Models Of Bipolar Disorder Research Articles

All the world's a (clinical) stage: rethinking bipolar disorder from a longitudinal perspective.

Psychiatric disorders have traditionally been classified using a static, categorical approach. However, this approach falls short in facilitating understanding of the development, common comorbid diagnoses, prognosis, and treatment of these disorders. We propose a “staging” model of bipolar disorder that integrates genetic and neural information with mood and activity symptoms to describe how the disease progresses over time. From an early, asymptomatic, but “at risk” stage to severe, chronic illness, each stage is described with associated neuroimaging findings as well as strategies for mapping genetic risk factors. Integrating more biologic information relating to cardiovascular and endocrine systems, refining methodology for modeling dimensional approaches to disease, and developing outcome measures will all be crucial in examining the validity of this model. Ultimately, this approach should aid in developing targeted interventions for each group that will reduce the significant morbidity and mortality associated with bipolar disorder.

Prognostic Models in Bipolar Disorder: Can the Prediction of the Long-Term Clinical Course Rely on the Integration of Clinical and Molecular Data?

Prognostic models in bipolar disorder: where are we now? Bipolar disorder (BD) is a heritable psychiatric illness characterized by the recurrence of depressive and hypomanic or manic episodes alternating with intervals of partial or full recovery. BD presents substantial hetero geneity in symptomatology, illness course, pattern of psychiatric and medical comorbidities, and treatment response [1]. Given that the onset of BD is in the early 20s [2] and the risk of recurrence remains constant over the lifespan up to the age of 70 years or later [3], the identification of predictors of long-term outcome has relevant implications for clinical management, treatment selection and, possibly, the elaboration of preventive strategies. This might be achieved through the development and validation of prognostic models [4] that rely on the integration of multiple, evidence-based and temporally stable predictors with clinical and/or biological relevance (i.e., biomarkers) [5]. In recent years, there has been a mounting interest in the development of staging models of BD [6,7]. Based on the concept of neuroprogression (i.e., “the pathological reorganization of the central nervous system along the course of severe mental illness” [8]), and on prognostic research [9], these models provide a heuristic framework to develop therapeutic intervention strategies specific for subgroups of BD patients at different stages of the illness [7]. Once validated in prospective cohorts [7], staging models could lead to a stratified medicine approach in BD. However, at present we do not have validated prognostic models for BD. Yet, in clinical settings, diagnostic and therapeutic decisions, implying to a certain extent prognostic ones too, are routinely made on the basis of the phenomenology of symptoms presented by BD patients, particularly in the early phases of the illness. We refer in particular to the core features of BD, namely the periodicity of affective episodes (i.e., the recurrence and length of hypomanic, manic and depressive episodes) in the illness course, and the demographic and clinical characteristics at BD onset. Here we propose that this set of features may be suitable for integration and testing in prognostic models of BD. In addition, since specific molecular changes (particularly gene-expression alterations) appear to be associated with the euthymic, depressive or manic/hypomanic phases [10], we suggest that genetic and transcriptomic data should be included in these prognostic models. Finally, we propose that prognostic models should implement clinical and biological biomarkers identified by the investigation of treatment-responsive subgroups of BD patients.

Characteristics of autobiographical memories and prospective imagery across a spectrum of hypomanic personality traits

Evidence of a strong causal relationship between mental imagery and emotion has informed psychological conceptualisations of disordered positive mood states (i.e., mania). Holmes et al.'s cognitive model of bipolar disorder asserts a prominent role for intrusive and affect-laden positive imagery of the past and the future in the amplification and maintenance of positive mood and associated manic behaviours. The aims of the current study were two-fold: (1) to test aspects of this model in a non-clinical population sampled for hypomanic personality traits and (2) to examine the phenomenological characteristics of positive autobiographical memories and imagery of the future. Undergraduate students (N = 80) completed a battery of self-report questionnaires and rated their positive and negative memories and images of the future on a number of dimensions. We found significant positive correlations between hypomanic tendencies and the (1) everyday experience and use of mental imagery, (2) experience of intrusive mental imagery of future events, (3) emotional intensity and sensory detail of positive but not negative autobiographical memories. Results are discussed in the context of their theoretical and clinical implications, and directions for future research are considered.

The Quantum-Like Approach of Psychosomatic Phenomena in Application

The quantum-like approach of psychosomatic phenomena suggests an explanation of the correlations between mind and body in terms of quantum-like entanglement, that is, without appealing to any concept of psychophysical, efficient causality. This approach is developed within the Hilbert space formalism and its general consequences are drawn. It is first illustrated by a simple, qualitative model of the placebo effect which shows that representing psychosomatic states by entangled states can explain that purely psychological factors can produce a-causal changes of physiological parameters. Then, a dynamical, quantitative and predictive model of bipolar disorder which makes use of the unitarity of the temporal evolution of psychosomatic states due to biological and psychological rhythms is worked out. This model can explain some current observations, like for example the severe fluctuations in mood between depression and mania, and it can forecast the moment of shifting. In addition, it justifies the efficiency of chronotherapy on theoretical basis.

Multimodal assessments of the hippocampal formation in schizophrenia and bipolar disorder: evidences from neurobehavioral measures and functional and structural MRI.

A potential clinical and etiological overlap between schizophrenia (SZ) and bipolar disorder (BD) has long been a subject of discussion. Imaging studies imply functional and structural alterations of the hippocampus in both diseases. Thus, imaging this core memory region could provide insight into the pathophysiology of these disorders and the associated cognitive deficits. To examine possible shared alterations in the hippocampus, we conducted a multi-modal assessment, including functional and structural imaging as well as neurobehavioral measures of memory performance in BD and SZ patients compared with healthy controls. We assessed episodic memory performance, using tests of verbal and visual learning (HVLT, BVMT) in three groups of participants: BD patients (n = 21), SZ patients (n = 21) and matched (age, gender, education) healthy control subjects (n = 21). In addition, we examined hippocampal resting state functional connectivity, hippocampal volume using voxel-based morphometry (VBM) and fibre integrity of hippocampal connections using diffusion tensor imaging (DTI). We found memory deficits, changes in functional connectivity within the hippocampal network as well as volumetric reductions and altered white matter fibre integrity across patient groups in comparison with controls. However, SZ patients when directly compared with BD patients were more severely affected in several of the assessed parameters (verbal learning, left hippocampal volumes, mean diffusivity of bilateral cingulum and right uncinated fasciculus). The results of our study suggest a graded expression of verbal learning deficits accompanied by structural alterations within the hippocampus in BD patients and SZ patients, with SZ patients being more strongly affected. Our findings imply that these two disorders may share some common pathophysiological mechanisms. The results could thus help to further advance and integrate current pathophysiological models of SZ and BD.

Bipolar disorder: A neural network perspective on a disorder of emotion and motivation

Bipolar disorder (BD) is a severe, chronic disease with a heritability of 60-80%. BD is frequently misdiagnosed due to phenomenological overlap with other psychopathologies, an important issue that calls for the identification of biological and psychological vulnerability and disease markers. Altered structural and functional connectivity, mainly between limbic and prefrontal brain areas, have been proposed to underlie emotional and motivational dysregulation in BD and might represent relevant vulnerability and disease markers. In the present laboratory review we discuss functional and structural neuroimaging findings on emotional and motivational dysregulation from our research group in BD patients and healthy individuals at risk to develop BD. As a main result of our studies, we observed altered orbitofrontal and limbic activity and reduced connectivity between dorsal prefrontal and limbic brain regions, as well as reduced integrity of fiber tracts connecting prefrontal and subcortical brain structures in BD patients and high-risk individuals. Our results provide novel insights into pathophysiological mechanisms of bipolar disorder. The current laboratory review provides a specific view of our group on altered brain connectivity and underlying psychological processes in bipolar disorder based on our own work, integrating relevant findings from others. Thereby we attempt to advance neuropsychobiological models of BD.

Dysfunctional Cognitions among Offspring of Individuals with Bipolar Disorder

Individuals with bipolar disorder often endorse dysfunctional beliefs consistent with cognitive models of bipolar disorder (Beck, 1976; Mansell, 2007). The present study sought to assess whether young adult offspring of those with bipolar disorder would also endorse these beliefs, independent of their own mood episode history. Participants (N = 89) were young adult college students with a parent with bipolar disorder (n = 27), major depressive disorder (MDD; n = 30), or no mood disorder (n = 32). Semi-structured interviews of the offspring were used to assess diagnoses. Dysfunctional beliefs related to Beck and colleagues' (2006) and Mansell's (2007) cognitive models were assessed. Unlike offspring of parents with MDD or no mood disorder, those with a parent with bipolar disorder endorsed significantly more dysfunctional cognitions associated with extreme appraisal of mood states, even after controlling for their own mood diagnosis. Once affected by a bipolar or depressive disorder, offspring endorsed dysfunctional cognitions across measures. Dysfunctional cognitions, particularly those related to appraisals of mood states and their potential consequences, are evident in young adults with a parent who has bipolar disorder and may represent targets for psychotherapeutic intervention.

Behavioral addictions in euthymic patients with bipolar I disorder: a comparison to controls.

BackgroundBipolar disorder may be associated with a hypersensitive behavioral approach system and therefore to increased reward sensitivity. The objective of this study is to explore the interrelationships between bipolar disorder, behavioral addictions, and personality/temperament traits in a group of euthymic outpatients with bipolar I disorder and in a group of comparison subjects.MethodsFifty clinically stable patients and 50 comparison subjects matched for age, sex, and educational level were administered the Temperament and Character Inventory-140 and the Behavioral Addiction Scale.ResultsThe patient group scored significantly higher than comparison subjects for two benign behavioral addictions (music, shopping) as well as for smoking. Comparison subjects scored higher on two harmful behavioral addictions (drugs, alcohol). Novelty Seeking was positively correlated with harmful addictions, and Cooperativeness was negatively correlated with harmful addictions, in both groups.DiscussionThe hypersensitive behavioral approach system model of bipolar disorder would predict higher levels of various addictions in bipolar patients as compared to controls. In this study, this was true for three behavioral addictions, whereas controls showed higher levels of behavioral addiction to drugs and alcohol. This may be because the patients in this study are stable, have received considerable psychoeducation, and are relatively adherent to their medication recommendations. Temperament and character traits may play roles both as risk and protective factors regarding behavioral addictions.

Reward sensitivity and anger in euthymic bipolar disorder

According to the hypersensitive behavioral approach system (BAS) model of bipolar disorder (BP), hypersensitivity of the BAS is a trait that should be present even in the euthymic state. This would be expected to result in increased anger and reward sensitivity, both of which are related to the approach system. This study examined these predictions through the use of tasks that assess different aspects of the BAS: reward sensitivity, anger and impulsivity. These characteristics were assessed using the probabilistic classification task (PCT), ultimatum game (UG) and single key impulsivity paradigm (SKIP), respectively. Participants were euthymic adult bipolar disorder patients (BP; N=40) and healthy controls (HC; N=41). In the UG, all participants showed the standard pattern of rejecting overtly unfair offers and accepting clearly fair offers; however, BPs rejected more of the moderately unfair offers than did HCs. BP and HC participants did not differ on their ability to learn, but did show different patterns of learning from reward and punishment. Learning for reward and punishment were negatively correlated in the BP group, suggesting that individuals could learn well either from reward or punishment, but not both. No correlation was found between these forms of learning in the HC group. BP patients show signs of their disorder even in the euthymic state, as seen by the dysbalance between reward and punishment learning and their residual anger in the UG.

Rodent models for mania: practical approaches

The scarcity of good animal models for bipolar disorder (BPD) and especially for mania is repeatedly mentioned as one of the rate-limiting factors in the process of gaining a better understanding into its pathophysiology and of developing better treatments. Standard models of BPD have some value but usually represent only one facet of the disease and have partial validity. A number of new approaches for modeling BPD and specifically mania have been suggested in the last few years and can be combined to improve models. These approaches include targeted mutation models representing reverse translation, the identification of advantageous strains for components of the disorder, a search for the most homologous species to address specific human pathology, and the exploration of individual differences of response including the separation between susceptible and resilient animals. Additionally, recent efforts have identified and developed new tests to distinguish between "normal" and "BPD-like" animals including the different utilization of known tests and novel tests such as the female-urine-sniffing test and behavior pattern monitor analysis. Additional tests relating to further domains of BPD are still needed. An ideal model for BPD that will encompass the entire disease and be useful for every demand will probably not become available until we have a full understanding of the pathophysiology of the disorder. However, the current advances in modeling should lead to better comprehension of the disorder and therefore to the gradual development of increasingly improved models.

A multi-state model to improve the design of an automated system to monitor the activity patterns of patients with bipolar disorder

This paper describes the role of mathematical modelling in the design and evaluation of an automated system of wearable and environmental sensors called PAM (Personalised Ambient Monitoring) to monitor the activity patterns of patients with bipolar disorder (BD). The modelling work was part of an EPSRC-funded project, also involving biomedical engineers and computer scientists, to develop a prototype PAM system. BD is a chronic, disabling mental illness associated with recurrent severe episodes of mania and depression, interspersed with periods of remission. Early detection of the onset of an acute episode is crucial for effective treatment and control. The aim of PAM is to enable patients with BD to self-manage their condition, by identifying the person's normal ‘activity signature’ and thus automatically detecting tiny changes in behaviour patterns which could herald the possible onset of an acute episode. PAM then alerts the patient to take appropriate action in time to prevent further deterioration and possible hospitalisation. A disease state transition model for BD was developed, using data from the clinical literature, and then used stochastically in a Monte Carlo simulation to test a wide range of monitoring scenarios. The minimum best set of sensors suitable to detect the onset of acute episodes (of both mania and depression) is identified, and the performance of the PAM system evaluated for a range of personalised choices of sensors.

Staging and Neuroprogression in Bipolar Disorder

The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression.

Abnormal baseline brain activity in bipolar depression: A resting state functional magnetic resonance imaging study

We examined resting state brain activity in the depressive phase of bipolar disorder (BD) by measuring the amplitude of low-frequency fluctuations (ALFF) in the functional magnetic resonance imaging (fMRI) signal. Unlike functional connectivity, the ALFF approach reflects local properties in specific regions and provides direct information about impaired foci. Groups of 26 patients with BD depression and 26 gender-, age-, and education-matched healthy subjects participated in fMRI scans. We examined group differences in ALFF findings as well as correlations between clinical measurements and ALFF in the regions showing significant group differences. Our results showed that patients with BD depression had significantly increased ALFF in the left insula, the right caudate nucleus, the temporal gyrus, the bilateral inferior frontal gyrus, and the posterior lobe of the cerebellum. They also had decreased ALFF in the left postcentral gyrus, the left parahippocampal gyrus, and the cerebellum. Moderate negative correlations were found between the Hamilton Depression Rating Scale score and ALFF in the left insular cortex in the patient group. These results support a model of BD that involves dysfunction in the prefrontal–limbic networks and associated striatal systems. We also demonstrated the feasibility of ALFF as a technique to investigate persistent cerebral dysfunction in BD.

Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: A voxel-based meta-analysis of functional magnetic resonance imaging studies

Neuroimaging studies have consistently shown functional brain abnormalities in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD). However, the extent to which these two disorders are associated with similar or distinct neural changes remains unclear. We conducted a systematic review of functional magnetic resonance imaging studies comparing BD and MDD patients to healthy participants using facial affect processing paradigms. Relevant spatial coordinates from twenty original studies were subjected to quantitative Activation Likelihood Estimation meta-analyses based on 168 BD and 189 MDD patients and 344 healthy controls. We identified common and distinct patterns of neural engagement for BD and MDD within the facial affect processing network. Both disorders were associated with increased engagement of limbic regions. Diagnosis-specific differences were observed in cortical, thalamic and striatal regions. Decreased ventrolateral prefrontal cortical engagement was associated with BD while relative hypoactivation of the sensorimotor cortices was seen in MDD. Increased responsiveness in the thalamus and basal ganglia were associated with BD. These findings were modulated by stimulus valence. These data suggest that whereas limbic overactivation is reported consistently in patients with mood disorders, future research should consider the relevance of a wider network of regions in formulating conceptual models of BD and MDD.

Amphetamine-Induced Conditioned Place Preference and Modeling Domains of Bipolar Disorder

The development of appropriate models for bipolar disorder (BPD) is a critical step in the efforts to further study the underlying pathology of the disorder and develop novel treatments. One approach to achieve better models is to develop a battery of tests for the different behavioral domains of the disease. Previous work examined ways to model reward-related behaviors in the context of BPD with some success. Because disregulation of the reward system is one of the hallmarks of BPD the present study was designed to evaluate the possibility of using amphetamine-induced conditioned place preference (CPP) as an additional method to model the reward seeking behavioral domain in BPD. To evaluate the pharmacological (predictive) validity of amphetamine-i nduced CPP for BPD, the study examined the effects of the prototypic mood stabilizer lithium in a biased (black/white) amphetamine-induced CPP paradigm. To delineate generalized effects of drugs, animals were also tested for locomotor activity at the end of the CPP paradigm. As expected, amphetamine pairing resulted in the development of CPP, evidenced by an increase in the time spent in the paired compartment from pre-conditioning to post-conditioning sessions. Lithium had no effects on the expression of CPP or on locomotor activity. The results suggest that amphetamine-induced CPP lacks pharmacological validity and it is therefore not a good choice as a model for the reward-seeking domain of BPD. Additional tests should be explored as suitable modes for this important component of the disorder.

Neuroimaging-based markers of bipolar disorder: Evidence from two meta-analyses

Bipolar disorder (BD) is often misdiagnosed or tardily detected, leading to inadequate treatment and devastating consequences. The identification of objective biomarkers, such as functional and structural brain abnormalities of BD might improve diagnosis and help elucidate its pathophysiology. To identify neurobiological markers of BD, two meta-analyses, one of functional neuroimaging studies related to emotional processing and a second of structural whole-brain neuroimaging studies in BD were conducted in the present study. Conducting a literature search on studies published up to September 2009 we identified 28 studies that were eligible for the meta-analyses: 13 functional magnetic resonance imaging studies, related to emotional processing and 15 structural imaging studies using whole-brain voxel-based morphometry. Only studies comparing patients with bipolar disorder to healthy controls were considered. Data were extracted or converted to a single anatomical reference (Talairach space). The activation likelihood estimation technique was used to assess the voxel-wise correspondence of results between studies. In patients with BD, decreased activation and diminution of gray matter were identified in a cortical-cognitive brain network that has been associated with the regulation of emotions. By contrast, patients with BD exhibited increased activation in ventral limbic brain regions that mediate the experience of emotions and generation of emotional responses. The present study provides evidence for functional and anatomical alterations in BD in brain networks associated with the experience and regulation of emotions. These alterations support previously proposed neurobiological models of BD and might represent valid neurobiological markers of the disorder. The specificity of these results to unipolar depression remains to be explored.

P01-216-Frontopolar cortical inefficiency underpins both “hot” and “cold” cognitive dysfunction in bipolar disorder

IntroductionEmotional dysregulation in Bipolar Disorder (BD) is thought to be linked with prefrontal cortex (PFC) dysfunction associated with cognitive control coupled with increased or aberrant activation within regions associated with emotional processing.ObjectivesTo determine the common and distinct patterns of functional brain abnormalities during affective and emotionally neutral cognitive processing in BD.AimsCurrent models of BD emphasise the relationship between mood dysregulation and fronto-limbic dysfunction during affective or “hot” processing. However, they do not account for deficits in emotionally neutral or “cold” tasks of memory and executive function which are also present in BD. Therefore the purpose of this study was to examine the neural correlates of affective decision making and working memory in BD.MethodsParticipants were 36 euthymic BD patients and 37 healthy controls matched for age, gender and IQ. FMRI was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task as respective exemplars of “hot” and “cold” processing.ResultsThere were no group differences in performance on either task. BD patients demonstrated a pattern of inefficient engagement within the ventral frontopolar PFC in both the IGT and n-back. These abnormalities showed task-related segregation along the medial-lateral dimension for “hot” and “cold” processing respectively. Patients also showed greater activation in the anterior cingulate cortex during the IGT and in the insula during the n-back. These regions are thought to respond to markers of autonomic arousal.ConclusionsThese data demonstrate ventral frontopolar PFC inefficiency as a shared abnormality underpinning both “hot” and “cold” processing deficits in BD.

Memantine reduces mania-like symptoms in animal models

Memantine, a selective antagonist of the N-methyl-D-aspartate receptor, is approved for the treatment of moderate to severe Alzheimer's disease. Ion dysregulation is thought to be involved in the pathophysiology of bipolar illness, suggesting that memantine may be effective in treating bipolar manic and/or depressive episodes. We utilized two preclinical models of mania that mimic pathophysiologic changes seen in bipolar illness to examine the potential efficacy of memantine in the treatment of this disorder. Locomotor hyperactivity of male Sprague–Dawley rats in an open field was induced with intracerebroventricular (ICV) administration of 10−3 M ouabain. Memantine (2.5, 5 or 7.5mg/kg), lithium (6.75mEq/kg), or vehicle were administered acutely via intraperitoneal injection immediately prior to ouabain, then chronically for 7days (oral memantine 20, 30, and 40mg/kg/day in water; lithium 2.4g/kg food). In a second model of bipolar disorder, cycling between population spikes and epileptiform bursts was investigated in rat hippocampal slices treated with ouabain (3.3μM) alone or in combination with memantine (0.5, 1.0, and 5.0μM). Ouabain-induced hyperlocomotion was normalized with acute and chronic lithium and chronic use of memantine. Memantine delayed the onset of ouabain-induced-cycling in hippocampal slices. Memantine may have antimanic properties.

The mania-like exploratory profile in genetic dopamine transporter mouse models is diminished in a familiar environment and reinstated by subthreshold psychostimulant administration

Bipolar Disorder (BD) is a neuropsychiatric disorder characterized by symptoms ranging from a hyperactive manic state to depression, with periods of relative stability, known as euthymia, in between. Although prognosis for BD sufferers remains poor, treatment development has been restricted due to a paucity of validated animal models. Moreover, most models focus on the manic state of BD with little done to characterize the longitudinal behavior of these models. We recently presented two dopamine transporter (DAT) mouse models of BD mania: genetic (DAT knockdown; KD, mice) and pharmacological (the selective DAT inhibitor GBR 12909). These models exhibit an exploratory profile consistent with the quantified exploratory profile of manic BD patients observed in the cross-species translational test, the Behavioral Pattern Monitor (BPM). To further explore the suitability of these models, we examined the effects of reduced DAT function on the behavior of mice tested after familiarization to the BPM environment. Testing with 16 mg/kg GBR 12909 in familiarized mice resulted in a consistent mania-like profile. In contrast, the mania-like profile of DAT KD mice disappears in a familiar environment, with partial reinstatement elicited by the introduction of novelty. In addition, we found that a subthreshold dose of GBR 12909 (9 mg/kg) reinstated the mania-like profile in DAT KD mice without affecting wildtype behavior. Thus, the mania-like exploratory profile of DAT KD mice is reduced in a familiar environment, partially reinstated with novelty, but is fully restored when administered a stimulant that is ineffective in wildtype mice. These mice may provide a model of BD from mania to euthymia and back again with stimulant treatment. Acute blockade of the DAT by GBR 12909 however, may provide a consistent model for BD mania.

Proteomics analysis of new animal models of bipolar disorder

Proteomics analysis of new animal models of bipolar disorder