RESUMO
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a widespread invasive procedure for treating drug-resistant epilepsy. Nonetheless, there is a persistent debate regarding the short-term and long-term efficacy and safety of ANT-DBS. Thus we conducted a systematic review and meta-analysis. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we searched PubMed, Cochrane, Embase, and Web of Science for studies treating refractory epilepsy with ANT-DBS. Short-term analysis was considered for studies with a mean follow-up of 3 years or less. The following outcomes were assessed for data extraction: procedure responders and nonresponders, increased seizure frequency, complications, and procedure-related mortality. Of 650 studies, 25 fit our inclusion criteria, involving 427 patients. Previous surgical treatments have been reported in 214 patients (50.1%) and a median average baseline seizure frequency of 64.9 monthly seizures. In the short-term analysis, we observed a proportion of 67% (95% confidence interval [CI] 54%-79%) of responders and 33% (95% CI 21%-46%) of nonresponders. In addition, 4% (95% CI 0%-9%) of the patients presented increased seizure frequency. In the long-term analysis, we observed 72% (95% CI 66%-78%) responders and 27% (95% CI 21%-34%) nonresponders. Moreover, there was a 2% (95% CI 0%-5%) increase in seizure frequency. No procedure-related mortality was reported at any follow-up. ANT-DBS effectively treats refractory epilepsy, with lasting short-term and long-term benefits. It remains safe and efficient despite complications, showing no procedure-linked fatalities, high patient responsiveness, and minimal increased seizures. Consistent results over time and low morbidity/mortality rates emphasize its worth. Further research is necessary to diminish the discrepancy among results.
Assuntos
Núcleos Anteriores do Tálamo , Estimulação Encefálica Profunda , Epilepsia Resistente a Medicamentos , Humanos , Estimulação Encefálica Profunda/métodos , Epilepsia Resistente a Medicamentos/terapia , Resultado do TratamentoRESUMO
Introducción: En pacientes con epilepsia del lóbulo temporal refractarios que no son candidatos a cirugía, se debe considerar la estimulación eléctrica cerebral como una opción. Contenido: La estimulación eléctrica cerebral es la administración directa de pulsos eléctricos al tejido nervioso que permite modular un sustrato patológico, interrumpir la manifestación clínica de las crisis y reducir la gravedad de estas. Así, dada la importancia de estos tratamientos para los pacientes con epilepsia del lóbulo temporal refractaria, se hace una revisión de cuatro tipos de estimulación eléctrica. La primera, la del nervio vago, es una buena opción en crisis focales y crisis generalizadas o multifocales. La segunda, la del hipocampo, es más útil en pacientes no candidatos a lobectomía por riesgo de pérdida de memoria, con resonancia magnética normal o sin esclerosis mesial temporal. La tercera, la del núcleo anterior, es pertinente principalmente en pacientes con crisis focales, pero debe realizarse con precaución en pacientes con alto riesgo de cambios cognitivos, como los ancianos, o en los que presentan alteración del estado de ánimo basal, y, por último, la del núcleo centromediano se recomienda para el tratamiento crisis focales en el síndrome de Rasmussen y crisis tónico-clónicas en el síndrome de Lennox-Gastaut. Conclusiones: El interés por la estimulación eléctrica cerebral ha venido aumentando, al igual que las estructuras diana en las cuales se puede aplicar, debido a que es un tratamiento seguro y eficaz en pacientes con epilepsia del lóbulo temporal para controlar las crisis, pues disminuye la morbimortalidad y aumenta la calidad de vida.
Introduction: In patients with refractory temporal lobe epilepsy who are not candidates for surgery, electrical brain stimulation should be considered as another option. Contents: Electrical brain stimulation is the direct administration of electrical pulses to nerve tissue that modulates a pathological substrate, interrupts the clinical manifestation of seizures, and reduces their severity. Thus, given the importance of these treatments for patients with refractory temporal lobe epilepsy, four types of electrical stimulation are reviewed. The first, vagus nerve stimulation, is a good option in focal seizures and generalized or multifocal seizures. The second, hippocampal stimulation, is more useful in patients who are not candidates for lobectomy due to the risk of memory loss, with normal MRI or without mesial temporal sclerosis. The third, the anterior nucleus, is mainly in patients with focal seizures, but with caution in patients at high risk of cognitive changes such as the elderly, or in those with baseline mood disturbance and, finally, the centromedian nucleus is recommended for the treatment of focal seizures in Rasmussen's syndrome and tonic-clonic seizures in Lennox-Gastaut syndrome. Conclusions: the interest in brain electrical stimulation has been increasing as well as the target structures in which it can be applied because it is a safe and effective treatment in patients with temporal lobe epilepsy to control seizures, decreasing morbidity and mortality and increasing quality of life
Assuntos
Núcleos Anteriores do Tálamo , Núcleos Intralaminares do Tálamo , Epilepsia do Lobo Temporal , Estimulação do Nervo Vago , Estimulação Elétrica , HipocampoRESUMO
BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an emerging therapy to provide seizure control in patients with refractory epilepsy, although its therapeutic mechanisms remain elusive. OBJECTIVE: We tested the hypothesis that ANT-DBS might interfere with the kindling process using three experimental groups: PTZ, DBS-ON and DBS-OFF. METHODS: 79 male rats were used in two experiments and exposed to chemical kindling with pentylenetetrazole (PTZ, 30 mg/kg i.p.), delivered three times a week for a total of 18 kindling days (KD). These animals were divided into two sets of three groups: PTZ (n = 26), DBS-ON (n = 28) and DBS-OFF (n = 25). ANT-DBS (130 Hz, 90 µs, and 200 µA) was paired with PTZ injections, while DBS-OFF group, although implanted remained unstimulated. After KD 18, the first set of PTZ-treated animals and an additional group of 11 naïve rats were euthanized for brain extraction to study adenosine kinase (ADK) expression. To observe possible long-lasting effects of ANT stimulation, the second set of animals underwent a 1-week treatment and stimulation-free period after KD 18 before a final PTZ challenge. RESULTS: ANT-DBS markedly attenuated kindling progression in the DBS-ON group, which developed seizure scores of 2.4 on KD 13, whereas equivalent seizure scores were reached in the DBS-OFF and PTZ groups as early as KD5 and KD6, respectively. The incidence of animals with generalized seizures following 3 consecutive PTZ injections was 94%, 74% and 21% in PTZ, DBS-OFF and DBS-ON groups, respectively. Seizure scores triggered by a PTZ challenge one week after cessation of stimulation revealed lasting suppression of seizure scores in the DBS-ON group (2.7 ± 0.2) compared to scores of 4.5 ± 0.1 for the PTZ group and 4.3 ± 0.1 for the DBS-OFF group (P = 0.0001). While ANT-DBS protected hippocampal cells, the expression of ADK was decreased in the DBS-ON group compared to both PTZ (P < 0.01) and naïve animals (P < 0.01). CONCLUSIONS: Our study demonstrates that ANT-DBS interferes with the kindling process and reduced seizure activity was maintained after a stimulation free period of one week. Our findings suggest that ANT-DBS might have additional therapeutic benefits to attenuate seizure progression in epilepsy.
Assuntos
Núcleos Anteriores do Tálamo , Estimulação Encefálica Profunda , Excitação Neurológica , Adenosina Quinase/metabolismo , Adenosina Quinase/farmacologia , Animais , Excitação Neurológica/fisiologia , Masculino , Pentilenotetrazol , Ratos , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/terapiaRESUMO
The thalamus is a deep cerebral structure that is crucial for proper neurological functioning as it transmits signals from nearly all pathways in the body. Insult to the thalamus can, therefore, result in complex syndromes involving sensation, cognition, executive function, fine motor control, emotion, and arousal, to name a few. Specific territories in the thalamus that are supplied by deep cerebral arteries have been shown to correlate with clinical symptoms. The aim of this review is to enhance our understanding of the arterial anatomy of the thalamus and the complications that can arise from lesions to it by considering the functions of known thalamic nuclei supplied by each vascular territory.
Assuntos
Artéria Basilar/anatomia & histologia , Infarto Encefálico/fisiopatologia , Círculo Arterial do Cérebro/anatomia & histologia , Artéria Cerebral Posterior/anatomia & histologia , Tálamo/irrigação sanguínea , Núcleos Anteriores do Tálamo/anatomia & histologia , Núcleos Anteriores do Tálamo/irrigação sanguínea , Núcleos Anteriores do Tálamo/fisiologia , Corpos Geniculados/anatomia & histologia , Corpos Geniculados/irrigação sanguínea , Corpos Geniculados/fisiologia , Humanos , Núcleos Laterais do Tálamo/anatomia & histologia , Núcleos Laterais do Tálamo/irrigação sanguínea , Núcleos Laterais do Tálamo/fisiologia , Núcleo Mediodorsal do Tálamo/anatomia & histologia , Núcleo Mediodorsal do Tálamo/irrigação sanguínea , Núcleo Mediodorsal do Tálamo/fisiologia , Pulvinar/anatomia & histologia , Pulvinar/irrigação sanguínea , Pulvinar/fisiologia , Tálamo/anatomia & histologia , Tálamo/fisiologia , Núcleos Ventrais do Tálamo/anatomia & histologia , Núcleos Ventrais do Tálamo/irrigação sanguínea , Núcleos Ventrais do Tálamo/fisiologiaRESUMO
Non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonists have been suggested to evoke psychotomimetic-like behaviors by selectively targeting GABAergic elements in cortical and thalamic circuits. In previous studies, we had reported the involvement of the reticular and anterior thalamic nuclei (ATN) in the MK-801-evoked hyperactivity and other motor alterations. Consistent with the possibility that these responses were mediated by thalamic disinhibition, we examined the participation of cortical and hippocampal areas innervated by ATN in the responses elicited by the systemic administration of MK-801 (0.2â¯mg/kg) and compared them to the effects produced by the microinjection of a subconvulsive dose of bicuculline (GABAA receptor antagonist) in the ATN. We used the expression of Fos related antigen 2 (Fra-2) as a neuronal activity marker in the ATN and its projection areas such as hippocampus (HPC), retrosplenial cortex (RS), entorhinal cortex (EC) and medial prefrontal cortex (mPFC). Dorsal (caudate-putamen, CPu) and ventral striatum (nucleus accumbens, core and shell, NAc,co and NAc,sh) were also studied. Behavioral and brain activation results suggest a partial overlap after the effect of MK-801 administration and ATN disinhibition. MK-801 and ATN disinhibition increases locomotor activity and disorganized movements, while ATN disinhibition also reduces rearing behavior. A significant increase in Fra-2 immunoreactivity (Fra-2-IR) in the ATN, mPFC (prelimbic area, PrL) and NAc,sh was observed after MK-801, while a different pattern of Fra-2-IR was detected following ATN disinhibition (e.g., increase in DG and NAc,sh, and decrease in PrL cortex). Overall, our data may contribute to the understanding of dysfunctional neural circuits involved in schizophrenia.
Assuntos
Núcleos Anteriores do Tálamo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Núcleos Anteriores do Tálamo/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Receptores de GABA-A , Giro do Cíngulo/metabolismo , Hipocampo/metabolismo , Masculino , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Esquizofrenia/metabolismoRESUMO
BACKGROUND: Deep brain stimulation (DBS) refers to the delivery of electric current to specific deep brain structures through implanted electrodes. Recently approved for use in United States, DBS to the anterior nucleus of thalamus (ANT) is a safe and effective alternative treatment for medically refractory seizures. Despite the anti-seizure effects of ANT DBS, preclinical and clinical studies have failed to demonstrate it actions at a whole brain level. OBJECTIVE: Here, we used a magnetic resonance imaging (MRI)-based approach in healthy adult rats to investigate the effects of ANT DBS through the circuit of Papez, which has central role in the generation and propagation of limbic seizures, in temporal lobe epilepsy (TLE). METHODS: After ANT electrode implantation and recovery, ANT DBS and SHAM (sham animals had electrodes implanted but were not stimulated) rats received one single injection of the contrast enhancer, manganese chloride (60 mg/kg, ip). Twelve hours after, rats underwent the baseline scan using the MEMRI (Manganese-Enhanced Magnetic Resonance Imaging) technique. We used the same MEMRI and parvalbumin sequence to follow the DBS delivered during 1 h (130 Hz and 200 µA). Perfusion was followed by subsequent c-Fos and parvalbumin immunostaining of brain sections. RESULTS: Acute unilateral ANT DBS significantly reduced the overall manganese uptake and consequently, the MEMRI contrast in the circuit of Papez. Additionally, c-Fos expression was bilaterally increased in the cingulate cortex and posterior hypothalamus, areas directly connected to ANT, as well as in amygdala and subiculum, within the limbic circuitry. CONCLUSION: Our data indicate that MEMRI can be used to detect whole-brain responses to DBS, as the high frequency stimulation parameters used here caused a significant reduction of cell activity in the circuit of Papez that might help to explain the antiepileptic effects of ANT DBS.
Assuntos
Núcleos Anteriores do Tálamo/metabolismo , Convulsões/terapia , Tonsila do Cerebelo/metabolismo , Animais , Núcleo Celular/metabolismo , Estimulação Encefálica Profunda/métodos , Eletrodos Implantados , Epilepsia/metabolismo , Epilepsia/terapia , Epilepsia do Lobo Temporal/terapia , Hipocampo/metabolismo , Sistema Límbico , Imageamento por Ressonância Magnética/métodos , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Convulsões/metabolismo , Tálamo/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: Cognitive impairment is a significant comorbidity of temporal lobe epilepsy that is associated with extensive hippocampal cell loss. Deep brain stimulation (DBS) of the anterior thalamic nucleus (ANT) has been used for the treatment of refractory partial seizures. In the pilocarpine model of epilepsy, ANT DBS applied during status epilepticus (SE) reduces hippocampal inflammation and apoptosis. When given to chronic epileptic animals it reduces hippocampal excitability and seizure frequency. Here, we tested whether ANT DBS delivered during SE and the silent phase of the pilocarpine model would reduce cognitive impairment when animals became chronically epileptic. MATERIALS AND METHODS: SE was induced by a systemic pilocarpine injection (320 mg/kg). Immediately after SE onset, rats were assigned to receive DBS during the first six hours of SE (n = 8; DBSa group) or during SE + the silent period (i.e., 6 h/day until the animals developed the first spontaneous recurrent seizure; n = 10; DBSs group). Four months following SE, animals underwent water maze testing and histological evaluation. Nonstimulated chronic epileptic animals (n = 13; PCTL group) and age-matched naïve rats (n = 11, CTL group) were used as controls. Results were analyzed by repeated-measures analyses of variance (RM_ANOVA) and one-way ANOVAs, followed by Newman-Keuls post hoc tests. RESULTS: Although all groups learned the spatial task, epileptic animals with or without DBS spent significantly less time in the platform quadrant, denoting a spatial memory deficit (p < 0.02). Despite these negative behavioral results, we found that animals given DBS had a significantly higher number of cells in the CA1 region and dentate gyrus. Mossy fiber sprouting was similar among all epileptic groups. CONCLUSIONS: Despite lesser hippocampal neuronal loss, ANT DBS delivered either during SE or during SE and the silent phase of the pilocarpine model did not mitigate memory deficits in chronic epileptic rats.
Assuntos
Núcleos Anteriores do Tálamo/fisiologia , Estimulação Encefálica Profunda/métodos , Epilepsia do Lobo Temporal/terapia , Aprendizagem Espacial/fisiologia , Animais , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Hipocampo/metabolismo , Hipocampo/patologia , Estudos Longitudinais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Agonistas Muscarínicos/toxicidade , Pilocarpina/toxicidade , Distribuição Aleatória , Ratos , Ratos Wistar , Aprendizagem Espacial/efeitos dos fármacosRESUMO
The ventral part of the anteromedial thalamic nucleus (AMv) is heavily targeted by the dorsal premammillary nucleus (PMd), which is the main hypothalamic site that is responsive to both predator and conspecific aggressor threats. This PMd-AMv pathway is likely involved in modulating memory processing, and previous findings from our group have shown that cytotoxic lesions or pharmacological inactivation of the AMv drastically reduced contextual fear responses to predator-associated environments. In the present study, we investigated the role of the AMv in both unconditioned (i.e., fear responses during social defeat) and contextual fear responses (i.e., during exposure to a social defeat-associated context). We addressed this question by placing N-methyl-d-aspartate (NMDA) lesions in the AMv and testing unconditioned fear responses during social defeat and contextual fear responses during exposure to a social defeat-associated context. Accordingly, bilateral AMv lesions did not change unconditioned responses, but decreased contextual conditioning related to social defeat. Notably, our bilateral AMv lesions also included, to a certain degree, the nucleus reuniens (RE), but single RE lesions did not affect innate or contextual fear responses. Overall, our results support the idea that the AMv works as a critical hub, receiving massive inputs from a hypothalamic site that is largely responsive to social threats and transferring social threat information to circuits involved in the processing of contextual fear memories.
Assuntos
Condicionamento Clássico/fisiologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Memória/fisiologia , Vias Neurais/fisiologia , Animais , Núcleos Anteriores do Tálamo/fisiologia , Comportamento Animal/fisiologia , Hipotálamo/fisiologia , Masculino , Processos Mentais/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Ratos WistarRESUMO
Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.