Modulation of Fibers to Motor Cortex During Thalamic DBS in Tourette Patients Correlates with Tic Reduction

brain sciences

Article Modulation of Fibers to Motor Cortex during Thalamic DBS in Tourette Patients Correlates with Tic Reduction

Pablo Andrade 1,* , Petra Heiden 1,2, Moritz Hoevels 1, Marc Schlamann 3, Juan C. Baldermann 4,5, Daniel Huys 4 and Veerle Visser-Vandewalle 1

1 Department of Stereotactic and Functional Neurosurgery, University Hospital of Cologne, 50397 Cologne, Germany; [email protected] (P.H.); [email protected] (M.H.); [email protected] (V.V.-V.) 2 Department of Neurosurgery, University Hospital of Cologne, 50397 Cologne, Germany 3 Department of Neuroradiology, University Hospital of Cologne, 50397 Cologne, Germany; [email protected] 4 Department of Psychiatry and Psychotherapy, University Hospital of Cologne, 50397 Cologne, Germany; [email protected] (J.C.B.); [email protected] (D.H.) 5 Department of Neurology, University Hospital of Cologne, 50397 Cologne, Germany * Correspondence: [email protected]; Tel.: +49-221-478-82737; Fax: +49-221-478-82824

Received: 12 April 2020; Accepted: 11 May 2020; Published: 15 May 2020

Abstract: Probabilistic tractography in Tourette syndrome (TS) patients have shown an alteration in the connectivity of the primary motor cortex and supplementary motor area with the striatum and thalamus, suggesting an abnormal connectivity of the cortico-striatum-thalamocortical-pathways in TS. Deep brain stimulation (DBS) of the centromedian nucleus–nucleus ventrooralis internus (CM-Voi complex) in the thalamus is an effective treatment for refractory TS patients. We investigated the connectivity of activated fibers from CM-Voi to the motor cortex and its correlation between these projections and their clinical outcome. Seven patients with TS underwent CM-Voi-DBS surgery and were clinically evaluated preoperatively and six months postoperatively. We performed diffusion tensor imaging to display the activated fibers projecting from the CM-Voi to the different motor cortex regions of interest. These analyses showed that the extent of tic reduction during DBS is associated with the degree of stimulation-dependent connectivity between CM-Voi and the motor cortex, and in particular, an increased density of projections to the presupplementary motor area (preSMA). Non-responder patients displayed the largest amount of active fibers projecting into cortical areas other than motor cortex compared to responder patients. These findings support the notion that an abnormal connectivity of thalamocortical pathways underlies TS, and that modulation of these circuits through DBS could restore the function and reduce symptoms.

Keywords: Tourette syndrome; deep brain stimulation; connectivity, tractography; imaging

1. Introduction Tourette syndrome (TS) is deﬁned as a chronic neuropsychiatric disorder characterized by sudden, uncontrolled, repetitive, stereotypical movements or vocalizations described as tics, typically starting during childhood [1]. The pathophysiology lying behind this disorder is still unclear. Some studies suggest a higher cortical excitability in the primary motor cortex [2], which could result from underlying alterations in the cortico-basal ganglia-thalamocortical (CBTC) loops [3]. TS patients have a higher functional disorganization and an increased global interaction in the CBTC circuits, suggesting a deﬁciency in brain [4]. Probabilistic tractography of TS patients have shown an alteration in the

Brain Sci. 2020, 10, 302; doi:10.3390/brainsci10050302 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, 302 2 of 12 connectivity of the primary motor cortex and supplementary motor area with the striatum and the thalamus. However, these reports resulted in contradictory conclusions, with some studies showing a decreased connectivity [5,6], while others showed an enhanced connectivity [7,8]. More than half of the patients become tic-free or only present with mild symptoms after reaching early adulthood, therefore not needing further treatment [9]. In severe cases refractory to behavioral therapies and pharmacological treatment that persist during adulthood, deep brain stimulation (DBS) can be considered as a therapeutic option [10]. Up until now, there are several different targets along the CSPT circuit that have been explored in TS patients, the most commonly used being the thalamus, the globus pallidus internus (GPi), the globus pallidus externus (GPe), the anterior limb of the internal capsule/nucleus accumbens (ALIC/NA) and the subthalamic nucleus (STN) [11]. Nevertheless, among these targets, the majority of cases have been performed on the medial thalamus and the GPi. Within the medial thalamus, various possible targets have been described, the most frequently used being the centromedian nucleus–nucleus ventrooralis internus (CM-Voi) and the centromedian nucleus–parafascicular (CM-Pf) complexes [12]. The clinical outcome of TS DBS in these targets is relatively variable within the same cohorts, with none showing a clear advantage over the others [13,14]. In recent years, diffusion tensor imaging (DTI) has emerged as a useful tool for optimizing targets in DBS for different anatomical targets. DTI allows to display fibers projecting from the tissue activated at a nominated target to different cortical and subcortical regions through tractography [15]. Previous studies on different neurological and psychiatric disorders have shown direct correlations between connectivity patterns and clinical outcome in patients, for instance, in obsessive-compulsive disorder (OCD) [16], Parkinson’s disease [17] and tremor [18]. The aim of this study is firstly to examine the connectivity of activated fibers in TS patients during CM-Voi DBS and secondly, to elucidate if connectivity patterns are correlated with a better clinical outcome after long-term CM-Voi DBS.

2. Materials and Methods

2.1. Patients and Study Design We retrospectively analyzed seven patients who underwent surgery for bilateral thalamic DBS for TS at the University Hospital of Cologne between 2016 and 2018. Patients were diagnosed based on the diagnostic and statistical manual of mental disorders ﬁfth edition and the Tourette syndrome diagnostic conﬁdence index [1]. The clinical evaluation was assessed using the Yale Global Tic Severity Scale (YGTSS), which was performed before, and six months after the surgery. This study was approved by the Medical Ethical Committee of the University Hospital of Cologne (Code 19-1421). All subjects granted their consent according to the Declaration of Helsinki.

2.2. Stereotactic Surgery The CM-Voi complex was targeted for stimulation with standard coordinates (midpoint AC/PC line coordinates: x = +/ 5 mm, y = 4 mm, z = 0 mm), adapted to the patient’s anatomy and with trajectory − − along the longest axis of Voi, based on preoperative magnetic resonance imaging (MRI) fused with stereotactic computed tomography (CT) scan with the atlas of the human brain (Schaltenbrand Atlas) overlaid (Cranial Software, version StealthStation™ S7, Medtronic, Minneapolis, MN, USA). Surgery was performed under analgosedation with intraoperative microelectrode recordings. All patients received quadripolar electrodes (Medtronic 3389) bilaterally, stereotactically guided. The accurate localization of the electrodes was conﬁrmed via postsurgical CT scan. For optimal stimulation, the frequency, voltage and pulse width were individually adapted for best results.

2.3. Fiber Tracking Based on previous studies [5,8], we selected the primary motor cortex (M1), the supplementary motor area (SMA) and pre-SMA as our seed regions. We deﬁned M1 manually in the ICBM 152 MNI Brain Sci. 2020, 10, 302 3 of 12

2009b asymmetrical cortical atlas and used the Human Motor Area Template [19] for SMA and preSMA. These cortical mask regions were transferred to each patient’s T2 sequence using FLIRT from the FSL (FMRIB Software Library, www.fmrib.ox.ac.uk/fsl) v6.0 program for affine linear matching, followed by deformable registration by the advanced normalization tools (ANTs, http://stnava.github.io/ANTs/)[20]. The seed regions were subsequently manually adjusted using the ITK-SNAP desktop app to each patient’s individual anatomy based on T1 sequences on the preoperative MRI [21]. Using the open-source software Lead-DBS (www.lead-dbs.org, Charité University Hospital, Berlin, Germany), we coregistered and normalized the preoperative MRI scans and the postsurgical CT scan to MNI space [22]. Afterwards, we reconstructed the electrodes and the active contacts. Using the model described by Dembek and colleagues [23], we estimated the area stimulated by the active contacts (VTA: volume of tissue activated) based on the stimulation parameters, with a general heuristic electric-field threshold of 0.2 V/mm. We transferred the VTAs, using the same transformation procedure as described above, into patient space. The DTIs were corrected for distortions and subject movement using FUGUE from FSL tools [24–27]. After this, we performed the probabilistic fiber tracking from the VTAs to the ipsilateral hemisphere as well as the ipsilateral M1, SMA and preSMA using the Oxford Centre for Functional MRI of the Brain (FMRIB), FSL probtrackx2 program [28,29]. For further analysis, we applied the seed regions as binary masks on the respective tracks using the fslmaths tool and quantified the mean and maximum intensity of voxels localized within the seed regions.

2.4. Statistical Analysis All data were analyzed using GraphPad Prism software (version 5, GraphPad Software, San Diego, CA, USA) with p-values under 0.05 considered as significant. In order to estimate the correlation between clinical improvement in the YGTSS and the fiber tract values, data were analyzed using a linear regression analysis. A Wilcoxon signed-rank test was performed to compare pre- and post-operative clinical YGTSS score differences between the samples. A Spearman rank’s test was performed to establish correlation analyses between different parameters. A power calculation was performed in order to calculate the amount of TS patients required for a significant statistical analysis (90% power, 0.05 alpha). The data that support the findings of this study, such as the DBS MRI datasets, are not publicly available due to data privacy regulations, but are available from the corresponding author upon reasonable request.

3. Results

3.1. Demographic and Clinical Characteristics Demographic and individual clinical data from patients included in this study (n = 7, six men and one woman, age mean 30 years SD = 9.1) are presented in Table1. Disease onset ranged from three to ten years of age. Comorbidities were present among the participants with the most frequent conditions including OCD and depression (n = 2, 28% each). Disability and impairment were severe in every patient with a mean total preoperative YGTSS score of 90 (SD = 8.7). The mean YGTSS score six months postoperatively was 52 (SD = 21.4), with a significant mean improvement in YGTSS score of 43.5% (SD = 18.9, p < 0.001) pre- versus post-operatively. Clinical response being defined as an improvement of at least 35% on the YGTSS, five patients were considered responders (mean improvement in YGTSS 52.7% with a range of 43.7–71.8%) and two as non-responders (mean improvement in YGTSS 20.5% with a range of 11–30%). Brain Sci. 2020, 10, 302 4 of 12

Table 1. Demographic Table. Summarizes the clinical outcome of each patient six months after surgery, individual deep brain stimulation (DBS) parameters including the active contacts responsible for stimulation, comorbidities and medication. YGTSS—Yale Global Tic Severity Scale, OCD—obsessive compulsive disorder, THC—Tetrahydrocannabinol.

Pat. Number Gender Age YGTSS Preop YGTSS Postop Improvement (%) Active Contacts Pat. 1 Male 22 78 22 71.8 0 and 1 Pat. 2 Male 32 89 44 50.6 2 and 3 Pat. 3 Female 26 95 47 50.5 1 and 2 Pat. 4 Male 37 81 43 46.9 2 and 3 Pat. 5 Male 20 87 49 43.7 2 and 3 Pat. 6 Male 46 100 70 30.0 2 and 3 Pat. 7 Male 27 100 89 11.0 1 and 2 Pat. Number Freq. Hz Pulse Width µs Ampl. V Comorbidity Medication Pat. 1 130 90 3.2 None Aripiprazole 10 mg, Citalopram 30 mg Pat. 2 130 90 3.3 None Tiapride 800 mg, Quetiapine 150 mg Escitalopram 10 mg, THC 5 mg, Pat. 3 100 90 3.0 Depression Risperidone 4 mg, Quetiapine 25 mg Opiate dependence Pat. 4 110 90 4.1 Methadone 28 mL (in substitution) Pat. 5 100 150 5.2 None None Aripiprazole 5 mg, Pat. 6 80 150 5.0 Depression, OCD Pipamperone 40 mg, Quetiapine 200 mg Impulse control Clonazepam 1 mg, Pregabaline 300 Pat. 7 80 300 4.7 disorder, OCD, mg, Risperidone 2 mg, THC 15 mg, anxiety disorder Venlafaxine 225 mg

3.2. Neuroimaging Analysis

3.2.1. Generation of Fiber Tracts and Cortical Projections The individual location of bilateral electrodes and the generated VTAs of all patients are shown in Figure1A,B, respectively. A clear di fference is seen among the generated VTAs between responders and non-responders, as shown in Figure1C,D, respectively. Non-responders presented with significant (p < 0.05) higher VTA-volumes (mean volume 2597 mm3, SD = 804) compared to responders (mean volume 1313 mm3, SD = 515). Furthermore, a direct comparison between volumetric values of individual VTAs and the percentage of improvement in the YGTSS six months after surgery showed a significant negative correlation in all participants (p < 0.01, R= 0.84), as shown in Figure2A. − Thus, the patients with better clinical outcomes showed smaller magnitudes in the generated VTAs. Derived from these results, we analyzed the amount of active fibers involved in the corresponding VTAs that projected to all cortical areas. This analysis showed a significant negative correlation between the amount of cortical fiber tracts and the percentage of improvement in the YGTSS six months after surgery (p < 0.05, R = 0.58), as displayed in Figure2B. Furthermore, the non-responder − patients presented with larger amount of fibers projecting to the cortex with higher variability between individuals (mean number of fibers 45,452,500, SD = 35,585,148) when compared to the responder participants (mean number of fibers 15,038,000, SD = 4,976,307). Therefore, the patients with better clinical outcomes displayed a general reduced cortical fiber activation in the whole brain when compared to the non-responders. Brain Sci. 2020, 10, x FOR PEER REVIEW 5 of 12

Brain Sci. 2020, 10, 302 5 of 12 Brain Sci. 2020, 10, x FOR PEER REVIEW 5 of 12

Figure 1. Anatomical location of electrodes and volume of tissue activated (VTAs) within the

thalamus. Overview of bilateral electrodes in the centromedian nucleus–nucleus ventrooralis internus Figure(CM-Voi)Figure 1. Anatomical 1. complex Anatomicallocation (A) locationandof cluster electrodes of electrodes for bilateral and volumeand VTAs volu ofme of tissue allof patientstissue activated activated on (VTAs) the MNI(VTAs) within space within the (B thalamus. ) thein sagittal, Overviewcoronalthalamus. ofand bilateral Overview axial views. electrodes of bilateral Volume in electrodes the of centromediantissue in theactivate centromedian nucleus–nucleusd three-dimensional nucleus–nucleus ventrooralis representation ventrooralis internus internus shown (CM-Voi) in light complexred(CM-Voi) for (A the) and complex best cluster clinical (A) forand responder bilateral cluster for VTAsin bilateral the of cohort, allVTAs patients ofonly all patients onpatient the MNIon1 representedthe space MNI space (B) in( C(B). sagittal,) inVolume sagittal, coronal of tissue andactivated axialcoronal views. andthree-dimensional axial Volume views. of Volume tissue representation activatedof tissue activate three-dimensional shownd three-dimensional in light red representation for representation the patient shown with shown inthe lightin worst light red clinical for red for the best clinical responder in the cohort, only patient 1 represented (C). Volume of tissue theoutcome best clinical in the responder cohort, only in the patient cohort, 7 represented only patient ( 1D represented). Thalamic segmentation (C). Volume of according tissue activated to cortical activated three-dimensional representation shown in light red for the patient with the worst clinical three-dimensionalconnectivity is shown representation in different shown colors in in light C and red D for in the order patient to exemplify with the the worst position clinical of outcomethe implanted in the cohort,outcome only in the patient cohort, 7 represented only patient (7D represented). Thalamic (D segmentation). Thalamic segmentation according to according cortical connectivityto cortical is electrodesconnectivity [30] is shown in different colors in C and D in order to exemplify the position of the implanted shown in diﬀerent colors in C and D in order to exemplify the position of the implanted electrodes [30]. electrodes [30]

Figure 2. Scatter plot depicting the correlation between postoperative improvement of the Yale Global Tic Severity Scale (YGTSS) after six months expressed in percentage and the volumetric measurements Figure 2. Scatter plot depicting the correlation between postoperative improvement of the Yale Global of theFigure generated 2. Scatter VTAs plot (( Adepicting), p < 0.01, theR correlation= 0.84) and between the numbers postoperative of fibers improvement in the VTA that of project the Yale to Global the Tic Severity Scale (YGTSS) after six− months expressed in percentage and the volumetric cortexTic ((SeverityB), p < 0.05, ScaleR = (YGTSS)0.58). Data after shown six inmonths this figure expressed represent in individual percentage patient and analysis the volumetric (n = 7). measurements of the generated VTAs ((A), p < 0.01, R = −0.84) and the numbers of fibers in the VTA measurements of the −generated VTAs ((A), p < 0.01, R = −0.84) and the numbers of fibers in the VTA For athat segmented project toanalysis the cortex of ((B each), p < hemisphere0.05, R = −0.58). (n Data= 14), shown please in this consult figure Figure represent A1. individual patient that project to the cortex ((B), p < 0.05, R = −0.58). Data shown in this figure represent individual patient analysis (n = 7). For a segmented analysis of each hemisphere (n = 14), please consult Figure A1. 3.2.2. Parcellationanalysis (n = of 7). Seed For a Regions segmented analysis of each hemisphere (n = 14), please consult Figure A1. Parcellation3.2.2. Parcellation of the of seed Seed regions Regions of interest in the motor cortex (preSMA, SMA and M1) showed that 3.2.2. Parcellation of Seed Regions non-responderParcellation patients of the displayed seed regions the of largest interest amount in the motor of active cortex fibers, (preSMA, but projecting SMA and M1) to cortical showedareas differentthatParcellation fromnon-responder the seed of regionsthepatients seed than displayedregions responder of the interest largest patients. inamou the Thisnt motor of means active cortex that,fibers, (preSMA, although but projecting SMA cortical andto connectivitycortical M1) showed in non-respondersthatareas non-responder different wasfrom patients generallythe seed displayed regions increased, than the itresponde waslargest primarily ramou patients.nt projecting of This active means fibers, to nonmotorthat, but although projecting areas, cortical as to shown cortical in Figureareasconnectivity different3. These in from activenon-responders the fibers seed projected regions was generally than in its responde majorityincreased,r toitpatients. was di ff erentprimarily This areas meansprojecting of the that, prefrontalto althoughnonmotor cortex, cortical as shownconnectivityareas,in as Figure shown in non-responders3 A.in RespondersFigure 3. These displayedwas active generally fibers generally princreased,ojected less in modulated itits was majority primarily connectivity to different projecting areas compared ofto thenonmotor with prefrontal cortex, as shown in Figure 3A. Responders displayed generally less modulated non-responders,areas, as shown which in Figure was highly 3. These clustered active towardsfibers pr theojected preSMA, in its SMA majority and M1to different cortices, asareas shown of the connectivity compared with non-responders, which was highly clustered towards the preSMA, SMA in Figureprefrontal3B. Moreover,cortex, as the shown total amountin Figure of cortical3A. Responders fibers originated displayed in the generally VTAs that less projected modulated to and M1 cortices, as shown in Figure 3B. Moreover, the total amount of cortical fibers originated in nonmotorconnectivitythe VTAs seed that compared regions projected showed with to nonmotor non-re a negativesponders, seed regions correlation which showed was with a negativehighly the percentage clustered correlation towards ofwith improvement the the percentage preSMA, in the SMA YGTSSand M1 six monthscortices, after as shown surgery in (pFigure< 0.05, 3B.R =Moreover,0.60), as the displayed total amount in Figure of 3corticalC. fibers originated in − the VTAs that projected to nonmotor seed regions showed a negative correlation with the percentage Brain Sci. 2020, 10, x FOR PEER REVIEW 6 of 12

Brain Sci. 2020, 10, 302 6 of 12 Brainof improvement Sci. 2020, 10, x FOR in the PEER YGTSS REVIEW six months after surgery (p < 0.05, R = −0.60), as displayed in Figure6 of 12 3C. of improvement in the YGTSS six months after surgery (p < 0.05, R = −0.60), as displayed in Figure 3C.

FigureFigure 3. Comparison 3. Comparison of structuralof structural connectivity connectivity between a anon-responder non-responder (A) ( Aand) and a good a good responder responder (B) patient,(B) patient, in sagittal in sagittal and and axial axial views. views. All All ﬁbersfibers traversing the the VTAs VTAs that that connect connect into into the preSMA the preSMA (presupplementaryFigure(presupplementary 3. Comparison motor motor of area),structural area), SMA SMA connectivity andand M1M1 (primarybetween(primary amotor non-responder motor cortex) cortex) cortices (A cortices) and are a good areshown shown responder in blue, in blue, while(whileB the) patient,rest the ofrest in the sagittalof ﬁbers the fibersand that axial projectthat views.project to other All to fibersother parts traversingparts of the of cortex the the cortex areVTAs shown are that shown connect in red. in Correlationintored. theCorrelation preSMA between the clinical(presupplementarybetween response the clinical and motorresponse the total area), and amount SMA the total ofand cortical amount M1 (prima projections of corticalry motor projections into cortex) nonmotor corticesinto nonmotor seed are regions shown seed (( inregionsC ),blue,p < 0.05, while the rest of the fibers that project to other parts of the cortex are shown in red. Correlation R = ((0.60).C), p < 0.05, R = −0.60). −between the clinical response and the total amount of cortical projections into nonmotor seed regions 3.2.3.3.2.3. Density(( DensityC), p of< 0.05, Fibers of FibersR = − in0.60). thein the Motor Motor Cortex Cortex

The3.2.3.The tractographyDensity tractography of Fibers of inof the thethe three Motorthree seed seedCortex regions regions analyzedanalyzed independently independently showed showed that thatall patients all patients displayed active fibers projecting to all cortices including preSMA, SMA and M1, as shown in Figure displayedThe active tractography fibers projecting of the three to all seed cortices regions including analyzed preSMA, independently SMA and showed M1, asthat shown all patients in Figure 4. 4. The density of the projections to the motor cortex was analyzed by investigating the mean amount The densitydisplayed of active the projections fibers projecting to the to motor all cortices cortex including was analyzed preSMA, by SMA investigating and M1, as theshown mean in Figure amount of of activated fibers per voxel inside the seed regions. This analysis showed a significant positive activated4. The fibers density per of voxel the projections inside the to seed the regions.motor cortex This was analysis analyzed showed by investigating a significant the positive mean amount correlation correlation between the mean density in all seed regions together (p < 0.05, R = 0.63) as well as in of activated fibers per voxel inside the seed regions.p This analysisR showed a significant positivep betweenpreSMA the mean (p < 0.05, density R = in0.61) all seedin association regions togetherwith the (percen< 0.05,tage =of0.63) improvement as well as in in the preSMA YGTSS ( six< 0.05, correlation between the mean density in all seed regions together (p < 0.05, R = 0.63) as well as in R = 0.61)months in associationafter surgery, with demonstrati the percentageng a higher of improvement density of projecting in the YGTSS fibers within six months these afterareas surgery,in preSMA (p < 0.05, R = 0.61) in association with the percentage of improvement in the YGTSS six demonstratingpatients with a higherbetter clinical density outcomes, of projecting as shown fibers in Figure within 5A,B. these SMA areas and in M1 patients showed withboth a better positive clinical months after surgery, demonstrating a higher density of projecting fibers within these areas in outcomes,tendency as on shown the mean in Figure density,5A,B. however, SMA it andwas not M1 significant showed when both aanalyzed positive independently tendency on (p the> 0.05 mean patients with better clinical outcomes, as shown in Figure 5A,B. SMA and M1 showed both a positive density,both, however, R = 0.25 and it was R = 0.46, not significantrespectively). when analyzed independently (p > 0.05 both, R = 0.25 and tendency on the mean density, however, it was not significant when analyzed independently (p > 0.05 R = 0.46, respectively). both, R = 0.25 and R = 0.46, respectively).

Figure 4. Connectivity-based segmentation of the seed areas. Representative tractographies of each patient. Images are shown in patient-space, where the most significant density of fibers was observed. FigureFigureTherefore, 4. Connectivity-based 4. Connectivity-based the most symbolic segmentation MRIsegmentation cut of each ofof pati thetheent seed was ar areas. depicted,eas. Representative Representative including the tractographies most tractographies representative of each of each patient.patient.hemisphere Images Images arein eachare shown shown individual. in in patient-space, patien Fiberst-space, originated wherewhere the thefrom most most the significant VTAs significant that density connect density of fibersto of M1 fibers wasare observed. wasshown observed. in Therefore, the most symbolic MRI cut of each patient was depicted, including the most representative Therefore,green, thewhereas most fibers symbolic connecting MRI cut to ofSMA each and patient preSMA was are depicted, shown inincluding orange and the blue, most respectively. representative hemisphere in each individual. Fibers originated from the VTAs that connect to M1 are shown in hemisphere in each individual. Fibers originated from the VTAs that connect to M1 are shown in green, green, whereas fibers connecting to SMA and preSMA are shown in orange and blue, respectively. whereas fibers connecting to SMA and preSMA are shown in orange and blue, respectively. Patients are separated in responders (green bar) and non-responders (red bar) in descending order from the best to the worst clinical outcome from left to right. Independently from their clinical outcome, all patients showed thalamic connectivity to the seed areas. Brain Sci. 2020, 10, x FOR PEER REVIEW 7 of 12

Patients are separated in responders (green bar) and non-responders (red bar) in descending order from the best to the worst clinical outcome from left to right. Independently from their clinical Brain Sci.outcome,2020, 10, 302all patients showed thalamic connectivity to the seed areas. 7 of 12

Figure 5. Correlation between postoperative improvement of YGTSS after six months expressed in percentage and the mean of fibers per voxel located within the cortical seed regions. All regions of interestFigure (ROIs,5. Correlationp < 0.05, betweenR = 0.63) postoperative summed together improvemen includingt of the YGTSS preSMA, after SMA six months and M1 expressed are shown in inpercentage (A), while theand independentthe mean of seedfibers regions per voxel are located shown separatelywithin the incortical (B) (preSMA, seed regions.p < 0.05, AllR regions= 0.61), of (Cinterest) (SMA ,(ROIs,p > 0.05, p < 0.05,R = 0.25)R = 0.63) and summed (D) (M1, togetherp >0.05, includingR = 0.11). th Datae preSMA, shown SMA in this and figure M1 are represent shown in individual(A), while patient the independent analysis (n =seed7). Forregions a segmented are shown analysis separately of each in hemisphere(B) (preSMA, (n p= <14), 0.05, please R = 0.61), consult (C) Figure(SMA, A2 p .> 0.05, R = 0.25) and (D) (M1, p >0.05, R = 0.11). Data shown in this figure represent individual patient analysis (n = 7). For a segmented analysis of each hemisphere (n = 14), please consult Figure 4. DiscussionA2. In the present study we investigated the connectivity between the CM-Voi complex in the 4. Discussion thalamus and the motor cortex during DBS in TS patients. Our findings showed that an increase in the densityIn the of present fiber projections study we to investigated the seed regions the connectivity of the motor between cortex, including the CM-Voi preSMA, complex SMA in and the M1,thalamuswas accompanied and the motorwith cortex better during clinical DBS outcomes. in TS pa Thesetients. results Our findings support theshowed concept that that an abnormalincrease in structuralthe density connectivity of fiber projections of thalamo-cortical to the seed pathways regions inof TSthe may motor be cortex, involved including in the generation preSMA, ofSMA motor and andM1, vocal was accompanied tics [8]. More with specifically, better clinical activation outcomes. of fibers These projecting results support to the preSMA the concept was that significantly abnormal higherstructural in responder connectivity patients. of thalamo-cortical In line with these pathways findings, in previousTS may be studies involved have in suggested the generation that tic of severitymotor isand correlated vocal tics with [8]. activations More specifically, in the premotor activation cortex of (SMA fibers and projecting preSMA) to [31 the]. AlthoughpreSMA thewas functionsignificantly of these higher cortical in areasresponder in TS patients. is still to In be determined,line with these it has findings, been proposed previous that studies its role have in planningsuggested of that movements, tic severity motor is correlated inhibition with and ac thereforetivations voluntaryin the premotor tic suppression cortex (SMA may and be preSMA) related to[31]. symptom Although reduction the function [32,33 of]. Furthermore,these cortical areas there in is TS evidence is still to that be thedetermined, urge to tic itis has associated been proposed with thethat SMA its role region, in planning thus DBS of formovements, TS may also motor act i bynhibition reducing and pathological therefore voluntary urges to tic tic suppression [34]. Although may previousbe related studies to symptom have reported reduction apparent [32,33]. conflicting Furthermore, results there about is connectivityevidence that in the TS patients,urge to ittic is is noteworthyassociated with to mention the SMA that region, certain thus diff erencesDBS for inTS the may design also act between by reducing studies pathological can be observed urges [5 to–8 tic]. For[34]. instance, Although Cheng previous and colleaguesstudies have reflect reported if progression apparent ofconflicting the disease results can playabout a connectivity role in reducing in TS connectivitypatients, it patternsis noteworthy in TS, sinceto mention they studied that certai a cohortn differences of adult patients in the design with a between mean disease studies duration can be ofobserved almost three [5–8]. decades For instance, [5]. Nevertheless, Cheng and colleagues Makki and reflec colleaguest if progression reported of comparablethe disease can results play witha role lowerin reducing probability connectivity of connection patterns between in TS, caudate since they nucleus studied and a anterior-dorsolateral-frontal cohort of adult patients with cortex a mean on thedisease left hemisphere duration inof childrenalmost withthree TS decades [6]. Another [5]. crucialNevertheless, difference Makki between and these colleagues two reports reported was thecomparable presence of results comorbidities. with lower While probability Cheng et of al. connection selected a cohort between of TS caudate patients nucleus without and psychiatric anterior- comorbidities,dorsolateral-frontal Makki cortex et al. studiedon the left a group hemisphere of individuals in children with with accompanying TS [6]. Another psychiatric crucial behaviordifference likebetween OCD. Thethese presence two reportsof other was disordersthe presence may of complicate comorbidities. the analysis While Cheng of these et results, al. selected since a multiple cohort of circuitsTS patients may involvewithout several psychiatric cortical comorbidities, structures simultaneously. Makki et al. studied Although a group our resultsof individuals confirm thewith relevanceaccompanying of these psychiatric cortical structures, behavior like there OCD. are stillThe certainpresence di ffoferences other disorders to these studies. may complicate Contrarily, the Thomallaanalysis andof colleaguesthese results, showed since enhanced multiple connectivity circuits may between involve the thalamusseveral cortical and the SMAstructures [7]. Insimultaneously. this study, the cohortAlthough may our be moreresults comparable confirm the to rele ourvance patients, of these where cortical younger structures, adult patients there are with still similar duration disease duration where included. However, our group of TS patients was fairly heterogeneous, with an almost equally divided sample of patients with comorbidities and without them. Brain Sci. 2020, 10, 302 8 of 12

Consequently, medication between participants was also quite diverse in our group. On the contrary, Thomalla et al. included TS patients with no psychiatric comorbidities and no medications at the inclusion to the study. Nevertheless, the same authors of this report discussed the very selected group of patients with these unique characteristics, which may not necessarily represent the majority of the TS population. In this regard, when we analyze the patients included in our study, two cases were also diagnosed with OCD, one of the most common comorbid conditions in TS. This finding could be interpreted by itself as a better representation of comorbidities of this disorder in our study than the ones reported in other studies. It could also be interpreted as a confounding factor, since these two patients with OCD had the worst clinical outcome. The connectivity profile of these two cases interestingly followed a similar pattern, showing a clear difference with the patterns of responders. Recapitulating, all these alterations in connectivity probably illustrate a process of adaptation between pathological input at diverse stages of the disease and the capacity of compensation according to the individual variables of each patient. In this context, it is relevant to mention that the connectivity displayed in our study is a stimulation-dependent connectivity, while the above-mentioned studies are based on structural connectivity paradigms. For this reason, it was of crucial importance that our DTIs were performed under anesthesia. This way we avoided movement-associated artifacts, since the slightest movement in TS patients could generate alterations in tractographies. We also demonstrated that non-responders displayed larger amount of active fibers than responder patients, but projecting to cortical areas different from the seed regions. These findings suggest that diffuse stimulation of several cortical areas simultaneously may have therapeutic implications on these patients. Since non-responder patients also displayed projections into the preSMA, SMA and M1 cortices, (however, with a lower density than the good responders) these findings may suggest that a more selective connectivity to these seed regions can reproduce better clinical outcomes. These observations translated directly into the size of the generated VTAs and the amount of fibers activated by these VTAs that projected into the entire cortex (preSMA, SMA, M1 and others). This assessment showed a clear negative correlation between higher VTAs volumes and the improvement in the YGTSS scores. Therefore, the consequence of these larger VTAs was the activation of a larger quantity of fibers that projected to the general cortex. Previous studies in different psychiatric disorders have shown a similar negative effect by an extensive activation of nonrelevant fibers during stimulation of the anterior limb of the internal capsule and nucleus accumbens in OCD patients [16]. In this study, the authors suggest that the activation of nonrelated structures may counteract the positive effect reached by the targeted fibers. In order to validate this concept, after we finished the interpretation of our results, we reanalyzed our data using fixed-size VTAs of 1, 2 and 3 Volts in all patients instead of the actual individual parameters of each subject. This analysis showed the same connectivity patterns of increased fiber projections to the general cortex and not primarily to the preSMA, SMA and M1 cortices in non-responders, therefore, demonstrating that the amount of activated fibers would ultimately be the most relevant factor, and not exactly the size of the VTAs. Although larger VTAs could activate more fibers, apparently this principle is dependent on the exact anatomical area that is stimulated. Moreover, not only the amount of fibers projecting to relevant areas may be critical for a positive outcome, but also the capacity to exclusively modulate the areas of interest. In order to achieve this objective, a more precise anatomical location of the active contacts within the thalamus may prove to be an essential factor. Our target is based on the positive clinical effect on Tourette symptoms of thalamotomies performed by Hassler and Dieckmann in 1970. Hassler and Dieckmann performed more than ten lesions per hemisphere, mainly in the median and intralaminar thalamic nuclei as well as the inner part of the ventral oral thalamic nucleus [35]. The rationale for the first DBS case was to strategically define one target so that the different nuclei lesioned by Hassler could be modulated by implantation of one lead per hemisphere [36]. This target was chosen at the anterior part of the centromedian nucleus (as part of the intralaminar thalamic nuclei), at its medial border with the medial thalamic nuclei, and along the Voi. DBS of this specific target has proven to be effective in a randomized controlled trial [37]. Brain Sci. 2020, 10, x FOR PEER REVIEW 9 of 12

per hemisphere [36]. This target was chosen at the anterior part of the centromedian nucleus (as part of the intralaminar thalamic nuclei), at its medial border with the medial thalamic nuclei, and along the Voi. DBS of this specific target has proven to be effective in a randomized controlled trial [37]. Comparable clinical results have been reported in up to four different targets within the CM Brain Sci. 2020, 10, 302 9 of 12 thalamic region [12], however anatomical differences between these nuclei should be taken into consideration. A recent study with a similar setting, in this case targeting the CM-Pf (parafascicular) region,Comparable showed clinicala high variability results have between been reported the clinical in up outcome to four and different the connectivity targets within [38]. the In CM this thalamicreport, the region cortical [12], projections however anatomicalassociated with differences better clinical between responses these nuclei were the should right be frontal taken middle into consideration.gyrus, the left A frontal recent superior study with sulci a similarregion setting,and the inleft this cingulate case targeting sulci region. the CM-Pf None (parafascicular) of these regions region,were particularly showed a high involved variability in our between study, the suggesting clinical outcome a potential and difference the connectivity between [38 ].the In connectivity this report, theof corticalthe CM-Voi projections and the associated CM-Pf complexes. with better clinical responses were the right frontal middle gyrus, the leftA frontal major superiorlimitation sulci of regionour study and is the the left limited cingulate size sulci of our region. sample, None in ofthe these context regions of such were a particularlyheterogeneous involved population. in our study, As we suggesting mentioned a potential before, dialthoughfference betweenthis factor the may connectivity represent of more the CM-Voiproperly and the the general CM-Pf TS complexes. population, in our case it could also fragment the data and extrapolate the outlierA major data. limitationTherefore, oflarger our cohorts study is with the limitedsimilar conditions size of our and sample, long-term in the follow-ups context of even such after a heterogeneousinitial clinical population. failure are required As we mentioned to validate before, the findings although ofthis our factorstudy. may However, represent to our more knowledge, properly thethis general is the first TS population, time that TS in patients our case with it couldongoin alsog stimulation fragment theof the data CM-Voi and extrapolate have been investigated the outlier data.with Therefore,stimulation-dependent larger cohorts tractographies with similar conditionsbased on high-definition and long-term dMRI follow-ups data. even after initial clinical failure are required to validate the findings of our study. However, to our knowledge, this is the5. firstConclusions time that TS patients with ongoing stimulation of the CM-Voi have been investigated with stimulation-dependentTo summarize, we tractographies demonstrate basedthat the on extent high-definition of tic reduction dMRI in data. TS patients after CM-Voi DBS is associated with the degree of connectivity between the stimulated area and the motor cortex. In 5. Conclusions particular, an increased density of projections to the preSMA, SMA and M1 areas correlates with betterTo summarize,clinical outcomes we demonstrate after chronic that DBS. the These extent findings of tic reduction reinforce inthe TS theory patients that after an abnormal CM-Voi DBSstructural is associated connectivity with the of degreethalamo-cortical of connectivity pathways between underlies the stimulated TS, and therefore area and the motormodulation cortex. of Inthese particular circuits, an through increased DBS density could ofreduce projections motor and to the vocal preSMA, tics. SMA and M1 areas correlates with better clinical outcomes after chronic DBS. These findings reinforce the theory that an abnormal Author Contributions: Conceptualization, P.A. and V.V.-V.; methodology, P.A., J.C.B., D.H. and V.V.-V.; structural connectivity of thalamo-cortical pathways underlies TS, and therefore the modulation of software, P.A., P.H. and M.H.; validation, P.A., P.H., M.S. and V.V.-V; formal analysis, P.A., P.H. and V.V.-V.; theseinvestigation, circuits through P.A., J.C.B., DBS D.H. could and reduce V.V.-V.; motor resources, and vocal P.A., tics.M.H., J.C.B. and M.S.; data curation, P.A., P.H., J.C.B., D.H. and V.V.-V.; writing—original draft preparation, P.A. and P.H.; writing—review and editing, P.A., Author Contributions: Conceptualization, P.A. and V.V.-V.; methodology, P.A., J.C.B., D.H. and V.V.-V.; software, P.A.,P.H., P.H. M.H., and M.S., M.H.; J.C.B., validation, D.H. and P.A., V.V.-V.; P.H., M.S. visualization, and V.V.-V; P.H., formal M.H. analysis, and M.S.; P.A., supervision, P.H. and V.V.-V.; P.A., P.H. investigation, and V.V.V.; P.A.,project J.C.B., administration, D.H. and V.V.-V.; P.A. resources, and V.V.-V P.A.,.;M.H., funding J.C.B. acquisition, and M.S.; dataN/A. curation, All authors P.A., have P.H., J.C.B.,read and D.H. agreed and V.V.-V.; to the writing—originalpublished version draft of preparation,the manuscript. P.A. and P.H.; writing—review and editing, P.A., P.H., M.H., M.S., J.C.B., D.H. and V.V.-V.; visualization, P.H., M.H. and M.S.; supervision, P.A., P.H. and V.V.V.; project administration, P.A. and V.V.-V.;Funding: funding This acquisition,research did N /notA. Allreceive authors any havespecific read grant and agreedfrom funding to the published agencies in version the public, of the commercial, manuscript. or not-for-profit sectors. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, orAcknowledgments: not-for-profit sectors. We would like to thank Julia Burkhardt for her expert assistance and help during the Acknowledgments:creation of the fiberWe tracking would images. like to thank Julia Burkhardt for her expert assistance and help during the creation of the fiber tracking images. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. Appendix A Appendix A

Figure A1. Scatter plot depicting the correlation between postoperative improvement of YGTSS after six months expressed in percentage and the volumetric measurements of the generated VTAs ((A), p < 0.001, R = 0.74) and the numbers of ﬁbers in the VTA that project to the cortex ((B), p < 0.01, − R = 0.58). Data shown in this ﬁgure represent a segmented analysis of each hemisphere (n = 14). − Brain Sci. 2020, 10, x FOR PEER REVIEW 10 of 12

Figure A1. Scatter plot depicting the correlation between postoperative improvement of YGTSS after six months expressed in percentage and the volumetric measurements of the generated VTAs ((A), p < 0.001, R = −0.74) and the numbers of fibers in the VTA that project to the cortex ((B), p < 0.01, R = Brain Sci.−0.58).2020, 10Data, 302 shown in this figure represent a segmented analysis of each hemisphere (n = 14). 10 of 12

Figure A2. Correlation between postoperative improvement of YGTSS after six months expressed in percentage and the mean of fibers per voxel located within the cortical seed regions. All regions of interest (ROIs, p < 0.05, R = 0.32) summed together including the preSMA, SMA and M1 are shown Figure A2. Correlation between postoperative improvement of YGTSS after six months expressed in in (A), while the independent seed regions are shown separately in figures (B) (preSMA, p < 0.001, percentage and the mean of fibers per voxel located within the cortical seed regions. All regions of R = 0.71), (C) (SMA, p > 0.05, R = 0.16) and (D) (M1, p > 0.05, R = 0.07). Data shown in this figure interest (ROIs, p < 0.05, R = 0.32) summed together including the preSMA, SMA and M1 are shown in represent a segmented analysis of each hemisphere (n = 14). (A), while the independent seed regions are shown separately in figures (B) (preSMA, p < 0.001, R = 0.71), (C) (SMA, p > 0.05, R = 0.16) and (D) (M1, p > 0.05, R = 0.07). Data shown in this figure represent References a segmented analysis of each hemisphere (n = 14). 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American ReferencesPsychiatric Association Publishing: Arlington, VA, USA, 2013. 2. Heise, K.-F.; Steven, B.; Liuzzi, G.; Thomalla, G.; Jonas, M.; Müller-Vahl, K.; Sauseng, P.; Münchau, A.; 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American Gerloff, C.; Hummel, F.C. Altered modulation of intracortical excitability during movement preparation in Psychiatric Association Publishing: Arlington, VA, USA, 2013. Gilles de la Tourette syndrome. Brain 2009, 133, 580–590. [CrossRef][PubMed] 2. Heise, K.-F.; Steven, B.; Liuzzi, G.; Thomalla, G.; Jonas, M.; Müller-Vahl, K.; Sauseng, P.; Münchau, A.; 3. Ganos, C.; Roessner, V.; Münchau, A. The functional anatomy of Gilles de la Tourette syndrome. Neurosci. Gerloff, C.; Hummel, F.C. Altered modulation of intracortical excitability during movement preparation in Biobehav. Rev. 2013, 37, 1050–1062. [CrossRef][PubMed] Gilles de la Tourette syndrome. Brain 2009, 133, 580–590, doi:10.1093/brain/awp299. 4. Worbe, Y.; Malherbe, C.; Hartmann, A.; Pélégrini-Issac, M.; Messé, A.; Vidailhet, M.; Lehéricy, S.; Benali, H. 3. Ganos, C.; Roessner, V.; Münchau, A. The functional anatomy of Gilles de la Tourette syndrome. Neurosci. Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome. Brain 2012, 135, Biobehav. Rev. 2013, 37, 1050–1062, doi:10.1016/j.neubiorev.2012.11.004. 1937–1946. [CrossRef][PubMed] 4. Worbe, Y.; Malherbe, C.; Hartmann, A.; Pélégrini-Issac, M.; Messé, A.; Vidailhet, M.; Lehéricy, S.; Benali, 5. Cheng, B.; Braass, H.; Ganos, C.; Treszl, A.; Biermann-Ruben, K.; Hummel, F.C.; Müller-Vahl, K.; Schnitzler, A.; H. Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome. Brain 2012, Gerloff, C.; Münchau, A.; et al. Altered intrahemispheric structural connectivity in Gilles de la Tourette 135, 1937–1946, doi:10.1093/brain/aws056. syndrome. NeuroImage Clin. 2013, 4, 174–181. [CrossRef] 5. Cheng, B.; Braass, H.; Ganos, C.; Treszl, A.; Biermann-Ruben, K.; Hummel, F.C.; Müller-Vahl, K.; Schnitzler, 6. Makki, M.I.; Govindan, R.M.; Wilson, B.J.; Behen, M.E.; Chugani, H.T. Altered Fronto-Striato-Thalamic A.; Gerloff, C.; Münchau, A.; et al. Altered intrahemispheric structural connectivity in Gilles de la Tourette Connectivity in Children with Tourette Syndrome Assessed with Diffusion Tensor MRI and Probabilistic Fibersyndrome. Tracking. NeuroImageJ. Child Neurol. Clin. 20132009, 4, ,24 174–181,, 669–678. doi:10.1016/j.nicl.2013.11.011. [CrossRef] 7. Götz, T.; Siebner, H.R.; Jonas, M.; Bäumer, T.; Biermann-Ruben, K.; Hummel, F.; Gerloff, C.; Müller-Vahl, K.; Schnitzler, A.; Orth, M.; et al. Structural changes in the somatosensory system correlate with tic severity in Gilles de la Tourette syndrome. Brain 2009, 132, 765–777. [CrossRef] 8. Worbe, Y.; Marrakchi-Kacem, L.; LeComte, S.; Valabregue, R.; Poupon, F.; Guevara, P.; Tucholka, A.; Mangin, J.-F.; Vidailhet, M.; Lehericy, S.; et al. Altered structural connectivity of cortico-striato-pallido-thalamic networks in Gilles de la Tourette syndrome. Brain 2014, 138, 472–482. [CrossRef] Brain Sci. 2020, 10, 302 11 of 12

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