Journal of

Clinical Medicine

Review
Deep Brain Stimulation in the Treatment of Tardive Dyskinesia
Adrianna Szczakowska 1 , Agata Gabryelska 2 , Oliwia Gawlik-Kotelnicka 3 and Dominik Strzelecki 3, *

1 Central Teaching Hospital, Medical University of Lodz, 92-213 Lodz, Poland

2 Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, 92-215 Lodz, Poland
3 Department of Affective and Psychotic Disorders, Medical University of Lodz, 92-216 Lodz, Poland
* Correspondence: [email protected]; Tel.: +48-426757371

Abstract: Tardive dyskinesia (TD) is a phenomenon observed following the predominantly long-term
use of dopamine receptor blockers (antipsychotics) widely used in psychiatry. TD is a group of
involuntary, irregular hyperkinetic movements, mainly in the muscles of the face, eyelid, lips, tongue,
and cheeks, and less frequently in the limbs, neck, pelvis, and trunk. In some patients, TD takes on
an extremely severe form, massively disrupting functioning and, moreover, causing stigmatization
and suffering. Deep brain stimulation (DBS), a method used, among others, in Parkinson’s disease,
is also an effective treatment for TD and often becomes a method of last resort, especially in severe,
drug-resistant forms. The group of TD patients who have undergone DBS is still very limited. The
procedure is relatively new in TD, so the available reliable clinical studies are few and consist mainly
of case reports. Unilateral and bilateral stimulation of two sites has proven efficacy in TD treatment.
Most authors describe stimulation of the globus pallidus internus (GPi); less frequent descriptions
involve the subthalamic nucleus (STN). In the present paper, we provide up-to-date information on
the stimulation of both mentioned brain areas. We also compare the efficacy of the two methods
by comparing the two available studies that included the largest groups of patients. Although GPi
stimulation is more frequently described in literature, our analysis indicates comparable results
(reduction of involuntary movements) with STN DBS.

Keywords: tardive dyskinesia; schizophrenia; antipsychotics; deep brain stimulation

Citation: Szczakowska, A.;

Gabryelska, A.; Gawlik-Kotelnicka,
O.; Strzelecki, D. Deep Brain 1. Introduction
Stimulation in the Treatment of Tardive dyskinesia (TD) is a group of symptoms characterized by irregular and invol-
Tardive Dyskinesia. J. Clin. Med. 2023, untary movements that most commonly affect the tongue, lips, jaw, face, and sometimes the
12, 1868. https://doi.org/10.3390/ peri-orbital areas. In some cases, patients also have irregular movement of the trunk and
jcm12051868 limbs [1,2]. Tardive dyskinesia (TD) might be also present as tremor, akathisia, dystonia,
Academic Editor: Lazzaro di Biase chorea, tics, or as a combination of different types of abnormal movements. In addition to
movement disorders (including involuntary vocalizations), TD patients may have various
Received: 9 November 2022 sensory symptoms, such as the urge to move (as in akathisia), pain, and paresthesia [3].
Revised: 15 February 2023
TD is a specific type of secondary dystonia, mainly caused by the chronic use of
Accepted: 21 February 2023
dopamine receptor antagonists. The onset of TD usually occurs after years of taking neu-
Published: 27 February 2023
roleptics but may also appear earlier, even after several months. The risk is related, among
others, to the strength of the drug binding to the dopaminergic D2 receptor. In the elderly,
symptoms may become apparent after a shorter period of use of the drug, the early onset
Copyright: © 2023 by the authors.
of these symptoms and their intensity may indicate features of organic brain damage [4].
Licensee MDPI, Basel, Switzerland. Due to the need for long-term treatment, neuroleptics are the main reason for TD’s appear-
This article is an open access article ance in clinical practice. Nevertheless, when using other antidopaminergic drugs such
distributed under the terms and as antiemetics (domperidone, bromopride, and metoclopramide); antidepressants such
conditions of the Creative Commons as trazodone, amitriptyline, clomipramine, fluoxetine; and sertraline or calcium channel
Attribution (CC BY) license (https:// blockers, the risk of TD appearance, while significantly lower, should be highlighted [5].
creativecommons.org/licenses/by/ Interestingly, tardive dyskinesia can appear both during the use and after the discon-
4.0/). tinuation of neuroleptics. The prevalence of tardive dyskinesia is estimated at 0.4–9% in

J. Clin. Med. 2023, 12, 1868. https://doi.org/10.3390/jcm12051868 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2023, 12, 1868 2 of 16

patients receiving antipsychotics, while some studies indicate a more frequent occurrence
of TD (20–50%) [6,7]. According to the DSM-5, TD can be diagnosed when antipsychotic-
induced tardive dyskinesia follows exposure to neuroleptics for at least three months (one
month in individuals aged ≥60 years) and persists for at least one month after the last dose
of the drug [8]. This iatrogenic complication may persist long after drug discontinuation
and might become permanent [1,6]. TD often results in disability, with mild to severe
functional impairment (significantly impaired gait, speech, and swallowing) in about 10%
of cases, causing a heavy burden on both patients and their caregivers [6]. In addition to
physical burden and pain, tardive dyskinesia leads to social exclusion and ostracism in
patients with these symptoms. The involuntary movements typical of TD are a significant
burden for patients in a social context, representing one of the archetypal images of mental
illness and a reason for stigmatization.
Aside from pharmacological interventions (changing the dose or the drug) or imple-
menting TD-targeted treatment, there is a promising method that may offer new opportu-
nities for this group of patients—deep brain stimulation (DBS). DBS is a clinical procedure
in which a precisely controlled electric current is passed through electrodes surgically
implanted in the brain. This method enables rapid and, more importantly, long-term
improvement in motor function and quality of life (QoL) in patients with TD [1,5].

2. Etiology and Risk Factors

It is of key importance that TD has a genetic predisposition, which mediates the
risk for TD development [5,9]. Nevertheless, the usage of dopamine receptor antagonists
is responsible for the exposure of this predisposition [10,11]. Table 1 shows the factors
associated with an increased risk of TD [12–19]. Table 2 summarizes the genetic factors that
modulate the risk of TD [20–23].

Table 1. Nonmodifiable and modifiable risk factors of TD.

Nonmodifiable Factors Modifiable Factors

Advanced age Type of dopamine receptor blocking agents
Female sex Duration of illness
Dosage and length of exposure
Caucasian or African ethnicity
to a dopamine receptor blocker
Intellectual disability Intermittent antipsychotic treatment
Brain damage Anticholinergic treatment
Smoking
Negative symptoms in schizophrenia Alcohol and cocaine abuse/dependence
Akathisia

The main pathogenetic mechanisms associated with the development of TD are the
hypersensitivity of postsynaptic D2 receptors and their upregulation associated with their
long-term blockade. This leads to changes in cortico-striatal transmission and motor
symptoms [24]. The abnormalities also concern the increase in blood flow in the prefrontal
cortex, the anterior cingulate gyrus, and the cerebellum, which accompany the increase in
the activity of the prefrontal and premotor cortex during the appearance of involuntary
movements, which may indicate a decrease in impulse selection and lead to the appearance
of involuntary movements [25]. The constant blocking of D2 receptors along with D1
activation may also be important to explain the appearance of symptoms over a longer
period of time and their irreversibility [26]. However, it seems that not only disorders
of dopaminergic transmission are involved in the development of TD, but changes in
serotonergic, glutamatergic, cholinergic, and opioid transmission may play a supportive
role [27,28]. The involvement of the serotonin system in TD is indicated by studies on animal
models. It was found that inhibition of serotonergic neurons with 8-OH-DPAT (8-hydroxy-
J. Clin. Med. 2023, 12, 1868 3 of 16

2-(dipropylamino)tetralin significantly reduces TD severity. 8-OH-DPAT is one of the first

discovered agonists of the serotonergic 5-HT1A receptors. It mediates hyperpolarization
and reduction of the firing rate of the postsynaptic neuron. Conversely, administration of
fenfluramine or fluoxetine (both increasing the level of serotonin) suppressed the previously
obtained improvement. Preclinical studies indicate that deep brain stimulation of the
subthalamic nucleus (STN DBS), a technique described latter in this article, reduced the
release of 5-HT in the hippocampus and prefrontal cortex, while deep brain stimulation of
the EPN (entopeduncular nucleus, internal globus pallidus (GPi) equivalent in rodents)
did not affect 5-HT release. Nevertheless, both STN and EPN DBS attenuate TD with equal
effectiveness, despite their different effects on the 5-HT system, leading to the conclusion
that the mechanism of 5-HT reduction does not determine the effectiveness of DBS in rats.

Table 2. Genes whose polymorphisms increase the risk of TD.

DRD2 and DRD3

HTR2A (5-HT2A receptors)
COMT
MnSOD
Cytochrome P450 (CYP2D6)
GSK-3ß
30 -Regulatory region of Nurr77 mRNA
SLC6A11, GABRB2, and GABRG3 related to GABAergic transmission
GRIN2A related to NMDA receptor and glutamatergic transmission
GSTM1, GSTP1, NOS3, and NQO1 involved in oxidative stress reactions
BDNF
GLI2
HSPG2
Genes DRD2 and DRD3—D2 and D3 receptor, D-dopamine; HTR2A-5—hydroxytryptamine receptor 2A, 5-HT–
serotonin; COMT—catechol-O-methyl-transferase; MnSOD—manganese super dismutase; CYP2D6—cytochrome
P450 2D6; GSK2ß—glycogen synthase kinase 2 beta; mRNA—messenger RNA; SLC6A11—solute carrier fam-
ily 6 member 11; GABRB2—gamma-aminobutyric acid type A receptor subunit beta 2; GABRG3—gamma-
aminobutyric acid type A-rho receptor subunit gamma 3; GABA—γ-aminobutyric acid; GRIN2A—glutamate
ionotropic receptor NMDA type subunit 2A; NMDA—N-methyl-D-aspartate; GSTM1—glutathione S-transferase
Mu 1; GSTP1—glutathione S-transferases P1; NOS3—nitric oxide synthase 3; NQO1—NAD(P)H quinone dehy-
drogenase 1; BDNF—brain-derived neurotrophic factor; GLI2—GLI family zinc finger 2; HSPG2—heparan sulfate
proteoglycan 2.

Oxidative stress and related neuronal damage both might also participate in the
etiology of TD. Antipsychotics, especially classic drugs, may be toxic by directly inhibiting
complex I of the mitochondrial electron transport chain. Toxicity may also result from the
increased production of free radicals and hydrogen peroxide, which are a consequence
of the blockade of the D2 receptor and an increase in dopamine turnover [20,29,30]. The
weakening of the antioxidant mechanisms may explain the progressive nature of the
changes and their irreversibility [31–33]. In neuroimaging studies, a decrease in the caudate
nucleus volume was observed in the group of patients diagnosed with schizophrenia with
TD compared to those with this psychosis without dyskinesia [10,34,35].

3. Assessment Tools
The most widely used instrument to assess TD is the Abnormal Involuntary Movement
Scale (AIMS). The patient performs several tasks described in the instructions. On that
basis, the severity of facial and oral movements, extremity movements, trunk movements,
and global judgments is scored on a 0–4 scale (up to 40 points in total) [36]. A separate
evaluation concerns dental status (with an annotation yes/no). Another scale is The
Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS), which consists of movement and
J. Clin. Med. 2023, 12, 1868 4 of 16

disability subscales. This tool measures dystonia in nine body regions (incl. the eyes,
mouth/speech and swallowing, neck, trunk, arms, and legs; each extremity is assessed
individually) with scores ranging from 0 (lack of symptoms) to 120 [37].

4. Pharmacological Treatment
TD treatment is difficult and often leads to disappointing results, so the best method
is to prevent its onset [38]. Atypical antipsychotics have a lower potential to cause TD. The
drugs should be used in the lowest effective doses, particularly if TD appeared earlier or
the current treatment induced its onset. When TD appears, initially, it is necessary to reduce
the drug dose or, if this does not eliminate TD, switch to a drug with a lower potential for
inducing TD, such as clozapine or quetiapine.
The pharmacological treatment of TD is challenging; conventionally administered
pharmacotherapies are only beneficial at the initial stage, and the available data point to a
lack of satisfactory outcomes in long-term use [6].
VMAT2 (vesicular monoamine transporter 2) inhibitors: tetrabenazine, valbenazine,
and deutetrabenazine are the first drug group recommended for TD treatment [2]. In
randomized controlled trials, valbenazine and deutetrabenazine demonstrated efficacy in
ameliorating TD symptoms with a favorable benefit–risk ratio. For this reason, valbenazine
and deutetrabenazine should be considered a first-line treatments for TD. While the cur-
rently available evidence suggests that tetrabenazine is another good option for TD, it is
not considered a first-line drug due to greater side effects than other VMAT2 inhibitors
and very few studies. Amantadine (300 mg per day) may be used when these treatments
are ineffective or contraindicated. However, evidence to support the use of amantadine
for TD is scarce and limited to short observations [2]. Another discussed treatment option
is the short-term administration of clonazepam, but the effectiveness of this method is
also limited. Furthermore, considering the acute and long-term consequences (sedation,
cognitive decline, tolerance, addiction, and risk of falls, especially in the elderly), routine
use of benzodiazepines is not recommended [2,6]. The use of Vitamin E does not improve
TD symptoms but may prevent their worsening. When other options fail, some authors
recommend pyridoxine (vitamin B6) use, but the optimal dose and treatment duration
has not been established yet [2]. In focal dystonia, such as cervical dystonia, botulinum
toxin injection may be applied. It is a highly effective approach, but the level of satis-
faction with this treatment is low in some of the patients, and they fail to follow up for
repeated injections. Therefore, the pharmacotherapeutic method should be regarded as
adjuvant therapy instead of a priority choice (the dose reduction of the TD-inducing drug
or change to another drug if possible) as the symptoms progress to the advanced stage [6].
The level B recommendations of the American Academy of Neurology for TD treatment
indicate clonazepam, Gingko biloba extract (EGb-761), and diltiazem, while amantadine,
tetrabenazine, galantamine, and eicosapentaenoic acid are level C. Other test substances,
including reserpine, bromocriptine, biperiden, selegiline, vitamin E, vitamin B6, baclofen,
and levetiracetam, have not received a recommendation from the academy at this stage [39].
Newer recommendations position new-generation VMAT2 inhibitors (deutetrabenazine
and valbenazine) at level A of recommendation, clonazepam and Ginkgo biloba at level
B, while amantadine, tetrabenazine, and GPi DBS (globus pallidus internus deep brain
stimulation) are at level C [40]. The American Psychiatric Association (APA) indicates a
reversible inhibitor of the VMAT2 (deutetrabenazine and valbenazine as more studied than
tetrabenazine) as the first-line treatment for TD [41].

5. Deep Brain Stimulation

In recent decades, DBS has been successfully used to treat several movement disorders,
including Parkinson’s disease and dystonia. More recently, DBS has also been used to
treat patients with tardive dyskinesia and OCD, especially in drug-resistant forms [6,7].
Monopolar (unilateral) stimulation modes are the most commonly used, although we
also have descriptions of bipolar mode [42–46]. In addition to the potential for rapid and
J. Clin. Med. 2023, 12, 1868 5 of 16

long-term improvement, the advantages of DBS include its relatively nondestructive nature,
adjustability, reversibility, and the ability to perform DBS bilaterally in a single surgical
session [6,47].
According to the available studies, this method is safe and minimally invasive, with
no severe complications during the follow-up periods [6]. The disadvantages of the DBS
technique are the requirement for continuous follow-up visits with repeated optimization
of pacing parameters (it can also offer potential parameter adjustments) and the risk of
hardware complications (incl. electrode displacement, battery depletion, inflammation
around parts of the device) [47]. When the effectiveness of pharmacotherapeutic methods
is unsatisfactory and symptoms are chronic and very severe, DBS becomes the treatment of
last resort [48].
The primary criterion for inclusion in DBS is a high severity of symptoms that signifi-
cantly impede function and have lasted for more than a year, with no satisfactory response
to pharmacological treatment with clozapine or tetrabenazine for at least four weeks at the
highest doses tolerated by the patient. Exclusion criteria are similar to those for patients
with other dystonias—significant cognitive impairment, unstable mental status, severe
depressive symptoms, and comorbid medical problems that may increase surgical risk; an
initial brain scan before the decision on DBS applicability is recommended [45].
In addition to correct patient selection and electrode placement (more effective by
image guidance or microelectrode recording implemented in leading centers), proper and
time-coordinated programming of the equipment is crucial. This is important because
we already have multisegment electrodes (from Abbott/St. Jude, Boston Scientific, and
Medtronic), and each segment’s current characteristics can be programmed separately. It
complicates programming (current of different amplitude, frequency, amperage, and pulse
width can be used) but certainly expands the possibilities for stimulation. Once the electrode
has been placed, the adjustment of the electrical field optimizes the clinical outcome. It
allows continuous monitoring of the effectiveness of the stimulation and provides an
opportunity to implement modifications, but it becomes vital when the initially planned
electrode placement has failed (in about 40%). The typical inaccuracy of surgical robots or
stereotaxic methods is 1–2 mm. In addition, during surgery, the brain can change position
by 2–4 mm, which can be minimized by a staged operation [49–58]. A similar problem
arises when the electrode is displaced. Reprogramming often avoids reoperation and allows
optimization of parameters if the dislocation is not critical [59,60]. It is worth adding that no
clear guidelines have been developed so far, although there are recommendations regarding
the programming of stimulators [61–63]. In programming, it is important to be aware of
the temporal sequence of observed changes—not all symptoms respond to stimulation
simultaneously. For example, during stimulation of the subthalamic nucleus in Parkinson’s
disease, first (in seconds) the tremor subsides, followed by rigidity (seconds–minutes),
bradykinesia (minutes–hours), and axial symptoms (hours–days). These symptoms appear
after the stimulation is turned off in the same order [64,65].
Previous research in TD patients has focused on the stimulation of two areas in the
brain: the inner globus pallidus (GPi) and the subthalamic nucleus (STN) belonging to
the basal ganglia. These nuclei belong to motor circuits, including cortico-thalamic-basal
ganglia junctions, which are believed to be the morphological substrate of TD. Most projects
focused on the stimulation of the GPi, the preferred target, while less is known about STN
stimulation [4,6]. Nevertheless, both STN and GPi stimulation were shown to be beneficial
in reducing TD [38].

5.1. Internal Globus Pallidus (GPi)

The primary target of GPi DBS is the posteroventrolateral part [46,47,66–69]. Several
descriptions concern the stimulation of the posteroventromedial area [70,71]. Ventral parts
of the posterior globus pallidus have a somatotopic organization associated with the motor
cortex, which determines the goals of stimulation; the median part is related to the limbic
cortex, while the dorsal area is associated with the prefrontal cortex [72].
J. Clin. Med. 2023, 12, 1868 6 of 16

Stereotactic techniques based on MRI (magnetic resonance imaging) or CT-MRI (a

combination of CT and MRI techniques) help correct electrode placement [73]. The op-
timal electrode placement is typically within 19–22 mm lateral to the line between the
anterior and posterior commissure, 4–6 mm inferior to that line, and 2–4 mm anterior
to the mid-commissural point [45,46,67,71,74–79]. In one description, the electrode po-
sition corresponded to the somatotopic face area [80]. The most common practice uses
microelectrode recordings (MERs) to detect discharges of neurons in the GPi and to order
“noisy signals” with DBS. The most common stimulation parameters used were the voltage
(amplitude) of the current (1.0–7.0 V) [43,67], frequency (60–185 Hz) [42,69,78,81], and pulse
width (60–450 µs) [42,45,78,81–83]. A detailed list of electrodes used, voltages, location,
and effectiveness of the treatments can be found in the study by Morigaki et al. [84]. With
several exceptions of bipolar modes [42–46], other reports concern monopolar stimulations.
Much of the literature was single-patient reports [43,47,68,70,73–75,77,78,80,82,85–89],
small groups of 2–4 people [46,48,67,69,71,79,90,91], or slightly larger groups [42,45,76,81,83,92–95],
and 19 patients comprised the largest cohort [38] (Table 3).

Table 3. Basic parameters and outcomes from GPi DBS studies.

Mono-/Bipolar Scale (% of Improvement)/Follow Up

Author [Reference] Localization
(N, When >1) (Months)
Pouclet-Courtemanche [38] PV-GPi M AIMS (63)/12–132
Sako [42] PV-GPi M/B (5) BFMDRS-M (58–100), BFMDRS-D (67–100)/3–49
Nandi [43] PV-GPi B BFMDRS-M (28), BFMDRS-D (39), AIMS (42)/ 12
BFMDRS-M (64-100), BFMDRS-D (25–100),
Gruber [45] PVL-GPi M/B (8)
AIMS (33–100)/26–80
Capelle [46] PVL-GPi B (4) BFMDRS-M (70–91), BFMDRS-D (50–100)/16–36
Kim [47] PVL-GPi M BFMDRS-M (97), BFMDRS-D (100)/20
Sobstyl [48] PVL-GPi B (2) BFMDRS-M (69–78), BFMDRS-D (56–73)/12–24
Franzini [67] PVL-GPi M (2) BFMDRS-M (86–88)/12
Kovacs [68] PVL-GPi ? BFMDRS-M (97), BFMDRS-D (96)/12
Starr [69] PVL-GPi ? (4) BFMDRS-M (6–100)/9–27
Trottenberg [70] PV-GPi M BFMDRS-M (73), AIMS (54)/6
Hälbig [71] PVM-GPi M (2) BFMDRS-M (77–93)/?
Spindler [73] GPi M AIMS (67)/<60
Magariños-Ascone [74] GPi ? BFMDRS-M (48), BFMDRS-D (44)/12
Eltahawy [75] PV-GPi M BFMDRS-M (60)/18
Trottenberg [76] PVM-GPi M (5) BFMDRS-M (75–98), BFMDRS-D (80–100)/6
Katsakiori [77] GPi M BFMDRS-M (94), BFMDRS-D (84)/12
Kefalopoulou [78] GPi M BFMDRS-M (91), AIMS (77)/6
Krause [79] GPi M (3) BFMDRS-M (−1–0), no benefit/≤36
Kosel [80] GPi M BFMDRS-M (35)/18
Shaikh [81] GPi M (8) BFMDRS-M (67–100)/6–60
Schrader [82] GPi M AIMS (63)/ 5
Egidi [83] GPi M BFMDRS-M (47), BFMDRS-D (55)/?
Pretto [85] GPi B BFMDRS (~90)/6
J. Clin. Med. 2023, 12, 1868 7 of 16

Table 3. Cont.

Mono-/Bipolar Scale (% of Improvement)/Follow Up

AuthorJ.[Reference] Localization
Clin. Med. 2023, 12, x FOR PEER REVIEW 7 of 16
(N, When >1) (Months)
Boulogne [86] PVL-GPi M AIMS (79)/120
Trinh Shaikh
[87] [81] GPi
GPi M (8) ? BFMDRS-MBFMDRS-M (90), BFMDRS-D (87)/18
(67–100)/6–60
Schrader [82]
Puri [88] GPi
GPi M ? AIMS (63)/ 5 AIMS (55)/6
OgataEgidi
[89] [83] GPi
PL-GPi M
B BFMDRS-M (47), BFMDRS-D (55)/?
BFMDRS-M (69), BFMDRS-D (64), AIMS (94)/7
Pretto [85] GPi B BFMDRS (~90)/6
Woo [90]
Boulogne [86] PV-GPi
PVL-GPi M M (3) BFMDRS-M (54–100)/3–120
AIMS (79)/120
CohenTrinh
[91] [87] GPi
GPi ? M (2) BFMDRS-M (90), BFMDRS-D
BFMDRS-M (87)/18
(63–88), BFMDRS-D (53–100)/7–13
Puri
Damier [88]
[92] GPi
PVL-GPi ? M (10) AIMS (55)/6AIMS (33–78)/6
Ogata [89] PL-GPi B BFMDRS-M (69), BFMDRS-D (64), AIMS (94)/7
BFMDRS-M (71), BFMDRS-D (48), AIMS
ChangWoo
[93][90] PV-GPi
PV-GPi M (3) M BFMDRS-M (54–100)/3–120
(77)/27–76
Cohen [91] GPi M (2) BFMDRS-M (63–88), BFMDRS-D (53–100)/7–13
Damier [92] PVL-GPi M (10) BFMDRS-M
AIMS (33–78)/6(90), BFMDRS-D (79), AIMS
Krause [94] GPi B (7)
Chang [93] PV-GPi M BFMDRS-M (71), BFMDRS-D (48),(73)/63–171
AIMS (77)/27–76
Krause
Koyama [95] [94] GPi
GPi B (7) BFMDRS-M
B (12) (90), BFMDRS-D (79), AIMS (73)/63–171
BFMDRS (78)/6–186
Koyama [95] GPi B (12) BFMDRS (78)/6–186
GPi—internal globus pallidus; DBS—deep brain stimulation; PV—posteroventral, PVL—posteroventral lateral;
GPi—internal globus
PVM—posteroventral pallidus;
medial; DBS—deep AIMS—Abnormal
PL—posterolateral; brain stimulation; PV—posteroventral,
Involuntary PVL—
Movement Scale; BFMDRS-M—
posteroventral lateral;
Burke–Fahn–Marsden PVM—posteroventral
Dystonia medial; PL—posterolateral;
Rating Scale, movement AIMS—Abnormal Invol-
subscale; BFMDRS-D—Burke–Fahn–Marsden Dystonia
untary
Rating Movement
Scale, disabilityScale; BFMDRS-M—Burke–Fahn–Marsden
subscale; BFMDRS—Burke–Fahn–Marsden Dystonia Rating
Dystonia Scale,
Rating movement
Scale, total score; ?—data
subscale; BFMDRS-D—Burke–Fahn–Marsden Dystonia Rating Scale, disability subscale;
not provided.
BFMDRS—Burke–Fahn–Marsden Dystonia Rating Scale, total score; ?—data not provided.

5.1.1. Motor
5.1.1. Effects
Motor Effectsof
of GPi DBS
GPi DBS
The reported
The reportedefficacy (reduction
efficacy (reduction in dystonia
in dystonia scores)
scores) rangesranges
from 28%from 28% with
to 100%, to 100%, with
mostmostreports
reportsshowing
showing ≧60% 60%improvement,
improvement, withwith a follow-up
a follow-up period period
of up to of up to[38].
11 years 11 years [38].
Improvement
Improvement is isdescribed
describedas as stable
stable even
evenafter
after4-year
4-year follow
follow up.up.
In addition to improve-
In addition to improvement
ment in symptoms,
in symptoms, most investigators
most investigators consistently
consistently reportaasignificantly
report significantly favorable
favorable change
change in the
in the quality of life and daily functioning. Nevertheless, there are also descriptions of no
quality of life and daily functioning. Nevertheless, there are also descriptions of no overall
overall change in this area [45,96].
change Clinical
in this responses
area [45,96].appear either during the surgical procedure and the first activation
of stimulation or in the appear
Clinical responses first dayseither duringonthe
after turning thesurgical
equipment procedure and the first activation
[45,46,67,68,70,76,86,91].
of stimulation or in the
If clinical responses are first daysshortly
observed after turning on theonequipment
after switching [45,46,67,68,70,76,86,91].
the device, we can precisely
If clinical
program responses
the equipment are observed
at the outset; shortly
in otherafter switching
cases, on the device,
patient adjustments we can
are carried out precisely
at follow-up
program visits or viaat
the equipment thethe
Internet,
outset;more recently
in other [97]. patient
cases, The manufacturer
adjustmentsrecommends
are carried out at
the lowest
follow-up sufficient
visits or viastimulator
the Internet, settings,
more combining
recentlyoptimal
[97]. Theperformance
manufacturerwith less load
recommends the
and then longer battery life or less frequent recharging.
lowest sufficient stimulator settings, combining optimal performance with less load and
Changes in the treatment of choreiform dyskinesia are noted earlier, tonic postural
thendystonia
longerresponds
battery life later,orsymptoms
less frequentimproverecharging.
gradually, and changes are observed after
Changes
weeks or even in months
the treatment of choreiform
of stimulation dyskinesia
[44,46,75,86,91–93]. aredystonias,
In fixed noted earlier, tonic postural
the efficacy
dystonia responds
of GPi DBS is lowerlater, symptoms improve gradually, and changes are observed after
[42,45,67,81].
weeks or even months of stimulation [44,46,75,86,91–93]. In fixed dystonias, the efficacy of
GPi5.1.2.
DBSSide Effects[42,45,67,81].
is lower of GPi DBS
Despite its invasiveness, DBS is characterized by a low number of complications and
is considered
5.1.2. a safe,
Side Effects effective,
of GPi DBS and well-tolerated method [4]. The frequency of all side
effects reaches 9%. Observations of nonmotor effects are very rare. DBS may induce tran-
Despite its invasiveness, DBS is characterized by a low number of complications and is
sient affective states (mild to moderate depressive syndrome in most cases); the authors
considered a safe, some
also emphasized effective, and
increase inwell-tolerated method
suicidal risk [73,98]. [4]. at
However, The frequency
longer follow up,of there
all side effects
reaches
was an 9%. Observations
improvement of nonmotor
in mood, which couldeffects
also beare very rare.
explained DBS
by relief frommaythe induce
burden transient
affective
of motorstates (mild disability,
symptoms, to moderate depressive
or social syndrome inInmost
impact [38,45,76,80,99]. cases);
one study, the authors also
six months
after treatment,
emphasized some one patient had
increase a brief psychotic
in suicidal episode,However,
risk [73,98]. and anotherat patient
longer hadfollow
symp- up, there
wastomatic improvementin
an improvement allowing
mood, the discontinuation
which could alsoofbeantipsychotic
explained by drugs [76].from
relief Contrary
the burden of
to the first reports, the negative influence of continuous pallidal (GPi) DBS on cognitive
motor symptoms, disability, or social impact [38,45,76,80,99]. In one study, six months after
functions has not been confirmed [38,45,71], while one study notes improvement [99].
treatment,
Theone patientofhad
procedure a briefthe
implanting psychotic
electrodeepisode, and another
(in both locations, patient
GPi and STN)had symptomatic
is asso-
improvement
ciated with theallowing theofdiscontinuation
possibility incorrect placement of or
antipsychotic drugs [76].
electrode displacement, Contrary to the
infections,
first reports, the negative influence of continuous pallidal (GPi) DBS on cognitive functions
has not been confirmed [38,45,71], while one study notes improvement [99].
J. Clin. Med. 2023, 12, 1868 8 of 16

The procedure of implanting the electrode (in both locations, GPi and STN) is asso-
ciated with the possibility of incorrect placement or electrode displacement, infections,
pain associated with the connection cable, intracranial hemorrhage, and seizure. Gait and
balance disturbances contributing to falls have also been observed. These disturbances
were transient and resolved after the optimization of DBS parameters [38]. The GPi is
involved in speech fluency; thus, slowing, halting, and imprecise oral articulation and
reduced voicing control are common symptoms during DBS in this area. Bilateral DBS
induces more speech difficulties [100]. Dysarthria occurs in almost 30% of patients; severe
cases may require speech therapy [38]. Despite the complications being infrequent, the
risk–benefit ratio always needs to be weighed. DBS becomes the last resort in patients with
severe TD when symptoms are severe, functioning is significantly impaired, and other
treatment options are insufficient. Table 4 shows the most common side effects, along with
the structures whose stimulation is responsible for their appearance.

Table 4. Side effects of GPi DBS and the areas whose stimulation is responsible for these symptoms.

Side Effect Brain Area

Mood and cognitive symptoms Ventral part of GPi
Motor side effects (corticospinal and
corticobulbar side, i.e., tonic muscle Posterior part of GPi/capsular fibers
contractions)
Phosphenes (seeing light without light entering
Ventral/optic tract
the eye)
Low threshold for capsular side effects
Medial GPi
(i.e., muscle contractions)
Speech impairment Internal capsule, medial and posterior to GPi
GPi—globus pallidus internus.

5.2. Subthalamic Nucleus (STN)

The subthalamic nucleus (STN), belonging to the basal ganglia, was the first neurosur-
gical target in the treatment of dystonia (thalamotomy), but data about STN DBS in treating
TD are still scarce. Less frequent use is, among others, related to psychiatric complications
(depression, suicidality, mania, and impulse-control problems) observed during DBS of this
brain structure in patients with Parkinson’s disease. The best control of motor symptoms is
provided by stimulation of the sensorimotor (dorsolateral) area of the STN [101].

5.2.1. Motor Symptoms of STN DBS

So far, only a limited number of cases of STN DBS for TD have been reported. In
addition to the Deng study, which we will discuss later [6], Zhang et al. published a
description of a series of nine patients treated with STN DBS for secondary dystonia (two
with tardive dystonia) [102]. In one case, the dystonia following neuroleptic treatment
improved by 92% in the BFMDRS 3 months after stimulator implementation. Long-term
observation of one of those patients with severe TD dystonic symptoms initially is described
by Meng et al.; the patient had no neurological symptoms after 144 months (6 and 12 years
after the operation BFMDRS total score was 0) [4]. Another study (12 patients with primary
dystonia and 2 with TD) using STN DBS showed improvement ranging from 76 to 100% in
the BFMDRS [103]. One patient underwent DBS electrode placement in the left and right
STN with a near-complete resolution of tremors [104] (data summarized in Table 5).
J. Clin. Med. 2023, 12, 1868 9 of 16

Table 5. Basic parameters and outcomes from STN DBS studies.

Mono-/Bipolar Scale (% of Improvement)

Author [Reference] Localization
(N, When >1) /Follow Up (Months)
BFMDRS (88), AIMS
Deng [6] STN B (10)
(94)/12–105
Zhang [102] STN B (2) BFMDRS (>90)/3–36
AIMS (63) BFMDRS
Sun [103] STN B (2)
(>77)/6–42
?, “near-complete resolution
Kashyap [104] STN B
of tremors”/24
STN—subthalamic nucleus; DBS—deep brain stimulation; BFMDRS—Burke–Fahn–Marsden Dystonia Rating
Scale, total score; AIMS—Abnormal Involuntary Movement Scale; ?—data not provided.

5.2.2. Side Effects of STN DBS

The anatomical location of the STN is very close to several functionally significant areas.
Therefore, the induced side effects are also associated with stimulating adjacent nuclei and
nerve tracts. Table 6 presents the most common side effects with the postulated structures
responsible for their appearance. Due to the lack of detailed descriptions regarding TD, the
table lists observations during STN DBS in Parkinson’s disease.

Table 6. Side effects and the brain area surrounding STN, which stimulation may be responsible for
the appearance of symptoms.

Side Effect Brain Area

Spastic muscle contraction Internal capsule
Fibers stemming from the frontal eye field running in
the internal capsule, fibers of the third nerve
Uni- or bilateral gaze deviation
(inferomedial to the STN and within the red nucleus),
sympathetic fibers within the zona incerta or STN
Autonomic symptoms Hypothalamus and red nucleus
Paresthesia Medial lemniscus
Internal capsule, the pallidal and cerebello-thalamic
fiber tracts medial and dorsal of the STN, medial
Speech impairment
left-sided STN stimulation in right-handed patients,
higher left STN voltage
Depression Substantia nigra
Mania Medial and ventral areas of STN
Ventromedial and limbic areas of STN, SNr, medial
Impulse control disorder
forebrain bundle
Ventral and medial parts of STN, perforation of the
Cognitive problems
caudate nucleus during surgery
STN—subthalamic nucleus, SNr—substantia nigra pars reticulata.

5.3. Internal Globus Pallidus (GPi) and Subthalamic Nucleus (STN) DBS Comparison
Authors suggest better results for STN DBS using lower stimulation parameters than
in GPi DBS, but no studies compared the effects of DBS in the two areas. In the following
section, we will compare the results of two studies of the GPi and STN involving the largest
groups of TD patients.
The largest study evaluating the efficacy of GPi DBS is by Pouclet-Courtemanche et al.
It originally included 19 patients, while 18 reached a 6-month follow up, 14 participants
were assessed at long-term follow up (6–11 years) [38]. Meanwhile, Deng et al. analyzed
STN DBS results in a group of 10 patients, with all included evaluations at 6 months and
 J. Clin. Med. 2023, 12, 1868 10 of 16

long-term follow up (12–105 months) [6]. The aforementioned time points were common for
both studies among other follow-up lengths. Furthermore, the mutual form of assessment 10 of 16
J. Clin. Med. 2023, 12, x FOR PEER REVIEW
of motor symptoms was only the AIMS. We compared the effectiveness of DBS at the
different sites using a two-sample z-test for proportions. In the case of the study by
Pouclet-Courtemanche et al., no median/mean data for the AIMS score were available at
all time points.
analysis Regardless,
presenting the calculation
a change in the AIMSof score
proportions
at the was possible
different basedups.
follow on the
Forgraph
the 6-month
analysis presenting
follow-up a change
time point, in the AIMS score
the proposition was at the(n
0.49 different follow
= 18) and ups.
0.15 (n For thefor
= 10) 6-month
the GPi DBS
follow-up
and the STNtimeDBS,
point, the proposition
respectively. wascomparison,
In the 0.49 (n = 18) and 0.15 (n = 10)did
the difference for not
the GPi
reachDBS
statistical
and the STN DBS, respectively. In the comparison, the difference did not reach statistical
significance with p = 0.079, mostly due to the small sample sizes in both studies, as the
significance with p = 0.079, mostly due to the small sample sizes in both studies, as the
trend
trend isis visible
visible(Figure
(Figure1).1).
WeWe diddid perform
perform a statistical
a statistical analysis
analysis of a long-term
of a long-term follow up
follow up
due to a disparity in the observation period, which could affect
due to a disparity in the observation period, which could affect the result. the result.

Figure 1. Proportion comparison of AIMS score (initial evaluation to 6-months follow up) between
Figure 1. Proportion comparison of AIMS score (initial evaluation to 6-months follow up) between
STN DBS and GPi DBS. AIMS—Abnormal Involuntary Movement Scale, DBS—deep brain stimula-
STN DBS and GPi DBS. AIMS—Abnormal Involuntary Movement Scale, DBS—deep brain stimula-
tion, GPi—internal globus pallidus, STN—subthalamic nucleus.
tion, GPi—internal globus pallidus, STN—subthalamic nucleus.
6. Discussion
6. Discussion
Deep brain stimulation (DBS) is an established treatment for patients with tardive
dyskinesia when pharmacological
Deep brain stimulation (DBS) therapy
is analone does nottreatment
established provide sufficient
for patientsreliefwith
or is tardive
associated with disabling side effects. With this method, patients achieve
dyskinesia when pharmacological therapy alone does not provide sufficient relief or is satisfactory
results in both the short and long term, with a relatively small number of complications.
associated with disabling side effects. With this method, patients achieve satisfactory re-
As we previously mentioned, the main sites with proven efficacy of stimulation are the
sults in both the short and long term, with a relatively small number of complications. As
subthalamic nucleus (STN) and internal globus pallidus (GPi). Although the GPi remains
we
the previously mentioned,
standard stimulation theour
target, main sites with
comparison proven
in small efficacy
groups showsofatstimulation are the sub-
least comparable
thalamic
efficacy ofnucleus
STN and (STN) and internal
GPi DBS, includingglobus
6-monthpallidus
follow(GPi). Although
up. Similar the GPicome
conclusions remains the
standard stimulation
from comparisons target,
of the our comparison
two methods in PD [105].inHowever,
small groups shows
further researchat least comparable
is needed
efficacy
to confirmof this
STNconclusion,
and GPi DBS, including
also because 6-month
the trend mayfollow
indicateup.
an Similar
advantage conclusions
for STN come
DBS. DBS
from studies inof
comparisons PDthe
allow
twosome conclusions
methods in PD that may
[105]. also apply
However, to the treatment
further research is of needed
TD with this method. The advantage of GPi stimulation lies in the possibility
to confirm this conclusion, also because the trend may indicate an advantage for STN DBS. of effective
use ofstudies
DBS the electrode
in PDunilaterally
allow some and somewhat easier
conclusions that mayoptimization
also applyof current
to the parameter
treatment of TD
programming. On the other hand, some researchers report that STN DBS may be less likely
with this method. The advantage of GPi stimulation lies in the possibility of effective use
of the electrode unilaterally and somewhat easier optimization of current parameter pro-
gramming. On the other hand, some researchers report that STN DBS may be less likely
to cause adverse symptoms in mood, cognitive function, gait, and speech [106]. The GPi
is occasionally indicated as the preferred target in treating oral TD and dystonia, while
J. Clin. Med. 2023, 12, 1868 11 of 16

to cause adverse symptoms in mood, cognitive function, gait, and speech [106]. The GPi is
occasionally indicated as the preferred target in treating oral TD and dystonia, while STN
DBS could be considered an effective and safe procedure in patients with predominant
tardive Parkinsonism and/or tardive tremor [104].
In contrast, studies by Sun et al. indicate some advantages of STN DBS stimulation in
dystonias, including TD. According to these authors, symptomatic improvement begins
immediately after stimulation, which allows for a quick selection of the best stimulation
parameters. The stimulation parameters used for the GPi are higher than those used during
STN DBS, resulting in longer battery life for STN DBS (longer intervals between charges).
According to the authors, STN DBS results in better symptomatic control than GPi DBS in
dystonia patients (compared to data obtained by other teams) [103].
To broaden knowledge and outline plans for necessary research, it is worth looking
at solutions employed in DBS procedures in patients with other health problems. DBS
is a method that has been implemented for years in various conditions such as dystonia,
Parkinson’s disease, and obsessive–compulsive disorder. This method is also recommended
for patients with severe and treatment-resistant forms of the disease. It is noteworthy that
the STN is the standard site of stimulation in PD [107]. According to the symptomatic
profile of PD, preferences include alternative targets, e.g., the thalamic ventral intermediate
nucleus (VIM) or the GPi. Recent research in this area has focused on the search for other
sites of stimulation such as the posterior subthalamic area (PSA) or the caudal zona incerta
(cZi). The PSA is located ventrally to the VIM, between the red nucleus and the STN. PSA
DBS is not significantly different from VIM DBS in suppressing tremor, but clinical benefit
from PSA DBS is attained at lower stimulation amplitudes [108]. Furthermore, several
open-label studies have shown a good effect in the reduction of PD symptoms with DBS in
the caudal zona incerta (cZi) [109].
While both TD and PD treatment have the same standard stimulation sites, it is worth
investigating other experimental stimulation sites in TD treatment, such as the PSA or the
cZi, or finding new targets. Treatment of refractory TD with DBS is not a low-cost method,
requiring an experienced neurosurgical team and precise instrumentation. It is also not a
life-saving method, but, if we want to have a full range of possible medical procedures that
may expand our understanding of the brain (we consider it crucial), this research must be
continued and intensified. The latest technical achievements in the field of construction
of stimulators and electrodes, e.g., modeling the shape of the impact field, as well as the
results of new studies focused on the paths connecting the gray matter of various brain
regions allow us to expect discoveries in research using DBS, hopefully also in TD.

Author Contributions: Conceptualization, D.S.; methodology, D.S.; validation, D.S.; formal analysis,
A.S., A.G. and D.S.; investigation, A.G. and D.S.; resources, D.S.; data curation, A.G. and D.S.; writing—
original draft preparation, A.S., A.G. and D.S.; writing—review and editing, A.G., O.G.-K. and D.S.;
visualization, A.G. and D.S.; supervision, D.S.; project administration, D.S.; funding acquisition, D.S.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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