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.

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.

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.

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.

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.

Bilateral subthalamic nucleus stimulation for generalized dystonia after bilateral pallidotomy.

BACKGROUND: Thalamotomies and pallidotomies were commonly performed before the deep brain stimulation (DBS) era. Although ablative procedures can lead to significant dystonia improvement, longer periods of analysis reveal disease progression and functional deterioration. Today, the same patients seek additional treatment possibilities. METHODS: Four patients with generalized dystonia who previously had undergone bilateral pallidotomy came to our service seeking additional treatment because of dystonic symptom progression. Bilateral subthalamic nucleus DBS (B-STN-DBS) was the treatment of choice. The patients were evaluated with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Dystonia Rating Scale (UDRS) before and 2 years after surgery. RESULTS: All patients showed significant functional improvement, averaging 65.3% in BFMDRS (P = .014) and 69.2% in UDRS (P = .025). CONCLUSIONS: These results suggest that B-STN-DBS may be an interesting treatment option for generalized dystonia, even for patients who have already undergone bilateral pallidotomy.

Endoscopic-guided percutaneous radiofrequency cordotomy.

The authors present the first clinical implementation of an endoscopic-assisted percutaneous anterolateral radiofrequency cordotomy. The aim of this article is to demonstrate the intradural endoscopic visualization of the cervical spinal cord via a percutaneous approach to refine the spinal target for anterolateral cordotomy, avoiding undesired trauma to the spinal tissue or injury to blood vessels. Initially, a lateral puncture of the spinal canal in the C1-2 interspace is performed, guided by fluoroscopy. As soon as CSF is reached by the guide cannula (17-gauge needle), the endoscope can be inserted for visualization of the spinal cord and its surrounding structures. The endoscopic visualization provided clear identification of the pial surface of the spinal cord, arachnoid membrane, dentate ligament, dorsal and ventral root entry zone, and blood vessels. The target for electrode insertion into the spinal cord was determined to be the midpoint from the dentate ligament and the ventral root entry zone. The endoscopic guidance shortened the fluoroscopy usage time and no intrathecal contrast administration was needed. Cordotomy was performed by a standard radiofrequency method after refining of the neurophysiological target. Satisfactory analgesia was provided by the procedure with no additional complications or CSF leak. The initial use of this technique suggests that a percutaneous endoscopic procedure may be useful for particular manipulation of the spinal cord, possibly adding a degree of safety to the procedure and improving its effectiveness.

Pilot study in neonates using low-level laser therapy in the immediate postoperative period of myelomeningocele / Estudo piloto em neonatos utilizando o laser de baixa intensidade no pós-operatório imediato de mielomeningocele

Objective: To analyze the tissue repair behavior after corrective surgical incision in neonates submitted to low-level laser therapy, in an attempt to diminish the incidence of postoperative dehiscence following the surgery for myelomeningocele performed immediately after birth. Methods: It is a prospective pilot study with 13 myelomeningocele patients submitted to surgery at birth who received adjuvant treatment with low-level laser therapy (Group A). Diode laser C.W., lambda = 685t nm, p = 21 mW, E = 0.19 J was punctually applied along the surgical incision, summing up 4 to 10 J energy delivered per patient, according to the surgical wound area and, then, compared with the previous results, which were obtained from 23 patients undergoing surgery without laser therapy (Group B). Results: This pilot study showed a significant decline in dehiscence of surgical wounds in neonates submitted to low-level laser therapy as compared to controls (7.69 versus 17.39%, respectively), demonstrating this is an effective, safe and noninvasive treatment method. Conclusion: This new adjuvant therapeutic proposal with low-level laser therapy aided healing of surgical wounds, preventing morbidities, as well as decreasing hospital stay, which implies cost of reduction for patients and for the institution.

Objetivo: Analisar o comportamento da reparação tecidual de incisão cirúrgica corretiva em neonatos submetidos ao laser de baixa intensidade, auxiliando a redução de incidência de deiscência pós-operatória de correção cirúrgica de mielomeningocele realizada imediatamente após o nascimento. Métodos: Estudo piloto, prospectivo, com 13 pacientes operados ao nascimento de mielomeningocele e submetidos ao laser de baixa intensidade como adjuvante. Foi aplicado, ao longo da incisão cirúrgica, o laser de diodo C.W., lambda = 685 nm, p = 21 mW, com E = 0,19 J por ponto, totalizando valores de energia entregue por paciente entre 4 e 10 J, de acordo com a área da cicatriz cirúrgica, e comparando com os resultados obtidos previamente de 23 pacientes operados sem a terapia com o laser (Grupo B). Resultados: Este estudo revelou significativa redução de deiscências no pós-operatório de neonatos, quando submetidos ao laser de baixa intensidade comparados ao controle (7,69 versus 17,39%, respectivamente), evidenciando ser um método de tratamento eficaz, seguro e não-invasivo. Conclusão: Esta nova proposta terapêutica adjuvante com o laser de baixa intensidade auxiliou na reparação tecidual da ferida operatória, evitando morbidades, além de diminuir o tempo de internação, sinalizando possível redução de custos tanto para os pacientes quanto para a instituição.

Pilot study in neonates using low-level laser therapy in the immediate postoperative period of myelomeningocele.

OBJECTIVE: To analyze the tissue repair behavior after corrective surgical incision in neonates submitted to low-level laser therapy, in an attempt to diminish the incidence of postoperative dehiscence following the surgery for myelomeningocele performed immediately after birth. METHODS: It is a prospective pilot study with 13 myelomeningocele patients submitted to surgery at birth who received adjuvant treatment with low-level laser therapy (Group A). Diode laser C.W., λ = 685t nm, p = 21 mW, E = 0.19 J was punctually applied along the surgical incision, summing up 4 to 10 J energy delivered per patient, according to the surgical wound area and, then, compared with the previous results, which were obtained from 23 patients undergoing surgery without laser therapy (Group B). RESULTS: This pilot study showed a significant decline in dehiscence of surgical wounds in neonates submitted to low-level laser therapy as compared to controls (7.69 versus 17.39%, respectively), demonstrating this is an effective, safe and noninvasive treatment method. CONCLUSION: This new adjuvant therapeutic proposal with low-level laser therapy aided healing of surgical wounds, preventing morbidities, as well as decreasing hospital stay, which implies cost of reduction for patients and for the institution.

Hemorragia subaracnóidea traumática: aspectos clínicos, radiológicos e complicações / Traumatic subarachnoid hemorrhage: clinical and radiological aspects and complications

Introdução: Recentes estudos têm demonstrados associação entre a presença de sangue no espaço subacnóide na primeira tomografia de crânio e o prognóstico dos pacientes com lesão cerebral traumática. Os autores realizaram uma revisão, buscando diretrizes específicas para sua classificação clínica e radiológica, prevenção e tratamento. Material e Método: Artigos elaborados no formato de revisão com levantamento de trabalhos citados na base Medline/Index Medicus/Lilacs, compreendendo período de janeiro de 1970 a março de 2008. Resultado: Neste período verificamos 192 trabalhos, 132 escritos em português ou inglês, destes selecionados os 37 de maior impacto. Conclusão: Hemorragia sucnóidea tramática é um marcador de pior prognóstico nos pacientes com TCE moderado e e grave e tratamento envolve medidas avançadas de neurointensivo.

Horner's syndrome after blunt cervical and chest trauma: case report.

Horner's syndrome is the triad of miosis, ptosis, and anhidrosis, resulting from disruption of the sympathetic pathways. This article describes an uncommon case of Horner's syndrome in a 22-year-old man after blunt trauma to the neck and chest without carotid artery dissection. The patient was brought to the emergency service after motorcycle fall. Neurologic examination revealed a patient presenting the score 15 at Glasgow Coma Scale. The left eyelid was 1-2 mm lower than the right. Carotid Doppler and angiotomography were undertaken and revealed no abnormalities of the carotid artery. CT disclosed a mediastinal hematoma extending to the left apex, compressing the left sympathetic chain. The understanding of this clinical entity may help the surgeon to make a better differential diagnosis in trauma patients in whom prompt diagnosis is critical to establish the correct treatment.

Horner's syndrome after blunt cervical and chest trauma: case report

Horner‘s syndrome is the triad of miosis, ptosis, and anhidrosis, resulting from disruption of the sympathetic pathways. This article describes an uncommon case of Horner‘s syndrome in a 22-year-old man after blunt trauma to the neck and chest without carotid artery dissection. The patient was brought to the emergency service after motorcycle fall. Neurologic examination revealed a patient presenting the score 15 at Glasgow Coma Scale. The left eyelid was 1-2 mm lower than the right. Carotid Doppler and angiotomography were undertaken and revealed no abnormalities of the carotid artery. CT disclosed a mediastinal hematoma extending to the left apex, compressing the left sympathetic chain. The understanding of this clinical entity may help the surgeon to make a better differential diagnosis in trauma patients in whom prompt diagnosis is critical to stablish the correct treatment.

A síndrome de Horner compreende a tríade de miose, ptose e anidrose, resultado de lesão em algum ponto das vias simpáticas. O referido estudo apresenta um caso da referida síndrome em um jovem de 22 anos vitima de queda de moto, com escoriações no tórax e no pescoço, sem dissecção carotídea. Ao exame neurológico, encontrava-se com 15 pontos na Escala de Coma de Glasgow, com miose à esquerda e ptose palpebral ipsilateral. Realizado Doppler de carótidas e angiotomografia dos vasos cérvico-cranianos não sendo evidenciadas anormalidades. A tomografia de tórax mostrou um hematoma no ápice pulmonar esquerdo, comprimindo a cadeia simpática ipsilateral. O conhecimento desta entidade clínica pode ajudar o cirurgião a fazer um diagnóstico diferencial adequado nos pacientes vítimas de traumas, nos quais o diagnóstico correto e eficaz pode ser fundamental para a definição da conduta a ser tomada.