Introduction
Psychosurgery existed long before the advent of the frontal lobotomy. There is an
archeological evidence of human skull trephinations as long as 5000 years ago in Europe
and Northern Africa which were performed on the basis of the psychological and spiritual
understandings of that time.[22] Gottlieb Burckhardt (1836 to 1907), a Swiss psychiatrist, was the first physician
to perform modern psychosurgery, in which the contemporary theories about brain-behavior
and brain-language relationships were interconnected and practically applied to patient
care.[77] However, the landmark text was dedicated to the Portuguese neurologist Egas Moniz
(1874 to 1955)[77] who proposed that the prefrontal region of the brain was the “psychic center” of
a person. Moniz instructed his surgical partner, Almeida Lima, to develop the “leukotome,”
a device that functioned as a neurosurgical apple corer, and they performed the first
prefrontal leukotomy in 1935.[8]
[22] Moniz's initial trial resulted in no deaths or serious morbidities, which were seen
in the other treatments available for psychological disorders, such as insulin coma
or electric shock therapy. The leukotomy appeared as a viable alternative and tens
of thousands of these procedures were performed, however, without adequate research
demonstrating the safety of the procedure or a substantial benefit for the patient.
Freeman and Watts developed a modification, the “transorbital leukotomy” and performed
it in ∼600 patients.[27] Outcomes were generally favorable, although the procedure was associated with significant
morbidity. Further modifications of the leukotomy resulted in “open” techniques and
included bilateral inferior leukotomy, bimedial frontal leukotomy, orbital gyrus undercutting,
cerebral topectomies, and anterior cingulotomies.[19] It was revealed that these procedures were not being used as ultima ratio in otherwise
untreatable patients with reported cases in which little investigation was done before
the operations. Neurosurgeons began to think of the procedures as imprecise and potentially
dangerous and psychiatrists thought of them as ineffective and unnecessarily invasive.
With the introduction of the psychoactive drugs in 1954 and the development of further
drugs, it soon became clear that these pharmaceutical therapies were safer and often
more effective than the surgical procedures.[22] However, psychosurgical procedures continued to be performed in the United States
and other countries and some clinicians believed that it was underused.[22] The development of stereotactic neurosurgery, which allowed more precise anatomical
targeting, led to safer and more effective means of operating on brain diseases. Also,
there was an expanded understanding of the neural circuitry involved in the pathogenesis
of neurologic and psychiatric disorders. Success in the field of movement disorders
with ablation of deep brain targets encouraged the development of similar ablative
procedures for treating mental illness. These operations included the limbic leukotomy,
subcaudate tractotomy, anterior internal capsulotomy, and cingulotomy.[21]
Now, with the marked development of modern imaging and concept driven psychiatric
interventions, newer surgical therapies focusing on neural modulation were introduced,
including the electrical stimulation of the vagus nerve (VNS) and deep brain stimulation
(DBS).[6] These methods were found more acceptable from the ethical standpoint because they
are relatively noninvasive and reversible.[56] With ongoing laboratory and clinical researches introducing new therapeutic targets,
the spectrum of psychiatric disorders that are treated with DBS continues to grow.
Overview of the Neuroanatomy of Behavior
Emotional Brain
The emotional brain consists of the regions involved in the Papez circuit (the hippocampus,
the fornix, the mammillary bodies, the mammillothalamic tract, the anterior thalamic,
the subgenual cingulate (SCG) [Brodman area 25 or Cg25], the parahippocampal gyrus,
and the entorhinal cortex) with the amygdala, the hypothalamus, the nucleus accumbens
(NAcc), and the orbitofrontal cortex[47] ([Fig. 1]). The emotional circuits do indeed form a border or connection point between the
neocortex (mediating external stimuli) and the hypothalamic and brainstem structures
(mediating internal stimuli).[38] Major pathways of the emotional system are demonstrated in [Fig. 2]. The cingulate cortex is considered as the receptive cortical region regarding emotional
stimuli. The cingulate cortex projects to the hippocampus, which then projects to
the hypothalamus by the fornix to elicit behavioral, endocrine, and autonomic responses
to emotional stimuli.[49]
[64] The mammillary bodies receive afferent projections from the hippocampus via the
fornix, and then project to the anterior thalamus nucleus to provide efferents to
the cingulate gyrus.[38] The hippocampal formation, located under the parahippocampal gyrus along the medial
temporal lobe, is made up of the hippocampus, the dentate gyrus, and the subiculum.
Its primary functions are learning, memory, and recognition of novelty.[38] Afferents are from the entorhinal cortex, the septal nuclei (indirectly via the
entorhinal cortex and directly via the fornix), the amygdala, supramammillary area
of the hypothalamus, and the brainstem (raphe nuclei, locus coeruleus, and ventral
tegmentum).[99] The primary efferent projection of the hippocampal formation is the fornix.[99] Ventrally to the foramen Monro, the fornix divides at the anterior commissure into
precommissural (projecting to septal nuclei) and postcommissural fibers (projecting
to mammillary body, hypothalamus, septal region, medial frontal cortex, anterior thalamus,
and tegmentum). The majority of fibers that enter the fornix originate in the subiculum,
which in turn receives extensive input from the hippocampus and dentate gyrus.[47] Damage to the hippocampus results in inability to convert recent memories into long-term
memories and inability to store them. The amygdaloid complex is made up of several
nuclei that are grouped into the basolateral (receive the lateral olfactory tract
projections) and the corticomedial groups (receive indirect olfactory projections
via the pyriform cortex).[47] The largest input to the amygdala is from the insular cortex. Other afferents are
from hypothalamus, hippocampus, thalamus, sensory association cortex, locus coeruleus,
ventral tegmental area, and nucleus basalis of Meynert (nbM). The nbM provides the
major efferent cholinergic projections to the amygdala and the cerebral cortex, thus
it is important in the diffuse cortical activation and shows marked degeneration in
Alzheimer's disease (AD).[38] The primary efferents from dorsomedian amygdala travel via the stria terminalis
to the anterior and ventromedian hypothalamus (VMH) and to the stria terminalis nuclei.
The primary efferents from the basolateral amygdala travel via ventral amygdalofugal
projections to the lateral hypothalamus (LH), septal region, mediodorsal thalamus
(MD), and the nucleus of the diagonal band.[99] Also, the amygdala projects to the neostriatum, ventral striatum, and cerebral cortex.
Via these connections, the amygdala generates drive of activity and modulates endocrine
activity, sexuality, reproduction, and autonomic responses.[38] Bilateral destruction of the amyglada can produce the Klüver–Bucy syndrome (docility,
hyperorality, and hypersexuality) and decreased conditioned fear response and decreased
ability to recognize the meaningfulness of facial and vocal expressions of anger in
others.[64]
Figure 1 A drawing demonstrating the anatomy of the limbic system.
Figure 2 A schematic drawing demonstarting the major pathways of the limbic system.
Hypothalamus
The hypothalamus governs body homeostasis by modulating the activity of the autonomic
nervous system, the endocrine system, and the limbic system. It also has a role in
emotional behavior. Hypothalamic efferents reach the cortex via a relay in the anterior
thalamic nuclei.[99] The hypothalamic anatomy and function are demonstrated in [Fig. 3].
Figure 3 A drawing demonstrating the hypothalamic anatomy and function.
Frontal Lobe
Although a simplified model, frontal lobe circuits can be divided into several groups[55]:
-
The motor circuit: originates from the sensorimotor cortex and projects to the dorsal
striatum. This pathway is involved in the mediation of somatic movement and converges
on the basal ganglia.
-
Dorsolateral circuit: originates in the dorsolateral prefrontal cortex (DLPFC) and
projects to the head of the caudate and medial putamen. This pathway influences behavior
and personality and has executive responsibilities involving activities such as formulating
plans, maintaining attention and concentration, and changing problem-solving strategies
when needed. The dorsolateral prefrontal syndrome is characterized by impairment of
executive functions, clinically evidenced by executive dysfunction such as perseveration.
-
Orbitofrontal circuit: originates in inferolateral prefrontal cortex and projects
to the medial caudate nucleus and NAcc. This pathway is the center of the biological
control of inhibition, emotions, and drive states. It is also part of the dopamine-driven
reward circuit of the brain (especially NAcc) and it is activated in drug addicts.
The orbitofrontal syndrome results in features that seem to have afflicted Phineas
Gage as well as a countless number of lobotomy patients. These features include disinhibition,
irritability, and lability.[16]
-
Anterior cingulate circuit: originates in the anterior cingulate gyrus and projects
to the ventromedial striatum. This pathway forms a major cortical-limbic pathway.
The anterior cingulate syndrome in its most dramatic manifestation results in akinetic
mutism and profound apathy.[7] These frontal lobe regions can be organized into two functionally related compartments:
the associative dorsal compartment (DLPFC + lateral orbitofrontal cortex [LOFC]) and
the limbic ventral compartment (cingulate + subgenual gyrus + medial orbitofrontal
cortex [MOFC]).[55]
Cortical-Subcortical Pathways
The basal ganglia are the initial target for all frontal lobe circuits and an understanding
of basal ganglia structure and function is essential. The basal ganglia comprise a
complex processing system that interprets diffuse cortical signals in the striatum
and returns information to the cortex through the globus pallidus, substantia nigra,
and thalamus. The dorsal component is related with the associative loop. Most of the
information in the dorsal compartment flows through central striatal regions, such
as the head of the caudate and portions of the NAcc core. The primary cortical association
of the limbic loop is the ventral component. Most of the information in the ventral
component flows through ventromedial striatal regions, such as the NAcc core and the
NAcc shell.[55] It is important to note that lesions of basal ganglia structures within the frontal
circuitry can give rise to disorders that resemble frontal lobe lesions themselves.
Although not as prevalent or extensively studied, such “striatal syndromes” also exist
in which disinhibition and executive dysfunction have been documented.[14]
The thalamocortical (TC) loop is thought to be the basic building block of behaviors
that span from motor activity to psychiatric phenomena. Each TC loop consists of a
specific region of cerebral cortex and its reciprocal excitatory connections with
a specific target within the thalamus. In parallel with this direct, topographically
organized TC activity is a circuit that involves the same regions of cortex and thalamus
but is directed through the basal ganglia.[55] The TC and the cortico-striato-thalamo-cortical (CSTC) loops and their association
with the basal ganglia represent a pivotal area in which dysfunction can lead to disordered
behavior.[48] Furthermore, such an area provides a rich anatomic nexus to surgically modulate
brain function. Thus, it stands to reason that these TC/CSTC loops are important when
considering DBS for psychiatric disease. Evidence from functional neuroimaging and
stereotactic lesioning procedures suggests that the most pertinent of the CSTC loops
in psychiatric illness are the prefrontal and limbic loops.[55] The dorsolateral prefrontal (associative) circuit involves the DLPFC and LOFC and
their associated projections via the anterior internal capsule to the thalamus. This
associative loop is believed to be integral to processes involving working memory,
spatial memory, and executive function. It is thought to play a role generally in
cognitive dysfunction, including patient insight about symptoms and ability to suppress
negative feelings and painful stimuli across several psychiatric disorders. The psychomotor
retardation of severe depression may also be a consequence of dysfunction of this
circuit.[55] The limbic loop consists mainly of the MOFC, the anterior cingulate, SCG, the agranular
insular cortex and their associated projections via the anterior internal capsule
to the caudate, and NAcc. Summary of the main TC/CSTC circuits within human brain
is demonstrated in [Fig. 4].
Figure 4 Schematic diagram illustrating the main cortico-striato-thalamo-cortical circuits
within human brain. This figure shows an arrangement of the motor (green), associative
(blue), and limbic (red) pathways. Neurons from the sensorimotor cortex project to
the posterolateral putamen. The GPi is the primary output nucleus of the basal ganglia
to the cortex via the ventrolateral thalamus. The associative circuit originates in
the dorsolateral prefrontal and lateral orbitofrontal cortices, which project to the
caudate nucleus and anteromedial portion of the putamen. From the striatum it projects
to the dorsomedial region of the GPi and anteromedial parts of the GPe and STN to
converge on the GPi and back to the cortex via the ventral anterior nuclei of the
thalamus. The limbic circuit starts in the hippocampus, amygdala, and paralimbic and
limbic cortices and projects to the ventral striatum (ventral portion of the caudate
and putamen, including NAcc). The ventral striatum projects to the limbic portion
of the GPe and medioventral STN and ventral GPi and to the cortex via the mediodorsal
nucleus of the thalamus. A, anterior; AC, associated cortex; CR, centrorostral; DL,
dorsolateral; DR, dorsorostral; DMpc, dorsomedial parvocellular; DMmc, dorsomedial
magnocellular; GPe, globus pallidus externus; GPi, globus pallidus internus; LC, limbic
cortex; PV, posteroventral; P, putamen; SMC, sensorimotor cortex; V, ventral; VM,
ventromedial; VL, ventrolateral; Vim, ventro-intermedius; VA, ventroanterior.
Mechanisms of Treatment
VNS
VNS is approved in the United States for treating chronic or refractory depression
in patients not showing an adequate response after four antidepressant treatments.
It works by having an electrode attached from a pacemaker implanted on the left side
of the chest to the left vagus nerve in the neck. Although its mechanism of action
remains unclear, it has been suggested that impulses from the vagus nerve are transmitted
to the following regions: locus coeruleus, raphe nuclei, and nucleus tractus solitarius,
which then project to other regions of the brain, ultimately affecting the limbic
system.[15] It is shown that parasubthalamic nucleus (PSTN) axons have massive projections to
the region of a column of parasympathetic preganglionic neurons in the brainstem,
starting in the salivatory region of the pons and proceeding caudally in the medial
part of the nucleus of the solitary tract and in rostral and intermediate regions
of the dorsal motor nucleus of the vagus nerve.[31] The STN and PSTN also are related to dorsolateral regions of the parvocellular reticular
nucleus between the nucleus of the solitary tract and the nucleus ambiguus, along
with the periambiguus region and a zone lateral to it where vagal fibers exit the
brainstem.[31] Also, more rostrally, the STN provides a sparse to moderate terminal field to ventromedial
regions of the caudoputamen, and it extends into adjacent regions of the NAcc. This
can explain the relation between the VNS and the effects upon the NAcc.[69] Histological studies on animal models showed markedly increased c-fos expression
in forebrain and brainstem regions. On the other hand, increased expression of cAMP
response element-binding protein and decreased expression of FosB were seen in NAcc;
both effects lead to increased motivation for natural rewards.[69] These findings support the idea that VNS therapy acts directly by stimulating brainstem
structures and indirectly by regulating the activity of neurons in limbic and cortical
regions involved in mood regulation.[52] Single photon emission computed tomography (SPECT) imaging studies after VNS showed
increased regional cerebral blood flow (rCBF) in the left middle frontal gyrus (BA
46) and reduced rCBF in the hippocampus/amygdala, left caudate, dorsal brainstem,
and other areas.[126] Also, significant reductions in the right DLPFC, left SCG, bilateral ventral anterior
cingulate, right dorsal anterior cingulate, bilateral amygdala, left hippocampus,
right thalamus, left caudate, and the brainstem were found.[126] Medial temporal findings included reduced rCBF in the amygdala and left hippocampus.
These studies showed that VNS may be a less focal method of electrical stimulation.
In fact, the lack of focality of this technique might be associated with the limited
clinical results. It might also be used in combination with another focal method of
brain stimulation. Many reports had shown good to moderate effects of VNS in the treatment
of depression,[15] migraine,[11] obsessive-compulsive disorder (OCD) (by effects on NAcc and improving the dysfunction
of the reward system in these patients),[18] AD (by stimulating the hypoactive locus coeruleus and the limbic circuit),[86] and eating disorders (by modulating cortico-limbic circuits and eating centers).[20] Therefore, VNS may be a promising form of treatment; however, the present evidence
supporting its use is still limited.
Ablative Surgery
Many psychiatric disorders have some common symptoms and similar grouping, and may
share similar pathological pathways.[65] For this reason, these disorders may derive significant benefit from procedures
targeting a common anatomical pathway. For example, anterior cingulotomy, which involves
bilateral lesions to the anterior cingulate gyrus, thus severing the cingulum bundle,
was reported to be significantly effective for the treatment of bipolar disorder (BD),
depression, and schizoaffective disorder.[65] Ablative techniques, including open microscopic resection, stereotactic electrode
ablation, and frameless stereotactic radiosurgery, all shares the characteristic of
being irreversible. Stereotactic electrode ablation is performed by radio frequency
electrocoagulation and has the advantage of the ability of microelectrode recording
and stimulation for the confirmation of the target location. Stereotactic radiosurgery
is noninvasive, however, lacks the important electrophysiological confirmation of
the target.[28]
DBS
The biological mechanisms of action remain unclear; three primary explanations have
been proposed for the biological mechanisms of DBS[122]: (1) it silences stimulated neurons, (2) it modulates neuronal network activity
and neurotransmission, and (3) it induces long-term synaptic changes (plasticity).
The first explanation is based on the observation that, functionally, DBS induces
a similar therapeutic effect to that of a lesion of the stimulated area. Evidence
for the second hypothesis has been provided by animal and imaging studies showing
that DBS-evoked activity propagates throughout the associated neuronal network to
modulate neuronal activity and neurotransmitter efflux in distal nuclei. The third
has been inferred from the delayed time course of therapeutic effects of stimulation.
It is thought that low-frequency stimulation (LFS) activates neurons,[5] whereas high-frequency stimulation (HFS) results in neuronal inhibition.[23] Extracellular recording revealed spontaneous activity caused by spindle wave generation.
Immediately after HFS, spindle wave activity was seen to be abolished, as noted by
the lack of neuronal activity.[118] However, recent data show that the effects of HFS are complex, and can cause both
inhibition and excitation. Tawfik et al[118] demonstrated that HFS elevates extracellular glutamate and adenosine levels, which
was not inhibited by treatments that block axonally dependent exocytotic release of
neurotransmitter from neurons. By contrast, NAcc HFS increases rhythmicity in the
cortex, which could be beneficial for the treatment of OCD and depression.[83] Other possible mechanisms of action for HFS DBS include local neuronal inhibition
with concomitant activation of surrounding fibers, thus resulting in increased synaptic
output and activation of afferent axon terminals.[58] Recordings of local field potentials from the STN in patients with Parkinson's disease
after neurosurgery showed strong increases in β (15 to 30 Hz) oscillatory activity
in the STN when the patients were without dopaminergic medication, which were subsequently
suppressed with both medication and therapeutic effective STN stimulation of more
than 70 Hz.[35] This suggests that some symptoms of Parkinson's disease might be linked to an abnormal
and potentially deleterious synchronization of basal ganglia output in the β frequency
band of ∼20 Hz.[35] It also strongly suggests that DBS stimulation could work through normalizing pathological
oscillations and synchronization of neuronal subpopulations in the β band in the closed
loop networks involved in motor control.[32] A hypothesis that takes into account all of these clinical observations is the hypothesis
of jamming (i.e., overwriting of pathological activity by introducing a frequency
that interferes with the pathological message).[58] The local effects of stimulation on neuronal activity, in turn, affect the flow
of information throughout the network.[122] The delayed time course of therapeutic effects of stimulation indicates that sudden
disruption of pathological network activity may provide only a minor component of
the therapeutic mechanism of action.[72] It has been hypothesized that DBS for neuropsychiatric disease has both short- and
long-term components resulting from complementary but distinct mechanisms of action.
Sudden symptom reprieve results from the immediate disruption of pathologic activity
in cortico-striatal-pallido-TC circuitry, whereas enduring improvements occur only
after long-term changes in synaptic effectiveness and/or connectivity have had time
to take effect.[72] Thus, the normalization of abnormal (hyper/hypo)metabolic changes may result from
activity-dependent mechanisms that work together to mediate neuronal plasticity (including
formation of new synapses, growth of new connections, and up- or down-regulation of
information flow at the synapse). Over time, this may ultimately result in global
changes in neuronal network processes that mediate the enduring therapeutic effects
of DBS.[72] However, clinical observation shows that symptoms relapse immediately within minutes
if the impulse generator is switched off. These observations do not exclude synaptic
plasticity caused by DBS but speak probably against fixed molecular changes. This
indicates that the mechanism of DBS effect is more complicated and many aspects are
not yet clear.
Surgical Applications
The most common surgical (ablative or DBS) targets for the treatment of psychiatric
diseases are demonstrated in [Fig. 5]. It must be remarked that these are experimental approaches for most indications.
Figure 5 A schematic drawing demonstrating the common surgical (ablative or DBS) targets for
the treatment of psychiatric diseases.
Major Depressive Disorder (MD)
MD is one of the most disabling and common diagnoses throughout psychiatric disorders.
It represents a current prevalence of 5 to 10% of the general population and up to
20 to 25% for the lifetime period.[107] Neurobiological correlates of depressive illness can be grouped into the following
three main components: cortical, subcortical, and limbic[115] ([Fig. 6]). The cortical component appears to give rise to the psychomotor and cognitive aspects
of depressive symptoms and consists of the prefrontal cortex, the dorsal portion of
the anterior cingulate gyrus, and areas of the premotor cortex. This cortical component
has access to the striatum and then creates a feedback loop via the thalamus. The
subcortical component involves the affective experiencing of depressive symptoms,
including anhedonia and sadness. This aspect of the neural circuit includes, among
others, SCG, orbitofrontal cortex, and limbic structures in the brain involved with
negative emotions, including the NAcc and amygdala. This component also interacts
with the striatum and subsequently the thalamus to create a loop. Brain imaging researches
of functional blood flow studies (positron emission tomography and functional magnetic
resonance imaging) support depressive illness involving decreases in cortical regions
activity with relative increases in limbic areas activity.[97] The limbic component is thought that it regulates the cortical and subcortical circuits
and includes the critical neuroendocrine aspects of depressive symptoms via inhibitory
projections to these circuits.[56] This “modulating pathway” involves the amygdala, the pregenual anterior cingulate
cortex, and the hypothalamic-pituitary-adrenal axis.
Figure 6 Neural circuitry of MD and DBS targets (dotted line).
Conventional treatment includes psychotherapy and many types of antidepressant drugs;
however, over 60% of treated patients respond unsatisfactorily, and almost one-fifth
becomes refractory to these treatments at long-term follow-up.[2] Therapy failure can lead to a life-threatening situation illustrated by the high
number of suicides occurring in up to 15% of individuals.[2] To identify the surgical candidate, patient must meet criteria for MD, must be in
a current major depressive episode (MDE) as determined by the Structured Clinical
Interview for DSM-IV Axis I Disorders-Patient Edition and have a minimum score of
20 on the Hamilton Rating Scale for Depression-17.[82] Essentially, the inclusion criteria required duration of at least 1 year for the
current MDE and treatment resistance as defined as failure to respond to a minimum
of four different treatments, including antidepressant pharmacotherapy of sufficient
dose and duration, evidence-based psychotherapy, and electroconvulsive therapy.[82] In an open-controlled multicenter European study, successful response has been described
in 53% of the patients, with complete remission in 33%.[113] VNS has shown low effectiveness rates immediately postoperatively and at short-term
follow-up.[113] However, its beneficial effect at long term in a substantial amount of patients,
together with its low number of unwanted side effects, makes this method an attractive
treatment for patients suffering from MD. Ablative surgical procedures for the treatment
of MD include lobotomy/leucotomy, orbital and cortical undercutting, cingulotomy,
subcaudate tractotomy, and limbic leucotomy. In the literature review of Leiphart
and Valone,[65] cingulotomy was reported as being significantly more effective for the treatment
of depression (77% improvement) than frontal leukotomy alone (60% improvement), frontal
leukotomy combined with cingulotomy (69% improvement), and subcaudate tractotomy (60
to 70% improvement).[4] Nowadays, seven main DBS targets of interest are reported ([Table 2]): SCG,[68] NAcc,[112] ventral caudate/striatum,[76] inferior thalamic peduncle,[45] lateral habenula,[109] globus pallidus internus (GPi),[57] and the cerebellum.[37] Lozano et al[70] reported DBS of SCG in 20 patients with MD. In this open label case series study,
they proposed that the SCG may be able to act as a fulcrum to modulate the activity
of both frontal cortex and limbic system and normalization of hyperactivity in the
SCG may represent a marker of antidepressant response.[81] In their case series, they reported that 60% cases responded to stimulation and
35% patients met criteria for remission.[70] On the other hand, Malone et al[76] reported 53.3% of cases responders to stimulation and 40% remission after ventral
caudate/striatum DBS. It is also important to mention the case series of Heath et
al[37] in 1979, in which they treated six MD patients with cerebellar DBS. They reported
that 83% of the patients showed significant improvement without necessity of postsurgery
medication.[37]
Table 2
Summary of DBS Targets for Depression and Outcomes
|
Author
|
No. of Patients
|
Target
|
Study Type
|
Outcome
|
|
Lipsman et al[68]
|
20
|
Subcallosal gyrus
|
Open label
|
53% response and 40% remission in HDRS17
|
|
Schlaepfer et al[112]
|
3
|
Nucleus accumbens
|
Double blind
|
Mean 78% reduction in HDRS24
|
|
Malone et al[76]
|
15
|
Ventral caudate/striatum
|
Open label
|
53% response and 40% remission in HDRS24
|
|
Jiménez et al[45]
|
1
|
Inferior thalamic peduncle
|
Uncontrolled case study
|
80% reductionin HDRS24
|
|
Sartorius et al[109]
|
1
|
Lateral habenula
|
Uncontrolled case study
|
Total remission
|
|
Kosel et al[57]
|
1
|
Globus pallidus internus
|
Uncontrolled case study
|
50% reductionin HDRS24
|
|
Heath et al[37]
|
6
|
Cerebellum
|
Retrospective
|
83% improvement (no scales)
|
DBS, deep brain stimulation; HDRS, Hamilton Depression Rating Scale.
Bipolar Disorder (BD)
BD is a complex disorder defined by the presence of mania (i.e., bipolar I disorder
BD-I]) and hypomania (bipolar II disorder [BD-II]) alternating with depression.[84] Compared with MD, BD seems to present with an earlier age of onset, more frequent
episodes, lower probability of recovery, greater chronicity and illness duration,
higher rate of suicidality, atypical features (e.g., hypersomnia), greater neurocognitive
impairment, and suboptimal response to conventional antidepressant medications.[84] The refractory nature of these symptoms and of depression, in particular, has led
to research exploring a surgical solution to debilitating and resistant disease. The
International Society for Bipolar Disorders Task Force recently defined treatment
response of BD as >50% improvement in the core DSM criteria for depression.[121] Lipsman et al[68] suggested that treatment-resistant BD, and therefore candidacy for DBS procedures,
can be defined as a disease state that is nonresponsive to adequate trials of monotherapy
with lithium or lamotrigine, as well as lithium or lamotrigine in combination with
at least one anticonvulsant or antipsychotic drug. Although well established in MD,
there are still no defined indications for surgery in BD and it is mainly regarded
by the treating physician's own apprehension and individual evaluation of each patient's
status.[68] In treatment-resistant cases of BD, VNS was found to have positive effect on the
mood with documented good response of the patients.[79] In a retrospective analysis using the subset of 25 patients with BD-I or BD-II diagnoses
from a larger trial, the short- and long-term (up to 2 years) effects of VNS on bipolar
and unipolar depression were similar.[93] In a recent review of Leiphart and Valone[65] of ablative psychosurgical treatments they evaluated patients of BD operated with
cingulotomy or frontal leukotomy. Cingulotomy was reported as significantly more effective
for the treatment of BD (85% symptom free) compared with frontal leukotomy (33% symptom
free). Spangler et al[116] published their results of their retrospective case series study after performing
bilateral cingulotomies in five patients with BD; two patients were responders, two
had a less significant improvement, and one did not respond to treatment. There were
no long-term complications associated with the procedures.[116] Recent studies indicate a hyperactivation of subcortical structures, specifically
the SCG, in depressed patients that corrects after treatment with pharmacotherapy
as well as DBS.[30] This supports the existence of functionally coupled cortical-subcortical loops that
govern mood and its alteration. The ability of patients who underwent SCG DBS to return
to work, establish goals, and reassimilate into their families could represent this
new ability to modulate their response to negative stimuli, both internal and external.
In a prospective study, Bewernick et al[9] used the NAcc as a target in 10 treatment-resistant depressed patients and achieved
in 50% significant reductions in depression scale scores at 1-year follow-up. In other
open-label study by Malone et al,[76] 15 patients underwent DBS of the ventral caudate/striatum, with 40% achieving a
remission at follow-up after more than 6 months. These results indicate that there
may not be a single best target for surgical modulation, but instead several targets
may exist along a dysfunctional cortico-striato-thalamic loop.
General Anxiety Disorder (GAD)
GAD is the most commonly diagnosed anxiety disorder, wherein the patient's intensity,
duration, or frequency of anxiety is far out of proportion to the actual likelihood
or impact of a feared event.[2] Compared with other anxiety disorders, GAD has chronic anxiety, oftentimes without
provocation.[2] Most of the surgically managed cases of GAD were treated by ablative means.[65] Surgical treatment options were anterior callosotomy, cingulotomy, frontal leukotomy
alone, frontal leukotomy combined with cingulotomy, and subcaudate tractotomy (innominatomy).
Frontal leukotomies consisted of stereotactic focal lesions in the medial frontal
lobe to interrupt frontothalamic and hypothalamic connections and did not consist
of total frontal disconnection.[65] Although only few patients underwent anterior capsulotomy, results from literature
review suggested that anterior capsulotomy was significantly more effective for the
treatment of GAD (91.6% improvement) than cingulotomy (66.6% improvement), anterior
callosotomy (23% improvement), and subcaudate tractotomy (41% improvement).[65]
Obsessive Compulsive Disorder (OCD)
OCD is a psychiatric illness in which intrusive thoughts or impulses (obsessions)
generate anxiety that is relieved through the engagement in ritualistic or repetitive
behaviors (compulsions). This is because performance of compulsions has an anxiolytic
effect. OCD is relatively common, with a lifetime prevalence of 2 to 3%.[103] Standard therapeutic options consist of selective serotonin reuptake inhibitors
and cognitive behavioral therapy.[43] However, 20 to 40% of patients with OCD have persistent symptoms leading to chronic
functional impairment.[95] Based on these findings, distinct neuronal circuits have been implicated in symptoms
of OCD involving feedback loops between the cortex, striatum, and thalamus. A multicircuit
hypothesis of OCD states that the primary pathogenic mechanism is a dysregulation
of the basal ganglia and limbic striatal circuitry working in concert with portions
of the orbitofrontal and anterior cingulate cortex. Simplified, one can postulate
the following three components to this model ([Fig. 7])[115]: (1) The excitatory cortico-thalamic pathway via the anterior limb of the internal
capsule (ALIC). (2) The inhibitory CSTC loop serves as a counterweight to the excitatory
positive feedback loop. (3) The component linking portions of the limbic circuits.
These connections are hypothesized to contribute to the affective anxiety component
of OCD symptoms. Bringing together these three components of the circuit, OCD symptoms
occur when there is an abnormal positive feedback in the orbitofronto-thalamic circuit
(# 1), that is, in turn, inadequately inhibited or modulated by the CSTC loop (# 2).
One would then expect OCD symptoms to appear when the CSTC loop is abnormally decreased
(too little inhibition), or when orbitofronto-thalamic activity is abnormally increased
(too much excitation). From a therapeutic standpoint, increasing activity of the CSTC
loop or decreasing activity of the orbitofronto-thalamic loop would be expected decreasing
symptoms of OCD. Lastly, decreasing activity in the limbic component of the circuit
(# 3) would decrease the distressing negative affects associated with obsessions.[115] Indications for the surgical treatment include verifying the diagnosis of OCD. Also,
the OCD must have been present for at least 5 years and patients must have been treatment
resistant, defined as less than 35% improvement on the Y-BOCS after the different
medical treatment regimens and complete cognitive-behavioral psychotherapy.[42] Surgical ablative techniques include: anterior capsulotomy, anterior cingulotomy,
frontal or limbic leukotomy, and subcaudate tractotomy.[65] However, clinical results were found to be more effective with anterior capsulotomy
than with the other methods,[65]
[87] with an improvement rate ranged between 64 and 73%.
Figure 7 Neural circuitry of obsessive compulsive disorder and DBS target (dotted line).
Greenberg et al[33] recently reviewed the combined long-term results from four centers in which the
VC/VS target is used. Response rates improved as the target was shifted posteriorly,
to within a millimeter of the posterior border of the anterior commissure, as the
fiber bundle being targeted grows more compact as it courses posteriorly.[66] The refinement in target selection was attended by an increase in the percentage
of patients manifesting ≥35% reductions in Y-BOCS scores (from 33 to 75%). As the
inferior anteromedial STN receives limbic and associative cortical input via CSTC
circuits originating in the OFC,[44] Mallet et al[75] reported Y-BOCS score reductions of 25% or more in 75% of patients with OCD after
anteromedial STN DBS. However, there were several serious adverse events, resolved
either spontaneously or promptly with adjustment of stimulator settings.[75] Electrical stimulation of the inferior thalamic peduncle (ITP) could reduce OCD
symptoms via effects propagated along the OFC and ventromedial striatum projections
entering the thalamus. Jiménez-Ponce et al[44] stimulated the ITP bilaterally, documenting Y-BOCS score reductions of at least
35% as well as dramatic global assessment of function increases in all patients. Moreover,
Huff et al[42] performed unilateral NAcc DBS in 5 patients with OCD and reported good results with
at least a 25% reduction in their Y-BOCS OCD symptom scores after 1 year. Studies
and clinical results of DBS in OCD are summarized in [Table 3].
Table 3
Summary of DBS for Obsessive-Compulsive Disorder and Outcomes
|
Author
|
No. of Patients
|
Target
|
Study Type
|
Outcome
|
|
Greenberg et al[112]
|
26
|
VC/VS
|
Crossover double-blind multicenter
|
35% reduction in Y-BOCS in 70% of patients
|
|
Mallet et al[75]
|
18
|
Anteromedial STN
|
Crossover double-blind multicenter
|
25% reduction in Y-BOCS in 75% of patients
|
|
Jiménez et al[44]
|
5
|
Inferior thalamic peduncle
|
Open label
|
35% reduction in Y-BOCS
|
|
Huff et al[42]
|
5
|
Unilateral NAcc
|
Double-blind sham-controlled crossover
|
25% reduction in Y-BOCS
|
DBS, deep brain stimulation; VC/VS, ventral capsular/ventral striatal; Y-BOCS, The
Yale–Brown Obsessive Compulsive Scale; STN, subthalamic nucleus; NAcc, nucleus accumbens.
Tourette's Syndrome (TS)
TS is a neuropsychiatric disorder characterized most prominently by childhood onset
of changing motor and vocal tics.[88] The tics are typically rapid, stereotyped movements, and/or vocalizations and many
resolve completely by the late teens. Motor tics typically involve the face, head,
and upper body. Vocal tics include grunting, sniffing, or barking that are associated
with contractions of the oropharynx and diaphragm.[88] For many TS patients their tics will remit after adolescence. However, in a significant
number of patients, tics persist into adulthood and for some, they become disabling.
Embarrassment from the tics can result in social isolation and failed relationships.[117] Severe motor tics can be quite painful and result in joint dislocation, cervical
radiculomyelopathy, and fractures.[102] The basal ganglia and related CSPTC pathways are thought to mediate the pathophysiology
of TS.[94]
It is hypothesized that patients with TS may have disinhibition of afferent TC signals
or impaired inhibition at the cortical level. This disinhibition of excitatory neurons
in the thalamus may, for example, result in the hyperexcitability of cortical motor
areas and production of tics.[14] Target sites included the frontal lobe (prefrontal lobotomy and bimedial frontal
leucotomy), the limbic system (limbic leucotomy and anterior cingulotomy), the thalamus,
and the cerebellum.[1]
[114]
[119] Combined ablative approaches have also been tried, such as anterior cingulotomies
plus infrathalamic lesions. The studies indicated that no single approach showed to
be superior in the treatment of TS.[119] Moreover, the results have often been unsatisfactory, or major adverse effects such
as hemiplegia or dystonia have occurred.
Indications for the surgical treatment by DBS in TS include the following[88]
[89]: confirmed diagnosis of TS by strict DSM-IV criteria; a Yale Global Tic Severity
Scale (YGTSS) of ≥35/50 for at least 12 months and the motor tic subscore ≥15; age
≥25 years to ensure a stable degree of severity and low probability of spontaneous
improvement; failed trials of medications from 3 different classes: an α-adrenergic
agonist, dopamine antagonists, and a benzodiazepine, if the tic is focal, failed trial
of botulinum toxin treatment; patients who do not have head banging tics that would
damage the stimulation hardware.
Implantation of electrodes in three target areas have proved to be effective: the
centro-median-parafascicular (CM-PF) complex of the thalamus,[36] the internal segment of the GPi,[1]
[80] and the ALIC.[24] The greatest experience in the DBS treatment of TS has been assembled in the thalamus;
internal ventro-oral nucleus, centromedian nucleus, and parafascicular nucleus. In
a large open prospective study involving 18 patients treated with thalamic DBS, the
average improvement rate for tic symptoms was around 70%, as measured using the most
frequently employed scale, the YGTSS.[114] Recently, the same group published the 24-month results of 15 of the 18 patients,
documenting continued amelioration of the symptoms.[100] Martínez-Fernández et al[80] targeted the posteroventral and anteromedial subregions of GPi, and documented responses
of 54 and 37%, respectively. On the other hand, Flaherty et al[24] performed ALIC stimulation in a single case and reported 25% decrease in YGTSS.
Studies and clinical results of DBS in TS are summarized in [Table 4].
Table 4
Summary of DBS Targets for Tourette's Syndrome and Outcomes
|
Author
|
No. of Patients
|
Target
|
Study Type
|
Outcome
|
|
Porter et al[100]
|
18
|
CM-PF
|
Open prospective
|
70% reduction in YGTSS
|
|
Martínez-Fernández et al[80]
|
5
|
Posteroventral GPi
Anteromedial GPi
|
Open label
|
Posteroventral GPi: 54% reduction in YGTSS
Anteromedial GPi: 37% reduction in YGTSS
|
|
Flaherty et al[24]
|
1
|
ALIC
|
Uncontrolled case study
|
25% reduction in YGTSS
|
DBS, deep brain stimulation; CM-PF, centro-median-parafascicular complex; YGTSS, Yale
Global Tic Severity Scale; GPi, globus pallidus internus; ALIC, anterior limb of internal
capsule.
Severe Aggressive Behavioral Disorders
Intermittent explosive disorder (IED) is a psychological illness characterized by
episodes of impulsive aggression that are disproportionate to the provocation.[12] The root of such behavior involves a disturbance to the emotional circuitry of the
brain.[17] Almost all patients with IED have brain damage, which is usually traumatic in nature
and occurs in the right frontobasal cortex. This damage is associated with a reduction
in serotonin binding in the region.[25] Mpakopoulou et al[91] described current perspectives on amygdalotomy. In their literature review they
determined improvement rates of aggression after bilateral amygdalotomy between 60
and 85%.[91] In a retrospective study, Kim et al[51] reported long-term follow-up of two patients with aggressive disorders in which
they performed bilateral stereotactic amygdalotomy and subcaudate tractotomy. They
found a decline in the Overt Aggression Scale scores at 2-week and 7-year follow-up
visits from 8 to 2, with improvement in social behavior.[51] DBS of the posterior hypothalamus has also been described in case reports as a means
of controlling intractable aggressive disorders, and showed complete elimination of
self-mutilation.[62] Based on the main role of the orbitofrontal cortex in generating explosive episodes,
recently Maley et al[74] performed DBS targeting the orbitofrontal projections to the hypothalamus in a woman.
Although results lacked immediate improvement, after 2 years the patient reported
absence of violent outbursts or physical altercations with marked socialization without
the need of any sedation or antipsychotic drugs.[74]
Schizophrenia
Schizophrenia is characterized by symptoms including hallucinations, delusions, disorganized
thoughts, incoherent speech, neglected personal hygiene, and disrupted cognitive and
social abilities among others. Psychosurgery of schizophrenia is still performed on
the ablative basis. However, in cases of uncontrollable violent behavior in schizophrenic
patients DBS of the posterior hypothalamus may show clinical improvement of the symptom
of aggression.[26] There was a statistically significant difference in reported outcomes based on the
stereotactic procedure performed for schizophrenia. Patients having cingulotomy had
the best reported outcomes (56.5% response), followed by anterior callosotomy (48.5%
response).[65] Significant improvement was not seen after frontal leukotomy and subcaudate tractotomy.
However, the best reported outcome for cingulotomy was poor in comparison with the
other disorders.[65]
Substance Addiction
Addiction or substance dependence is a chronic relapsing disease characterized by
a strong psychological and physical dependence, resulting in a withdrawal syndrome
when use of the drug is stopped.[71] Functional imaging studies have shown that, when an individual takes a psychoactive
substance, dopamine is released in the NAcc, which causes “the high” state.[54]
[71] By an increased dopamine release in the NAcc, the inhibition of the output neurons
is decreased, which causes activation of the reward system.[54] However, although that the mesolimbic dopaminergic system activation causes reward
behavior and the dopaminergic system is considered an indicator for reward, the exact
mechanism is still not clear. The feeling of well-being produced by activation of
the reward system can be seen as positive reinforcement. Negative reinforcement involves
escaping from or avoiding withdrawal symptoms, which occur after cessation of the
substance use.[54] Impairment of inhibitory control and decision making is seen due to the dysfunction
of the dopaminergic neurotransmission system in the prefrontal cortex and the anterior
cingulate gyrus.[54]
[71] Procedures such as cingulotomy, hypothalamotomy, and resection of the substantia
innominata and NAcc had been described as a treatment for severe addictive disorders.
Medvedev et al[85] investigated the long-term effects of bilateral cryocingulotomy in 348 patients
with strong heroin dependence. After 2 years, 45% of the 187 patients interviewed
had completely abstained from drugs and 17% were in remission for >2 years after 1
or 2 instances of drug taking in the past. In 13% there was a partial improvement
and 12% showed no change. Kerr and Pozuelo[50] performed stereotactic hypothalamotomy (of the ventromedial nucleus) unilaterally
or bilaterally and it seemed to help the patients regain their self-control. All patients
showed a reduction in sexual drive. In patients who underwent bilateral hypothalamotomy,
most suffered from severe side effects: lack of impulse, amnestic syndrome, vision
disorder, and vegetative crisis were reported. The only report of resection of the
substantia innominata for the treatment of addiction was described by Knight.[53] He reported good outcomes of the patients, however, he did not explain logic of
this target choice and there was no information given about patient characteristics
and no details were provided about the outcome. Gao et al[29] reported stereotactic bilateral ablation of the NAcc to treat addiction. This would
prevent craving for drugs after detoxification and in this way cause reduction in
the relapse rate. He reported 25% complete recovery, 35.7% relapse after 6 months,
and 19.2% of memory loss. In a recent review of Leiphart and Valone,[65] it was found that all ablative procedures had similar treatment results. Bilateral
NAcc DBS for drug addiction have been extensively studied in animal models with favorable
results.[40] However, there are only few anecdotal preliminary reports on NAcc DBS for addiction
in humans.[39]
[59]
[92] These reports showed disappearance of craving behavior immediately after NAcc stimulation.
Most of the patients remained completely abstinent in the 1-year follow-up period,
and alcohol consumption was reduced considerably in the rest. In a patient who received
DBS for the primary purpose of alleviating severe anxiety and depression, stimulation
in the NAcc had the unintended consequence of improving the patient's comorbid alcohol
dependence.[61] The rate of abstinence was 20% after 1 year and 30% after 2 years.[39]
[61]
[92] Interestingly, animal experiments showed that STN DBS can treat cocaine addiction
and craving in rats without diminishing the motivation for other more naturally rewarding
activities.[104] According to these findings, behavioral addictions and addiction to dopaminergic
drugs in Parkinson's disease (PD) patients with a dopamine dysregulation syndrome
can be improved by STN DBS, leading to marked decreases in dopaminergic medications.[120]
Eating Disorders
The LH has long been implicated in feeding behavior and energy expenditure. Its role
in appetite regulation was well described in early studies of LH lesioning, which
induced leanness.[3] Stereotactic electrocoagulation of the LH in obese humans was performed safely more
than 30 years ago, resulting in significant, although transient, appetite suppression,
and slight weight reduction.[101] DBS stimulation of the LH was tested exclusively in animals. It was shown that HFS
resulted in weight loss without changes in eating frequency, while LFS resulted in
less eating frequencies and early satisfaction resulted in weight loss.[108] Recently, Welkenhuysen et al[124] induced an animal model of anorexia by LH stimulation. VMH has also been implicated
in appetite regulation and the maintenance of energy homeostasis. Lesions of the VMH
have been shown to induce weight gain in obese animals and lesions resulted in substantially
more carcass lipid and hyperinsulinemia in rats.[13] LFS of VMH inhibited feeding in hungry rats and eating resumed once the stimulation
was terminated. Other effects of stimulation included fear, aversion, restlessness,
and attempts at escape, which may have partially accounted for the decreased feeding
behavior in these animals.[105] Heightened metabolism induced by VMH stimulation was sustained by utilization of
fat stores, most likely due to noradrenergic turnover.[105] The NAcc is integral to the modulation of reward sensation shown to be associated
with palatability of foods. Inhibition of NAcc resulted in dopamine depletion with
significant attenuation of food hoarding and weight loss due to its effect upon the
rewarding system, and resulted also in a concomitant smoking cessation in a reported
case.[78] Also, leukotomy was found to have an effect in the treatment of anorexia, however,
it is not proposed as a surgical option in resistant case.[90]
Persistent Vegatative State (PVS)
PVS is defined as a degree of consciousness after severe brain injury whereby a patient
has developed wakefulness with some degree of sleep-wake cycling but without any demonstration
of environmental awareness.[73] These patients have a functional brainstem and various dispersed “islands” of dysfunctional
cortex.[73] There is an important role of the intralaminar nuclei in maintaining attention and
memory based upon their anatomical neural connections. A specific type of thalamic
neuron thought to be involved in the more basic function of activating cortical networks.[46] More recent research has demonstrated that such neural connections between the central
lateral nuclei and the cortex are reciprocal and that these nuclei are densely innervated
by brainstem arousal systems as well.[111] Patients with specific ischemic infarctions of these nuclei primarily demonstrated
disturbances in attention and subsequent SPECT imaging revealed decreased blood flow
to the frontal cortices.[123] It was found that stimulation of the frontocortical–striatopallidal–TC mesocircuit
activates the frontal cortex with the aim of improving consciousness, awareness, or
cognitive skills.[110] The most recent series study was performed by Yamamoto and Katayama[125] in a total of 21 patients targeting CM-PF complex and mesencephalic reticular formation;
eight patients improved in ability to obey verbal commands. Despite the large number
of patients in the more recent trials, this study was limited by the timing of DBS
therapy within the accepted 1-year time frame of spontaneous recovery. Recently, Schiff
et al[110] reported that a case was diagnosed as a minimally conscious state 6 years after
a traumatic brain injury. Before DBS stimulation, the patient demonstrated visual
pursuit and intermittently followed simple commands.[110] After DBS implantation and therapy, they reported improvements in level of arousal
(sustained eye opening, head turning to voices), functional limb movements, ability
to feed orally, and 66% improvement in the JFK Coma Recovery Scale-Revised score despite
a 6-year history of minimal consciousness. The patient was soon able to name objects,
move objects with his hands, and feed himself.
Alzheimer's Disease (AD)
AD is the most common form of dementia and is characterized by a progressive disturbance
in cognitive function, with memory being particularly affected. Various pathological
processes, including the deposition of fibrillar forms of amyloid β protein, neuronal
degeneration, synaptic loss, defects in neurotransmission, and disruption of neural
network activity, have been implicated as possible contributors to the dysfunction.[96] There is also losing the expected deactivation and toggling of the default network
during cognitive tasks.[96] VNS had been shown to have a positive effect on cognition in the form of motor speed,
psychomotor function, language, and executive functions after stimulation.[106] In a pilot study by Merrill et al,[86] they reported 17 AD patients followed-up after VNS. After 12 months, 7 patients
(41.2%) improved and 12 patients (70.6%) did not worsen. Behavior and mood disturbances,
usually associated with disease progress, were not seen. Instead, modest improvements
in mood and quality-of-life variables were found. They also found that median change
in cerebrospinal fluid tau at 1 year was a reduction of 4.8%, with 5.0% increase in
phosphotau.
The importance of the fornix in memory function is supported by the observation that
lesions in the fornix in experimental animals and humans are well known to produce
memory deficits.[10] Laxton et al[63] hypothesized that it might be possible to use DBS of the fornix to drive its activity
and to modulate the circuits mediating memory function in patients with impairments
in this domain. Hamani et al[34] recently reported that the possibility of modulating memory in a patient with obesity
using DBS of the fornix and ventral hypothalamus provoked reversible memory phenomena
with acute high-intensity stimulation. DBS has effects on brain areas that closely
overlap with the brain default mode network ([Fig. 8]). Recently, the Toronto group leaded by A. M. Lozano reported the preliminary phase
I results of DBS stimulation of the anterior fornix in 6 patients with AD after 1
year of follow-up.[63] They documented 4.2 increase in the mean AD Assessment Scale, Cognitive Subscale.
The results are promising and final results are waited to be published.
Figure 8 A schematic drawing demonstrating the mechanism of action and the activated pathways
after anterior fornix DBS in Alzheimer's disease.
