A longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment

doi:10.1016/j.jad.2013.04.020

Journal of Affective Disorders

Volume 150, Issue 2, 5 September 2013, Pages 629-633

https://doi.org/10.1016/j.jad.2013.04.020 Get rights and content

Abstract

In order to assess the association between therapeutic response to lithium treatment and fronto-limbic brain structures’ volumes in bipolar I patients (BPI) 24 BPI and 11 healthy comparisons underwent MRI scans at baseline and 4 weeks later. The BPIs received lithium during the 4 week period with a goal of achieving therapeutic blood levels of >0.5 mEq/L (mean level 0.67 mEq/L). Mood symptoms were rated with the Hamilton Depression and the Young Mania Rating Scales at baseline and after 4 weeks, and response was defined as >50% decrease on either scale. Hippocampus, amygdala, prefrontal (PFC), dorsolateral prefrontal (DLPFC), and anterior cingulate cortex (ACC) volumes were obtained by Freesurfer image analysis suite. According to baseline symptoms and treatment response, patients were assigned to three groups: euthymics (n=6), responders (n=12) and non-responders (n=6). Taken over both time periods, non-responders had smaller right amygdala than healthy comparisons and euthymic BPI (p=0.035 and p=0.003, respectively). When baseline and after treatment volumes were compared, there was a significant enlargement in left PFC and left DLPFC in BPI who responded to treatment (p=0.002 and p=0.006, respectively). Left hippocampus and right ACC volumes decreased in non-responders (p=0.02 and p=0.0001, respectively). According to the findings decreased left hippocampus and right ACC volumes may be markers of non-response to lithium amongst BPI. Smaller right amygdala may reflect symptomatic remission and be a marker of treatment non-response. Increases in left PFC and left DLPFC as a result of lithium treatment may relate to lithium's neurotrophic effects.

Introduction

Bipolar type I (BPI) disorder has been associated with regional changes in brain volume (Beyer and Krishnan, 2002). There are available treatments that help a substantial proportion of these patients, but their exact mechanisms of action are not yet clear. The effect of psychotropics on regional brain volumes of patients with BD is a major research focus in the quest to reveal the mechanisms of action of these drugs. Several studies have evaluated lithium, one of the mainstay treatments in BD, and reported its effect on specific brain regions (Monkul et al., 2007, Moore et al., 2009). Previous findings showed fronto-limbic volumetric increases during lithium treatment in patients with BD (Hallahan et al., 2011). However, no longitudinal study comparing healthy subjects and BD patients has so far been reported. Here we report changes in specific fronto-limbic regional brain volumes in BD subjects undergoing lithium treatment compared to untreated healthy comparison subjects.

Section snippets

Methods

Thirty BPI patients, diagnosed according to DSM-IV-TR criteria, and 11 healthy comparison subjects were enrolled. The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders Axis I (SCID I) was applied to patients in order to confirm the diagnosis of BPI. Subjects were right-handed according to the Edinburgh Inventory (Oldfield, 1971) and drug-free for at least 2 weeks before the study, and they had no comorbid psychiatric disorders, no severe systemic

Results

There were no significant differences between groups on age and sex (t=−0.808, p=0.434 and χ²=0.012, p=0.913, respectively). Some of the clinical variables are presented in Table 1. According to the baseline symptoms and the response definition described above, six patients were classified as euthymics, 12 were responders and six were non-responders after 4 weeks of lithium treatment. All patients, who were classified as euthymics at baseline, remained euthymic throughout the study.

Taken over

Discussion

We observed both disease-related between group differences and treatment-related within group changes in regional brain volumes of bipolar patients during lithium treatment.

Role of funding source

This study is partly supported by MH 68766 and RR 20571.

Conflict of interest

Dr. Soares received research grants from Repligen, GSK, Merck, BMS and Forrest, and served as consultant/speaker for Pfizer and Abbott. Dr. Hatch served as a paid consultant to the Biomedical Development Corporation, the Academy for Academic Leadership, and The University of Texas Health Science Center at Houston and his work was funded by the NIH. Dr. Selek received travel grant from Society of Biological Psychiatry. The other authors declare no conflict of interest.

Acknowledgments

This study is partly supported by MH 68766 and RR 20571.

References (23)

C.M. Adler et al.
Voxel-based study of structural changes in first-episode patients with bipolar disorder
Biological Psychiatry
(2007)
J.R.C. Almeida et al.
Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder: significant effects of gender and trait anxiety
Psychiatry Research: Neuroimaging
(2009)
M. Atmaca et al.
Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine
Journal of Psychiatric Research
(2007)
B. Hallahan et al.
Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data
Biological Psychiatry
(2011)
X. Han et al.
Reliability of MRI-derived measurements of human cerebral cortical thickness: the effects of field strength, scanner upgrade and manufacturer
Neuroimage
(2006)
M.P. López-Larson et al.
Regional prefrontal gray and white matter abnormalities in bipolar disorder
Biological Psychiatry
(2002)
R.S. McIntyre et al.
Measurable outcomes in psychiatric disorders: remission as a marker of wellness
Clinical Therapeutics
(2006)
E.S. Monkul et al.
Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study
Neuroscience Letters
(2007)
R.C. Oldfield
The assessment and analysis of handedness: the Edinburgh inventory
Neuropsychologia
(1971)
R. Sassi et al.
Reduced left anterior cingulate volumes in untreated bipolar patients
Biological Psychiatry
(2004)

V. Sharma et al.

An MRI study of subgenual prefrontal cortex in patients with familial and non-familial bipolar I disorder

Journal of Affective Disorders

(2003)

Cited by (32)

Cortical thickness abnormalities in patients with bipolar disorder: A systematic review and meta-analysis
2022, Journal of Affective Disorders
Citation Excerpt :
Two studies indicate that comorbidities may also alter brain phenotype in BD patients: one found the interactions between the diagnoses of BD and attention-deficit hyperactivity disorder (ADHD) diagnoses have an effect on CT mainly in the left subgenual cingulate and right OFC (Hegarty et al., 2012); another study reported the effects of premenstrual dysphoric disorder (PMDD) on CT in the left superior temporal gyri (Syan et al., 2018). Correlation results suggest that lithium may have an effect of increasing CT (Abe et al., 2016; Abramovic et al., 2016; Hatton et al., 2013), in line with previous reports that lithium is associated with normalization of frontal CT (Selek et al., 2013; Bearden et al., 2007). Additionally, some studies demonstrated that CT is related to age of onset (Niu et al., 2017; Oertel-Knoechel et al., 2015), illness duration (Lyoo et al., 2006; Foland-Ross et al., 2011), number of episodes (Niu et al., 2017) and disease severity (Lan et al., 2014; Maller et al., 2014; Qiu et al., 2013).
An increasing number of neuroimaging studies report alterations of cortical thickness (CT) related to the neuropathology of bipolar disorder (BD). We provide here a whole-brain vertex-wise meta-analysis, which may help improve the spatial precision of these identifications.
A comprehensive meta-analysis was performed to investigate the differences in CT between patients with BD and healthy controls (HCs) by using a newly developed mask for CT analysis in seed-based d mapping (SDM) meta-analytic software. We used meta-regression to explore the effects of demographics and clinical characteristics on CT. This meta-review was conducted in accordance with PRISMA guideline.
We identified 21 studies meeting criteria for the systematic review, of which 11 were eligible for meta-analysis. The meta-analysis comprising 649 BD patients and 818 HCs showed significant cortical thinning in the left insula extending to left Rolandic operculum and Heschl gyrus, the orbital part of left inferior frontal gyrus (IFG), the medial part of left superior frontal gyrus (SFG) as well as bilateral anterior cingulate cortex (ACC) in BD. In meta-regression analyses, mean patient age was negatively correlated with reduced CT in the left insula.
All enrolled studies were cross-sectional; we could not explore the potential effects of medication and mood states due to the limited data.
Our results suggest that BD patients have significantly thinner frontoinsular cortex than HCs, and the results may be helpful in revealing specific neuroimaging biomarkers of BD patients.
Biomarkers in bipolar disorder: An overview
2022, Biomarkers in Bipolar Disorders
To date, no objective biological measure is available to support clinical decision-making in the management of bipolar disorder (BD). However, given the complexity and heterogeneity of BD in terms of clinical presentation, treatment response and illness course, clinicians would benefit from the identification of objective biological markers (or biomarkers) to improve diagnosis accuracy and guide treatment selection in a more personalized way. Major technical advances have helped to gain knowledge on the mechanisms associated with susceptibility to BD, disease expression, and treatment response, which are allowing to identify an increasing number of promising candidate biomarkers for BD. Along this chapter we will provide an overview of the field of biomarkers in BD, from general concepts and potential uses of biomarkers in BD, to the limitations for implementing current candidate biomarkers in clinical practice and the future directions of the biomarker field in BD.
Accumulation of Lithium in the Hippocampus of Patients With Bipolar Disorder: A Lithium-7 Magnetic Resonance Imaging Study at 7 Tesla
2020, Biological Psychiatry
Lithium (Li) is a first-line treatment for bipolar disorder (BD). To study its cerebral distribution and association with plasma concentrations, we used ⁷Li magnetic resonance imaging at 7T in euthymic patients with BD treated with Li carbonate for at least 2 years.
Three-dimensional ⁷Li magnetic resonance imaging scans (N = 21) were acquired with an ultra-short echo-time sequence using a non-Cartesian k-space sampling scheme. Lithium concentrations ([Li]) were estimated using a phantom replacement approach accounting for differential T₁ and T₂ relaxation effects. In addition to the determination of mean regional [Li] from 7 broad anatomical areas, voxel- and parcellation-based group analyses were conducted for the first time for ⁷Li magnetic resonance imaging.
Using unprecedented spatial sensitivity and specificity, we were able to confirm the heterogeneity of the brain Li distribution and its interindividual variability, as well as the strong correlation between plasma and average brain [Li] ([Li]_B ≈ 0.40 × [Li]_P, R = .74). Remarkably, our statistical analysis led to the identification of a well-defined and significant cluster corresponding closely to the left hippocampus for which high Li content was displayed consistently across our cohort.
This observation could be of interest considering 1) the major role of the hippocampus in emotion processing and regulation, 2) the consistent atrophy of the hippocampus in untreated patients with BD, and 3) the normalization effect of Li on gray matter volumes. This study paves the way for the elucidation of the relationship between Li cerebral distribution and its therapeutic response, notably in newly diagnosed patients with BD.
A proof of concept machine learning analysis using multimodal neuroimaging and neurocognitive measures as predictive biomarker in bipolar disorder
2020, Asian Journal of Psychiatry
Concomitant use of complementary, multimodal imaging measures and neurocognitive measures is reported to have higher accuracy as a biomarker in Alzheimer’s dementia. However, such an approach has not been examined to differentiate healthy individuals from Bipolar disorder. In this study, we examined the utility of support vector machine (SVM) technique to differentiate bipolar disorder patients and healthy using structural, functional and diffusion tensor images of brain and neurocognitive measures.
30 patients with Bipolar disorder-I and 30 age, sex matched individuals participated in the study. Structural MRI, resting state functional MRI and diffusion tensor images were obtained using a 1.5 T scanner. All participants were administered neuropsychological tests to measure executive functions. SVM, a supervised machine learning technique was applied to differentiate patients and healthy individuals with k-fold cross validation over 10 trials.
The composite marker consisting of both neuroimaging and neuropsychological measures, had an accuracy of 87.60 %, sensitivity of 82.3 % and specificity of 92.7 %. The performance of composite marker was better compared to that of individual markers on classificatory.
We were able to achieve a high accuracy for machine learning technique in distinguishing BD from HV using a combination of multimodal neuroimaging and neurocognitive measures. Findings of this proof of concept study, if replicated in larger samples, could have potential clinical applications.
The mechanisms of action of lithium in bipolar disorder
2020, Neurobiology of Bipolar Disorder: Road to Novel Therapeutics
Lithium has mood stabilization, neuroprotective, and antisuicidal effects. However, the mechanism of lithium remains unclear. The genetic basis for lithium treatment response in bipolar disorder is likely through upregulating and/or downregulating specific genes in neurons and other cells. The regulation of gene expression is believed through intracellular pathways in which calcium level and glycogen synthase kinase-3 are key elements. Modulation of enzymes and proteins of lithium can affect neuronal shapes and dendritic spines, release of neurotransmitters, production of cytokines, regulation of circadian rhythm, and reduction of oxidative burden. These functions are essential for cell survival, neuroplasticity, and prevention of cell death. However, most of these benefits more likely occur in lithium responders. Changes in brain volumes and neuronal connectivity and functional differences between lithium-treated and nonlithium-treated patients and between lithium responders and lithium nonresponders support the neurotrophic and neuroprotective effects of lithium.
Lithium, Stress, and Resilience in Bipolar Disorder: Deciphering this key homeostatic synaptic plasticity regulator
2018, Journal of Affective Disorders
Citation Excerpt :
A recent preliminary longitudinal study evaluating fronto-limbic structures in BD subjects treated with lithium for 4-weeks showed a decrease in the left hippocampus and right ACC volumes associated with non-response to lithium. In the same study, an increase in left PFC was associated with favorable response to lithium (Selek et al., 2013). Longer lithium exposure was also associated with improved white matter integrity in older adults with BD (Gildengers et al., 2015).
Lithium is the lightest metal and the only mood stabilizer that has been used for over half a century for the treatment of bipolar disorder (BD). As a small ion, lithium is omnipresent, and consequently, its molecular mechanisms and targets are widespread. Currently, lithium is a crucial pharmacotherapy for the treatment of acute mood episodes, prophylactic therapy, and suicide prevention in BD. Besides, lithium blood level is the most widely used biomarker in clinical psychiatry. The concept of stress in BD characterizes short- and long-term deleterious effects at multiple levels (from genes to behaviors) and the ability to establish homeostatic regulatory mechanisms to either prevent or reverse these effects. Within this concept, lithium has consistently shown anti-stress effects, by normalizing components across several levels associated with BD-induced impairments in cellular resilience and plasticity.
A literature search for biomarkers associated with lithium effects at multiple targets, with a particular focus on those related to clinical outcomes was performed. An extensive search of the published literature using PubMed, Medline and Google Scholar was performed. Example search terms included lithium, plasticity, stress, efficacy, and neuroimaging. Articles determined by the author to focus on lithium's impact on neural plasticity markers (central and periphery) and clinical outcomes were examined in greater depth. Relevant papers were evaluated, selected and included in this review.
Lithium induces neurotrophic and neuroprotective effects in a wide range of preclinical and translational models. Lithium's neurotrophic effects are related to the enhancement of cellular proliferation, differentiation, growth, and regeneration, whereas its neuroprotective effects limit the progression of neuronal atrophy or cell death following the onset of BD. Lithium's neurotrophic and neuroprotective effects seem most pronounced in the presence of pathology, which again supports its pivotal role as an active homeostatic regulator.
Few studies associated with clinical outcomes. Due to space limitations, the author was unable to detail all findings, in special those originated from preclinical studies.
These results support a potential role for biomarkers involved in neuroprotection and activation of plasticity pathways in lithium's clinical response. Evidence supporting this model comes from results evaluating macroscopic and microscopic brain structure as well neurochemical findings in vivo from cellular to sub-synaptic (molecules and intracellular signaling) compartments using central and peripheral biomarkers. Challenges to precisely decipher lithium's biological mechanisms involved in its therapeutic profile include the complex nature of the illness and clinical subtypes, family history and comorbid conditions. In the context of personalized medicine, it is necessary to validate predictive biomarkers of response to lithium by designing longitudinal clinical studies during mood episodes and associated clinical dimensions in BD.

View all citing articles on Scopus

View full text

Preliminary communicationA longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Role of funding source

Conflict of interest

Acknowledgments

Biological Psychiatry

Psychiatry Research: Neuroimaging

Journal of Psychiatric Research

Biological Psychiatry

Neuroimage

Biological Psychiatry

Clinical Therapeutics

Neuroscience Letters

Neuropsychologia

Biological Psychiatry

Journal of Affective Disorders

Preliminary communication
A longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment