What functional neurosurgery can offer to psychiatric patients: a neuropsychiatric perspective☆

1. Introduction 

When reviewing the history of functional neurosurgery, the World Health Organization defined functional neurosurgery, additionally known as limbic system surgery or psychosurgery, as the following in 1976: “The selective surgical removal or destruction of nerve pathways for the purposes of influencing behavior” [6]. More than 30 years later, this previous statement proves to be rather limited, as techniques such as DBS are no longer ablative. As defined by the development of its dynamic history, functional neurosurgery has ultimately become a field that has expanded its role to involve areas such as neurology, psychiatry, and pain.

Berrios [2] provides a contemporary definition of psychosurgery based on 4 criteria which is imperative to consider before reviewing its history, which includes (1) direct interference with brain tissue, (2) irreversibility of the procedure, (3) normality of the tissue operated upon, and (4) the aim of the procedure is the alleviation of illness. These principles facilitated in defining the historical perspective of functional neurosurgery. Retrospectively, the historical highlight was at the end of the 19th century through the controversial works of Burckhardt [2], who ultimately performed the first topectomies on 6 patients considered to be mentally ill. As the 6 patients were affected by illnesses such as dementia and paranoia, Burckhardt decided to create specific lesions in the frontal and temporal regions of the brain to overall alleviate symptoms [2]. The results from these operations ranged from reducing levels of excitement and violence to the death of one patient a few days after the operation. Consequently, some researchers believed that his scientific approach was unethical; however, despite the controversy of his experiment, Burckardt facilitated in defining the role of psychosurgery and its effects in contemporary times, now considered one of the pioneers in the field.

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Furthermore, psychosurgery continued to progress, with highlights including the works of Egas Moniz and Almeida Lima who operated on and published the findings of 20 leukotomies of the frontal lobe [6]. Their works delineated the concept that more of the affective symptoms of these patients were resolved after undergoing this particular operation. In the advent of the 1930s, Moniz established his psychosurgical perspective after reviewing and combining the previous work of colleagues, specifically the “substitution” and “fixed connection” principles [2]. The substitution principle relates to the brain's adaptation to function after replacement of damaged areas. Furthermore, there was the underlying basis that the alteration of connections by damaging pertinent fibers within the pathway would ultimately lead to the improvement of overall function of the patient. In addition, the fixed connections principle involves learning techniques by the brain by creating functional circuits for further development [2]. Moniz's work was centered on 20 patients, targeting the frontal lobes in hopes of reducing emotions such as anxiety. As a result of these experiments, one third of the patients markedly improved, one third minimally improved, and the last third showed no change in alleviating their illnesses. After much debate about the significance of his results, his contributions regarding the lobotomy used as a therapeutic approach ultimately won him the Nobel Prize in Medicine in 1949.

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With the incorporation of the initial findings by Moniz and Lima, leukotomy soon became known as lobotomy in the United States and was advanced further by neuropsychiatrist Freeman and neurosurgeon Watts through the 1940s and 1950s. Moreover, the Papez model of the limbic system as well as the development of the 4 psychosurgical techniques used in modern times for refractory psychiatric illnesses ensued [6]. Although this particular period for functional neurosurgery appeared to flourish, its history would also confront its own obstacles. Major concerns, for example, were the allegations that this particular type of surgery was being used to control minority groups in society or to produce unethical side effects. In addition, during this period in history, the primary solution to treatment of mentally ill patients was a form of isolation from families and ultimately placement into asylums. There was no pharmacologic treatment, until the advent and use of lithium and phenothiazines, specifically chlorpromazine, which alleviated some of the symptoms experienced in depression and mania in the early1950s. Consequently, fewer individuals were found institutionalized, paving the way for directing the attention toward developing alternative treatments. However, despite these various obstacles, the lobotomy became more prevalent, and further advancement of the field continued.

Later during the 1950s, 2 researchers named Earnest Spiegel and Henry Wycis introduced human stereotactic surgery [7]. Procedural indications were particularly for individuals with movement disorders as well as its establishment as an alternative to preclude the complications associated with the lobotomy. With these objectives, Wycis and Spiegel ultimately created an apparatus from an existing model that would allow optimal precision by identifying landmarks within their surgery [7]. Distinctively, the objective of the operations was to provide treatment by targeting various aspects of the extrapyramidal pathways. Examples of these areas included the globus pallidus, dorsomedial and ventrolateral thalamus, and mesencephalon for pain. In fact, the first patient had Huntington chorea, an illness that would benefit from the alteration of the extrapyramidal pathways. Overall, the surgery demonstrated that lesions created could affect movement, while sparing a loss of weakness or control (Fig. 1).

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Fig. 1. Working apparatus design for stereotactic surgery from Wycis and Spiegel.

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With the continued advancement in psychosurgery, there became the critical need for strict regulation for the experiments that were performed. More specifically, federal regulations were implemented, hindering its use in certain countries including some areas of the US. For example, a US legislation was passed in the 1970s, legitimizing the methods of functional neurosurgery but also emphasized the importance of using ethical boards regarding the selection of patients and the protection of human subjects [6]. Currently, strict regulations on criteria, patient selection, and techniques are still prevalent as this discipline continues to progress.

Since the commencement of regulations in the 1970s, functional neurosurgery continues to be an integral component of refractory psychiatric therapy. A few of the developments from the last 30 years include exploring neural transplantation, developing neurotrophic electrodes for improving cerebral communication, and using genetic engineering to encode for neurotransmitters in the central nervous system [18]. Furthermore, the role of imaging such as within the area of radiosurgery [14] has also facilitated in developing these advancements by providing imaging modalities to assist within this realm of surgery. Consequently, imaging has improved its potential within various areas of medicine, particularly within the last decade, as it is regarded as minimally invasive.

More recently, the advent and advancement of DBS has also created an impact toward the therapeutic role of refractory psychiatric illnesses. Since the 1980s to the present times, this technique has displayed its capability to widen its potential for treatment. Originally, DBS stimulated the thalamus to treat essential and parkinsonian tremor [19]. As a result, DBS is not only a modality to treat functional disorders but also an aid in the management of neuropsychiatric illnesses.

From delving into the controversy of the first topectomies to defining the impact of high-frequency stimulation, functional neurosurgery has constructed a rich and exciting history over the period of years to delineate its role in management. Furthermore, the array of studies continues to serve as evidence of the importance of this realm as supportive therapy for patients with intractable psychiatric illnesses for years to come.

The World Health Organization defined functional neurosurgery, additionally known as psychosurgery, as the following in 1976: “The selective surgical removal or destruction of nerve pathways for the purposes of influencing behavior.” However, since the past 3 decades or so, the field of functional neurosurgery has been constantly changing, expanding to include areas such as neurology, psychiatry, and pain. The objective was to explore to what extent functional neurosurgery aided in the therapeutic treatment toward individuals who have intractable psychiatric illnesses where medications have failed. These primary illnesses include anxiety disorder, major depression disorder, and obsessive-compulsive disorders. Selected studies will be reviewed concerning 4 psychosurgical techniques, specifically cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leukotomy.

2. Techniques in functional neurosurgery 

There are 4 techniques used by functional neurosurgery that became the foundations of the field: cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leukotomy. The following will describe and highlight some of the important studies, not inclusive of all the experiments performed over the years.

2.1. Cingulotomy 

The first technique is cingulotomy which usually involves 1-cm bilateral lesioning of the cingulum using thermoregulation, affecting the pathways involved with intractable anxiety disorders, OCD, and treatment-resistant depression [12] (Fig. 2).

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Fig. 2. Axial T2-weighted (A) and sagittal T1-weighted (B) magnetic resonance images of anterior cingulotomy lesions.

Ballantine et al [1] ascertained more data through operative results including the use of thermal electrodes to produce 1.2-cm bilateral burr holes on either side of the midline. After the procedure, more than 60% of the individuals experienced improvements in their well-being such as alleviation of depression, anxiety, and OCD. Another study published by Kim et al [10] in 2003 involved using this same technique to treat refractory OCD. Fourteen patients participated, with 6 patients reflecting improvements in clinical severity, according to the Y-BOCS score. More research ensued as 17 individuals with refractory OCD were followed for more than 2 years in a study by Jung et al [9]. Consequently, stereotactic techniques with magnetic resonance imaging as a guide were used to create the lesions. Eight of the individuals responded positively with improvement of Y-BCOS score from their baseline [9]. In addition, Dougherty et al [5] provided a significant prospective study of 44 patients with refractory OCD by the Harvard group validating this technique. These patients, after no response to medical management, underwent one or more cingulotomies for treatment. Ultimately, after a 6-month follow-up, approximately up to 45% of the patients responded at least partly to the therapy, specifically 20 patients after one cingulotomy and 7 of the 18 patients who undertook multiple cingulotomies that were affected [5].

2.2. Capsulotomy 

The second technique is capsulotomy, where the therapy entails creating particular lesions in the anterior limb of the internal capsule to interrupt pathways between the thalamus and the orbitofrontal cortex. These lesions focus specifically on providing therapy for illnesses such as generalized anxiety disorder. The Rück et al [15] study, for example, included 26 individuals with a majority of the participants having the diagnosis of general anxiety disorder, followed by panic disorder and social phobia which were refractory to both pharmacologic and psychological treatment. Furthermore, these patients were followed for 1 year with neuropsychological testing after the capsulotomy. After using the Brief Scale for Anxiety and Montgomery-Asberg Depression Rating Scale for analysis, it was ascertained that 50% of the subjects showed an overall reduction of symptoms with no statistical significance between the different diagnoses involved in the study [15]. In addition, it was discussed, however, that adverse outcomes occurred after surgery, such as one patient committing suicide and a few patients with a decline in daily functioning. Despite the studies that have occurred, capsulotomy may be helpful in the treatment of patients with treatment-resistant anxiety disorders. However, of note, there is not yet a consensus that this technique could be helpful for patients with refractory OCD and treatment-resistant depression (Fig. 3).

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Fig. 3. Axial T1-weighted magnetic resonance image of anterior capsulotomy lesions.

2.3. Subcaudate tractotomy 

Developed in 1964 by Knight, the third technique is subcaudate tractotomy which targets modulation of frontal subcortical circuits. The fundamental methodology behind this particular technique involves bilateral lesions produced anterior to the caudate nucleus, affecting the limbic loop explored by Papez which was defined as the loop of emotion [12]. In addition, it explores treating individuals with OCD, anxiety, and affective disorders particularly resistant depression. The overall goal was to construct orbitofrontal lesions to modify the mood, while sparing alterations involving intellect. Subcaudate tractotomy is the only type of psychosurgery performed at the Geoffrey Knight Unit in London where nearly 1300 operations have taken place since 1961 [3]. Consequently, 40% to 60% of the patients ultimately live normal or near normal lives, while continuing medications in some instances. There was also a reduction of suicide rate to 1% postoperatively, compared to 15% in cases of uncontrolled affective disorders. Considered to be the last resort for treatment, no controlled trial against a comparable treatment is possible. However, it appears reasonable to offer this procedure to patients with suicidal and deluded depression or with frequently swinging moods, not responding to other treatments (Fig. 4).

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Fig. 4. Axial T2-weighted magnetic resonance image of subcaudate tractotomy lesions.

2.4. Limbic leukotomy 

Limbic leukotomy is a technique that involves the combination of cingulotomy and stereotactic subcaudate tractotomy. The objective of this surgical procedure is to provide treatment that affects the anxiety and depressive symptoms of patients with OCD (Fig. 5).

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Fig. 5. Target area of limbic leucotomy.

Montoya et al [13] produced one study with 21 patients with OCD and MDD during the years 1993 to 1999 at the Massachusetts General Hospital. The lesions developed specifically targeted the cingulate cortex, affecting learning and memory. The average postoperative follow-up period was approximately 2 years, with side effects including headaches, seizures, and wound infections. It was found that up to 36% to 50% of patients were considered responders, alleviating symptoms and ultimately improving their global functioning. In addition, the 2005 Sachdev and Sachdev [17] report explored 76 individuals with refractory depression who were treated with bilateral limbic leukotomy [16] with magnetic resonance imaging guidance between the years 1973 and 1995. There was a postoperative follow-up 1 year later, with the results of 2 cases of epilepsy and one case of alcohol abuse and poor motivation. The study, additionally, created global outcome categories consisting of (a) “fully recovered,” where there was no residual depression or side effects altering daily function; (b) “much improved,” where there were mild symptoms or relapse; (c) “mild improvement” including symptomatic improvement and minimal alteration of daily functioning; (d) no change, and (e) “worse,” where there were symptomatic or functionally worse outcomes and suicides [17]. Overall, outcomes showed that there was a good representation of improvement between 30% and 73% of the patients, according to the abovementioned scale.

These 4 techniques within the realm of functional neurosurgery are currently being used in centers around the world for the treatment of selected patients with intractable anxiety, OCD, and disorders of depression. As the techniques continue to evolve, brain imaging–guided surgery establishes itself as an important role in surgical procedures. Therefore, further research with similar diagnostic groups, neuropsychological outcome, and long-term follow-up is warranted.

3. Deep brain stimulation 

Deep brain stimulation is a therapeutic approach to treating individuals used by functional neurosurgeons as early as the 1980s. This particular technique, primarily used to treat movement disorders such as Parkinson's disease, is targeting other conditions such as refractory illnesses of OCD and MDD. With research continuing to explore the precise mechanisms of this technique, McIntyre e al [11] explored the fundamental concepts of DBS using constant, high-frequency stimulation and activating stimulated structures transmitted through various brain networks [13]. The article additionally discusses DBS constructing a 3-point connection for either stimulation or inhibition. This creation involves local cells near the electrode, afferent inputs making connections, and fibers of passage creating a path for this signal. The final result depends on physiologic and behavioral outputs surrounding the electrodes placed. Deep brain stimulation focuses on altering voltage-gated currents near the electrodes, using synaptic transmission and depression to produce a therapeutic response in patients. Chang [4] in his 2004 article discuss the use of high-frequency stimulation electrodes from DBS to the targeted areas, which ultimately creates long-lasting inhibition of pathways associated with movement disorders. Specifically, blocking sodium and calcium currents produces a firing rate that defines the therapeutic effect from DBS. As a result, high-frequency stimulation, overall, causes a firing rate increase in the internal segment of the globus pallidus while decreasing the thalamic firing rate within the basal ganglia pathways (Fig. 6).

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Fig. 6. Lead location for DBS.

One study has focused on DBS's objective to target the ventral striatum and the anterior internal capsule to treat individuals with refractory OCD. Data formulated included 10 individuals in whom 4 stimulatory leads were placed in the target brain regions of these participants. Activation of the DBS was performed 3 weeks later. Patients were then monitored every few months to determine the level of symptoms using the Y-BOCS scale. After following most of the individuals for 3 years, the results gathered showed that there was an overall 25% reduction of severity with the illness [8]. Side effects included surgical complications, one instance of an intracranial hemorrhage, and one intraoperative seizure. Despite these effects, DBS appears to be more of a benefit to refractory psychiatric illness. However, as there was a development of adverse effects seen within patients who experienced DBS, the promising benefits of therapy demonstrate a need for further development in treating refractory psychiatric illnesses.

4. Functional neurosurgery and psychiatric illness 

Functional neurosurgery and its advancement through the years have been used in the treatment of psychiatric illnesses such as OCD, anxiety, and MDD by focusing on specific circuits that are involved in their respective pathology. Functional neurosurgery has confirmed through imaging findings that OCD pathophysiology is based on the circuitry involving the orbital frontal cortex, caudate nucleus, and anterior cingulate gyrus. Other illnesses are involved with other mechanisms, such as MDD, which affects the frontal and temporal lobes as well as causes an imbalance of neutrotransmitters in the brain, which include norepinephrine, dopamine, and serotonin. The impact of functional neurosurgery in targeting these pathways creates precise lesions and, ultimately, alters the circuitry and affects the neurobiological basis that underlies the disease. With continued support and efforts of incorporating functional neurosurgery in the treatment of psychiatric patients, more refractory illnesses will benefit from this new modality of treatment. As functional neurosurgery progresses, other neurobiological procedures such as DBS, vagal nerve stimulation, and transcranial magnetic stimulation will open new avenues in the management of psychiatric conditions such as treatment-resistant depression, anxiety, and intractable OCD [20].

5. Conclusion 

To successfully treat refractory psychiatric illnesses with the use of functional neurosurgery, it is imperative to develop a multidisciplinary team composed of neurosurgeons, neurologists, psychiatrists, neuroradiologists, and brain imaging specialists. With the progression of research, to continue the advancement of psychosurgery in the treatment of refractory psychiatric illnesses, policies must be implemented for success. An ethics committee should also be established to foster the need for further research, and good assessment and strict criteria for the selection of patients are mandatory. It is evident that necessary steps are needed to ensure that the development of psychosurgery will reach its fullest potential in creating an impact in therapy in the realm of neurosurgery, neurology, and psychiatry in the future.