PHENOMENOLOGY, COURSE, & NEUROBIOLOGY OF REFRACTORY AFFECTIVE DISORDERS

该科特别强调 对神经生物学的描述和理解 从慢性化看情感性障碍的纵向病程 这种疾病及其复发的压倒性倾向。这个 骑自行车的频率加速和发作的趋势 随着时间的推移变得不那么依赖心理社会压力是 潜在敏化过程的证据。这一假设具有 现已由丹麦患者登记处在23,000人中进行验证 患者，表明潜伏期和复发率 抑郁发作的数量与抑郁发作次数成正比 曾因单相和双相抑郁而住院 疾病(Kessling等人)。我们找到了新的证据证明 慢性阻塞性肺疾病患者发作本身的病理学意义 情感障碍：有较多既往病史的患者 情感性疾病的发作增加了各种功能障碍 神经心理测试。我们还发现了一段历史 早期压力(言语、身体或性虐待)与 超快(超快)自行车的模式。我们的 治疗难治的情感性疾病患者也显示出 人脸表情识别及导航中的应用 地理空间，这两者都与 正电子发射断层扫描的神经生理异常 (PET)扫描。理解分子的临床前模型 行为反应性增加的机制 随着时间的推移，同样的刺激措施导致了影响的假设 对基因表达的压力和插曲。这 理论框架表明，周期性的存在或不存在 可能与情感障碍的相对比例有关 基因表达的病理性变化与适应性变化。这 模型为临床研究和治疗提供了新的靶点，而不是 不仅在试图抑制病理变化，而且还增强 内源性适应机制，如TRH。积极的一面 鞘内和肠外TRH的抗抑郁作用 抑郁症的给药提供了对 假设抑郁症患者TRH升高可能是一种 补偿性适应。除了发现一些人 神经肽，如生长抑素，在 抑郁症患者的脑脊液呈状态依赖的方式，我们有 现在获得了神经肽失调的更多证据 哪些重要的肽相互关系通常是 在我们的患者中观察到的健康对照对象是缺失的 人口，反之亦然。此外，我们还继续 发现亚组中局部脑功能障碍的异质性 用正电子发射计算机断层扫描对情感疾病患者进行评估。单相抑郁 患者表现为典型的额叶下垂(伴 扣带回的减少与疾病的严重程度相关 汉密尔顿抑郁评分)与大年龄相比-以及 性别匹配的正常志愿者分组。双相I型患者 倾向于表现出相反的模式，相对高代谢 腹侧(膝下)前扣带回和小脑。这个 单相抑郁患者额叶下移与认知功能的关系 (焦虑抑郁)贝克抑郁量表的组成部分， 而双相情感障碍患者的纹状体新陈代谢与 精神运动--非享乐性因素。局麻药 普鲁卡因已被PET发现是一种边缘选择性探针，并且 情绪性疾病患者对 普鲁卡因与正常志愿者相比，表明 抑郁症患者边缘轴的病理改变 假设的。我们的边缘系统功能障碍的证据 患者，基于非药物治疗的正电子发射计算机断层扫描评估 患者在基线水平，以及PET研究对 心理探查(快乐、悲伤、愤怒和焦虑的诱发 影响)和药理探针(普鲁卡因)，已经引导我们 在体探讨边缘功能障碍的临床前机制 杏仁核点燃和猝灭的研究，与 Susan Weiss，以及在杏仁核片的体外制备，在 与何琳和迈克尔·罗加夫斯基的实验室合作。这些 数据帮助发现了新的直流电流-和 长期变化的频率依赖机制 神经元兴奋性本身是很重要的，但是 也有助于生成考虑以下问题的理论框架 情感刺激频率的差异性效应 反复经颅磁刺激(RTMS)患者 大脑的一部分。

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 episodes to become less dependent on psychosocial stresses over time are evidence of a potential sensitization process. This postulate 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 (Kessling et al). We have found new evidence of the possible pathological significance of episodes themselves in patients with affective disorder: those patients with a greater number of prior episodes of affective illness have increased dysfunction on a variety of neuropsychological tests. We have also found that a history of early stress (verbal, physical,or sexual abuse) is related to the pattern of ultra-ultra rapid (ultradian) cycling. Our treatment-refractory affectively ill patients also show deficits in the recognition of facial emotional expression and in navigation in geographic space, both of which are associated with neurophysiological abnormalities on positron emission tomography (PET) scans. Preclinical 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 TRH. 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 finding 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 (with decrements in the cingulate gyrus correlating 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 in the ventral (subgenual) anterior cingulate and cerebellum. The hypofrontality in unipolar depression relates to the cognitive (anxious depressive) components of the Beck depression inventory, while bipolar patients show relationships of striatal metabolism to a psychomotor-anhedonic factor on the Beck. 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. 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 novel DC current- 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 considering the differential effects of the frequency of stimulation of affectively ill patients with repeated transcranial magnetic stimulation (rTMS) of the brain.