Decision making and neuropsychiatry

Abnormal decision making is a central feature of neuropsychiatric disorders. Recent investigations of the neural substrates underlying decision making have involved qualitative assessment of the cognition of decision making in clinical lesion studies (in patients with frontal lobe dementia) and neuropsychiatric disorders such as mania, substance abuse and personality disorders. A neural network involving the orbitofrontal cortex, ventral striatum and modulatory ascending neurotransmitter systems has been identified as having a fundamental role in decision making and in the neural basis of neuropsychiatric diseases. This network accounts for the dissociations among decision-making deficits in different clinical populations. Ultimately, a more refined and sophisticated characterization of such deficits might guide the early diagnosis and cognitive and therapeutic rehabilitation of these patients.     

Catecholamine modulation of prefrontal cortical cognitive function

The prefrontal cortex (PFC) utilizes working memory to guide behavior and to release the organism from dependence on environmental cues and is commonly disrupted in neuropsychiatric disorders, normal aging, or exposure to uncontrollable stress. This review posits that the PFC is very sensitive to changes in the neuromodulatory inputs it receives from norepinephrine (NE) and dopamine (DA) systems and that this sensitivity can lead to marked changes in the working-memory functions of the PFC. While NE and DA have important beneficial influences on processing in this area, very high levels of catecholamine release, for example, during exposure to uncontrollable stress, disrupt the cognitive functions of the PFC. This fresh understanding of the neurochemical influences on PFC function has led to new treatments for cognitive disorders such as Attention Deficit Hyperactivity Disorder (ADHD), and may help to elucidate the prevalence of PFC dysfunction in other mental disorders.     

Response of the norepinephrine system to antidepressant drugs

Environmental stimuli and drugs affect the norepinephrine (NE) system and may be linked to the manifestation and treatment of anxiety and affective disorders. The activity of locus ceruleus NE neurons in the brainstem can alter the function of forebrain structures associated with several psychiatric disorders. In particular, NE neurons send and receive projections from sensory afferents, limbic areas, and cortical areas implicated in higher-order brain malfunctions and the symptomatology of anxiety and affective disorders. In turn, anxiolytic and antidepressant drugs are able to offset perturbations of NE activity and forebrain structures with a time course congruent with their therapeutic action. All antidepressants, even the agents selective for other biogenic amines or peptides, act on the NE system. In the present review, the effects of antidepressants on NE neurons are summarized and applied to the treatment of neuropsychiatric disorders, with emphasis placed on mechanisms of action.     

应激激素对恐惧消退作用的神经生理机制

恐惧消退是指反复呈现条件刺激（conditioned stimulus, CS）而不匹配无条件刺激（unconditioned stimulus, US）,从而消除个体已有的恐惧反应。应激激素,如去甲肾上腺素（Norepinephrine,NE）和糖皮质激素（Glucocorticoids,GCs）,可通过影响腹内侧前额叶、杏仁核和海马等与消退学习有关的神经回路的活动,调节恐惧消退学习效果。NE和GCs对恐惧消退学习的调节作用受激素水平与激素用药时间的影响,且其调节效果存在性别差异。未来研究需进一步探索应激激素如何影响恐惧消退学习效果,并思考如何利用其影响效果促进暴露疗法疗效。     

Obsessive-compulsive disorder: boundary issues

The boundaries between obsessive-compulsive disorder (OCD) and other neuropsychiatric disorders remain unresolved and may well differ from one disorder to another. Endophenotypes are heritable, quantitative traits hypothesized to more closely represent genetic risk for complex polygenic mental disorders than overt symptoms and behaviors. They may have a role in identifying how closely these disorders are associated with another and with other mental disorders with which they share major comorbidity. This review maps the nosological relationships of OCD to other neuropsychiatric disorders, using OCD as the prototype disorder and endophenotype markers, such as cognitive, imaging, and molecular data as well as results from demographic, comorbidity, family, and treatment studies. Despite high comorbidity rates, emerging evidence suggests substantial endophenotypic differences between OCD and anxiety disorders, depression, schizophrenia, and addictions, though comparative data is lacking and the picture is far from clear. On the other hand, strong relationships between OCD, Tourette syndrome, body dysmorphic disorder, hypochondriasis, grooming disorders, obsessive-compulsive personality disorder, and pediatric autoimmune neuropsychiatric disorders associated with streptococcus are likely. Studies designed to delineate the cause, consequences, and common factors are a challenging but essential goal for future research in this area.     

Eugenol as an anti-stress agent: modulation of hypothalamic-pituitary-adrenal axis and brain monoaminergic systems in a rat model of stress

Stress is the leading psychopathological cause for several mental disorders. Physiological and psychological responses to stress are mediated by the hypothalamic?pituitary?adrenal (HPA), sympathoadrenal system (SAS), and brain monoaminergic systems (BMS). Eugenol is reported to substantially modulate brain functions by regulating voltage-gated cation channels and release of neurotransmitters. This study was designed to evaluate the anti-stress effect of eugenol in the 4-h restraint model using rats. Ulcer index was measured as a parameter of the stress response. HPA axis and the SAS were monitored by estimating plasma corticosterone and norepinephrine (NE), respectively. Analysis of NE, serotonin (5-HT), dopamine, and their metabolites in discrete brain regions was performed to understand the role of BMS in the anti-stress effect of eugenol. Stress exposure increased the ulcer index as well as plasma corticosterone and NE levels. Eugenol pretreatment for 7 days decreased the stress-induced increase in ulcer index and plasma corticosterone but not NE levels, indicating a preferential effect on the HPA axis. Furthermore, eugenol showed a ?U?-shaped dose?response curve in decreasing ulcer index and plasma corticosterone levels. Eugenol also reversed the stress-induced changes in 5-HT levels in all brain regions, whereas NE levels were reversed in all brain regions except hippocampus. These results suggest that eugenol possesses significant anti-stress activity in the 4-h restraint model and the effect is due to modulation of HPA and BMS.     

The Role of the Cerebellum in Cognition and Emotion: Personal Reflections Since 1982 on the Dysmetria of Thought Hypothesis,and Its Historical Evolution from Theory to Therapy

The cognitive neuroscience of the cerebellum is now an established multidisciplinary field of investigation. This essay traces the historical evolution of this line of inquiry from an emerging field to its current status, with personal reflections over almost three decades on this journey of discovery. It pays tribute to early investigators who recognized the wider role of the cerebellum beyond motor control, traces the origins of new terms and concepts including the dysmetria of thought theory, the universal cerebellar transform, and the cerebellar cognitive affective syndrome, and places these developments within the broader context of the scientific efforts of a growing community of cerebellar cognitive neuroscientists. This account considers the converging evidence from theoretical, anatomical, physiological, clinical, and functional neuroimaging approaches that have resulted in the transition from recognizing the cerebellar incorporation into the distributed neural circuits subserving cognition and emotion, to a hopeful new era of treatment of neurocognitive and neuropsychiatric manifestations of cerebellar diseases, and to cerebellar-based interventions for psychiatric disorders.     

Genetics of emotion

Emotion is critical to most aspects of human behavior, and individual differences in systems recruited to process emotional stimuli, expressed as variation in emotionality, are characteristic of several neuropsychiatric disorders. We examine the genetic origins of individual differences in emotion processing by focusing on functional variants at five genes: catechol-O-methyltransferase (COMT), serotonin transporter (SLC6A4), neuropeptide Y (NPY), a glucocorticoid receptor-regulating co-chaperone of stress proteins (FKBP5) and pituitary adenylate cyclase-activating polypeptide receptor (ADCYAP1R1). These represent a range of effects of genes on emotion as well as the variety of mechanisms and factors, such as stress, that modify these effects. The new genomic era of genome-wide association studies (GWAS) and deep sequencing may yield a wealth of new loci modulating emotion. The effects of these genes can be validated by neuroimaging, neuroendocrine and other studies accessing intermediate phenotypes, deepening our understanding of mechanisms of emotion and variation in emotionality.     

高唤醒对创伤后应激障碍形成发展的影响及其神经机制

高唤醒是创伤后应激障碍(PTSD)的主要症状之一, 对创伤后应激障碍的形成与发展起核心作用。急性应激期产生的高唤醒可以预测其后PTSD的回避与麻木、再体验等症状的形成, 在创伤后早期, 降低唤醒程度可以减轻PTSD相关的症状表现。下丘脑-垂体-肾上腺轴异常变化会导致去甲肾上腺素(NE)、促肾上腺皮质激素释放因子(CRF)过度释放, 同时皮质醇(酮)水平下降, 这二者是高唤醒产生与维持的主要原因。另外, 5-羟色胺(5-HT)系统的高度激活也影响了高唤醒的形成。食欲素神经肽与NE、CRF与5-HT系统有密切的神经联系, 可能参与高唤醒的调节, 是近年来研究的一个热点。     

Sex differences in prenatal epigenetic programming of stress pathways

Maternal stress experience is associated with neurodevelopmental disorders including schizophrenia and autism. Recent studies have examined mechanisms by which changes in the maternal milieu may be transmitted to the developing embryo and potentially translated into programming of the epigenome. Animal models of prenatal stress have identified important sex- and temporal-specific effects on offspring stress responsivity. As dysregulation of stress pathways is a common feature in most neuropsychiatric diseases, molecular and epigenetic analyses at the maternal-embryo interface, especially in the placenta, may provide unique insight into identifying much-needed predictive biomarkers. In addition, as most neurodevelopmental disorders present with a sex bias, examination of sex differences in the inheritance of phenotypic outcomes may pinpoint gene targets and specific windows of vulnerability in neurodevelopment, which have been disrupted. This review discusses the association and possible contributing mechanisms of prenatal stress in programming offspring stress pathway dysregulation and the importance of sex.     

Efficacy of noradrenergic-selective agents in the treatment of neuropsychiatric diseases

In recent years, a number of antidepressants with varying degrees of selectivity for the noradrenergic neurotransmitter system have become available. However, these agents represent a pharmacologically heterogeneous group and differ in terms of their precise side-effect profile and, possibly, their clinical efficacy. Bupropion, which is thought to act on both the dopamine and norepinephrine (NE) systems, has not been widely used as an antidepressant and has more recently been licensed as adjunctive therapy for smoking cessation. The serotonin-NE reuptake inhibitors venlafaxine and nefazodone, the noradrenergic and specific serotonergic antidepressant mirtazapine, and the selective NE reuptake inhibitor reboxetine (the only truly NE-selective agent available) have all demonstrated efficacy in the treatment of depressive disorders. Evidence is now emerging for their use in the treatment of anxiety and panic disorders. There is some suggestion of a role for noradrenergic agents in other disorders, including attention-deficit/hyperactivity disorder and social phobia. The full range of disorders for which noradrenergic agents can be used remains to be seen and further research in this area is necessary.     

情绪唤醒影响记忆巩固过程的神经生理机制

白鼠和人类都对情绪唤醒的经历有更好的记忆。情绪唤醒影响记忆巩固的神经生理机制主要有以下几种方式:(a)情绪唤醒或急性应激,会引发个体内部应激激素的释放,从而增强其记忆巩固过程。(b1)杏仁核的激活对情绪唤醒影响记忆巩固过程十分重要,杏仁核内部去甲肾上腺素(NE)的释放影响记忆巩固过程。(b2)杏仁核投射到负责不同类型记忆加工的脑区,如海马和皮层,从而影响记忆。(c)应激激素影响记忆巩固的过程中,杏仁核内NE的激活在这一过程中扮演着重要角色。综上,情绪唤醒影响记忆巩固的过程,涉及到激素调节、神经调节及二者的共同作用。     

Amygdala modulation of memory consolidation: interaction with other brain systems

There is a strong consensus that the amygdala is involved in mediating influences of emotional arousal and stress on learning and memory. There is extensive evidence that the basolateral amygdala (BLA) is a critical locus of integration of neuromodulatory influences regulating the consolidation of several forms of memory. Many drug and stress hormone influences converge in activating the release of norepinephrine (NE) within the BLA. Evidence from studies using in vivo microdialysis and high-performance liquid chromatography indicates that increases in amygdala NE levels assessed following inhibitory avoidance training correlate highly with subsequent retention. Other evidence indicates that NE influences on memory consolidation require muscarinic cholinergic activation within the BLA provided by projections from the nucleus basalis magnocellularis (NB). Evidence from several experiments indicates that activation of the BLA plays an essential role in modulating memory consolidation processes involving other brain regions. These findings provide strong support for the hypothesis that the BLA plays a critical role in regulating the consolidation of lasting memories of significant experiences.     

THE RELATIONSHIP BETWEEN FEMININE GENDER ROLE STRESS, BODY IMAGE, AND EATING DISORDERS

The Feminine Gender Role Stress (FGRS) scale was used in two studies to determine whether eating disorders could be linked to the cognitive tendency among women to appraise specific situations as highly stressful because of rigid adherence to the traditional feminine gender role. Study 1 showed the FGRS scale could distinguish eating disorders from other psychiatric disorders in an inpatient setting and from normal college women. This suggests that women who have eating disorders report higher than usual levels of stress as a result of rigid adherence to the traditional feminine gender role. Study 2 looked at cardiovascular reactivity to a "feminine" (i.e., body image threat) and a control stressor and determined the FGRS scale could predict which women are threatened by feminine stressors. Results from these studies suggest feminine gender role stress may be the missing link between cultural values of femininity and vulnerability for eating disorders.     

Pessimism moderates negative emotional responses to naturally occurring stress

Repeated experiences with stress and negative emotion (NE) can decrease psychological and physical well-being. Ruminating on stressful events can further prolong NE responses, especially for those who are pessimistic. For three days participants (N = 68) reported hourly on their current stress, rumination, perceived control, and NE. Tests of mediation conducted using multilevel modeling suggested that rumination mediated same-time reports of stress on NE, and predicted perpetuation of NE over time. Tests of moderated mediation indicated that the pathways from previous stress to rumination, and from rumination to current NE were moderated by pessimism, but not optimism. Perception of control also accounted for some of the variability between concurrent stress and NE, though these associations were not affected by pessimism.     

Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety

Stress initiates a series of neuronal responses that prepare an organism to adapt to new environmental challenges. However, chronic stress may lead to maladaptive responses that can result in psychiatric syndromes such as anxiety and depressive disorders. Corticotropin-releasing factor (CRF) has been identified as a key neuropeptide responsible for initiating many of the endocrine, autonomic and behavioral responses to stress. The amygdala expresses high concentrations of CRF receptors and is itself a major extrahypothalamic source of CRF containing neurons. Within the amygdala, the basolateral nucleus (BLA) has an important role in regulating anxiety and affective responses. During periods of stress, CRF is released into the amygdala and local CRF receptor activation has been postulated as a substrate for stress-induced alterations in affective behavior. Previous studies have suggested that synaptic plasticity in the BLA contributes to mechanisms underlying long-term changes in the regulation of affective behaviors. Several studies have shown that acute glutamate receptor-mediated activation, by either GABA-mediated disinhibition or CRF-mediated excitation, induces long-term synaptic plasticity and increases the excitability of BLA neurons. This review summarizes some of the data supporting the hypotheses that stress induced plasticity within the amygdala may be a critical step in the pathophysiology of the development of chronic anxiety states. It is further proposed that such a change in the limbic neural circuitry is involved in the transition from normal vigilance responses to pathological anxiety, leading to syndromes such as panic and post-traumatic stress disorders.     

Neuropsychiatric disorders in children of divorced marriages]

From the standpoint of polyethiological methods of treating children's neuropsychiatric disorder images, the present paper is concerned with the question of environmental morbific agents which play a part in the genesis of these disorders. The results have made it clear that children of divorced marriages have to be treated at medical establishments for psychiatric disorders more frequently than those coming from normal family relationships, with a marked dependence on the environment to be observed in certain groups of diagnoses. The encephalopathic child must be regarded as being particularly endangered. Suggestions are given as to the prophylaxis of such disorders, which must primarily be oriented towards the family.     

Neuropsychological Issues in the Assessment of Refugees and Victims of Mass Violence

Brain injury, stressor severity, depression, premorbid vulnerabilities, and PTSD are frequently intertwined in trauma populations. This interaction is further complicated when the neuropsychologist evaluates refugees from other cultures. In addition, the observed psychiatric symptoms reported in refugees and victims of mass violence may in fact not be the primary features of PTSD and depression but psychiatric symptoms secondary to the effects of traumatic brain injury. This paper reviews the occurrence of starvation, torture, beatings, imprisonment, and other head injury experiences in refugee and POW populations to alert treators to the presence of chronic and persistent neuropsychiatric morbidity, with implications for psychosocial adjustment. The concept of fixed neural loss may also interact with environmental and emotional stresses, and a model of neuropsychological abnormalities triggered by traumatic events and influenced by subsequent stress will also be considered. Neuropsychologists working with refugees play an important role in assessing the possibility of traumatic brain injury with tools that are relatively culture-fair.     

Genetic factors and neurocognitive traits

Genetic contributions to phenotypic variation in general intelligence have been studied extensively. Less research has been conducted on genetic contributions to specific cognitive abilities, such as attention, memory, working memory, language, and motor functions. However, the existing data indicate a significant role of genetic factors in these abilities. Stages of information processing, such as sensory gating, early sensory registration, and cognitive analysis, also show evidence of genetic contributions. Recent molecular studies have begun to identify candidate genes for specific cognitive functions. Future research, identifying endophenotypes based on cognitive profiles of neuropsychiatric disorders, may also assist in the detection of genes that increase susceptibility to major psychiatric disorders.     

不同感觉功能对抑郁的影响及其神经机制

大脑通过视觉、听觉、嗅觉、味觉和触觉等感官通道接收来自外界的信息。不同感觉功能受损涉及抑郁发生的中枢机制,而基于不同感官通道进行适当刺激以及多感官联合干预也可能发挥显著的抑郁治疗作用。笔者以症状-脑区-机制-治疗为逻辑主线,首次系统梳理了五种主要感觉障碍人群的抑郁临床症状、抑郁神经机制以及基于感觉刺激的抗抑郁治疗。结果表明,不同感觉功能障碍对抑郁相关神经机制的影响可能表征了不同的抑郁病理,涉及神经元电活动(某些神经元放电和神经环路激活等)和神经生化改变(神经可塑性和神经发生、炎症免疫和HPA轴、神经激素和神经递质等),且主要发生在边缘系统及其附近脑区,涉及岛叶、颞叶、额叶等。因此,未来研究可聚焦于机体对不同感觉信息的提取,这将为人类抑郁的病因和治疗提供新的研究视角。