
==== Front
Neurol Med Chir (Tokyo)
Neurol Med Chir (Tokyo)
Neurologia medico-chirurgica
0470-8105
1349-8029
The Japan Neurosurgical Society

38897940
10.2176/jns-nmc.2023-0254
Special Topic
Surgical Concepts and Long-term Outcomes of Thalamic Deep Brain Stimulation in Patients with Severe Tourette Syndrome: A Single-center Experience
MORISHITA Takashi 1
SAKAI Yuki 2
IIDA Hitoshi 3
TANAKA Hideaki 1
PERMANA Galih I. 14
KOBAYASHI Hiromasa 1
TANAKA Saori C. 25
ABE Hiroshi 1
1 Department of Neurosurgery, Fukuoka University Faculty of Medicine, Fukuoka, Fukuoka, Japan
2 ATR Brain Information Communication Research Laboratory Group, Soraku, Kyoto, Japan
3 Department of Psychiatry, Fukuoka University Faculty of Medicine, Fukuoka, Fukuoka, Japan
4 Department of Neurosurgery, Dr. Moewardi General Academic Hospital, Central Java, Indonesia
5 Division of Information Science, Nara Institute of Science and Technology, Ikoma, Nara, Japan
Corresponding author: Takashi Morishita, MD, PhD

Department of Neurosurgery, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan Ward, Fukuoka 814-0180, Japan.

e-mail: tmorishita@fukuoka-u.ac.jp

19 6 2024
8 2024
64 8 289298
30 10 2023
1 4 2024
© 2024 The Japan Neurosurgical Society
https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives International License.
Tourette syndrome (TS) is a developmental neuropsychiatric disorder that is characterized by tic movements. Deep brain stimulation (DBS) may be a treatment option for severe cases refractory to medical and behavioral therapies. In this study, we reviewed the surgical techniques used for DBS in patients with severe TS and its clinical outcomes and sought to determine the optimal surgical procedure and current issues based on our experience and the literature. A total of 14 patients, consisting of 13 men and 1 woman, who underwent centromedian thalamic DBS and were followed up for a mean duration of 2.3 ± 1.0 years, participated in this study. The mean Yale Global Tic Severity Scale severity score significantly improved from 41.4 ± 7.0 at baseline to 19.8 ± 11.4 at 6 months (P = 0.01) and 12.7 ± 6.2 at the last follow-up (P < 0.01). Moreover, the mean Yale Global Tic Severity Scale impairment score significantly improved from 47.1 ± 4.7 at baseline to 23.1 ± 11.1 at 6 months (P < 0.01) and 7.6 ± 2.9 at the last follow-up (P < 0.01). However, there were problems with continuous postoperative monitoring (three cases were lost to follow-up) and surgery-related adverse events, including one case each of lead misplacement and a delayed intracerebral hemorrhage due to severe self-injurious tics. This study aimed to highlight not only the clinical efficacy of DBS for TS but also its challenges. Clinicians should understand the three-dimensional brain anatomy so that they can perform precise surgical procedures, avoid adverse events, and achieve favorable outcomes of DBS for TS.

Tourette syndrome
deep brain stimulation
thalamus
adverse events
microlesion effect
==== Body
pmcIntroduction

Tourette syndrome (TS) is a relatively common neuropsychiatric disorder that is characterized by tic movements in childhood and may progress to become debilitating. Deep brain stimulation (DBS) could be a treatment option for cases with severe symptoms that do not respond to medical and behavioral therapies. Several international groups have confirmed the clinical efficacy of DBS1-3) since the first report of its use in TS.4) However, there are several issues regarding the use of DBS in TS.

Since TS is considered to originate in the cortico-striato-thalamo-cortical loops, various targets for electrical stimulation, such as the centromedian thalamic nucleus, globus pallidus interna, and ventral capsule/ventral striatum, have been proposed.3,5) It has been reported that these procedures are equally effective;2,3) however, the best stimulation brain region has not been identified. Another issue is that the phenomenology in TS and the response to DBS vary from patient to patient. This problem is complicated by various factors, such as optimal patient selection and optimal lead placement and stimulation parameters, and there are still no established patient selection criteria like those created for DBS in Parkinson's disease. Furthermore, lead misplacement has been linked to DBS failure in TS.6,7) No algorithm for adjustment of the stimulation parameters has been established. In addition to the above issues, clinical management requires special attention by a multidisciplinary team to avoid unexpected adverse events.

In this study, we reviewed our surgical techniques and the clinical outcomes of DBS for TS. Centromedian thalamic DBS is among the surgical strategies proposed for TS in the literature, which we have used at our center and previously reported our observations.6,7) This study also discusses the optimal surgical procedures and current issues in DBS for severe TS based on our experience and the literature.

Methods

Study design

The clinical data analyzed in this study were prospectively recorded and linked with neuroimaging data. Our institutional review board approved the study protocol (approval numbers 2017M098 and U22-02-012). Written informed consent was obtained from all study participants. Consecutive patients who underwent centromedian thalamic DBS in our department between May 2018 and January 2023 were enrolled in this study. At our center, DBS is indicated for patients aged 12 years or older who have severe medication-refractory symptoms of TS. A multidisciplinary preoperative evaluation was performed by our multidisciplinary team consisting of a psychiatrist, neurologist, neurosurgeon, and pediatrician (in cases of pediatric case) for candidacy as recommended by the guidelines.6,8) Patients with high Yale Global Tic Severity Scale (YGTSS) scores greater than 35 are typically appropriate candidates for DBS surgery. However, if the quality of life is disturbed due to tics and/or there are any life-threatening conditions such as self-injurious tics, DBS surgery is recommended even with relatively low YGTSS scores. Patients with functional movement disorders and high-risk patients for general anesthesia are excluded. The primary outcome measure was the YGTSS score. All patients were followed up at 6 months, 1 year, and annually thereafter. Adverse events related to chronic stimulation and surgical procedures were also recorded. Records of mood changes were based on self-reported complaints.

Stereotactic targeting

High-resolution magnetic resonance imaging (MRI) inclusive of volumetric contrasted T1-weighted and volumetric fast gray matter acquisition T1 inversion recovery sequences was performed. For DBS lead placement, stereotactic planning was conducted using iPlan Stereotaxy software (BrainLab, Munich, Germany). The MRI sequences were fused automatically, and the midcommissural point was defined after setting up the anterior and posterior commissure points to anchor the Cartesian coordinate system. The tentative target was set as follows: 5 mm lateral to the midline and 4 mm posterior to the midcommissural point at the level of anterior-posterior commissure plane. The trajectory was then determined according to the visualized thalamic structures and safe insertion angle.6,9,10) The centromedian thalamic nucleus was identified as a relatively high intensity area on the fast gray matter acquisition T1 inversion recovery images, and other landmark structures such as the mammillothalamic tract and red nucleus were also determined on the images. The trajectory was planned so that the ventral two contacts of the DBS electrode would be located in the centromedian thalamic nucleus. Table 1 summarizes the planned targeting coordinates and angles, and Fig. 1 shows the representative targeting image.

Table 1 Stereotactic targeting coordinates

Case	Left	Right	
X	Y	Z	AC-PC angle	CTR-line angle	X	Y	Z	AC-PC angle	CTR-line angle	
1	6	−4.5	0	53.6	38	5.5	−3	0	49.8	49.8	
2	4.5	−3	−0.5	66.4	33.6	4.5	−3.5	−0.5	64.7	31.6	
3	4	−6	−0.5	62.1	35.3	4	−5.5	−0.5	62.8	32.9	
4	4	−6.5	−1.5	49.8	34.6	4	−6.5	−1.5	50.8	32.9	
5	4	−6.5	−0.5	57.4	36.5	3.5	−6.5	−0.5	59.1	37.8	
6	4.5	−6.5	−0.5	47.5	41.8	4	−7	−0.5	46.2	26.9	
7	4	−5	−0.5	51	43.5	4	−6.5	−1	51	32.9	
8	4.5	−6	−0.5	70.8	39.2	4.5	−5.5	−0.5	79	32.9	
9	4	−6	−1.5	56.2	31.2	3.5	−5.5	−1.5	49.7	32.2	
10	5	−6	−0.5	48.5	33.8	5	−6.5	−0.5	53.8	27.7	
11	5.5	−4.5	−1	52.4	32.6	5	−4.5	−1	53.3	42.7	
12	4.5	−5	−1	49	39.8	4.5	−5.5	−0.5	52.7	35.4	
13	6.5	−6	−1	66.9	34.2	5.5	−6	0	65.4	29.9	
14	6	−7	−1	66.9	33.3	6	−6	−0.5	62.7	36.6	
Mean ± SD	4.8 ± 0.9	−5.6 ± −1.1	−0.75 ± −0.4	57.0 ± 8.1	36.2 ± 3.7	4.5 ± 0.8	−5.6 ± −1.2	−0.6 ± −0.5	57.2 ± 8.9	34.4 ± 6.0	
AC, anterior commissure; CTR, center; PC, posterior commissure; SD, standard deviation

Fig. 1 Representative preoperative stereotactic targeting images (case 8).

Purple and red dotted lines indicate the right and left lead trajectories, respectively, in the preoperative planning. A. Axial T1-weighted image with contrast. B. Coronal T1-weighted image with contrast. C. Sagittal T1-weighted image with contrast. D. Axial FGATIR image. E. Coronal FGATIR image. F. Sagittal FGATIR image. CM, centromedian nucleus; FGATIR, fast gray matter acquisition T1 inversion recovery; MD, mediodorsal nucleus; MTT, mammillothalamic tract; RN, red nucleus (Adapted from reference 6).

Surgical procedure

Following attachment of a Leksell G frame (Elekta, Stockholm, Sweden) to the head, the stereotactic computed tomography (CT) scan was performed. The patient was then brought to the operating room for the surgical procedure. The first four patients underwent DBS surgery under local anesthesia using microelectrode recording, but three of them could not tolerate the procedure while awake. Moreover, meaningful data regarding the electrode position could not be obtained throughout the procedure. The remaining ten cases underwent the procedure under general anesthesia without microelectrode recording, and simultaneous bilateral implantation of DBS leads (model 3,387; Medtronic, Minneapolis, MN, USA) was performed under C-arm guidance. We then implanted an implantable pulse generator (Activa RC [Medtronic] for the first nine cases; Percept PC [Medtronic] from case 10 onward) on the same day under general anesthesia.

DBS programming

Electrical stimulation was started 2 weeks following DBS surgery to activate the second-most ventral contacts bilaterally. The patient was asked to visit our DBS clinic once a month during the first 6 months of follow-up, and the stimulation intensity was gradually increased. Usually, the immediate response to changes in stimulation parameters could not be observed in clinical settings. If the maximum stimulation intensity was reached within the therapeutic window in a single monopolar setting, the adjacent contact was activated to apply interleaving, multiple monopolar, or bipolar stimuli. If the chronic stimulation-induced side effects, such as depressed mood or worsening of tic symptoms, were suspected, stimulation intensity was decreased and/or active contacts were changed.

Localization of DBS leads

A CT scan was performed to identify the lead location on postoperative day 9, and the image was fused with a preoperative scan to evaluate the electrode positions. Lead-DBS (http://www.lead-dbs.org/) was used to preprocess the imaging data.6,11,12) Images inclusive of postoperative CT and preoperative MRI scans were coregistered linearly to the preoperative T1-weighted images using SPM software (https://www.fil.ion.ucl.ac.uk/spm/software/spm12/). Nonlinear bias associated with DBS surgery was minimized by refining the registration between preoperative T1-weighted images and postoperative CT scans by linear registration within the subcortical target region of interest.13) All data were normalized to the standard Montreal Neurological Institute space. The procedure was performed using whole-brain nonlinear SyN registration in Advanced Normalization Tools (http://stnava.github.io/ANTs/)14) with the “effective” (low variance) setting and subcortical refinement performed in Lead-DBS.12) We automatically prereconstructed electrode trajectories and contacts using the PaCER algorithm15) and manually adjusted them with Lead-DBS. Subject-independent three-dimensional (3D) atlases of the thalamic nuclei evaluated the lead trajectory and contact positions.16)

Moreover, subject-independent 3D atlases of the thalamic nuclei also determined the lead trajectory and contact positions. The contacts were deemed to be present within those thalamic nuclei when spherical regions with a radius of 0.2 mm around the contacts overlapped with the centromedian, mediodorsal, ventrolateral, and ventroposterior nuclei. Detected electrodes and thalamic nuclei were visualized using Lead-DBS.

Statistical analysis

The Kruskal-Wallis H test was used to compare the YGTSS scores at three different time points (baseline, 6 months, and last follow-up). The post hoc Bonferroni correction was applied to tests for multiple comparisons. A P-value of <0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics 26 software (IBM Corp., Armonk, NY).

Results

Clinical outcomes

A total of 14 patients, consisting of 13 men and 1 woman, were included in this study. The mean age at surgery was 25.6 ± 9.6 years. The mean age at onset of TS was 7.6 ± 2.9 years and the mean age at diagnosis was 12.1 ± 4.3 years (Table 2). The mean follow-up duration was 2.3 ± 1.0 years. All study participants completed their 6 months of follow-up, except for one patient (case 12). A Kruskal-Wallis H test showed that there was a statistically significant difference in YGTSS severity scores [H(2) = 24.789, P < 0.001] and YGTSS impairment scores [H(2) = 28.613, P < 0.001] between the baseline, 6 months of follow-up, and last follow-up. Post hoc comparisons were conducted at three different times using multiple pairwise comparisons with Bonferroni. The mean YGTSS severity score significantly improved from 41.4 ± 7.0 at baseline to 19.8 ± 11.4 at 6 months (P = 0.01) and 12.7 ± 6.2 at the last follow-up (P < 0.01). The mean YGTSS impairment score also significantly improved from 47.1 ± 4.7 at baseline to 23.1 ± 11.1 at 6 months (P < 0.01) and 7.6 ± 2.9 at the last follow-up (P < 0.01). Scores at the last follow-up tended to be lower than those at 6 months, but the differences were not statistically significant (P = 0.586 for the YGTSS severity score, P = 0.683 for the YGTSS impairment score). Table 3 summarizes the changes in the YGTSS scores, and Fig. 2 shows the box plot.

Table 2 Patient demographics

Case	Sex	Age at onset, years	Age at diagnosis, years	Age at surgery, years	Medications tried before DBS	
1	Male	7	22	39	Haloperidol, aripiprazole, clonazepam, bromazepam	
2	Male	14	16	26	Risperidone, aripiprazole, fluvoxamine, atomoxetine	
3	Female	5	10	26	Aripiprazole, haloperidol, risperidone, fluvoxamine, pimozide, clonazepam, olanzapine, chlorpromazine	
4	Male	5	12	18	Aripiprazole, haloperidol, risperidone	
5	Male	8	8	12	Aripiprazole, fluvoxamine, biperiden	
6	Male	7	8	17	Aripiprazole, haloperidol, risperidone, fluvoxamine	
7	Male	5	14	19	Aripiprazole, haloperidol, risperidone	
8	Male	9	10	18	Aripiprazole, clonazepam, etizoram	
9	Male	9	15	26	Aripiprazole, haloperidol, risperidone	
10	Male	8	8	22	Aripiprazole, clonazepam, risperidone	
11	Male	3	10	34	Haloperidol, sulpiride, lurasidone	
12	Male	8	17	24	Aripiprazole, flunitrazepam, and others*	
13	Male	7	7	48	Aripiprazole, risperidone, and others*	
14	Male	12	12	29	Haloperidol, quetiapine, brexpiprazole, and others*	
Mean ± SD	13 males, 1 female	7.6 ± 2.9	12.1 ± 4.3	25.6 ± 9.6		
Cases 12, 13, and 14 could not remember the names of all medications tried in the past. DBS, deep brain stimulation; SD, standard deviation

Table 3 Clinical outcomes

Case	F/U period (years)*	YGTSS severity	YGTSS impairment	
Baseline	6 months	Last F/U	Baseline	6 months	Last F/U	
1	3.5**	40	20	17	50	30	20	
2	4	50	23	4	50	30	10	
3	1**	32	15	14	40	20	10	
4	3	47	19	15	50	20	20	
5	3	50	43	20	50	40	20	
6	3	48	44	16	50	30	20	
7	3	25	9	0	50	0	0	
8	2**	43	12	3	40	10	0	
9	3	44	21	13	50	30	20	
10	2	37	14	11	50	30	10	
11	2	41	8	13	40	10	10	
12	1	39	-	20	50	-	40	
13	1	45	14	17	50	30	30	
14	0.5	39	15	15	40	20	20	
Mean ± SD	2.3 ± 1.0	41.4 ± 7.0	19.8 ± 11.4	12.7 ± 6.2	47.1 ± 4.7	23.1 ± 11.1	16.4 ± 11.8	
P-value	N/A	N/A	0.01	<0.01	N/A	<0.01	<0.01	
Comparison of scores between baseline and 6 months and between baseline and last follow-up.

Comparisons between 6 months and last follow-up scores were not significant (P = 0.586 for YGTSS severity score; P = 0.683 for YGTSS impairment score).

*F/U periods are defined as the time when last available YGTSS scores were recorded. **These cases were lost to follow-up after the last visit. F/U, follow-up; N/A, not applicable; SD, standard deviation; YGTSS, Yale Global Tic Severity Scale

Fig. 2 YGTSS scores at baseline, 6 months, and the last follow-up. F/U, follow-up; YGTSS, Yale Global Tic Severity Scale

Three patients (cases 1, 3, and 8) were lost to follow-up following their last evaluation visit, and one (case 12) missed the 6-month follow-up visit but returned thereafter. Cases 1 and 3 reported that they did not feel sufficient improvement. Case 8 visited our center from a remote area and was lost to follow-up after the start of the COVID-19 pandemic. However, he was satisfied with the suppression of tics. Case 12 also complained of a lack of immediate therapeutic effect, but his family convinced him to continue visiting our clinic.

Case 4 opted to turn the stimulation off due to stimulation-induced adverse events. He complained of a “strong sensation” regardless of the stimulation intensity. Although his motor tics subsided, strong vocal tics persisted. The YGTSS scores for this patient were recorded at the last visit made before stimulation was turned off.

Lead locations and stimulation parameters

At least 1 contact of 28 electrodes was inserted into the centromedian nucleus. We diagnosed lead misplacement when the DBS electrode was located more than 2 mm away from the originally planned trajectory and/or clinical efficacy was inadequate. Figure 3 and Table 4 show how these electrodes were implanted in the thalamus in the normalized brain space.

Fig. 3 Deep brain stimulation electrode positions in a normalized brain space.

Lead electrodes with the CM nucleus (peach), red nucleus (red), MD nucleus (purple), and VL nucleus (yellow). The lead electrodes of each patient were displayed in different colors.

Table 4 Each contact location in the thalamic region

Case	Left	Right	
Contact 0	Contact 1	Contact 2	Contact 3	Contact 8	Contact 9	Contact 10	Contact 11	
1	CM	MD/VL	VL	VL	CM/VP	VL	VL		
2	VP	VL	VL			CM	VL	VL	
3	CM	CM/MD/VP	VL	VL	CM	CM	MD	VL	
4	CM	MD	MD	MD/VL		CM	CM/MD	VL	
4 postrevision	CM	CM/MD	VL	VL					
5	CM	CM	VL/VP	VL	CM	CM	VL/VP	VL	
6	CM	CM/MD	MD/VL	VL	CM	CM/MD	VL	VL	
7		VL/VP	VL		CM	CM	MD/VL	VL	
8	CM	CM	MD/VL	VL	CM	CM/MD	MD	MD	
9	CM	CM	MD/VL	VL	CM	CM	CM/VL/VP	VL	
10	CM	CM/MD	MD/VL	VL		CM	CM	CM/MD	
11	CM	MD/VL	VL	VL		CM/VP	VL	VL	
11 postrevision		CM/VL/VP	VL	VL					
12	CM	CM/VP	VL	VL	CM	CM/MD	MD/VL	VL	
13	CM	CM/MD	MD	MD	CM	CM	MD/VL	VL	
14	VP	CM/VP	VL/VP	VL	CM	CM	CM	CM/MD/VL	
CM, centromedian; MD, mediodorsal; VL, ventrolateral; VP, ventroposterior

Table 5 summarizes the stimulation parameters.

Table 5 The stimulation parameters at last follow-up

Case	Left	Right	
Cathode	Anode	PW (μsec)	Frequency (Hz)	Amplitude (mA)	Cathode	Anode	PW (μsec)	Frequency (Hz)	Amplitude (mA)	
1	3	2	90	130	3.5	11	10	90	130	3.5	
2	3	1	100	130	3.5	3	1	100	130	3.5	
3	2	3	60	130	3.7	11	10	60	130	3.0	
4	0	3	230	160	2.0	8	11	230	160	2.0	
5*	2	Case	120	125	3.7	10	Case	130	125	3.7	
1	Case	100	125	3.0	9	Case	100	125	3.0	
6*	1	Case	150	125	2.2	9	Case	150	125	2.2	
3	Case	150	125	3.5	11	Case	150	125	3.5	
7*	2	Case	150	125	1.2	10	Case	150	125	1.2	
3	Case	180	125	1.5	11	Case	180	125	1.5	
8*	3	Case	60	125	2.8	3	Case	60	125	2.8	
2	Case	90	125	3.8	2	Case	90	125	3.5	
9	2	3	220	210	1.8	10	11	220	210	1.8	
10**	1	Case	150	180	1.9	2	Case	150	180	1.9	
2	Case	150	180	0.8	3	Case	150	180	0.8	
11**	1	Case	100	145	1.2	1	Case	100	145	1.2	
2	Case	100	145	1.3	2	Case	100	145	1.3	
3	Case	100	145	1.4	3	Case	100	145	1.4	
12**	2	Case	90	130	1.5	9	Case	90	130	1.5	
3	Case	90	130	0.3	10	Case	90	130	0.3	
13*	2	Case	90	125	1.8	10	Case	90	125	1.8	
3	Case	100	125	2.1	11	Case	100	125	2.1	
14	2	Case	110	130	1.9	10	Case	110	130	1.9	
*Interleaving stimulation settings were applied.

**Double or triple monopolar settings were applied.

PW, pulse width

Adverse events

Surgical adverse events included wound dehiscence and lead misplacement. In particular, wound dehiscence at the incision site on the scalp required wound revision in three patients (cases 1, 4, and 10). Left DBS lead revision was required in one case due to insufficient suppression of phonic tics despite improvement in his motor tics in the first year after DBS surgery. Left lead misplacement was observed in case 11 on postoperative day 9 because the lead was more than 2 mm away from the intended trajectory despite appearance of microlesion effects; therefore, the patient underwent revision surgery on postoperative day 12 before discharge. Another patient (case 13) experienced an intracerebral hemorrhage along the left DBS electrode due to severe self-injurious tics. To prevent further problems, we sedated the patient for several days and increased her medication and stimulation intensity to control the strong tics. Furthermore, five patients (cases 1, 2, 3, 4, and 10) reported depressed mood, although this side effect was reversible by adjustment of the stimulation parameter.

Discussion

This is one of very few studies of DBS surgery for TS performed in Japan. This study demonstrated the clinical efficacy of DBS of the centromedian nucleus for this condition.17-19) Our targeting method is in line with the concept explained in the pioneering paper by Visser-Vandewalle et al.20) We aimed at the anteromedial area of the centromedian nucleus passing through the ventrolateral nucleus. Figure shows the stereotactic planning. DBS electrodes were implanted consistently in the intended area, and this precise lead placement may explain our consistent clinical outcomes (Fig. 3, Table 4). We believe that clinicians who perform this procedure should have a thorough understanding of the abovementioned concept and 3D structures in the thalamus.21)

In our previous study, we reported that the microlesion effect resulting from subtle lesions along the electrode trajectory may be a sign of optimal DBS lead placement for TS, in a similar way to that established for essential tremor and Parkinson's disease.7,22,23) Moreover, we investigated the association of the locations of 12 electrodes with the severity of tics in 6 cases and found that the optimal location for this phenomenon may exist in the area that includes the anteromedial area of the centromedian nucleus and the medial area of the ventrolateral nucleus (Fig. 4).7) This finding was consistent with those of other studies.1,24,25)

Fig. 4 Precision mapping of implanted deep brain stimulation electrodes in an atlas.

In each panel, the upper row shows the coronal plane and the lower row shows the axial plane. Colored lines enclose areas of the thalamic nuclei (centromedian nucleus, peach; red nucleus, red; mediodorsal nucleus, purple). Montreal Neurological Institute coordinates are shown above each image. (A) Heat map of overlapping microlesion areas. Color bar: percent overlap among patients. (B) Improvement-related area. Color bar: percent improvement in tic symptoms (Adapted from reference 7).

Furthermore, we have previously found that the frequency of tics in the off-DBS condition was lower at the 6-month follow-up visit than at baseline even after a 24-h stimulation washout.7) This phenomenon may be partly explained by the long-lasting microlesion effect in view of previous studies that found a long-lasting microlesion effect that persists at 6 months after surgery22,23) and another study that reported complete resolution of symptoms.26) However, it should be noted that a neuroplasticity effect may be induced by chronic stimulation.

Since TS is not a degenerative disorder, unlike Parkinson's disease and essential tremor, neuroplasticity should be considered when deciding on the long-term treatment strategy. Smeets et al. reported on six patients with TS who decided to either turn off the stimulator permanently or switch to stimulation of the globus pallidus interna due to stimulation-induced adverse events, such as a reduced energy level, especially at high intensity.27) Stimulation-induced adverse events are usually reversible in patients with movement disorders, but some are not willing to stop treatment and prefer to continue with stimulation at a low intensity. One patient (case 4) in our cohort was faced with a similar situation. We suggested that he continue DBS therapy at a lower intensity, but he felt differently from baseline at the last visit. We consider that neuroplasticity can be induced in such a direction that the brain becomes sensitized to electrical stimulation if stimulation-induced adverse events are continuously induced.

In contrast, Kimura et al. described two patients in whom symptoms resolved following long-term thalamic DBS and in whom YGTSS scores did not return to the baseline values even after turning the stimulator off permanently.17) Their report is noteworthy for the fact that YGTSS scores of a patient showed complete remission. Moreover, in this study, the YGTSS scores were better at the last follow-up than those at 6 months. In this context, the optimal stimulation parameters may induce neuroplasticity that reorganizes the brain circuits in a direction that promotes a healthy state.

We have also published a paper demonstrating the relationships between volume of tissue activated (VTA) and the clinical effects.6) The findings of that study indicated that while therapeutic effects were induced by stimulation in the dorsal area of the target, a depressed mood was likely to be induced when the stimulation current was applied to the mediodorsal nucleus of the thalamus. Moreover, we analyzed the normative connectomes associated with these effects and found that when the therapeutic VTA was mainly connected to the frontal cortices, including the motor areas, the VTA associated with depressed mood had connections to limbic areas, such as the orbitofrontal area and amygdala. Therefore, we usually recommend that patients start with relatively lower intensity stimulation and gradually increase the intensity with careful observation.

Although our clinical outcomes indicate that DBS has favorable clinical effectiveness overall, this study highlights the challenges associated with use of DBS for TS in practice. First, there is a technical issue with DBS in the centromedian nucleus, which raises concern regarding the difficulty of precise lead placement in the centromedian thalamic DBS procedure. This might be partly due to the steep center-line (lateral to medial) angle. Our procedures were performed under C-arm guidance, but intraoperative CT or MRI may be needed to address this issue in the future. Second, there was a problem with follow-up, wherein four patients were either temporarily or permanently lost to follow-up. This problem seems to be related to patient satisfaction. Of 14 patients, 3 stopped coming to the clinic due to dissatisfaction with the therapeutic effects of DBS despite improvement in their YGTSS scores. This dissatisfaction problem has been addressed in the literature.27)

There are several perspectives for the future in this field. Neuroimaging technologies have been developing in the past decade, with increasing use of connectomic analysis in the DBS research field.6,11,28) Recent reports have addressed the possibility of targeting specific fiber tracts in the brain to tailor the stimulation effects to the individual patient.29,30) Another recent paper has investigated the potential use of closed-loop DBS for TS31) and suggested that identifying the pathological biomarker in the neuronal circuit may be useful for more efficient stimulation without unwanted effects. Moreover, a recent paper reported the potential role of cortical and thalamic activity changes as a trigger of responsive DBS.32) A multidisciplinary team approach involving not only clinicians but also basic scientists may help to further our understanding of the pathophysiology of TS and development of technologies to treat it.

Conclusion

This study considered the surgical concepts of thalamic DBS for TS, demonstrated the effectiveness of this procedure in TS, and discussed clinical issues associated with this treatment. When using DBS to treat patients with TS, clinicians should understand the 3D brain anatomy so that they can achieve favorable outcomes after this procedure while avoiding adverse effects. Since TS is a developmental neuropsychiatric disorder, optimal stimulation may induce the best effect in terms of neuroplasticity. Further development of neuroimaging techniques and a better understanding of the neurophysiology of TS may help clinicians to achieve better long-term outcomes.

Abbreviations

ANTs, Advanced Normalization Tools; CM, centromedian; CT, computed tomography; DBS, deep brain stimulation; IPG, implantable pulse generator; MRI, magnetic resonance imaging; TS, Tourette syndrome; VTA, volume of tissue activated; YGTSS, Yale Global Tic Severity Scale

Fundings

This study was partially supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (C) (grant numbers 18K08956 and 23K08555), the Central Research Institute of Fukuoka University (grant number 201,045), Takeda Science Foundation, JSPS KAKENHI Grants (grant numbers JP16H06396 and JP21H05172), and AMED (grant number: JP18dm0307008).

Author Contributions

Takashi Morishita and Yuki Sakai contributed equally to the study.

Conflicts of Interest Disclosure

None.
==== Refs
1) Dowd RS , Pourfar M , Mogilner AY : Deep brain stimulation for Tourette syndrome: a single-center series. J Neurosurg 128 : 596-604, 2018 28387621
2) Baldermann JC , Schüller T , Huys D , et al : Deep brain stimulation for tourette-syndrome: A systematic review and meta-analysis. Brain Stimul 9 : 296-304, 2016 26827109
3) Martinez-Ramirez D , Jimenez-Shahed J , Leckman JF , et al : Efficacy and safety of deep brain stimulation in Tourette syndrome: the international Tourette syndrome deep brain stimulation public database and registry. JAMA Neurol 75 : 353-359, 2018 29340590
4) Vandewalle V , van der Linden C , Groenewegen HJ , Caemaert J : Stereotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus. Lancet 353 : 724, 1999
5) Hariz MI , Robertson MM : Gilles de la Tourette syndrome and deep brain stimulation. Eur J Neurosci 32 : 1128-1134, 2010 21039952
6) Morishita T , Sakai Y , Iida H , et al : Neuroanatomical considerations for optimizing thalamic deep brain stimulation in Tourette syndrome. J Neurosurg 136 : 231-241, 2022 34359039
7) Morishita T , Sakai Y , Iida H , et al : Precision mapping of thalamic deep brain stimulation lead positions associated with the microlesion effect in Tourette syndrome. Neurosurgery 93 : 875-883, 2023 37057914
8) Pringsheim T , Okun MS , Müller-Vahl K , et al : Practice guideline recommendations summary: treatment of tics in people with Tourette syndrome and chronic tic disorders. Neurology 92 : 896-906, 2019 31061208
9) Morishita T , Higuchi MA , Saita K , Tsuboi Y , Abe H , Inoue T : Changes in motor-related cortical activity following deep brain stimulation for Parkinson's disease detected by functional near infrared spectroscopy: A pilot study. Front Hum Neurosci 10 : 629, 2016 28018196
10) Morishita T , Higuchi MA , Kobayashi H , Abe H , Higashi T , Inoue T : A retrospective evaluation of thalamic targeting for tremor deep brain stimulation using high-resolution anatomical imaging with supplementary fiber tractography. J Neurol Sci 398 : 148-156, 2019 30716581
11) Morishita T , Sakai Y , Mishima T , et al : Case report: GPi DBS for non-parkinsonian midline tremor: A normative connectomic comparison to a failed thalamic DBS. Front Hum Neurosci 15 : 709552, 2021 34413730
12) Horn A , Li N , Dembek TA , et al : Lead-DBS v2: towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage 184 : 293-316, 2019 30179717
13) Schönecker T , Kupsch A , Kühn AA , Schneider GH , Hoffmann KT : Automated optimization of subcortical cerebral MR imaging-atlas coregistration for improved postoperative electrode localization in deep brain stimulation. AJNR Am J Neuroradiol 30 : 1914-1921, 2009 19713324
14) Avants BB , Epstein CL , Grossman M , Gee JC : Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 12 : 26-41, 2008 17659998
15) Husch A , Petersen MV , Gemmar P , Goncalves J , Hertel F : PaCER - A fully automated method for electrode trajectory and contact reconstruction in deep brain stimulation. Neuroimage Clin 17 : 80-89, 2018 29062684
16) Ilinsky I , Horn A , Paul-Gilloteaux P , Gressens P , Verney C , Kultas-Ilinsky K : Human motor thalamus reconstructed in 3D from continuous sagittal sections with identified subcortical afferent territories. eNeuro 5 : 2018
17) Kimura Y , Ikegaya N , Iijima K , et al : Withdrawal of deep brain stimulation in patients with Gilles de la Tourette syndrome. Mov Disord 34 : 1925-1926, 2019 31737941
18) Kimura Y , Iijima K , Takayama Y , et al : Deep brain stimulation for refractory Tourette syndrome: electrode position and clinical outcome. Neurol Med Chir (Tokyo) 61 : 33-39, 2021 33239475
19) Kaido T , Otsuki T , Kaneko Y , Takahashi A , Omori M , Okamoto T : Deep brain stimulation for Tourette syndrome: a prospective pilot study in Japan. Neuromodulation 14 : 123-128; discussion 9, 2011 21992198
20) Visser-Vandewalle V , Temel Y , Boon P , et al : Chronic bilateral thalamic stimulation: a new therapeutic approach in intractable Tourette syndrome. Report of three cases. J Neurosurg 99 : 1094-1100, 2003 14705742
21) Vázquez-Medina A , Diano G , Papageorgakopoulou MA , Otamendi-Lopez A : Letter to the Editor. Tourette syndrome: tripartite considerations in DBS. J Neurosurg 137 : 1198-1199, 2022 35523264
22) Mann JM , Foote KD , Garvan CW , et al : Brain penetration effects of microelectrodes and DBS leads in STN or GPi. J Neurol Neurosurg Psychiatry 80 : 794-797, 2009 19237386
23) Morishita T , Foote KD , Wu SS , et al : Brain penetration effects of microelectrodes and deep brain stimulation leads in ventral intermediate nucleus stimulation for essential tremor. J Neurosurg 112 : 491-496, 2010 19663554
24) Johnson KA , Fletcher PT , Servello D , et al : Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study. J Neurol Neurosurg Psychiatry 90 : 1078-1090, 2019 31129620
25) Kakusa B , Saluja S , Barbosa DAN , et al : Evidence for the role of the dorsal ventral lateral posterior thalamic nucleus connectivity in deep brain stimulation for Gilles de la Tourette syndrome. J Psychiatr Res 132 : 60-64, 2021 33045620
26) Kondziolka D , Lee JY : Long-lasting microthalamotomy effect after temporary placement of a thalamic stimulating electrode. Stereotact Funct Neurosurg 82 : 127-130, 2004 15305085
27) Smeets AYJM , Duits AA , Leentjens AFG , et al : Thalamic deep brain stimulation for refractory Tourette syndrome: clinical evidence for increasing disbalance of therapeutic effects and side effects at long-term follow-up. Neuromodulation 21 : 197-202, 2018 28102636
28) Wang Q , Akram H , Muthuraman M , et al : Normative vs. patient-specific brain connectivity in Deep Brain Stimulation. Neuroimage 224 : 117307, 2021 32861787
29) Wong JK , Mayberg HS , Wang DD , et al : Proceedings of the 10th annual deep brain stimulation think tank: advances in cutting edge technologies, artificial intelligence, neuromodulation, neuroethics, interventional psychiatry, and women in neuromodulation. Front Hum Neurosci 16 : 1084782, 2022 36819295
30) Hollunder B , Ganos C , Horn A : Deep brain stimulation: from sweet spots to sweet networks? Biol Psychiatry Cogn Neurosci Neuroimaging 6 : 939-941, 2021 34625219
31) Molina R , Okun MS , Shute JB , et al : Report of a patient undergoing chronic responsive deep brain stimulation for Tourette syndrome: proof of concept. J Neurosurg 129 : 308-314, 2018 28960154
32) Okun MS , Cagle J , Gomez J , et al : Responsive deep brain stimulation for the treatment of Tourette syndrome. Sci Rep 14 : 6467, 2024 38499664
