Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

Impact of selective dorsal rhizotomy to cerebral palsy children caregivers' burden.

PURPOSE: It is known that cerebral palsy (CP) children's caregivers suffer from burden, depression, and stress, impairing their quality of life (QoL). The more severe the CP, the more burden the caregiver has. Psychosocial support, education, therapies, and financial support are inversely related to the level of stress of the caregiver. Most parents of CP patients submitted to selective dorsal rhizotomy (SDR) report improvement not just on spasticity, but also in the functional role of the children, what can impact on caregiver's QoL. Our objective was to evaluate the burden of CP children's caregivers with and without previous SDR. METHODS: Spastic CP children caregivers were divided into two groups: those who take care of children without previous SDR (control group) and those that children were previously submitted to SDR (surgical group). The burden index was compared between groups using Burden Interview Questionnaire (BIQ). For statistical analysis, we used SPSS. RESULTS: The control group had enrolled 31 participants and the surgical group 36. The mean GMFCS level on the control and surgical groups was 3.94 ± 1.26 and 3.74 ± 1.12 (p = 0.61), respectively. The surgical group caregivers presented less burden related to the feeling that they should be doing more to their child (p = 0.003) and if they could do a better job in caring (p = 0.032), compared to controls. The total BIQ index was not significantly different between groups (surgical 32.14 ± 12.34 vs. control 36.77 ± 12.77; p = 0.87). Low economic status had a weak correlation to a higher BIQ index (R2 = 0.24). After age-matching, there was a significative higher BIQ index in the control group (p = 0.008). CONCLUSION: Caregivers of spastic CP children who were previously submitted to SDR presented less burden related to feeling of the amount of given care than those without previous surgery. The impression that they could do a better job with their kids was higher in the control group. The severity of CP and low economic status were related to more burden in both groups. After pairing groups by age, the control group had a significative higher BIQ index compared to the SDR group. CLINICAL TRIAL REGISTRATION: Trial registration number: CAAE 73407317.6.0000.0068 (Ethical and Research Committee of University of Sao Paulo, Sao Paulo, Brazil, approved on 08/06/2021). All the subjects were freely given an informed consent to participate in the study that was obtained from all participants. Non-consented ones were excluded from the study.

Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation.

Frontal circuits play a critical role in motor, cognitive, and affective processing - and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)function remains largely elusive. Here, we study 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregate the frontal cortex into circuits that became dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to rostral, ranging from interconnections with sensorimotor cortices in dystonia, with the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairment in the human brain.

Unilateral Campotomy of Forel for Acquired Hemidystonia: An Open-Label Clinical Trial.

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.

Directional Deep Brain Stimulation of the Posteromedial Hypothalamus for Refractory Intermittent Explosive Disorder: A Case Series Using a Novel Neurostimulation Device and Intraoperative Microdialysis.

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.

Use of computational fluid dynamics for 3D fiber tract visualization on human high-thickness histological slices: histological mesh tractography.

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.

Longitudinal Changes After Amygdala Surgery for Intractable Aggressive Behavior: Clinical, Imaging Genetics, and Deformation-Based Morphometry Study-A Case Series.

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.

Directional deep brain stimulation of the posteromedial hypothalamus for refractory intermittent explosive disorder: a case series using a novel neurostimulation device and intraoperative microdialysis

Intermittent Explosive Disorder (IED) is a psychiatric disorder characterized by recurrent outbursts of aggressive behaviour. 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. Objective To evaluate efficacy and safety of pHyp-DBS using eight-contact directional leads in patients with refractory IED (rIED) and the accompanying changes in neurotransmitters. Methods 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 eight-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 yr) were included. All patients were diagnosed with rIED and severe intellectual disability. Two patients had congenital rubella, one has co-diagnosis of infantile autism and the fourth presents with drug-resistant epilepsy. There was a marked increase in the levels of GABA and glycine during intraoperative stimulation. The average improvement in aggressive behaviour in the last follow-up was 6 points (Δ: 50%, p= 0.003) while also documenting an important improvement of the SF-36 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 refractory Intermittent Explosive Disorder and to demonstrate the corresponding mechanism of action through increases in GABA and glycine concentration in the pHyp.

Computer-assisted craniometric evaluation for diagnosis and follow-up of craniofacial asymmetries: SymMetric v. 1.0.

PURPOSE: The current assessment of patients with craniofacial asymmetries is accomplished by physical examination, anamnesis and radiological imaging. We propose a semi-automated, computer-assisted craniofacial evaluation (SymMetric v 1.0) based on orthogonal photography of the patient's head in 3 positions. The system is simple, low-cost, no-radiation or special resources needed. Although it does not substitute CT in cases of doubt between craniosynostosis and positional plagiocephaly, multiple numeric evaluations indicate regional deformities and severity of the asymmetry, which can help in the clinical decision of indicating or not the orthosis in positional deformities, determining treatment duration or evaluating surgical outcomes after correction. METHODS: A Matlab-based tool was developed for digital processing of photographs taken in 3 positions (anterior, superior and lateral). The software guides the user to select visible and reproducible landmarks in each photograph acquisition and calculates multiple indexes and metrics, generating a set of comprehensive plots to offer the user an overview of head and facial symmetry across the orthogonal views. For purposes of demonstration, we evaluated 2 patients (one control and one with non-sinostotic deformity). RESULTS: The results show a clear differentiation of the control and plagiocephalic patient metrics mainly in the superior view, showing potential for diagnosis of the condition, and also detected the clinical improvement during helmet treatment in the follow-up, 3 and 5 months after orthosis' use. CONCLUSION: We presented a proof-of-concept for a low cost, no radiation evaluation system for craniofacial asymmetries, that can be useful in a clinical context for diagnosis and follow-up of patients.

Amygdala and Hypothalamus: Historical Overview With Focus on Aggression.

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.

Pedunculopontine Nucleus Cholinergic Deficiency in Cervical Dystonia.

BACKGROUND: The etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus. OBJECTIVES: The objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors. METHODS: Formalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus. RESULTS: Decreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls. CONCLUSIONS: Our findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. © 2018 International Parkinson and Movement Disorder Society.

High thickness histological sections as alternative to study the three-dimensional microscopic human sub-cortical neuroanatomy.

Stereotaxy is based on the precise image-guided spatial localization of targets within the human brain. Even with the recent advances in MRI technology, histological examination renders different (and complementary) information of the nervous tissue. Although several maps have been selected as a basis for correlating imaging results with the anatomical locations of sub-cortical structures, technical limitations interfere in a point-to-point correlation between imaging and anatomy due to the lack of precise correction for post-mortem tissue deformations caused by tissue fixation and processing. We present an alternative method to parcellate human brain cytoarchitectural regions, minimizing deformations caused by post-mortem and tissue-processing artifacts and enhancing segmentation by means of modified high thickness histological techniques and registration with MRI of the same specimen and into MNI space (ICBM152). A three-dimensional (3D) histological atlas of the human thalamus, basal ganglia, and basal forebrain cholinergic system is displayed. Structure's segmentations were performed in high-resolution dark-field and light-field microscopy. Bidimensional non-linear registration of the histological slices was followed by 3D registration with in situ MRI of the same subject. Manual and automated registration procedures were adopted and compared. To evaluate the quality of the registration procedures, Dice similarity coefficient and normalized weighted spectral distance were calculated and the results indicate good overlap between registered volumes and a small shape difference between them in both manual and automated registration methods. High thickness high-resolution histological slices in combination with registration to in situ MRI of the same subject provide an effective alternative method to study nuclear boundaries in the human brain, enhancing segmentation and demanding less resources and time for tissue processing than traditional methods.

Thalamic deep brain stimulation for tremor in Parkinson disease, essential tremor, and dystonia.

OBJECTIVE: To report on the long-term outcomes of deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) in Parkinson disease (PD), essential tremor (ET), and dystonic tremor. METHODS: One hundred fifty-nine patients with PD, ET, and dystonia underwent VIM DBS due to refractory tremor at the Grenoble University Hospital. The primary outcome was a change in the tremor scores at 1 year after surgery and at the latest follow-up (21 years). Secondary outcomes included the relationship between tremor score reduction over time and the active contact position. Tremor scores (Unified Parkinson's Disease Rating Scale-III, items 20 and 21; Fahn, Tolosa, Marin Tremor Rating Scale) and the coordinates of the active contacts were recorded. RESULTS: Ninety-eight patients were included. Patients with PD and ET had sustained improvement in tremor with VIM stimulation (mean improvement, 70% and 66% at 1 year; 63% and 48% beyond 10 years, respectively; p < 0.05). There was no significant loss of stimulation benefit over time (p > 0.05). Patients with dystonia exhibited a moderate response at 1-year follow-up (41% tremor improvement, p = 0.027), which was not sustained after 5 years (30% improvement, p = 0.109). The more dorsal active contacts' coordinates in the right lead were related to a better outcome 1 year after surgery (p = 0.029). During the whole follow-up, forty-eight patients (49%) experienced minor side effects, whereas 2 (2.0%) had serious events (brain hemorrhage and infection). CONCLUSIONS: VIM DBS is an effective long-term (beyond 10 years) treatment for tremor in PD and ET. Effects on dystonic tremor were modest and transient. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is an observational study.

The Retrograde Ventriculosinusal Shunt in an Animal Experimental Model of Hydrocephalus.

Currently, hydrocephalus treatment is performed mainly with ventriculoperitoneal shunting. This experimental study aims at assessing whether the experimental model of hydrocephalus in dogs is applicable to the laboratory study of the retrograde ventriculosinusal shunt (RVSS). Four mongrel dogs were assessed. After randomization, the animals were divided into two groups: an experimental group that underwent the induction of hydrocephalus/RVSS and a control group, for the measurement of the mean arterial pressure, intracranial pressure and pressure in the superior sagittal sinus (SSS). The controls presented a mean arterial pressure of 68 mm Hg (71 and 65), an intracranial pressure of 163 mm H2O (149.6 and 176.8) and a pressure at the SSS of 40 mm H2O (40 and 40). The kaolin injection into the cisterna magna at a concentration of 0.3 mg/ml was capable of inducing the clinical and radiological mechanism of hydrocephalus (intracranial pressure = 250 mm H2O, pressure at the SSS = 50 mm H2O). The caliber of the SSS was 2.5 ± 1.0 mm. The fact that the SSS caliber of the dog was the same size as the external diameter of the catheter used resulted in the complete obstruction of the SSS when the catheter was inserted. We believe we could design and perform an experimental model to test the RVSS. It is applicable and feasible. The model of hydrocephalus, the surgical apparatus and the scenario were adequate, but the shunt system needs to be proportionally made to the canine anatomy.

Oncostatic effects of fluoxetine in experimental colon cancer models.

Colon cancer is one of the most common tumors in the human population. Recent studies have shown a reduced risk for colon cancer in patients given the antidepressant fluoxetine (FLX). The exact mechanism by which FLX might protect from colon cancer remains however controversial. Here, FLX reduced the development of different colon tumor xenografts, as well as proliferation in hypoxic tumor areas within them. FLX treatment also decreased microvessel numbers in tumors. Although FLX did not increase serum and tumor glucose levels as much as the colon chemotherapy gold standard Fluorouracil did, lactate levels were significantly augmented within tumors by FLX treatment. The gene expression of the MCT4 lactate transporter was significantly downregulated. Total protein amounts from the third and fifth mitochondrial complexes were significantly decreased by FLX in tumors. Cell culture experiments revealed that FLX reduced the mitochondrial membrane potential significantly and disabled the reactive oxygen species production of the third mitochondrial complex. Furthermore, FLX arrested hypoxic colon tumor cells in the G0/G1 phase of the cell-cycle. The expression of key cell-cycle-related checkpoint proteins was enhanced in cell culture and in vivo experiments. Therefore, we suggest FLX impairs energy generation, cell cycle progression and proliferation in tumor cells, especially under condition of hypoxia. This then leads to reduced microvessel formation and tumor shrinkage in xenograft models.

Subregional basal forebrain atrophy in Alzheimer's disease: a multicenter study.

Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD.

Models of functional cerebral localization at the dawning of modern neurosurgery.

The concept of a functional cerebral localization gave the needed support for the development of neurosurgery as a specialty. It should be noted though that the presence of functions on discrete areas of the cortex was a very controversial topic at that time. The objective of this paper is to review models of cortical organization at the end of the 19th century, highlighting beliefs, theories, and controversies behind them. A better understanding of this historical moment is essential to appreciate the debate between holists and localizers that stirred neuroscientists worldwide in the first half of the 20th century.