Anterior capsulotomy combined with subthalamic nucleus deep brain stimulation for tardive dystonia.

BACKGROUND: Deep brain stimulation (DBS) has been reported as a therapy option for the motor dysfunction of severe tardive dystonia (TD). The major psychiatric diseases, however, are contraindications to DBS treatment in TD patients. METHODS: Six severe, medically refractory TD patients undergoing bilateral anterior capsulotomy combined with bilateral subthalamic nucleus (STN)-DBS treatment were studied retrospectively at two time points: pre-operation, and 1-3 years post-operation. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) was used to assess the dystonia and disability. Depressive, anxiety, psychiatric symptoms, and Quality of Life (QoL) were evaluated using the 17-item Hamilton Depression Scale (HAMD-17), the 14-item Hamilton Anxiety Scale (HAMA-14), the Positive and Negative Syndrome Scale (PANSS), and 36-item Short-Form Health Survey (SF-36), respectively. RESULTS: After receiving the combination treatment for 25 ± 11.6 months (range, 12-41 months), significant clinical symptom improvements were reported in TD patients. BFMDRS motor and disability scores were ameliorated by 78.5 ± 32.0% (p = 0.031) and 76.5 ± 38.6% (p = 0.031), respectively. The HAMD-17 and HAMA-14 scores were reduced by 60.3 ± 27.9% (p = 0.007) and 60.0 ± 24.6% (p = 0.009), respectively. Furthermore, the PANSS scores of the comorbidity schizophrenia TD patients decreased by 58.1 ± 6.0% (p = 0.022), and the QoL improved by 59.7 ± 14.1% (SF-36, p = 0.0001). During the research, there were no notable adverse effects or problems. CONCLUSION: Bilateral anterior capsulotomy combined with bilateral STN-DBS may be an effective and relatively safe treatment option for severe TD comorbid with major psychiatric disorders.

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression.

BACKGROUND: Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. METHODS: Six patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. RESULTS: Depression and anxiety symptoms improved after 3-6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LIMITATIONS: This study was limited to the small sample size and lack of a healthy control group. CONCLUSIONS: Chronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

Parameter-based analysis of clinical efficacy of combined bed nucleus of the stria terminalis-nucleus accumbens deep brain stimulation for treatment-resistant depression.

OBJECTIVE: Treatment-resistant depression (TRD) is a severely disabling psychiatric condition that responds poorly to conventional treatments. Deep brain stimulation (DBS) has been proposed for the treatment of patients with TRD in numerous studies. Several deep brain nuclei are considered as potential targets for TRD-DBS, but their clinical efficacy needs further validation. This study carried out dual-target combined stimulation of the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAc) to investigate the effectiveness of the treatment for TRD patients. METHODS: An 8-contact DBS electrode was used in the study with a surgical path that crossed the BNST and NAc targets. Stimulation parameters and the corresponding severity of symptoms evaluated by the 17-item Hamilton Depression Rating Scale (HAMD-17) and other scales were obtained at each follow-up. The accuracy of electrode positions, the effect of combined stimulation, and the corresponding stimulation parameters were evaluated. Sweet spot prediction models were used to assess the effective stimulation sites in the treatment. RESULTS: The study included 23 TRD patients undergoing DBS at a single center from March 2021 to May 2023. At the last follow-up (range 4-24 months), 14 patients had responded to the treatment (HAMD-17 score improved ≥ 50%), 7 of whom had achieved clinical remission (HAMD-17 score ≤ 7). Electrode position analysis suggested that the BNST may be more important for the improvement of depressive symptoms than the NAc. Overlapped volumes of volume of tissue activated (VTA) and BNST were significantly correlated with absolute (ρleft = -0.377, p < 0.001; ρright = -0.251, p < 0.001) and percent (ρleft = -0.249, p < 0.001; ρright = -0.098, p = 0.102) changes in HAMD-17 score. The sweet spot model of HAMD-17 improvement also suggested that the VTA overlap with the dorsal side of BNST was associated with the impact on depressive symptoms (t = -4.10, p < 0.05). CONCLUSIONS: Combined BNST-NAc stimulation of TRD can effectively improve depressive symptoms, in which the BNST seems to have a dominant therapeutic effect. The results of this study not only help to optimize the DBS programming parameters, but also offer an opportunity to further understand the differences between the two targets. In the future, larger prospective cohorts are needed to verify the results of combined BNST-NAc DBS.

Anterior Capsulotomy for Refractory Obsessive-Compulsive Disorder: A Tractography and Lesion Geometry study.

INTRODUCTION: A bilateral anterior capsulotomy effectively treats refractory obsessive-compulsive disorder (OCD). We investigated the geometry of lesions and disruption of white matter pathways within the anterior limb of the internal capsule (ALIC) in patients with different outcomes. METHODS: In this retrospective study, we analyzed data from 18 patients with refractory OCD who underwent capsulotomies. Patients were grouped into "responders" and "nonresponders" based on the percentage of decrease in the Yale-Brown Obsessive-Compulsive Scale (YBOCS) after surgery. We investigated neurobehavioral adverse effects and analyzed the overlap between lesions and the ventromedial prefrontal (vmPFC) and dorsolateral prefrontal (dlPFC) pathways. Probabilistic maps were constructed to investigate the relationship between lesion location and clinical outcomes. RESULTS: Of the 18 patients who underwent capsulotomies, 12 were responders (>35% improvement in YBOCS), and six were nonresponders. The vmPFC pathway was more involved than the dlPFC pathway in responders (p = 0.01), but no significant difference was observed in nonresponders (p = 0.10). The probabilistic voxel-wise efficacy map showed a relationship between ventral voxels within the ALIC with symptom improvement. Weight gains occurred in 11/18 (61%) patients and could be associated with medial voxels within the ALIC. CONCLUSION: The optimal outcome after capsulotomy in refractory OCD is linked to vmPFC disruption in the ALIC. Medial voxels within the ALIC could be associated with weight gains following capsulotomy.

Differences in olfactory dysfunction and its relationship with cognitive function in schizophrenia patients with and without auditory verbal hallucinations.

Olfactory discrimination dysfunction has been observed in patients with schizophrenia (SCZ), but its relationship with cognitive function has not been clarified. The purpose of this study was to examine the differences in olfactory identification function in SCZ patients with and without auditory verbal hallucinations (AVHs) and its relationship with cognitive function. Olfactory identification function was measured in 80 SCZ patients with AVHs, 57 SCZ patients without AVHs, and 87 healthy controls (HC). Clinical symptom scores and neuropsychological measures were also administered to all corresponding subjects. Compared to HC, SCZ patients showed significant deficits in olfactory identification and cognitive function, but there were no differences in olfactory identification dysfunction and cognitive dysfunction between the two subgroups. In the non-AVHs subgroup only, poorer Olfactory Stick Identification Test for Japanese (OSIT-J) scores were significantly and positively correlated with total and delayed recall (Bonferroni correction, p < 0.002). Stepwise regression analysis revealed that factors affecting olfactory identification impairment differed in the two SCZ patient subgroups. In conclusion, this study highlights the commonality of olfactory identification dysfunction in SCZ patients and the importance of olfactory assessment of different subtypes of SCZ patients.

Structural and functional correlates of the response to deep brain stimulation at ventral capsule/ventral striatum region for treatment-resistant depression.

BACKGROUND: Though deep brain stimulation (DBS) shows increasing potential in treatment-resistant depression (TRD), the underlying neural mechanisms remain unclear. Here, we investigated functional and structural connectivities related to and predictive of clinical effectiveness of DBS at ventral capsule/ventral striatum region for TRD. METHODS: Stimulation effects of 71 stimulation settings in 10 TRD patients were assessed. The electric fields were estimated and combined with normative functional and structural connectomes to identify connections as well as fibre tracts beneficial for outcome. We calculated stimulation-dependent optimal connectivity and constructed models to predict outcome. Leave-one-out cross-validation was used to validate the prediction value. RESULTS: Successful prediction of antidepressant effectiveness in out-of-sample patients was achieved by the optimal connectivity profiles constructed with both the functional connectivity (R=0.49 at p<10-4; deviated by 14.4±10.9% from actual, p<0.001) and structural connectivity (R=0.51 at p<10-5; deviated by 15.2±11.5% from actual, p<10-5). Frontothalamic pathways and cortical projections were delineated for optimal clinical outcome. Similarity estimates between optimal connectivity profile from one modality (functional/structural) and individual brain connectivity in the other modality (structural/functional) significantly cross-predicted the outcome of DBS. The optimal structural and functional connectivity mainly converged at the ventral and dorsal lateral prefrontal cortex and orbitofrontal cortex. CONCLUSIONS: Connectivity profiles and fibre tracts following frontothalamic streamlines appear to predict outcome of DBS for TRD. The findings shed light on the neural pathways in depression and may be used to guide both presurgical planning and postsurgical programming after further validation.

Correlation between abnormal N-acetyl-aspartate levels in posterior cingulate cortex and persistent auditory verbal hallucinations in Chinese patients with chronic schizophrenia.

The aim of this study was to investigate the relationship between persistent auditory verbal hallucinations (pAVHs) and N-acetyl-aspartate (NAA) levels in posterior cingulate cortex (PCC). 117 schizophrenia (SCZ) patients (61 pAVHs and 56 non-AVHs) and 66 healthy controls were included. The P3 item of the Positive and Negative Syndrome Scale and the Auditory Hallucinations subscale of the Psychotic Symptom Rating Scale were used to assess the severity of pAVHs. NAA levels were significantly lower in the AVHs group, and were negatively correlated with pAVHs. Therefore, increasing the NAA levels in PCC may be helpful in treating pAVHs.

Subthalamic deep brain stimulation for refractory Gilles de la Tourette's syndrome: clinical outcome and functional connectivity.

BACKGROUND: Deep brain stimulation (DBS) is a promising novel approach for managing refractory Gilles de la Tourette's syndrome (GTS). The subthalamic nucleus (STN) is the most common DBS target for treating movement disorders, and smaller case studies have reported the efficacy of bilateral STN-DBS treatment for relieving tic symptoms. However, management of GTS and treatment mechanism of STN-DBS in GTS remain to be elucidated. METHODS: Ten patients undergoing STN-DBS were included. Tics severity was evaluated using the Yale Global Tic Severity Scale. The severities of comorbid psychiatric symptoms of obsessive-compulsive behavior (OCB), attention-deficit/hyperactivity disorder, anxiety, and depression; social and occupational functioning; and quality of life were assessed. Volumes of tissue activated were used as seed points for functional connectivity analysis performed using a control dataset. RESULTS: The overall tics severity significantly reduced, with 62.9% ± 26.2% and 58.8% ± 27.2% improvements at the 6- and 12-months follow-up, respectively. All three patients with comorbid OCB showed improvement in their OCB symptoms at both the follow-ups. STN-DBS treatment was reasonably well tolerated by the patients with GTS. The most commonly reported side effect was light dysarthria. The stimulation effect of STN-DBS might regulate these symptoms through functional connectivity with the thalamus, pallidum, substantia nigra pars reticulata, putamen, insula, and anterior cingulate cortices. CONCLUSIONS: STN-DBS was associated with symptomatic improvement in severe and refractory GTS without significant adverse events. The STN is a promising DBS target by stimulating both sensorimotor and limbic subregions, and specific brain area doses affect treatment outcomes.

Differences in Cortical Thickness in Schizophrenia Patients With and Without Auditory Verbal Hallucinations.

Auditory verbal hallucinations (AVHs) are one of the most common and severe symptoms of schizophrenia (SCZ), but the neuroanatomical mechanisms underlying AVHs remain unclear. This study aimed to investigate whether persistent AVHs (pAVH) are associated with cortical thinning of certain brain regions in patients with SCZ. With the use of the 3T magnetic resonance imaging (MRI) technology, we acquired and analyzed data from 79 SCZ patients with pAVH (pAVH group), 60 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group). The severity of pAVH was assessed by the P3 hallucination items in the Positive and Negative Syndrome Scale (PANSS) and the Auditory Hallucinations Rating Scale (AHRS). Cortical thickness analysis was used to compare the region of interest (ROI) cortical thickness between the groups. The relationship between the severity of pAVH and cortical thickness was also explored. Compared with the non-AVH and HC groups, the pAVH group exhibited significantly reduced cortical thickness in the bilateral lateral orbitofrontal region (p < 0.0007, after Bonferroni correction); no significant difference was found between the non-AVH group and the HC group. The cortical thickness of the left lateral orbitofrontal cortex (P3: r = -0.44, p < 0.001; AHRS: r = -0.45, p < 0.001) and the right lateral orbitofrontal cortex (P3: r = -0.36, p = 0.002; AHRS: r = -0.33, p = 0.004) were negatively correlated with the severity of pAVH (after Bonferroni correction, p < 0.0125). Therefore, abnormal thickness of the bilateral lateral orbitofrontal cortices might be associated with pAVHs in SCZ patients.

Deficits in Sense of Body Ownership, Sensory Processing, and Temporal Perception in Schizophrenia Patients With/Without Auditory Verbal Hallucinations.

It has been claimed that individuals with schizophrenia have difficulty in self-recognition and, consequently, are unable to identify the sources of their sensory perceptions or thoughts, resulting in delusions, hallucinations, and unusual experiences of body ownership. The deficits also contribute to the enhanced rubber hand illusion (RHI; a body perception illusion, induced by synchronous visual and tactile stimulation). Evidence based on RHI paradigms is emerging that auditory information can make an impact on the sense of body ownership, which relies on the process of multisensory inputs and integration. Hence, we assumed that auditory verbal hallucinations (AVHs), as an abnormal auditory perception, could be linked with body ownership, and the RHI paradigm could be conducted in patients with AVHs to explore the underlying mechanisms. In this study, we investigated the performance of patients with/without AVHs in the RHI. We administered the RHI paradigm to 80 patients with schizophrenia (47 with AVHs and 33 without AVHs) and 36 healthy controls. We conducted the experiment under two conditions (synchronous and asynchronous) and evaluated the RHI effects by both objective and subjective measures. Both patient groups experienced the RHI more quickly and strongly than HCs. The RHI effects of patients with AVHs were significantly smaller than those of patients without AVHs. Another important finding was that patients with AVHs did not show a reduction in RHI under asynchronous conditions. These results emphasize the disturbances of the sense of body ownership in schizophrenia patients with/without AVHs and the associations with AVHs. Furthermore, it is suggested that patients with AVHs may have multisensory processing dysfunctions and internal timing deficits.

Metabolite differences in the medial prefrontal cortex in schizophrenia patients with and without persistent auditory verbal hallucinations: a 1H MRS study.

Studies of schizophrenia (SCZ) have associated auditory verbal hallucinations (AVH) with structural and functional abnormalities in frontal cortex, especially medial prefrontal cortex (mPFC). Although abnormal prefrontal network connectivity associated with language production has been studied extensively, the relationship between mPFC dysfunction (highly relevant to the pathophysiology of SCZ) and AVH has been rarely investigated. In this study, proton magnetic resonance spectroscopy was used to measure metabolite levels in the mPFC in 61 SCZ patients with persistent AVH (pAVH), 53 SCZ patients without AVH (non-AVH), and 59 healthy controls (HC). The pAVH group showed significantly lower levels of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA) and glutamate + glutamine (Glx), compared with the non-AVH (tNAA: p = 0.022, Glx: p = 0.012) and HC (tNAA: p = 0.001, Glx: p = 0.001) groups. No difference was found in the levels of tNAA and Glx between non-AVH and HC. The levels of tNAA and Glx in the mPFC was negatively correlated with the severity of pAVH (tNAA: r = -0.24, p = 0.014; Glx: r = -0.30, p = 0.002). In conclusion, pAVH in SCZ patients might be related to decreased levels of tNAA and Glx in the mPFC, indicating that tNAA or Glx might play a key role in the pathogenesis of pAVH.

Rescue Anterior Capsulotomy after Failure of Nucleus Accumbens Deep Brain Stimulation in Anorexia Nervosa: A Case Report.

Anorexia nervosa (AN) is a highly disabling mental disorder with high rates of morbidity and mortality. Few psychological treatments and pharmacotherapy are proven to be effective for adult AN. Two invasive stereotactic neurosurgical interventions, deep brain stimulation (DBS) and anterior capsulotomy, are now commonly used as investigational approaches for the treatment of AN. Here, we report the long-term safety and efficacy of rescue bilateral anterior capsulotomy after the failure of bilateral nucleus accumbens (NAcc)-DBS in an 18-year-old female patient with life-threatening and treatment-resistant restricting subtype AN. Improvements in the neuropsychiatric assessment were not documented 6 months after the NAcc-DBS. Rescue bilateral anterior capsulotomy was proposed and performed, resulting in a long-lasting restoration of body weight and a significant and sustained remission in AN core symptoms. The DBS pulse generator was exhausted 2 years after capsulotomy and removed 3 years postoperatively. No relapse was reported at the last follow-up (7 years after the first intervention). From this case, we suggest that capsulotomy could be a rescue treatment for patients with treatment-resistant AN after NAcc-DBS failure. Further well-controlled studies are warranted to validate our findings.

Object discrimination performance and dynamics evaluated by inferotemporal cell population activity.

We have previously reported an increase in response tolerance of inferotemporal cells around trained views. However, an inferotemporal cell usually displays different response patterns in an initial response phase immediately after the stimulus onset and in a late phase from approximately 260 ms after stimulus onset. This study aimed to understand the difference between the two time periods and their involvement in the view-invariant object recognition. Responses to object images with and without prior experience of object discrimination across views, recorded by microelectrodes, were pooled together from our previous experiments. With a machine learning algorithm, we trained to build classifiers for object discrimination. In the early phase, the performance of classifiers created based on data of responses to the object images with prior training of object discrimination across views did not significantly differ from that based on data of responses to the object images without prior experience of object discrimination across views. However, the performance was significantly better in the late phase. Furthermore, compared to the preferred stimulus image in the early phase, we found 2/3 of cells changed their preference in the late phase. For object images with prior experience of training with object discrimination across views, a significant higher percentage of cells responded in the late phase to the same objects as in the early phase, but under different views. The results demonstrate the dynamics of selectivity changes and suggest the involvement of the late phase in the view-invariant object recognition rather than that of the early phase.

Deep brain stimulation telemedicine programming during the COVID-19 pandemic: treatment of patients with psychiatric disorders.

OBJECTIVE: The ongoing coronavirus disease 2019 (COVID-19) pandemic has considerably affected the delivery of postoperative care to patients who have undergone deep brain stimulation (DBS) surgery. DBS teleprogramming technology was developed and deployed in China before the COVID-19 outbreak. In this report, the authors share their experiences with telemedical DBS treatment of patients with psychiatric disorders during the COVID-19 outbreak. METHODS: Four patients (2 with obsessive-compulsive disorder, 1 with major depressive disorder, and 1 with anorexia nervosa) underwent DBS surgery at Ruijin Hospital and received continuous postoperative DBS telemedicine case management from January 2020 to July 2020. DBS teleprogramming, individualized psychological support, and medical consultations were provided via the authors' DBS telemedicine platform, which also incorporated a synchronous real-time video communication system. RESULTS: Forty-five DBS telemedicine sessions were conducted; there was no unexpected loss of network connection during the sessions. Of these, 28 sessions involved DBS teleprogramming. Adjustments were made to the stimulation voltage, frequency, pulse width, and contact site in 21, 12, 9, and 9 sessions, respectively. Psychological support and troubleshooting were provided during the remaining telemedicine sessions. Modest to substantial clinical improvements after DBS surgery were observed in some but not all patients, whereas stimulation-related side effects were reported by 2 patients and included reversible sleep and mood problems, headache, and a sensation of heat. CONCLUSIONS: DBS telemedicine seems to offer a feasible, safe, and efficient strategy for maintaining the delivery of medical care to psychiatric patients during the COVID-19 outbreak. The authors propose that implementation of a comprehensive DBS telemedicine system, which combines DBS teleprogramming with psychological counseling, medical consultations, and medication prescriptions and delivery, could be an efficient and effective approach to manage the mental health and quality of life of patients with psychiatric disorders during future local or global public health crises.

Alteration of the gut microbiome in first-episode drug-naïve and chronic medicated schizophrenia correlate with regional brain volumes.

The human gut microbiome plays an important role in the basic neurodevelopmental processes of the central nervous system and has been implicated in several neuropsychiatric disorders. However, the connection between the gut microbiome and the underlying pathogenesis of schizophrenia (SCZ) is poorly defined. Here we analyzed the faecal samples from 40 first-episode drug-naïve SCZ (FSCZ) patients, 85 chronically antipsychotic-treated SCZ (TSCZ) patients and 69 healthy controls (HCs) using 16S rRNA gene sequence to determine whether the alterations of the gut microbiome were associated with SCZ or antipsychotic treatment. In addition, we acquired the T1-weighted brain imaging data by using structural magnetic resonance imaging to test whether microbial composition correlated with structural brain signatures. Our analyses revealed low microbiome alpha-diversity indexes in TSCZ patients but not in FSCZ patients as compared to HCs. Importantly, both FSCZ and TSCZ patients had distinct changes in gut microbial composition at certain taxa including Christensenellaceae, Enterobacteriaceae, Pasteurellaceae, Turicibacteraceae at the family level and Escherichia at genus level as compared to HCs. We also found significant disturbances of gut microbial composition in TSCZ versus FSCZ patients (eg. Enterococcaceae and Lactobacillaceae). Most interestingly, our exploratory analyses found specific SCZ-associated microbiota to be correlated with the right middle frontal gyrus (rMFG) volume which was aberrant in SCZ patients. Our findings extend prior work and suggest a possible link between the gut microbiome and brain structure which may be implicated in the pathology of SCZ.

Association of telomere length and mitochondrial DNA copy number with risperidone treatment response in first-episode antipsychotic-naïve schizophrenia.

Accumulating evidence indicates a putative association of telomere length and mitochondrial function with antipsychotics response in schizophrenia (SCZ). However, pharmacological findings were limited and no previous work has assessed this in a prospective longitudinal study. This study assessed telomere length and mitochondrial DNA copy number in first-episode antipsychotic-naïve SCZ patients with 8-week risperidone treatment to evaluate the association between these biomarkers and clinical treatment response. We recruited 137 first-episode antipsychotic-naive SCZ patients (and 144 controls) at baseline and 89 patients completed the 8-week follow-up. Patients, completed follow-up, were divided into Responders (N = 46) and Non-Responders (N = 43) according to the percentage of symptoms improvement. Linear regression analyses show that SCZ patients had significantly lower mtDNA copy number (ß = -0.108, p = 0.002), and no alteration of telomere length when compared with healthy controls. In addition, compared with Non-Responders, Responders had significantly lower mtDNA copy number (ß = -0.178, p = 0.001), and longer telomere length (ß = 0.111, p = 0.071) before the 8-week treatment. After treatment, Responders persisted lower mtDNA copy number comparing with No-Responders (partial η(2) = 0.125, p = 0.001). These findings suggest that telomere length and mtDNA copy number may hold the potential to serve as predictors of antipsychotic response of SCZ patients.