A narrative review on invasive brain stimulation for treatment-resistant depression

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Effects of crocin on brain oxidative damage and aversive memory in a 6-OHDA model of Parkinson's disease / Efeitos da crocina no dano oxidativo cerebral e na memória aversiva em um modelo 6-OHDA de doença de Parkinson

ABSTRACT The purpose of the present study was to investigate the effect of crocin on brain oxidative damage and memory deficits in a 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease. Male Wistar rats were subjected to unilateral injection of 6-OHDA (16 µg) into the medial forebrain bundle and treated with crocin (30 and 60 mg/kg) for six weeks. The rats were tested for memory performance at six weeks after 6-OHDA infusion, and then were killed for the estimation of biochemical parameters. The increase in thiobarbituric acid reactive substances (TBARS) and nitrite levels in the hippocampus were observed in the 6-OHDA lesioned rats, which was accompanied by memory deficits in a passive avoidance test at the end of week 6. Moreover, treatment with crocin decreased TBARS and nitrite levels in the hippocampus, and improved aversive memory. The present study conclusively demonstrated that crocin acts as an antioxidant and anti-inflammatory agent in the hippocampus of parkinsonian rats and could improve aversive memory through its properties.

RESUMO O objetivo do presente estudo foi investigar o efeito da crocina no dano oxidativo cerebral e nos déficits de memória em um modelo 6-OHDA de doença de Parkinson. Ratos Wistar machos foram submetidos à injeção unilateral de 6-OHDA (16 μg) em MFB e tratados com crocina (30 e 60 mg/kg), durante 6 semanas. Os ratos foram testados quanto ao desempenho da memória 6 semanas após a infusão de 6-OHDA, e, em seguida, foram sacrificados para a estimativa dos parâmetros bioquímicos. O aumento nos níveis de TBARS e de nitrito no hipocampo foram observados em ratos 6-OHDA lesionados, acompanhado por déficits de memória em um teste de esquiva passiva no final da semana 6. Além disso, o tratamento com crocina diminuiu os níveis de nitrito e de TBARS no hipocampo e melhorou a memória aversiva. O presente estudo demonstrou conclusivamente que a crocina age como um antioxidante e um agente anti-inflamatório no hipocampo de ratos parkinsonianos e pode melhorar a memória aversiva através de suas propriedades.

Impaired Voluntary Wheel Running Behavior in the Unilateral 6-Hydroxydopamine Rat Model of Parkinson's Disease

OBJECTIVE: The aim of this study was to investigate voluntary wheel running behavior in the unilateral 6-hydroxydopamine (6-OHDA) rat model. METHODS: Male Sprague-Dawley rats were assigned to 2 groups : 6-OHDA group (n=17) and control group (n=8). The unilateral 6-OHDA rat model was induced by injection of 6-OHDA into unilateral medial forebrain bundle using a stereotaxic instrument. Voluntary wheel running activity was assessed per day in successfully lesioned rats (n=10) and control rats. Each behavioral test lasted an hour. The following parameters were investigated during behavioral tests : the number of running bouts, the distance moved in the wheel, average peak speed in running bouts and average duration from the running start to the peak speed. RESULTS: The number of running bouts and the distance moved in the wheel were significantly decreased in successfully lesioned rats compared with control rats. In addition, average peak speed in running bouts was decreased, and average duration from the running start to the peak speed was increased in lesioned animals, which might indicate motor deficits in these rats. These behavioral changes were still observed 42 days after lesion. CONCLUSION: Voluntary wheel running behavior is impaired in the unilateral 6-OHDA rat model and may represent a useful tool to quantify motor deficits in this model.

Differential Activation of Microglia in the Substantia Nigra and Lesioned Site Following Medial Forebrain Bundle Transection / 대한해부학회지

Medial forebrain bundle (MFB) transmits the nigrostriatal dopaminergic (DA) axons, and previously we reported that transection of the MFB causes apotosis-like neurodegeneration of nigral DA neurons. On the other hand, it is likely to occur necrosis at the lesioned site where MFB is cut, due to direct mechanical transection of the brain tissue. To clarify the pathological dynamics of microglia reacting to the two different types of neuronal cell death, immunophenotypic and morphological features of microglia were compared and analyzed in the substantia nigra (SN) and lesioned site of the MFB axotomized rat brain. OX42 (mouse anti-rat CD 11b; pan-microglia marker), ED1 (mouse anti-rat lysosomal enzyme; phagocytic marker), and OX6 (mouse anti-rat MHC II) were used as primary antibodies for immunohistochemical localization of microglia, ED2 (mouse anti-rat macrophage) for macrophages, and anti-tyrosine hydro-xylase (TH) antibody for DA neurons. Quite numerous activated microglia with strong OX42 immunoreactivity were found in the SN at 1 day post-lesion (dpl), but most of them were ED1-and OX6-negative except only a few which were ED1-positive. This phenomenon was thought to be related with the stage of alert, the first step of microglial activation. It could be presumed that microglial phagocytosis may precede MHC II expression, because ED1-positive microglia appeared from 1 dpl while OX6-positive ones from 3 dpl. Number of activated microglia showing strong ED1, OX6 and OX42 immunoreactivity increased significantly by 7 ~14 dpl, and they specifically stick to various parts of dendrites and somas of TH-immunoreactive neurons of the SN. The phagocytic microglia of the SN maintained ramified form although they retained enlarged soma and shortened, thickened processes. The lesioned site was surrounded by numerous microglia showing strong OX42 and ED1 immunoreactivity as early as 1 dpl, indicating that microglial phagocytosis starts earlier in the lesioned site than in the SN. OX42-positive microglia of the lesioned site were ED2-negative, and showed amoeboid morphology already from 1 dpl. The amoeboid microglia became to be enlarged in their soma size by 3 dpl, and fused each other to form clumps within the necrotic zone by 5 ~7 dpl. The entire necrotic zone was completely filled with microglia of obscure outline with strong OX42 and ED1 immuno-reactivity. However, the majority of amoeboid microglia of the lesioned site were OX6-negative except a few. These results clearly demonstrate that activated microglia reacting to apoptotic neurodegeneration show different pathodynamic characteristics in terms of immunological phenotypes and morphology from those reacting to necrotic, mechanical lesion.