LEARNING OBJECTIVES

After reading this article you will be able to:

• • delineate the indications for NMD as well as its legal framework in the UK

• • outline the two surgical procedures in use in the UK (ACING and ACAPS)

• • outline the potential adverse effects of NMD and how they could be better studied.

Neurosurgery for mental disorder (NMD), a rarely discussed subject, is highly invasive – some procedures changing the brain irreversibly as well as potentially altering the individual's personality and affecting cognition. The Clinical Resource and Audit Group (CRAG) for Mental Illness launched the largest enquiry into the use of NMD in the UK, concluding that ‘subject to existing and recommended additional safeguards and procedures, neurosurgery for mental disorder should continue to be available in Scotland, but only as a treatment for intractable obsessive–compulsive disorder and affective disorders (e.g., major depressive illness)’ (CRAG Working Group on Mental Illness 1996). The Mental Health Act 1983 mandates that for neurosurgery patients must have capacity to provide sustained informed consent and also that a statutory second opinion must be provided by a three-person team, two of whom are not medical and whose role is to confirm that the patient is capacitous and consenting, as well as a second opinion appointed doctor (SOAD) (Zigmond Reference Zigmond2016).

The neurosurgical procedures

ACING

Anterior cingulotomy (ACING) involves the placement of bilateral lesions in the anterior cingulate cortex (ACC) under stereotactic guidance (Fig. 1). Steele et al studied eight patients who underwent ACING (six for severe depression without psychotic symptoms, one for severe depression with psychotic symptoms and one for recurrent depressive disorder) and found that at 12 months two patients met criteria for response and three met criteria for remission based on improvement in Hamilton Rating Scale for Depression (HRSD) scores (Steele Reference Steele, Christmas and Eljamel2008). This scale considers activities of daily living (‘work and activities’) as well as mood, suicidality and other symptoms, such as insomnia. Of the remaining three patients, two had a clinically insignificant decrease in HRSD score and one had an increased HRSD score.

FIG 1 Para-sagittal T₁-weighted magnetic resonance imaging of the left hemisphere, showing the anterior cingulotomy (ACING) lesions on (a) post-operative day 1 and (b) 78 months later. This patient had a ‘triple’ dorsal anterior cingulotomy, meaning three pairs of lesions were made in a single procedure. Reproduced with permission from Sheth et al (Reference Sheth, Neal and Tangherlini2013); © 2013 American Association of Neurological Surgeons.

The study also found that a superior clinical response at 1 year was associated with lesions that were more anteriorly placed and, unexpectedly, of smaller volume. Importantly, there were no significant differences found between scores at baseline and 12-month follow-up for cognitive functioning (IQ) and verbal fluency (Steele Reference Steele, Christmas and Eljamel2008).

Regarding refractory obsessive–compulsive disorder (OCD), Sheth et al studied 64 patients who had undergone cingulotomy between 1989 and 2009 (Sheth Reference Sheth, Neal and Tangherlini2013). Of these 64 individuals, 34 had had cingulotomy with no other subsequent procedure, and of these, 15 had achieved a full response and a further 3 showed a partial response at the first follow-up. On average there was a 36% reduction on the Yale–Brown Obsessive Compulsive Scale in the ACING-only group.

Importantly, of the 24/64 patients with either a full or partial response at initial follow-up, 83% (20) retained at least a partial response by their most recent follow-up (at a mean of 63.8 months) (Sheth Reference Sheth, Neal and Tangherlini2013), arguing against any benefit being attributable to the placebo effect (known to be large with surgery (Wartolowska Reference Wartolowska, Judge and Hopewell2014)) and showcasing the durability of this treatment method.

The Dundee Advanced Interventions Service is currently the only centre in the UK that regularly provides NMD using ACING.

Issues regarding effectiveness

The numbers of patients in these studies are, unsurprisingly, small, reflecting the fact that ablative NMD is utilised as a procedure of last resort. Further studies, particularly larger ones, are therefore required to confirm these findings; however, complicating this, surgical practice (e.g. ablative procedure type and ablation method/tool) varies considerably from centre to centre as well as from patient to patient. We mentioned above that changing the lesion placement and volume may be key determinants of clinical outcome (Steele Reference Steele, Christmas and Eljamel2008). Additionally, variation regarding patient inclusion and exclusion criteria (e.g. inclusion of individuals with personality disorder and other comorbidities) further confounds comparison of reports between centres. Moreover, what makes a procedure attractive is how it compares with existing alternatives, in particular, how ACING and ACAPS compare with non-ablative procedures such as vagal nerve stimulation (VNS) or deep brain stimulation (DBS). However, even in this regard, comparison is difficult, as patients with, for example, OCD or depression, may be offered ACAPS if DBS proved unsuccessful (Christmas Reference Christmas, Eljamel and Butler2010), meaning that their illness is in fact more refractory than for the cohort receiving DBS. There are no head-to-head trials comparing DBS and ablative surgeries for OCD (Arumugham Reference Arumugham, Balachander and Srinivas2019). Obviously, an advantage of DBS over ablative NMD is its reversibility, but DBS is much more costly and although both procedures share the common complications of surgery, there are also complications specific to DBS, for example intracerebral haemorrhage with repositioning or removal of implanted electrodes. Recent development of non-invasive stereotactic (Gamma Knife^®) radiosurgery (Lopes Reference Lopes, Greenberg and Canteras2014) means that the incidence of such adverse effects with NMD might diminish in the future. Furthermore, as well as safety, the success of NMD will likely improve as it becomes possible to identify targets based on a specific patient's brain connectome (van den Heuvel Reference van den Heuvel and Sporns2019) as these inter-individual differences may partly account for the person-to-person variation in outcomes. Importantly, while NMD may reduce symptom severity in depression or OCD, pharmacological therapy is still needed alongside NMD.

Moreover, although we have earlier stated that ablative procedures may be a promising form of treatment, for non-ablative NMD, particularly DBS, the data on treating depression have been uncertain. A recent multicentre randomised sham-controlled trial was halted early because of the lack of statistically significant antidepressant response to active subcallosal cingulate DBS at the a priori 6-month time point (Cromwell Reference Crowell, Riva-Posse and Holtzheimer2019); it also remains unclear whether benefits are sustained after stimulation is discontinued.

We next discuss the role of the ACC in cognition and why its lesions or lesions to its connections with the hippocampus, amygdala or thalamus can have a therapeutic effect on refractory depressive disorder and OCD.

The anterior cingulate cortex

The ACC receives input from the orbitofrontal cortex (OFC), an area which processes the value of stimuli (‘reward’ or ‘pleasure’/hedonic value), and its damage can have a variety of effects. Lesions of the ACC in rats impair their ability to take account of the costs of actions (Rushworth Reference Rushworth, Walton and Kennerley2004). Functional magnetic resonance imaging (fMRI) studies in humans (Fig. 2) indicate that activity in regions of the ACC correlates with subjective pleasantness/unpleasantness of a stimulus (such as odour, labelled in Fig. 2 as 3–10) (Rolls Reference Rolls2019).

FIG 2 Functional magnetic resonance imaging maps of subjective pleasure (‘hedonic tone’ or ‘liking’) in the orbitofrontal cortex (ventral view, left) and the anterior cingulate cortex (sagittal view, right). Numbers in red indicate sites where activations correlate with subjective pleasantness and those in white indicate sites where activations correlate with subjective unpleasantness. Reproduced under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) from Rolls (Reference Rolls2019).

Damage to the ACC in humans has been noted to influence the subjective experience of emotions. For example, one study (Hornak Reference Hornak2003) looked at patients who had had selective surgical lesions, including lesions of the anterior ventral part of the ACC and/or medial prefrontal cortex (Brodmann area 9, BA9), for a variety of medical reasons, including tumours and epilepsy. Participants were asked on a questionnaire whether, since the surgery, they had had a change in either the intensity or the frequency of their experience of emotions that featured in two (one facial and one vocal) expression identification tests. Hypersensitivity to sad events was reported by seven out of ten patients whose lesions included the medial BA9/ACC region, and several of these individuals described themselves as having become far more ‘emotional’ compared with before surgery. Five individuals reported that both sadness and happiness had increased in intensity and frequency, suggesting that lesions in medial BA9/ACC regions can exaggerate both positive and negative affective responses.

ACC damage can also produce impoverished action generation in the presence of normal motor ability – individuals with such lesions can show akinetic mutism, leading to the proposal that the ACC has a primary role in motivating or ‘energising’ behaviour (Holroyd Reference Holroyd and Yeung2012). There are models that variously relate the ACC to several different functions, including conflict monitoring, reward processing, action selection and decision-making. However, damage to the ACC mostly spares performance on tasks that exercise these functions, but as stated above, it leads to impoverished action generation. Trying to offer a unifying model, Holroyd & McClure (Holroyd Reference Holroyd and McClure2015) have proposed a rostral/caudal model of the ACC, the hierarchical reinforcement learning (HRL) ACC model, where mid-level modules associated with a caudal region of the ACC select tasks for execution and apply control signals that attenuate effort-related costs incurred by an action selection mechanism in the striatum. Conversely, high-level modules located in the rostral ACC select the ‘meta-task’ for execution and apply a control signal over the caudal ACC that attenuates effortful costs incurred in task switching, facilitating shifts between different task strategies (Holroyd Reference Holroyd and McClure2015). According to this model, the role of the ACC in rodent model foraging relates to increased control by caudal ACC for exploiting a current patch versus increased control by rostral ACC for switching to alternative patches.

Location of the anterior cingulotomy lesion

The optimal location and volume of ACING lesions are not known. Interestingly, the rostral ACC has been identified in neuroimaging studies as the region of the ACC most affected in people with depressive illness (Ebmeier Reference Ebmeier, Donaghey and Steele2006) and there is evidence that rostral ACING lesions placed within this region are more therapeutically effective (Steele Reference Steele, Christmas and Eljamel2008) (Fig. 3).

FIG 3 The location of anterior cingulotomy (ACING) lesions in a cohort of individuals with major depression. The kidney-shaped region indicates finding of abnormality on neuroimaging in the medial prefrontal region in individuals with clinical depression; the two black stars show the most anterior and posterior ACING lesion locations in the cohort. The more therapeutically effective anterior ACING lesions lie within the region reported to be abnormal; the more ineffective posterior lesions do not. Reproduced with permission from Steele et al (Reference Steele, Christmas and Eljamel2008); © 2008 Society of Biological Psychiatry.

Notably, Boccard et al (Boccard Reference Boccard, Pereira and Moir2014) have described the efficacy of DBS targeting the rostral aspect of the dorsal ACC in the treatment of chronic pain refractory to medical treatment; this led them to suggest that this area is key in conferring emotional valence to pain. According to Holroyd & McClure (Holroyd Reference Holroyd and McClure2015), lesions placed more anteriorly in rodents damage higher level modules implicated in task switching. It has previously been reported that patients treated with ACING and/or ACAPS exhibit a general impairment in accuracy of recognition of dynamic emotional displays (i.e. a changing processing task involving identifying the key emotion portrayed in each video in a set of 28 clips) compared with healthy, never-depressed controls (Ridout Reference Ridout, O'Carroll and Dritschel2007). There were three groups in the study: neurosurgery-treated and non-depressed following treatment (n = 4); neurosurgery-treated and still depressed (n = 5); and never-depressed healthy controls (n = 20). Both neurosurgery-treated groups were significantly impaired in recognition of emotions compared with the healthy controls, but there was no significant difference between the treated groups (Ridout Reference Ridout, O'Carroll and Dritschel2007). This would suggest that the surgery itself leads to this neurocognitive problem. However, it also suggests that creating this impairment in emotion recognition is not therapeutic for all patients with depression, who present with different constellations of symptoms.

It is possible that rostral lesions within the ACC can affect task switching in emotional processing as well as task switching in the motor domain. As regards subjective emotional processing, such lesions could be reversing the fixed ambivalence, loss of interest or pleasure and feelings of worthlessness characteristic of a depressive episode. The change in motor task switching could be reversing the slowing of thought and motor activity as well as the reduced ability to concentrate or the indecisiveness shown by severely depressed people.

Profiling NMD patients