PHENOMENOLOGY, COURSE, & NEUROBIOLOGY OF REFRACTORY AFFECTIVE DISORDERS

本节特别强调描述和理解情感性障碍的纵向过程的神经生物学鉴于疾病的慢性和其压倒性的复发倾向。随着时间的推移，循环频率加速的趋势和发作对社会心理压力的依赖性减弱的趋势是潜在致敏过程的证据。这一假设现在已经被丹麦患者登记处的23000名患者验证，表明抑郁症发作的潜伏期和复发发生率与先前因抑郁症住院治疗的次数成正比，无论是单极还是双相疾病（Kessling等）。我们发现了新的证据，证明情感性疾病患者发作本身可能具有病理意义：那些先前情感性疾病发作次数较多的患者在各种神经心理测试中功能障碍增加。我们还发现，早期压力（言语、身体或性虐待）的历史与超快速循环的模式有关。我们的难治性情感疾病患者也表现出面部情绪表达识别和地理空间导航的缺陷，这两者都与正电子发射断层扫描（PET）的神经生理异常有关。随着时间的推移，对相同刺激的行为反应性增加所涉及的分子机制的临床前模型已经导致压力和事件本身对基因表达的影响的假设。这一理论框架表明，情感功能障碍的周期性存在或不存在可能与基因表达中病理性与适应性变化的相对比例有关。该模型为临床研究和治疗提供了新的靶点，不仅可以抑制病理变化，还可以增强TRH等内源性适应机制。鞘内注射和肠外注射TRH对抑郁症的积极抗抑郁作用初步证实了抑郁症中TRH的增加可能是一种代偿性适应的假设。除了发现一些神经肽，如生长抑素，在抑郁症患者的脑脊液中以一种状态依赖性的方式显着降低外，我们现在还获得了神经肽失调的额外证据，其中在健康对照受试者中通常观察到的重要肽相互关系在我们的患者群体中不存在，反之亦然。此外，我们继续发现在PET评估的情感疾病患者亚组中区域脑功能障碍的异质性。与年龄和性别匹配的正常志愿者相比，单极抑郁症患者表现出典型的额下功能低下（扣带回的减少与汉密尔顿抑郁症评分的严重程度相关）。双相I型患者倾向于表现出相反的模式，在腹侧（亚属）前扣带和小脑有相对的高代谢。单极抑郁症的低额与贝克抑郁量表的认知（焦虑抑郁）成分有关，而双相患者的纹状体代谢与贝克抑郁量表上的精神运动-快感缺乏因子有关。局部麻醉剂普鲁卡因已被PET发现是一种边缘选择性探针，与正常志愿者相比，患有情感疾病的患者对普鲁卡因的反应明显低灌注，这表明抑郁症患者的边缘轴存在实质性病理，正如之前所假设的那样。我们的患者边缘系统功能障碍的证据，基于无药物的PET评估在基线的情感疾病患者，以及PET研究对心理探针（诱导快乐，悲伤，愤怒和焦虑的影响）和药理学探针（普鲁卡因）的反应，使我们在体内杏仁核点燃和熄灭的研究中探索边缘功能障碍的临床前机制。以及与何力和迈克尔·罗加斯基实验室合作进行的体外杏仁核切片制备。这些数据有助于揭示神经元兴奋性长期变化的新的直流电流和频率依赖机制，这些机制本身就很重要，但也有助于产生一个理论框架，以考虑反复经颅磁刺激（rTMS）的情感疾病患者的刺激频率的差异效应。

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 Rogawskis 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.