Deep brain stimulation in the management of paediatric neuropsychiatric conditions: Current evidence and future directions

Abstract

Introduction
Neurosurgery has provided an alternative option for patients with refractory psychiatric indications. Lesion procedures were the initial techniques used, but deep brain stimulation (DBS) has the advantage of relative reversibility and adjustability. This review sets out to delineate the current evidence for DBS use in psychiatric conditions, with an emphasis on the paediatric population, highlighting pitfalls and opportunities.

Methods
A systematic review of the literature was conducted on studies reporting the use of DBS in the management of psychiatric disorders. The PRISMA guidelines were employed to structure the review of the literature. Data was discussed focusing on the indications for DBS management of psychiatric conditions in the paediatric age group.

Results
A total of seventy-three full-text papers reported the use of DBS surgery for the management of psychiatric conditions matching the inclusion criteria. The main indications were Tourette Syndrome (GTS) (15 studies), Obsessive Compulsive Disorder (OCD) (20), Treatment Resistant Depression (TRD) (27), Eating Disorders (ED) (7) and Aggressive Behaviour and self-harm (AB) (4). Out of these, only 11 studies included patients in the paediatric age group (≤18 years-old). Among the paediatric patients, the indications for surgery included GTS, AB and ED.

Conclusions
The application of deep brain stimulation for psychiatric indications has progressed at a steady pace in the adult population and at a much slower pace in the paediatric population. Future studies in children should be done in a trial setting with strict and robust criteria. A move towards personalising DBS therapy with new stimulation paradigms will provide new frontiers and possibilities in this growing field.

Keywords
Deep brain stimulationPaediatricsPsychiatric diseasesEthicsEating disordersTourette syndromeObsessive compulsive disorderMajor depressive disorderAggressive behaviour

Full text

Deep brain stimulation in the management of paediatric
neuropsychiatric conditions: Current evidence and future directions
Keyoumars Ashkan
a
,
b
, Asfand Baig Mirza
a
,
b
, Kantharuby Tambirajoo
a
,
b
,
Luciano Furlanetti
a
,
b
,
*
a
Department of Neurosurgery, King’s College Hospital NHS Foundation Trust, London, UK
b
King’s Health Partners Academic Health Sciences Centre, London, UK
article info
Article history:
Received 18 May 2020
Received in revised form
21 August 2020
Accepted 21 September 2020
Keywords:
Deep brain stimulation
Paediatrics
Psychiatric diseases
Ethics
Eating disorders
Tourette syndrome
Obsessive compulsive disorder
Major depressive disorder
Aggressive behaviour
abstract
Introduction: Neurosurgery has provided an alternative option for patients with refractory psychiatric
indications. Lesion procedures were the initial techniques used, but deep brain stimulation (DBS) has the
advantage of relative reversibility and adjustability. This review sets out to delineate the current evidence
for DBS use in psychiatric conditions, with an emphasis on the paediatric population, highlighting pitfalls
and opportunities.
Methods: A systematic review of the literature was conducted on studies reporting the use of DBS in the
management of psychiatric disorders. The PRISMA guidelines were employed to structure the review of
the literature. Data was discussed focusing on the indications for DBS management of psychiatric con-
ditions in the paediatric age group.
Results: A total of seventy-three full-text papers reported the use of DBS surgery for the management of
psychiatric conditions matching the inclusion criteria. The main indications were Tourette Syndrome
(GTS) (15 studies), Obsessive Compulsive Disorder (OCD) (20), Treatment Resistant Depression (TRD)
(27), Eating Disorders (ED) (7) and Aggressive Behaviour and self-harm (AB) (4). Out of these, only 11
studies included patients in the paediatric age group (18 years-old). Among the paediatric patients, the
indications for surgery included GTS, AB and ED.
Conclusions: The application of deep brain stimulation for psychiatric indications has progressed at a
steady pace in the adult population and at a much slower pace in the paediatric population. Future
studies in children should be done in a trial setting with strict and robust criteria. A move towards
personalising DBS therapy with new stimulation paradigms will provide new frontiers and possibilities
in this growing field.
©2020 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................. 00
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... ........................ 00
2.1. Systematic review of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .......................................... 00
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................... ....... 00
3.1. Gilles de la Tourette Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................................... 00
3.2. Obsessive compulsive disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . .......................................... 00
3.3. Treatment resistant depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................................... 00
3.4. Eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . ............................................... 00
3.5. Aggressive behaviour and self-harm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .......................................... 00
3.6. Autism spectrum disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................................... 00
*Corresponding author. Department of Neurosurgery, King’s College Hospital
NHS Foundation Trust, Denmark Hill, SE 5 9RS, London, UK.
E-mail address: luciano.furlanetti@nhs.net (L. Furlanetti).
Contents lists available at ScienceDirect
European Journal of Paediatric Neurology
https://doi.org/10.1016/j.ejpn.2020.09.004
1090-3798/©2020 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
European Journal of Paediatric Neurology xxx (xxxx) xxx
Please cite this article as: K. Ashkan, A.B. Mirza, K. Tambirajoo et al., Deep brain stimulation in the management of paediatric neuropsychiatric
conditions: Current evidence and future directions, European Journal of Paediatric Neurology, https://doi.org/10.1016/j.ejpn.2020.09.004

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ ............. 00
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............................. 00
Financial support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . ..... ........................ 00
Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........................... .. 00
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................................... 00
References ................................................................. ....................................................... 00
1. Introduction
A significant number of patients with psychiatric illnesses
remain refractory to treatment despite significant advances in the
field. Neurosurgery has provided an alternative option for patients
with refractory psychiatric indications. Ablative therapy, including
anterior cingulotomy, capsulotomy, limbic leucotomy were proven
to be highly effective [1], however the advantages conferred by
non-destructive, reversible and adjustable deep brain stimulation
(DBS) therapy has favoured it over ablative procedures as the first
choice option in most neurosurgical units worldwide.
Psychiatric neurosurgery has had a controversial history, stem-
ming from historical misuse and technological abuse in diverse
patient populations with lack of ethical and regulatory oversight for
ambiguous indications associated with considerable morbidity [2].
Given this background, current approach to neuromodulation with
DBS in psychiatry has had to largely follow a structured ethical and
regulatory route whilst advances in neuroimaging, stereotactic
methods and neurosurgical tools have reduced the surgical risks.
Nonetheless, DBS therapy at present remains investigational for
most psychiatric conditions with a lack of large-scale controlled
studies to assess its efficacy and outcomes. At least partly this is
related to the heterogenous symptoms and complex anatomy and
biology of psychiatric disorders which make such studies difficult.
This is even more evident in the paediatric population, where the
stakes are significantly higher and where modulating the devel-
oping brain raises additional concerns. This review sets out to
delineate the current evidence for DBS use in psychiatric condi-
tions, highlighting the work done thus far in the paediatric
population. We aim to particularly emphasise how the experience
from the adult setting can inform future developments and appli-
cations of DBS for the childhood psychiatric disease.
2. Methods
2.1. Systematic review of the literature
The databases PubMed, Medline, EMBASE and Scopus were used
to conduct searches on studies reporting the use of DBS in the
management of psychiatric disorders. The PRISMA guidelines were
employed to structure the review of the literature [3]. The Medical
Subject Headings (deep brain stimulation) AND (Tourette)OR
(depression)OR(obsessive compulsive disorder)OR(OCD)OR(pae-
diatrics)OR(eating disorders)OR(anorexia)OR(obesity)OR
(aggressivity)OR(self-injurious behaviour)OR(psychiatry)OR
(autism) were used for search. Results were limited to those pub-
lished in English. The inclusion criteria were: (1) to be a primary
peer-reviewed clinical study, (2) to have involved the use of DBS in
the management of psychiatric disorders and to have included a
minimum of four patients in the study, (3) to have reported data on
the methods used for stereotactic surgery, age group and number of
patients studied, outcome data and length of follow-up time.
Studies not published in full-text or containing incomplete infor-
mation were excluded fromthe analysis. The different phases of the
systematic review were summarized in the flow diagram depicted
in Fig. 1.
3. Results
The initial search identified 1707 publications, but after appli-
cation of language filter and exclusion of duplicates 990 studies
remained. A total of seventy-three full-text papers reporting the
use of DBS surgery for the management of psychiatric conditions
matched the inclusion criteria, i.e. 15 studies on GTS (Table 1), 20 on
OCD (Table 2), 27 on TRD (Table 3), 7 on ED (Table 4) and 4 on AB
(Table 5). A total of 1215 patients with mean age 47.4 ±12.40 years
(range, 11e71 years) were studied. Out of these, only 11 studies
included patients in the paediatric age group (18 years-old).
Among the paediatric patients, the indications for surgery
included GTS (six papers), AB (three papers) and ED (two studies).
The various brain targets approached for the treatment of the
psychiatric conditions reported included the GPi, the ALIC or (VC/
VS), the NAc, different nuclei of the Thalamus, BNST, the STN, cg25,
slMFB and the pHyp (Fig. 2).
3.1. Gilles de la Tourette Syndrome
Table 1 summarizes papers published and outcomes on DBS for
the management of GTS [4e19].
GTS is characterised by motor and vocal tics with a disease onset
usually occurring before 18 years of age [20]. The onset of tic
symptoms often begins in childhood, reaches a peak during the
prepubertal period before gradually decreasing in the adolescence.
Abbreviations
DBS deep brain stimulation
TRD treatment resistant depression
OCD obsessive compulsive disorder
ED eating disorder
AB aggressive behaviour and self-harm
GTS Gilles de la Tourette Syndrome
ALIC anterior limb of the internal capsule
NAc Nucleus Accumbens
STN Subthalamic Nucleus
BNST Bed Nucleus of Stria Terminalis
VC/VS ventral internal capsule/ventral striatum
GPi Globus pallidus internus [am ¼anteromedial,
pv ¼posteroventral]
CM Centromedian Nucleus of the Thalamus
cg25 Broadman’s Area 25
pHyp posterior Hypothalamus
slMFB superolateral branch of the Medial Forebrain
Bundle
ITP Inferior Thalamic Peduncle
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
2

Approximately 75% of children with GTS will experience a signifi-
cant improvement in their symptoms by adulthood [20]. Children
with severe and debilitating symptoms often have impaired quality
of life (QoL) which is complicated by the presence of other
Fig. 1. Flow diagram summarising the systematic review of the literature.
Table 1
Review of the literature of Deep Brain Stimulation for Gilles de la Tourette Syndrome.
Author/Year Study design N. of
patients
Age, years at
surgery (range)
Indication DBS target (s) Uni/
Bilateral
Results (YGTSS %
improvement, mean)
Follow-up (mean,
months)
Maciunas et al., 2007 randomized/open label 5 18e34 GTS CM-Thalamus bilateral 40% 3
Servello et al., 2009*observational, open
label
35 17e57 GTS Thalamus GPi-pv
ALIC/NAc
bilateral 50.3% 3e24
Marceglia et al., 2010 observational cohort 7 24e52 GTS Thalamus (VOp) bilateral 33% 24
Dehning et al., 2011 observational cohort 4 25e44 GTS GPi-pv bilateral 40% 17.5
Ackermans et al.,
2011
prospective,
randomized, crossover
635e48 GTS cm-Thalamus bilateral 49% 12
Motlagh et al., 2013*open-label prospective 8 16e48 GTS Thalamus, Gpi-am,
GPi-pv
bilateral 45% 69
Okun et al., 2013 observational cohort 5 28e39 GTS cm-Thalamus bilateral 17.8% 6
Huys et al., 2014 prospective open label 8 19e56 GTS Thalamus bilateral 58% 12
Nair et al., 2014*observational cohort 4 15e43 GTS GPi-am bilateral 82.1% 42.5
Dehning et al., 2014 observational cohort 6 25e44 GTS GPi-pv bilateral 67.2% 32
Sachdev et al., 2014*observational cohort 17 17e51 GTS GPi-am bilateral 44.8% 24.1
Kefalopoulou et al.,
2015
randomized, double-
blind
15 24e55 GTS GPi-am, GPi-pv bilateral 15.3% (blinded) 40.1%
(open)
6
Wardell et al., 2015 observational cohort 5 19e55 GTS GPi-am, GPi-pv bilateral 36.6% 32.4
Johnson el al 2019*multicentric,
retrospective
110 14e61 GTS CM, GPi-am, GPi-pv,
NAc/ALIC
bilateral 46.7% 33.7
Martinez-Ramirez
et al., 2019*
multicentric,
prospective
185 13e58 GTS CM, GPi-am, GPi-pv,
NAc/ALIC
bilateral 45.1% 12
Total/(mean) - 420 - - - - (46.3%) (23.3)
GTS ¼Gilles de la Tourette Syndrome; *¼included pediatric patients (<18 years-old); N/A ¼not available; GPi ¼globus pallidus internus; am ¼anteromedial;
pv ¼posteroventral; cm ¼centromedian nucleus of the Thalamus; ALIC ¼anterior limb of the internal capsule; NAc ¼Nucleus Accumbens; YGTSS ¼Yale Global Tic Severity
Scale.
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
3

psychiatric co-morbidities such as attention deficit/hyperactive
disorder (ADHD), OCD, anxiety, depression and AB [21].
The first DBS surgery in 3 patients with GTS was performed in
1999 by Vandewalle et al. using the centromedian nucleus - sub-
stantia periventricularis - nucleus ventro-oralis internus complex
(CM-Spv-Voi) target which was based on the stereotactic target
used for ablative procedures introduced by Hassler and Dieckmann
[22]. Multiple targets are currently in use including the dorsome-
dial nucleus of the thalamus, ventral anterior and ventrolateral
motor part of thalamus, GPi (anteromedial part [am] and poster-
oventrolateral part [pl]), NAc and the ALIC (Table 1). A pooled
analysis of studies demonstrated that DBS for GTS had the highest
efficiency amongst the psychiatric diseases [23].
Most of the studies for DBS in GTS have been conducted in adults
with moderate to good clinical outcomes (Table 1). The first case
series in 1999 of 3 patients aged 28e45 years had a 70e90%
reduction in tic frequency and intensity over a follow up of 1e5
years [22]. A systematic review and meta-analysis of 57 studies
involving 156 cases with a median age of 30.0 years ±9.8 years
(15e60 years) demonstrated a 52.68% reduction in the Yale Global
Tic Severity Scale (YGTSS) scores [24]. No significant difference was
seen in score reduction between the different targets used. Overall
vocal tic control was better than motor control [24]. Another long
term study of post-DBS clinical outcomes in 110 patients in 13
centres demonstrated a median time of 13 months to achieve a 40%
improvement in tics associated with a significant improvement in
obsessive-compulsive behaviour with no appreciable differences
across brain targets [17]. A prospective DBS database and registry of
185 patients in 31 centres with a mean age of 29 years (13e58
years) showed significant improvements in YGTCC score, motor and
phonic tics [15]. There was a 35.4% incidence of adverse events (AE),
with 3% rate of infections and 6% rate of dysarthria [15]. Another
study reported on 15% risk of apathy exclusively seen with thalamic
stimulation [25].
The European Society for the study of Tourette Syndrome (ESSTS)
initial guidelines in 2011 recommended that DBS should be reserved
for resistant disease with well managed co-morbidities, an age limit
of above 25 years, with the operation to be carried out in an expe-
rienced multi-disciplinary unit [26]. The updated guidelines in 2014
removed the 25-year-old age limit but recommended that ethical
review should be sought for patients aged less than 18 years with
careful and robust data collection [27]. A meta-analysis specifically
looking at safety and efficacy of DBS in 58 children and young adults
(mean age 17.9 ±2.7 years, range 12e21 years) demonstrated an
average of 57.5% ±24.6% improvement in the YGTSS across the
studies [16]. The presence of co-morbid depression correlated
negatively with outcome and 25% experienced side effects, the
majority of which were classed minor in nature. A single case report
of a 15-year-old patient with extremely refractory GTS with associ-
ated OCD demonstrated an 81% improvement in YGTCC score and
Table 2
Review of the literature of Deep Brain Stimulation for Obsessive Compulsive Disorder.
Author/Year Study Design N. of
Patients
Age, years at
surgery (range)
Indication DBS
target (s)
Uni/
Bilateral
Results (% improvement Y-BOCS, mean or
otherwise specified)
Follow-up (mean,
months)
Nuttin et al., 1999 observational cohort 4 N/A OCD vALIC bilateral beneficial effects in 75% of the patients N/A
Nuttin et al., 2003 double-blind crossover 6 18e60 OCD vALIC bilateral 17.6e57.8% (range) 18.3
Abelson et al.,
2005
randomized, double-
blind
427e52 OCD vALIC bilateral 19.08% 12.8
Greenberg et al.,
2006
observational,
open label
10 22e45 OCD vALIC bilateral 31.3% 6e36
Mallet et al., 2008 Randomized, double-
blind, crossover
16 29e56 OCD amSTN bilateral 40.7% 10
Jimenez-Ponce
et al., 2009
observational,
open label
521e65 OCD ITP bilateral 49.1% 12
Servello et al.,
2009
observational,
open label
425e47 OCD vALIC/
NAc
bilateral 9e60% (range) 9e19
Denys et al., 2010 open label/double-blind,
crossover
16 21e59 OCD NAc bilateral 37.5% (open) 21
Greenberg et al.,
2010
open label, multicentric 26 22e57 OCD VC/VS bilateral 43.9% 31.4
Goodman et al.,
2010
prospective, randomized 6 27e52 OCD VC/VS bilateral Response in 66.7%;
36.7% Y-BOCS
12
Huff et al., 2010 double-blind, crossover 10 25e44 OCD NAc/ALIC uni/
bilateral
21.1% 12
Tsai et al., 2012 observational,
open label
421e30 OCD VC/VS bilateral 33.0% 15e21
Chabardes el at
2012
observational,
open label
435e43 OCD amSTN bilateral 64.5% 6
Roh et al., 2012 observational,
open label
419e47 OCD VC/VS bilateral 45.7e61.1% (range) 24
Baas et al., 2014 double-blind, crossover 8 27e60 OCD VC/VS bilateral N/A 1
Luyten et al., 2016 double-blind, crossover 24 (17) 24e52 OCD vALIC/
BNST
bilateral 48.5% 72
Barcia et al., 2018 randomized, double-
blind
728e46 OCD NAc bilateral 52.4% (6/7 responders) 3
Tyagi et al., 2019 double-blind, crossover 6 38e62 OCD amSTN,
VC/VS
bilateral 45.1% 3
Mench
on et al.,
2019
prospective
open label
30 41 (mean) OCD ALIC bilateral 42% 12
Denys et al., 2020 open observational 70 41.7 (mean) OCD NAc/
vALIC
bilateral 40% 12
Total/(mean) - 264 - - - - (44.4%) (16.9)
OCD ¼Obsessive Compulsive Disorder; N/A ¼not available; BNST ¼bed nucleus of the stria terminalis; VC/VS ¼ventral capsule/ventral striatum; vALIC ¼ventral anterior
limb of the internal capsule; ITP ¼inferior thalamic peduncle; amSTN ¼anteromedial Subthalamic nucleus; NAc ¼Nucleus Accumbens.
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
4

complete resolution of the OCD symptoms at 1 year after stimulation
of ALIC/bed nucleus of stria terminalis (BST), emphasising that
young age should not be a contraindication for stimulation therapy
in well selected patients [28].
3.2. Obsessive compulsive disorder
Table 2 summarizes papers published and outcomes on DBS for
the management of OCD [14,29e47].
OCD is characterised by persistent thoughts (obsessions) and
repetitive ritualistic behaviours (compulsions) with a significant
negative impact on normal functional capabilities. Even with the
best available medical and behavioural therapy, around 10% of pa-
tients are refractory to treatment [48]. DBS targets that have been
used include the VC/VS, ALIC, STN and NAc [49]. Responders are
defined as 35% reduction in the Yale-Brown Obsessive Compul-
sion Scale (Y-BOCS) score from the baseline [50].
Nuttin et al. (1999) provided proof of principle, in the first study
of DBS in 4 patients with OCD, that electrical stimulation of the ALIC
is effective in controlling symptoms [29]. Three out of the four
patients experienced significant improvements as assessed by the
Profile of Mood States Test in a double-blind assessment of
Table 3
Review of the literature of Deep Brain Stimulation for Treatment Resistant Depression.
Author/Year Study Design N. of
Patients
Age, years at surgery
(mean)
Indication DBS target
(s)
Uni/
Bilateral
Response
(%)
Remission
(%)
Follow-up (mean,
months)
Mayberg et al.,
2005
observational,
open label
6 47 TRD cg25 bilateral 67 33 6
Lozano et al., 2008 observational,
open label
20 47.4 TRD cg25 bilateral 60 35 12
Malone et al., 2009 multicenter,
open label
15 46.3 TRD VC/VS bilateral 53 40 23
Malone et al., 2010 multicenter,
open label
17 46.3 TRD VC/VS bilateral 53 N/A 37
Kennedy et al.,
2011
observational,
open label
20 47.4 TRD cg25 bilateral 64 43 39
Lozano et al., 2012 prospective,
multicenter study
21 47.3 TRD cg25 bilateral 29 N/A 12
Holtzheimer et al.,
2012
single-blind/sham stimulation 17 42 TRD cg25 bilateral 43 18 6
Bewernick et al.,
2012
prospective,
open label
11 48.6 TRD NAc bilateral 45 9 12e48
Merkl et al., 2013 observational,
open label
6 50.6 TRD cg25 bilateral 50 33 6
Ramasubbu et al.,
2013
prospective, double-blind 4 50.2 TRD cg25 bilateral 50 0 9
Schlaepfer et al.,
2013
prospective,
open label
7 42.6 TRD slMFB bilateral 85 57 3e8
Millet et al., 2014 prospective,
open label
4 52 TRD NAc bilateral 75 25 15
Dougherty et al.,
2015
randomized blinded,
sham-controlled
30 47.7 TRD VC/VS bilateral 20 0 4
Puigdemont et al.,
2015
double-blind randomized 8 47.4 TRD cg25 bilateral 63 50 12
Bergfeld et al., 2016 randomized double-blind,
cross-over
25 53.2 TRD vALIC bilateral 40 20 13
Holtzheimer et al.,
2017
multicentric,
double-blind/open label
90 40 TRD cg25 bilateral 29 14 12
Bewernick et al.,
2017
prospective,
open label
8 41.9 TRD slMFB bilateral 75 50 12
Raymaekers et al.,
2017
double-blind
cross-over
7 50 TRD BNST/ITP bilateral 71 29 36
Fitzgerald et al.,
2018
prospective,
open label
5 44.6 TRD BNST bilateral 40 20 12
Fenoy et al., 2018 prospective,
open label
6 50.2 TRD slMFB bilateral 67 67 52
Riva-Posse et al.,
2018
retrospective cohort study 11 48.7 TRD cg25 bilateral 82 55 12
Eitan et al., 2018 multicentric, double-blind 9 46 TRD cg25 bilateral 44 0 13
Merkl et al., 2018 randomised, doble-blind/
open-label
825e65 (range) TRD cg25 bilateral 33 33 24
Crowell et al., 2019 prospective
open label cohort
28 45 TRD cg25 bilateral 50 30 96
Coenen et al., 2019 double-blind
sham-controlled
16 51.6 TRD slMFB bilateral 100 50 12
Ramasubbu et al.,
2020
double-blind, randomised 22 46.4 TRD cg25 bilateral 45 23 12
van der Wal et al.,
2020
observational, cohort 25 52.5 TRD vALIC bilateral 44 28 24
Total/(mean) - 446 (48.0) - - - (54.7) (28.2) (21)
TRD ¼Treatment Resistant Depression; cg25 ¼Broadman Area 25, subcingulate gyrus; N/A ¼not available; slMFB ¼superolateral medial forebrain bundle; BNST ¼bed
nucleus of the stria terminalis; VC/VS ¼ventral capsule/ventral striatum; vALIC ¼ventral anterior limb of the internal capsule; ITP ¼inferior thalamic peduncle;
Response ¼50% reduction in HAM-D (Hamilton Depression Rating Scale) or MADRS (Montgomery-Åsberg Depression Rating Scale); Remission HAM-D 7 or MADRS 10 or
otherwise specified.
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
5

videotaped recordings [29]. Later, a 3-year follow up study of DBS in
10 patients aged 21e58 years with a preoperative Y-BOCS score of
32e38, using the VC/VS as the target, found more than 25%
reduction in Y-BOCS score in 6 patients, 4 of whom had more than
35% reduction [31]. These patients also experienced significant
reduction in their anxiety and depression scores, and improvement
in their Global Assessment of Functioning (GAF) scores [31]. Using
the STN as the target, a cross-over double-blind multicentre study
was carried out in 16 patients demonstrating a 25% improvement in
Y-BOCS and GAF in 75% of patients [32]. Fifteen serious AE including
one intracranial haemorrhage and two infections were reported in
this study.
Denys et al. (2020) evaluating the long-term effects of ventral
ALIC stimulation in 70 patients defined a full and partial response
as 35% and 25% decrease in Y-BOCS score respectively [33].
Combining patients from their previous study of 16 patients [34],
they categorised 52% of patients as full responders, 17% as partial
responders and 31% as non-responders. OCD symptom improve-
ment were also positively correlated with improvements in QoL
[34].
A long-term study of VC/VS stimulation in 26 OCD patients
across four international study groups demonstrated significant
symptom reductions and functional improvement in about two-
thirds of the patients [35]. Full and partial responders were also
defined as 35% or 25% decrease in Y-BOCS scores respectively.
Table 4
Review of the literature of Deep Brain Stimulation for Eating Disorders and Obesity.
Author/Year Study Design N. of
patients
Age, years at surgery
(range)
Indication DBS target (s) Uni/
Bilateral
% BMI change, (absolute pre/postop
values kg/m
2
)
Follow-up (mean,
months)
Franco et al.,
2018
observational cohort 4 18e28 Obesity
(Prader-Willi)
Lateral
hypothalamus
bilateral þ5.8% (39.6e41.9)
x
6
Lipsman et al.,
2013
prospective
open label
624e57 Anorexia cg25 bilateral þ21%, (13.7e16.6) 9
Lispman et al.,
2017
prospective
open label
16 21e57 Anorexia cg25 bilateral þ26%, (13.8e17.4) 12
Wang et al.,
2013
observational cohort
study
8
#
18e28 Anorexia NAc bilateral þ51%, (13.3e20.1) 12
Zhang et al.,
2013*
observational cohort 6 13e17 Anorexia NAc bilateral þ28% (12.2e15.6) 1
Wu et al.,
2012*
observational cohort 4 16e17 Anorexia NAc bilateral þ65%, (11.9e19.6) 38
Liu et al., 2020 prospective, cohort,
open label
28 18e32 Anorexia NAc bilateral þ36%, (13.0e17.7) 24
Total/(mean) - 72 - - - - (33.2%) (14.5)
cg25 ¼Broadman Area 25, subcingulate gyrus; NAc ¼Nucleus Accumbens; N/A ¼not available; x¼DBS ineffective (increase of BMI); # ¼six patients had radiofrequency
ablation and two patients had DBS; *¼included pediatric patients (<18 years-old).
Table 5
Review of the literature of Deep Brain Stimulation for Aggressive Behaviour and Self-harm.
Author/Year Study design N. of
Patients
Age, years at surgery
(range)
Indication DBS target
(s)
Uni/
Bilateral
Results (% improvement,
mean)
Follow-up (range,
months)
Franzini et al., 2013 observational cohort
study
720e64 AB/
Epilepsy
pHyp bilateral 65% (OAS);
50% reduction in DRE (2
patients)
24 to 132
Torres et al., 2013*observational cohort
study
617e48 AB/
Epilepsy
pHyp bilateral 47% (ICAP);
30% reduction in DRE
6e82
Benedetti-Isaac et al., 2015*observational cohort
study
916e33 AB/
Epilepsy
pHyp bilateral 65% (OAS);
89.6% seizure reduction
2e48
Tambirajoo &Furlanetti et al.,
2020*
#
observational cohort
study
411e16 Lesch-
Nyhan
amGPi/
pmGPi
bilateral 60.5% (BPI-Frequency)
64% (BPI-Severity)
22e98
Total/(mean) - 26 - - - - - -
AB ¼aggressive behaviour and self-harm; *¼included pediatric patients (<18 years-old); OAS ¼Overt Aggression Scale; pHyp ¼posterior hypothalamus; DRE ¼drug
resistant epilepsy; ICAP ¼Inventory for Client and Agency Planning (maladaptative behaviour index); N/A ¼not available; BPI ¼Behaviour Problems Inventory;
#
¼accepted
for publication.
Fig. 2. Three-dimensional anatomical representation of brain structures most
commonly targeted for deep brain stimulation in the management of psychiatric
disorders. ALIC ¼anterior limb of the internal capsule; NAc ¼Nucleus Accumbens;
STN ¼Subthalamic Nucleus; BNST ¼Bed Nucleus of Stria Terminalis; GPi ¼Globus
pallidus internus; CM ¼Centromedian Nucleus of the Thalamus; cg25 ¼Broadman’s
Area 25; post Hyp ¼posterior Hypothalamus; lat Hyp ¼lateral Hypothalamus;
slMFB ¼superolateral branch of the Medial Forebrain Bundle; ITP ¼Inferior Thalamic
Peduncle; Globus pallidus externus; CC ¼Corpus Callosum; Th ¼Thalamus;
LV ¼lateral ventricle; Ic ¼Internal Capsule; Ins ¼Insula; Ru ¼Red Nucleus; Pu ¼
Putamen; CN ¼Caudate Nucleus; Mm ¼Mammillothalamic Fasciculus; Fx ¼Fornix,
column. (For interpretation of the references to colour in this figure legend, the reader
is referred to the Web version of this article.)
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
6

Seventy-three percent of patients achieved 25% improvement in
the Y-BOCS score with a large majority achieving 35% improve-
ment. A significant increase in GAF scores was also observed indi-
cating improved functional outcomes in work, school and
homemaking functioning, independent living, activities of daily
living and social engagement. Twenty-three serious AE were re-
ported including 2 post-operative intracerebral haematomas and 4
incidences of increased suicidal ideation/depression in three pa-
tients [35].
Alonso et al. (2015) reported results of a meta-analysis on
treatment outcome and predictors of response to DBS treatment for
OCD. The authors found an estimated 45% global reduction in Y-
BOCS and a 60% responder rate [51]. Older age at symptom onset
and presence of sexual/religious obsessions and compulsions were
associated with better responses. No significant difference was
found in the efficacy of different targets used but significant in-
crease in Short Form-36 vitality scores were seen after 1 year of
stimulation of ALIC and adjacent ventral striatum [51].
A recent systematic review of randomised controlled trials in
OCD (80 patients in 8 studies) reported an overall mean reduction
in Y-BOCS score of 38.7% as assessed at the end of the double-blind
phase, which met the criterion for a full response [52]. Five severe
surgical AE (three intracerebral haemorrhages and 2 infections) and
8 mood-related severe AE (1 suicide, 3 suicide attempts and 4
suicidal thoughts and depression) were noted. Overall improve-
ment in depressive symptoms were noted but paradoxically, DBS
was also associated with suicidal thoughts in some cases. Efficacy
for STN and striatal anatomical targets (ALIC, NAc, VC/VS and BST)
was 41.94% vs 38.53% for Y-BOCS reduction respectively [52].
DBS not only improves the symptoms of OCD but also has a
beneficial effect on reducing anxiety and depression [49]. Stimu-
lation of the NAc [34], the ALIC [33] or VC/VS [35] targets resulted in
mood improvement as measured with the Hamilton Depression
Rating Scale (HDRS) and sustained reduction in anxiety as
measured with the Hamilton Anxiety Scale (HAS) as opposed to
STN-DBS [32] which did not confer such benefit. A temporary
elevation in anxiety and panic symptoms following stimulation of
striatal areas which resolved with stimulation parameter changes
[35] and transient hypomania following STN or ventral striatal
targets stimulation [32] have also been reported. A study on the
risks following DBS therapy revealed that the most frequent AE in
OCD patients was mood changes (38.3%) especially prevalent in the
ALIC-stimulated group (44.4%, n ¼20/45) compared to NAc (42.8%,
n¼12/28) and STN (33.3%, n ¼7/21) stimulation groups, particu-
larly present during the titration phase, and also apparently
dependent on the modulation of distinct sites within the limbic
neural circuit [25]. Another multi-centre study analysing safety of
DBS for OCD in 30 patients noted that all of them experienced AEs
with the majority being mild (52%) or moderate (37%), with a
median time to resolution of 22 days and mainly related to stim-
ulation rather than surgery [44].
An improved QoL is one of the positive impacts of DBS therapy in
OCD. One study demonstrated a 90% overall QoL improvement as
assessed with the brief version of the World Health Organization
Quality of Life Scale Brief Version [53]. These improvements were
seen in the physical (39.5%), psychological (39.5%) and environ-
mental domains (16%). As QoL improvements were seen in both
responders and non-responders, it is postulated that DBS improves
QoL independent of OCD symptom improvement [53].
The application of DBS for OCD in the paediatric population is
sparsely reported. Many children with OCD can spontaneously
remit as they grow up [54,55]. Also, the combination of pharma-
cotherapy and cognitive behavioural therapy can achieve remission
rates as high as 50% [54,55]. A recent study, utilising a symptom
provocation paradigm in a fMRI experiment, showed that the
position of the best active contact varied between patients and was
more frequently located in the caudate nucleus (66%) than in the
NAc (33%), corresponding to a more dorsal striatal sweet-spot
across responders [43]. A more personalised approach in the se-
lection of stimulation targets may be warranted in future studies if
the technique is to be optimised and its application safelyextended.
3.3. Treatment resistant depression
Table 3 summarizes papers published and outcomes on DBS for
the management of major depressive disorder [56e82].
Depression is a major psychiatric disorder with high worldwide
prevalence and is the leading cause of disability and a major risk
factor for suicide [83]. Up to 30% of patients will fail to respond to
multiple pharmacological and/or psychological treatment mea-
sures [84] with failure to respond to two or more treatment steps
labelled as treatment resistant depression (TRD) [85]. DBS in pa-
tients with TRD remains investigational. Multiple deep brain tar-
gets have been utilised in both open label and randomised studies.
The commonly used targets include the subgenual anterior cingu-
late cortex (cg25), slMFB, ALIC, VC/VS, BNST, lateral habenula, ITP
and NAc (Table 3).
The first open-label study of cg25 stimulation in 6 patients with
TRD resulted in at least 50% reduction on the baseline HDRS
(response) in 4 patients, whereas 2 patients presented remission
(defined as a HDRS <8) at 6 month follow-up [56]. A follow-up
study with 20 patients including the first six patients demon-
strated a 35% remission rate at 1-year and 43% at 3 years or last
follow-up (up to 6 years) [57,59]. A multi-centre trial of 21 patients
showed a response rate of 29% at 1 year which increased to 62%
when response was re-defined as 40% reduction on baseline
HDRS [58]. More recently, Holtzheimer et al. (2017) reported the
results of a randomised sham-controlled 6-month multi-centre
trial, confirming the safety and feasibility of cg25 stimulation.
However, the study failed to demonstrate statistically significant
superiority of DBS versus sham-stimulation at six-month follow-up
(primary end-point) [62]. Sankar et al. (2020) described pre-
existing structural brain features as neuroanatomical predictors
for response to cg25-DBS. The authors identified that structural
integrity of the subcallosal cingulate gyrus target area and its
connected subcortical areas, smaller cortical grey matter volume
and lower cortical grey matter/white matter ratio were predictive
of response to cg25-DBS [86]. In a randomised double blind study of
high frequency (130 Hz) versus low frequency (20 Hz) cg25-DBS,
the former conferred better long term results [82]. A small study
investigating neurocognitive predictors of response to cg25-DBS
concluded that psychomotor speed (assessed with Finger Tap
Test) and executive function (evaluated with the Wisconsin Card
Sorting Task) may be useful as part of the preoperative neuropsy-
chological evaluation. Responders had significantly less baseline
psychomotor dysfunction and improved to a better extent than
non-responders following cg25-DBS [87]. In line with previous
reports [63], no adverse effects on cognition was noted [87].
Improvement in HDRS and other neuropsychological scores af-
ter capsulotomies performed for OCD sparked an interest in using
the ALIC or VC/VS as a target for TRD [88]. Contradicting results
from randomised controlled trials investigating this target have
emerged. Dougherty et al. (2015) reported no significant difference
between the sham and active DBS groups (response rates of 14.3%
and 20% respectively) and failed to achieve primary end-point in a
double-blind randomized trial of VC/VS-DBS for TRD [65]. Later,
Bergfeld et al. (2016) reported significant reduction in depressive
symptoms (40% responder rate) during the open-label phase of a
study, which included a total of 25 patients [64]. Furthermore, the
authors reported superiority of ALIC-DBS versus sham-stimulation
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
7

in a double-blind analysis of a subset of that cohort [64]. An open-
label long-term evaluation of the same patients reported sustained
response rate at 2-year follow-up [70]. The neurophysiological
relationship of the ventral striatum with neurocircuits involved in
depression led authors to investigate the NAc as a potential DBS
target [63,74,89,89]. Bewernick et al. (2012) showed NAc-DBS to be
associated with antidepressant, anxiolytic and precognitive effects
in a cohort of eleven patients with TRD [63]. Five patients (45%)
were classified as responders at one-year follow-up and remained
stable with sustained response for at least 4 years [63].
While two large RCTs failed to show superiority of DBS versus
sham stimulation at short time in the treatment of TRD [62,65],
Schlaepfer et al. reported rapid and long-term response of DBS of
the slMFB in a cohort of 7 patients, with 85% response and 57%
remission at 8 months follow-up [69]. Interestingly, the only pa-
tient who did not respond to DBS treatment was diagnosed with a
small bleed in the trajectory of one of the electrodes [69,90]. Post-
hoc tractographic analysis showed the left slMFB disrupted by the
lesion, which could have caused a lack of response to DBS [90].
Although the positive results of slMFB-DBS have been replicated
[73]. [81], a randomized controlled trial in a larger cohort of pa-
tients is needed to corroborate these findings.
A systematic review and meta-analysis of randomised
controlled trials of active versus sham treatment for TRD (190 pa-
tients in 9 studies) concluded that patients on active treatment had
a significantly higher response and reductions in mean depression
scores [91]. However, these results were not statistically significant
when analyses was restricted to parallel group studies and for other
outcomes (GAF, QoL, neuropsychiatric outcomes) [91]. In an anal-
ysis of surgical risks in 96 patients undergoing DBS for TRD, the
most frequent AEs seen were hardware related (11.4%) and suici-
dality (9.3%) and were most frequently seen in cg25-DBS. No long-
term stimulation related side effects were reported [25].
At present, thereare no reportedcases for DBS use inthe paediatric
TRD population. Results from adult open label studies suggests that
around a third achieve complete remission, another third showed
some improvements and the final third experience no benefits from
stimulation [92]. Overall though, there is no sufficient data presently
to justify the use of DBS for TRD in the paediatric population.
3.4. Eating disorders
Table 4 summarizes papers published and outcomes on DBS for
the management of Eating disorders [93e99].
Even though early treatment of adolescents with anorexia
nervosa (AN) is successful in 30e60% of patients, management of
patients with symptom duration of longer than 3 years is more
challenging [100]. Outcomes are poor with a high mortality rate in
those with an established disease despite the best available psy-
chological treatments [101]. Patients with severe AN are extremely
aversive to eating and weight gain with pathologically rewarding
behaviours of food restriction and other weight-loss behaviours
[102]. AN has a strong association as a comorbidity with other
psychiatric disorders and has shown improvement in outcomes
after DBS for concomitant OCD or TRD [102,103].
Blomstedt et al. (2017) reported a female patient with TRD and
AN who had DBS of BST with resultant subjective improvement in
food and eating anxiety without any significant effects on the BMI
[104]. Another paper reports of a female patient with refractory OCD
and AN who underwent VC/VS-DBS with subjective improvement in
AN symptoms with neuromodulation [105]. A single case report of a
female patient with restrictive AN and chronic recurrent depression
who underwent subgenual cingulate stimulation resulted in a BMI
sustained above 19.1 for 2 years with no further interventions or
hospitalisation required for the AN [106].
A pilot study looking at DBS in AN specifically was carried out in
6 patients using the subcallosal cingulate as the target [93]. Fifty
per cent of patients maintained BMI greater than at baseline at 9
months with a similar number reporting improved QoL. One
adverse event (Seizure) was attributed to metabolic disturbances
[93]. A one-year follow-up open label trial of 16 patients (aged
20e60 years) with an average BMI of 13.83 and 88%incidence of co-
morbid mood disorders, anxiety disorders or both demonstrated
significant improvements in depression, anxiety and affective
regulation with subcallosal cingulate stimulation [94]. Interest-
ingly, significant changes in glucose metabolism in key AN-related
structures were noted at 6- and 12-months post stimulation. 44%
had serious AEs related to the underlying illness and 2 patients
requested device removal or deactivation during the study [94].
Another study of two adult patients with intractable AN who
underwent stimulation of the NAc reported improved BMI at 1 year
with no AE [95]. Wu et al. specifically focused on the role of DBS in
paediatric AN [96]. They undertook a study in 4 female patients
aged 16e17 years with an average baseline BMI of 11.9, using the
NAc as the target. Three patients had OCD and the fourth had
generalised anxiety disorder. Significant increase in BMI was seen
in all four patients with an average 65% increase in body weight
after a mean follow-up of 38 months [96].
Despite the promising initial results, including in the paediatric
age group, DBS in AN is high-risk and remains experimental with a
current lack of consensus on the optimal target [103]. Severe
chronic malnutrition leads to an increased risk of surgical compli-
cations and longer-term clinical outcomes are currently unknown.
An ongoing longitudinal study is presently investigating the feasi-
bility and efficacy of NAc-DBS in severe and enduring AN with a
further aim to assess any subsequent neural changes and to develop
an ethical gold standard to guide treatment applications [107].
What is already clear though is the need for multimodal therapy in
this difficult to treat disorder where DBS’s success will be highly
dependent on other measures, including pre-surgical weight opti-
misation, psychological input and metabolic resuscitation.
On the other end of the eating disorders spectrum lies binge
eating and obesity. To date, only few studies have reported the use
of neuromodulation in the management of obesity with conflicting
results. Pre-clinical and clinical studies have shown that neuro-
modulation of the lateral hypothalamic area (LHA) can result in
weight loss [108e110 ]. Hamani et al. reported a loss of 12 kg in 5
months in a patient treated with LHA-DBS [110 ]. By turning off
stimulation, the patient reverted to binging and weight gain [110].
However, Franco et al. showed LHA to be ineffective in improving
anthropometric measures in a cohort of four obese patients with
Prader-Willi Syndrome [98]. Four other case reports have investi-
gated the role of neuromodulation of the NAc in the management of
obesity (total of 6 patients) [111,112]. Despite evidence of weight
loss with NAc-DBS, one patient committed suicide and another
decided to have the DBS system removed after 13 months [111].
Authors caution other groups regarding the high risk and
complexity of these patients due to the associated psychiatric
comorbidities, such as refractory depression, anxiety and person-
ality disorders, and the need for well-designed studies, strict
enrolment criteria and close psychiatric monitoring in trials
addressing DBS management in morbidly obese patients [111].
3.5. Aggressive behaviour and self-harm
Table 5 summarizes papers published and outcomes on DBS for
the management of self-injurious behaviour [113 e116 ].
Self-harm behaviour is usually caused by perinatal insults, brain
malformations and/or genetic syndromes, and is usually associated
with mental and cognitive impairment, hyperkinesia,
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
8

destructiveness of objects and aggressiveness [113,115]. This dra-
matic condition is often refractory to medical treatment, precludes
proper care and makes the use of restraining measures necessary in
order to avoid harm to the patient and carers. Historically, stereo-
tactic surgical procedures have been employed in an attempt to
alleviate these symptoms, such as cingulotomy, amygdalotomy,
dorsomedial thalamotomy and [115], also the posteromedial hypo-
thalamotomy as proposed by Sano et al. [117] Lesion of the pHyp was
shown to be effective, to some extent, in 95% of the patients, with
results considered “satisfactory”in up to 84% of the cases [117]. More
recently, three groups reported on the use of bilateral DBS of the
pHyp in a total of 22 patients with self-harm behaviour, refractory
epilepsy and severe cognitive impairment [113e115 ]. Franzini et al.
reported an overall 65% improvement of the Overt Aggression Scale
(OAS) and 50% improvement of epilepsy in two out of seven adult
patients. Torres et al. (2013) and Benedetti-Isaac et al. (2015) also
included paediatric patients in their series, reporting dramatic
behavioural improvement in eight out of 10 patients with long-term
follow-up (mean, 44 months) [113,115 ].
The ethical consideration on surgery for behavioural disorders
limit the widespread application. Nonetheless the current evidence
does suggest clinical benefit in carefully selected patients, including
children, with severe self-harm refractory behaviour such as in
Lesch-Nyhan syndrome [118].
Our group recently published the long-term clinical outcomes
and connectivity profiles in four children undergoing GPi-DBS for
Lesch-Nyhan syndrome [116]. Bilateral DBS of the posteroventral
(motor) and anteromedial (cognitive/behavioural) GPi using four
electrodes led to clinical improvement of self-harm behaviour and
motor control, which was not only dependenton the position of the
active contacts within the GPi itself, but also strongly correlated
with specific connectivity patterns between the basal ganglia and
distant cortical brain regions. These findings shed light on the un-
derlying mechanisms of DBS in the treatment of this complex
condition and, in line with the literature, indicate a potential
benefit of DBS in the management of drug-refractory aggressive
behaviour in selected cases.
3.6. Autism spectrum disorder
ASD consists of a group of neurodevelopmental conditions
altering cognitive and behavioural function, with an estimated
prevalence of 1% worldwide [49]. The DSM-5 defines autism
spectrum with high functioning patients capable of living on their
own at one end, and those with severe symptoms at the other. Core
to the definition of ASD are: 1) early-onset difficulties in social
interaction and communication, 2) repetitive, restricted behaviours
and interests [119]. Patients in the low functioning end of the ASD
spectrum very often present with self-injurious behaviour, poor
social interaction and other potentially life-threatening psychiatric
features [49,120]. Although medical management may improve
some of these symptoms, a considerable subset of the patients
turns out to be refractory to conservative treatment. Recently, re-
ports have emerged on the use of DBS as an adjuvant tool in the
management of a total of four severe refractory ASD patients,
mainly as an attempt to decrease aggressivity and self-harm
[121e123]. The basolateral nucleus of the amygdale (BLn) was
targeted in two patients [122,123], the GPi in one patient and both
the GPi and the ALIC in the other [121]. The authors concluded that
neuromodulation of the BLn may be an effective adjuvant tool for
the management of self-harm behaviour and aggression, whereas
the GPi or ALIC could be a target for the treatment of OCD-like
symptoms in these patients. Nevertheless, clearly further long-
term controlled trials are needed to better understand the role of
surgical management in ASD.
4. Discussion
This systematic review of the literature identified a total of
seventy-three clinical studies on the application of DBS in the
treatment of a range of psychiatric disorders.
Eleven studies (15%) involved paediatric patients. The main
neuropsychiatric conditions underlying the indications for DBS in
patients under 18 years-old were GTS (including patients with
OCD-like features), ED, aggressivity and self-harm behaviour.
In the field of neuropsychiatric disorders, GTS represents the
largest experience in terms of application of DBS as a treatment
option in children. Since the first published case report over 20
years ago, there is now some evidence to support DBS as an
effective and safe option for the treatment of medically refractory
GTS in selected children and young adults. However, GTS is asso-
ciated with high remission rates by early adulthood unlike move-
ment disorders such as primary dystonia. Therefore, arguments for
use of DBS in children for diseases that will have an eventual
decrease in severity will need to include a rationale for possible
persistence and for marked disability during symptomatic periods
[124]. Uncontrolled GTS, especially if associated with other
comorbidities such as OCD, in a child may hinder social and
educational development, irrespective of possible remission later in
childhood and DBS offers the possibility of symptom control during
this critical time [124]. However, the risk-benefit ratio of DBS needs
to be considered in the light of symptom severity and adverse effect
of alternative treatment [25]. Large prospective studies with long-
term follow-up are needed for a better understanding of the
impact of neuromodulation at different targets on the course of the
disease in children.
In patients with refractory eating disorders, DBS appears to be
feasible and of some advantage. Six clinical studies, including
prospective trials [93,94,97,97], reported on the safety and efficacy
of DBS treatment of anorexia. Two other papers focused on or
included paediatric patients in their analysis, showing a mean in-
crease in BMI ranging from 28% to 65% with no additional risks
compared to older patients with AN undergoing surgery (Table 4)
[96,99].
The mechanism of action of DBS in eating disorders is unclear
and there remains scope for optimisation, an area worthy of further
exploration given the high rate of morbidity and mortality associ-
ated with AN. Pre-clinical and clinical studies have shown that the
mechanisms of reward and neural networks involved in eating
disorders overlap, to some extent, at key structures along the
fronto-striatal and mesolimbic pathways with circuits responsible
for other neuropsychiatric disorders, such as depression, OCD and
addiction [125,126]. The ventral tegmental area sends mesolimbic
and mesocortical dopaminergic projections to the NAc and to the
prefrontal cortex via medial forebrain bundle [125,126]. During the
last decades, different structures of this network, such as slMFB,
ALIC, NAc and cg25, have been targeted using ablative or neuro-
modulation techniques in the management of various neuropsy-
chiatric conditions [125]. Therefore, further understanding of the
underlying mechanisms of the diseases will allow a more person-
alised treatment, choosing the correct target for the correct indi-
vidual patient.
The rates of serious surgical complications of DBS for psychiatric
diseases are low, and in general comparable to those seen with DBS
for movement disorders [25]. The most serious reported AE in
psychiatric patients submitted to DBS were intracranial haemor-
rhage and suicide/suicidality. However, since psychiatric patients
are usually younger, the risk of intracranial haemorrhage is ex-
pected to be lower [25]. On the other hand, Saleh et al. (2015) has
shown higher suicidality rate (5.9%), increased in not only patients
with TRD but also those with OCD and GTS [25] OCD patients had a
K. Ashkan, A.B. Mirza, K. Tambirajoo et al. European Journal of Paediatric Neurology xxx (xxxx) xxx
9

high rate of postoperative mood changes [25]. Hardware related
complications and infection occurred in 14.3% and 7.7% of the pa-
tients with higher infection rates in the GTS group. Of particular
relevance to the paediatric patients, the infection risks tend to be
higher compared to the adult patients. We recently reported a
surgical site infection rate of around 10% in 129 patients undergoing
DBS for dystonia with a mean age of 10.8 y (range 3.0e18.75) at a
mean follow up of 3.3y (range 0.5e10.3). However, the DBS infec-
tion rate was 4.7% in the under 7-year-old cases [127]. Specific
strategies are therefore required to reduce and manage these risks.
A number of ethical considerations arise when considering DBS
in psychiatric conditions. The selection of potential participants is
important for optimising efficacy and safety. Although limited
standardised criteria exist at present [27], selection criteria should
include patients who are physically, emotionally and cognitively
capable of understanding and undergoing surgery [128]. This is
particularly important in the children and will require specific
frameworks and pathways. The presence of a stable social envi-
ronment and the family members is also imperative. Informed
consent can be challenging but with the inherent risks that DBS
surgery carries, it is crucial that a comprehensive informed consent
is obtained. As DBS procedures are often considered as “last resort”
options, desperation on a patient or carer’s part can undermine the
informed consent process due to possibly unreasonable high ex-
pectations clouding the appreciation of the various treatment op-
tions and alternatives [129]. Pre-surgical expectation management
and goal setting are therefore critical to achieve good patient
satisfaction, both at the short and long term, highly relevant to the
paediatric patients and their carers [130 ].
Interest in neuromodulation in the management of neuropsy-
chiatric disorders continues to grow and remains an area of active
research. Three main factors have been expressed as potential
causes of failure of important clinical trials evaluating DBS in the
management of neuropsychiatric disorders, and should be
addressed in future prospective studies: a) premature evaluation
endpoints; b) variable surgical protocols and selection of idealbrain
targets; c) heterogeneous patient selection and lack of biomarkers
predictive of favourable outcome [62,64,131]. Although current
data available may support surgical intervention for the treatment
of some refractory psychiatric conditions in the paediatric popu-
lation, large long-term randomised trials are rare and thus the
threshold for surgical neuromodulation in a child must remain
high. A multidisciplinary approach to assessment and treatment by
an experienced team is paramount if surgery is being considered.
High quality research to further explore the ideal brain targets for
specific indications, incorporating the ethical concerns and the
potential influence of DBS therapy on the developing brain and vice
versa, is needed. Well-designed translational neuromodulation
research and functional connectivity analysis using cutting-edge
imaging technology might shed light on the brain networks
involved, the plasticity of the developing brain and the underlying
mechanisms of neuropsychiatric disorders in paediatric patients
paving the way towards personalised neuromodulation
[17,62,132e134].
5. Conclusion
The application of DBS for psychiatric indications has pro-
gressed at a steady pace in the adult population and at a much
slower pace in the paediatric population. Despite of its approved
use as an adjuvant strategy in the management of OCD, and
encouraging results reported in the treatment of GTS and TRD, DBS
for psychiatric disorders in paediatric patients remains largely
investigational. The stakes are much higher in children and ado-
lescents. Future multidisciplinary studies in children should be
done in a long-term trial setting with strict and robust criteria and
conduct to minimise the effect of harm and maximise the data and
evidence on efficacy and safety of DBS therapy. A move towards
personalising DBS therapy and exploration of new stimulation
techniques will provide new frontiers and possibilities in this
growing field.
Financial support
This research did not receive any specific grants from funding
agencies in the public, commercial or not-for-profit sectors.
Authorship statement
AM, KT and LF organised, executed, wrote and reviewed the
study. KA conceived, organised, supported and reviewed the study.
All authors have seen and approved the final version of manuscript
being submitted. The article is the authors' original work, hasn’t
received prior publications and isn’t under consideration for pub-
lication elsewhere.
Declaration of competing interest
KA has received education grants and honoraria from Med-
tronic, Abbott Medical and Boston Scientific companies. The other
authors have no disclosures to report.
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