PHENOMENOLOGY, COURSE, & NEUROBIOLOGY OF REFRACTIVE AFFECTIVE DISORDERS

该科特别强调了说明和 对情感的纵向过程的神经生物学的理解 根据疾病的慢性性及其压倒性的 复发的倾向 骑自行车的频率倾向于 加速，和沉淀的情节变得不那么依赖 随着时间的推移，心理社会压力，谈到了潜在的敏感性， 前几集的过程。 这个概念是由本处分支率先提出的， 丹麦患者登记处在23，000名患者中进行了验证， 表明抑郁症的潜伏期和复发率 发作次数与既往住院次数成正比 治疗抑郁症的药物 的新证据 患者发作本身的病理意义 情感性精神障碍是从我们的观察中得出的， 先前的情感性疾病发作次数增加， 在各种神经心理学测试中表现出功能障碍。 我们 难治性情感疾病患者也有功能障碍， 面部表情的识别，以及导航， 地理空间，两者都与神经生理学有关 正电子发射断层扫描（PET）异常。 临床前模型用于理解参与的分子机制 随着时间的推移，对同一刺激的行为反应增加， 压力和事件本身对基因的影响的假设 表情 这一理论框架表明， 情感功能障碍的存在可能与 基因表达的病理性变化和适应性变化。 该模型为临床研究和治疗提供了新的靶点， 不仅试图抑制病理变化，而且还增强 内源性适应机制，如TRH的假定增加， 抑郁发作 鞘内给药的积极抗抑郁作用 和胃肠外TRH给药提供了初步的 证实了抑郁症中TRH增加的假设， 可能是一种补偿性适应。 除了发现一些 神经肽，如生长抑素，在脑脊液中显着降低， 抑郁症患者在一个国家依赖的方式，我们现在已经获得 神经肽失调的额外证据，其中显著 在健康对照中通常观察到的肽相互关系 我们的患者人群中没有受试者，反之亦然。 此外，我们还继续发现了区域性的异质性。 评估情感性疾病患者亚组的脑功能障碍 用石油 单相抑郁症患者表现出典型的 前额叶功能减退（与汉密尔顿抑郁评分的严重程度相关） 与年龄和性别匹配的正常志愿者群体相比。 双相I型患者倾向于表现出相反的模式， 高代谢，特别是中颞叶结构。 双极 II型患者具有更大的变异性，似乎代表了 低代谢和高代谢亚型，产生通常不显著的 与正常志愿者对照组的差异。 PET已发现局部麻醉剂普鲁卡因是一种 边缘选择性探针，和情感病患者是显着的 与正常志愿者相比， 提示抑郁症患者的边缘轴存在实质性病理改变 患者，如前所述。 灵长类动物的初步数据 在普鲁卡因作用中涉及毒蕈碱M-2受体。 我们的患者边缘系统功能障碍的证据，基于 基线时情感疾病患者的无药物PET评估， 以及PET研究，以响应心理探针（诱导 快乐、悲伤、愤怒和焦虑情绪）和药理学探针 （普鲁卡因），使我们探索边缘系统的临床前机制， 在杏仁核点燃和淬灭的研究中， 与Susan韦斯的合作，以及在体外杏仁核切片中， 准备，与何莉和迈克尔·罗加夫斯基的 实验室 这些数据有助于揭示小说， 神经元长期变化的频率依赖性机制 兴奋性本身就很重要， 在产生一个理论框架的差分频率， 情感性疾病患者反复经颅刺激 磁刺激（rTMS）。

The Section has given special emphasis to the description and understanding of the neurobiology of the longitudinal course of affective disorders in light of the chronicity of the illness and its overwhelming proclivity for recurrence. The tendency for the frequency of cycling to accelerate, and the precipitation of episodes to become less dependent on psychosocial stresses over time, speaks to a potential sensitization process of prior episodes. This concept, pioneered in our Branch, has now been validated by the Denmark Patient Registry in 23,000 patients, demonstrating that the latency and incidence of recurrence of depressive episodes is directly proportional to the number of prior hospitalizations for depression in both unipolar and bipolar illness. New evidence of the pathological significance of episodes themselves in patients with affective disorder is derived from our observations that patients with a greater number of prior episodes of affective illness have increased dysfunction on a variety of neuropsychological tests. Our treatment-refractory affectively ill patients also have dysfunction in the recognition of facial emotional expression, as well as in navigation in geographic space, both of which are associated with neurophysiological abnormalities on positron emission tomography (PET) scans. Pre-clinical models for understanding molecular mechanisms involved in increased behavioral responsivity to the same stimulus over time have led to the postulate of the impact of stresses and episodes themselves on gene expression. This theoretical framework suggests that the cyclic presence or absence of affective dysfunction could be related to the relative ratio of pathological versus adaptive changes in gene expression. This model provides new targets for clinical study and therapeutics, not only in attempting to inhibit pathological changes, but also enhance endogenous adaptive mechanisms, such as the putative increases in TRH in depressive episodes. The positive antidepressant effects to intrathecal and parenteral TRH administration in depression provide preliminary confirmation of the hypothesis that the increases in TRH in depression could be a compensatory adaptation. In addition to the findings that some neuropeptides, such as somatostatin, are significantly low in the CSF of depressed patients in a state-dependent fashion, we have now obtained additional evidence of neuropeptide dysregulation in which significant peptide interrelationships that are normally observed in healthy control subjects are absent in our patient population, and vice-versa. In addition, we have continued to uncover heterogeneity of regional cerebral dysfunction in subgroups of affectively ill patients assessed with PET. Unipolar depressed patients show the classical picture of hypofrontality (correlated with severity on Hamilton depression ratings) compared with large age- and gender-matched groups of normal volunteers. Bipolar I patients tend to show the opposite pattern, with relative hypermetabolism, particularly in mediotemporal lobe structures. Bipolar II patients have greater variability and appear to represent a mixture of the hypo- and hypermetabolic subtypes, yielding generally nonsignificant differences from normal volunteer controls. The local anesthetic procaine has been found by PET to be a limbic-selective probe, and affectively ill patients are markedly hypoperfused in response to procaine compared with normal volunteers, suggesting substantial pathology in this limbic axis in depressed patients, as previously postulated. Preliminary data in primates implicate muscarinic m-2 receptors in procaine actions. The evidence of limbic system dysfunction in our patients, based on medication-free PET assessments in affectively ill patients at baseline, as well as PET studies in response to psychological probes (induction of happy, sad, angry, and anxious affects) and pharmacological probes (procaine), has led us to explore preclinical mechanisms of limbic dysfunction in vivo in studies of amygdala kindling and quenching, in collaboration with Susan Weiss, as well as in vitro in the amygdala slice preparation, in collaboration with He Li and Michael Rogawski's laboratory. These data have helped uncover the novel and frequency-dependent mechanisms for long-term changes in neuronal excitability that are of importance in their own right, but also helpful in generating a theoretical framework for differential frequencies of stimulation of affectively ill patients with repeated transcranial magnetic stimulation (rTMS) of the brain.