Literature Review
Surgical Approaches in Psychiatry: A Survey of the World Literature on Psychosurgery
Felix Neumaier1, Mario Paterno2, Serdar Alpdogan1, Etienne E. Tevoufouet1, Toni Schneider1, Jürgen Hescheler1,
Walid Albanna3
Key words
- Ablative surgery
- Frontal lobotomy/leucotomy
- Functional stereotactic microsurgery
- Neuromodulation
- Neuropsychiatric deep brain stimulation (DBS)
- Treatment-resistant mental disorders
Abbreviations and Acronyms
AN: Anorexia nervosa
DBS: Deep brain stimulation
EpCS: Epidural prefrontal cortical stimulation
GTS: Gilles de la Tourette syndrome
LNS: Lesch-Nyhan syndrome
MAD: Major affective disorder
MRI: Magnetic resonance imaging
OCD: Obsessive-compulsive disorder
From the 1Institutes for Neurophysiology and 2Anatomy,
University of Cologne, Cologne; and 3Department of
Neurosurgery, RWTH Aachen University, Aachen, Germany
To whom correspondence should be addressed:
Felix Neumaier, B.Sc., M.Sc.
[E-mail: felix@neumaier-net.de]
Supplementary digital content available online.
Citation: World Neurosurg. (2017) 97:603-634.
http://dx.doi.org/10.1016/j.wneu.2016.10.008
Journal homepage: www.WORLDNEUROSURGERY.org
Available online: www.sciencedirect.com
1878-8750/$ - see front matter ª 2016 Elsevier Inc. All
rights reserved.
INTRODUCTION
Although advances in pharmacotherapy
and cognitive behavioral intervention have
improved the management of mental dis-
orders, as many as 10%e30% of patients
with major affective, anxiety, or obsessive-
compulsive disorders (OCDs) remain re-
fractory to all conventional forms of treat-
ment.1-3 These patients have debilitating
depression with suicidal ideations, chronic
anxiety, or recurrent intrusive thoughts and
compulsions, which typically foreclose a
normal life. Several surgical ablative and
neuromodulatory approaches, colloquially
referred to as psychosurgery, have been
used in the management of certain
treatment-resistant patients. In its most
well-known form, psychosurgery entails
disconnection of the frontal lobes from the
rest of the brain (frontal leucotomy) to
WORLD NEUROSURGERY 97: 603-634, JANUARY 2017
Brain surgery to promote behavioral or affective changes in humans remains one
of the most controversial topics at the interface of medicine, psychiatry,
neuroscience, and bioethics. Rapid expansion of neuropsychiatric deep brain
stimulation has recently revived the field and careful appraisal of its 2 sides is
warranted: namely, the promise to help severely devastated patients on the one
hand and the dangers of premature application without appropriate justification
on the other. Here, we reconstruct the vivid history of the field and examine its
present status to delineate the progression from crude freehand operations into
a multidisciplinary treatment of last resort. This goal is accomplished by a
detailed reassessment of numerous case reports and small-scale open or
controlled trials in their historical and social context. The different surgical
approaches, their rationale, and their scientific merit are discussed in a manner
comprehensible to readers lacking extensive knowledge of neurosurgery or
psychiatry, yet with sufficient documentation to provide a useful resource for
practitioners in the field and those wishing to pursue the topic further.
interfere with aberrant signaling in fronto- there is accumulating evidence that many
limbic circuits. A crude form of these patients with otherwise intractable mental
techniques, practiced by blind insertion of disorders may benefit from modern
cutting instruments into the brain, was surgical interventions. Increasing
popularized in the late 1930s, when avail- recognition that these disorders can be
able pharmacotherapy was still limited to understood in terms of dysfunction in
heavy sedation with barbiturates or chloral. specific brain circuits4 and new
Public enthusiasm and the urgent need for techniques such as deep brain stimulation
effective and cost-efficient psychiatric (DBS) have once again renewed interest in
treatment led to indiscriminate application psychosurgery (Figure 1). Although these
of these freehand operations worldwide, developments hold out the prospect of a
although the high incidence of complica- more reversible and adaptable form of
tions and serious side effects was soon treatment, they also warrant a careful
recognized by the medical community. In reconsideration of the history of
parallel, several neurosurgeons worldwide psychosurgery to highlight both the
developed more targeted approaches, some dangers of inappropriate use of these
of which laid the groundwork for present- techniques as well as their promise to
day stereotactic microsurgery. This first help severely devastated patients. Early
wave of operations ended in the late 1950s, pioneers in the field lacked the
when psychosurgery was largely super- sophisticated instruments and validated
seded by pharmacologic approaches outcome measures available currently, but
(Figure 1). Realization that certain patients their successes and failures have helped to
did not benefit from pharmacotherapy and define the indications and targets for
improved surgical techniques initiated a modern psychosurgery. Although
second wave of stereotactic operations in numerous articles have addressed the
the early 1970s, but a public backlash in history or present status of psychosurgery,
the ensuing years almost drove the field to few attempts have been made to
extinction (Figure 1). It remained a niche systematically summarize the information
application and still faces massive public contained in the enormous amount of
and political pressures brought about medical and scientific literature in the
largely by its chequered past. However, field, which spans more than a century
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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

and comes from more than 40 countries.

The aim of the present work is to close
this gap and facilitate integration of
previous experiences into current progress
by providing a detailed overview of past
and present surgical approaches in their
historical context. Although still far from
complete, the article offers a framework
and starting point by 1) considering many
case series and small-scale open or
controlled trials together with the relevant
secondary literature and 2) providing the
first comprehensive summary of targets
and indications for neuropsychiatric DBS.
The topic is discussed in a manner
Figure 1. Temporal evolution of psychosurgery between 1935 and 2015. Graph compiled from 361
comprehensible to readers lacking exten- articles describing the technique or results of different psychosurgical operations (not included are
sive knowledge of neurosurgery, psychia- reviews and historical articles). They can be roughly separated into 1) a first wave consisting of the
try, or bioethics, yet with sufficient various forms of frontal leucotomy (solid black line) and several more targeted operations (dashed
black line), 2) a second wave consisting almost exclusively of stereotactic operations (solid blue
reference to the relevant primary and sec- line), some of which were specifically intended to modify behavior (dashed blue line), and 3) a third
ondary literature to make the article useful wave consisting of stereotactic operations (solid blue line) and deep brain stimulation (dashed
as a resource for practitioners in the field or orange line). Note that the annual number of articles is not proportional to the annual rate of
those wishing to pursue the topic further. operations.

The rest of the first section is used to

address the choice of terminology and the
comparability of indications and outcome
measures over time.
Terminology
Because of the stigma associated with the
term psychosurgery, alternative designa-
tions such as “psychiatric neurosurgery”
or “limbic system neurosurgery” have
sometimes been used to refer to the more
recent surgical procedures. Although this
notional distinction may be sensible from
a semantic point of view, it also contrib-
utes to the common misconception that
present-day operations have nothing in
common with the procedures used in the
past. Here, these terms are used inter-
changeably to denote all neurosurgical
interventions intended to modify behavior
or affect, either by destruction (ablative
psychosurgery) or selective stimulation
(neuromodulatory psychosurgery) of
certain brain regions. As is pointed out
throughout the article, all forms of ablative
microsurgery still in use can be traced
back to the early periods of psychosurgery
(Figures 1 and 2) and most targets for DBS
have been adopted from or inspired by
previous ablative approaches as well.
Indications and Outcome Measures
A statistical or meta-analytical assessment
of psychosurgery is undermined by several
problems, including but not limited to the
nonhomogenous populations studied, the
general lack of appropriate control groups
with untreated patients, diagnostic inac-
curacies, and temporal changes in center
bias. A thorough discussion of these as-
pects is beyond the scope of this article
and can be found elsewhere,5,6 but some
important factors concerning the compa-
rability of presurgical and postsurgical
evaluation between different periods
should be clarified.
Before the development of standardized
rating instruments, therapeutic success
was commonly measured using the rate of
discharge from hospital or work adjust-
ment after surgery. This strategy was su-
perseded by psychiatric ratings of global
measures, such as the Pippard 5-graded
rating scale,7 which described the
patients’ postoperative improvements in
terms of broad categorical statements
(ie, symptom free, much improved,
some improvement, no change, worse).
Evaluation was usually performed by the
surgeon or associated psychiatrists based
on variable and often ill-defined criteria,
although it has been argued that in practice,
objectivity is rarely undermined by this sit-
uation per se.6 Because there appears to be
at least some clinical validity of these
scales,8,9 original data reported in this
form have herein been adopted to a
common 4-graded scale (Tables 1e3),
where category 1 (response) corresponds to
ratings such as “free of symptoms,”
“remission,” and “excellent” or “marked
improvement,” 2 (partial response) to rat-
ings such as “slight,” “some,” or “moderate
improvement,” 3 (no response) to ratings
such as “unchanged” or “no improve-
ment,” and 4 (deterioration) to ratings such
as “worse” and “dead.”a A simple head-
counting approach such as this can clearly
not substitute for a critical qualitative
analysis of the individual operations, and is
thus intended to convey a general idea
rather than a strict comparison between
different techniques.
More recent procedures, which have
typically been evaluated based on the
reduction of symptom severity (with
response defined as a set reduction in
standardized scores such as the Yale-
Brown Obsessive Compulsive Scale, 17-
Item Hamilton Depression Rating Scale,
or the Montgomery-Asberg Depression
Rating Scaleb) or global improvement
(with response defined based on
standardized scores such as the Clinical
Global Improvement Scale or the Global
Assessment of Functioning Scalec) are
a
Only articles available to the authors in full text and with
sample size
3 have been included in the tables.
b
Y-BOCS, Yale-Brown Obsessive Compulsive Scale; HDRS-17,
17-Item Hamilton Depression Rating Scale; MADRS,
Montgomery-Asberg Depression Rating Scale.
c
CGI, Clinical Global Improvement Scale; GAF, Global
Assessment of Functioning Scale.

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

Figure 2. Timeline of individual operative techniques in psychosurgery
between 1935 and 2015. The first wave of psychosurgery began with the
introduction of frontal leucotomies in the 1930s followed by several
techniques intended to simplify the treatment (transorbital leucotomy) or
reduce the incidence of adverse effects (all other procedures). Among the
latter group were the first stereotactic operations (highlighted in blue),
which enabled the targeting of subcortical structures and development of
minimally invasive or noninvasive techniques during the second wave of
psychosurgery. The third wave was initiated at the turn of the twentieth
century, when deep brain stimulation (DBS) of different targets
(highlighted in orange) was first used to replace ablative techniques in
psychiatric patients. AC, anterior cingulate; ALIC, anterior limb of the
internal capsule; ITP, inferior thalamic peduncle; LHB, lateral habenula;
MFB, medial forebrain bundle; NAc, nucleus accumbens; SGC, subgenual
cingulate; STN, subthalamic nucleus; VC/VS, ventral capsule/ventral
striatum.

compiled in terms of the original outcome
measures (Tables 4 and 5).
A truly valid comparison among different
therapeutic procedures also requires reli-
able and consistent diagnostic schemes, a
prerequisite clearly not met in the case of
psychosurgery. This situation is com-
pounded further by the fact that early psy-
chosurgical procedures were used for a
variety of often poorly defined diagnoses,
which varied from surgeon to surgeon as
well as over time. Based on overt differ-
ences in the reported responsiveness to
psychosurgery, indications of first-
generation and second-generation opera-
tions (eg, Tables 1 and 2) have herein been
roughly separated into mood disorders (ie,
affective and anxiety disorders) on the one
hand and personality disorders (ie,
schizophrenia, psychopathy, and
psychoses) on the other (but see Early
Restricted Operations). Indications for
second-generation behavioral surgery
(Table 3) have likewise been divided based
on clinical responsiveness and the presence
or absence of structural brain damage/
electroencephalography abnormalities
into the 2 umbrella terms organic
disorders and inorganic disorders,
respectively (but see Behavioral
Psychosurgery). A more detailed overview
of the exact diagnostic labels included in
the different categories is provided in the
text and figures.d
THE ORIGINS OF PSYCHOSURGERY
The earliest physical evidence of success-
ful neurosurgical intervention in humans
was presented by Alt et al.,115 who
described signs of repeated surgical
manipulation at the cranium of an adult
man discovered in a neolithic burial site
in France. The well-preserved skull
showed clear evidence of 2 successful
trepanations, a procedure whereby parts of
the cranial vault are surgically removed or
d
See Figures 6, 8, and 10.
a hole is drilled into the skull to expose
the intracranial contents.115,116 Trepana-
tion experienced a more widespread use in
later centuries and evidence indicates that
ancient civilizations worldwide commonly
practiced the technique, with surprisingly
low morbidity and mortality. Of 288 hu-
man skulls recovered from archaeological
excavations in the Andean region of
southern Peru, 8% showed evidence of
trepanation, with half of them showing
clear evidence of proper healing.117 A
similar examination of 384 skulls from
south-western Germany, dated back to
the early medieval period, showed evi-
dence of trepanation in 8 cases (2.1%), of
which 7 showed signs of healing and
survival.118 A look into contemporary
medical literature provides insight into
the beliefs underlying the practice of
trepanation and a description of the
procedure itself. In the last years of the
twelfth century, Rogerius Salernitanus
advised in his Practica Chirugiae119 (“The
Practice of Surgery”) that mania and

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FELIX NEUMAIER ET AL.
melancholy should be treated by
penetration of the cranium “to permit
the noxious material to exhale to the
outside.” Robert Burton in his famous
book Anatomy of Melancholy120 (1652)
similarly advocated boring a cranial hole
“to let out the fuliginous vapors” and
went on to describe a case of remission
in a patient with intractable melancholy
after injury to the skull. The latter shows
how clinicopathologic correlation of
neurologic insults gave rise to the
development of early surgical strategies
and inevitably reminds of a similar
incident with major influence on
psychosurgery: the case of Phineas Gage.
On 13 September 1848, premature
explosion of a charge drove a 109-cm-
long and 3-cm-thick iron rod through the
skull and forebrain of the 25-year-old
Vermont railroad worker.121 Gage survived
the accident and quickly recovered, but it
was not long until his family and friends
noted fundamental changes in his
personality. These changes, described by
Gale’s physician, Dr. John Harlow, as a
disruption of “the equilibrium [.]
between his intellectual faculties and
animal propensities,”121 led to a climate
of brain-behavior correlation during the
latter half of the nineteenth century. Sub-
sequent work carried out by Paul Broca
and others showed that different functions
are localized in specific brain regions122-124
and spurred interest in the potential to
treat psychiatric diseases via neurosurgical
intervention. In 1888 and 1889, Gottlieb
Burckhardt, a Swiss psychiatrist with no
formal education in surgery, experimented
with brain surgery on a few “demented
and aggressive” patients. Two years later,
he published a detailed report of his
work,125 which involved ablation of the
cortex at multiple sites in the frontal,
parietal, and temporal lobe and is often
regarded as the birth of modern
psychosurgery. Responses of the medical
community were mostly
unfavorable,126,127 leading Burckhardt to
abandon his work. In the following
years, Leonardo Bianchi in Italy128
evaluated the effect of cerebral lesions in
dog and monkey, and articles by Erich
Feuchtwanger129 and Karl Kleist130 from
Germany systematically analyzed the
differential effects of frontal lobe injury
on personality and affect of veterans of
World War I. In 1910, the Estonian
606 www.SCIENCEDIRECT.com
neurosurgeon Lodovicus Puusepp
sectioned fibers between the frontal and
parietal lobe of 3 patients with manic
depression, but he was dissatisfied with
the results and did not report on his
work until after the public advent of
psychosurgery.131,132 More than 20 years
later, Swiss neurosurgeon Francois Ody
performed resection of the right
prefrontal lobe in a schizophrenic
patient,133 but he delayed publication of
his work for several years as well. It was
thanks to the Second World Congress of
Neurology in 1935 that psychosurgery
experienced a major progression. A work
on the calming effects of bilateral frontal
lobectomy in chimpanzees, presented by
Yale physiologist John Fulton, is believed
to have inspired Portuguese neurologist
Egas Moniz to start experimenting with a
similar procedure in human patients.134
He soon coined the term psychosurgery
and heralded the era of frontal lobotomy.
THE ERA OF FRONTAL LEUCOTOMY
(C. 1935e1960)
Although Moniz is often erroneously
referred to as the first to perform a suc-
cessful psychosurgical operation, his work
without doubt popularized the field and
led to its enthusiastic implementation
worldwide.135 Because Moniz was not
trained as a surgeon and his hands were
malformed by gout, his procedures were
carried out by the skilled neurosurgeon
Pedro Almeida Lima, acting under
Moniz’s directions.127,135 Starting in
November 1935, they operated on a first
group of 8 patients, using bilateral
injection of absolute alcohol into the
white matter of the frontal lobe.136
Multiple injections were often required
to arrive at a favorable outcome and
Moniz soon decided on a new method.
In subsequent cases, a custom-made sur-
gical instrument, consisting of a rod with
a retractable wire loop (leucotome), was
used to disconnect the frontal lobes from
the rest of the brain (Figure 3A). It was
inserted into the brain through a burr
hole at the top of the skull and rotated
with the wire loop bowed out at the tip
to produce circular lesions (Figure 3B).136
Within 4 months, Moniz published a
number of reports describing his first 20
experiments and his assistant presented
the work at a meeting of the Société
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LITERATURE REVIEW
SURGICAL APPROACHES IN PSYCHIATRY
Médico-Psychologique in Paris.138-140
Contrary to Moniz’s hopes, first
reactions were hostile and resembled
those to the work of Burckhardt 50 years
earlier.127 However, despite the lack of
objective data or long-term evaluation,
Moniz’s ideas became widely adopted in
the following years, especially in Italy,
where first comparative studies and hun-
dreds of case records appeared within 2
years (reviewed in Reference141).
Subsequently, Moniz’s technique was
taken up at a variable pace by
neurosurgeons in more than 40 other
countries worldwide (reviewed in
Reference142), among them 2 American
physicians from the George Washington
Medical School, who initiated the
widespread use of psychosurgery in the
United States.
Prefrontal Lobotomy
Walter Freeman and James Watts had
been impressed by the work of Moniz and
began experimenting with frontal leucot-
omy in 1936.136 Results with the technique
described by Moniz were unsatisfactory
and many of their patients experienced
relapse after a short period. Using
iodinated oil and cranial radiography to
visualize the plane and extent of their
incisions, these investigators found the
position of the lesion to be highly
variable.143,144 In the ensuing operations,
they developed and refined their own
method, which became known as the
prefrontal lobotomy or standard
leucotomy.135,136,145 It was performed
with a flat calibrated knife (precision
leucotome), which was inserted through
lateral burr holes at the level of the
coronal suture (Figure 4A) and pivoted
up and down, thereby massively dividing
frontolimbic projections in the desired
plane (Figure 4B). The cuts were then
deepened by means of a blunt knife
(radial stab incisor) pushed through the
burr hole (Figure 4B) and the procedure
was repeated on the contralateral side. In
1942, they published results from 200
cases, reporting a success rate of 63%,
with a further 23% of patients showing
unchanged and 14% worsened conditions
or death.143 Based on postmortem
findings of retrograde degeneration in
thalamic nuclei.147,148 Freeman regarded
section of frontothalamic connections
during leucotomy as the most important
 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

Figure 3. Frontal leucotomy as introduced by Egas Moniz in
1935. (A) After his initial attempts with injection of alcohol,
Moniz devised a custom-made leucotome, which consisted of a
rod with a retractable wire loop. (B) After insertion of the
leucotome through burr holes at the top of the skull, the
instrument was rotated with the wire loop bowed out. (C) The
procedure was performed in both hemispheres and from
different angles to produce 3 bilateral circular lesions in the
white matter of the frontal lobes. (A) and (C) redrawn from
Valenstein (1986), p. 106.137

factor for “freeing the intellect from prefrontal cortex (Figure 5).135,136 performing hundreds of transorbital
excessive emotional hold.”e,143,146 In the Freeman devised the method as an leucotomies himself. He later remarked
following years, the standard leucotomy outpatient procedure, which was to be that “this method proved unacceptable
was adapted with minor modifications by performed by any physician within to my surgical colleagues for the most
several British and American approximately 15e20 minutes.161 His part, though they were impressed by the
neurosurgeons,149-155 although some of associate and neurosurgeon Watts was accuracy and symmetry of the
them expressed serious concern about highly skeptic of the crude technique lesions.”162 Despite a high incidence of
the lack of visual control.155 For the latter and quit their collaboration, and fatal hemorrhaging and other
reason, others used an open type of Freeman began visiting hospitals and complications, Freeman’s mission
surgery, introduced by John Lyerly in asylums all over the United States, proved to be successful and culminated
1937 to reduce the risk for hemorrhage of promoting his procedure and in sensationalized reports by popular
the anterior cerebral artery.16,156-159

Transorbital Leucotomy
In an effort to streamline the closed pro-
cedure, Freeman introduced the trans-
orbital leucotomy, an approach first
practiced by Italian psychiatrist Amarro
Fiamberti.160 It was performed by
rendering the patient unconscious with
electroconvulsive treatment and inserting
an ice pickelike instrument (transorbital
leucotome) above the eyes, driving it
through the orbital roof with the tap of
a mallet and sweeping it across the
Figure 4. Prefrontal lobotomy as devised by Freeman and Watts in 1937. (A) Freeman and Watts
e developed their own operative technique, which was performed through lateral burr holes at the
Modern MRI-guided analysis of patients subjected to these
level of the coronal suture. (B) 1) A calibrated knife (precision leucotome) was inserted into the brain
operations shows damage in several white and gray matter and moved in a sweeping motion to divide frontolimbic fibers. 2) After the sweeping incisions, a
structures such as sagittal stratum and anterior thalamic radial stab incisor was used to further deepen the cuts without damage to local blood vessels.
radiation as well as orbitofrontal, dorsolateral prefrontal, Redrawn from Freeman & Watts (1950), p. 42.146
and anterior cingulate cortex.257

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magazines such as Newsweek, Time, and

Reader’s Digest.134,136 In 1948, Freeman Table 1. Results of Nonspecific Treatment and First-Generation Freehand
organized the First International Psychosurgery
Psychosurgery Congress in Lisbon, Personality Disorders Mood Disorders
which attracted attendance from 26
countries.135,163 One year later, Moniz
R PR NR D R PR NR D
was awarded the Nobel Prize in
Medicine and Physiology “for his Nonspecific treatment (%) 33 — 29 38 55 — 30 15
discovery of the therapeutic value of 10
Fuller, 1930 144 — 1036 20 226 — 918 56
leucotomy in certain psychoses.”164
Given the enthusiastic news coverage Fuller, 193111 12220 — 9798 15055 3351 — 1018 951
and the scientific appeal provided by Gelperin, 193912 94 — 127 14 — — — —
Moniz’s Nobel Prize, it seems inevitable
Cheney and Drewry, 193813 185 — 315 0 — — — —
that affected individuals and their
families started to apply for the Whitehead, 193814 32 — 56 2 — — — —
procedure.136 In 1949, Freeman still Rennie, 1939 15
205 — 287 3 — — — —
emphasized that “psychosurgery must be ¼ Total 12880 — 11619 15094 3577 — 1936 1007
considered the last resort, the measure
of desperation”.165 However, in the Frontal leucotomy (%) 28 35 32 5 59 22 12 7
16
following years, he and his colleagues Lyerly, 1944 1 2 3 0 33 15 11 0
came to believe that surgical treatments Govindaswamy and Rao, 194417 7 6 10 2 — — — —
were most effective when used early in
the course of psychiatric illness.166,167 Board of Control, 194718 100 288 198 38 131 93 33 25
Moreover, transorbital leucotomies Scoville et al., 195119 2 9 16 0 1 3 0 0
provided an attractive and cost-efficient Stevenson and Wilson, 1951 20
1 5 6 0 13 8 2 0
way to achieve a general calming of 21
McKissock, 1951 — — — — 10 10 14 0
restless and agitated patients, making
them more manageable and reducing the Hohman et al., 195122 10 100 56 3 24 27 11 1
requisition of trained personal. Over- McCausland and Wickware, 195823 18 36 60 0 32 37 17 0
crowding of psychiatric hospitals and a
Tooth and Newton, 196124 1844 2028 1967 307 1348 406 235 150
lack of alternative treatments added to
the widespread use of psychosurgery, ¼ Total 1983 2474 2316 350 1592 599 323 176
which turned into a first line of treatment Cortical undercutting (%) 20 39 40 1 55 30 14 1
in many state hospitals and was often
Scoville et al., 195119 1 15 17 0 2 7 0 0
performed by surgically untrained physi-
21
cians and psychiatrists.135 McKissock, 1951 — — — — 9 13 26 2
Tow and Lewin, 195325 3 3 5 0 4 3 2 0
Early Restricted Operations 26
Knight and Tredgold, 1955 6 8 3 1 17 13 4 0
Because the number of cases kept
27
increasing, and first follow-up studies Ström-Olsen and Northfield, 1955 1 7 6 0 7 5 0 1
reached publication in the late 1940s, the Lewin, 196128 6 9 9 0 18 11 7 0
magnitude of side effects and personality
Knight, 196429 24 38 43 1 217 96 27 4
changes often associated with frontal leu-
cotomies became evident.168-176 Reporting ¼ Total 41 80 83 2 274 148 66 7
about patients leucotomized for intractable Topectomy (%) 21 22 57 0 44 6 50 0
pain, John Dynes and James Poppen at the Heath and Pool, 194830 2 1 1 0 — — — —
Lahey Clinic in Boston noted that they were
often “slowed upward in thinking as well as Pool et al., 194931 7 8 23 0 7 1 8 0
acting [.], at times completely without ¼ Total 9 9 24 0 7 1 8 0
emotional expression,, whereas others Cingulectomy (%) 0 4 96 0 61 16 22 0
receiving the same operation were “unin-
hibited and euphoric.”177 Others found that Whitty et al., 195232 0 0 13 0 3 3 5 0
“these patients are not only no longer Tow et al., 1954 33
0 1 9 0 — — — —
distressed by their mental conflicts but Gaches et al., 197234 — — — — 16 2 2 0
also seem to have little capacity for any
¼ Total 0 1 22 0 19 5 7 0
emotional experiences - pleasurable or
otherwise”.175 Moreover, intelligence and Continues
psychometric tests performed by Swedish

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FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

question if and how many patients

Table 1. Continued benefited from the treatment. A review
Personality Disorders Mood Disorders performed by the Board of Control in
Great Britain18 found that 35.3% of 1000
leucotomized patients were discharged in
R PR NR D R PR NR D
a condition regarded as improved or
Thalamotomy (%) 26 28 46 0 42 25 33 0 recovered18; 9.3% subsequently relapsed,
Spiegel et al., 195335 10 11 18 0 5 3 4 0 such that a sustained benefit was achieved
in only 26% of cases. This study and a
¼ Total 10 11 18 0 5 3 4 0
later survey by Tooth and Newton24 on
R, response, defined as ratings such as “free of symptoms,” “remission” and “excellent,” “marked,” or significant” more than 10,000 leucotomy cases also
improvement; PR, partial response, defined as ratings such as “slight,” “some,” or “moderate” improvement; NR, no showed that patients with personality
response, defined as ratings such as “unchanged” or “no improvement”; D, deterioration, defined as ratings such as disorders (almost exclusively
“worse” or “dead.” schizophrenics), who made up more than
two thirds of the patients operated on
(Figure 6), showed the least favorable
psychiatrist Gosta Rylander178 indicated cerebrum. Likewise, autopsy evidence outcome, although better results were
significant reductions in IQ and presented by John Walsh181 indicated that achieved in patients with mood disorders
abstraction ability of patients subjected to the transorbital leucotomy was not only (Table 1). Because these studies lacked
standard leucotomy. Several investigators imprecise but also highly unreliable, appropriate control groups with untreated
pointed out the inaptness of using the because the cutting movements of the patients, their outcomes have to be
coronal suture as a landmark,171,179 which leucotome after puncture of the brain weighed up against the rates of
was confirmed by Rowland and Mettler180 tended to simply shift the frontal lobes spontaneous (ie, without specific
in a large series of cadavers, showing laterally. The subjective and biased nature treatment) remission, which could be in
considerable variability in the relation of of the available medical literature from the order of 20%e50% (Table 1).
lateral burr holes to the underlying this time makes it difficult to answer the Variation with respect to indications,
follow-up, and duration of illness prevents
strict comparison between different
studies, but taken in the aggregate, there
seems to be little evidence that psychosur-
gery provided significant advantages over
nonspecific treatment. Thus, a compre-
hensive analysis of the literature performed
by Staudt and Zubin182 showed that more
initial discharges in psychosurgery
candidates was typically offset by more
readmissions in the years after surgery,
such that the main advantage was a
reduction in mortality immediately after
surgery.f Most of the few works using a
matched control group of untreated
patients likewise indicated that there was
no significant difference in the course of
illness between leucotomized and
untreated patients.183-186 Freeman was
still performing his procedures with
unchanged enthusiasm, but neuro
surgeons worldwide began working
towards a less destructive and more
targeted type of surgery (reviewed in
Figure 5. Transorbital leucotomy as developed by Amarro Fiamberti and
adopted by Freeman in 1946. To simplify the technique and allow for its use Reference187) (Figure 7).
outside the operating room, Freeman promoted the transorbital leucotomy. It
was performed by means of an ice pickelike instrument (transorbital Limited Frontal Leucotomies. Early attempts
leucotome) inserted through the orbital roof of patients rendered unconscious
with electroconvulsive treatment. Because the transorbital leucotome
to reduce the incidence of personality
frequently broke during the subsequent sweeping motions used to divide
frontolimbic projections, Freeman later commissioned a stronger and more f
durable form of the instrument (the orbitoclast). Redrawn from Freeman & Due to poor hygienic conditions and overcrowding in mental
Watts (1950), p. 52.146 hospitals, mortality among institutionalized psychiatric
patients far exceeded that of the general population.

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 LITERATURE REVIEW
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Figure 6. Indications for first-generation freehand
psychosurgery. (A) Comparison of the relative (length of the
bars) and absolute (values on the bars) number of patients with
mood (blue) versus personality (orange) disorders (for definition
see [B] and [C]) subjected to different psychosurgical operations.
(B) Distribution of diagnostic labels subsumed under the term
mood disorders. (C) Distribution of diagnostic labels subsumed
under the term personality disorders. OCD,
obsessive-compulsive disorder.

changes consisted of restricted frontal leu-

cotomies, targeting only the lower medial
quadrants of the frontal lobes (bimedial
leucotomy).188-192 A project performed at
the Boston Psychopathic Hospital
compared the long-term effects of standard
open and limited bimedial frontal leucot-
omy and reported that 5 years after surgery,
patients treated with the bimedial proced-
ure showed better work performance and
significantly more initiative.193,194
The American William Beecher Scoville
devised a method of cortical undercutting,
in which the frontal lobes were lifted with
a spatula and the fibers beneath the orbital
surface sectioned with an aspiration can-
nula.19,195-197 The procedure was per-
formed through burr holes at the forehead
and under direct visual control, thus
allowing for a relatively selective and
anatomically localized placement of le-
sions. Summarizing their observations
Figure 7. Approaches used to selectively interrupt frontolimbic circuits. The aim to reduce adverse
made in a total of 114 undercutting oper-
effects and complications associated with frontal leucotomy led to distinct forms of restricted ations and 33 standard frontal leucoto-
operations targeting different aspects of frontolimbic circuits. 1) Several surgeons developed limited mies, he and his associates at the Institute
forms of frontal leucotomy, targeting only certain parts of the frontolimbic projection fibers. 2) of Living in Connecticut estimated 60% of
Others resorted to resection of their presumed cortical target regions, thus reducing the risk of
hemorrhage and damage to other structures. 3) A third approach consisted of targeting the the patients to be significantly improved.19
subcortical pole of frontolimbic circuits and led to the introduction of human stereotactic They recommended undercutting of the
neurosurgery. orbitofrontal surface for cases of neurosis

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

cerebral lesion was produced) in 4 of

Table 2. Results of Second-Generation Stereotactic Psychosurgery his patients. They were carried through
Personality Disorders Mood Disorders the whole postoperative routine and
reportedly showed no signs of
improvement until after a true operation
R PR NR D R PR NR D
was performed in the following months.202
Subcaudate tractotomy (%) 0 44 56 0 47 27 25 1
Selective Cortical Ablations. An alternative
36
Ström-Olsen and Carlisle, 1971 0 2 3 0 71 32 37 1 approach investigated to reduce destruc-
Goktepe et al., 197537 0 2 2 0 77 27 16 0 tion of unrelated brain tissue was to excise
Hodgkiss et al., 199538 — — — — 69 65 63 5
and remove parts of the cortex, akin to the
early work of Burckhardt and Ody. In its
¼ Total 0 4 5 0 217 124 116 6 most drastic form, this approach involved
Cingulomotomy (%) 10 63 13 13 58 28 7 7 resection of the anterior portion of both
Cassidy et al., 196539 — — — — 7 6 2 0 frontal lobes (prefrontal lobectomy),203
40
parts of the temporal lobes (temporal
Ballantine et al., 1967 0 7 3 0 8 12 6 0 lobectomyg), or periamygdaloid and
Hunter-Brown and Lighthill, 196841 — — — — 87 7 5 1 prepyriform cortex (uncotomy).204 A more
Ballantine et al., 1987 42
3 12 1 4 49 47 6 16 restricted resection of individual gyri
(gyrectomy) was used with little clinical
¼ Total 3 19 4 4 151 72 19 17
success by Wilder Penfield.205-207 The
Mesoloviotomy (%) 75 12 12 0 33 33 33 0 technique was refined by Heath and Pool
Laitinen, 1972 43
4 1 2 0 0 1 2 0 in the United States,30,31 Jacques Le Beau
and Ferey in France,208-212 and Whitty and
Laitinen and Vilkki, 197344 14 2 1 0 6 5 4 0
associates in Great Britain32,33,213 into the
¼ Total 18 3 3 0 6 6 6 0 topectomy, a topical resection of cortex at
Limbic leucotomy (%) 57 29 14 0 48 26 16 10 the surface of the frontal lobes, which
produced patterns of retrograde thalamic
Mitchell-Heggs et al., 197645 4 2 1 0 27 14 6 4
degeneration comparable with
46
Hay et al., 1993 — — — — 10 6 6 4 conventional leucotomies.30,31,208 As
¼ Total 4 2 1 0 37 20 12 8 noted by Lawrence Pool and his
colleagues, the regions to be operated on,
Anterior capsulotomy (%) — — — — 73 22 5 0
broadly defined according to the limits of
47
Lopez-Ibor and Lopez-Ibor Alino, 1977 — — — — 42 10 5 0 Brodmann’s areas, usually “evolved after
Bingley et al., 197748 — — — — 25 10 0 0 considerable trial.”31 When used for the
treatment of severe anxiety or intractable
67 20 5 0
pain, topectomy involved fractional
R, response, defined as ratings such as “free of symptoms,” “remission” and “excellent,” “marked,” or “significant” resection of gray matter from the
improvement; PR, partial response, defined as ratings such as “slight,” “some,” or “moderate” improvement; NR, no dorsolateral prefrontal (standard
response, defined as ratings such as “unchanged” or “no improvement”; D, deterioration, defined as ratings such as topectomy), anterior prefrontal (polar
“worse” or “dead.” topectomy), or orbitofrontal and insular
(orbital topectomy) cortex.30,31,208,209 In
cases of psychomotor agitation and
and mild affective disorders, noting an In a few cases, Scoville also experi- violence independent of anxiety, the
“almost complete absence of personality mented with undercutting of the medial procedure was instead performed on parts
change.” In cases of schizophrenia and cingulate cortex, a region already impli- of the anterior cingulate cortex
severe affective psychoses, they found cated in emotion by Papez in 1937, but this (cingulectomy).32,209,211,214 In Poland,
that outcomes comparable with standard proved to be more challenging and was Stanislaw Ziemnowicz devised his own
leucotomies, but with significantly less often associated with serious complica- operative technique, the topischemia,
marked adverse effects, could be tions and less favorable outcomes.19,197 A which involved temporary or permanent
achieved by undercutting of the superior similar procedure was used by Kenneth deprivation of blood flow to selectively
surface. Similar results were reported by Livingston at the Veterans Administration ablate the superficial cortical layers.215,216
others who investigated the same or Hospital in Oregon for the treatment of Given the delicate selection of targets in
related approaches, most notably psychoses and psychoneuroses.202 He was the frontal lobes, it is not surprising that
Geoffrey Knight25-29 and Wylie one of the first to assess the possibility of the practice of topectomies was quickly
McKissock21 in Great Britain, Eduard placebo effects and, without knowledge
Busch in Denmark,198,199 and later Sadao of the patients or other hospital staff, g
Referred to as medial temporal lobotomy in the original
Hirose in Japan200,201 (Table 1). performed sham operations (ie, no publication.

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

Figure 8. Indications for second-generation stereotactic
psychosurgery. (A) Comparison of the relative (length of the
bars) and absolute (values on the bars) number of patients with
mood (blue) versus personality (orange) disorders (for definition
see [B] and [C]) subjected to different psychosurgical operations.
(B) Distribution of diagnostic labels subsumed under the term
mood disorders. (C) Distribution of diagnostic labels subsumed
under the term personality disorders. OCD,
obsessive-compulsive disorder.

abandoned, especially because these
operations seemed to provide little if any
advantage over standard leucotomies
(Table 1).
Subcortical Limbic Targets. A third approach
to disrupt aberrant signaling in cortico-
limbic circuits involved targeting the limbic
relay stations, and was first advocated by
Fulton6 as a possible means to reduce
intellectual deterioration. Based on his
appeal and the postmortem findings of
retrograde degeneration in thalamic
nuclei, Earnest Spiegel and Henry Wycis
investigated treatment of psychiatric
patients by bilateral destruction of the
dorsomedial thalamus (dorsomedial
thalamotomy). To locate and reach the
target with minimal damage to unrelated
brain tissue, they used a self-build stereo-
tactic device modified from the Horsleye
Clarke apparatus for animal experimenta-
tion.217,218 Precise guidance of a needle
electrode for electrocoagulation was ach-
ieved by combining ventriculography and
radiography to visualize intracerebral
anatomic landmarks and electroencepha-
lography to record the exact position in the
thalamus.218,219 In a few cases, additional
lesions were placed in structures such as
the anterior thalamic nucleus, hypothala-
mus, or the pain-conducting spinothalamic
tract in the midbrain.35,220,221 However,
despite this sophisticated approach, the
results of these operations were at best on
par with previous methods (Table 1) and
they proved to be associated with
considerable adverse effects, so that their
use in psychiatric patients was quickly
abandoned.221 The principle of human
stereotactic brain surgery based on
landmarks in the brain itself, on the other
hand, was soon adapted or developed
independently by neurosurgeons
worldwide.222-225 Jean Talairach in France
devised a stereotactic operation to section
fibers between the prefrontal cortex and
dorsomedial thalamus at the level of the
anterior limb of the internal capsule,226
thereby sparing a substantial part of the
anterior thalamic radiation. Consistent
with previous experience, the technique
had little beneficial effects in
schizophrenic patients, but was reported
to provide satisfactory results in cases
of anxious neuroses. A similar technique
was used in the United
States227 and Iraq228 to selectively
target thalamocingulate projections
(thalamocingulate fasciculotomy and
cingulotractotomy, respectively). Lars
Leksell in Sweden recognized that a single
heavy dose of radiation, administered by
sharply focused beams, could be used to
create a lesion completely noninvasively,
thus eliminating the risk of bleeding or
infection. In 1951, he introduced his
concept of stereotactic radiosurgery,
which laid the groundwork for
development of the Gamma Knife
technique in the late 1980s.229 The idea of
patient-specific, minimally invasive place-
ment of small lesions as a cure for psychi-
atric disease arose, and worldwide
development of new procedures targeting
subcortical structures of the limbic system
followed promptly. However, resistance
towards the widespread use of psychosur-
gery increased, with several journals of
professional reputation featuring articles
on the inherent risks and adverse ef-
fects.186,230-232 It was the introduction of a
viable alternative that nearly drove psycho-
surgery to extinction.

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

THE ERA OF STEREOTACTIC the Brook General Hospital in London,235 with the procedure, the team around
PSYCHOSURGERY (C. 1960e1990) where he refined Scoville’s technique of Knight’s successor John Bartlett reported
In 1954, chlorpromazine was approved by cortical undercutting to selectively lesion effects enabling “normal or near-normal
the U.S. Food and Drug Administration supraorbital frontolimbic white matter lives” in 40%e60% of cases.38,237
and introduced in the United States under tracts in the substantia innominata. Different outcome reviews by diagnosis
the trade name Thorazine by Smith, Kline Knight used a stereotactic procedure, in indicated response rates of 33%e50% in
& French.233 Within 1 year, 2,000,000 which multiple radioactive yttrium seeds patients with OCD, 25%e63% in patients
patients were administered the drug in were implanted bilaterally from above with anxiety disorders, and 34%e68% in
the United States alone, and similar into a region corresponding to the last 2 patients with major affective disorders
antipsychotics, first antidepressants and cm of the undercutting incision (MADs) (Table 2).36-38 Knight240 also
then anxiolytics, quickly appeared on the (Figure 9).235 Between 1961 and 1973, reported postoperative alleviation of
international market.234 The cost- approximately 1300 stereotactic withdrawal in 6 patients addicted to
effectiveness and comparable safety of subcaudate tractotomies were carried out barbiturates or heroin, but he provided
pharmacologic treatment was widely at the Brook General Hospital to treat no details about the patient
recognized by the scientific and medical patients with depressive disorders, characteristics or outcome. Common
community and meant a tentative end to OCDs, or chronic anxiety237 after all adverse effects included transient
psychosurgery. However, interest into nonsurgical options had been pursued by disorientation (10%), likely caused by
surgical approaches soon revived, as it an interdisciplinary team.238,239 postoperative edema, seizures (1.6%),
became increasingly evident that certain Summarizing their 12-year experience and suicide (1%).239 Mortality of the
patients did not benefit from pharmaco-
logic treatment or required ever-increasing
doses associated with severe side effects.
In the meantime, the field had continued
to be practiced on a smaller scale,
although it remains difficult to estimate
the extent, because the results of many
operations have never been published.
Based largely on questionnaire surveys
and personal communications, Elliot
Valenstein estimated that the number of
psychosurgical operations performed per
year between 1971 and 1976 was in the
order of 400e500 in the United States and
Canada, 200e250 in Great Britain, 83 in
Australia, and 10e61 in countries such as
India, Czechoslovakia, and Mexico.6 The
decrease in the number of operations
was accompanied by a drastic change in
the selection of patients in most
countries, such that between 1971 and
1976, only 3% of patients operated on in
the United Kingdom were schizophrenics
and the major indications for surgery had
become depressive disorders (42%),
obsessive-compulsive neuroses (22%),
anxiety disorders (19%), and psychotic
behavior associated with seizures (8%)6
(Figure 8). The techniques refined during
this time laid the groundwork for
present-day stereotactic microsurgery,
and some of them have remained in
practice with only minor changes in sur-
gical technique. Figure 9. Overview of brain structures and pathways targeted by stereotactic psychosurgical
operations. A, amygdala; ALIC, anterior limb of the internal capsule; AT, anterior thalamus; CB,
cingulum bundle; CC, corpus callosum; CG, cingulate gyrus; DMT, dorsomedial thalamus; F, fornix; G,
Subcaudate Tractotomy and Innominotomy nucleus of Gudden; HC, hippocampus; HT, hypothalamus; MB, mammillary bodies; OFC, orbitofrontal
cortex; P, periaqueductal gray; S, septum; UF, unicate fasciculus. Redrawn and combined from
Stereotactic subcaudate tractotomy References.6,40,236
emerged from Geoffrey Knight’s work at

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

procedure was favorably low, with only 1

death in 1300 cases, caused by Table 3. Results of Second-Generation (Behavioral) Stereotactic Psychosurgery
malpositioning of an yttrium seed in the Inorganic Disorders Organic Disorders
striatum.237 In Finland between 1971 and
1975, a similar procedure based on
R PR NR D R PR NR D
thermocoagulation of tissue in the
substantia innominata (innominotomy) Thalamotomy (%) 44 44 12 0 30 42 28 0
was used by Lauri Laitinen and his 49
Hassler and Dieckmann, 1970 2 1 0 0 — — — —
team241 for the treatment of depression
50
in 12 cases, but no details about the Andy and Jurko, 1972 — — — — 6 14 10 0
outcome or adverse effects have been Hassler and Dieckmann, 197351 4 5 0 0 — — — —
provided.
Andy, 197552 — — — — 5 1 0 0
Cappabianca et al., 198753 1 1 2 0 — — — —
¼ Total 7 7 2 0 11 15 10 0
Cingulomotomy
A stereotactic form of Scoville’s under- Amygdalotomy (%) 32 4 64 0 54 23 22 1
cutting of the medial cingulate cortex Narabayashi et al., 196354 56 — 9 1
targeting the cingulum bundle (cingulo- Heimburger, 1966 55
— — — — 16 — 4 0
motomy) was first described by Foltz and
Vaernet and Madsen, 197056 3 1 1 0 4 2 1 0
White in 1962242 for pain relief in anxious
57
or depressed patients. Later, Thomas Kiloh et al., 1974 1 0 7 0 3 3 4 0
Ballantine and his colleagues at the Small et al., 1977 58
4 — 8 0 13 — 19 0
Massachusetts General Hospital in
Mempel et al., 198059 — — — — 8 45 17 0
Boston39,40 reported positive effects of
the procedure in patients with affective Narabayashi, 198060 — — — — 51 16 9 0
disorders. They used bilateral ¼ Total 8 1 16 0 151 66 63 1
pneumoencephalography-guided thermo-
Hypothalamotomy (%) 50 44 3 3 79 16 5 0
coagulation of the cingulum bundle to
61
produce 2 or more 8-mm to 10-mm Balasubramaniam et al., 1971 3 4 1 0 — — — —
diameter lesions about 2 cm dorsally Sano et al., 197262 13 28 1 1 — — — —
from the corpus callosum (Figure 9).69,243
Schvarcz et al., 197263 2 1 0 0 5 2 1 0
The procedure proved to be safe, with no
64
treatment-related deaths and complica- Müller et al., 1973 15 5 1 1 — — — —
tions limited to hemiplegia (0.3%), Arjona, 197465 — — — — 10 1 0 0
medication-responsive seizures (1%), and 66
Dieckmann and Hassler, 1975 5 1 0 0 — — — —
suicide (9%h). In a 24-year retrospective
investigation on 198 patients observed Dieckmann and Hassler, 197767 4 0 0 0 — — — —
68
over a mean follow-up period of 8.6 Nadvornik et al., 1977 6 3 0 1 — — — —
years,42 long-term response to treatment ¼ Total 48 42 3 3 15 3 1 0
was observed in 62% of cases, with the
magnitude of improvement related to R, response, defined as ratings such as “free of symptoms,” “remission” and “excellent,” “marked,” or “significant”
diagnosis (Table 2). Cingulomotomy was improvement; PR, partial response, defined as ratings such as “slight,” “some,” or “moderate” improvement; NR, no
most effective in treating anxiety (50%) response, defined as ratings such as “unchanged” or “no improvement”; D, deterioration, defined as ratings such as
“worse” or “dead.”
and affective disorders (41%). The
response was less dramatic in patients
with OCD (25%) and multiple operations
were often required to arrive at a
favorable outcome, such that nearby A more anterior part of the cingulum Laitinen in Finland44,245 operated on
structures such as the corpus callosum bundle was targeted by Brown and subrostral parts of the cingulum bundle
were affected as well. No evidence for Lighthill41 for treating various affective located directly in front of and below the
intellectual impairments, changes in and anxiety disorders, including OCD. genu of the corpus callosum (reviewed
emotional tone, or behavioral and They reported marked acute clinical in Reference241). He concluded that
neurologic deficits were detected in this improvements in 87 of 100 patients. lesions restricted to the cingulum bundle
study.42 Again, radiograms in the original had little beneficial effect in patients
publication244 indicate that at least in with OCD unless they were combined
h
All 18 patients lost to suicide had preoperatively reported some cases, parts of the corpus callosum with lesions in the genu of the corpus
suicidal intentions and 13 had actually attempted suicide. were affected by the lesion as well. callosum.245,246

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

Based on the observation that cingulo-

Table 4. Results of Third-Generation Stereotactic Psychosurgery in Patients with motomy for the treatment of pain was
Obsessive-Compulsive Disorder or Major Affective Disorder often associated with an absence of with-
Obsessive- Major Affective drawal or drug craving after surgery,242,247
Compulsive Disorder Disorder a team around Vijay Balasubraniam in In-
dia248 investigated the procedure for the
Follow-Up,
months R PR NR R PR NR treatment of addictive behavior with an
obsessive-compulsive component.
Anterior cingulotomy (%) 32 9 59 43 22 35 Reporting on a total of 73 patients addic-
Spangler et al., 199669 17 4a 4b 8 8a 3b 4
ted to opioids or alcohol and operated on
70 c d
between 1970 and 1976, these in-
Dougherty et al., 2002 32 14 6 24 — — — vestigators249 considered the outcome to
Richter et al., 200471 12 1c — 12 — — — be favorable (ie, no relapse) in 60%e
Kim et al., 2003 72
12 6 e
— 8 — — — 90% of patients observed over a period
73 e
of 1e6 years but made no mention of
Jung et al., 2006 24 8 — 9 — — — possible neurophysiologic changes.
Steele et al., 200874 12 — — — 2f — 6
75 g h
Shields et al., 2008 30 — — — 7 6 4 Mesoloviotomy
¼ Total 33 10 61 17 9 14
Based on the favorable effects of high-
frequency stimulation or ablation of the
Limbic leucotomy (%) 42 0 58 47 29 24 genu of the corpus callosum, Laitinen43
76 i i
Montoya et al., 2002 26 5 — 7 3 — 3 specifically targeted this region in an
Shields et al., 200875 30 — — — 4g 8h 4 operation he called anterior
mesoloviotomy (derived from the Greek
Cho et al., 200877 84 — — — 11i 3j 2 word mesolovion for corpus callosum)
¼ Total 5 0 7 18 11 9 (Figure 9) (reviewed in Reference241).
Thermal capsulotomy (%) 59 14 27 50 0 50 Short-term clinical results were best in
78 k b
patients with schizophrenia, whereas
Lippitz et al., 1999 100 9 5 8 — — —
there was little benefit in patients with
Oliver et al., 200379 12 4k 4d 7 — — — depression or OCD (Table 2).43,44
Liu et al., 200880
12 22 k
10 l
2 — — — Psychological assessment showed
81 c immediate improvements in psychomotor
Rück et al., 2008 132 7 — 9 — — —
performance, short-term and long-term
Christmas et al., 201182 84 — — — 10m — 10 memory, and emotional state. After a
Zhan et al., 2014 83
12 41 c
— 12 — — — mean follow-up period of 2 years, a battery
of psychological tests still detected no
¼ Total 83 19 38 10 0 10
deficits (compared with preoperative tests)
Gamma capsulotomy (%) 50 2 48 — — — but maintained improvements in memory
Lippitz et al., 1999 78
100 7 k
1 b
5 — — — function and intelligence of 31 patients
operated on for different indications.250
Rück et al., 200881 132 5c — 4 — — —
Based on the clinical condition at follow-
84 k
Lopes et al., 2009 48 3 — 2 — — — up, fears were reduced in 67%, tension
Lopes et al., 201485 12 7e — 5 — — — in 71%, and anxiety in 72% but depression
86 e in only 37% of the patients.
Batistuzzo et al., 2015 12 6 — 11 — — —
¼ Total 28 1 27 — — —
Limbic Leucotomy
R, response, defined as CGPS score
3 and Clinical Global Improvement (CGI) Scale score 2;
35% reduction in
a c
Introduced by Desmond Kelly and asso-
Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score; e
35% reduction in Y-BOCS score and CGI score 2; f
50% ciates in 1973,251 limbic leucotomy
reduction in 17-Item Hamilton Depression Rating Scale (HDRS-17) and Montgomery-Asberg Depression Rating Scale essentially represents a combination of
(MADRS) score; g
50% improvement in BDI score and CGI score 2; iCGPS score
3; k
50% reduction in Y-BOCS bilateral anterior cingulomotomy and
score; m
50% reduction in HDRS-17 or MADRS score or CGI score 2; PR, partial response, defined as b5-50%
subcaudate tractotomy, thus targeting
reduction of Y-BOCS score; d24e35% reduction of Y-BOCS score; h
35% improvement in BDI score or CGI score 2;
both limbic circuits (cingulomotomy) and
j
CGPS score ¼2; l20e50% reduction in Y-BOCS score; NR, no response.
BDI, Beck Depression Inventory; CGPS, Clinical Global Psychiatric-Social Status.
frontolimbic projections (subcaudate
tractotomy). The technique emerged

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

Figure 10. Indications for second-generation behavioral [C]) mental disorders subjected to different psychosurgical
psychosurgery. (A) Comparison of the relative (length of the operations. (B) Distribution of diagnostic labels subsumed under
bars) and absolute (values on the bars) number of patients with the term inorganic disorders. (C) Distribution of diagnostic labels
inorganic (blue) versus organic (orange) (for definition see [B] and subsumed under the term organic disorders.

from the observation that cingulomotomy
alone was often ineffective in treating
patients with OCD, whereas better
results could be achieved when small
orbitofrontal lesions were added.252 It
was performed either in a single
operation or as a staged procedure, such
that patients unresponsive to anterior
cingulomotomy alone underwent a
subsequent subcaudate tractotomy.
Limbic leucotomy was mainly practiced
in the United Kingdom and generally
used less frequently than cingulomotomy
or subcaudate tractotomy. Retrospective
follow-up investigation45 in 66 cases over
a mean period of 16 months after surgery
showed improvements in 89% of patients
with OCD, 78% of patients with major
depression, and 66% of patients with
anxiety disorders (Table 2). In a later
study with a retrospectively matched
control group, blinded preoperative and
postoperative evaluation, and a mean
follow-up period of 10 years,46 marked
improvements were observed in 38% of
26 patients with OCD treated surgically,
whereas there were no evident changes
in untreated control individuals.
Evaluation of cognitive function and
memory formation showed no significant
differences between surgically treated
and control individuals, except for
moderate impairments of operated
patients in a Wisconsin Card Sort Test.46
Anterior Capsulotomy
Anterior capsulotomy dates back to the
stereotactic operation introduced by
Talairach,226 but it was first practiced on
a clinical scale by Leksell in Sweden
and Laitinen in Finland (reviewed
in Reference241) using stereotactic
thermocoagulation or focused irradiation
(ie, radiosurgery) in the anterior limb of
the internal capsule (Figure 9).48,253,254
The results in cases of chronic anxiety
(20% response) and schizophrenia
(27% response) were unsatisfactory, but
anterior capsulotomy was concluded to
provide significant improvement in
approximately 50%e70% of patients with
intractable OCD47,48,255-257 (Table 2).
The most concerning adverse effects
were transient cognitive and affective
dysfunction, observed in some cases in
the form of decreased initiative and
mental drive. These effects have been
attributed to postoperative edema,258
which is consistent with multiple long-
term assessments showing no significant
adverse effects on personality.9,259,260
Behavioral Psychosurgery
One controversial aim of targeting subcor-
tical limbic structures was the treatment of
various poorly defined behavioral disorders
subsumed under headings such as aggres-
sion, hyperreactive syndrome, or sexual
deviations (Figure 10). Several operations,
referred to by some investigators as
sedative neurosurgery, emerged from the
central observations that 1) emotional
responses (eg, feelings of fear, anxiety, or
aggression) could be elicited or
suppressed by electric stimulation of
limbic structures in conscious human
patients62,261,262 and 2) lesions in the same
regions had a taming effect on behavior in
nonhuman primates and several other
mammalian species.263-268 As pointed out
by Valenstein,6 most of these animal
studies described complex behavioral
changes, which could hardly be described
as a simple taming. However, a similar
extent of adverse effects has rarely been
reported in human patients, as described
later.

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FELIX NEUMAIER ET AL.
Amygdalotomy. Stereotactic amygdalot-
omy for the treatment of intractable
aggressive or self-mutilating behavior was
first used by Hirotaro Narabayashi and his
associates in Japan in 1961.54,i Two years
later, they reported significant
improvement or normalization of social
behavior in 85% of their initial 66
patients. A follow-up investigation of 40
of these patients in 1966 found maintained
improvements in 68% of cases.269 Similar
trials reporting rates of postoperative
improvement between 33% and 100%
were performed by Hatai Chitanondh in
Thailand,270 Balasubramaniam et al. in
India,271-273 Mempel et al. in
Poland,59,274,275 Heimburger et al. in the
United States,55,58 van Manen et al. in
the Netherlands,276,277 Kiloh et al. in
Australia,57 Vaernet and Madsen in
Denmark,56 and Hitchcock and Cairns in
Scotland278 (reviewed in
References279-281). In many cases, the
operations were performed on children
as young as 5 years old, which
contributed to a public backslash in the
following years (but see The Era of
Neuromodulation (c. 1990e2015)). The
most consistent observation in these
studies was that amygdalotomy had little
to offer for the treatment of inorganic
mental disorders but could be effective in
patients with evident brain damage or
epileptic seizures corresponding to the
expression of abnormal behavior
(Table 3). Similar findings were made by
Keijo Sano and associates at the
University of Tokyo Hospital,282,283 who
used fornicotomy (transcallosal or
stereotactic sectioning of the fornix) and
upper mesencephalic reticulotomy
(stereotactic sectioning of the most
rostral parts of the reticular formation)
(Figure 9) for sedative surgery in a few
patients. The former procedure in
particular often led to memory
impairments and outcomes were deemed
unsatisfactory, so that in 1962, these
investigators started to use bilateral
stereotactic hypothalamotomy.62,284-286
Hypothalamotomy. As described earlier,
hypothalamotomy was already practiced
by Spiegel and Wycis in the early
i
A first report on the use of “freehand” amygdalectomy in
schizophrenic patients had already been published in 1954
by Masaichi Sawa.453
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1950s,35,221,287 but the first larger cases operation, severe adverse effects such as
studies of patients with violent, aggres- vegetative crisis, lack of impulse, or visual
sive, or restless behavior came from the disturbances were observed post-
team around Sano.62 To selectively target operatively.296 However, it was the use of
the ergotropic zone in the posteromedial behavioral surgery on sexual delinquents
hypothalamus, electric stimulation was that led to a heated controversy in 1977
used to identify the area of maximum that prompted surgeons to refrain from
sympathetic response, which was further operations (but see The era of
subsequently eliminated by neuromodulation (c. 1990e2015)).
thermocoagulation.283,284 These
investigators encountered 1 postoperative
Thalamotomy. Irving Cooper at the St.
death but considered the outcome to be
Barnabas Hospital in New York was the
good or excellent in more than 95% of
first to use stereotactic thalamotomies for
the remaining 42 patients.62 Similar
the treatment of Gilles de la Tourette
results in the treatment of severe
syndrome (GTS). Between 1962 and 1969,
heteroaggression or autoaggression,
he performed ablations of the ventrolateral
restlessness, and hyperkinetic or
thalamic nucleus in 6 patients, but
destructive behavior were reported by
described only 1 illustrative case without
Schwarcz et al. in Argentinia63,288 and
providing information about the remain-
Balasubramanian et al. in India61,289,290
ing patients.297,298 A more detailed
(Table 3). The Danish surgeon
description with respect to the acute ef-
Quaade291,292 used unilateral stereotactic
fects of thalamic lesions on tics was pro-
thermocoagulation of the lateral
vided by Hassler and Dieckmann in their
hypothalamus in 3 patients with morbid
seminal article on stereotactic thalamot-
obesity and reported a significant but
omy for intractable GTS.j These
transient reduction of calorie intake and
investigators reported 70%e100%
a temporary decrease of body weight. In
subjective improvement in 3 patients
West Germany between 1962 and 1976,
treated with 10e14 coagulations in the
unilateral hypothalamotomies (often
intralaminar and medial thalamic nuclei
combined with lesions in other brain
of both hemispheres.49 A later work by
regions such as the lateral tuber
the same investigators claimed similar
cinereum or parts of the nucleus
results in 9 patients after unilateral or
infundibularis) were performed on more
bilateral surgery but made no mention of
than 70 patients with sexual deviations,
the duration of follow-up.51 Adverse
most of them either imprisoned or
effects included personality changes,
involuntarily committed to a mental
difficulties concentrating, gait problems,
institution64,66,67,293 (reviewed in
and mental confusion.49,51 Less favorable
References294,295). These operations,
outcomes were reported by Cappabianca
which took place in Hamburg (Müller
and associates,53,299 who targeted the
and associates), Göttingen (Fritz Roedler
same region in 4 patients with GTS and
and associates), and Homburg (Gerd
observed transient effects in 3 but a
Dieckmann and associates), were
sustained tic resolution only in 1 patient.
reported to provide high rates of success,
The largest case series was described by
but the objectivity and sophistication of
Babel and coworkers,300 who used
evaluation have been severely
unilateral or bilateral lesions in the zona
criticized.294,295 It is likely that they
incerta and/or thalamic nuclei of 16
resulted in a general blunting of sex
patients, several of whom experienced
drive rather than a specific reduction of
complications such as hemiparesis or
certain expressions thereof.6 Thus,
hemiballism. A case published in the
Dieckmann and associates296 also
Russian literature301 mentioned favorable
investigated unilateral or bilateral
results of stereotactic lesions in the
hypothalamotomy for the treatment of
ventrolateral thalamic nucleus but also
addiction and noted a similar reduction
reported a transient postoperative loss of
of sex drive in all 15 of their patients.
speech. The potential risk of infrathalamic
These investigators reported that the
lesions to produce permanent adverse
procedure was also associated with
increased self-control, but in 4 of the 6
patients who received a bilateral j
English translation in Reference.454
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FELIX NEUMAIER ET AL.
effects has been reported by Leckman and
associates,302 who described the fate of a
patient with GTS and OCD treated by a
combination of cingulotomy and
thalamotomy. After extension of the
thalamic lesion during a second
operation, the patient developed
sustained and severe neurologic deficits,
including disturbances in speech,
swallowing, and gait, and there was a
reemergence of tics at 8 months follow-up.
In most of the articles described,
target localization or verification was
limited to the anatomic expertise of the
surgeon, such that claims regarding the
structures destroyed should be taken
with caution. From an ethical point of
view, these operations have been criti-
cized for the lack of rationale and for
the inappropriate timing of interven-
tion. Thus, very young patients were
frequently subjected to this form of
irreversible treatment, although the
symptoms of GTS are often self-limiting
and generally decrease or remit in early
adulthood.
There are also 2 case reports303,304
describing the use of stereotactic dorso-
medial thalamotomy in 3 patients with
intractable anorexia nervosa (AN), who
reportedly achieved remission or a signif-
icant improvement in their quality of life
for at least 2e4 years after surgery.
THE ERA OF NEUROMODULATION
(C. 1990e2015)
In 1970, a book published by 2 Harvard
Medical School professors sparked a debate
on the use of surgery for behavioral modifi-
cation and renewed the sharp public criti-
cism that psychosurgery had drawn
previously. Titled Violence and the Brain, the
controversial work305 addressed the role of
acquired brain disease for abnormal
behavior and argued that pathologic
aggression was often caused by damage in
temporal lobe structures associated with
psychomotor seizures. The authors
emphasized that violent behavior was not
necessarily related to brain damage and
pointed out the importance of identifying
those cases in which expression of
pathologic behavior was accompanied by
abnormal electric activity. The book was an
instant sensation but reached an audience
still under the impression of the excesses
during the lobotomy era. In the
618 www.SCIENCEDIRECT.com
antiestablishment cultural milieu of the
1970s, the concept of surgery to modify
behavior raised concerns of government-
sponsored operations to suppress political
opponents, which were fuelled by question-
able experiments on the surgical control of
overt behavior and sexual orientation per-
formed by Robert Heath at the Tulane Uni-
versity in New Orleans.306,307 Public concern
was further raised by surfacing reports of
behavioral surgery to produce “satisfactory
obedience” and “constantly steady mood” in
children aged 5e13 years and characterized
by preoperative hyperactivity, unsteadiness,
and poor concentration.269,308 As a direct
response to these developments, the Inter-
national Society for Psychiatric Surgery was
established in 1970 during the second Inter-
national Conference on Psychosurgery in
Copenhagen.309 Intended to counter
increasing pressure from the public and “to
examine the scientific basis of
psychosurgery,” the International Society
for Psychiatric Surgery was officially
founded 5 years later with the ratification of
a constitution during the fourth
International Conference on Psychosurgery
in Madrid.309 In the United States, public
scrutiny culminated in an ethical
investigation of psychosurgery by the
National Commission for the Protection of
Human Subjects of Biomedical and
Behavioral Research.310 However, contrary
to public expectations, results were mostly
in favor of psychosurgery, discrediting
claims of frequent abuse or unethical side
effects and encouraging its use as a
treatment of last resort, not to be used in
minors, prisoners, or individuals incapable
of giving informed consent.310,311 In
Germany, public debate on the use of
hypothalamotomies in sexual delinquents
led to the appointment of a commission
comprising both supporters and opponents
at the Federal Health Office in Berlin. In
1978, the commission submitted its final
report,312 recommending the establishment
of an independent and interdisciplinary
advisory board to 1) reanalyze the available
data on previous operations, 2) establish
possible indications, 3) develop a
hypothesis-driven scientific support pro-
gram, and 4) assess future applicants for the
operation with regard to indication and
informed consent. Despite these surprisingly
positive evaluations, public opposition led to
a ban or heavy restriction of psychosurgery in
several countries, including Germany, Japan,
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LITERATURE REVIEW
SURGICAL APPROACHES IN PSYCHIATRY
and several American states.313-316 In the
late 1980s and early 1990s, only a few
centers in England,42,238 Sweden,255
the Netherlands,317 Australia, and
New Zealand318 kept investigating
psychosurgical procedures, each of them
typically focusing on a specific method
for certain indications. Criteria for
participation were handled more
stringently, requiring documentation that
intensive nonsurgical treatment had failed.
Furthermore, written informed consent
from both the patient and a family member
was usually required and operations were
preceded by detailed multidisciplinary
assessment of the case.239 It remains
unclear how common ablative
psychosurgery is in current clinical practice,
but there has been a clear decline in the
number of cases reported in the literature
and a concomitant shift toward the use of
DBS as a more reversible approach
(Figure 1 and Tables 4 and 5).
Cingulotomy and Cingulomotomy
In the United States, Scotland, and South
Korea, the most frequently reported psy-
chosurgical operation involves stereotactic
placement of lesions in the anterior
cingulate cortex (anterior cingulotomy),
and/or section of the cingulum bundle (ie,
cingulomotomy).69,70,73-75,319,320 Findings
from several small trials using magnetic
resonance imaging (MRI)-guided anterior
cingulotomy (Table 4) and a retrospective
meta-analysis of cingulotomy effects in
different psychiatric disorders257 suggest
that it may be a viable option in cases of
intractable MADs and, to a lesser extent,
OCD or GTS. Effects of the procedure
could involve compensatory changes in
the limbic system, because clinical
improvements often occur after a delay
of several months.72,73,75
Between 1998 and 2002, surgeons at the
Institute of the Human Brain in St. Peters-
burg used bilateral anterior cingulotomy for
the treatment of heroin addiction in 348
patients until the program was halted by
the Russian government (reviewed or dis-
cussed in References321-323). A retrospective
study of 187 patients followed for at least 2
years324 reported a nonrelapse rate of 45%,
with another 17% of patients being
abstinent for more than 2 years after 1 or 2
relapses in the months immediately after
surgery.

FELIX NEUMAIER ET AL.
Limbic Leucotomy
There are a few reports on the use of MRI-
guided limbic leucotomy, with the most
recent articles dating back to 2008. Two
prospective studies with follow-up periods
of 26e30 months performed at the Mas-
sachusetts General Hospital in Boston re-
ported response rates of 36% in patients
with OCD and 25%e50% in patients with
MAD, and a Chinese study of 16 patients
with MAD a response rate of 68% after 7
years (Table 4).
Thermal and Gamma Knife Capsulotomy
More favorable outcomes in patients with
OCD have been achieved with anterior
capsulotomy, which is the most common
ablative technique still used in Spain79
(reviewed in Reference325), Sweden,78,81
Brasil,84-86 Canada,326,327 China,80,83 and
Mexico.328 In its present form,
capsulotomy entails MRI-guided stereo-
tactic thermocoagulation (thermal capsu-
lotomy) or radiosurgery (Gamma Knife
capsulotomy) targeting of the anterior
third of the internal capsule (Figure 9).329
Several open-label trials performed be-
tween 1999 and 2014 showed clinical im-
provements in 48%e92% of patients with
intractable OCD (Table 4).257
Two topographic lesion analyses based
on long-term MRI data by Lippitz
et al.78,330 have addressed the relation be-
tween site and size of the capsular lesion
and clinical outcome. These investigators
identified a right-sided anatomically
defined lesion volume in the anterior limb
of the internal capsule, which appears to
be decisive for a favorable outcome in
patients treated with thermal or Gamma
Knife capsulotomy.78 These findings,
together with anecdotal evidence for
beneficial effects of unilateral
capsulotomy,331 indicate that some
patients may not require a bilateral
operation (see also Internal capsule and
ventral striatum/nucleus accumbens).
Possible adverse effects of anterior
capsulotomy include mild transient
personality changes, cognitive deficits
and memory impairments, transient
hallucinations, urinary incontinence,
seizures, and postoperative
edema.78-81,83,84 The first double-blind
randomized sham-controlled trials of
Gamma Knife capsulotomy in patients
with OCD provided further support for the
efficiency of the procedure and indicated
WORLD NEUROSURGERY 97: 603-634, JANUARY 2017
that it may even improve performance in
certain neuropsychologic domains.85,86,332
However, more recent studies333,334 also
challenge the concept that radiosurgery is
simply a less invasive form of ablation and
indicate that it may rather act by modu-
lating cellular function and preserve basic
processing in the target regions.
Some groups have also used a combi-
nation of anterior capsulotomy and cin-
gulotomy for the treatment of OCD,335
depression,336 or intractable
aggression.337,338 However, the latter
indication in particular remains highly
controversial because there is no
rationale for the use of these operations
(either alone or in combination) in
patients with aggressive behavior
(discussed in Reference339).
Stereotactic Ablation of the Nucleus
Accumbens
Based on the well-known role of the nu-
cleus accumbens for drug reinforcement
and a small series of animal experiments,
Gao et al. in 2000340 started a pilot study
on the treatment of opiate psychological
dependence by bilateral stereotactic
radiofrequency ablation of the nucleus
accumbens. Three years later, they
described their experience with the first
28 patients observed over a mean follow-
up period of 15 months and reported a
nonrelapse rate of roughly 40%. After
their publication, the technique was
rapidly taken up by other neurosurgeons
in China and it is estimated that more
than 1000 patients were operated on
within 1 year until the government
stopped the procedure in 2004.341 A
retrospective analysis of 272 detoxified
heroin addicts treated by the team
around Gao showed a 1-year nonrelapse
rate of 69.5% and a nationwide analysis of
100 patients indicated a 5-year nonrelapse
rate of 58%.341 Two large prospective
studies with postsurgical MRI lesion
verification by the same team reported 4-
year and 5-year nonrelapse rates of 53.8%
(78 patients)341 and 47.4% (60 patients),342
but it is not clear whether both studies
refer to the same population of patients.
Between 2007 and 2013, these in-
vestigators extended the indications for
surgery to alcohol dependence and
intractable AN, reporting 6-month and 12-
month nonrelapse rates of 81.8% and
63.6% in 16 alcoholics343 and almost
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LITERATURE REVIEW
SURGICAL APPROACHES IN PSYCHIATRY
complete normalization of body weight
within 12 months in 6 patients with
anorexia.344
As discussed in more detail elsewhere,
the punitive nature of drug policy and the
lack of alternative treatments in countries
such as China or Russia raise serious
doubts about the ability of drug-addicted
patients to give free and informed
consent.
DBS
With its increasing implementation for the
treatment of movement disorders,345 it is
often overlooked that DBS evolved in
parallel to stereotactic psychosurgery in
the early 1950s. Electric stimulation was
routinely used for intraoperative target
localization during ablative surgery,62,346
applied through chronically implanted
electrodes before (and for) incremental
placement of lesions347-349 or used as an
experimental form of therapy in itself 350
(reviewed in References351,352). An
important step toward the use of chronic
stimulation was the observation that
high-frequency stimulation (>100 Hz)
often resulted in an apparent inhibition of
the target area, thereby producing some
kind of functional ablation. Although DBS
was not commonly used for mental dis-
orders before 1999, it has since largely
replaced ablative techniques and hundreds
of patients have already received this form
of treatment under research protocols.
Possible adverse effects include 1) periop-
erative complications such as hemorrhage
(1.3%e4%), seizures (0.4%e2.8%), or
death (0.4%); 2) hardware-related com-
plications such as infection (2.8%e6.1%),
electrode misplacement/migration (5.1%),
or skin erosion (1.3%e2.0%); and 3)
target-specific and patient-specific side
effects of stimulation, as described
later.353 In most cases, indications for
surgery have been limited to intractable
OCD, GTS, or MAD, but a few teams
have also used DBS for the treatment of
drug addiction, eating disorders, and
certain forms of severe heteroaggression
or autoaggression. Although all of these
indications are discussed in the following
sections, the substantive literature on
DBS for OCD or MAD is summarized in
Table 5. A (to our knowledge) complete
list of articles presenting first-hand data
on neuropsychiatric DBS is presented in
Supplementary Table 1.
619

FELIX NEUMAIER ET AL.
Internal Capsule and Ventral Striatum/Nu-
cleus Accumbens. A Belgian team around
Bart Nuttin was the first to replace ablative
surgery in patients with OCD by bilateral
high-frequency stimulation of the anterior
limb of the internal capsule. In 1999, they
reported beneficial effects in 3 of 4 pa-
tients,354 a finding reproduced by a later
study with improved assessment and
blinded crossover design (alternating
stimulation on/off periods) performed by
the same investigators (Table 5).
However, because of the unusually high
amplitudes required to achieve beneficial
effects, the stimulator batteries had to be
replaced every 5e12 months. This factor,
together with anatomic findings and
clinical observations in patients treated
with anterior capsulotomy, led a German
team around Volker Sturm to specifically
target a more posterior site, with
electrode contacts located in ventral
aspects of the anterior limb of the
internal capsule and in the nucleus
accumbens. In a pilot study of 4 patients
with OCD, these investigators observed
best results during unilateral stimulation
of the right nucleus accumbens, whereas
no further improvement was achieved
with bilateral stimulation.355 These
findings are in line with the results by
Lippitz et al (described in Thermal and
Gamma Knife capsulotomy) that lesions
in the right hemisphere are decisive for
successful anterior capsulotomy. In a
subsequent double-blind sham-controlled
crossover study of unilateral DBS in the
right nucleus accumbens by Huff et al., 5
of 10 patients with OCD reached at least a
partial response, but only 1 of them was
classified as a full responder111 (Table 5).
Moreover, a case report of 2 patients by
Juan Barcia and colleagues356 observed
most pronounced relief of OCD
symptoms during unilateral stimulation
of the left nucleus accumbens, although
in both patients, additional electrodes
were implanted in the subthalamic
nucleus (but see Subthalamic nucleus).
Favorable results in patients with OCD
have also been observed in several case
reports and small-scale open or controlled
trials of bilateral DBS in the anterior limb
k
The term “ventral capsule/striatum” was introduced by
Greenberg et al. in 2006 to refer to their target site
located at the junction of ventral aspects of the anterior
limb of the internal capsule and the nucleus accumbens.90
620 www.SCIENCEDIRECT.com
of the internal capsule,87,89,357 the nucleus
accumbens,110,358 or the ventral capsule/
striatumk,90,92,94,95,359(Table 5) (reviewed
in References360-362).
Based on the antidepressant effect of
stimulating these regions in patients with
OCD and concomitant depres-
sion,90-92,358,363 they have also been tar-
geted for the treatment of intractable MAD
(Table 5) (reviewed in References97,364).
However, despite encouraging results in
the first open-label studies, a recent pro-
spective randomized trial of DBS in the
ventral capsule/striatum for treatment-
resistant depression failed to show sig-
nificant differences between active and
control groups 16 weeks postoperatively.96
This finding may be attributable to the
typical overestimation of beneficial
effects in uncontrolled trials or other
factors such as suboptimal stimulation
parameters, inconsistent targeting, lack
of statistical power, or insufficient
duration of follow-up. After 24 months
of open-label continuation, the same study
observed response and remission rates in
the order of 20% (Table 5).
Adverse effects observed during DBS in
the internal capsule or nucleus accumbens
included transient sadness, euphoria or
anxiety, olfactory and gustatory sensa-
tions, verbal perseveration, signs of
cognitive or behavioral disinhibition, and
sustained fatigue or weight gain.88,365
Apart from OCD and MAD, internal
capsule and/or nucleus accumbens DBS
has been used in a few patients with
intractable GTS366-368 (reviewed in Refer-
ence),369 AN344,370,371 (reviewed in
References372,373), and alcohol374-376 or
heroin377 psychological dependence
(reviewed in References322,372,378-380). The
bioethical questions raised by some of
these procedures have been discussed
elsewhere.381-385
Subthalamic Nucleus. Based on the obser-
vation that subthalamic stimulation often
decreased compulsive symptoms in pa-
tients with Parkinson disease and coex-
isting severe OCD,386-389 Mallet et al.
investigated bilateral DBS of the sub-
thalamic nucleus for the treatment of
OCD.386 In 2008, they published results
from a multicenter double-blind sham-
controlled crossover study of 16 patients
assessed over a period of 3 months post-
operatively, showing a significant and
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reversible reduction of obsessive-
compulsive symptoms with no apparent
changes of neuropsychological function in
patients under active compared with sham
stimulation113 (Table 5). However, 11 of the
patients experienced serious adverse
effects, such as stimulation-induced tran-
sient depression with suicidal ideations,
anxiety, or hypomanic states. Although
these findings highlight the potential risks
of subthalamic DBS, 3 patients also re-
ported depression and anxiety during
sham stimulation. A later report by Cha-
bardes et al. of 4 patients (2 of whom also
participated in the study by Mallet et al.)
with at least 6 months of follow-up
showed a marked treatment response
(>70% reduction in Yale-Brown Obsessive
Compulsive Scale score) in 3 patients and
a partial response in 1 patient.114 As
mentioned in the preceding section,
Barcia et al.356 described 2 patients with
OCD implanted with electrodes in the
nucleus accumbens and subthalamic
nucleus to screen for the optimal target
region. Different stimulation
combinations were applied in a
randomized fashion to show that
bilateral stimulation of either structure
produced similar effects; the most
favorable clinical response in both
patients was achieved during combined
unilateral stimulation of the left nucleus
accumbens and left subthalamic nucleus.
Inferior Thalamic Peduncle. Promising re-
sults in patients with OCD have also been
reported by Jiménez-Ponce et al. using
bilateral stimulation of the inferior
thalamic peduncle, which contains con-
nections between the thalamus and orbi-
tofrontal cortex (Table 5). The same
investigators described a single case of
successful treatment in a patient with
intractable depression.390 Adverse effects
were reportedly limited to reversible
states of anxiety with tachycardia,
perspiration, and hypertension observed
in all patients during stimulation in a
region (anterior hypothalamus) below the
target structure and transient confusion
observed in 1 patient during stimulation
in a region above the target structure.
Given the few patients in these studies
by 1 research group, the results clearly
have to be taken with particular caution.
 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

Subgenual and Anterior Cingulate. Mayberg

and associates from Canada97 were the Table 5. Results of Third-Generation Neuromodulatory Psychosurgery in Patients with
first to describe positive effects of DBS in Obsessive-Compulsive Disorder or Major Affective Disorder
the white matter tracts adjacent to the Obsessive-
subgenual cingulate cortex (Brodmann Compulsive Major Affective
area 25) in patients with intractable Disorder Disorder
MAD. The approach was based on Follow-Up,
functional neuroimaging studies showing months Rm R NR Rm R NR
involvement of this region in acute
sadness, depression, and antidepressant Internal capsule (anterior limb) (%) — 55 45 — — —
treatment effects. After their report in Gabriels et al., 2003 87
33 — 2 a
1 — — —
2005, the region has been targeted in
Nuttin et al., 200388 21 — 3a 1 — — —
several small-scale open-label trials,
89 a
reporting response rates in the order of Abelson et al., 2005 23 — 1 3 — — —
60%, with almost half of the responders ¼ Total 6 5 — — —
being in remission (Table 5) (reviewed in
Ventral capsule/striatum (%) 6 62 38 25 40 60
References391,392). To investigate the
90 a
relationship between stimulation Greenberg et al., 2006 36 — 4 4 — — —
parameters and clinical response, Goodman et al., 201091 12 — 4e 2 — — —
Rajamannar Ramasubbu and 92 a
Greenberg et al., 2010 36 — 7 5 — — —
associates106 performed a pilot study with
93 f g
double-blind stimulus optimization phase Malone, 2010 37 — — — 6 12 5
and open-label follow-up in 4 patients. Roh et al., 201294 24 2k 4a 0 — — —
These investigators reported that longer
Tsai et al., 201295 15 — 2a 2 — — —
pulse widths were associated with short-
96
term improvement and positive mood re- Dougherty et al., 2014 24 — — — 6f 7g 23
sponses in 3 patients, 2 of whom showed a ¼ Total 2 21 13 12 19 28
clinical response after 6 months of open-
Subgenual cingulate (%) — — — 28 58 42
label follow-up. A Spanish team around
Dolors Puigdemont described the results Mayberg et al., 200597 6 — — — 2b 4c 2
98 d c
of a 6-month randomized sham-controlled McNeely et al., 2008 12 — — — 3 4 2
trial in 5 implanted patients who had Lozano et al., 200899 12 — — — 7b 11c 9
already experienced full remission. These 100 c
investigators’ data show a significant ef- Hamani et al., 2009 12 — — — — 11 9
101 d c
fect of active stimulation, with higher Kennedy et al., 2011 36 — — — 10 15 5
depression scores during sham stimula- Holtzheimer et al., 2012102 24 — — — 7b 11c 1
tion.393 Surprisingly, these favorable 103 c
findings have been contested by recent Lozano et al., 2012 12 — — — — 6 15
discontinuation of a prospective Puigdemont et al., 2012104 12 — — — 4d 5c 3
multicenter randomized trial of Merkl et al., 2013 105
6 — — — 2 f
2 g
4
subgenual cingulate DBS in 30 patients 106 c
Ramasubbu et al., 2013 6 — — — — 2 2
with treatment-resistant depression.364
Discontinuation was to the result of low ¼ Total — — — 35 71 52
probability of a successful study outcome Inferior thalamic peduncle (%) — 100 0 — — —
(17.2%), as determined by a futility 107 h
Jiménez-Ponce et al., 2009 12 — 5 0 — — —
analysis 6 months after surgery. Given
the early termination and the delay of Jiménez-Ponce et al., 2013108 36 — 3h 0 — — —
antidepressant effects observed in ¼ Total — 8 0 — — —
previous trials on subgenual cingulate
Nucleus accumbens (%) — 38 62 5 48 52
DBS97,99,104 (see especially Reference)394
109 1 j
or cingulotomy,72,73,75 further Bewernick et al., 2010 12 — — — 0 5 5
investigations with longer follow-up are Rm, remission, defined as 17-Item Hamilton Depression Rating Scale (HDRS-17) score 8; HDRS-17 score 7;
b d

required to confirm these findings. f

In 2010, Mimi Israel and associates395
described a patient with intractable
depression who experienced complete
remission of comorbid AN over a period
of 3 years after initiation of subgenual
Montgomery-Asberg Depression Rating Scale (MADRS) score 10; 128-Item Hamilton Depression Rating Scale (HDRS-
28) score 10; kYale-Brown Obsessive Compulsive Scale (Y-BOCS) score 15; R, response, defined as a
35% reduction
in Y-BOCS score; c
50% reduction in HDRS-17 score; e
35% reduction in Y-BOCS score and Y-BOCS score 16;
g

50% reduction in MADRS score; h
50% reduction in Y-BOCS score; j
50% reduction in HDRS-28 score; NR, no or
partial response.
Continues

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 LITERATURE REVIEW
FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

GTS.405,411-414 Two studies comparing the

Table 5. Continued effects of thalamic versus pallidal DBS
Obsessive- found that both procedures showed
Compulsive Major Affective approximately equal effectiveness, with
Disorder Disorder no further reduction in tic severity during
Follow-Up,
simultaneous stimulation.405,412 A case
months Rm R NR Rm R NR series of 5 patients with GTS stimulated
in different subregions of the globus
110 a
Denys et al., 2010 21 — 9 7 — — — pallidus internus concluded that the
Huff et al., 2010111 12 — 1a 9 — — — most convincing improvements were
Bewernick et al., 2012 112
48 — — — 1 1
5 j
6
observed during stimulation of the
anteromedial region.415
¼ Total — 10 16 1 10 11 Bilateral DBS of the globus pallidus
Subthalamic nucleus (%) — 50 50 — — — internus has also been used for the treat-
Mallet et al., 2008 113
3 — 7 h
9 — — — ment of involuntary self-injurious behavior
in patients with Lesch-Nyhan syndrome
Chabardes et al., 2013114 6 — 3a 1 — — — (LNS). This indication emerged from the
¼ Total — 10 10 — — — serendipitous observation that pallidal
stimulation for the control of dystonic
Rm, remission, defined as 17-Item Hamilton Depression Rating Scale (HDRS-17) score 8; HDRS-17 score 7; Mont-
b d f
movements in a patient with LNS led to
gomery-Asberg Depression Rating Scale (MADRS) score 10; 128-Item Hamilton Depression Rating Scale (HDRS-28)
score 10; kYale-Brown Obsessive Compulsive Scale (Y-BOCS) score 15; R, response, defined as a
35% reduction in
disappearance of self-mutilating
Y-BOCS score; c
50% reduction in HDRS-17 score; e
35% reduction in Y-BOCS score and Y-BOCS score 16; g
50% behavior.416 There have been several
reduction in MADRS score; h
50% reduction in Y-BOCS score; j
50% reduction in HDRS-28 score; NR, no or partial promising case reports about DBS in this
response. region,417-419 describing motor
improvements and complete remission
of self-injurious behavior associated with
cingulate DBS. Three years later, Lipsman DBS in a patient with refractory GTS. LNS after follow-up periods between 2.5
et al. reported results from a Canadian The electrodes were implanted into the and 5 years. It is unknown if the behav-
phase 1 pilot trial on the safety of intralaminar and medial thalamic nuclei ioral effects are mediated via the basal
subgenual cingulate DBS in 6 patients already targeted for thalamotomy by ganglia circuits targeted for dystonia or
with AN, half of whom had reached a Hassler and Dieckmann in 1970. A later represent a nonspecific epiphenomenon
body mass index greater than their case study of 3 patients by the same of pallidal stimulation. One study
historical baseline after 9 months of investigators402 reported complete observed unilateral recurrence of symp-
follow-up.396-398 cessation of all major motor and vocal toms after contralateral lead fracture,420
Side effects of subgenual cingulate DBS tics after a follow-up period between 8 possibly indicating a lateralization of
included moderate to mild transient months and 5 years. Adverse effects neurobehavioral deficits in LNS. The
memory impairments, gastrointestinal included stimulation-induced sedation in most commonly reported adverse effects
(nausea, vomiting, or diarrhea) and all 3 patients and changes in sexual drive of pallidal DBS include feelings of
musculoskeletal (tremor, spasms or stiff- or function in 2 patients. DBS in the same constant tiredness and fatigue, transient
ness) problems, psychiatric changes or nearby regions of the thalamus in pa- nausea, and anxiety as well as 1 case of
(agitation, irritability), and a transient tients with GTS has also been used by permanent but well-tolerated pronation/
decline of manual motor speed.98,99,102,103 surgeons in Italy,403 France,404,405 supination bradykinesia of the left
The anterior cingulum bundle and China,406 and Germany.407 Two extremities.404,405,415
cingulate cortex, which were targeted in prospective randomized double-blind A related target region reported to show
most cingulomotomy and cingulotomy crossover trials have since reported sig- efficiency in a few patients with GTS is the
operations, have only recently been nificant improvements in tic frequency limbic aspects of the globus pallidus
investigated as a DBS target for treating and severity 1e12 months after externus. Based on ticlike stereotyped
the affective component of chronic surgery.408,409 movements observed after bicucullin
neuropathic pain (reviewed in Refer- microstimulation of this region in
ence399). In 11 patients followed up for 13.2 Globus Pallidus. Another target that has nonhuman primates,421,422 Vilela Filho
months, bilateral stimulation in this been investigated for DBS in patients with et al.423 hypothesized that GTS is a clinical
region was reported to provide GTS is the posteroventral part of the expression of hyperactivity in the globus
significant improvement in quality of life globus pallidus internus. Since the first pallidus externus and prefrontal area.
and physical functioning.400 short-term case report in 2002,410 multiple Promising results from an ongoing
small clinical trials have provided support double-blind prospective controlled study
Thalamus. In 1999, Visser-Vandewalle and for the effectiveness of unilateral or by the Brazilian group have been pub-
associates401 described a marked bilateral DBS in this region for treating lished only in abstract form.424,425 A more
reduction of tic severity during thalamic tics and behavioral symptoms of detailed report of their technique is

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FELIX NEUMAIER ET AL.
available for 1 patient treated in Argentina
who received bilateral DBS for 2 years.426
Benefits in tic severity were observed
within 24 hours after starting stimulation
and reached a plateau after 10 days, such
that the patient reported a perceived
global reduction of tics by 80%.
Objective assessment of global tic
severity, anxiety, depression, and global
functioning showed clinical
improvements of 36.4%e58.8% after 3
months and 36.4%e82.3% after 6
months of follow-up. After battery
exhaustion after 2 years of stimulation,
there was a significant but partial loss of
therapeutic effects (residual improvement
of 9%e82.3%), supporting the beneficial
action of DBS in this region and indicating
persistence of some effects even without
stimulation.
Hypothalamus. Based on the report by
Quaade (described in Hypothalamotomy)
and findings from animal experiments, the
lateral hypothalamus has been proposed
as a target for DBS in patients with morbid
obesity (reviewed in Reference427). A pilot
study of 3 patients observed over a mean
follow-up period of 35 months confirmed
the general safety of the procedure and
provided some evidence for the possible
effectiveness of this approach.428 An
interesting side effect observed during
DBS of the ventral hypothalamus for the
same indication was improvements in
certain memory functions.429
In addition, DBS of the posteromedial
hypothalamus has been investigated as a
restorative treatment for disruptive
behavior in a few cases in Italy,430,431 Ger-
many,432 and Spain.433 The targeted brain
volume in these cases has been the same
as that previously used by Sano et al. for
stereotactic radiofrequency ablation.
Hernando et al.433 reported alleviation of
mental retardationeassociated drug-
resistant aggression in a patient during
low-frequency hypothalamic stimulation,
which is in contrast to the high-frequency
stimulation used in other studies430-432
and to the commonly assumed mecha-
nism of action of DBS. Available data434
indicate that adverse effects are limited to
increased thresholds for simple detection
of cold and warm stimuli and mild
orthostatic arterial hypotension as a result
of enhanced excitatory sympathetic drive
on the cardiovascular system. However,
WORLD NEUROSURGERY 97: 603-634, JANUARY 2017
these operations have generally been used
as an alternative to major restraint
measures in patients with severe self-
injurious behavior or aggression second-
ary to epilepsy, brain damage, or mental
retardation. This group of patients may
lack the intellect or self-awareness to
communicate possible adverse effects.
They also often lack the capacity to provide
informed consent, which is typically ob-
tained by their family. Given the nature of
aggressive disorders, this transfer of con-
sent poses a high risk for conflicts of in-
terest and may threaten the principle of
patient autonomy. It is therefore imperative
that those in the field remain vigilant about
the transparency and ethical rigor of new
studies of behavioral surgery, especially in
patients unable to give informed consent.
Other Targets. There are several reports
about DBS in additional targets, although
in most cases, evidence for the effective-
ness remains at best anecdotal. Sartorious
and associates from Germany435 reported
remission of treatment-resistant depres-
sion in a single patient after 4 months of
stimulation in the lateral habenula, a
structure with prominent limbic and
cortical inputs that directly projects to
dopaminergic, serotonergic, and norad-
renergic systems. Promising results in 6 of
7 patients with depression have also been
achieved by a German team around
Thomas Schlaepfer436 using DBS in the
superolateral branch of the medial
forebrain bundle. The latter study is
notable because the onset of
antidepressant effects was rapid and
clinical improvements detectable within
days after onset of stimulation. Adverse
effects included headache, vision
disturbances, increased sweating, and
dizziness.436 The team around Volker
Sturm437 described a single case of
successful amygdaloid DBS in a patient
with autism disorder and life-threatening
self-injurious behavior. These in-
vestigators reported improvements in
autism symptoms and self-injurious
behavior during stimulation in the baso-
lateral amygdala without adverse effects
over a follow-up period of 24 months. No
beneficial effects were observed during
stimulation in the paralaminar or central
amygdala or the supra-amygdaloid pro-
jection system (which includes the inferior
thalamic peduncle). For obvious reasons,
www.WORLDNEUROSURGERY.org
LITERATURE REVIEW
SURGICAL APPROACHES IN PSYCHIATRY
the ethical problems addressed in the
preceding section apply to this case as
well.
Some investigators have described an
alternative approach to neuromodulation
in patients with refractory depression,
termed epidural prefrontal cortical stimu-
lation (EpCS), which entails bilateral or
unilateral placement of electrodes over the
anterior frontal and midlateral prefrontal
cortex438 or over the left dorsolateral
prefrontal cortex,439 respectively. A
prospective sham-controlled single-blind
feasibility study of 12 patients treated by
EpCS in the left dorsolateral prefrontal
cortex439 detected no significant effects
but a trend toward efficiency with the
active stimulation group. The same study
reported profound antidepressant effects
during the open-label phase, with 4 pa-
tients achieving remission and 5 patients
achieving
50% improvement on the 17-
Item Hamilton Depression Rating Scale
“at some point during the study”. How-
ever, as has been pointed out else-
where,440 the outcome was less impressive
at the study end point and the single-
blinded study design makes the results
prone to potential rater bias. Considering
the lack of information on adverse effects,
further studies are clearly required before
EpCS can be regarded as a promising
treatment for refractory depression.
CONCLUSIONS AND FUTURE DIRECTIONS
Public perception of ablative psychosur-
gery has largely been determined by the
indiscriminate application of frontal leu-
cotomies between 1935 and 1950, a time
characterized by the urgent need for
effective and cost-efficient psychiatric
treatment. Devised and often practiced by
surgically untrained physicians, these early
freehand leucotomies were crude and
highly variable techniques, which often
resulted in serious and disabling adverse
effects. Since then, several neurosurgeons
have developed more targeted approaches,
aimed at reducing the incidence of com-
plications and personality changes. Their
work, together with a drastic change in the
selection of patients, provided the
groundwork for present-day psychosur-
gery, which is practiced by multidisci-
plinary teams and assessed based on
standardized rating scales. Although most
current psychosurgical procedures still
623

FELIX NEUMAIER ET AL.
lack level I evidence with randomized
controlled trials, a large body of level II
evidence argues for their safety and effi-
ciency in treating intractable OCD and
MAD. Several other indications have been
investigated as well, but most of them
remain controversial and some lack a clear
scientific rationale. Although DBS could
provide the opportunity for a more
reversible and adjustable form of psycho-
surgery, its use for mental disorders is still
at an investigational stage. Given that the
therapeutic mechanism of this form of
treatment is essentially unknown, its
superiority to ablative surgery as well as its
long-term reversibility remain to be
scientifically proved. In this context, the
rapid replacement of ablative psychosur-
gery by DBS in the last quarter century can
be explained neither by an inadequate
risk-benefit ratio of ablative surgery nor by
evidence for a better risk-benefit ratio of
DBS. As discussed in more detail else-
where,441,442 it was largely driven by a
complex interplay between the legacy of
early ablative operations and some (un-
founded) denigration of present-day
lesional surgery as well as a general
euphoria surrounding the use of DBS. In
particular, the euphoria surrounding the
use of DBS raises several important as-
pects that need to be pointed out. On the
one hand, public perception of DBS has
clearly helped to overcome part of the
stigma associated with psychosurgery and
its reversibility, if proved, could alleviate
some of the inherent ethical obstacles.
However, on the other hand, unfounded
enthusiasm may interfere with evidence-
based clinical decisions and could create
unrealistic expectations in patients and
doctors alike. Although this observation
applies to all forms of medical treatment,
it remains a particular challenge in the
field of psychosurgery, in which the past
has shown that public perception can
rapidly change and is influenced by a va-
riety of social, historical, moral, and cul-
tural issues.
The perceived safety has led to an
expansion of experimental DBS to in-
dications such as aggression or drug
addiction, which were considered dubious
in the preceding lesional area and
contributed to its decline. Although this
strategy may be justified in patients with
severe treatment-refractory and life-
threatening conditions, it is imperative to
624 www.SCIENCEDIRECT.com
remain vigilant about the scientific ratio-
nale, transparency, and ethical rigor of
such studies, because they may otherwise
jeopardize the entire field. Given recent
considerations on the use of DBS for
“shaping individual morality”443 or
enhancing cognition in healthy
individuals,444,445 it is not surprising that
some investigators have expressed concern
of a slippery slope in the future use of DBS
for indications beyond intractable forms of
illness.442,446 To address these issues,
several ethical requirements and
guidelines have been proposed,447-450 the
most recent one authored by a worldwide
group of neurosurgeons, neurologists,
psychiatrists, and ethicists.451 In their
statement entitled Consensus on Guidelines for
Stereotactic Neurosurgery for Psychiatric
Disorders, they emphasize the experimental
character of DBS in psychiatry and
explicitly state that psychosurgery “should
never be performed for political, law
enforcement or social purposes, but with
therapeutic intent aimed at the restoration
of normal function and amelioration of
distress and suffering.” These investigators
furthermore highlight the requirement for
multidisciplinary cooperation, careful
selection of treatment-resistant patients
capable of giving informed consent, and
appropriate long-term follow-up based on
established rating scales. They address the
need for dissemination of all results, both
positive and negative, to allow for a
balanced assessment of efficiency and
safety. This point is of utmost importance,
because the excessive reliance on case re-
ports and small-scale studies makes the
field vulnerable to the risk of publication
bias.452 Creation of an independent
comprehensive registry of all initiated
treatments (both trials and individual
cases), as was already recommended in the
late 1970s, thus remains one of the
preconditions for responsible and
transparent research practices.
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Conflict of interest statement: This work was supported by
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Received 19 August 2016; accepted 1 October 2016
Citation: World Neurosurg. (2017) 97:603-634.
http://dx.doi.org/10.1016/j.wneu.2016.10.008
Journal homepage: www.WORLDNEUROSURGERY.org
Available online: www.sciencedirect.com
1878-8750/$ - see front matter ª 2016 Elsevier Inc. All
rights reserved.
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FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

APPENDIX

Supplementary Table 1. Summary of Articles Providing Firsthand Data on Neuropsychiatric Deep Brain Stimulation
Indication Target Reference Design n

OCD ALIC BL Nuttin et al. 1999 CS 4

OCD ALIC BL Nuttin et al. 2003 RCT 4
OCD ALIC BL Anderson and Ahmed 2003 CR 1
OCD ALIC BL Gabriëls et al. 2003 CS 3
OCD ALIC BL Abelson et al. 2005 RCT 4
GTS ALIC BL Flaherty et al. 2005 CR 1
OCD NAc UL Sturm et al. 2003 CS 4
OCD þ MAD NAc BL Aouizerate et al. 2004 CR 1
OCDþS NAc UL Plewnia et al. 2008 CR 1
OCD NAc UL Huff et al. 2010 RCT 10
OCD NAc BL Denys et al. 2010 RCT 16
OCD þ MAD NAc BL Franzini et al. 2010 CR 2
OCD NAc/STN UL Barcia et al. 2014 RCT 2
MAD NAc BL Schlaepfer et al. 2008 RCT 3
MAD NAc BL Bewernick et al. 2010 CS 10
MAD NAc BL Grubert et al. 2011 CS 10
MAD NAc BL Bewernick et al. 2012 CS 11
GTS NAc Kuhn, Lenartz, Mai, et al. 2007 CR 1
GTS NAc BL Neuner et al. 2009 CR 1
DA NAc BL Kuhn, Lenartz, Huff, et al. 2007 CR 1
DA NAc BL Mueller et al. 2009 CR 3
DA NAc Kuhn et al. 2011 CR 1
DA NAc BL Kuhn et al. 2014 CR 2
AN NAc BL Wu et al. 2013 CS 4
AN NAc BL Wang et al. 2013 CR 2
OCD þ AN VC/VS BL McLaughlin et al. 2013 CR 1
MAD VC/VS BL Malone et al. 2009 CS 15
MAD VC/VS BL Malone 2010 CS 17
MAD VC/VS BL Dougherty et al. 2014 RCT 30
OCD VC/VS BL Greenberg et al. 2006 CS 8
OCD VC/VS BL Greenberg et al. 2010 CS 12
OCD VC/VS BL Tsai et al. 2012 CS 4
OCD VC/VS BL Corveleyn, Nuttin, and Gabriëls 2013 CR 1
OCD VC/VS BL Roh et al. 2012 CS 6
OCD VC/VS BL Goodman et al. 2010 RCT 6
OCD VC/VS UL Hiss et al. 2015 3

Continues

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Supplementary Table 1. Continued

Indication Target Reference Design n

OCD STN BL Mallet et al. 2002 CR 2

OCDþP STN BL Fontaine et al. 2004 CR 1
OCD STN BL Mallet et al. 2008 RCT 16
OCD STN BL Chabardès et al. 2013 4
OCD ITP BL Jiménez-Ponce et al. 2009 CS 5
OCD ITP BL Jiménez-Ponce et al. 2013 CR 3
MAD ITP BL Jiménez-Ponce et al. 2005 CR 1
MAD SGC BL Mayberg et al. 2005 CS 6
MAD SGC BL Kennedy et al. 2011 CS 20
MAD SGC BL Lozano et al. 2008 CS 20
MAD SGC BL Lozano et al. 2012 CS 21
MAD SGC BL McNeely et al. 2008 CS 6
MAD SGC BL Neimat et al. 2008 CR 1
MAD SGC UL Guinjoan et al. 2010 CR 1
MAD SGC BL Holtzheimer and Mayberg 2010 CR 1
MAD SGC BL Holtzheimer et al. 2012 12
MAD SGC BL Puigdemont et al. 2012 CS 8
MAD SGC BL Puigdemont et al. 2015 RCT 5
MAD SGC BL Ramasubbu et al. 2013 UCT 4
MAD SGC BL Merkl et al. 2013 RCT 6
MAD þ AN SGC BL Israël et al. 2010 CR 1
Lipsman et al. 2013 UCT 3
MAD lHb BL Sartorius et al. 2010 CR 1
MAD MFB BL Schlaepfer et al. 2013 CS 7
GTS Th BL/UL Kuhn et al. 2012 CR 3
GTS Th BL/UL Huys et al. 2014 CS 8
GTS Th BL Visser-Vandewalle et al. 1999 CR 1
GTS Th BL Visser-Vandewalle et al. 2003 CR 3
GTS Th BL Bajwa et al. 2007 CR 1
GTS Th BL Lee et al. 2011 CR 1
GTS Th BL Servello et al. 2008 CT* 18
GTS Th BL Ackermans et al. 2006 CR 1
GTS Th BL Ackermans et al. 2011 RCT 6
GTS Th BL Maciunas et al. 2007 RCT 5
GTS Th/GP BL Houeto 2005 1
GTS Th/GP BL Welter et al. 2008 RCT 3
A Hyp BL Kuhn et al. 2008 CR 1
A Hyp BL Franzini et al. 2007 CR 2
A Hyp BL Franzini et al. 2005 CR 2

Continues

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FELIX NEUMAIER ET AL. SURGICAL APPROACHES IN PSYCHIATRY

Supplementary Table 1. Continued

Indication Target Reference Design n

A Hyp BL Hernando et al. 2008 CR 1

MO Hyp BL Hamani et al. 2008 CR 1
MO Hyp BL Whiting et al. 2013 UCT 3
A Am BL Sturm et al. 2013 CR 1
A (LN) GP BL Abel et al. 2014 CR 1
A (LN) GP BL Cif et al. 2007 CR 1
A (LN) GP BL Deon et al. 2012 CR 1
A (LN) GP BL Piedimonte et al. 2015 CR 1
A (LN) GP BL Taira, Kobayashi, and Hori 2003 CR 1
GTS GP BL Dehning et al. 2008 CR 1
GTS GP BL Hwynn et al. 2012 CR 1
GTS GP BL Martinez-Fernandez et al. 2011 CS 5
GTS GP UL Dong et al. 2012 CR 2
GTS GP BL Ackermans et al. 2006 CR 1
GTS GP BL Diederich et al. 2005 CR 1
GTS GP BL Kefalopoulou et al. 2015 RCT 15
GTS GP BL van der Linden et al. 2002 CR 1

OCD, obsessive compulsive disorders; ALIC, anterior limb of the internal capsule; BL, bilateral stimulation; CS, case series; RCT, randomized controlled trial; CR, case report; GTS, Gilles de la
Tourette syndrome; NAc, nucleus accumbens; UL, unilateral stimulation; MAD, major affective disorder; S, schizophrenia; STN, subthalamic nucleus; DA, drug addiction; AN, anorexia
nervosa; VC/VS, ventral capsule/striatum; P, Parkinson disease; ITP, inferior thalamic peduncle; SGC, subgenual cingulate; UCT, uncontrolled trial; lHb, lateral habenula; MFB, medial
forebrain bundle; Th, thalamus; GP, globus pallidus; A, aggression; HT, hypothalamus; MO, morbid obesity; Am, amygdale; LN, Lesch-Nyhan syndrome.
*On-off and sham-off only in first 9 patients.
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