David Cousins

The role of dopamine in bipolar disorder

OBJECTIVE Despite effective pharmacological treatments for bipolar disorder, we still lack a comprehensive pathophysiological model of the illness. Recent neurobiological research has implicated a number of key brain regions and neuronal components in the behavioural and cognitive manifestations of bipolar disorder. Dopamine has previously been investigated in some depth in bipolar disorder, but of late has not been a primary focus of attention. This article examines the role of dopamine in bipolar disorder, incorporating recent advances into established models where possible. METHODS A critical evaluation of the literature was undertaken, including a review of behavioural, neurochemical, receptor, and imaging studies, as well as genetic studies focusing on dopamine receptors and related metabolic pathways. In addition, pharmacologic manipulation of the central dopaminergic pathways and comparisons with other disease states such as schizophrenia were considered, principally as a means of exploring the hypothesised models. RESULTS Multiple lines of evidence, including data from pharmacological interventions and structural and functional magnetic resonance imaging studies, suggest that the dopaminergic system may play a central role in bipolar disorder. CONCLUSION Future research into the pathophysiological mechanisms of bipolar disorder and the development of new treatments for bipolar disorder should focus on the dopaminergic system.

Atrophy of the putamen in dementia with Lewy bodies but not Alzheimer’s disease An MRI study

Objective: To compare the volume of the putamen on MRI in subjects with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) and age-matched normal control subjects, along with the relationship between putamen volume and severity of both extrapyramidal signs and cognitive impairment. Methods: MRI-based volumetric measurements at 1.5 T of total intracranial volume, total brain volume, and putamen volume were acquired in elderly patients with AD (n = 27; 77.6 years) and DLB (n = 14; 76.2 years) and normal control subjects (n = 37; 75.4 years). Patients and control subjects also underwent a standardized neuropsychiatric examination including the motor subsection of the Unified Parkinson’s Disease Rating Scale (UPDRS III) and the Cambridge Cognitive Examination (CAMCOG) with Mini-Mental State Examination (MMSE). Results: Patients with DLB had smaller raw putamen volumes than control subjects (right 12.5% reduction, p = 0.007; left 13.7% reduction, p = 0.003). When putamen volume was normalized to total intracranial volume, patients with DLB had significantly smaller volume ratios than both controls and patients with AD. Patients with AD did not differ from control subjects on any measure of putamen volume. Putamen volume did not correlate with age or with scores on UPDRS III, CAMCOG, or MMSE in any of the groups. Conclusions: Atrophy of the putamen is a feature of DLB. This may be important in understanding the etiology of parkinsonian features seen in DLB, though in this study, no direct correlation was found between degree of volume loss and severity of parkinsonism.

Functional Connectivity in Late-Life Depression Using Resting-State Functional Magnetic Resonance Imaging

OBJECTIVE To investigate whether there are differences in brain connectivity in late-life depression (LLD) and nondepressed subjects using the left and right heads of caudate nuclei (hCN) as the seed regions. DESIGN Resting-state functional magnetic resonance imaging (fMRI) data were collected using a 3-Tesla MRI System. SETTING Subjects were recruited from primary or secondary care services in the Newcastle area. PARTICIPANTS Thirty-three subjects aged 65 years and older; 16 who had a recent episode of LLD and 17 nondepressed subjects. MEASUREMENTS Functional connectivity was analyzed by extracting the temporal signal variation from the left and right hCN and cross correlating with the rest of the brain. RESULTS Significant connectivity between the hCN and frontal areas was observed in the nondepressed group, whereas in LLD, connectivity was seen over a much wider area. Regions showing significantly greater connectivity (p < or =0.05) in LLD compared with the nondepressed group were frontal (precentral, subgyral, middle frontal, and paracentral lobule), sublobar (thalamus and insula), limbic (cingulate), parietal (postcentral gyrus, precuneus, inferior parietal lobule, and supramarginal gyrus), and temporal (superior temporal gyrus). Conversely, no brain regions showed greater connectivity in the nondepressed group than LLD. In both groups, the right hCN showed significantly greater connectivity than the left in numerous brain regions, but connectivity for the left hCN did not exceed the right in any brain regions. CONCLUSIONS This resting-state study showed increased connectivity in specific brain regions in LLD compared with the nondepressed group, which supports the view that functional connectivity is altered in depression.

Lithium, Gray Matter, and Magnetic Resonance Imaging Signal

BACKGROUND Magnetic resonance imaging studies have reported that lithium can increase the volume of gray matter in the human brain, a finding that has been ascribed to the established neurotrophic or neuroprotective effects of the drug. Lithium, however, might directly influence the intensity of the magnetic resonance signal so it is possible that the volumetric findings are artifactual, essentially a consequence of altered image contrast. METHODS Anatomical and quantitative magnetic resonance scans were acquired on 31 healthy young men before and after taking either lithium or placebo for 11 days. Brain volume change was derived with two established techniques: voxel-based morphometry (a statistical approach using signal intensity to segment images into tissue types), and Structural Image Evaluation, using Normalization, of Atrophy (a technique that operates by detecting changes in the position of the boundaries of the brain). In a subgroup (n = 12), tissue-specific magnetic resonance relaxation times were compared before and after lithium with quantitative T1-mapping techniques. RESULTS Voxel-based morphometry revealed that gray matter volume was increased by lithium but not placebo (p = .001), whereas Structural Image Evaluation, using Normalization, of Atrophy showed no difference between lithium and placebo (p = .23). Taking lithium reduced the T1 relaxation of the gray matter only (p = .008). CONCLUSION Magnetic resonance images of the brain differ before and after lithium, but this difference might derive from a change in the characteristics of the signal rather than a tangible increase in volume.

White matter lesions in euthymic patients with bipolar disorder

Objective:  We aimed to quantify both load and regional distributions of hyperintensities on magnetic resonance imaging (MRI) in prospectively verified euthymic bipolar patients and matched controls.

Pituitary volume and third ventricle width in euthymic patients with bipolar disorder.

BACKGROUND Many of the clinical and neuroendocrine features of bipolar disorder involve hypothalamic structures. Although current neuroimaging techniques inadequately resolve the structural components of the hypothalamus, evidence of derangement can be sought by examining the adjacent third ventricle and the functionally related pituitary. AIMS To investigate the structure and function of the hypothalamic-pituitary-adrenal axis in euthymic patients with bipolar disorder. METHOD Euthymic adult patients with bipolar disorder (n=49) were compared with matched normal control subjects (n=47). Pituitary volume and third ventricle width were assessed on MRI scans. Basal salivary cortisol levels were measured. RESULTS The width of the third ventricle in patients with bipolar disorder exceeded that of controls (mean +/- SD (in mm): 3.87 +/- 1.96 versus 2.56 +/- 1.34; d=0.76, ANOVA F=12.7, p=0.001), with the greatest differences found in males. Third ventricle width increased with age across the groups (F=16.97, p<0.001). Pituitary volumes did not differ between patients and controls (mean +/- SD (in mm(3)): 632 +/- 176 versus 679 +/- 159). Overall, females had larger pituitaries than males (703 +/- 160 versus 595 +/- 161; d=0.67, F=9.65, p=0.003; all subjects), but female patients had smaller pituitaries compared to female controls (637 +/- 178 versus 756 +/- 126; d=0.65, F=5.04, p=0.03). No difference was found in a comparable analysis of males. Pituitary volume did not differ between patients prescribed and not prescribed antipsychotic drugs. Basal salivary cortisol levels did not differ between patients and controls. CONCLUSIONS In euthymic patients with normal basal cortisol levels, pituitary volume and third ventricle width were found to differ from normal controls. These differences were related to gender, may be important in the pathogenesis of bipolar disorder and could link the vegetative and endocrine abnormalities seen in this condition. Such findings may reflect a trait abnormality or be a consequence of previous episodes.

Brain networks: Foundations and futures in bipolar disorder

Background: Bipolar affective disorder is a common psychiatric illness with an often episodic nature, the neurobiological basis of which remains elusive. Symptom clusters in bipolar disorder can be conceptualized in terms of disordered brain networks, and doing so may aid our understanding of the varied presentations, differing illness courses and treatment responses. Aims: To review the rationale behind proposed disordered brain network function in bipolar disorder and the evidence of network dysfunction from imaging studies together with an overview of more novel techniques pertinent to this field. Methods: Medline databases were searched using the terms bipolar disorder, imaging, connectivity and brain networks. Relevant articles were reviewed and bibliographic cross-referencing was used to focus on key areas of interest, supplemented by additional Medline searches as required. Results: Structural and functional imaging studies support the concept of brain network dysfunction in bipolar disorder. Novel techniques such as diffusion tensor imaging and resting state network analysis can assess such dysfunction more directly, but there are few studies specific to bipolar disorder. Conclusions: Brain network dysfunction is a useful framework for considering the varied presentations of bipolar disorder. Advanced imaging techniques are increasingly available, with the potential to provide insights into this important area.

Interpreting Magnetic Resonance Imaging Findings in Bipolar Disorder

The episodic nature of bipolar disorder together with the ostensibly polar extremes of mania and depression have favored the acceptance of a functional model postulating regionally disturbed brain activity returning to normal with time or treatment. Seemingly contrary to that view, anatomical imaging studies have demonstrated abnormalities in brain structure which could reflect neurodegeneration or represent disturbed neuronal development. Resolution may come from an appreciation of adult neurogenesis, especially given the neuroprotective properties of drugs, such as lithium and their effects on brain volume. The brain regions vulnerable to structural changes also show evidence of dysfunction, giving rise to corticolimbic dysregulation interpretations of bipolar disorder. This article reviews the structural and functional magnetic resonance imaging data in bipolar disorder. Its focus is on the interpretation of findings in light of recent developments in the fields of neurobiology and image analysis, with particular attention paid to both the confounding effects of medication and the baseline energy state of the brain.

Quantitative lithium magnetic resonance spectroscopy in the normal human brain on a 3 T clinical scanner

Lithium (Li) is a core for many neuropsychiatric conditions. The safe serum range of Li treatment is narrow, and regular monitoring by blood test is required, although serum levels are thought to be a poor indicator of Li concentration in the brain itself. Brain Li concentration can be measured by magnetic resonance spectroscopy. However, little data exist in the healthy human brain, and there are no studies of the relaxation properties of brain 7Li at 3 T. Here, 11 healthy male subjects were prescribed Li over a period of 11 days. In seven subjects, the in vivo T1 of 7Li was measured to be 2.1 ± 0.7 s. In the remaining subjects, spectroscopic imaging (1D) yielded a mean brain 7Li concentration of 0.71 ± 0.1 mM, with no significant difference between gray and white matter. Mean serum concentration was 0.9 ± 0.16 mM, giving a mean brain/serum ratio of 0.78 ± 0.26. Magn Reson Med, 2011.

Reply to: Effects of Lithium on Magnetic Resonance Imaging Signal Might Not Preclude Increases in Brain Volume After Chronic Lithium Treatment

To the Editor: We thank Hajek and Vernon for their informed appraisal of our article (1) in which they acknowledge that lithium might alter image contrast but argue that this does not preclude an increase in brain volume after chronic treatment. Their stance is valid, but we submit that a tangible increase in brain volume is neither necessary nor sufficient to account for the imaging findings. We hypothesized (in shorthand) that “the reported volume change might be an artifact of the signal acquisition and image analysis process,” but this is not how we expressed our conclusion. We advanced a biophysical explanation of the imaging findings, arguing that atomic level interactions might combine with biological effects to shorten T1 relaxation, altering signal intensity and thus voxel-based morphometry (VBM) estimates of gray matter (GM) volume. Tangible brain volume increase could thus be part of the explanation, but our findings demonstrate that it is not a requirement. We assert that a tangible increase in brain volume is insufficient explanation for the magnetic resonance imaging (MRI) study findings. Unlike previous studies (2,3), Vernon et al. (4) reported that, compared with placebo, lithium-treated male rats have larger brains on MRI and postmortem. Their 4.8% increase in whole brain volume (WBV) on MRI at 8 weeks is substantial, but we note that derived percentage changes were not corrected for total intracranial volume (TIV). Although not statistically significant, there is a clear numerical difference in TIV between the lithiumand placebo-treated rats that, together with the wide variability in the data, would usually be taken as a strong indication to individually correct for TIV, particularly as the direction of change could drive an increase in the apparent effects of lithium. Hajek and Vernon assert that the effect of lithium “was maintained 8 weeks after the drug withdrawal,” but after drug withdrawal (at 16 weeks), the MRI WBV of lithiumtreated rats was actually 6.2% greater than those administered placebo (4). A neurotrophic account might argue that this represents new neurons slowly maturing to size, but this cannot be the case, because the location of the volume change on MRI was not stable (reversal of MRI cortical changes). Crucially, although the difference in WBV postmortem was significant, it appears less substantial than the MRI findings (we estimate 3%– 4% from their graphical representation). We would seek clarification on the actual numerical value, because it might usefully advance the interpretation of the wider field. The discrepancy might be reconciled by accepting the modest increase in actual WBV while acknowledging that the effects of lithium on signal intensity conspire to exaggerate the MRI findings—a biophysical account. Should this proposed exaggeration prove quantifiable, it might be amenable to systematic correction. It is also interesting that MRI WBV increased, numerically at least, after the ostensible withdrawal of lithium; stopping the administration of lithium is no guarantee of a cessation of its effects. Preclinical data demonstrate that lithium is laid down in bone at a rate proportional to the rate of bone growth (5) to reach concentrations in excess of serum levels (6). Much of this bone fraction is released soon after stopping lithium, but an appreciable portion remains over an extended period. Slow release of this remaining fraction would be inadequate to directly interfere with the magnetic resonance