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1.
Brain Stimul ; 16(2): 445-455, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36746367

RESUMO

BACKGROUND: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. METHODS: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. RESULTS: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). CONCLUSIONS: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.


Assuntos
Estimulação Encefálica Profunda , Tremor Essencial , Humanos , Tremor Essencial/terapia , Tremor Essencial/etiologia , Tremor/terapia , Disartria/etiologia , Disartria/terapia , Estimulação Encefálica Profunda/métodos , Tálamo , Parestesia/etiologia , Resultado do Tratamento
2.
Neuroimage ; 178: 198-209, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29787868

RESUMO

The success of deep brain stimulation (DBS) surgeries for the treatment of movement disorders relies on the accurate placement of an electrode within the motor portion of subcortical brain targets. However, the high number of electrodes requiring relocation indicates that today's methods do not ensure sufficient accuracy for all patients. Here, with the goal of aiding DBS targeting, we use 7 Tesla (T) MRI data to identify the functional territories and parcellate the globus pallidus pars interna (GPi) into motor, associative and limbic regions in individual subjects. 7 T MRI scans were performed in seventeen patients (prior to DBS surgery) and one healthy control. Tractography-based parcellation of each patient's GPi was performed. The cortex was divided into four masks representing motor, limbic, associative and "other" regions. Given that no direct connections between the GPi and the cortex have been shown to exist, the parcellation was carried out in two steps: 1) The thalamus was parcellated based on the cortical targets, 2) The GPi was parcellated using the thalamus parcels derived from step 1. Reproducibility, via repeated scans of a healthy subject, and validity of the findings, using different anatomical pathways for parcellation, were assessed. Lastly, post-operative imaging data was used to validate and determine the clinical relevance of the parcellation. The organization of the functional territories of the GPi observed in our individual patient population agrees with that previously reported in the literature: the motor territory was located posterolaterally, followed anteriorly by the associative region, and further antero-ventrally by the limbic territory. While this organizational pattern was observed across patients, there was considerable variability among patients. The organization of the functional territories of the GPi was remarkably reproducible in intra-subject scans. Furthermore, the organizational pattern was observed consistently by performing the parcellation of the GPi via the thalamus and via a different pathway, going through the striatum. Finally, the active therapeutic contact of the DBS electrode, identified with a combination of post-operative imaging and post-surgery DBS programming, overlapped with the high-probability "motor" region of the GPi as defined by imaging-based methods. The consistency, validity, and clinical relevance of our findings have the potential for improving DBS targeting, by increasing patient-specific knowledge of subregions of the GPi to be targeted or avoided, at the stage of surgical planning, and later, at the stage when stimulation is adjusted.


Assuntos
Globo Pálido/diagnóstico por imagem , Globo Pálido/patologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Transtornos dos Movimentos/diagnóstico por imagem , Transtornos dos Movimentos/patologia , Adulto , Idoso , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Estimulação Encefálica Profunda , Imagem de Tensor de Difusão/métodos , Imagem de Tensor de Difusão/normas , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/normas , Imageamento por Ressonância Magnética/normas , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Cuidados Pré-Operatórios , Reprodutibilidade dos Testes , Tálamo/diagnóstico por imagem , Tálamo/patologia
3.
Curr Biol ; 25(22): 2997-3003, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26549257

RESUMO

Hypothalamic tanycytes are considered to function as sensors of peripheral metabolism. To facilitate this role, they express a wide range of receptors, including fibroblast growth factor receptor 1 (FGFR1). Using a monoclonal antibody (IMC-H7) that selectively antagonizes the FGFR1c isoform, we investigated possible actions of FGFR1c in a natural animal model of adiposity, the Siberian hamster. Infusion of IMC-H7 into the third ventricle suppressed appetite and increased energy expenditure. Likewise, peripheral treatment with IMC-H7 decreased appetite and body weight and increased energy expenditure and fat oxidation. A greater reduction in body weight and caloric intake was observed in response to IMC-H7 during the long-day fat state as compared to the short-day lean state. This enhanced response to IMC-H7 was also observed in calorically restricted hamsters maintained in long days, suggesting that it is the central photoperiodic state rather than the peripheral adiposity that determines the response to FGFR1c antagonism. Hypothalamic thyroid hormone availability is controlled by deiodinase enzymes (DIO2 and DIO3) expressed in tanycytes and is the key regulator of seasonal cycles of energy balance. Therefore, we determined the effect of IMC-H7 on hypothalamic expression of these deiodinase enzymes. The reductions in food intake and body weight were always associated with decreased expression of DIO2 in the hypothalamic ependymal cell layer containing tanycytes. These data provide further support for the notion the tanycytes are an important component of the mechanism by which the hypothalamus integrates central and peripheral signals to regulate energy intake and expenditure.


Assuntos
Anticorpos Monoclonais/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Adiposidade/fisiologia , Animais , Anticorpos Monoclonais/imunologia , Ritmo Circadiano/fisiologia , Cricetinae , Hipotálamo/metabolismo , Masculino , Modelos Animais , Phodopus , Fotoperíodo , Isoformas de Proteínas/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/imunologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Magreza/metabolismo , Hormônios Tireóideos/metabolismo , Redução de Peso/efeitos dos fármacos
4.
Clin Sci (Lond) ; 127(5): 315-22, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24611892

RESUMO

Acylcarnitine accumulation in skeletal muscle and plasma has been observed in numerous models of mitochondrial lipid overload and insulin resistance. Fish oil n3PUFA (omega-3 polyunsaturated fatty acids) are thought to protect against lipid-induced insulin resistance. The present study tested the hypothesis that the addition of n3PUFA to an intravenous lipid emulsion would limit muscle acylcarnitine accumulation and reduce the inhibitory effect of lipid overload on insulin action. On three occasions, six healthy young men underwent a 6-h euglycaemic-hyperinsulinaemic clamp accompanied by intravenous infusion of saline (Control), 10% Intralipid® [n6PUFA (omega-6 polyunsaturated fatty acids)] or 10% Intralipid®+10% Omegaven® (2:1; n3PUFA). The decline in insulin-stimulated whole-body glucose infusion rate, muscle PDCa (pyruvate dehydrogenase complex activation) and glycogen storage associated with n6PUFA compared with Control was prevented with n3PUFA. Muscle acetyl-CoA accumulation was greater following n6PUFA compared with Control and n3PUFA, suggesting that mitochondrial lipid overload was responsible for the lower insulin action observed. Despite these favourable metabolic effects of n3PUFA, accumulation of total muscle acylcarnitine was not attenuated when compared with n6PUFA. These findings demonstrate that n3PUFA exert beneficial effects on insulin-stimulated skeletal muscle glucose storage and oxidation independently of total acylcarnitine accumulation, which does not always reflect mitochondrial lipid overload.


Assuntos
Carnitina/análogos & derivados , Ácidos Graxos Ômega-3/farmacologia , Resistência à Insulina/fisiologia , Lipídeos/farmacologia , Adulto , Carnitina/metabolismo , Óleos de Peixe , Glicogênio/metabolismo , Humanos , Insulina/farmacologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Triglicerídeos
5.
Clin Neurophysiol ; 119(9): 2148-58, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18632304

RESUMO

OBJECTIVE: The goal of this study was to develop, evaluate, and apply a method to quantify the unknown spatial extent of activation in deep brain stimulation (DBS) of the ventral intermedius nucleus (Vim) of the thalamus. METHODS: The amplitude-distance relationship and the threshold amplitudes to elicit clinical responses were combined to estimate the unknown amplitude-distance constant and the distance between the electrode and the border between the Vim and the ventrocaudal nucleus (Vc) of the thalamus. We tested the sensitivity of the method to errors in the input parameters, and subsequently applied the method to estimate the amplitude-distance constant from clinically-measured threshold amplitudes. RESULTS: The method enabled estimation of the amplitude-distance constant with a median squared error of 0.07-0.23V/mm2 and provided an estimate of the distance between the electrode and the Vc/Vim border with a median squared error of 0.01-0.04mm. Application of the method to clinically-measured threshold amplitudes to elicit paresthesias estimated the amplitude-distance constant to be 0.22V/mm2. CONCLUSIONS: The method enabled robust quantification of the spatial extent of activation in thalamic DBS and predicted that stimulation amplitudes of 1-3.5V would produce a mean effective radius of activation of 2.0-3.9mm. SIGNIFICANCE: Knowing the spatial extent of activation may improve methods of electrode placement and stimulation parameter selection in DBS.


Assuntos
Estimulação Encefálica Profunda/instrumentação , Estimulação Encefálica Profunda/métodos , Tálamo/fisiologia , Tálamo/efeitos da radiação , Simulação por Computador , Limiar Diferencial/fisiologia , Relação Dose-Resposta à Radiação , Eletrodos , Estudos de Avaliação como Assunto , Lateralidade Funcional , Humanos , Modelos Biológicos
6.
IEEE Trans Neural Syst Rehabil Eng ; 15(2): 190-7, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17601188

RESUMO

The mechanisms by which deep brain stimulation (DBS) alleviates tremor remain unclear, but successful treatment can be achieved with properly selected frequency and amplitude. The clinical tremor response to thalamic DBS for essential tremor is dependent on the stimulation frequency and amplitude, and for high frequencies (> or = 90 Hz), increasing amplitude suppressed tremor, whereas for low frequencies (< 60 Hz), increasing amplitude aggravated tremor. We studied the effects of stimulation frequency and amplitude on the output of a population of intrinsically active model neurons to test the hypothesis that regularization of neuronal firing patterns is responsible for the clinical effectiveness of DBS. The firing patterns of model thalamocortical neurons were dependent on stimulation frequency and amplitude in a manner similar to the clinical tremor response. Above a critical frequency, increasing amplitude reduced the coefficient of variation (CV) of the neuronal firing pattern, whereas for low frequencies, increasing the amplitude increased the CV of neuronal activity. The correlation between the changes in tremor and the changes in the CV of neuronal firing supports the hypothesis that regularization of neuronal firing pattern during DBS is one of the mechanisms underlying the suppression of tremor.


Assuntos
Estimulação Encefálica Profunda/métodos , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Neurônios , Tálamo/fisiopatologia , Tremor/prevenção & controle , Tremor/fisiopatologia , Potenciais de Ação , Adaptação Fisiológica , Relógios Biológicos , Simulação por Computador , Humanos , Plasticidade Neuronal
7.
Clin Neurophysiol ; 116(5): 1227-34, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15826866

RESUMO

OBJECTIVE: The neuronal elements mediating the effects of deep brain stimulation (DBS) are unknown. The objective was to determine the strength-duration properties of the neuronal elements that mediate paresthesias evoked by thalamic microstimulation. METHODS: The strength-duration properties of the neuronal elements causing paresthesias were measured using intraoperative microstimulation of the human thalamus. The sample included both concordant (reported in the same region as the mapped sensory receptive fields) and discordant paresthesias (reported in a region different than the mapped sensory receptive fields). RESULTS: There were no significant differences between the chronaxies of concordant and discordant paresthesias. There was no significant correlation between chronaxie and rheobase for concordant paresthesias, but a strong negative correlation existed for discordant paresthesias. CONCLUSIONS: Chronaxies did not distinguish the neuronal elements mediating concordant and discordant paresthesias, but correlations between chronaxie and rheobase suggest that concordant paresthesias were produced by activation of local cells while discordant paresthesias were caused by activation of axons of passage. SIGNIFICANCE: The similarity between the strength-duration properties of paresthesias evoked by thalamic stimulation, tremor reduction evoked by thalamic DBS, and EMG responses to thalamic DBS does not mean that these effects are caused by the same neural elements.


Assuntos
Cronaxia/fisiologia , Estimulação Encefálica Profunda , Modelos Neurológicos , Parestesia , Tálamo/fisiologia , Eletrodos Implantados , Humanos , Período Intraoperatório , Microeletrodos , Fatores de Tempo
8.
Cancer Chemother Pharmacol ; 50(2): 163-6, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12172984

RESUMO

PURPOSE: Chemokines are a family of small proteins that regulate leukocyte infiltration into inflamed tissue and play key roles in the pathogenesis of many diseases. Some chemokines can also reversibly inhibit the proliferation of hematopoietic progenitors. We have previously found that the chemokine CCL21 (Exodus-2/SLC/6Ckine/TCA4) is a potent inhibitor of the proliferation of normal hematopoietic progenitors. In this study we sought to determine whether this inhibition of proliferation could be therapeutically exploited by protecting normal marrow progenitors from the cytotoxicity of the S phase-active chemotherapeutic agent Ara-C. METHODS: Untreated and CCL21-pretreated mice were given doses of Ara-C that are toxic to marrow myeloid progenitors. The recovery of these myeloid progenitors was analyzed by colony formation assays. RESULTS: It was found that pretreatment with small doses of CCL21 prevented the death of normal murine marrow progenitors from the toxic effects of Ara-C. CONCLUSIONS: The chemokine CCL21 may be able to prevent Ara-C myelosuppression during acute leukemia induction chemotherapy, and thereby decrease morbidity and mortality of such therapy, and shorten hospital stays.


Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Doenças da Medula Óssea/prevenção & controle , Medula Óssea/efeitos dos fármacos , Quimiocinas CC/uso terapêutico , Citarabina/antagonistas & inibidores , Células-Tronco Hematopoéticas/efeitos dos fármacos , Animais , Doenças da Medula Óssea/induzido quimicamente , Divisão Celular/efeitos dos fármacos , Quimiocina CCL21 , Ensaio de Unidades Formadoras de Colônias , Citarabina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Camundongos , Fase S/efeitos dos fármacos
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