PHENOMENOLOGY, COURSE, & NEUROBIOLOGY OF REFRACTORY AFFECTIVE DISORDERS

该科特别重视对情感障碍纵向病程的神经生物学的描述和理解，考虑到这种疾病的长期性及其极易复发的倾向。随着时间的推移，骑行的频率越来越快，发作对心理社会压力的依赖程度越来越低，这些都是潜在的敏化过程的证据。这一假设现已被丹麦患者登记处在23,000名患者中验证，表明抑郁发作的潜伏期和复发率与单相和双相疾病以前因抑郁而住院的次数成正比(Kessling等人)。我们已经发现了情感性障碍患者发作本身可能具有病理学意义的新证据：那些先前有较多情感性疾病发作的患者在各种神经心理测试中功能障碍增加。我们还发现，早期应激史(言语、身体或性虐待)与超快(超传统)自行车运动模式有关。我们的难治性情感疾病患者在面部情感表达和地理空间导航方面也显示出缺陷，这两者都与正电子发射断层扫描(PET)上的神经生理异常有关。临床前模型用于理解随着时间推移对相同刺激的行为反应性增加所涉及的分子机制，导致了应激和事件本身对基因表达的影响的假设。这个理论框架表明，周期性情感功能障碍的存在或不存在可能与基因表达的病理变化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，不仅试图抑制病理变化，而且还增强了TRH等内源性适应机制。鞘内和肠外给予TRH对抑郁症的积极抗抑郁作用初步证实了抑郁症患者TRH升高可能是一种代偿适应的假说。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状态依赖的方式显著降低外，我们现在还获得了神经肽失调的额外证据，其中正常情况下在健康对照组受试者中观察到的显著的多肽相互关系在我们的患者群体中缺失，反之亦然。此外，我们继续发现，在PET评估的情感性疾病患者亚组中，局部脑功能障碍的异质性。与大量年龄和性别匹配的正常志愿者相比，单相抑郁症患者显示出典型的额叶下部特征(扣带回减少与汉密尔顿抑郁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，腹侧(膝下)前扣带回和小脑相对高代谢。单相抑郁的额叶下移与Beck抑郁量表中的认知(焦虑抑郁)部分有关，而双相患者的纹状体代谢与Beck上的精神运动-非享乐因素有关。PET发现局麻药普鲁卡因是一种边缘选择性探针，与正常志愿者相比，情感性疾病患者对普鲁卡因的反应明显降低，这表明抑郁症患者的这一边缘轴存在实质性的病理改变。我们的患者边缘系统功能障碍的证据，基于基线时对有情感障碍的患者进行的非药物PET评估，以及对心理探测(诱导高兴、悲伤、愤怒和焦虑的影响)和药理探测(普鲁卡因)的PET研究，导致我们与Susan Weiss合作，在体内杏仁核点燃和猝灭研究中探索边缘系统功能障碍的临床前机制，以及与何琳和Michael Rogawskis实验室合作，在体外杏仁核切片制备中探索边缘功能障碍的临床前机制。这些数据帮助揭示了神经元兴奋性长期变化的新的直流电流和频率依赖机制，这些机制本身具有重要意义，但也有助于生成一个理论框架，用于考虑反复经颅磁刺激(RTMS)对情感性疾病患者刺激频率的不同影响。

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.