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The pedunculopontine nucleus (PPN) has been proposed as target for deep brain stimulation (DBS) in patients with postural instability and gait disorders due to its involvement in muscle tonus adjustments and control of locomotion. However, it is a deep-seated brainstem nucleus without clear imaging or electrophysiological markers. Some studies suggested that diffusion tensor imaging (DTI) may help guiding electrode placement in the PPN by showing the surrounding fiber bundles, but none have provided a direct histological correlation. We investigated DTI fractional anisotropy (FA) maps from in vivo and in situ post-mortem magnetic resonance images (MRI) compared to histological evaluations for improving PPN targeting in humans. A post-mortem brain was scanned in a clinical 3T MR system in situ. Thereafter, the brain was processed with a special method ideally suited for cytoarchitectonic analyses. Also, nine volunteers had in vivo brain scanning using the same MRI protocol. Images from volunteers were compared to those obtained in the post-mortem study. FA values of the volunteers were obtained from PPN, inferior colliculus, cerebellar crossing fibers and medial lemniscus using histological data and atlas information. FA values in the PPN were significantly lower than in the surrounding white matter region and higher than in areas with predominantly gray matter. In Nissl-stained histologic sections, the PPN extended for more than 10 mm in the rostro-caudal axis being closely attached to the lateral parabrachial nucleus. Our DTI analyses and the spatial correlation with histological findings proposed a location for PPN that matched the position assigned to this nucleus in the literature. Coregistration of neuroimaging and cytoarchitectonic features can add value to help establishing functional architectonics of the PPN and facilitate neurosurgical targeting of this extended nucleus.

Sara CB Casagrande,1 Rubens G Cury,1 Eduardo JL Alho,2 Erich Talamoni Fonoff2 1Department of Neurology, School of Medicine, Movement Disorders Center, University of São Paulo, São Paulo, Brazil; 2Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil Abstract: Tourette’s syndrome (TS) is a neurodevelopmental disorder that comprises vocal and motor tics associated with a high frequency of psychiatric comorbidities, which has an important impact on quality of life. The onset is mainly in childhood and the symptoms can either fade away or require pharmacological therapies associated with cognitive-behavior therapies. In rare cases, patients experience severe and disabling symptoms refractory to conventional treatments. In these cases, deep brain stimulation (DBS) can be considered as an interesting and effective option for symptomatic control. DBS has been studied in numerous trials as a therapy for movement disorders, and currently positive data supports that DBS is partially effective in reducing the motor and non-motor symptoms of TS. The average response, mostly from case series and prospective cohorts and only a few controlled studies, is around 40% improvement on tic severity scales. The ventromedial thalamus has been the preferred target, but more recently the globus pallidus internus has also gained some notoriety. The mechanism by which DBS is effective on tics and other symptoms in TS is not yet understood. As refractory TS is not common, even reference centers have difficulties in performing large controlled trials. However, studies that reproduce the current results in larger and multicenter randomized controlled trials to improve our knowledge so as to support the best target and stimulation settings are still lacking. This article will discuss the selection of the candidates, DBS targets and mechanisms on TS, and clinical evidence to date reviewing current literature about the use of DBS in the treatment of TS. Keywords: deep brain stimulation, DBS, Tourette’s syndrome, tics

Wellingson Silva Paiva,1 Erich Talamoni Fonoff,1 Marco Antonio Marcolin,2 Edson Bor-Seng-Shu,1 Eberval Gadelha Figueiredo,1 Manoel Jacobsen Teixeira11Division of Neurosurgery, Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil; 2Transcranial Magnetic Stimulation Laboratory, Institute of Psychiatry, School of Medicine, University of Sao Paulo, Sao Paulo, BrazilAbstract: Since the introduction of microscopic techniques, radical surgery for cavernous angiomas has become a recommended treatment option. However, the treatment of motor area cavernous angioma represents a great challenge for the surgical team. Here, we describe an approach guided by frameless neuronavigation and preoperative functional mapping with transcranial magnetic stimulation (TMS), for surgical planning. We used TMS to map the motor cortex and its relationship with the angioma. We achieved complete resection of the lesions in the surgeries, while avoiding areas of motor response identified during the preoperative mapping. We verified the complete control of seizures (Engel class 1A) in the patients with previous refractory epilepsy. Postsurgery, one patient was seizure-free without medication, and two patients required only one medication for seizure control. Thus, navigated TMS appears to be a useful tool, in preoperative planning for cavernous angiomas of the motor area.Keywords: neurosurgical procedures, brain mapping, neuronavigation

Francisco Nêuton de Oliveira Magalhães, Sandra Correia Soares, Jaqueline Melo Torres, Arthur Ungaretti, Mariana Fillipi Cacciacarro, Manoel Jacobsen Teixeira, Erich Talamoni FonoffPain Center and Division of Functional Neurosurgery, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, BrazilIntroduction: In the last two decades, ozone has emerged as a treatment for low back pain, applied by means of minimally invasive techniques. Objective: The aim of this study is to assess the effect and safety of ozone therapy applied in the epidural space for chronic pain related to failed back surgery syndrome.Methods: The investigators studied 13 sequential patients of both sexes, between 18 and 70 years old, with persistent chronic pain (more than six months) in the lumbar region and in the lower limbs related to failed back surgery syndrome (FBSS). Pain was classified as neuropathic and non-neuropathic regarding the topography (lumbar and lower limb), based on the DN4 questionnaire. The patients received the ozone gas in the lumbar epidural space via spinal-sacral endoscopy. Clinical evaluation was performed before, immediately after (24 hours), and 1, 3, and 6 months after intervention with visual analog scale and Oswestry Disability Index (ODI).Results: Overall, the patients had 43.7% reduction of lumbar pain, 60.9% reduction in leg pain in six months followed by 44.0% of improvement in ODI. The reduction of pain and in the disability index was markedly greater in patients with non-neuropathic predominant pain, 95.2%, 80.6%, and 75.3% improvement in lumbar, leg pain, and ODI respectively, while neuropathic predominant pain patients experienced only 12.5%, 42.4%, and 20.9% improvement, also respectively. No neurological or infectious complications were observed acutely or during the follow-up. The present data suggests that epidural ozone might be a therapeutic option for persistent low back pain, especially in non-neuropathic predominant pain patients, but double-blind controlled studies are still required to prove its efficacy.Keywords: pain, failed back surgery syndrome, neuropathic pain, epiduroscopy, spinal endoscopy, ozone, minimally invasive surgery

Manoel Jacobsen Teixeira, Eloy Rusafa Neto, José Cláudio Marinho da Nóbrega, Jairo Silva dos Ângelos, Miguel San Martin, Bernardo Assumpção de Monaco, Erich Talamoni FonoffDepartment of Neurology, Division of Functional Neurosurgery of the Institute of Psychiatry, University of São Paulo School of Medicine, São Paulo, BrazilAbstract: Optimal treatment of oncologic pain is a challenge to all professionals who deal with cancer and its complications. The management of upper abdominal pain is usually difficult and it is often refractory to conservative therapies. In this context, celiac plexus neurolysis (CPN) appears to be an important and indispensable tool because it alleviates pain, gives comfort to patients and is a safe procedure. In this study, the importance of CPN is reviewed by a retrospective study of 74 patients with pain due to upper abdominal cancer. Almost all cases evaluated (94.6%) had an excellent result after CPN and the majority of side effects were transitory.Keywords: pain, celiac plexus, alcohol neurolysis, cancer

Matheus Schmidt Soares, Wellingson Silva Paiva, Eda Z Guertzenstein, Robson Luis Amorim, Luca Silveira Bernardo, Jose Francisco Pereira, Erich Talamoni Fonoff, Manoel Jacobsen Teixeira Division of Neurosurgery, Hospital das Clínicas, University of Sao Paulo Medical School, Sao Paulo, Brazil Abstract: Following the early studies of Moniz and Lima, psychosurgery had considerable scientific credibility until the advent of modern antipsychotics in the mid 1950s. Thereafter, psychosurgery was almost abandoned in large medical centers as a common treatment for schizophrenia, although is still used for some affective and anxiety disorders. We reviewed relevant papers cited in the Medline/Index Medicus, Cochrane, and Scielo databases from 1930 to 2012. In our review of the literature, we show from recent studies that there are still many patients with schizophrenia who have serious deficits even after being treated with current noninvasive therapies. The value of psychosurgery remains controversial. There are no data available to support the use of stereotactic procedures for schizophrenia. Well designed controlled trials are needed to establish the effectiveness of psychosurgery in patients with schizophrenia. Keywords: psychosurgery, schizophrenia, treatment, stereotactic techniques

Eduardo Santamaria Carvalhal Ribas, Wellingson Silva Paiva, Natali Cordeiro Pinto, Lin Tchia Yeng, Massako Okada, Erich Talamoni Fonoff, Maria Cristina Chavantes, Manoel Jacobsen TeixeiraPain Center, Department of Neurology, Hospital das Clínicas School of Medicine, University of São Paulo, BrazilAbstract: Debilitating stump pain following amputation surgery is a major problem when it affects the patient's quality of life, often making the patient totally dependent on others for their day-to-day care. Attempts have been made to treat those patients through pharmacological, psychological, and physical therapies, but in many cases these fail to relieve the pain. This article focuses on three patients with chronic, intense, and debilitating stump pain who were previously treated with pain medications, but with little success. These patients underwent nine sessions of low-intensity laser therapy (LILT) to the stump – this is a new treatment that has been used to treat other pain disorders. All patients reported a decrease in the intensity of their pain and increased ability to perform daily living activities during a 4-month follow-up.Keywords: pain, laser therapy, amputation stumps

Wellingson S Paiva1, Erich T Fonoff1, Marco A Marcolin2, Hector N Cabrera1, Manoel J Teixeira11Division of Functional Neurosurgery, Hospital das Clinicas, 2TMS Laboratory of the Psychiatry Institute, Hospital das Clinicas, University of São Paulo School of Medicine, São Paulo, BrazilAbstract: Transcranial magnetic stimulation (TMS) is a promising method for both investigation and therapeutic treatment of psychiatric and neurologic disorders and, more recently, for brain mapping. This study describes the application of navigated TMS for motor cortex mapping in patients with a brain tumor located close to the precentral gyrus.Materials and methods: In this prospective study, six patients with low-grade gliomas in or near the precentral gyrus underwent TMS, and their motor responses were correlated to locations in the cortex around the lesion, generating a functional map overlaid on three-dimensional magnetic resonance imaging (MRI) scans of the brain. To determine the accuracy of this new method, we compared TMS mapping with the gold standard mapping with direct cortical electrical stimulation in surgery. The same navigation system and TMS-generated map were used during the surgical resection procedure.Results: The motor cortex could be clearly mapped using both methods. The locations corresponding to the hand and forearm, found during intraoperative mapping, showed a close spatial relationship to the homotopic areas identified by TMS mapping. The mean distance between TMS and direct cortical electrical stimulation (DES) was 4.16 ± 1.02 mm (range: 2.56–5.27 mm).Conclusion: Preoperative mapping of the motor cortex with navigated TMS prior to brain tumor resection is a useful presurgical planning tool with good accuracy.Keywords: transcranial magnetic stimulation, cortical mapping, brain tumor, motor cortex

Bernardo Assumpção de Monaco, Erich Talamoni Fonoff, Manoel Jacobsen TeixeiraDivision of Functional Neurosurgery, Department of Neurology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, BrazilAbstract: The treatment of uncomplicated osteoma consists of an en bloc resection, or curettage, of the tumor, followed by cranioplasty. Here, we present a case report of a patient treated for a parietal osteoma, followed by a calcium phosphate cranioplasty, with early resorption after 3 months, which was presented by a sinking flap above the resection area. This case suggests that synthetic cranioplasty should be preferred, even in small skull-gap areas.Keywords: cranioplasty, bone cement, osteoma, calcium phosphate, resorption

STUDY DESIGN: Case series. OBJECTIVE: Presentation of results of dorsal root entry zone lesions in 10 patients suffering from severe neuropathic pain due to brachial plexopathy or radiation-induced trigeminal neuropathy. SUMMARY OF BACKGROUND DATA: Radiation-induced neuropathy is an uncommon but serious complication of radiotherapy. It may cause delayed motor and sensitive impairment associated with severe treatment-resistant pain. Various therapeutic approaches have been reported aimed at controlling radiation-induced neuropathy-pain, demonstrating poor outcomes. METHODS: Eight patients with plexopathy underwent dorsal root entry zone lesion in the cervical spinal cord, while 2 other subjects received stereotactic trigeminal nucleotractotomy. Subjects were followed prospectively before and after brachial dorsal root entry zone or trigeminal caudal operations (range 0.5-36 months). RESULTS: All patients experienced improvement in pain conditions. A total of 8 patients reported full pain relief (visual analog scale = 0) by the end of the follow-up period. The remaining patients had partial control of pain. One patient required reoperation to achieve optimal pain relief. Both patients who underwent trigeminal nucleotractotomy had transient ataxia in the ipsilateral upper limb. One of the patients treated by dorsal root entry zone lesion had minor aggravation of weakness of the ipsilateral lower limb. CONCLUSION: The present results suggest that the trigeminal nucleotractotomy and dorsal root entry zone lesions in cervical spinal cord are an effective procedure for the treatment of pain associated with actinic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) represents a distinctive technique for non-invasive brain stimulation. Recent advancements in image processing have enabled the enhancement of TMS by integrating magnetic resonance imaging (MRI) modalities with TMS via a neuronavigation system. The aim of this study is to assess the efficacy of navigated TMS for cortical mapping in comparison to surgical mapping using direct electrical stimulation (DES). This study involved 30 neurosurgical procedures for tumors located in or adjacent to the precentral gyrus. The DES points were compared with TMS responses based on the original distances of vectorial modules. There was a notable similarity in the points obtained from the two mapping methods. The distances between the geometric centers of TMS and DCS were 4.85 ± 1.89 mm. A strong correlation was identified between these vectorial points (r = 0.901, p < 0.001). The motor threshold in TMS was highest in the motor cortex adjacent to the tumor compared to the normal cortex ( p < 0.001). Patients with deficits exhibited excellent accuracy in both methods. In view of this, TMS demonstrated reliable and precise application in brain mapping, which is a promising method for preoperative functional mapping in motor cortex tumor surgery.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Pain control after deep brain stimulation (DBS) in Parkinson's disease (PD) remains unclear. Following six months, subthalamic (STN)-DBS reduced sensory complaints related to parkinsonism and bodily discomfort, increasing central beta-endorphin level. Pallidal GPi-DBS decreased bodily discomfort and beta-endorphin levels. Unexplained pain by other conditions and bodily discomfort were negatively correlated with beta-endorphin levels. Thus, DBS regulates central opioids, and prioritizing STN is important for PD patients with significant sensory complications., (© 2024. The Author(s).)

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas - together with patient age - were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network., Competing Interests: FG, JG, GE, AB, AL, AL, CT, WC, RM, EF, JB, PG, PA, HY, GI, NL, AL, CH No competing interests declared, (© 2023, Gouveia, Germann et al.)

Epidural motor cortex stimulation (MCS) is an effective treatment for refractory neuropathic pain; however, some individuals are unresponsive. In this study, we correlated the effectiveness of MCS and refractoriness with the expression of cytokines, neurotrophins, and nociceptive mediators in the dorsal root ganglion (DRG), sciatic nerve, and plasma of rats with sciatic neuropathy. MCS inhibited hyperalgesia and allodynia in two-thirds of the animals (responsive group), and one-third did not respond (refractory group). Chronic constriction injury (CCI) increased IL-1β in the nerve and DRG, inhibited IL-4, IL-10, and IL-17A in the nerve, decreased β-endorphin, and enhanced substance P in the plasma, compared to the control. Responsive animals showed decreased NGF and increased IL-6 in the nerve, accompanied by restoration of local IL-10 and IL-17A and systemic β-endorphin. Refractory animals showed increased TNF-α and decreased IFNγ in the nerve, along with decreased TNF-α and IL-17A in the DRG, maintaining low levels of systemic β-endorphin. Our findings suggest that the effectiveness of MCS depends on local control of inflammatory and neurotrophic changes, accompanied by recovery of the opioidergic system observed in neuropathic conditions. So, understanding the refractoriness to MCS may guide an improvement in the efficacy of the technique, thus benefiting patients with persistent neuropathic pain.

Introduction: Deep brain stimulation (DBS) is a well-established treatment for patients with Parkinson's disease (PD) improving quality of life, motor, and non-motor symptoms. However, non-motor effects in PD subtypes are understudied. We hypothesized that patients with 'postural instability and gait difficulty' (PIGD) experience more beneficial non-motor effects than 'tremor-dominant' patients undergoing DBS for PD., Methods: In this prospective, observational, international multicentre study with a 6-month follow-up, we assessed the Non-Motor Symptom Scale (NMSS) as primary and the following secondary outcomes: Unified PD Rating Scale-motor examination (UPDRS-III), Scales for Outcomes in PD (SCOPA)-activities of daily living (ADL) and -motor complications, PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose (LEDD). We analysed within-group longitudinal changes with Wilcoxon signed-rank test and Benjamini-Hochberg correction for multiple comparisons. Additionally, we explored outcome between-group differences of motor subtypes with Mann-Whitney U-tests., Results: In 82 PIGD and 33 tremor-dominant patients included in this study, baseline NMSS total scores were worse in PIGD patients, both groups experienced postoperative improvements of the NMSS sleep/fatigue domain, and between-group differences in postoperative outcomes were favourable in the PIGD group for the NMSS total and miscellaneous domain scores., Conclusions: This study provides evidence of a favourable outcome of total non-motor burden in PIGD compared to tremor-dominant patients undergoing DBS for PD. These differences of clinical efficacy on non-motor aspects should be considered when advising and monitoring patients with PD undergoing DBS., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons with impaired motor and non-motor symptoms. It has been suggested that motor asymmetry could be caused due to an imbalance in dopamine levels, as visualized by dopamine transporter single emission computed tomography test (DAT-SPECT), which might be related to indirect measures of neurodegeneration, evaluated by the Montreal Cognitive Assessment (MOCA) and α-synuclein levels in the cerebrospinal fluid (CSF). Therefore, this study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and α-synuclein levels in PD., Methods: A total of 28 patients in the moderate-advanced stage of PD were subjected to neurological evaluation, TRODAT-1-SPECT/CT imaging, MOCA, and quantification of the levels of α-synuclein., Results: We found that α-synuclein in the CSF was correlated with global cognition (positive correlation, r 2 = 0.3, p = 0.05) and DAT-SPECT concentration in the putamen (positive correlation, r 2 = 0.4, p = 0.005), and striatum (positive correlation, r 2 = 0.2, p = 0.03), thus working as a neurodegenerative biomarker. No other correlations were found between DAT-SPECT, CSF α-synuclein, and cognition, thus suggesting that they may be lost with disease progression., Conclusions: Our data highlight the importance of understanding the dysfunction of the dopaminergic system in the basal ganglia and its complex interactions in modulating cognition.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is considered the gold-standard treatment for PD; however, underlying therapeutic mechanisms need to be comprehensively elucidated, especially in relation to glial cells. We aimed to understand the effects of STN-microlesions and STN-DBS on striatal glial cells, inflammation, and extracellular glutamate/GABAergic concentration in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Rats with unilateral striatal 6-OHDA and electrodes implanted in the STN were divided into two groups: DBS OFF and DBS ON (5 days/2 h/day). Saline and 6-OHDA animals were used as control. Akinesia, striatal reactivity for astrocytes, microglia, and inflammasome, and expression of cytokines, cell signaling, and excitatory amino acid transporter (EAAT)-2 were examined. Moreover, striatal microdialysis was performed to evaluate glutamate and GABA concentrations. The PD rat model exhibited akinesia, increased inflammation, glutamate release, and decreased glutamatergic clearance in the striatum. STN-DBS (DBS ON) completely abolished akinesia. Both STN-microlesion and STN-DBS decreased striatal cytokine expression and the relative concentration of extracellular glutamate. However, STN-DBS inhibited morphological changes in astrocytes, decreased inflammasome reactivity, and increased EAAT2 expression in the striatum. Collectively, these findings suggest that the beneficial effects of DBS are mediated by a combination of stimulation and local microlesions, both involving the inhibition of glial cell activation, neuroinflammation, and glutamate excitotoxicity., Competing Interests: The authors declare that they have no competing interests.

Background: Hemidystonia (HD) is characterized by unilateral involuntary torsion movements and fixed postures of the limbs and face. It often develops after deleterious neuroplastic changes secondary to injuries to the brain. This condition usually responds poorly to medical treatment, and deep brain stimulation often yields unsatisfactory results. We propose this study based on encouraging results from case reports of patients with HD treated by ablative procedures in the subthalamic region., Objective: To compare the efficacy of stereotactic-guided radiofrequency lesioning of the subthalamic area vs available medical treatment in patients suffering from acquired HD., Methods: This is an open-label study in patients with secondary HD allocated according to their treatment choice, either surgical or medical treatment; both groups were followed for one year. Patients assigned in the surgical group underwent unilateral campotomy of Forel. The efficacy was assessed using the Unified Dystonia Rating Scale, Fahn-Marsden Dystonia Scale, Arm Dystonia Disability Scale, and SF-36 questionnaire scores., Results: Patients in the surgical group experienced significant improvement in the Unified Dystonia Rating Scale, Fahn-Marsden Dystonia Scale, and Arm Dystonia Disability Scale (39%, 35%, and 15%, respectively) 1 year after the surgery, with positive reflex in quality-of-life measures, such as bodily pain and role-emotional process. Patients kept on medical treatment did not experience significant changes during the follow-up. No infections were recorded, and no neurological adverse events were associated with either intervention., Conclusion: The unilateral stereotaxy-guided ablation of Forel H1 and H2 fields significantly improved in patients with HD compared with optimized clinical treatment., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Motor cortex stimulation via surgically implanted electrodes has been used as an off-label treatment for chronic neuropathic pain, but its efficacy has not been fully established. We aimed to objectively study the efficacy of motor cortex stimulation and characterize potential predictors of response. In this randomized, double-blind, sham-controlled, single centre trial, we recruited 18 patients with chronic neuropathic pain who did not adequately respond to conventional treatment and had a numerical pain rating scale (NRS) score ≥6. Patients were initially assigned to receive 3 months of active ('on') or sham ('off') stimulation in a double-blind cross-over phase. This was followed by a 3-month single-blind phase, and 6 months of open-label follow-up. A meaningful response in our trial was defined as a ≥30% or 2-point reduction in NRS scores during active stimulation. Using Bayesian statistics, we found a 41.4% probability of response towards on versus off motor cortex stimulation. The probability of improvement during active stimulation (double-blind, single-blind and open-label phases) compared to baseline was 47.2-68.5%. Thirty nine per cent of the patients were considered long-term responders, 71.4% of whom had facial pain, phantom limb pain or complex regional pain syndrome. In contrast, 72.7% of non-responders had either post-stroke pain or pain associated with brachial plexus avulsion. Thirty-nine per cent of patients had a substantial postoperative analgesic effect after electrode insertion in the absence of stimulation. Individuals with diagnoses associated with a good postoperative outcome or those who developed an insertional effect had a near 100% probability of response to motor cortex stimulation. In summary, we found that ∼40% of patients responded to motor cortex stimulation, particularly those who developed an insertional effect or had specific clinical conditions that seemed to predict an appropriate postoperative response., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Intermittent explosive disorder (IED) is a psychiatric disorder characterized by recurrent outbursts of aggressive behavior. Deep brain stimulation (DBS) in the posteromedial nucleus of the hypothalamus (pHyp) is an alternative therapy for extreme cases and shows promising results. Intraoperative microdialysis can help elucidate the neurobiological mechanism of pHyp-DBS. We sought to evaluate efficacy and safety of pHyp-DBS using 8-contact directional leads in patients with refractory IED (rIED) and the accompanying changes in neurotransmitters., Methods: This was a prospective study in which patients with a diagnosis of rIED were treated with pHyp-DBS for symptom alleviation. Bilateral pHyp-DBS was performed with 8-contact directional electrodes. Follow-up was performed at 3, 6, and 12 months after surgery., Results: Four patients (3 men, mean age 27 ± 2.8 years) were included. All patients were diagnosed with rIED and severe intellectual disability. Two patients had congenital rubella, one had a co-diagnosis of infantile autism, and the fourth presented with drug-resistant epilepsy. There was a marked increase in the levels of gamma-aminobutyric acid and glycine during intraoperative stimulation. The average improvement in aggressive behavior in the last follow-up was 6 points (Δ: 50%, P = 0.003) while also documenting an important improvement of the Short Form Health Survey in all domains except bodily pain. No adverse events associated with pHyp-DBS were observed., Conclusions: This is the first study to show the safety and beneficial effect of directional lead pHyp-DBS in patients with rIED and to demonstrate the corresponding mechanism of action through increases in gamma-aminobutyric acid and glycine concentration in the pHyp., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aggressive behaviors comprise verbal and/or physical aggression directed toward oneself, others, or objects and are highly prevalent among psychiatric patients, especially patients diagnosed with autism spectrum disorder and severe intellectual disabilities. Some of these patients are considered refractory to treatment, and functional neurosurgery targeting the amygdala can result in widespread plastic brain changes that might reflect ceasing of some abnormal brain function, offering symptom alleviation. This study investigated cortical thickness changes in refractory aggressive behavior patients that were treated with bilateral amygdala ablation and compared to control patients presenting non-refractory aggressive behavior [three refractory and seven non-refractory patients, all males diagnosed with autism spectrum disorder (ASD) and intellectual disabilities]. The Overt Aggression Scale (OAS) was used to quantify behavior and magnetic resonance imaging was performed to investigate cortical thickness. Before surgery, both groups presented similar total OAS score, however refractory patients presented higher physical aggression against others. After surgery the refractory group showed 88% average reduction of aggressive behavior. Imaging analysis showed that while refractory patients present an overall reduction in cortical thickness compared to non-refractory patients across both timepoints, the local pattern of thickness difference found in areas of the neurocircuitry of aggressive behavior present before surgery is diminished and no longer detected after surgery. These results corroborate the hypotheses on induction of widespread neuronal plasticity following functional neurosurgical procedures resulting in modifications in brain morphology and improvement in behavior. Further studies are necessary to determine the underlying cause of these morphological changes and to better understand and improve treatment options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gouveia, Germann, Devenyi, Fonoff, Morais, Brentani, Chakravarty and Martinez.)

Persistent pain is a prevalent symptom of Parkinson's disease (PD), which is related to the loss of monoamines and neuroinflammation. Motor cortex stimulation (MCS) inhibits persistent pain by activating the descending analgesic pathways; however, its effectiveness in the control of PD-induced pain remains unclear. Here, we evaluated the analgesic efficacy of MCS together with serotonergic and spinal glial modulation in an experimental PD (ePD) rat model. Wistar rats with unilateral striatal 6-OHDA and MCS were assessed for behavioral immobility and nociceptive responses. The immunoreactivity of dopamine in the substantia nigra and serotonin in the nucleus raphe magnus (NRM) and the neuronal, astrocytic, and microglial activation in the dorsal horn of the spinal cord were evaluated. MCS, without interfering with dopamine loss, reversed ePD-induced immobility and hypernociception. This response was accompanied by an exacerbated increase in serotonin in the NRM and a decrease in neuronal and astrocytic hyperactivation in the spinal cord, without inhibiting ePD-induced microglial hypertrophy and hyperplasia. Taken together, MCS induces analgesia in the ePD model, while restores the descending serotonergic pathway with consequent inhibition of spinal neurons and astrocytes, showing the role of MCS in PD-induced pain control.

Understanding the intricate three-dimensional relationship between fiber bundles and subcortical nuclei is not a simple task. It is of paramount importance in neurosciences, especially in the field of functional neurosurgery. The current methods for in vivo and post mortem fiber tract visualization have shortcomings and contributions to the field are welcome. Several tracts were chosen to implement a new technique to help visualization of white matter tracts, using high-thickness histology and dark field images. Our study describes the use of computational fluid dynamic simulations for visualization of 3D fiber tracts segmented from dark field microscopy in high-thickness histological slices (histological mesh tractography). A post mortem human brain was MRI scanned prior to skull extraction, histologically processed and serially cut at 430 µm thickness as previously described by our group. High-resolution dark field images were used to segment the outlines of the structures. These outlines served as basis for the construction of a 3D structured mesh, were a Finite Volume Method (FVM) simulation of water flow was performed to generate streamlines representing the geometry. The simulations were accomplished by an open source computer fluid dynamics software. The resulting simulation rendered a realistic 3D impression of the segmented anterior commissure, the left anterior limb of the internal capsule, the left uncinate fascicle, and the dentato-rubral tracts. The results are in line with clinical findings, diffusion MR imaging and anatomical dissection methods.

Introduction: Hereditary spastic paraplegia is a heterogeneous group of genetic disorders characterized by degeneration of the corticospinal tracts, coursing with progressive weakness and spasticity of the lower limbs. To date, there are no effective treatments for progressive deficits or disease-modifying therapy for those patients. We report encouraging results for spastic paraparesis after spinal cord stimulation., Methods: A 51-year-old woman suffering from progressive weakness and spasticity in lower limbs related to hereditary spastic paraplegia type 4 underwent spinal cord stimulation (SCS) and experienced also significant improvement in motor function. Maximum ballistic voluntary isometric contraction test, continuous passive motion test and gait analysis using a motion-capture system were performed in ON and OFF SCS conditions. Neurophysiologic assessment consisted of obtaining motor evoked potentials in both conditions., Results: Presurgical Spastic Paraplegia Rating Scale (SPRS) score was 26. One month after effective SCS was initiated, SPRS went down to 15. At 12 months follow up, she experienced substantial improvement in motor function and in gait performance, with SPRS scores 23 (OFF) and down to 20 (ON). There was an increased isometric muscle strength (knee extension, OFF: 41 N m; ON: 71 N m), lower knee extension and flexion torque values in continuous passive motion test (decrease in spastic tone) and improvement in gait (for example, step length increase)., Conclusion: Despite being a case study, our findings suggest innovative lines of research for the treatment of spastic paraplegia., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Deep brain stimulation (DBS) is one of the most important clinical therapies for neurological disorders. DBS also has great potential to become a great tool for clinical neuroscience research. Recently, the National Engineering Laboratory for Neuromodulation at Tsinghua University held an international Deep Brain Stimulation Initiative workshop to discuss the cutting-edge technological achievements and clinical applications of DBS. We specifically addressed new clinical approaches and challenges in DBS for movement disorders (Parkinson's disease and dystonia), clinical application toward neurorehabilitation for stroke, and the progress and challenges toward DBS for neuropsychiatric disorders. This review highlighted key developments in (1) neuroimaging, with advancements in 3-Tesla magnetic resonance imaging DBS compatibility for exploration of brain network mechanisms; (2) novel DBS recording capabilities for uncovering disease pathophysiology; and (3) overcoming global healthcare burdens with online-based DBS programming technology for connecting patient communities. The successful event marks a milestone for global collaborative opportunities in clinical development of neuromodulation to treat major neurological disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sui, Tian, Ko, Wang, Jia, Horn, De Ridder, Choi, Bari, Wang, Hamani, Baker, Machado, Aziz, Fonoff, Kühn, Bergman, Sanger, Liu, Haber and Li.)

Background: Intractable aggressive behavior (iAB) is a devastating behavioral disorder that may affect psychiatric patients. These patients have reduced quality of life, are more challenging to treat as they impose a high caregiver burden and require specialized care. Neuromodulatory interventions targeting the amygdala, a key hub in the circuitry of aggressive behavior (AB), may provide symptom alleviation., Objective: To Report clinical and imaging findings from a case series of iAB patients treated with bilateral amygdala ablation., Methods: This series included 4 cases (3 males, 19-32 years old) who underwent bilateral amygdala radiofrequency ablation for iAB hallmarked by life-threatening self-injury and social aggression. Pre- and postassessments involved full clinical, psychiatric, and neurosurgical evaluations, including scales quantifying AB, general agitation, quality of life, and magnetic resonance imaging (MRI)., Results: Postsurgery assessments revealed decreased aggression and agitation and improved quality of life. AB was correlated with testosterone levels and testosterone/cortisol ratio in males. No clinically significant side effects were observed. Imaging analyses showed preoperative amygdala volumes within normal populational range and confirmed lesion locations. The reductions in aggressive symptoms were accompanied by significant postsurgical volumetric reductions in brain areas classically associated with AB and increases in regions related to somatosensation. The local volumetric reductions are found in areas that in a normal brain show high expression levels of genes related to AB (eg, aminergic transmission) using gene expression data provided by the Allen brain atlas., Conclusion: These findings provide new insight into the whole brain neurocircuitry of aggression and suggest a role of altered somatosensation and possible novel neuromodulation targets., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Periodontal disease (PD) is an infectious-inflammatory oral disease that is highly prevalent among adolescence and adulthood and can lead to chronic orofacial pain and be associated with anxiety, stress and depression. This study aimed to identify anxiety-like behaviors in the ligature-induced murine preclinical model of PD in different phases of the disease (i.e., acute vs. chronic). Also, we investigated orofacial mechanical allodynia thresholds and superficial cortical plasticity along the orofacial motor cortex in both disease phases. To this aim, 25 male Wistar rats were randomly allocated in acute (14 days) or chronic (28 days) ligature-induced-PD groups and further divided into active-PD or sham-PD. Anxiety-like behavior was evaluated using the elevated plus maze, mechanical allodynia assessed using the von Frey filaments test and superficial motor cortex mapping was performed with electrical transdural stimulation. We observed increased anxiety-like behavior in active-PD animals in the acute phase, characterized by decreased number of entries into the open arm extremities [ t (1,7) = 2.42, p = 0.04], and reduced time spent in the open arms [ t (1,7) = 3.56, p = 0.01] and in the open arm extremities [ t (1,7) = 2.75, p = 0.03]. There was also a reduction in the mechanical allodynia threshold in all active-PD animals [Acute: t (1,7) = 8.81, p < 0.001; Chronic: t (1,6) = 60.0, p < 0.001], that was positively correlated with anxiety-like behaviors in the acute group. No differences were observed in motor cortex mapping. Thus, our findings show the presence of anxiety-like behaviors in the acute phase of PD making this a suitable model to study the impact of anxiety in treatment response and treatment efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Varotto, Martinez, Gouveia, Antunes, Fabri, Ballester, Antequera, de Siqueira, Fonoff, Teixeira and de Siqueira.)

Background: Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson's disease (PD). However, few studies have compared their nonmotor effects., Objective: To compare nonmotor effects of STN-DBS and GPi-DBS., Methods: In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, -III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size., Results: In both groups, PDQ, UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains., Conclusions: To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients' individual motor and nonmotor profiles., Competing Interests: Declaration of competing interest Keyoumars Ashkan has received honoraria for educational meetings, travel and consultancy from Medtronic and Boston Scientific which manufacture deep brain stimulation systems used in this study. Monty Silverdale reports no potential conflict of interest. Julian Evans reports no potential conflict of interest. Raquel C.R. Martinez reports no potential conflict of interest. Rubens G. Cury reports no potential conflict of interest. Stefanie T. Jost reports no potential conflict of interest. Michael T. Barbe reports grants from Boston Scientific and Medtronic which manufacture deep brain stimulation systems used in this study. Gereon R. Fink reports no potential conflict of interest. Angelo Antonini reports personal consultancy fees from Medtronic and Boston Scientific which manufacture deep brain stimulation systems used in this study. K. Ray Chaudhuri reports no potential conflict of interest. Pablo Martinez-Martin reports no potential conflict of interest. Erich Talamoni Fonoff is a consultant for Medtronic and Boston Scientific which manufacture deep brain stimulation systems used in this study. Lars Timmermann reports grants, personal fees and nonfinancial support from Medtronic and Boston Scientific which manufacture deep brain stimulation systems used in this study. This paper is independent research funded by the German Research Foundation (Grant KFO 219), the National Institute of Health Research (NIHR) Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King’s College London. Additionally, an unrestricted peer reviewed educational grant was provided to support coordination of the UK dataset from Medtronic., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson's disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN-DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.

Avoidance behavior is a hallmark in pathological anxiety disorders and results in impairment of daily activities. Individual differences in avoidance responses are critical in determining vulnerability or resistance to anxiety disorders. Dopaminergic activation is implicated in the processing of avoidance responses; however, the mechanisms underlying these responses are unknown. In this sense, we used a preclinical model of avoidance behavior to investigate the possibility of an intrinsic differential dopaminergic pattern between good and poor performers. The specific goal was to assess the participation of dopamine (DA) through pharmacological manipulation, and we further evaluated the effects of systemic injections of the dopaminergic receptor type 1 (D1 antagonist - SCH23390) and dopaminergic receptor type 2 (D2 antagonist - sulpiride) antagonists in the good performers. Additionally, we evaluated the effects of intra-amygdala microinjection of a D1 antagonist (SCH23390) and a D2 antagonist (sulpiride) in good performers as well as intra-amygdala microinjection of a D1 agonist (SKF38393) and D2 agonist (quinpirole) in poor performers. Furthermore, we quantified the contents of dopamine and metabolites (3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) in the amygdala, evaluated the basal levels of tyrosine hydroxylase expression (catecholamine synthesis enzyme) and measured the volume of the substantia nigra, ventral tegmental area and locus coeruleus. Our results showed that it could be possible to convert animals from good to poor performers, and vice versa, by intra-amygdala (basolateral and central nucleus) injections of D1 receptor antagonists in good performers or D2 receptor agonists in poor performers. Additionally, the good performers had lower levels of DOPAC and HVA in the amygdala, an increase in the total volume of the amygdala (AMG), substantia nigra (SN), ventral tegmental area (VTA) and locus coeruleus (LC), and an increase in the number of tyrosine hydroxylase-positive cells in SN, VTA and LC, which positively correlates with the avoidance behavior. Taken together, our data show evidence for a dopaminergic signature of avoidance performers, emphasizing the role of distinct dopaminergic receptors in individual differences in avoidance behavior based on pharmacological, immunohistochemical, neurochemical and volumetric analyses. Our findings provide a better understanding of the role of the dopaminergic system in the execution of avoidance behavior., Competing Interests: The authors report no conflicts of interest., (© 2020 The Authors.)

Background: Pain is highly prevalent in Parkinson's disease and is associated with significant reduction in health-related quality of life. Subthalamic deep brain stimulation can produce significant pain relief in a subset of patients after surgery. However, the mechanism by which deep brain stimulation modulates sensory function in Parkinson's disease remains uncertain. Objective: To describe the motor and pain outcomes of deep brain stimulation applied to a series of patients with Parkinson's disease and to determine whether the structural connectivity between the volume of tissue activated and different regions of the brain was associated with the changes of these outcomes after surgery. Methods: Data from a long-term prospective cohort of 32 Parkinson's disease patients with subthalamic stimulation were combined with available human connectome to identify connections consistently associated with clinical improvement (Unified Parkinson Disease Rating Scale), pain intensity, and experimental cold pain threshold after surgery. Results: The connectivity between the volume of tissue activated and a distributed network of sensory brain regions (prefrontal, insular and cingulate cortex, and postcentral gyrus) was inversely correlated with pain intensity improvement and reduced sensitivity to cold pain after surgery ( p < 0.01). The connectivity strength with the supplementary motor area positively correlated with motor and pain threshold improvement ( p < 0.05). Conclusions: These data suggest that the pattern of the connectivity between the region stimulated and specific brain cortical area might be responsible, in part, for the successful control of motor and pain symptoms by subthalamic deep brain stimulation in Parkinson's disease., (Copyright © 2020 Cury, Teixeira, Galhardoni, Silva, Iglesio, França, Arnaut, Fonoff, Barbosa and Ciampi de Andrade.)

Objective: Motor cortex stimulation (MCS) is a neurosurgical technique used to treat patients with refractory neuropathic pain syndromes. MCS activates the periaqueductal gray (PAG) matter, which is one of the major centers of the descending pain inhibitory system. However, the neurochemical mechanisms in the PAG that underlie the analgesic effect of MCS have not yet been described. The main goal of this study was to investigate the neurochemical mechanisms involved in the analgesic effect induced by MCS in neuropathic pain. Specifically, we investigated the release of γ-aminobutyric acid (GABA), glycine, and glutamate in the PAG and performed pharmacological antagonism experiments to validate of our findings., Methods: Male Wistar rats with surgically induced chronic constriction of the sciatic nerve, along with sham-operated rats and naive rats, were implanted with both unilateral transdural electrodes in the motor cortex and a microdialysis guide cannula in the PAG and subjected to MCS. The MCS was delivered in single 15-minute sessions. Neurotransmitter release was evaluated in the PAG before, during, and after MCS. Quantification of the neurotransmitters GABA, glycine, and glutamate was performed using a high-performance liquid chromatography system. The mechanical nociceptive threshold was evaluated initially, on the 14th day following the surgery, and during the MCS. In another group of neuropathic rats, once the analgesic effect after MCS was confirmed by the mechanical nociceptive test, rats were microinjected with saline or a glycine antagonist (strychnine), a GABA antagonist (bicuculline), or a combination of glycine and GABA antagonists (strychnine+bicuculline) and reevaluated for the mechanical nociceptive threshold during MCS., Results: MCS reversed the hyperalgesia induced by peripheral neuropathy in the rats with chronic sciatic nerve constriction and induced a significant increase in the glycine and GABA levels in the PAG in comparison with the naive and sham-treated rats. The glutamate levels remained stable under all conditions. The antagonism of glycine, GABA, and the combination of glycine and GABA reversed the MCS-induced analgesia., Conclusions: These results suggest that the neurotransmitters glycine and GABA released in the PAG may be involved in the analgesia induced by cortical stimulation in animals with neuropathic pain. Further investigation of the mechanisms involved in MCS-induced analgesia may contribute to clinical improvements for the treatment of persistent neuropathic pain syndromes.

Deep brain stimulation of the subthalamic nucleus is an effective and established therapy for patients with advanced Parkinson's disease improving quality of life, motor symptoms and non-motor symptoms. However, there is a considerable degree of interindividual variability for these outcomes, likely due to variability in electrode placement and stimulation settings. Here, we present probabilistic mapping data from a prospective, open-label, multicentre, international study to investigate the influence of the location of subthalamic nucleus deep brain stimulation on non-motor symptoms in patients with Parkinson's disease. A total of 91 Parkinson's disease patients undergoing bilateral deep brain stimulation of the subthalamic nucleus were included, and we investigated NMSScale, NMSQuestionnaire, Scales for Outcomes in Parkinson's disease-motor examination, -activities of daily living, and -motor complications, and Parkinson's disease Questionnaire-8 preoperatively and at 6-month follow-up after surgery. Leads were localized in standard space using the Lead-DBS toolbox and individual volumes of tissue activated were calculated based on clinical stimulation settings. Probabilistic stimulation maps and non-parametric permutation statistics were applied to identify voxels with significant above or below average improvement for each scale and analysed using the DISTAL atlas. All outcomes improved significantly at follow-up. Significant spatial distribution patterns of neurostimulation were observed for NMSScale total score and its mood/apathy and attention/memory domains. For both domains, voxels associated with below average improvement were mainly located dorsal to the subthalamic nucleus. In contrast, above average improvement for mood/apathy was observed in the ventral border region of the subthalamic nucleus and in its sensorimotor subregion and for attention/memory in the associative subregion. A trend was observed for NMSScale sleep domain showing voxels with above average improvement located ventral to the subthalamic nucleus. Our study provides evidence that the interindividual variability of mood/apathy, attention/memory, and sleep outcomes after subthalamic nucleus deep brain stimulation depends on the location of neurostimulation. This study highlights the importance of holistic assessments of motor and non-motor aspects of Parkinson's disease to tailor surgical targeting and stimulation parameter settings to patients' personal profiles., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Spinal cord stimulation (SCS) has been used for the treatment of chronic pain for nearly five decades. With a high degree of efficacy and a low incidence of adverse events, it is now considered to be a suitable therapeutic alternative in most guidelines. Experimental studies suggest that SCS may also be used as a therapy for motor and gait dysfunction in parkinsonian states. The most common and disabling gait dysfunction in patients with Parkinson's disease (PD) is freezing of gait (FoG). We review the evolution of SCS for gait disorders from bench to bedside and discuss potential mechanisms of action, neural substrates, and clinical outcomes.

Pain is a common nonmotor symptom of Parkinson's disease (PD) that remains neglected and misunderstood. Elucidating the nondopaminergic circuitry may be key to better understanding PD and improving current treatments. We investigated the role of monoamines in nociceptive behavior and descending analgesic circuitry in a rat 6-hydroxydopamine (6-OHDA)-induced PD model and explored the resulting motor dysfunctions and inflammatory responses. Rats pretreated with noradrenaline and serotonin reuptake inhibitors were given unilateral striatal 6-OHDA injections and evaluated for mechanical hyperalgesia and motor impairments. Through immunohistochemistry, the number and activation of neurons, and the staining for astrocytes, microglia and enkephalin were evaluated in specific brain structures and the dorsal horn of the spinal cord. The PD model induced bilateral mechanical hyperalgesia that was prevented by reuptake inhibitors in the paw contralateral to the lesion. Reuptake inhibitors also prevented postural immobility and asymmetric rotational behavior in PD rats without interfering with dopaminergic neuron loss or glial activation in the substantia nigra. However, the inhibitors changed the periaqueductal gray circuitry, protected against neuronal impairment in the locus coeruleus and nucleus raphe magnus, and normalized spinal enkephalin and glial staining in lesioned rats. These data indicate that the preservation of noradrenergic and serotonergic systems regulates motor responses and nociceptive circuitry during PD not by interfering directly with nigral lesions but by modulating the opioid system and glial response in the spinal cord. Taken together, these results suggest that nondopaminergic circuitry is essential to the motor and nonmotor symptoms of PD and must be further investigated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aggressiveness has a high prevalence in psychiatric patients and is a major health problem. Two brain areas involved in the neural network of aggressive behavior are the amygdala and the hypothalamus. While pharmacological treatments are effective in most patients, some do not properly respond to conventional therapies and are considered medically refractory. In this population, surgical procedures (ie, stereotactic lesions and deep brain stimulation) have been performed in an attempt to improve symptomatology and quality of life. Clinical results obtained after surgery are difficult to interpret, and the mechanisms responsible for postoperative reductions in aggressive behavior are unknown. We review the rationale and neurobiological characteristics that may help to explain why functional neurosurgery has been proposed to control aggressive behavior., (© Congress of Neurological Surgeons 2019.)

Parkinson's disease (PD) is a neurodegenerative disorder that causes progressive dysfunction of dopaminergic and non-dopaminergic neurons, generating motor and nonmotor signs and symptoms. Pain is reported as the most bothersome nonmotor symptom in PD; however, pain remains overlooked and poorly understood. In this study, we evaluated the nociceptive behavior and the descending analgesia circuitry in a rat model of PD. Three independent experiments were performed to investigate: i) thermal nociceptive behavior; ii) mechanical nociceptive behavior and dopaminergic repositioning; and iii) modulation of the pain control circuitry. The rat model of PD, induced by unilateral striatal 6-hydroxydopamine (6-OHDA), did not interfere with thermal nociceptive responses; however, the mechanical nociceptive threshold was decreased bilaterally compared to that of naive or striatal saline-injected rats. This response was reversed by apomorphine or levodopa treatment. Striatal 6-OHDA induced motor impairments and reduced dopaminergic neuron immunolabeling as well as the pattern of neuronal activation (c-Fos) in the substantia nigra ipsilateral (IPL) to the lesion. In the midbrain periaqueductal gray (PAG), 6-OHDA-induced lesion increased IPL and decreased contralateral PAG GABAergic labeling compared to control. In the dorsal horn of the spinal cord, lesioned rats showed bilateral inhibition of enkephalin and μ-opioid receptor labeling. Taken together, we demonstrated that the unilateral 6-OHDA-induced PD model induces bilateral mechanical hypernociception, which is reversed by dopamine restoration, changes in the PAG circuitry, and inhibition of spinal opioidergic regulation, probably due to impaired descending analgesic control. A better understanding of pain mechanisms in PD patients is critical for developing better therapeutic strategies to improve their quality of life., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Motor cortex stimulation (MCS) is an effective therapy for refractory neuropathic pain. MCS increases the nociceptive threshold in healthy rats via endogenous opioids, inhibiting thalamic nuclei and activating the periaqueductal gray. It remains unclear how the motor cortex induces top-down modulation of pain in the absence of persistent pain. Here, we investigated the main nuclei involved in the descending analgesic pathways and the spinal nociceptive neurons in rats that underwent one session of MCS and were evaluated with the paw pressure nociceptive test. The pattern of neuronal activation in the dorsal raphe nucleus (DRN), nucleus raphe magnus (NRM), locus coeruleus (LC), and dorsal horn of the spinal cord (DHSC) was assessed by immunoreactivity (IR) for Egr-1 (a marker of activated neuronal nuclei). IR for serotonin (5HT) in the DRN and NRM, tyrosine hydroxylase (TH) in the LC, and substance P (SP) and enkephalin (ENK) in the DHSC was also evaluated. MCS increased the nociceptive threshold of the animals; this increase was accompanied by activation of the NRM, while DRN activation was unchanged. However, cortical stimulation induced an increase in 5HT-IR in both serotonergic nuclei. MCS did not change the activation pattern or TH-IR in the LC, and it inhibited neuronal activation in the DHSC without altering SP or ENK-IR. Taken together, our results suggest that MCS induces the activation of serotonergic nuclei as well as the inhibition of spinal neurons, and such effects may contribute to the elevation of the nociceptive threshold in healthy rats. These results allow a better understanding of the circuitry involved in the antinociceptive top-down effect induced by MCS under basal conditions, reinforcing the role of primary motor cortex in pain control.

Introduction  Surgical treatment of brain tumors in eloquent areas has always been considered a major challenge because removal-related cortical damage can cause serious functional impairment. However, few studies have investigated the association between small craniotomies and the higher risk of incidence of motor deficits and prolonged recovery time. Here, we analyzed neurologic deficits and the prognostic variables after surgery guided by navigation for motor cortex tumors under general anesthesia. Methods  This was a prospective study that included 47 patients with tumors in the precentral gyrus. All surgeries were performed with neuronavigation and cortical mapping, with direct electrical stimulation of the motor cortex. We evaluated the prognostic evolution of patients with pre- and postoperative Karnofsky Performance Scale using the Eastern Cooperative Oncology Group scale. Results  Complete resection was verified in all 18 cases of metastasis, 13 patients with glioblastoma multiforme, and 5 patients with low-grade gliomas. An analysis of the motor deficits revealed that 11 patients experienced worsening of the deficit on the first day after surgery. Only four patients developed new deficits in the immediate postoperative period, and these improved after 3 weeks. After 3 months, only two patients had deficits that were worse those experienced prior to surgery; both patients had glioblastoma multiforme. Conclusion  In our series, motor deficits prior to surgery were the most important factors associated with persistent postoperative deficits. Small craniotomy with navigation associated with intraoperative brain mapping allowed a safe resection and motor preservation in patients with motor cortex brain tumor.

Objective: Real-life observational report of clinical efficacy of bilateral subthalamic stimulation (STN-DBS), apomorphine (APO), and intrajejunal levodopa infusion (IJLI) on quality of life, motor, and nonmotor symptoms (NMS) in Parkinson's disease (PD)., Methods: In this prospective, multicenter, international, real-life cohort observation study of 173 PD patients undergoing STN-DBS (n = 101), IJLI (n = 33), or APO (n = 39) were followed-up using PDQuestionnaire-8, NMSScale (NMSS), Unified PD Rating Scale (UPDRS)-III, UPDRS-IV, and levodopa equivalent daily dose (LEDD) before and 6 months after intervention. Outcome changes were analyzed with Wilcoxon signed-rank or paired t test when parametric tests were applicable. Multiple comparisons were corrected (multiple treatments/scales). Effect strengths were quantified with relative changes, effect size, and number needed to treat. Analyses were computed before and after propensity score matching, balancing demographic and clinical characteristics., Results: In all groups, PDQuestionnaire-8, UPDRS-IV, and NMSS total scores improved significantly at follow-up. Levodopa equivalent daily dose was significantly reduced after STN-DBS. Explorative NMSS domain analyses resulted in distinct profiles: STN-DBS improved urinary/sexual functions, mood/cognition, sleep/fatigue, and the miscellaneous domain. IJLI improved the 3 latter domains and gastrointestinal symptoms. APO improved mood/cognition, perceptual problems/hallucinations, attention/memory, and the miscellaneous domain. Overall, STN-DBS and IJLI seemed favorable for NMSS total score, and APO favorable for neuropsychological/neuropsychiatric NMS and PDQuestionnaire-8 outcome., Conclusions: This is the first comparison of quality of life, nonmotor. and motor outcomes in PD patients undergoing STN-DBS, IJLI, and APO in a real-life cohort. Distinct effect profiles were identified for each treatment option. Our results highlight the importance of holistic nonmotor and motor symptoms assessments to personalize treatment choices. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)