Physical treatment

Neurosurgery for mental disorder, vagus nerve stimulation, and deep brain stimulationDavid mB christmas

stephen curran

Keith matthews

muftah s eljamel

Abstractadvanced treatment options are available from a few tertiary centres for

patients with the most severe and treatment-refractory forms of depres-

sion and obsessive–compulsive disorder. these treatments include ablative

neurosurgery and electrical stimulation procedures directed against differ-

ent neural targets. they include vagus nerve stimulation (Vns) and deep

brain stimulation (DBs). ablative procedures, such as anterior cingulotomy,

are the best established of these alternatives, although the newer electri-

cal stimulation procedures confer potential advantages with respect to

surgical morbidity and reversibility. Whilst evidence for Vns as an effective

therapy for depression is accruing, DBs remains an experimental treat-

ment, with definitive evidence of efficacy awaited. all neurosurgical proce-

dures used to treat psychiatric disorder should be provided by specialist

multidisciplinary teams with expertise in the management of psychiatric

disorder by pharmacological and psychological treatment methods. all

psychiatric neurosurgical procedures should be subject to detailed long-

term clinical audit to determine efficacy and adverse effect burden.

Keywords depression; electrical stimulation; mood disorders; neuro-

surgery; OcD; treatment resistance

Neurosurgery for mental disorder

Neurosurgery for mental disorder (NMD), previously known as psychosurgery, can be defined as a neurosurgical procedure

David MB Christmas MBChB MD MRCPsych is Consultant Psychiatrist with

the Advanced Interventions Service, Ninewells Hospital and Medical

School, Dundee, UK. Conflicts of interest: none declared.

Stephen Curran MB MRCPsych is Consultant General Adult Psychiatrist at

Murray Royal Hospital, Perth, UK. Conflicts of interest: none declared.

Keith Matthews MD PhD is Professor and Head of the Section of

Psychiatry and Behavioural Sciences at the Centre for Neuroscience,

University of Dundee, Ninewells Hospital and Medical School. Conflicts

of interest: none declared.

Muftah S Eljamel MBBCh MD FRCS FRCSEd FRCS FABI is Consultant

Neurosurgeon with the Advanced Interventions Service at Ninewells

Hospital and Medical School, and Reader in Surgical Neurology at the

University of Dundee, UK. Conflicts of interest: none declared.

Psychiatry 8:4 13

conducted upon the brain with the specific intention of alleviat-ing severe, treatment-refractory symptoms of mental illness.

Historical aspects

Originally introduced by Egas Moniz in 1936 as a treatment for schizophrenia prior to the discovery of effective drug treatments, leucotomy (and its successor, frontal or prefrontal lobotomy) came to be used widely as a treatment for a broad range of poorly specified mental pathologies and behavioural disturbances. Many thousands of crude, extensive, frontal lobe lesioning procedures were conducted across Europe and the USA between the late 1930s and early 1950s. Undoubtedly, these now obsolete lobot-omy and leucotomy procedures were overused, with an absence of critical appraisal of efficacy and adverse effects. Modern NMD bears little relation to such procedures and might better be con-sidered alongside the use of neurosurgical techniques to man-age intractable pain or movement disorder. With refinement of the precision and targeting of surgery, notably the application of stereotactic neurosurgical techniques, evidence has accrued over a sustained period to support the use of irreversible focal tissue ablation in the management of a restricted population of severely disabled patients with defined psychopathology.

Neurosurgery for mental disorder today

Ablative NMD is performed by a small number of tertiary centres around the world. There are two active centres in the UK, Cardiff and Dundee, each of which performs only a few procedures each year. Advances in stereotactic neurosurgical technology permit the accurate placement of millimetre-scaled thermal lesions in neural structures implicated in the symptoms of depression and obsessive–compulsive disorder (OCD). All modern NMD proced-ures ablate, or disconnect, ventral and medial prefrontal cortical areas. Although these targets (Figures 1 and 2) evolved empiri-cally, recent structural, functional, and neuroanatomical studies have confirmed their involvement in the pathophysiology of both depression and OCD. Although widely represented as a treat-ment of ‘last resort’, NMD is best viewed as an adjunctive treat-ment for a restricted population of severely disabled patients. Certainly, other treatment modalities (including medication and psychological interventions) must continue after NMD, even for patients experiencing the best clinical responses.

IndicationsThe two contemporary recognized indications for NMD are chronic treatment-refractory depression and OCD. To fulfil minimum eligibility criteria for assessment for NMD, disabling mental dis-order must have been present for at least 3 years, with at least two years of unremitting symptoms despite adequate, sustained trials of both psychological and physical treatment methods. The capacity to provide informed consent is also required.

ContraindicationsContraindications to NMD include: • absence of adequate treatment trials of pharmacological and

psychological treatment methods • incapacity to give sustained, informed consent • a diagnosis of substance misuse

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Physical treatment

• an organic brain syndrome • confirmed presence of a primary diagnosis of personality dis-

order or pervasive developmental disorder.

Efficacy

Although there are many reviews of NMD, the accumulated litera-ture on outcome remains unsatisfactory. There are no prospective, randomized, double-blind, placebo-controlled trials for any proce-dure. To perform sham intracranial surgery, with all of its hazards, would be unethical. There are methodological concerns with most published studies and a positive reporting bias is likely. Neverthe-less, five studies have employed retrospective control groups for comparison, and each demonstrated improved outcomes following NMD. Consolidated reviews of different NMD procedures, used for different diagnoses and based on global outcome measures, suggest that around 50% of patients achieve significant benefit, with perhaps as many as 33% experiencing dramatic functional improvement. Unfortunately, much of this evidence base relates to procedures that are no longer performed (e.g. stereotactic subcau-date tractotomy).1 In Dundee, anterior cingulotomy (see Figure 1) is performed for treatment-resistant depressive disorder in the light of the favourable outcomes reported by other centres2 and our own experience.3 For intractable OCD, although other procedures have also been reported to offer benefit; anterior capsulotomy (see Figure 2) and anterior cingulotomy are the best-established cur-rent treatment options. Following NMD, it is recommended that physical and psychological treatments are maintained and tailored to maximize any clinical improvement. It is not unknown for treat-ment approaches that have failed when used before NMD to elicit benefit afterwards. Improvement is often gradual and may extend over years. Clinical deterioration is also possible, but appears to be less common.

Adverse effects

The adverse effects associated with NMD can be separated into general risks associated with any intracranial surgery, and risks

Figure 1 sagittal view of human brain displaying medial surface of

cerebral hemisphere. yellow shading depicts the anterior cingulate

gyrus. Blue shading depicts the location and size of a typical anterior

cingulotomy lesion.

Psychiatry 8:4 140

specific to NMD. The main general risks are those of vascular injury, confusional states, and post-surgical epilepsy. The sur-gical death rate for NMD is less than 1% – no higher than for stereotactic intracranial surgery performed for other clinical indications. The risk of acquiring major neurological deficit by vascular injury as a consequence of frame-based stereotactic surgery is also less than 1%. Transient confusional states (<21 days) are not uncommon following intracranial neurosurgery, with increased rates in elderly patients; rates following stereo-tactic NMD procedures are very low. Epilepsy rates are similarly low, even where lesions are large. The risk of experiencing one or more seizures post-cingulotomy (with no previous history of epilepsy) is less than 10% over 10 years. When they do occur, such seizures are generally responsive to anticonvulsant mono-therapy. Weight gain of clinical significance has been reported with anterior capsulotomy and other, older, NMD procedures, but not with cingulotomy.

Personality and intellectual functionPersonality changes following lobotomy, or other widespread lesions, were very common. However, there is surprisingly little evidence to support their occurrence with modern NMD and there is, in fact, some evidence to the contrary. However, valid, sensi-tive, and repeatable methods for the measurement of personality are lacking and the cited rates of 0.4–4% may be an underesti-mate.4 There is no evidence that modern stereotactic NMD results in significant general intellectual impairment. Indeed, improve-ments have been reported, presumably following improved atten-tional capacity associated with symptom relief. Although some measures of frontal functioning have detected transient impair-ments with some NMD procedures, evidence for enduring deficit is scant. However, sensitive specific tests of many aspects of front- al lobe functioning have generally not been applied.

Legal, ethical, and other issues

Although NMD was considered an established treatment for patients with malignant forms of mental disorder for much of the

Figure 2 axial (horizontal) view of human brain through basal ganglia.

yellow shading depicts the anterior limbs of the internal capsule. Blue

shading depicts the location and size of typical anterior capsulotomy

lesions.

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Physical treatment

twentieth century, its disquieting history ensures that it remains subject to specific legislative control and controversy. NMD is currently offered only to a small number of carefully selected patients following detailed exploration of all reasonable treat-ment alternatives. • In England and Wales, under Section 57 of the 1983 Mental Health Act, NMD requires the provision of informed consent and certification of both the capacity to consent and the advisability of treatment by a Secretary of State (Mental Health Act Commission)-appointed doctor and two non-medical appointees. The Mental Health Act 2007 amends the 1983 Act, but not these principles. • In Scotland, under the Mental Health (Care and Treatment) (Scotland) Act 2003, informed consent, certified by a Designated Medical Practitioner and two lay people appointed by the Mental Welfare Commission for Scotland, is required. If the patient is incapable of consenting and does not resist or object, treatment may be considered if a Designated Medical Practitioner and two Mental Welfare Commission-appointed lay people certify that the procedure appears likely to confer benefit and the Court of Session in Edinburgh authorizes the procedure.

Vagus nerve stimulation

The vagus nerve is the 10th cranial nerve and adopts a wandering course from the brainstem to organs in the neck, chest, and abdo-men. Around 80% of fibres within the vagus nerve are sensory afferent fibres carrying information from the viscera to the brain. Many of these fibres connect with cells in the nucleus tractus soli-tarius (NTS), a brainstem nucleus on either side of the medulla. The NTS has projections to the forebrain, amygdala, hypothala-mus, and median raphe nucleus and locus coeruleus. The last two represent the dominant sources of serotonergic and noradrenergic innervation to limbic and cortical brain areas, respectively.

In 1938, Bailey and Bremner found that electrical stimulation of the vagus nerve in cats desynchronized the EEG waveforms, and further studies discovered that vagus nerve stimulation (VNS) could reduce inter-ictal epileptiform activity.

VNS involves subcutaneous implantation of a pulse genera-tor of a similar size to, and in a similar location to, a cardiac pacemaker. A bipolar electrode extends from the device and is

Psychiatry 8:4 14

wrapped around the left vagus nerve as it passes through the neck. In most cases, the stimulator will activate for 30 seconds every 5 minutes, but the frequency, intensity, and waveform characteristics of the stimulation are controllable using a tele-metric wand connected to a palmtop computer.

The first human VNS implant was performed in 1988 and it has established itself as a safe and effective treatment for the treatment of drug-resistant epilepsy.5 By 2004, more than 28,000 patients with epilepsy in 24 countries had been treated with VNS.

Adverse effectsVNS is generally well tolerated, although some patients experi-ence some adverse effects in the early stages of treatment. These are almost invariably associated with stimulator activation and are typically mild. Common adverse effects include: • voice alteration (53%) • headache (23%) • neck pain (17%) • dyspnoea (17%) • cough (13%).Most adverse effects reduce significantly over time, with only voice alteration persisting in more than 10% of patients (in 21%). Reducing the pulse width or current intensity can improve adverse effects, and patients are issued with magnets that can temporarily switch off the stimulator when held over the device. There are isolated reports of unwanted cardiac effects with VNS, with asystole occurring in 0.1% of patients when the stimulator is first turned on. No deaths or long-term cardiac sequelae have been reported. Psychiatric adverse effects are uncommon, although there have been two cases of mania in 30 patients receiving VNS for treatment-refractory depression,6 with 1 case of mania, 7 cases of worsening depression, and 2 suicides over a period of 12 months in a subsequent open study of 74 patients conducted in Europe.7

Outcomes of vagus nerve stimulation in treatment-resistant depressionThese are summarized in Table 1. Thus far, VNS promises to be most effective for patients with low to moderate antidepres-sant drug treatment resistance, with lesser responses in ‘extreme’

Outcomes of open trials of vagus nerve stimulation in major depression (percentage of patients)

Reference n 3 months 6 months 12 months

Responsea Remissionb Responsea Remissionb Responsea Remissionb

sackeim et al., 2001,8,c 60 30.5 15.3 n/a n/a n/a n/a

marangell et al., 20026 30 40 17 55 31 46 29

rush et al., 2003,9,d 174 14 7 17 6.5 30 17

schlaepfer et al., 20087 74 37 17 n/a n/a 53 33

aDefined as ≥50% reduction in baseline 28-item hamilton rating scale for Depression (hrsD-28).bDefined as hrsD-28 ≤10.cthis study includes the 30 patients in the first study.dresponse was defined as a ≥50% reduction on hrsD-24, and remission was hrsD-24 ≤9.n/a, data not available.

Table 1

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Overview of key studies reporting putative therapeutic effects of deep brain stimulation for psychiatric disorder

Reference n Diagnosis Lesion site Mean follow-up

(months)

% responsea Severe adverse

effects reported

Notes

nuttin et al.,

199910

4 OcD anterior limb of

internal capsule

– – – –

Gabriëls et al.,

2003,11,b

3 OcD anterior limb of

internal capsule

35 66 – no detectable

change in

neuropsychological

performance;

personality scores

(measured with

the mmPi) did not

deteriorate

nuttin et al.,

200312

6 (double-

blind

crossover

in 4)

OcD anterior limb of

internal capsule

– – 3/4 patients had

severe worsening

of mood and

suicidal ideation

during OFF-phase;

battery power

problematic

2 patients went on

to have anterior

capsulotomy

sturm et al.,

200313

4 ‘anxiety

disorders

and OcD’

nucleus

accumbens

24–30;

individual

follow-up not

stated

75 none reported response

not defined

prospectively; no

data on previous

treatment of patients

abelson et al.,

200514

4 OcD anterior limb of

internal capsule

12.9 (4–23) 25 1 patient

committed suicide

3 patients had

co-morbid major

depressive disorder

mayberg et al.,

200517

6 5 mDD, 1

bipolar ii

subgenual

anterior cingulate

gyrus

– 66 2 patients had

infections requiring

intravenous

antibiotics

–

Greenberg et

al. 200615

8 OcD anterior limb of

internal capsule

36 50 1 intracerebral

bleed,

1 ‘hypomanic’

episode

–

lozano et al.,

200818

20 19 mDD, 1

bipolar ii

subgenual

anterior cingulate

gyrus

12 55 1 perioperative

seizure,

2 worsening

depression,

4 infections

includes 6 patients

from mayberg et al.

(2005) report

mallet et al.

200816

16 OcD subthalamic

nucleus

10 75 (40

to sham

stimulation)

1 intracerebral

haemorrhage,

3 ‘hypomanic’

episodes

2 patients implanted

and removed from

study

mDD, major depressive disorder; mmPi, minnesota multiphasic Personality inventory.a≥35% reduction in baseline yale–Brown Obsessive compulsive scale (y-BOcs) for obsessive–compulsive disorder (OcD); ≥50% reduction in baseline hamilton rating scale for Depression (hamD) for major depressive disorder.bthis study involved long-term follow-up of 3 patients from the first study.

Table 2

antidepressant resistance. Response rates are reported as 78% in those who have had two or three failed antidepressant treat-ments, 63% in those with four or five failed treatments, and 25% in those with six or seven failed treatments.6 Patients who

Psychiatry 8:4 142

have received ECT and have responded poorly are less likely to respond to VNS.6 VNS was granted approval in July 2005 by the US Food and Drug Administration (FDA) as a long-term adjunctive treatment in chronic or recurrent treatment-resistant

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Physical treatment

depression that has not responded to at least four adequate anti-depressant treatments.

Deep brain stimulation

Deep brain stimulation (DBS) is used to treat movement disor-ders, including Parkinson’s disease, where tremor can be allevi-ated by stimulation of the subthalamic nucleus or globus pallidus. DBS for psychiatric disorder is a much newer procedure and has tended to target the anterior limbs of the internal capsules (broadly the same target as for ablative anterior capsulotomy), and the majority of cases so far reported are for treatment of OCD.10–15 There is also one positive report from a blinded study of subthalamic nucleus stimulation in OCD.16 Additionally, recent reports have described beneficial outcomes at 12 months for 55% of 20 patients with chronic depression treated by stimulation of white-matter projections from the anterior cingulate.17,18

DBS involves the bilateral implantation of electrodes, usu-ally under local anaesthesia, in the anterior limbs of the inter-nal capsule (or in white-matter projections from the anterior cingulate), under computed tomography or magnetic resonance imaging guidance. Subcutaneous programmable generators are subsequently implanted in the abdomen and connected to the electrodes by subcutaneous wires.

DBS for the treatment of psychiatric illness remains experi-mental. There are, however, a number of small case series that suggest putative clinical effects of stimulation. A summary of these is given in Table 2.

Battery longevity has been a problem in studies so far. There have also been reports of transient depression, involuntary laugh-ter, and hypomania/mania during DBS. Hardware and implanta-tion associated infection is not uncommon (up to 25%). ◆

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FuRTHER READINg

Freeman c, crossley D, eccleston D. neurosurgery for mental disorder.

report from the neurosurgery Working Group of the royal college

of Psychiatrists. council report cr89. london: royal college of

Psychiatrists, 2000.

(A detailed review of the evidence base for NMD procedures for

different clinical indications.)

Practice points

• modern nmD bears little relation to the crude, destructive

procedures known as lobotomy or leucotomy

• the targets for modern nmD evolved empirically, yet they

appear consonant with recent advances in our understanding

of the anatomy and neurobiology of depression and OcD

• a substantial proportion of patients experience a good

outcome following modern nmD

• ablative nmD remains an important treatment option for

intractable depressive disorder and OcD

• the Us FDa has approved Vns as a treatment for chronic

major depression

• DBs is currently a promising, but experimental, therapy

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