Na+, K+-ATPase α Isoforms and Endogenous Cardiac Steroids in Prefrontal Cortex of Bipolar Patients and Controls

Bipolar disorder is a chronic multifactorial psychiatric illness that affects the mood, cognition, and functioning of about 1–2% of the world’s population. Its biological basis is unknown, and its treatment is unsatisfactory. The α1, α2, and α3 isoforms of the Na+, K+-ATPase, an essential membrane transporter, are vital for neuronal and glial function. The enzyme and its regulators, endogenous cardiac steroids like ouabain and marinobufagenin, are implicated in neuropsychiatric disorders, bipolar disorder in particular. Here, we address the hypothesis that the α isoforms of the Na+, K+-ATPase and its regulators are altered in the prefrontal cortex of bipolar disease patients. The α isoforms were determined by Western blot and ouabain and marinobufagenin by specific and sensitive immunoassays. We found that the α2 and α3 isoforms were significantly higher and marinobufagenin levels were significantly lower in the prefrontal cortex of the bipolar disease patients compared with those in the control. A positive correlation was found between the levels of the three α isoforms in all samples and between the α1 isoform and ouabain levels in the controls. These results are in accordance with the notion that the Na+, K+-ATPase-endogenous cardiac steroids system is involved in bipolar disease and suggest that it may be used as a target for drug development.

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Brain functional changes in first-degree relatives of patients with bipolar disorder: evidence for default mode network dysfunction

Psychological Medicine ◽

10.1017/s0033291716001148 ◽

2016 ◽

Vol 46 (12) ◽

pp. 2513-2521 ◽

Cited By ~ 7

Author(s):

S. Alonso-Lana ◽

M. Valentí ◽

A. Romaguera ◽

C. Sarri ◽

S. Sarró ◽

...

Keyword(s):

Bipolar Disorder ◽

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Default Mode Network ◽

Healthy Controls ◽

Whole Brain ◽

Default Mode ◽

Functional Changes ◽

Significant Difference ◽

Bipolar Patients

BackgroundRelatively few studies have investigated whether relatives of patients with bipolar disorder show brain functional changes, and these have focused on activation changes. Failure of de-activation during cognitive task performance is also seen in the disorder and may have trait-like characteristics since it has been found in euthymia.MethodA total of 20 euthymic patients with bipolar disorder, 20 of their unaffected siblings and 40 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance (ANOVA) was fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant difference among the groups were used as regions of interest to compare mean activations/de-activations between them.ResultsA single cluster of significant difference among the three groups was found in the whole-brain ANOVA. This was located in the medial prefrontal cortex, a region of task-related de-activation in the healthy controls. Both the patients and their siblings showed significantly reduced de-activation compared with the healthy controls in this region, but the failure was less marked in the relatives.ConclusionsFailure to de-activate the medial prefrontal cortex in both euthymic bipolar patients and their unaffected siblings adds to evidence for default mode network dysfunction in the disorder, and suggests that it may act as a trait marker.

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Dorsolateral prefrontal N-acetyl-aspartate concentration in male patients with chronic schizophrenia and with chronic bipolar disorder

European Psychiatry ◽

10.1016/j.eurpsy.2007.07.006 ◽

2007 ◽

Vol 22 (8) ◽

pp. 505-512 ◽

Cited By ~ 43

Author(s):

V. Molina ◽

J. Sánchez ◽

J. Sanz ◽

S. Reig ◽

C. Benito ◽

...

Keyword(s):

Bipolar Disorder ◽

Prefrontal Cortex ◽

Chronic Schizophrenia ◽

The Other ◽

Resonance Spectroscopy ◽

Dorsolateral Prefrontal ◽

Prefrontal Region ◽

Healthy Control ◽

Male Patients ◽

Bipolar Patients

AbstractObjectivesA study of N-acetyl-aspartate (NAA) can provide data of interest about cortical alterations in psychotic illnesses. Although a decreased NAA level in the cerebral cortex is a replicated finding in chronic schizophrenia, the data are less consistent for bipolar disease. On the other hand, it is likely that NAA values in schizophrenia may differ in men and women.MethodsWe used proton magnetic resonance spectroscopy (1H MRS) to examine NAA levels in the prefrontal cortex in two groups of male patients, one with schizophrenia (n = 11) and the other with bipolar disorder (n = 13) of similar duration, and compared them to a sample of healthy control males (n = 10). Additionally, we compared the degree of structural deviations from normal volumes of gray matter (GM) and cerebrospinal fluid (CSF) in the dorsolateral prefrontal cortex.ResultsCompared to controls, schizophrenia and bipolar patients presented decreased NAA to creatine ratios, while only the schizophrenia group showed an increase in CSF in the dorsolateral prefrontal region. There were no differences in choline to creatine ratios among the groups.ConclusionsThese data suggest that the decrease in NAA in the prefrontal region may be similar in schizophrenia and bipolar disorder, at least in the chronic state. However, cortical CSF may be markedly increased in schizophrenia patients.

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Anatomical MRI Abnormalities in Bipolar Disorder: Do They Exist and Do They Progress?

Australian & New Zealand Journal of Psychiatry ◽

10.1080/j.1440-1614.2005.01571.x ◽

2005 ◽

Vol 39 (4) ◽

pp. 222-226 ◽

Cited By ~ 3

Author(s):

E. Serap Monkul ◽

Gin S. Malhi ◽

Jair C. Soares

Keyword(s):

Bipolar Disorder ◽

Prefrontal Cortex ◽

Brain Imaging ◽

Grey Matter ◽

Brain Structures ◽

Brain Regions ◽

Anterior Cingulate ◽

Imaging Studies ◽

Neuroprotective Effects ◽

Bipolar Patients

Aim: Morphometric brain imaging studies have revealed regional brain abnormalities in patients with bipolar disorder, which may play a role in illness pathophysiology. It is not known whether such changes are of neurodevelopmental, neurodegenerative, or combined origin. We reviewed the anatomical brain imaging literature in bipolar disorder, in an attempt to determine whether there is evidence to suggest that such abnormalities are progressive. Method: Literature searches were conducted using MEDLINE for the period from 1966 to June 2004, using specific key words; bipolar disorder and the names of the individual brain structures. Papers were selected according to their salience in relation to whether reported changes are progressive. Results: Available findings suggest reduced grey matter in prefrontal brain regions such as anterior cingulate and subgenual prefrontal cortex, and abnormalities in amygdala size in adult and paediatric bipolar patients. White matter hyperintensities, which are non-specific abnormalities, are also common in bipolar patients. Bipolar patients may lose more brain grey matter by ageing. There is also evidence for impaired myelination of the corpus callosum in bipolar disorder. Lithium may reverse or prevent grey matter prefrontal cortex abnormalities in bipolar patients by its neuroprotective effects. Conclusions: Both early developmental and later neurodegenerative processes may play a role in the pathophysiology of bipolar disorder. Findings from anatomical brain imaging studies implicate key regions involved in mood regulation. The evidence for the progressive nature of this illness is tentative, as no follow-up study with bipolar patients has been reported to this date.

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A functional MRI study of verbal fluency in adults with bipolar disorder and their unaffected relatives

Psychological Medicine ◽

10.1017/s0033291710000127 ◽

2010 ◽

Vol 40 (12) ◽

pp. 2025-2035 ◽

Cited By ~ 40

Author(s):

M. P. G. Allin ◽

N. Marshall ◽

K. Schulze ◽

M. Walshe ◽

M.-H. Hall ◽

...

Keyword(s):

Bipolar Disorder ◽

Prefrontal Cortex ◽

Verbal Fluency ◽

Retrosplenial Cortex ◽

Control Group ◽

Verbal Fluency Task ◽

Easy Condition ◽

Bipolar Patients ◽

Mri Study ◽

Fluency Task

BackgroundIndividuals with a history of bipolar disorder demonstrate abnormalities of executive function, even during euthymia. The neural architecture underlying this and its relationship with genetic susceptibility for illness remain unclear.MethodWe assessed 18 remitted individuals with bipolar disorder, 19 of their unaffected first degree relatives and 19 healthy controls using functional magnetic resonance imaging (fMRI) and a paced verbal fluency task with two levels of difficulty.ResultsBipolar patients made significantly more errors in the easy level of the verbal fluency task than their relatives or controls. Analysis of variance of fMRI data demonstrated a significant main effect of group in a large cluster including retrosplenial cortex and adjacent precuneate cortex (x=7, y=−56, x=15). All three groups showed deactivation in these areas during task performance relative to a neutral or rest condition. Group differences comprised a lesser amount of deactivation in unaffected relatives compared with controls in the easy condition [F(2, 55)=3.42, p=0.04] and in unaffected relatives compared with bipolar patients in the hard condition [F(2, 55)=4.34, p=0.018]. Comparison with the control group indicated that both bipolar patients and their relatives showed similar deficits of deactivation in retrosplenial cortex and reduced activation of left prefrontal cortex.ConclusionsBipolar disorder may be associated with an inherited abnormality of a neural network incorporating left prefrontal cortex and bilateral retrosplenial cortex.

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Patients’ adherence to smartphone apps in the management of bipolar disorder: a systematic review

International Journal of Bipolar Disorders ◽

10.1186/s40345-021-00224-6 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Marie-Camille Patoz ◽

Diego Hidalgo-Mazzei ◽

Bruno Pereira ◽

Olivier Blanc ◽

Ingrid de Chazeron ◽

...

Keyword(s):

Systematic Review ◽

Bipolar Disorder ◽

Mobile Health ◽

Smartphone Apps ◽

Exclusion Criteria ◽

Future Studies ◽

Health Apps ◽

Definition Of ◽

Bipolar Patients ◽

Digital Or

Abstract Background Despite an increasing number of available mental health apps in the bipolar disorder field, these tools remain scarcely implemented in everyday practice and are quickly discontinued by patients after downloading. The aim of this study is to explore adherence characteristics of bipolar disorder patients to dedicated smartphone interventions in research studies. Methods A systematic review following PRISMA guidelines was conducted. Three databases (EMBASE, PsychInfo and MEDLINE) were searched using the following keywords: "bipolar disorder" or "mood disorder" or “bipolar” combined with “digital” or “mobile” or “phone” or “smartphone” or “mHealth” or “ehealth” or "mobile health" or “app” or “mobile-health”. Results Thirteen articles remained in the review after exclusion criteria were applied. Of the 118 eligible studies, 39 did not provide adherence characteristics. Among the selected papers, study length, sample size and definition of measures of adherence were strongly heterogeneous. Activity rates ranged from 58 to 91.6%. Conclusion The adherence of bipolar patients to apps is understudied. Standardised measures of adherence should be defined and systematically evaluated in future studies dedicated to these tools.

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Hippocampal regenerative medicine: neurogenic implications for addiction and mental disorders

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00587-x ◽

2021 ◽

Author(s):

Lee Peyton ◽

Alfredo Oliveros ◽

Doo-Sup Choi ◽

Mi-Hyeon Jang

Keyword(s):

Decision Making ◽

Prefrontal Cortex ◽

Executive Function ◽

General Population ◽

Mental Disorders ◽

Psychiatric Illness ◽

Neural Circuitry ◽

Brain Regions ◽

Neuropsychiatric Disease ◽

Motivated Behavior

AbstractPsychiatric illness is a prevalent and highly debilitating disorder, and more than 50% of the general population in both middle- and high-income countries experience at least one psychiatric disorder at some point in their lives. As we continue to learn how pervasive psychiatric episodes are in society, we must acknowledge that psychiatric disorders are not solely relegated to a small group of predisposed individuals but rather occur in significant portions of all societal groups. Several distinct brain regions have been implicated in neuropsychiatric disease. These brain regions include corticolimbic structures, which regulate executive function and decision making (e.g., the prefrontal cortex), as well as striatal subregions known to control motivated behavior under normal and stressful conditions. Importantly, the corticolimbic neural circuitry includes the hippocampus, a critical brain structure that sends projections to both the cortex and striatum to coordinate learning, memory, and mood. In this review, we will discuss past and recent discoveries of how neurobiological processes in the hippocampus and corticolimbic structures work in concert to control executive function, memory, and mood in the context of mental disorders.

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Response Processes to Looming Appetitive and Aversive Cues in Euthymic Bipolar Patients and Their First-Degree Relatives: An Exploratory Study

Indian Journal of Psychological Medicine ◽

10.1177/0253717620975285 ◽

2020 ◽

pp. 025371762097528

Author(s):

Velprashanth Venkatesan ◽

Christoday R J Khess ◽

Umesh Shreekantiah ◽

Nishant Goyal ◽

K. K. Kshitiz

Keyword(s):

Bipolar Disorder ◽

Healthy Controls ◽

Sensitivity To Reward ◽

Bipolar Group ◽

First Degree Relatives ◽

Vulnerability Model ◽

Increased Sensitivity ◽

Appetitive Cues ◽

Spectrum Disorders ◽

Bipolar Patients

Background: Patients with bipolar disorder demonstrate increased sensitivity to appetitive/rewarding stimuli even during euthymia. On presentation of arousing pictures, they show a peculiar response, suggesting heightened vigilance. While responding to looming arousing cues, studies show subjects with anxiety spectrum disorders exhibit increased reaction time (RT), explained by the “looming-vulnerability model.” This study aimed to investigate the responses to looming arousing cues in euthymic bipolar patients and their first-degree relatives, as compared to healthy controls. Method: A looming appetitive and aversive cue paradigm was designed for assessing the RT of patients to process appetitive and aversive cues. The behavioral inhibition/activation and sensitivity to reward/punishment amongst the groups were also assessed. Results: The bipolar group showed significantly longer RT to process appetitive cues irrespective of the looming condition. Aversive cues elicited significantly longer RT in both the bipolar group and in first-degree relatives, but only when presented with the looming condition. Significant looming bias was elicited in the bipolar group which suggested a particular cognitive style to looming cues. A composite measure of RT along with sensitivity to reward/punishment distinguishes the bipolar group and their first-degree relatives from the healthy controls. Conclusion: The looming vulnerability model may provide important insights for future exploration of cognitive endophenotypes in bipolar disorder.

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Involvement of the nuclear factor-κB transcriptional complex in prefrontal cortex immune activation in bipolar disorder

Translational Psychiatry ◽

10.1038/s41398-020-01092-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kaitlyn M. Roman ◽

Aaron K. Jenkins ◽

David A. Lewis ◽

David W. Volk

Keyword(s):

Bipolar Disorder ◽

Prefrontal Cortex ◽

Immune Activation ◽

Family Members ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Transcript Levels ◽

Immune Related Genes ◽

Transcriptional Complex ◽

Shared Risk

AbstractBipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.

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