Behavioral Approach System and Behavioral Inhibition System sensitivities and bipolar spectrum disorders: prospective prediction of bipolar mood episodes

Objectives:  Research has found that bipolar spectrum disorders are associated with Behavioral Approach System (BAS) hypersensitivity and both unipolar and bipolar depression are associated with high Behavioral Inhibition System (BIS) sensitivity, but prospective studies of these relationships are lacking. We tested whether BAS and BIS sensitivities prospectively predicted the time to new onsets of major depressive and hypomanic and manic episodes in bipolar spectrum individuals.
Methods:  We followed 136 bipolar II or cyclothymic and 157 demographically matched normal control individuals prospectively for an average of 33 months. Participants completed the BIS/BAS scales and symptom measures at Time 1 and semi-structured diagnostic interviews every four months of follow-up.
Results:  The bipolar spectrum group exhibited higher Time 1 BAS, but not BIS, scores than the normal controls, controlling for Time 1 symptoms. Among bipolar spectrum participants, high BAS sensitivity prospectively predicted a shorter time to onset of hypomanic and manic episodes, whereas high BIS sensitivity predicted less survival time to major depressive episodes, controlling for initial symptoms.
Conclusions:  Consistent with the BAS hypersensitivity model of bipolar disorder, a highly responsive BAS provides vulnerability to onsets of (hypo)manic episodes. In addition, a highly sensitive BIS increases risk for major depressive episodes.     

Brain glucose metabolism difference between bipolar and unipolar mood disorders in depressed and euthymic states

Background

Functional brain imaging studies have consistently demonstrated abnormalities in regional cerebral glucose metabolism in the prefrontal cortex in patients with mood disorders (MD). These studies, however, have not clarified the differential characteristics of glucose metabolism between depressed and euthymic states, or between bipolar mood disorder (BP) and unipolar mood disorder (UP).

Methods

We used [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to evaluate the differences in glucose metabolism at resting state. We compared 30 depressed and 17 euthymic female patients with mood disorders with age-, IQ-, and socioeconomically matched 20 healthy controls (HCs). Then, BP and UP patients were separately analyzed. The PET data were objectively analyzed by statistical parametric mapping (SPM).

Results

Compared with HCs, the depressed MD patients showed significantly lower glucose metabolism in the bilateral frontal gyri, left cingulate gyrus, bilateral temporal gyri, right insula, bilateral inferior parietal lobules, and right occipital gyrus. In contrast, the euthymic MD patients demonstrated fewer areas with significant reduction. When the depressed BP patients were separately compared with HCs, the glucose metabolism was found to be significantly lower in the bilateral frontal gyri, right cingulate gyrus, and bilateral inferior parietal lobules. Meanwhile, the depressed UP patients showed a significantly lower metabolism in the bilateral frontal gyri, left cingulate gyrus, bilateral temporal gyri, bilateral insulae, bilateral inferior parietal lobules, and right occipital gyrus.

Conclusions

The results of this study provide evidence of persistent hypometabolism in depressed MD patients, particularly in the frontal gyrus. Although the conclusions are limited in the cross-sectional study, these findings suggest that abnormalities in the right frontal gyrus, left temporal gyrus, and left cingulate gyrus tend to normalize as the depression symptoms improve, although those in the left frontal gyrus, right cingulate gyrus, and right temporal gyrus persist. This study also elucidated the cerebral hypofunction specific to each BP and UP. BP patients showed a decrease in glucose metabolism in the right anterior cingulate and UP patients did in the right temporal gyrus, right insula, and left posterior cingulate. This study clarified the differences between subtypes.     

Reward bias and lateralization in gambling behavior: behavioral activation system and alpha band analysis

The present research explored the main factors that can influence subjects’ choices in the case of decisions. In order to elucidate the individual differences that influence the decisional processes, making their strategies more or less advantageous, we tested the effect of a reward sensitivity in the behavioral activation system (BAS-Reward) constructed on the ability to distinguish between high- and low-risk decisions. Secondly, the lateralization effect, related to increased activation of the left (BAS-related) hemisphere, was explored. Thirty-one subjects were tested using the Iowa Gambling Task, and the BAS-Reward measure was applied to distinguish between high-BAS and low-BAS groups. Behavioral responses (gain/loss options) and alpha-band modulation were considered. It was found that high-BAS group increased their tendency to opt in favor of the immediate reward (loss strategy) rather than the long-term option (win strategy). Secondly, high-BAS subjects showed an increased left-hemisphere activation in response to losing (with immediate reward) choices in comparison with low-BAS subjects. A “reward bias” effect was supposed to explain both the bad strategy and the unbalanced hemispheric activation for high-BAS and more risk-taking subjects.     

From inhibition to activation,from emotional hyporeactivity to emotional hyperreactivity: Two pathways to discriminate mood in bipolar disorders

To better explore the clinical heterogeneity of bipolar mood states, we developed a dimensional scale for assessing all mood episodes (depressive, hypomanic, manic, mixed states) using the same tool. The Multidimensional Assessment of Thymic States (MATHYS) (Henry et al., 2008) provides two scores, a total score measuring a level of activation and a sub-score of emotional reactivity. The aim of this study was to establish the appropriate cut-off in total activation versus inhibition and in the emotional reactivity sub-score in bipolar disorders. Patients (n=187) during an acute episode and controls (n=89) filled in the MATHYS. Receiver Operating Characteristic (ROC) curves were obtained to estimate the sensitivity and specificity of the global score and the emotional reactivity sub-score of the MATHYS, in order to differentiate patients from controls. ROC curves showed very satisfactory sensitivity and specificity levels both for the total score and the sub-score of emotional reactivity, thus providing an appropriate cut-off. Concerning the total score between 0 and 200, patients with a score lower than 91 had significant global inhibition and those with a score higher than 109 had significant global activation. Regarding the emotional reactivity sub-score between 0 and 40, patients with a score lower than 16 had significant emotional hyporeactivity and those with a score higher than 24 had significant emotional hyperreactivity. Our results provide cut-offs for the MATHYS to identify patients in an acute phase.     

Neural and behavioral substrates of mood and mood regulation.

A review of behavioral and neurobiological data on mood and mood regulation as they pertain to an understanding of mood disorders is presented. Four approaches are considered: 1) behavioral and cognitive; 2) neurobiological; 3) computational; and 4) developmental. Within each of these four sections, we summarize the current status of the field and present our vision for the future, including particular challenges and opportunities. We conclude with a series of specific recommendations for National Institute of Mental Health priorities. Recommendations are presented for the behavioral domain, the neural domain, the domain of behavioral-neural interaction, for training, and for dissemination. It is in the domain of behavioral-neural interaction, in particular, that new research is required that brings together traditions that have developed relatively independently. Training interdisciplinary clinical scientists who meaningfully draw upon both behavioral and neuroscientific literatures and methods is critically required for the realization of these goals.     

单相抑郁与双相情感障碍遗传效应及方式的对照研究

为寻找情感性障碍可能是一组异源性疾病的根据，调查了１７例单相抑郁和９６例双相情感障碍患者一、二级亲属中的情感性障碍患病率，并对二组亚型的遗传效应及方式作了对照分析。结果显示，单相抑郁的家族聚集性明显高于双相情感障碍。单相抑郁和双相情感障碍的加权平均遗传率分别为１３１．２％和８８．９％。单相抑郁和双相情感障碍都符合多基因遗传，但单相抑郁的遗传率明显高于双相情感障碍，且单相抑郁的二级亲属同病者均集中在母系。提示两者可能属异源性疾病。     

Evidence of weekly cyclicity in mood and functional impairment in those with a bipolar disorder

A key characteristic of bipolar disorder is fluctuation in mood symptoms and functional capacity, yet assessment of bipolar symptomatology often relies heavily on interval measurement that is unable to capture the full range of daily symptom variability and severity. The current study provides a detailed analysis of the variability in mood symptoms, functional impairment and medication compliance in a large sample of individuals newly diagnosed with bipolar disorder. Individuals diagnosed with bipolar disorder in the previous 12 months (n=192) rated their mood, functional impairment, medication compliance and symptom triggers daily over 10 consecutive weeks. High mood, low mood and functional impairment were found to vary on a weekly cycle, independently of medication compliance. Low mood and functional impairment were worse on weekdays, particularly Mondays and Tuesdays, whereas mood was most elevated on Saturdays. Work-related stressors were the most common symptom triggers on weekdays, whereas sleep-related problems and positive social events were the most common triggers on weekends. This study provides evidence that individuals newly diagnosed with bipolar disorder experience fluctuations in mood and functioning that vary according to a weekly cycle. This finding has implications for the assessment and treatment of patients, and for future research.     

Sex differences in the behavioral inhibition system and ventromedial prefrontal cortex connectivity

The reinforcement sensitivity theory proposes brain–behavioral systems that underlie individual differences in sensitivity to punishment and reward. Such trait sensitivity is assessed using the behavioral inhibition/activation system (BIS/BAS) scales. Recent studies have reported sex-linked neuroanatomical correlates of the BIS/BAS, especially in the regions belonging to the valuation and salience networks that are associated with the representation of subjective value (SV), whereas less effort has been focused on investigating the neurofunctional aspects associated with sex differences in the BIS/BAS. We tested whether functional connectivity (FC) of the regions associated with the representation of SV mediates the relationship between sex and BIS sensitivity in healthy young adults by using resting-state functional magnetic resonance imaging data and self-reported BIS/BAS measures. Compared with males, females had heightened BIS sensitivity and increased FC between the ventromedial prefrontal cortex (vmPFC) seed and posterior parietal areas; this FC mediated the impact of sex on BIS sensitivity. Given that the observed vmPFC FC maps are considered part of the default-mode network, which is involved in ruminative processes, and that the BIS is associated with rumination and negative affect, our results may have implications for psychiatric disorders such as depression and anxiety, both of which have high incidence in females.     

Critical role of brain-derived neurotrophic factor in mood disorders

The purpose of this review is to integrate what is currently known about the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Pre-clinical studies suggest that the expression of BDNF might be a downstream target of antidepressant treatments and mood stabilizers such as lithium and valproate, and that BDNF exerts antidepressant activity in animal models of depression. Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. Clinical studies have demonstrated that serum levels of BDNF in drug-naive patients with MDD are significantly decreased as compared with normal controls, and that BDNF might be an important agent for therapeutic recovery from MDD. Moreover, recent findings from family-based association studies have suggested that the BDNF gene is a potential risk locus for the development of BD. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders. New agents capable of enhancing BDNF levels may lead aid the development of novel therapeutic drugs for patients with mood disorders.     

Tolerance to the prophylactic effects of carbamazepine and related mood stabilizers in the treatment of bipolar disorders

Tolerance development after successful long-term treatment of bipolar disorder is under recognized, as are ways to prevent or show its occurrence or reverse it once it has occurred. We review the clinical literature which suggests that tolerance can develop to most treatment approaches in bipolar illness and present an animal model of tolerance development to anticonvulsant effects of carbamazepine or lamotrigine on amgydala-kindled seizures. In this model tolerance does not have a pharmacokinetic basis, but is contingent upon the drug being present in the brain at the time of amygdala stimulation. The occurrence of seizures in the absence of drug is sufficient to reverse tolerance and re-establish anticonvulsant efficacy. Based on the model, we hypothesize that some episode-induced compensatory adaptive changes in gene expression fail to occur in tolerant subjects and that episodes off medication re-induce these changes and renew drug effectiveness. Approaches that slow or reverse tolerance development in the animal model are reviewed so that they can be tested for their applicability in the clinic. Criteria for assessing tolerance development are offered in the hope that this will facilitate a more systemic literature about its prevalence, prevention, and reversal. Careful longitudinal monitoring of episode occurrence is essential to understanding tolerance development in the affective disorder and its treatment.     

Low peripheral mitochondrial DNA copy number during manic episodes of bipolar disorders is associated with disease severity and inflammation

Mitochondria (Mt) are intra-cellular components essential for cellular energy processes whose dysfunction may induce premature cellular senescence and/or inflammation, both observed in bipolar disorders (BD). We investigated mitochondrial DNA copy number (mtDNAcn) levels in patients with BD being in manic, depressive or euthymic phase and in healthy controls (HC) both characterized for the levels of blood-based inflammatory markers and stigma of pathogens.312 patients with BD were compared to 180 HC. mtDNAcn were measured using a digital droplet PCR. Serum levels of 14 inflammatory molecules and 3 anti-infectious IgG stigma were respectively evaluated by electro-chemiluminescence, ELISA and dedicated immunoassays. The statistical analyses were performed using Spearman’s correlation, Wilcoxon signed-rank and Kruskal-Wallis rank sum tests. P-values were adjusted for multiple testing with Benjamini-Hochberg method.We found low levels of mtDNAcn in BD patients as compared to HC (P = 0.008) especially during manic episodes (P = 0.0002). We also observed that low levels of mtDNAcn are negatively correlated with mood and psychotic scales (PANSS, YMRS and CGI) (adjusted P (Adj P) = 0.02, 0.003 and 0.05 respectively) and positively with the GAF severity scale (Adj P = 0.002). They were also correlated with high levels of both intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Adj P = 0.003 and 0.001) along with a trend toward increased IL-2, IL-10 and B2M circulating levels (Adj P = 0.05).Here, we report correlations between marker of mitochondria functioning and both clinical scales and inflammatory markers in BD patients experiencing manic episodes. If replicated, these finding might allow to predict transition between disease phases and to design accurate therapeutic options.     

Impairment of endothelial function in unipolar and bipolar depression.

BACKGROUND: Previous studies have suggested an association between abnormal endothelial function and depression. We therefore tested this hypothesis in patients with depression in the course of mood disorders and assessed the effect of antidepressant treatment. METHODS: Psychometric evaluation and hemodynamic and endothelial function studies using pulse wave analysis were performed on a group of 31 patients with unipolar or bipolar depression. The control group consisted of 18 healthy subjects, age- and gender-matched. RESULTS: Arterial endothelial function was impaired in patients compared with that in control subjects, both during a depressive episode and when in remission after pharmacological treatment. The diagnosis, intensity of depression, and type of antidepressant drugs did not influence the results. CONCLUSIONS: The impairment of endothelial function might constitute a trait marker of the biological make-up of patients with mood disorders and might contribute to the increased frequency of cardiovascular conditions observed in these patients.     

Influence of trait behavioral inhibition and behavioral approach motivation systems on the LPP and frontal asymmetry to anger pictures

Behavioral approach and avoidance are fundamental to the experience of emotion and motivation, but the motivational system associated with anger is not well established. Some theories posit that approach motivational processes underlie anger, whereas others posit that avoidance motivational processes underlie anger. The current experiment sought to address whether traits related to behavioral approach or avoidance influence responses to anger stimuli using multiple measures: ERP, electroencephalographic (EEG) α-asymmetry and self-report. After completing the behavioral inhibition system/behavioral approach system (BIS/BAS) scales, participants viewed anger pictures and neutral pictures. BAS predicted larger late positive potentials (LPPs) to anger pictures, but not to neutral pictures. In addition, BAS predicted greater left-frontal asymmetry to anger pictures. Moreover, larger LPPs to anger pictures related to greater left-frontal EEG asymmetry during anger pictures. These results suggest that trait approach motivation relates to neurophysiological responses of anger.     

Behavioral inhibition system (BIS), behavioral activation system (BAS) and schizophrenia: relationship with psychopathology and physiology

OBJECTIVE: The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been conceptualized as two neural motivational systems that regulate sensitivity to punishment (BIS) and reward (BAS). Imbalance in BIS and BAS levels has been reported to be related to various forms of psychopathology. Since sensitivity to stress has been supposed to be a pathway for the development of psychotic symptoms, the aim of this study is to examine BIS and BAS scores in schizophrenia and their relationship with psychopathology and physiology. METHOD: Forty-two patients with schizophrenia (26 men, 16 women), stable on atypical antipsychotics, and 37 healthy controls (17 men, 20 women) were assessed with the use of the Behavioral Inhibition and Behavioral Activation scales. Since increased average heart rate (HR) and decreased heart rate variability (HRV) have been reported in patients with schizophrenia and have been shown to correlate with inhibited behaviour, these psychophysiological measures were also obtained. The BIS/BAS data and HR/HRV data were both analyzed by a (M)ANOVA. Correlation coefficients were computed for associations between BIS/BAS data, HR/HRV data, and patient variables. RESULTS: On the BIS, patients showed higher sensitivity to threat than control subjects. Higher BIS sensitivity correlated with longer duration of illness, and lower negative symptoms on the PANSS. The BAS scores did not reveal differences between patients and controls. In patients, low BAS sensitivity correlated with low dosage of medication. On the physiological measures patients showed a significantly higher HR and lower HRV compared to controls, which was limited to clozapine treated patients. No correlations were found between HR/HRV scores and BIS/BAS scores or patient variables. CONCLUSIONS: Male as well as female patients with schizophrenia are more sensitive to threat than healthy controls. This may reflect a trait-related characteristic, and is not reflected in state-related psychophysiological measures.     

The temporal course of anxiety sensitivity in outpatients with anxiety and mood disorders: relationships with behavioral inhibition and depression

The present study evaluated the temporal course of three dimensions of anxiety sensitivity (AS; concerns over physical symptoms, mental incapacitation, and social embarrassment) and their relationships with behavioral inhibition (BI) and depression (DEP) in 606 outpatients with anxiety and mood disorders. A semi-structured interview and self-report questionnaires were administered on three occasions over a two-year period. All three constructs decreased over the study period and AS temporally functioned more similar to DEP than BI. Cross-sectional and temporal correlations supported the discriminant validity of AS from BI. As expected, initial levels of BI predicted less improvement in all AS dimensions. In contrast, higher initial levels of mental incapacitation AS were associated with greater improvement in DEP. Our results are discussed in regard to the measurement of AS in clinical samples, conceptualizations of AS as a lower-order vulnerability, and prognostic implications of directional paths between BI and AS and AS and DEP.     

Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression.

BACKGROUND: Cognitive dysfunction persists in the euthymic phase of bipolar disorder and may provide a marker of underlying neuropathology and disease vulnerability. This study aimed to replicate a deficit in sustained attention in euthymic bipolar patients and investigate sustained attention in first-degree relatives of bipolar probands and in remitted patients with major depressive disorder. METHODS: The rapid visual information processing (RVIP) task was used to measure sustained attention in 15 euthymic patients with bipolar disorder and 15 control subjects in experiment 1 and in 27 first-degree relatives of bipolar probands, 15 remitted patients with major depressive disorder, and 46 control subjects in experiment 2. RESULTS: Sustained attention deficit was confirmed in the euthymic bipolar patients in experiment 1, but the deficit was not statistically significant in remitted major depressed patients or in the relatives of bipolar probands. CONCLUSIONS: A deficit of sustained attention is not present in patients with recurrent major depression tested during remission nor is it discriminable in the first-degree relatives of bipolar probands. Thus, the confirmed abnormality in euthymic bipolar patients may be acquired as a consequence of bipolar illness. However, future studies of relatives will require larger sample sizes to exclude or utilize small genetic effects.     

Distinct profiles of neurocognitive function in unmedicated unipolar depression and bipolar II depression.

BACKGROUND: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. Few studies have directly compared depressed subjects with major depressive disorder (MDD) and bipolar disorder (BD), and many are confounded by medication status across subjects. In this study, we compared the performance of unmedicated currently depressed MDD and BD groups on a battery of neuropsychological tests that included measures of risk taking and reflection impulsivity. METHODS: Twenty-two MDD, seventeen BDII, and 25 healthy control subjects (HC), matched for age and IQ, were assessed on a battery of neuropsychological tests. RESULTS: The depressed groups showed comparable ratings of depression severity and age of illness onset. The MDD group was impaired on tests of spatial working memory and attentional shifting, sampled less information on a test of reflection impulsivity, and was oversensitive to loss trials on a decision-making test. The BDII subjects were generally intact and did not differ significantly from control subjects on any test. CONCLUSIONS: These data indicate differing profiles of cognitive impairment in unmedicated depressed MDD versus BDII subjects. Moderately depressed BDII subjects displayed relatively intact cognitive function, whereas MDD subjects demonstrated a broader range of executive impairments. These cognitive deficits in depression were not attributable to current medication status.