Brain-derived neurotrophic factor and subcallosal deep brain stimulation for refractory depression

Objectives. Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising experimental treatment for treatment-resistant depression (TRD). Given the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity and antidepressant efficacy, we examined the effect of SCC-DBS on serum BDNF in TRD. Methods. Four patients with TRD underwent SCC-DBS treatment. Following a double-blind stimulus optimization phase of 3 months, patients received continuous stimulation in an open label fashion for 6 months. Clinical improvement in depressive symptoms was evaluated bi-weekly for 6 months using the Hamilton Depression Rating Scale (HDRS). Mature serum BDNF levels were measured before and 9–12 months after surgery. Results. Three patients responded to SCC-DBS: two showed full clinical response (50% reduction in HDRS scores) and one had partial response (35% reduction in HDRS scores) at the clinical endpoint. Interestingly, all four patients showed reduction in serum BDNF concentration from pre-DBS baseline. Conclusions. SCC-DBS for TRD may be associated with decreased levels of serum BDNF. Longitudinal studies with multiple measurements in a larger sample are required to determine the role of BDNF as a biomarker of SCC-DBS antidepressant efficacy.     

脑源性神经营养因子及其信号通路与抑郁症

抑郁症是以持续的心境低落为主要临床特征的一种精神疾病.抑郁症最严重的症状--自杀,使得抑郁症成为高病死率的疾病,已引起广泛重视.关于抑郁症的发病机制一直在研究中,但病因始终不明.     

Brain-derived neurotrophic factor and post-stroke depression

Brain-derived neurotrophic factor (BDNF) is well known to play a critical role in cognition. Its role in mood disorders, including post stroke depression (PSD), is also recognized with more evidence surfacing. In patients with PSD, their serum BNDF level is lower than in those without depression. Furthermore, antidepressants could enhance BDNF expression in the brain, resulting in an alleviation of depression symptoms. Such therapeutic effect can be abolished in animals with the BDNF gene deleted. In PSD patients, the presence of stroke may contribute to the development of depression, including affecting the expression of BDNF. However, the mechanisms of BDNF in the development of PSD remain largely unknown. Lower BDNF levels may have existed in some patients before stroke onset, making them vulnerable to develop depressive symptoms. Meanwhile, the hypoxic environment induced by stroke could possibly downregulate BDNF expression in the brain. Current antidepressant treatments are not specific for PSD and there is a lack of treatments to address the linkage between stroke and PSD. This review summarizes the current knowledge of BDNF in PSD. By regulating BDNF expression, a synergistic effect may be achieved when such treatments are applied together with existing antidepressants.     

重复经颅磁刺激对首发精神分裂症患者血清脑源性神经营养因子的影响

目的分析高频重复经颅磁刺激(rTMS)对首发精神分裂症患者血清脑源性神经营养因子(BDNF)的影响。方法选取82例以阴性症状为主的首发精神分裂症患者,使用随机数表将82例患者分为对照组41例和观察组41例,2组均使用常规药物治疗,观察组同时予以真刺激治疗,对照组予以假刺激治疗,对比2组治疗结果。结果治疗4周后观察组PANSS(阳性和阴性症状量表)总分、阴性症状评分、一般病理评分及血清BDNF浓度均优于治疗前,且优于对照组(P0.05);对照组PANSS总分、阴性症状评分、阳性症状评分、一般病理评分及血清BDNF浓度与之前相比无明显变化(P0.05)。观察组BDNF浓度变化与PANSS总分及各因子的变化无明显相关性(P0.05)。结论rTMS可显著增加首发精神分裂症患者的血清BDNF水平,但血清BDNF水平变化与其临床症状的改善无明显相关性。     

Brain-derived neurotrophic factor and its related enzymes and receptors play important roles after hypoxic-ischemic brain damage

Brain-derived neurotrophic factor(BDNF) regulates many neurological functions and plays a vital role during the recovery from central nervous system injuries. However, the changes in BDNF expression and associated factors following hypoxia-ischemia induced neonatal brain damage, and the significance of these changes are not fully understood. In the present study, a rat model of hypoxic-ischemic brain damage was established through the occlusion of the right common carotid artery, followed by 2 hours in a hypoxic-ischemic environment. Rats with hypoxic-ischemic brain damage presented deficits in both sensory and motor functions, and obvious pathological changes could be detected in brain tissues. The m RNA expression levels of BDNF and its processing enzymes and receptors(Furin, matrix metallopeptidase 9, tissuetype plasminogen activator, tyrosine Kinase receptor B, plasminogen activator inhibitor-1, and Sortilin) were upregulated in the ipsilateral hippocampus and cerebral cortex 6 hours after injury; however, the expression levels of these m RNAs were found to be downregulated in the contralateral hippocampus and cerebral cortex. These findings suggest that BDNF and its processing enzymes and receptors may play important roles in the pathogenesis and recovery from neonatal hypoxic-ischemic brain damage. This study was approved by the Animal Ethics Committee of the University of South Australia(approval No. U12-18) on July 30, 2018.     

Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays critical roles in the survival, growth, and maintenance of brain and peripheral neurons. We report the presence of BDNF protein in human platelets and its release upon agonist stimulation. The BDNF content of washed platelets varied widely, from 3.5 to 67 ng/4 x 10(8) platelets, averaging 25.2 +/- 21.2 ng/4 x 10(8) platelets (mean+/-SD). The BDNF concentration in platelet-poor plasma was low (1.7+/-1.7 ng/ml, n = 11). Thrombin, collagen, the Ca++ ionophore A23187, and shear stress each induced a rapid release of BDNF from platelets. Up to only half of platelet BDNF was secreted upon agonist stimulation, suggesting that platelets may have a non-releasable pool of BDNF, or that the released BDNF binds to a recognition site on the platelet surface and is internalized, as occurs with serotonin. However, the cognate BDNF receptor, TrkB, was not detected in platelets. Nevertheless, the ability of BDNF to bind washed platelets was shown by FACS analysis confocal microscopy and by the binding and apparent internalization of [125I]-BDNF by platelets. A very high affinity site (Kd = 130 x 10(-15) M, approximately 80 sites/platelet) and a moderately high affinity site (Kd = 20 nM, approximately 3750 sites/platelet) were identified. The BDNF content in two megakaryocytic cell lines, DAMI and Meg-01, was only 0.1% of the content measured in platelets. No BDNF mRNA was detected by Northern blotting in these cell lines or in platelets. The pituitary gland was also ruled out as a source for platelet BDNF, since the BDNF content of rat platelets did not decrease 2 weeks after hypophysectomy. Thus, platelet BDNF is not acquired from the megakaryocyte or pituitary gland, but is probably acquired from other sources via the blood circulation. Platelets appear to bind, store and release BDNF upon activation at the site of traumatic injury to facilitate the repair of peripheral nerves or other tissues that contain TrkB.     

Brain-derived neurotrophic factor and its intracellular signaling pathways in cocaine addiction

Cocaine addiction is one of the severest health problems faced by western countries, where there is an increasing prevalence of lifelong abuse. The most challenging aspects in the treatment of cocaine addiction are craving and relapse, especially in view of the fact that, at present, there is a lack of effective pharmacological treatment for the disorder. What is required are new pharmacological approaches based on our current understanding of the neurobiological bases of drug addiction. Within the context of the behavioral and neurochemical actions of cocaine, this paper considers the contribution of brain-derived neurotrophic factor (BDNF) and its main intracellular signaling mechanisms, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K), in psychostimulant addiction. Repeated cocaine administration leads to an increase in BDNF levels and enhanced activity in the intracellular pathways (PI3K and MAPK/ERK) in the reward-related brain areas, which applies especially several days following withdrawal. It has been hypothesized that these neurochemical changes contribute to the enduring synaptic plasticity that underlies sensitized responses to psychostimulants and drug-conditioned memories leading to compulsive drug use and frequent relapse after withdrawal. Nevertheless, increased BDNF levels could also have a role as a protection factor in addiction. The inhibition of the intracellular pathways, ERK and PI3K, leads to a disruption in sensitized responses and conditioned memories associated with cocaine addiction and suggests new, potential therapeutic strategies to explore in the dependence on psychostimulants.     

Brain-derived neurotrophic factor,stress and depression: A minireview

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, and is widely expressed in the adult mammalian brain. Besides its well known neuroprotective activity after traumatic brain injury the evidences regarding its activity dependent release by the pathophysiology of major depression are rapidly replicating. Considering the data that stress plays an important role by the development of depression which is characterized with prominent hippocampal cell death, as well as the well known neuroprotective effects of BDNF, we aimed to investigate the link between the BDNF, stress and depression. Thus we prepared a minireview in order to evaluate the neuroprotective role of BDNF by psychiatric disorders which are characterized with prominent neuronal cell death.     

重复经颅磁刺激对首发精神分裂症患者血清脑源性神经营养因子的影响

目的：初步探讨高频重复经颅磁刺激（rTMS）对以阴性症状为主的首发精神分裂症患者血清脑源性神经营养因子（BDN F ）水平的影响。方法采用随机、双盲、对照研究,选取符合国际疾病分类第十版（ICD－10）中精神分裂症诊断标准的门诊患者70例。在常规抗精神病药物治疗的基础上,按照随机数字表法分为真刺激组（n ＝35）和伪刺激组（n ＝35）,并在基线时和治疗4周末时进行BDNF浓度测定和PANSS评估。结果治疗4周后,真刺激组的PANSS总分、阴性症状分和一般精神病理分均低于伪刺激组,BDNF浓度高于伪刺激组,差异均有统计学意义（P ＜0．05）。真刺激组BDNF浓度变化值与PANSS总分及各因子分变化值均无相关性（P ＞0．05）。两组不良反应差异无统计学意义（P ＞0．05）。结论 rTMS治疗可显著增加首发精神分裂症患者的血清BDNF浓度,但其浓度变化与临床症状（尤其是阴性症状）的改善无相关性。     

Brain-derived neurotrophic factor gene polymorphisms and Alzheimer's disease

Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimer's disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP)--i.e., C270T and G196A--in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, p = 0.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, p = 0.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, p = 0.035) or positive for AD family history (2.8 vs. 7.1%, p = 0.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.     

Brain-derived neurotrophic factor prevents low-frequency inputs from inducing long-term depression in the developing visual cortex.

Brain-derived neurotrophic factor (BDNF) is reported to enhance synaptic transmission and to play a role in long-term potentiation in hippocampus and neocortex. If so, a shortage or blockade of BDNF might lead to another form of synaptic plasticity, long-term depression (LTD). To test this possibility and to elucidate mechanisms if it is the case, EPSCs evoked by test stimulation of layer IV were recorded from layer II/III neurons in visual cortical slices of young rats in the whole-cell voltage-clamp mode. LTD was induced by low-frequency stimulation (LFS) at 1 Hz for 10-15 min if each pulse of the LFS was paired with depolarization of neurons to -30 mV but was not induced if their membrane potentials were kept at -70 mV. Such an LTD was blocked by exogenously applied BDNF, probably through presynaptic mechanisms. Suppression of endogenous BDNF activity by the anti-BDNF antibody or an inhibitor for BDNF receptors made otherwise ineffective stimuli (LFS without postsynaptic depolarization) effective for LTD induction, suggesting that endogenous BDNF may prevent low-frequency inputs from inducing LTD in the developing visual cortex.     

Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses

Disturbed neural development has been postulated as a crucial factor in the pathophysiology of schizophrenic psychoses. The neurobiochemical basis for such changes of cytoarchitecture and changed neural plasticity could involve an alteration in the regulation of neurotrophic factors. In order to test this hypothesis, BDNF and NT-3 levels in post-mortem brain tissue from schizophrenic patients were determined by ELISA. There was a significant increase in BDNF concentrations in cortical areas and a significant decrease of this neurotrophin in hippocampus of patients when compared with controls. NT-3 concentrations of frontal and parietal cortical areas were significantly lower in patients than in controls. These findings lend further evidence to the neurotrophin hypothesis of schizophrenic psychoses which proposes that alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity, thus being an important event in the etiopathogenesis of schizophrenic psychoses.     

Combined transcranial alternating current stimulation and continuous theta burst stimulation: a novel approach for neuroplasticity induction

Non‐invasive brain stimulation can induce functionally relevant plasticity in the human cortex, making it potentially useful as a therapeutic tool. However, the induced changes are highly variable between individuals, potentially limiting research and clinical utility. One factor that might contribute to this variability is the level of cortical inhibition at the time of stimulation. The alpha rhythm (~ 8–13 Hz) recorded with electroencephalography (EEG) is thought to reflect pulsatile cortical inhibition; therefore, targeting non‐invasive brain stimulation to particular phases of the alpha rhythm may provide an approach to enhance plasticity induction. Transcranial alternating current stimulation (tACS) has been shown to entrain cortical oscillations in a frequency‐specific manner. We investigated whether the neuroplastic response to continuous theta burst stimulation (cTBS) was enhanced by timing bursts of stimuli to the peak or the trough of a tACS‐imposed alpha rhythm. While motor evoked potentials (MEPs) were unaffected when cTBS was applied in‐phase with the peak of the tACS‐imposed oscillation, MEP depression was enhanced when cTBS was applied in‐phase with the trough. This enhanced MEP depression was dependent on the individual peak frequency of the endogenous alpha rhythm recorded with EEG prior to stimulation, and was strongest in those participants classified as non‐responders to standard cTBS. These findings suggest that tACS may be used in combination with cTBS to enhance the plasticity response. Furthermore, the peak frequency of endogenous alpha, as measured with EEG, may be used as a simple marker to pre‐select those individuals likely to benefit from this approach.     

脑源性生长因子与神经损伤的修复及再生

背景：脑源性生长因子具有促进神经元生长存活,引导轴突延伸塑型的作用。周围神经损伤后的再生和髓鞘形成需要内源性脑源性神经生长因子。目的：归纳总结脑源性生长因子的研究现状。方法：以中文检索词“神经再生;脑源性生长因子”和英文检索词“nerve,regeneration,BDNF”检索2000-01/2009-08中国期刊全文数据库和Pubmed数据库。纳入具有原创性、论点论据可靠的试验文章,观点明确,分析全面的文章,及文献主题与此课题关系紧密的文章。排除重复性研究和综述文章。结果与结论：神经损伤后在髓鞘形成过程中脑源性神经生长因子通过高亲和力Trk受体和低亲和力受体P75NTR促进髓鞘形成。与神经生长因子在周围靶组织合成不同,脑源性神经生长因子主要在中枢神经系统中合成,但当周围神经受损后其mRNA表达增多,大量的实验表明正常周围神经的许旺细胞同样有少量脑源性神经生长因子表达。现在人们通过将脑源性神经生长因子基因通过病毒介导转染干细胞后移植到神经损伤区域治疗疾病,有望成为新的治疗方法。