Happy Birthday “One Flew Over the Cuckoo's Nest”: A Momentous Tale in the Quest for an Effective and Ethical Approach to Psychosurgery

Abstract

The anniversary of the publication of 'One Flew Over the Cuckoo's Nest' by Ken Kesey offers an opportunity for reflection on the use of neurosurgery in psychiatry. We used a narrative, historical and dialectical method to deliver an account of the controversial subject. A balanced representation of the negative and positive aspects, acknowledging some of the questionable ethical practices while describing well-reasoned applications is provided. It includes neurosurgeons, psychiatrists who have embraced these procedures with unwarranted enthusiasm and those who have opposed. Neurosurgical techniques for the treatment of severe mental disorders have evolved from rudimentary procedures which were used to ‘correct' unwanted behaviours associated with a wide range of severe mental disorders to more refined and selective approaches used as a last resort to treat specific mental health conditions. In the absence of specific aetiological models to guide ablative surgical targets, non-ablative, stimulatory techniques have more recently been developed to allow reversibility when surgical treatment fails to obtain a sizeable improvement in quality of life. The subject is concretely illustrated by two eloquent clinical images: one on a series of brain computed tomography scans carried out on a Canadian population of subjects, who underwent leukotomy decades ago, and the other more contemporary on an implantation surgery to epidural stimulation. Alongside technical advances in psychosurgery, a regulatory framework has gradually developed to ensure vigilance in the appropriateness of patients’ selection. Nevertheless, harmonisation of protocols around the world is necessary to ensure consistency in obtaining and maintaining the highest possible ethical standards for the benefit of patients. If the neurosciences promise today, in their new, better framed, and reversible applications, to provide answers to unmet therapeutic needs, we still must remain attentive to drifts linked the introduction of intrusive technologies for purposes of domination or behaviour modification that would impede our individual freedom.

Keywords

brain imaging lobotomy deep brain stimulation ethics history of psychiatry philosophy catatonia leucotomy epidural stimulation

Man, when you lose your laugh, you lose your footing.¹

Introduction

Last year (2022), marked 60 years since Ken Kesey's bestselling novel “One Flew Over the Cuckoo's Nest” was published.¹ This highly acclaimed and hugely celebrated work is considered one of Time's 100 Best English novels (1923–2005) and is one of the best-loved written works on record (BBC's 200 best-loved novels). The homonymous film directed by Miloš Forman, won 5 major Academy Awards in 1976 with a stunning performance by Jack Nicholson immortalizing the protagonist Randle McMurphy, a delinquent in a quest to avoid a custodial sentence by feigning mental illness. His transfer to a mental institution spirals from despair to tragedy when Randle's brain is subject to a lobotomy, ultimately linked to his premature death. The film immerses us in the dilapidating realism of this particularly risky psychosurgery which reached its peak in 1940 in the USA to the point of being performed on an outpatient basis by Walter Freeman through the skull orbits, using an ice-pick, moving from place to place with his “lobomobile.”

Lobotomy or leucotomy conventionally refers to a surgical procedure that involves cutting a lobe or a portion of the frontal brain, generally part of the prefrontal cortex and the connecting fibres.² This technique earned its inventor Egas Moniz, a Portuguese neurologist and politician, the Nobel Prize for Medicine in 1949.^3–5 Surgical techniques to treat mental illness were introduced in 1937⁶ and became popular until the introduction of chlorpromazine in 1952. Women were more frequently subject to leucotomies⁷ which might reflect epidemiological differences and possibly societal inequalities.^8,9 This trend included institutions in Canada^10–14 and some cases were related to homosexuality.^8–10

The decline of psychosurgery was associated with the emergence of effective treatments such as antipsychotics and was also due to the limited evidence for their use (based on small-scale longitudinal studies), the lack of randomized controlled trials, the absence of clear diagnostic indications for its use, risky procedures, adverse effects, and ethical violations involved in its implementation.¹⁵

Here we provide an overview of the current state of neurosurgery for the treatment of psychiatric disorders, discuss some of the most relevant past and present ethical considerations whilst providing clinical examples, and offer a view of what the future of psychosurgery is likely to entail. Above all, clinicians must remain aware that there are always risks that may limit the application of neurosurgery in mental health, for example, anesthesia, infection, convulsions, etc.

Current Neurosurgical Techniques to Treat Mental Health Conditions

Ablative Methods

Mental health conditions amenable to ablative psychosurgery primarily include disorders with documented involvement of the cortico-striato-thalamo-cortical pathways such as obsessive-compulsive disorders (OCD), Tourette syndrome (TS) and major depressive disorders (MDD).^15,16 Nowadays these procedures are carried out by a few specialized neuroscience centres.

The absence of distinct macroscopic brain pathology specifically associated with these mental disorders within the cortico-striato-thalamo-cortical pathways renders precise identification of brain surgical targets challenging, resulting in variable clinical improvement.¹⁷ Target regions are chosen based on the balance between the desired outcome and the risk of side effects whilst surgery is offered only to patients with severe syndromes with multiple less invasive treatment failures. Current ablative techniques include anterior capsulotomy for OCD and MDD, cingulotomy for OCD, MDD and addiction (Add), limbic leucotomy (OCD), subcaudate tractotomy (OCD and MDD) and lesions in the nucleus accumbens (Add). The ablation is achieved with the use of thermocoagulation, radiosurgery (gamma knife) and more recently transcranial-focused ultrasounds, guided by magnetic resonance imaging (MRI). Thermocoagulation requires the opening of the skull whilst radiosurgery uses gamma radiations. Capsulotomy for OCD is the main gamma knife approach.¹⁵

Nonablative Methods

Nonablative neurosurgical methods are invasive techniques based on implanting an electric stimulator in a key brain node. The implant can be “switched on” and “adjusted” whereas, in case of a lack of efficacy, it can be “switched off” without incurring irreversible brain damage.¹⁷ These features provide important opportunities to establish the efficacy of these approaches. There is the potential to do blinded studies where the stimulus can be turned on and off or modified with either the patient and/or rater blind to what has been changed. This could also lead to new experimental paradigms for n-of-1 trials.

These approaches include deep brain stimulation (DBS), vagus nerve stimulation (VNS), and epidural stimulation. DBS became first available in the 1980s thanks to a better understanding of brain circuitry regulating movement, combined with technological advances in neuroimaging, neurosurgical techniques and the development of pacemakers and spinal neurostimulation devices. In contrast to mental health applications, the use of DBS to treat neurological disorders including epilepsy, pain syndromes, Parkinson's disease and dystonia is more established, even in relatively early stages of disease progression.^17,18

In DBS, an anode and cathode are implanted within the brain, under MRI and stereotactic guidance, in deep brain regions to deliver a small electric current. The electrodes are connected to a stimulator located under the skin of the upper chest. The activation of the stimulator creates an electric circuit with a current circulating between the anode and cathode which stimulates the anterior limb of the internal capsule for OCD, MDD and anorexia nervosa (AN), the nucleus accumbens for OCD, MDD, AN and Add, the subgenual cortex for MDD, the globus pallidus for TS, the habenula for MDD, the posterior hypothalamus for aggressive behaviour, the centromedian nucleus of the thalamus for TS, the subthalamic nucleus for OCD, the inferior thalamic peduncle for MDD, the nucleus basalis for Alzheimer's disease (AD), the fornix for AD and the basolateral nucleus of the amygdala for posttraumatic stress disorder. Similarly, to DBS, VNS stimulation requires surgical placement of electrodes wired to a stimulator. The electrodes are placed around the left vagus nerve in the neck to treat MDD refractory to treatment.¹⁹

Epidural stimulation involves the neurosurgical placement of an electric wire on the surface rather than within the brain and it is believed to modulate local and distal connected brain regions. Psychiatric applications include stimulation of either the dorsolateral prefrontal cortex or the orbitofrontal cortex in the treatment of MDD.²⁰ It has also been used in Canada for catatonia.²¹

Ablative Versus Nonablative Methods and Clinical Examples

Neurosurgical techniques for the treatment of severe mental disorders have evolved from rudimentary procedures designed to modify unwanted behaviours associated with a wide range of severe mental disorders, to more refined and selective approaches used as a last resort to treat specific mental health conditions.²² In the absence of specific aetiological models to guide ablative surgical targets, nonablative, stimulatory techniques, although still surgical in nature, allow reversibility of brain stimulation. The goal is to obtain a sizeable improvement in quality of life without compromising brain structure. This evolution in neurosurgical approaches from leucotomies to nonablative neurosurgery can be illustrated with 2 clinical examples.

The first example refers to a rare cohort of 19 patients (10 females) who received prefrontal leucotomies and were followed up over the next few decades in Montreal.^23,24 Figure 1 (left picture) shows a collection of computed tomography brain images of individuals diagnosed with chronic schizophrenia (N = 14), schizoaffective disorder (N = 2), bipolar disorder (N = 2), and personality disorder (N = 1). These patients were treated with neurosurgery between 1948 and 1972, the average period of hospitalization was 44 years and the age at the time of scanning was 74 years. The brain images presented are quite different from patient to patient. This variability in the surgical frontal lesions is in keeping with Dr Moniz's observation of the lack of precision of white matter ablations in these frontal tracts and would not be acceptable in contemporary practice.

Figure 1.

(Left picture): Computer tomography of patients who underwent prefrontal leucotomy. The yellow arrow shows variable dilatation of ventricles particularly the frontal horns of the lateral ventricles and often excessive space in the frontal sulci suggesting variable degrees of frontal atrophy. There is evidence of substantial damage of the genu of the corpus callosum consistent with callosal atrophy. (Right picture): Epidural stimulation in Catatonia. This patient was followed by a panel of experts and an ethics consultant. After 2 years on rTMS without ECT, frontal lobes epidural stimulation, to improve autonomy and recovery was suggested. Two electrodes with 4 contact paddles implanted on the dura mater over the DLPFC through small craniotomies and under neuro-navigation (Stip et al.²¹). A persistent improvement in catatonia was objectively documented. The patient remains with symptoms of schizophrenia and requires long-term antipsychotic treatment with the cognitive deficits linked to the evolution of his serious illness and linked to the numerous ECTs he has undergone in the past. On one occasion, he went to the emergency room for slapping a professional in connection with refusing to take his antipsychoctic. He never received ECT again with a follow-up of 8 years.

The other example illustrates the use of epidural stimulation, a more recently developed nonablative technique, to treat a case of refractory catatonic schizophrenia at the University of Montreal.²¹ The device was applied to a 43-year-old forensic male patient with a 20-year history of illness who only responded to electroconvulsive therapy (ECT). After 560 ECT sessions followed by a 2-year period of weekly and subsequently monthly sessions of repetitive transcranial magnetic stimulation, an epidural stimulator was implanted under neuro-navigation guidance (Figure 1, right picture). This technique allows for a total of 6560 potential combinations of stimulations in each session with 4 electrodes placed in each hemisphere.²¹ The patient has not fully recovered from psychosis since epidural stimulation implantation but has remained stable as an outpatient at year-8 follow-up, without the need for inpatient admission to forensic services. The patient can be evaluated after implantation in the prestimulation and poststimulation periods. Thus, it is not only the technology that has improved, but also the research methodology to establish efficacy in these cases.

Questions About Current Evidence for Psychosurgery in Psychiatric Disorders

Is the current evidence on psychosurgery limited to case reports, case series or systematic reviews? Do the cases to date provide optimism about the usefulness of these approaches when treatment resistance is well established? Since 2020, for example, only 4 meta-analyses have been published in total for depression and OCD. As a stand-alone neurosurgical procedure, bilateral anterior capsulotomy appears to be the most effective and safest of all ablative targets for treatment-resistant depression (TRD).²⁵ A limitation of this conclusion is the paucity of published case series where sample sizes are small. Contemporary ablative neurosurgical procedures (N = 1414 patients) were significantly associated with improvements in depression, obsessive-compulsive symptoms, anxiety, and global clinical impression. Ablative surgery is safe and effective for a large proportion of patients with severe, treatment-resistant OCD (N = 459 patients), with capsulotomy appearing to be the most effective. Although few studies have analysed preoperative imaging to predict response to psychiatric surgery (N = 101 patients), most studies implicate hyperactivity in the frontostriatal limbic network as correlating with clinical response.^26,27 There are no meta-analyses on epidural stimulation. While enthusiasm for DBS treatment in TRD has been tempered by recent randomized trials, a meta-analysis reveals a significant effect for DBS in the treatment of TRD (N = 186 patients).²⁷ Another meta-analysis showed equal efficacy for ablative neurosurgery (N = 444 patients) and DBS (N = 253 patients) in the treatment of refractory OCD.²⁸ Adjunctive VNS appeared to be effective and relatively safe in the treatment of TRD (N = 1048).²⁹ In an umbrella review, despite limited certainty, biological nonpharmacological interventions including DBS are effective and safe for numerous mental conditions.³⁰

Ethical Considerations and Legislative Framework

When psychosurgery was introduced in clinical practice, there was no ethical framework regulating its use.³¹ From 1955 to 1975, legislative institutions in countries such as Germany, Japan, and many US states voted for prohibiting psychosurgery. In France, the United Kingdom, Sweden, Spain, India, Belgium, the Netherlands, and a few American states the practice was allowed under close scrutiny.³²

In the early 1970s in New Orleans, the “Electrical Brain Stimulation Research Program” at Tulane University was investigated. The program raised concerns because of its dubious benefits for patients. One of these cases in 1972 involved a man with schizophrenia whose homosexual inclination was treated to achieve a “more acceptable” heterosexual behaviour.

The program had been launched in 1950 and consisted of implantation of brain electrodes to treat schizophrenia, neurosis, obesity, narcolepsy, aggressive behaviours, and epilepsy.

In the US, Congress launched an investigation as part of a vast legislative movement intended to regulate medical research more closely. In 1977 in the US, a federal commission evaluated the effectiveness and safety of psychosurgical interventions and deliberated that there was value to psychosurgery so that proscription was not indicated.⁴ This period coincided with the peak of the “antipsychiatry” movement and the release of great literary and cinematic successes such as “A Clockwork Orange” by Stanley Kubrick and indeed “One Flew Over the Cuckoo's Nest.” These events helped raise public awareness and promote reforms within psychiatric institutions resulting in improvements in therapeutic approaches which fostered compassion, individuality, humanity, and, above all, dignity.

Current practice dictates that ablative neurosurgical techniques should only be considered to treat severe and disabling mental disorders,³³ that is, schizophrenia, bipolar disorder, and TRD. Indeed, historically, surgical interventions had been limited in their application to those who were found to be resistant to all evidence-based interventions which, for illnesses such as schizophrenia, would include, according to guidelines, clozapine, and ECT.

At a patient, level it is essential to demonstrate the clinical need for invasive procedures and that less invasive therapies have been tried and have failed to bring distinctive clinical and quality-of-life improvements. As surgical brain therapies modify intimate brain connections intertwined with individuality and personality and hold the potential of affecting the very human characteristics of the treated individual,³⁴ they require a balanced and favourable risk-benefit evaluation.³⁵

In 2017, the Royal College of Psychiatrists in the United Kingdom issued a statement indicating that neurosurgical procedures are to be considered investigative and require an ethically approved research protocol.³² This means that most psychiatric neurosurgery is to be considered research rather than established care and should be suggested as a last resort. The World Society of Stereotactic and Functional Neurosurgery supports the importance of a careful selection of patients with chronic mental disorders refractory to treatment prior to considering neurosurgical therapy. In line with the above, invasive treatments are proposed only for patients who have been assessed by specialized clinical teams that evaluate the risks and benefits of the considered procedure within duly mandated multidisciplinary teams.³³ However, this approach is not always followed around the world with evidence of the use of stereotactic ablative neurosurgery, for example, to indiscriminately destroy the nucleus accumbens in heroin addicts in China and Russia.^34,35 Due to discrepancies around the world and the absence of clear standardization to guide clinical practice, international experts recommend the creation of an independent international registry to keep track of patients undergoing psychosurgery. Central to protecting patients is a necessity that independent ethics committees scrutinize the need for psychosurgery and play an overarching role in ensuring compliance with, and monitoring the fundamental principles of bioethics. These include vigilance over issues related to current clinical research data, evidence of informed consent and scrutiny of conflicts of interest to minimize the occurrence of misuse and ward-off new threats. Ethical standards would need to undergo international harmonization, although the scope, types of regulations and mechanisms to carry out such a complex process across different countries (and variable clinical practice) remain undefined.

At the heart of the ethical framework for psychosurgery, irrespective of the likely clinical variability, the indication for surgical treatment should always be evaluated and if deemed acceptable, consideration should be given to ablative neurosurgery versus functional neurosurgery (or other less invasive stimulatory techniques).³⁶ Clinical decisions on the use of invasive procedures should always be guided by the latest available clinical data with patients’ best interest in mind and the likely improvement of quality of life versus irreversible side effects, including permanent changes affecting personality structure.

Recommendations Towards an Ethical Approach to Psychosurgery

As this is an evolving field due to new technological approaches, much of the data comes from integrated clinical research, but sometimes only from case series or isolated clinical observations. It is therefore necessary to distinguish an ethical approach to research in psychosurgery from an ethical approach to the clinical application of psychosurgery. Referring only to clinical application, the key recommendation would be that there should be a consensus amongst experts in the field that there is sufficient research evidence to support a clinical application. Otherwise, for controlled clinical research, it is inherently bound by its own well-established ethical requirements.

Knowledge appraisal and transfer:

Differentiate “classic” lobotomies from “functional neurosurgery.”

Discriminate between noninvasive cerebral stimulation versus procedures requiring neurosurgical interventions.

Redefine new ablative neurosurgery.

Integration between neurosurgical techniques and psychotherapeutic strategies to foster recovery.

Importance of neurosurgical data collection of psychiatric applications (with and without meta-analyses).

Close evaluation of clinical indications for surgery.

Benefit versus harm analysis: for example, is the quality of life likely to benefit versus potential personality changes?

Appraisal of the potential stigmatizing impact of procedures.

Legal and ethical evaluation with decisions entrusted and monitored by multidisciplinary teams (including psychiatrists, neurosurgeons, psychologists, etc.).

Long-term monitoring of outcome, including technical issues such as battery life.

Absence of discrimination and inequalities when recommending surgery (e.g., sex, social status, minority groups, political beliefs, etc.).⁷

Conclusion and Future Directions

In the context of our current knowledge, the importance of research is crucial. There remains a need to establish rigorous evidence of efficacy before psychosurgery can be approved for clinical application.^37,38 Neurosurgery to treat psychiatric disorders has shifted from relatively simple invasive techniques to more selective and minimally invasive (stereotactic) neurosurgical approaches. The range of mental health conditions treated surgically has become more selective and treatment resistance staging procedures have become common practice to identify patients likely to benefit from this approach. Nowadays nonsurgical ablative treatments such as radiosurgery and more recently high-intensity focused ultrasound techniques have become available. The lack of firm aetiological models of mental disorders combined with technological progress has fuelled a transition from irreversible to reversible surgical techniques which use stimulators placed in critical brain functional nodes. There has also been tremendous progress in the development of ethical frameworks to help select patients likely to benefit the most from these procedures, although variability and lack of standardization around the world require further work to homogenize clinical practice.

Tomorrow's neurosurgery is likely to further shift from ablative procedures to functional techniques which focus on miniaturization and integration of implanted systems. Next-generation devices will no longer just stimulate but will also record brain activity and tailor neurostimulation according to brain responses. There is a push towards financing brain research entrepreneurship (iBrain, https://neurovigil.com) and new technologies could be adapted to neurostimulation applications, including optogenetics for example and newly developed portable brain activity monitors. It is predictable that psychosurgery combined with newly developed intelligent devices will allow interaction with brain function and human behaviour in a much more complex way. This evolution might challenge the existing legislation framework designed to safeguard patients.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

E. Stip

S. F. Javaid

D. Arnone

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