Neurosurgical interventions for psychiatric disorders have shown great promise, including creating lesions for the treatment of obsessive-compulsive disorder (OCD) and deep brain stimulation (DBS) in the treatment of major depressive disorder (MDD).1,2 Despite this promise, these functional procedures have followed a controversial lineage. From trepanation to prefrontal lobotomy (and to anterior cingulotomies and beyond), early procedures involving removing brain matter have contributed to public distrust of psychosurgery.3,4 These surgeries have declined in popularity due to the aforementioned stigma and the development of effective pharmacological interventions for psychiatric diseases. However, the intolerable side effects of many medications for schizophrenia, combined with the fact that an estimated 50% of patients with this disease do not comply with medication regimens, make alternative, long-term treatment modalities desirable.5 Emerging evidence suggests that specific functional neurosurgical procedures may hold significant therapeutic efficacy for severe psychiatric disorders, including schizophrenia.4–6
Despite having a relatively low prevalence (0.28% globally), the burden of illness due to schizophrenia is estimated to contribute to 13.4 million years of life lived with disability globally, ranking it 15th among all causes of years lived with disability worldwide.7,8 Thus, for cases of refractory schizophrenia in which there are no currently valid pharmacological alternatives (especially clozapine-resistant schizophrenia, which makes up 40%–70% of treatment-resistant schizophrenia), other avenues of treatment may be indicated.9 These include electroconvulsive therapy and repetitive transcranial magnetic stimulation (TMS), which, although effective in the short term, do not confer long-term benefits for patients.
Patients who undergo this maximum level of medical management and remain symptomatic are then potential candidates for neurosurgical interventions, including DBS. After receiving a humanitarian device exemption in 2009 for treating OCD, DBS has been undergoing trials as a therapeutic modality for a broad spectrum of psychiatric disorders, including addiction, depression, and schizophrenia.10,11
Coupled with strong efforts to elucidate the neural network dysfunction underlying psychiatric disease, the emergence of DBS is timely. More specifically, increased interest in DBS for schizophrenia and other psychiatric disorders has occurred in parallel with an effort to understand functional correlates—and potential neurosurgical targets—implicated in neuropsychiatric dysfunction.12 This renewed interest creates opportunities for careful consideration of neurosurgical interventions in psychiatric disorders. In the present review, we discuss our current understanding of the pathophysiology of schizophrenia and the rationale for neurosurgical targets that have been proposed and clinically evaluated thus far.
Methods
Systematic Search for Neurosurgical Interventions in Schizophrenia: Animal and Human Trials
To identify all studies reporting neurosurgical interventions for schizophrenia, we systematically queried the PubMed, Scopus, and Web of Science databases using the following boolean search term: (Neurosurgery OR DBS OR ablation OR tractotomy) AND (Schizophrenia). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. We adhered to the following inclusion criteria: studies published between 2012 and 2022 involving animal or human neurosurgical treatments for schizophrenia. Articles were excluded if the target was not clearly identified, schizophrenia was not the primary clinical interest, the studies were not primary sources, or outcomes were not reported. A summary of the studies identified is recorded in Table 1, and the literature review process is shown in Fig. 1.
Characteristics of literature review studies
| Authors & Year | Country | Study Design | Sample Size |
|---|---|---|---|
| Liu et al., 201426 | China | Prospective cohort (human) | 116 |
| Corripio et al., 201647 | Spain | Case study (human) | 1 |
| Corripio et al., 202017 | Spain | Prospective cohort (human) | 7 |
| Wang et al., 202018 | China | Prospective cohort (human) | 2 |
| Zhang et al., 202119 | China | Prospective cohort (human) | 2 |
| Vilela-Filho et al., 202122 | Brazil | Retrospective cohort (human) | 5 |
| Cascella et al., 202120 | US | Case study (human) | 1 |
| Galkin et al., 202224 | Russia | Case study (human) | 1 |
| Bikovsky et al., 201616 | Israel | Prospective cohort (animal) | 27 |
| Hadar et al., 201821 | Germany | Prospective cohort (animal) | 104 |
PRISMA flow diagram of studies included in the final analysis. Data added to the PRISMA template (from Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71) under the terms of the Creative Commons Attribution License.
Systematic Search for Current Clinical Trials
To identify ongoing research on neurosurgical interventions for schizophrenia, a separate search was conducted. Specifically, the United States National Library of Medicine’s ClinicalTrials.gov database and the International Clinical Trials Registry Platform were queried. In a manner consistent with the previous literature search, the boolean search term (Neurosurgery OR DBS OR ablation OR tractotomy) AND (Schizophrenia) was used by two separate authors to identify relevant trials according to PRISMA guidelines. Duplicate trials were identified and removed. Once all trials that met inclusion criteria were identified, the specific neurosurgical intervention, registration date, public title, target sample size, study design, target(s), and country were recorded for each trial in Table 2.
Characteristics and findings of clinical studies
| Procedure | Authors & Year | Sample Size | Max FU | Outcomes | Complications |
|---|---|---|---|---|---|
| NAcc-DBS | Corripio et al., 201647 | 1 | 11 mos | PANSS positive score reduction from 13 to 5 (61.54% reduction), PANSS negative score reduction from 18 to 12 (33.4% reduction) | Akathisia, mitigated by switching to unilat stimulation |
| Corripio et al., 202017 | 3 | 20 mos | 2 pts met symptomatic improvement criteria (58% & 86% reduction in PANSS total) | Akathisia (n = 1), mitigated by switching to unilat stimulation; hypomania (n = 1); "electrical sensations" (n = 1) | |
| Subgenual ACC-DBS | Corripio et al., 202017 | 4 | 20 mos | 2 pts met symptomatic improvement criteria (37% & 68% reduction in PANSS total) | Rt internal capsule hemorrhage followed by infection (n = 1) |
| HB-DBS | Wang et al., 202018 | 2 | 12 mos | 1 pt had a 32% improvement in PANSS total at 12-mo FU | 1 pt had a 20.3% improvement in PANSS total at 7-mo FU, but a 9.5% worsening in PANSS total at 10 mos, prompting discontinuation of DBS |
| Zhang et al., 202119 | 2 | 1 mo | Heart rate, pain, & involuntary movements increased w/ voltage; no schizophrenia-specific symptoms evaluated | Feelings of pain constantly throughout trial (n = 1) & involuntary eye closure (n = 1) | |
| SNpr-DBS | Cascella et al., 202120 | 1 | 12 mos | BPRS score decreased from 42 (extremely severe) to 20; hallucination (initially 6) & unusual thought content (initially 7) scores both decreased to 1 (i.e., not present) | Increased appetite reported |
| Subcaudate tractotomy | Vilela-Filho et al., 202122 | 5 | 72 mos | 2 pts had improvement of delusions & hallucinations, 2 had remission of delusions & hallucinations, & 1 pt had recurrence of psychotic symptoms 1 mo after surgery | Bacterial meningitis secondary to surgical wound infection (n = 1) & ischemia of the posterior limb of left internal capsule (n = 1) |
| Anterior capsulotomy | Liu et al., 201426 | 116 | 24 mos | PANSS negative & positive scores decreased after surgery & 2-yr FU significantly (n = 100; 16 did not return for FU) & reduced dosage of medications (n = 71) | Urinary incontinence (n = 18), disorientation (n = 4), sleep disorder (n = 2), & fatigue (n = 10) were short-term symptoms; bulimia (n = 9), memory loss (n = 7), personality change (n = 6); intracranial hemorrhages & seizures each occurred w/ 1% of surgeries |
| Galkin et al., 202224 | 1 | 13 mos | Decrease in YBOCS score from 36 to 27 at 13-mo FU; HADS score decreased from 21 & 19 to 16 & 8 at 13-mo FU, respectively | None reported |
FU = follow-up; HADS = Hospital Anxiety and Depression Scale; max = maximum; pts = patients; YBOCS = Yale-Brown Obsessive-Compulsive Scale.
Quality Assessment
The quality of all included studies was assessed using the ROBINS-I (Risk of Bias in Nonrandomized Studies of Interventions) tool.13
Results
There were 1265 records identified through the searches of PubMed, Scopus, and Web of Science. Duplicates were identified using Rayyan software, and then manually excluded. Title and abstract screening were performed independently by two authors (B.P. and M.L.), and 1252 articles were excluded. A total of 13 full-text articles were assessed for eligibility, and 2 records were excluded due to lack of neurosurgical intervention. One record was excluded because it stemmed from the same data published in another study. Ultimately, 8 human studies and 2 animal studies exploring neurosurgical intervention for schizophrenia were included.
Overview of Studies Identified
As shown in Table 1, 3 of the human studies were conducted in China, 2 in Spain, 1 in Brazil, 1 in the US, and 1 in Russia. These studies were published between 2014 and 2021. The intervention used in 5 of these studies was DBS, with a total of 5 targets, although some studies included more than 1 target. Two targeted the nucleus accumbens (NAcc), 1 targeted the subgenual anterior cingulate cortex (ACC), 2 targeted the habenula (HB), and 1 targeted the substantia nigra pars reticulata (SNpr). Three additional studies performed neuroablations to treat refractory schizophrenia. In 1 study subcaudate tractotomies were performed, whereas anterior capsulotomies were performed in 2 others. The procedures, authors, publication years, sample sizes, follow-ups, outcomes, and complications are displayed in Table 2.
Two studies were identified that reported the investigation of DBS for schizophrenia by using animal models. Both of these studies used the Wistar rat poly(I:C) model, which hyperactivates the disrupted-in-schizophrenia 1 (DISC1) gene.14 One targeted the medial prefrontal cortex (mPFC) (n = 6) and the NAcc (n = 8), whereas the other larger study targeted the prefrontal cortex (PFC) (n = 104) solely. The outcomes of these studies are presented in Table 3.
Characteristics and findings of animal studies
| Procedure | Authors & Year | Sample Size | Animal | Outcomes | Complications |
|---|---|---|---|---|---|
| NAcc-DBS | Bikovsky et al., 201616 | 8 (8 saline) | Wistar rats | Improved prepulse & latent inhibition in schizophrenia models & controls | None reported |
| mPFC-DBS | Bikovsky et al., 201616 | 6 (5 saline) | Wistar rats | Improved prepulse & latent inhibition in schizophrenia models | None reported |
| Hadar et al., 201821 | 104 (46 saline) | Wistar rats | Improved prepulse & latent inhibition in schizophrenia models | None reported |
Nucleus Accumbens
Among the human studies identified in this review, 3 of 4 patients experienced symptomatic improvement (n = 2) or remission (n = 1) with DBS of the NAcc.15 Patients ranged in age from 35 to 46 years, 2 were female, and all of them had undergone unsuccessful treatment attempts with clozapine prior to NAcc-DBS. Although side effects included akathisia, hypomania, and "electrical sensations" in 1 patient, follow-up showed decreases in Positive and Negative Syndrome Scale (PANSS) scores, as described in Table 2. The patient who developed akathisia underwent a change from bilateral to unilateral stimulation, which resolved the symptoms. The same change was implemented in the patient who experienced electrical sensations, and the sensations resolved. Another patient (who achieved symptom remission) developed hypomanic symptoms after electing to discontinue antipsychotic medication postoperatively. After antipsychotic medication (aripiprazole) was reinstated, these hypomanic symptoms were resolved.
A potential therapeutic benefit of NAcc-DBS was demonstrated in the Wistar rat poly(I:C) model of schizophrenia. NAcc-DBS was associated with improved sensorimotor gating as measured by prepulse and latent inhibition in the acoustic startle reflex and thirst-motivated conditioned emotional response assay, respectively.16 NAcc-DBS was also observed to increase activity of the striatum, ventral hippocampus, parietal cortex, and NAcc, while reducing activity in the brainstem, periaqueductal gray matter, hypothalamus, and cerebellum.16
Subgenual ACC
A 2020 study by Corripio and colleagues that investigated DBS of the subgenual ACC found that 2 of 4 patients experienced significant (37% and 68%) reduction in PANSS total scores.17 Among the patients included in the study, ages ranged from 34 to 54 years, 2 were female, and all of them had undergone unsuccessful treatment attempts with clozapine prior to subgenual ACC-DBS.
One of the patients suffered a hemorrhage immediately after the procedure and, as a consequence of subsequent infection, did not undergo stimulation. Rather, the patient underwent electrode removal 3 months after the initial surgery. Following electrode removal, the patient experienced improvement in psychotic symptoms for up to 7 months after the initial implantation; however, the symptoms eventually returned. He developed seizures, which were controlled by anticonvulsant medication, and an anterior right internal capsule lesion was found.
Habenula
Wang and colleagues reported on the results of their pilot study investigating bilateral HB-DBS for treatment of severe, treatment-resistant schizophrenia in 2 male patients (ages 21 and 26 years).18 The PANSS was used to assess the primary outcome: the severity of positive and negative symptoms. Clinical improvement was observed in both patients over the first 6 months of the study. However, at the 12-month follow-up, only one patient maintained clinically significant improvement, whereas the second patient demonstrated significant worsening of symptoms and required hospitalization at the 10-month follow-up.
Another study by Zhang and colleagues investigated HB-DBS in schizophrenia, but no psychotic symptom changes (improvement or worsening) were evaluated in the study.19 The patients (n = 2) were reported to have experienced increases in heart rate, pain, and involuntary movements with increasing voltage.
Given that the therapeutic potential of HB-DBS vis-à-vis psychotic symptoms has been assessed only in a small cohort of 2 patients, definitive conclusions regarding its effectiveness cannot be made. The observation that 1 patient exhibited significant, sustained clinical improvement supports the possibility that HB-DBS may be efficacious in a subset of patients and merits further consideration. Future studies may provide further insights regarding optimal patient selection for HB-DBS.
Substantia Nigra Pars Reticulata
The individual (a 35-year-old woman) who received SN-DBS reported an immediate cessation of chronic hallucinations and a complete remission of delusions after 12 weeks.20 The patient experienced increased appetite and weight gain for the first 3 months following the procedure. Additionally, measures of her verbal and visuospatial learning and memory declined. Conversely, her measured phonemic and semantic verbal fluency was increased postoperatively.
Although PANSS scores were not included in the study, the patient’s Brief Psychiatric Rating Scale (BPRS) score decreased from 42 (extremely severe) to 20. Her hallucination (initially 6) and unusual thought content (initially 7) scores both decreased to 1 (i.e., not present).
Medial Prefrontal Cortex
The animal studies that investigated mPFC-DBS using the Wistar rat poly(I:C) model of schizophrenia reported normalized prepulse and lateral inhibition, which are implicit in normal sensorimotor function, and improvement in behavioral deficits in response to organismal stress. These metrics of schizophrenia-like symptomatic improvement were measured through acoustic startle reflex (prepulse inhibition) and thirst-motivated conditioned emotional response (latent inhibition) assays.16,21
Subcaudate Tractotomy
In 2021, Vilela-Filho et al. found that 4 of 5 patients (age range 27–65 years, all male) who underwent subcaudate tractotomy experienced complete cessation of delusions and hallucinations.22 However, 2 of the 4 patients with symptom resolution experienced severe surgical complications, including bacterial meningitis secondary to wound infection and ischemia of the left internal capsule.
Of note, patients in this study had all undergone bilateral amygdalotomy and bilateral anterior cingulotomy (with no success) prior to the subcaudate tractotomy. The authors suggest that combination effects of all three neuroablative procedures may be responsible for the resolution of psychotic symptoms, rather than the subcaudate tractotomy alone.
Anterior Capsulotomy
A recent case report by Galkin and colleagues reported on a 36-year-old man with both schizophrenia and severe comorbid OCD symptoms who was treated with Gamma Knife capsulotomy.24 Previous research on stereotactic ablation of the anterior limb of the internal capsule (ALIC) indicated, in line with this recent study, that anterior capsulotomy can effectively treat obsessive-compulsive symptoms.23,25 The other anterior capsulotomy study identified in this review, published by Liu et al. in 2014, indicated a 74% success rate with significant decreases across PANSS scores in 100 treatment-resistant patients (55 male, 45 female; age range 18–59 years) who underwent the procedure.26 However, many of these patients experienced a constellation of side effects, including transient incontinence, bulimia, and memory loss.
Current Clinical Trials
Our search for ongoing clinical trials yielded 5 investigations that are currently registered (1 withdrawn, 1 completed, and 3 recruiting). Two trials are in Spain, and 1 trial each is in Canada, the US, and China. Of note, the largest current study (n = 162) compares NAcc and hippocampal DBS to noninvasive antipsychotic treatments. One study that targeted the NAcc, ventral striatum, and ventral tegmental area (VTA) was withdrawn. The two other recruiting studies include one targeting the ACC and NAcc and another targeting the SNpr. The study titles, statuses, interventions, start dates, sample sizes, targets, and countries are displayed in Table 4.
Characteristics of registered clinical trials
| Study Title | Status | Intervention | Start Date | Target Sample Size | Target(s) | Country |
|---|---|---|---|---|---|---|
| Deep Brain Stimulation Recovery in Treatment-Resistant Schizophrenia | Recruiting | DBS | 1/2021 | 6 (actual: 6) | ACC & NAcc | Spain |
| Deep Brain Stimulation (DBS) for the Management of Treatment Refractory Negative Symptoms in Schizophrenia | Withdrawn | DBS | 9/2012 | 6 (actual: 0) | NAcc/ventral striatum & VTA | Canada |
| Deep Brain Stimulation in Treatment Resistant Schizophrenia | Completed | DBS | 1/2013 | 8 (actual: 8) | NAcc & mPFC | Spain |
| Deep Brain Stimulation in Treatment Resistant Schizophrenia | Recruiting | DBS | 6/2012 | 3 (actual: 3) | SNpr | US |
| SMART Design to Compare Antipsychotic Treatments in Treatment-Resistant Schizophrenia | Recruiting | DBS vs clozapine vs clozapine + amisulpride vs clozapine + Ginkgo biloba vs MECT vs MST | 12/2020 | 162 | NAcc & hippocampus | China |
MECT = modified electroconvulsive therapy; MST = magnetic seizure therapy; SMART = sequential multiple assignment randomized trial.
Quality Assessment
Overall, there was moderate risk of bias among the studies included in this review. Quality assessment revealed one study with moderate postinterventional risk of bias due to a subset of patients (16/116) not completing follow-up evaluation after their neurosurgical intervention, which could introduce nonresponse bias.26 Another study was identified that was defined as having a moderate postinterventional risk of bias because the follow-up time for patients was only 1 month.16 The assessment also revealed two studies with moderate preinterventional risk of bias in which electroconvulsive therapy was offered to and accepted by some participants, even though it was not included in the criteria used to determine treatment-refractory status.17,22 Furthermore, in the other study with moderate preinterventional risk of bias, 1 patient’s symptomatic improvement mysteriously reversed at approximately the 10-month follow-up, which was later found to be due to an accidental discontinuation of stimulation.17 The remainder of the studies were found to possess a low risk of preinterventional, interventional, and postinterventional bias on account of thorough psychiatric history, similar procedure and follow-up windows, and standardized methods of outcome assessment.16,18,21
Discussion
Schizophrenia: Merging Pathophysiology, Neuroimaging Findings, and Neurosurgical Applications
In the 1950s, schizophrenia was theorized to arise from an imbalance of dopamine release in the basal ganglia and PFC.27 Prior to the advent of advanced neuroimaging modalities, this hypothesis was based solely on pharmacological observations. The positive symptoms of schizophrenia, such as hallucinations and delusions, were attributed to hyperdopaminergic activity in the mesolimbic pathway, whereas negative symptoms, such as flat affect and social withdrawal, were believed to arise from dopamine deficiency in the mesocortical pathway.28–31 However, given the wide spectrum of clinical presentations, the dopamine theory probably grossly oversimplifies the underlying pathophysiology. More recently, studies have implicated other neurotransmitters as well, such as glutamate, serotonin, γ-aminobutyric acid (GABA), acetylcholine, and even inflammatory mediators (cytokines).32
Evidence from neuroimaging studies supports a role for aberrant dopamine neurotransmission in schizophrenia. PET studies have demonstrated increased dopamine release in the striatum of schizophrenic patients,33 whereas functional MRI studies have associated hallucinations and delusions with activations in the hippocampus, striatum, and midbrain.12 Furthermore, voxel-based morphometry of structural MRI has identified significantly decreased gray matter in the PFCs of schizophrenic patients as well as an overall decreased frontal lobe volume, which may explain the hallmark feature of executive dysfunction observed in schizophrenia.34,35 Other findings have included decreased hippocampal gray matter and volume loss, decreased functional connectivity between the hippocampus and PFC, decreased functional connectivity between the hippocampus and default mode network, and hyperconnectivity between the hippocampus and the lateral occipital cortex.36–42
TMS is a noninvasive form of neuromodulation that induces electrical currents in brain tissue by applying a magnetic field to an area of cerebral cortex. TMS has provided unique insights into cortical excitability in schizophrenia by means of paired-pulse paradigms that measure intracortical facilitation and inhibition.12 Abnormalities in these parameters are believed to indicate alterations in GABAergic and glutamatergic neurotransmission, respectively. Interestingly, positive symptoms of schizophrenia have been associated with reduced short-interval cortical inhibition, which suggests that there is a baseline heightened cortical excitability that may be related to deficient GABAA receptor signaling. Negative symptoms, on the other hand, have been associated with shortening of the cortical silent period, which is the period in which electromyographic activity is suppressed following a TMS pulse to the contralateral motor cortex.43 The cortical silent period is believed to occur due to the activity of GABAB receptors in the motor cortex. The severity of negative symptoms in schizophrenia is observed to be associated with an inversely proportional shortening of the cortical silent period, and this is taken to indicate that negative symptoms may be related to alterations in GABAB neurotransmission.
DBS: Targets, Evidence, and Rationale
The success of DBS for treatment of movement disorders suggests that this modality may be similarly applied to brain circuits involved in psychiatric disorders. Although the mechanisms contributing to psychiatric disturbances are less understood than those of Parkinson’s disease, the success of DBS and neuroablative techniques for depression and OCD is encouraging.2 This progress lends plausible credibility to analogous procedures for schizophrenia, especially considering that schizophrenia shares similar features with MDD and OCD. For example, the negative symptoms of schizophrenia parallel core symptoms of MDD, and deficiencies in executive functions, particularly those involving the orbitofrontal cortex, may be similar to those observed in OCD. Anatomical regions and networks used in neuromodulation treatments for MDD and OCD may then be strong candidates for DBS in schizophrenia. As an example, cognitive deficits observed in both MDD and OCD have been linked to the subgenual ACC, one of the regions stimulated in humans.44–46 In the following section, neuromodulatory target selection for schizophrenia, as based on pathophysiological findings associated with this disorder, will be reviewed.
Nucleus Accumbens
The NAcc (Fig. 2) has long been implicated in schizophrenia, and thus naturally represents one of the regions that has been tested as a potential therapeutic target of DBS in humans.15,17,47 Although pathophysiology in schizophrenia is diverse and heterogeneous in both source and clinical presentation, a constellation of schizophrenia-related symptoms and neurological dysfunction has been linked to the NAcc.48 The fact that the NAcc is a key player in lateral inhibition, which decreases stimulation leading to acute hallucinations and delusions, may explain its role in the positive, neuroexcitatory symptoms observed in schizophrenia.49
Left: Sagittal MRI slice showing NAcc outlined in red. Right: Coronal MRI slice showing NAcc outlined in red. User (left panel): Was a bee. Wikimedia Commons. Public domain. User (right panel): Geoff B. Hall. Wikimedia Commons. Public domain. Used with permission from Wiki Commons. Available online.
For example, a study by Goto and O’Donnell suggested that abnormal PFC activation triggers symptoms of schizophrenia in animal models by increasing glutaminergic drive in the NAcc.50 Furthermore, increased NAcc volume was found among patients with first-episode psychosis compared to controls, which also extended to negative symptom severity in people with schizophrenia.51 More recently, studies have considered the role of the NAcc in signaling and functional connectivity. For example, mouse models of schizophrenia treated with risperidone show ameliorated neuronal atrophy, lessened dendritic spine damage, and normalized inflammatory pathways.52
Subgenual ACC
The subgenual ACC has been associated with schizophrenia in addition to other psychiatric disorders, including bipolar disorder and MDD.45,46 One major component of this association appears to involve astrocyte density. A study comparing post-mortem schizophrenic brains to those with other psychiatric disorders and to control brains found that schizophrenic brains are distinctly characterized by decreased fibrillary astrocyte density in the white matter of the subgenual cingulate cortex.53 This finding suggests a highly specific mechanism that is unique to the pathophysiology of schizophrenia. Other glial cell types, such as oligodendrocytes, are not deficient in schizophrenic brains, strengthening the association between astrocytes and schizophrenia pathology.54 Furthermore, specific symptoms of schizophrenia (e.g., anhedonia) have been linked to altered resting-state functional activity in the subgenual ACC.55
Habenula
The HB has been investigated as a potential therapeutic target in schizophrenia due to its role in suppressing the substantia nigra pars compacta and VTA, both of which are sources of dopamine release and may contribute to aberrant dopamine signaling.56 Increased habenular calcification has been noted in CT studies of postmortem human brain slices of patients with schizophrenia, suggesting a potential link between anatomical modification of the HB and schizophrenia.57
Substantia Nigra Pars Reticulata
The SNpr is associated with dopaminergic dysfunction in Parkinson’s disease and has been studied in schizophrenia as well. SN hyperactivity and increased glutamatergic neurotransmission in the SN have been associated with schizophrenia. Mabry et al. examined glutamatergic axon terminals in the SN of post-mortem schizophrenic brains compared to control brains. Among controls, they observed a negative correlation between the density of vesicular glutamate transporter 1 and that of glutamate hydroxylase. However, among schizophrenic brains, increased vesicular glutamate transporter 1 density was positively correlated with the density of glutamate hydroxylase.58 This finding, along with the finding of increased SN glutamate hydroxylase activity in schizophrenia,59 suggests that altered GABAergic output of the SN plays a role in schizophrenia pathophysiology. Another study has found that axons in the SN of schizophrenic brains had a significantly higher percentage of cytoplasmic inclusions in their myelin sheaths compared to normal controls.60 Evidence from human studies also suggests that SN-DBS may be efficacious in the treatment of schizophrenia. One study found that functional hyperactivity of the SN accurately predicts an individual’s psychosis level.61
Medial Prefrontal Cortex
Altered dopaminergic and GABAergic signaling in the mPFC is believed to contribute to cognitive dysfunction in schizophrenia.62 Researchers have identified polygenic risk factors affecting mPFC-hippocampal functional connectivity that appear to lead to the development of schizophrenia pathology.37 Furthermore, the amplitude of low-frequency fluctuations in the default mode network, including the mPFC, was found to be decreased among subjects with schizophrenia, which is thought to contribute to cognitive impairments.63
Neuroablative Procedures
Subcaudate Tractotomy
Neuroablative procedures may also hold promise for treatment of schizophrenia. The goal of the subcaudate tractotomy is to sever connections between the caudate nucleus and brain regions that putatively contribute to schizophrenia pathology.22,64 Crespo-Facorro et al. found a positive correlation between caudate nucleus volume and the severity of psychotic symptoms among schizophrenic patients, although there was no significant difference in caudate nucleus volume between patients and controls.65 Furthermore, compared to controls,66 enhanced functional connectivity has been found between the caudate nucleus and the posterior cingulate cortex, temporal, and occipital regions in patients with schizophrenia.
Whether or not subcaudate tractotomy, which does not require implantation of a medical device, is preferable to DBS for treatment-refractory schizophrenia remains to be determined. Regardless, it is apparent that the caudate and the subcaudate nucleus merit further investigation as anatomical targets in neurosurgical interventions for schizophrenia.
Anterior Capsulotomy
The ALIC has long been targeted in psychiatric disorders, the first documented anterior capsulotomy having been performed in 1949 by Jean Talairach, as discussed in Zanello et al.67 Connections between the thalamus and the PFC run in the ALIC, and anterior capsulotomy, which severs these connections, has been performed in treatment for multiple psychiatric conditions, especially OCD.23
The two studies featuring anterior capsulotomy identified in this review showed some promise (e.g., one showed a 74% success rate with significant decreases across PANSS scores in 100 patients). However, the relatively high incidence of cognitive side effects calls for further investigation, especially considering that the procedure is irreversible.24,26
Ethical Considerations
There are unique ethical concerns regarding studies of neuromodulation for psychiatric disorders due to a combination of factors, particularly regarding informed consent and the vulnerability of the patient population. All selected trial participants should meet clinical criteria for treatment-resistant schizophrenia to ensure that another, less invasive treatment modality has not been overlooked. For example, included participants may be patients in whom multiple pharmacological trials, one of which must have been clozapine, have failed. These patients may also fall within set parameters on multiple neuropsychiatric measures and demonstrate severely impaired functioning for at least 5 years.68 In participant selection, the 4 pillars of medical ethics must be honored: respect for autonomy, beneficence, nonmaleficence, and justice. Of particular importance are respect for autonomy and justice; the surgeon must be confident that the patient can provide informed consent, and that the intervention is in line with the goals and personal values of the patient.69 Neuropsychiatric evaluation is required prior to surgery to establish the baseline cognitive function of the patient and to estimate the risk of decline from undergoing an elective surgical procedure.
Neurosurgical interventions carry inherent risks, and these risks must be weighed against the potential benefits of treatment. In the case of psychosurgery, these benefits are variable and uncertain at best. The risk of lesion- or stimulation-related side effects must also be considered. For example, although adverse side effects with NAcc subgenual ACC were infrequent, in the study by Corripio et al., 2 of 7 patients developed persistent negative symptoms (apathy and mood instability).17
Conclusions
The pathophysiology of schizophrenia is complex and probably reflects dysfunction of multiple brain circuits. A culmination of evidence from both animal and human studies implicates global deterioration in prefrontal brain regions that normally inhibit subcortical structures. Imbalances between dopamine signals in the ventral striatum and inhibitory projections from the PFC may underlie positive symptoms in schizophrenia, whereas gray matter loss and aberrant neurotransmission in the PFC may be responsible for negative symptoms. Schizophrenia may in fact represent a spectrum of cortical and subcortical brain circuit dysfunction, and modulation of the same target may not be sufficient in all patients. The results of trials of DBS for psychiatric disorders suggest that the source of dysfunction among patients with the same diagnosis can be variable, leading to heterogeneous responses. As a result of multiple barriers to conducting high-quality preclinical studies, such as ethical concerns and a relative lack of translational animal models, we are having to work backward, performing trials of multiple interventions with little knowledge of the dysfunctional circuits we are attempting to correct. Nevertheless, through these efforts, insights into the origins of psychiatric disease will be gained as we investigate the differences between responders and nonresponders. As we progress in our understanding of psychiatric disturbances, we may need to shift our focus from the clinical disorder to the underlying mechanisms of the disorder in the individual patient.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Paff, Dutta, Picton, Brown, Yang. Acquisition of data: Paff, Dutta, Picton, Lee. Analysis and interpretation of data: Paff, Dutta, Picton, Brown, Yang, Lopez. Drafting the article: all authors. Critically revising the article: Paff, Dutta, Picton, Brown, Yang, Lee, Lopez. Reviewed submitted version of manuscript: Paff, Dutta, Picton, Brown, Yang, Lee, Lopez. Statistical analysis: Dutta. Administrative/technical/material support: Yang, Lopez. Study supervision: Brown, Lopez.
References
- 1.↑
Dandekar MP, Fenoy AJ, Carvalho AF, Soares JC, Quevedo J. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry. 2018;23(5):1094–1112.
- 2.↑
Shah DB, Pesiridou A, Baltuch GH, Malone DA, O’Reardon JP. Functional neurosurgery in the treatment of severe obsessive compulsive disorder and major depression: overview of disease circuits and therapeutic targeting for the clinician. Psychiatry (Edgmont). 2008;5(9):24–33.
- 3.↑
Faria MA Jr. Violence, mental illness, and the brain—a brief history of psychosurgery: Part 2—From the limbic system and cingulotomy to deep brain stimulation. Surg Neurol Int. 2013;4:75.
- 4.↑
Schweder PM, Cosgrove GR. A history of psychosurgery. In: Winn HR, ed. Youmans Neurological Surgery. Elsevier; 2011:1001-1004.
- 5.↑
Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry. 2002;63(12):1121–1128.
- 6.↑
Lapidus KAB, Kopell BH, Ben-Haim S, Rezai AR, Goodman WK. History of psychosurgery: a psychiatrist’s perspective. World Neurosurg. 2013;80(3-4):S27.e1–e16.
- 7.↑
Charlson FJ, Ferrari AJ, Santomauro DF, et al. Global epidemiology and burden of schizophrenia: findings from the Global Burden of Disease Study 2016. Schizophr Bull. 2018;44(6):1195–1203.
- 8.↑
2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211–1259.
- 9.↑
Chakrabarti S. Clozapine resistant schizophrenia: newer avenues of management. World J Psychiatry. 2021;11(8):429–448.
- 10.↑
Kisely S, Li A, Warren N, Siskind D. A systematic review and meta-analysis of deep brain stimulation for depression. Depress Anxiety. 2018;35(5):468–480.
- 11.↑
Wang TR, Moosa S, Dallapiazza RF, Elias WJ, Lynch WJ. Deep brain stimulation for the treatment of drug addiction. Neurosurg Focus. 2018;45(2):E11.
- 12.↑
Mikell CB, Sinha S, Sheth SA. Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target. J Neurosurg. 2016;124(4):917–928.
- 13.↑
Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.
- 14.↑
Abazyan B, Nomura J, Kannan G, et al. Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry. 2010;68(12):1172–1181.
- 15.↑
Roldán A, Portella MJ, Sampedro F, et al. Brain metabolic changes in patients with treatment resistant schizophrenia treated with deep brain stimulation: a series of cases. J Psychiatr Res. 2020;127:57–61.
- 16.↑
Bikovsky L, Hadar R, Soto-Montenegro ML, et al. Deep brain stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia. Exp Neurol. 2016;283(Pt A):142–150.
- 17.↑
Corripio I, Roldán A, Sarró S, et al. Deep brain stimulation in treatment resistant schizophrenia: a pilot randomized cross-over clinical trial. EBioMedicine. 2020;51:102568.
- 18.↑
Wang Y, Zhang C, Zhang Y, et al. Habenula deep brain stimulation for intractable schizophrenia: a pilot study. Neurosurg Focus. 2020;49(1):E9.
- 19.↑
Zhang C, Lai Y, Zhang Y, Xu X, Sun B, Li D. Deep brain stimulation-induced transient effects in the habenula. Front Psychiatry. 2021;12:674962.
- 20.↑
Cascella N, Butala AA, Mills K, et al. Deep brain stimulation of the substantia nigra pars reticulata for treatment-resistant schizophrenia: a case report. Biol Psychiatry. 2021;90(10):e57–e59.
- 21.↑
Hadar R, Bikovski L, Soto-Montenegro ML, et al. Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia. Mol Psychiatry. 2018;23(4):943–951.
- 22.↑
Vilela-Filho O, Ragazzo PC, Canêdo D, et al. The impact of subcaudate tractotomy on delusions and hallucinations in psychotic patients. Surg Neurol Int. 2021;12:475.
- 23.↑
Mithani K, Davison B, Meng Y, Lipsman N. The anterior limb of the internal capsule: anatomy, function, and dysfunction. Behav Brain Res. 2020;387:112588.
- 24.↑
Galkin MV, Zaitsev OS, Golanov AV, et al. Gamma Knife capsulotomy for correction of obsessive-compulsive symptoms in a patient with schizophrenia: case report. Prog Brain Res. 2022;272(1):23–31.
- 25.↑
Axer H, Lippitz BE, von Keyserlingk DG. Morphological asymmetry in anterior limb of human internal capsule revealed by confocal laser and polarized light microscopy. Psychiatry Res. 1999;91(3):141–154.
- 26.↑
Liu W, Hao Q, Zhan S, et al. Long-term follow-up of MRI-guided bilateral anterior capsulotomy in patients with refractory schizophrenia. Stereotact Funct Neurosurg. 2014;92(3):145–152.
- 27.↑
Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull. 2009;35(3):549–562.
- 28.↑
Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188(4194):1217–1219.
- 29.
Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261(5562):717–719.
- 30.
Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. J Neuropsychiatry Clin Neurosci. 1996;8(2):223–226.
- 31.↑
Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148(11):1474–1486.
- 32.↑
Yang AC, Tsai SJ. New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci. 2017;18(8):1689.
- 33.↑
Laruelle M, Abi-Dargham A, van Dyck CH, et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A. 1996;93(17):9235–9240.
- 34.↑
Hirayasu Y, Tanaka S, Shenton ME, et al. Prefrontal gray matter volume reduction in first episode schizophrenia. Cereb Cortex. 2001;11(4):374–381.
- 35.↑
Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res. 2001;49(1-2):1–52.
- 36.↑
Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl). 2004;174(1):151–162.
- 37.↑
Liu S, Li A, Liu Y, et al. Polygenic effects of schizophrenia on hippocampal grey matter volume and hippocampus-medial prefrontal cortex functional connectivity. Br J Psychiatry. 2020;216(5):267–274.
- 38.
Bitsch F, Berger P, Nagels A, Falkenberg I, Straube B. Impaired right temporoparietal junction-hippocampus connectivity in schizophrenia and its relevance for generating representations of other minds. Schizophr Bull. 2019;45(4):934–945.
- 39.
Wegrzyn D, Juckel G, Faissner A. Structural and functional deviations of the hippocampus in schizophrenia and schizophrenia animal models. Int J Mol Sci. 2022;23(10):5482.
- 40.
Cachia A, Cury C, Brunelin J, et al. Deviations in early hippocampus development contribute to visual hallucinations in schizophrenia. Transl Psychiatry. 2020;10(1):102.
- 41.
Nelson EA, Kraguljac NV, Maximo JO, et al. Hippocampal Dysconnectivity and altered glutamatergic modulation of the default mode network: a combined resting-state connectivity and magnetic resonance spectroscopy study in schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging. 2022;7(1):108–118.
- 42.↑
Whitfield-Gabrieli S, Thermenos HW, Milanovic S, et al. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci U S A. 2009;106(4):1279–1284.
- 43.↑
McClintock SM, Freitas C, Oberman L, Lisanby SH, Pascual-Leone A. Transcranial magnetic stimulation: a neuroscientific probe of cortical function in schizophrenia. Biol Psychiatry. 2011;70(1):19–27.
- 44.↑
Tadayonnejad R, Deshpande R, Ajilore O, et al. Pregenual anterior cingulate dysfunction associated with depression in OCD: an integrated multimodal fMRI/1H MRS study. Neuropsychopharmacology. 2018;43(5):1146–1155.
- 45.↑
Bouras C, Kövari E, Hof PR, Riederer BM, Giannakopoulos P. Anterior cingulate cortex pathology in schizophrenia and bipolar disorder. Acta Neuropathol. 2001;102(4):373–379.
- 46.↑
Coryell W, Nopoulos P, Drevets W, Wilson T, Andreasen NC. Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. Am J Psychiatry. 2005;162(9):1706–1712.
- 47.↑
Corripio I, Sarró S, McKenna PJ, et al. Clinical improvement in a treatment-resistant patient with schizophrenia treated with deep brain stimulation. Biol Psychiatry. 2016;80(8):e69–e70.
- 48.↑
Mikell CB, McKhann GM, Segal S, McGovern RA, Wallenstein MB, Moore H. The hippocampus and nucleus accumbens as potential therapeutic targets for neurosurgical intervention in schizophrenia. Stereotact Funct Neurosurg. 2009;87(4):256–265.
- 49.↑
Gray JA, Joseph MH, Hemsley DR, et al. The role of mesolimbic dopaminergic and retrohippocampal afferents to the nucleus accumbens in latent inhibition: implications for schizophrenia. Behav Brain Res. 1995;71(1-2):19–31.
- 50.↑
Goto Y, O’Donnell P. Prefrontal lesion reverses abnormal mesoaccumbens response in an animal model of schizophrenia. Biol Psychiatry. 2004;55(2):172–176.
- 51.↑
Forns-Nadal M, Bergé D, Sem F, et al. Increased nucleus accumbens volume in first-episode psychosis. Psychiatry Res Neuroimaging. 2017;263:57–60.
- 52.↑
Tendilla-Beltrán H, Coatl-Cuaya H, Meneses-Prado S, et al. Neuroplasticity and inflammatory alterations in the nucleus accumbens are corrected after risperidone treatment in a schizophrenia-related developmental model in rats. Schizophr Res. 2021;235:17–28.
- 53.↑
Williams M, Pearce RKB, Hirsch SR, Ansorge O, Thom M, Maier M. Fibrillary astrocytes are decreased in the subgenual cingulate in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2014;264(4):357–362.
- 54.↑
Williams MR, Hampton T, Pearce RKB, et al. Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2013;263(1):41–52.
- 55.↑
Yan C, Yang T, Yu QJ, et al. Rostral medial prefrontal dysfunctions and consummatory pleasure in schizophrenia: a meta-analysis of functional imaging studies. Psychiatry Res. 2015;231(3):187–196.
- 56.↑
Abraham ME, Ong V, Gendreau J, et al. Investigating deep brain stimulation of the habenula: a review of clinical studies. Neuromodulation. Published online July 13, 2022. doi:10.1016/j.neurom.2022.05.005
- 57.↑
Sandyk R. Pineal and habenula calcification in schizophrenia. Int J Neurosci. 1992;67(1-4):19–30.
- 58.↑
Mabry SJ, McCollum LA, Farmer CB, Bloom ES, Roberts RC. Evidence for altered excitatory and inhibitory tone in the post-mortem substantia nigra in schizophrenia. World J Biol Psychiatry. 2020;21(5):339–356.
- 59.↑
Schoonover KE, McCollum LA, Roberts RC. Protein markers of neurotransmitter synthesis and release in postmortem schizophrenia substantia nigra. Neuropsychopharmacology. 2017;42(2):540–550.
- 60.↑
Walker CK, Roche JK, Sinha V, Roberts RC. Substantia nigra ultrastructural pathology in schizophrenia. Schizophr Res. 2018;197:209–218.
- 61.↑
Yoon JH, Minzenberg MJ, Raouf S, D’Esposito M, Carter CS. Impaired prefrontal-basal ganglia functional connectivity and substantia nigra hyperactivity in schizophrenia. Biol Psychiatry. 2013;74(2):122–129.
- 62.↑
Xu P, Chen A, Li Y, Xing X, Lu H. Medial prefrontal cortex in neurological diseases. Physiol Genomics. 2019;51(9):432–442.
- 63.↑
Meda SA, Wang Z, Ivleva EI, et al. Frequency-specific neural signatures of spontaneous low-frequency resting state fluctuations in psychosis: evidence from Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Consortium. Schizophr Bull. 2015;41(6):1336–1348.
- 64.↑
Göktepe EO, Young LB, Bridges PK. A further review of the results of sterotactic subcaudate tractotomy. Br J Psychiatry. 1975;126:270–280.
- 65.↑
Crespo-Facorro B, Roiz-Santiáñez R, Pelayo-Terán JM, et al. Caudate nucleus volume and its clinical and cognitive correlations in first episode schizophrenia. Schizophr Res. 2007;91(1-3):87–96.
- 66.↑
Kirino E, Tanaka S, Fukuta M, Inami R, Inoue R, Aoki S. Functional connectivity of the caudate in schizophrenia evaluated with simultaneous resting-state functional MRI and electroencephalography recordings. Neuropsychobiology. 2019;77(4):165–175.
- 67.↑
Zanello M, Pallud J, Baup N, et al. History of psychosurgery at Sainte-Anne Hospital, Paris, France, through translational interactions between psychiatrists and neurosurgeons. Neurosurg Focus. 2017;43(3):E9.
- 68.↑
Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–796.
