in both the Unified Parkinson Disease Rating Scale part III and L-dopa equivalent daily dose. Areas consistently connected to the VTA included the brainstem (100%), cerebellum (94%), dorsal (i.e. supplementary motor area) and lateral premotor cortex (94%), and primary motor cortex (72%). An involvement of the hyperdirect pathway (HDP) connecting the STN and the (pre)motor cortex was demonstrated. Conclusions: The connectivity patterns observed in this study suggest that the therapeutic effects of STN-DBS are mediated through the modulation of distributed, large-scale motor networks. Specifically, the depiction of projection neurons connecting the stimulated area/STN to the (pre)motor cortex, reinforce the growing evidence that the HDP might be a potential therapeutic target in PD. If further replicated, these findings could raise the possibility that DTI-FT reconstruction of the HDP may critically improve DBS targeting and stimulation parameters selection, through the development of programming tools that incorporate VTA modelling and patient-specific DTI-FT data.