Hippocampal volumes in adults with bipolar disorder.

Functional neuroimaging studies have implicated the hippocampus formation in the pathophysiology of bipolar disorder, but findings from volumetric studies have been less consistent. The authors aim to further investigate the existence of volumetric abnormalities in the hippocampus of individuals with bipolar disorder. In addition to methodological inconsistencies, many previous studies have been lacking clinical robustness with respect to characterizing bipolar patients and comparison subjects. Hence, the present study matched the groups closely across a number of demographic parameters. Using MRI, hippocampal volumes of 24 bipolar patients were compared to 24 sex-, age-, and education-matched comparison subjects, and these findings were further investigated in relation to both illness and treatment factors. A significantly larger (8.5%) right hippocampus was seen in bipolar patients than in comparison subjects, and this difference was not associated with a history of psychosis, familial illness, or lithium treatment, after controlling for potential confounds. Patients reporting fewer affective episodes did however have significantly larger left hippocampus volumes than comparison subjects. The authors found that the left hippocampus was larger in a group of adult bipolar subjects relative to the healthy comparison group. The reason for this is unclear, but in this sample, it was not associated with family history, psychotic features, or medication exposure. A negative association was found between left hippocampal volume and number of episodes or duration of illness, suggesting the hippocampus might be larger in the early phase of bipolar disorder but becomes smaller with time.

Anatomical abnormalities of the anterior cingulate and paracingulate cortex in patients with bipolar I disorder.

Abnormalities of the anterior cingulate cortex (ACC) are thought to be involved in the pathophysiology of bipolar disorder, but structural Magnetic Resonance Imaging (MRI) studies have reported variable findings. Reasons for this include a failure to consider variability in regional cortical folding patterns and a reliance on relatively coarse measures (e.g., volume) to index anatomical change. We sought to overcome these limitations by combining a novel protocol for parcellating the ACC and adjacent paracingulate cortex (PaC) that accounts for inter-individual variations in sulcal and gyral morphology with a cortical surface-based approach that allowed calculation of regional grey matter volume, surface area and cortical thickness in 24 patients with bipolar I disorder and 24 matched controls. No changes in grey matter volume or surface area were identified in any region, but patients did show significant reductions in cortical thickness in the left rostral PaC and right dorsal PaC that were not attributable to group differences in cortical folding patterns. These findings suggest that bipolar disorder is associated with more pronounced changes in the PaC, and that reliance on volumetric measures alone may obscure more subtle differences.

Reduced activation to implicit affect induction in euthymic bipolar patients: an fMRI study.

OBJECTIVE: To examine whether euthymic bipolar patients engage similar or contrasting brain regions as healthy subjects when responding to implicit affect induction. METHODS: The study examined 10 euthymic patients with bipolar I disorder, and 10 age- and gender-matched healthy subjects using event-related functional magnetic resonance imaging (fMRI) while subjects engaged in a modified word-based memory task designed to implicitly evoke negative, positive or no affective change. The activation paradigm involved nominating whether a target word was contained within a previously presented word list using specified response keys. RESULTS: The fMRI task produced significantly greater activation in healthy subjects as compared to patients in response to both negative and positive affect in the anterior and posterior cingulate, medial prefrontal cortex, middle frontal and right parahippocampal gyri. Only negative affect produced significantly greater activation in the postcentral gyrus, inferior parietal lobule, thalamus and putamen and only positive affect achieved the same in the precentral, superior temporal and lingual gyri, precuneus, cuneus, caudate, pons, midbrain and cerebellum. There were no brain regions in which responses were greater in patients as compared to healthy subjects. There were no statistically significant differences between the groups with respect to speed or accuracy. CONCLUSIONS: Diminished prefrontal, cingulate, limbic and subcortical neural activity in euthymic bipolar patients as compared to healthy subjects is suggestive of emotional compromise that is independent of cognitive and executive functioning. This finding is of clinical importance and has implications both for the diagnosis and treatment of bipolar disorder. Future studies should aim to replicate these findings and examine the development of bipolar disorder, investigating in particular the effects of medication.

The psychological and neurophysiological concomitants of mindfulness forms of meditation.

OBJECTIVE: To provide a comprehensive review and evaluation of the psychological and neurophysiological literature pertaining to mindfulness meditation. METHODS: A search for papers in English was undertaken using PsycINFO (from 1804 onward), MedLine (from 1966 onward) and the Cochrane Library with the following search terms: Vipassana, Mindfulness, Meditation, Zen, Insight, EEG, ERP, fMRI, neuroimaging and intervention. In addition, retrieved papers and reports known to the authors were also reviewed for additional relevant literature. RESULTS: Mindfulness-based therapeutic interventions appear to be effective in the treatment of depression, anxiety, psychosis, borderline personality disorder and suicidal/self-harm behaviour. Mindfulness meditation per se is effective in reducing substance use and recidivism rates in incarcerated populations but has not been specifically investigated in populations with psychiatric disorders. Electroencephalography research suggests increased alpha, theta and beta activity in frontal and posterior regions, some gamma band effects, with theta activity strongly related to level of experience of meditation; however, these findings have not been consistent. The few neuroimaging studies that have been conducted suggest volumetric and functional change in key brain regions. CONCLUSIONS: Preliminary findings from treatment outcome studies provide support for the application of mindfulness-based interventions in the treatment of affective, anxiety and personality disorders. However, direct evidence for the effectiveness of mindfulness meditation per se in the treatment of psychiatric disorders is needed. Current neurophysiological and imaging research findings have identified neural changes in association with meditation and provide a potentially promising avenue for future research.

An event-related functional MRI study of working memory in euthymic bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) is emerging as an illness marred by neurocognitive deficits, many of which do not resolve on recovery. Deficits affecting working memory (WM) in particular appear to be significant. WM comprises temporally separated biological processes that involve the on-line retention and manipulation of information. Previous neuroimaging studies have not sought to dissect the individual contributions of WM and examined WM subprocesses in euthymic BD. In this study, we investigated the encode, delay and response components of WM to identify the neural substrates and respective contributions to the WM deficits found in BD. METHODS: We used event-related functional magnetic resonance imaging and a parametric WM task, incorporating 3 load conditions, to delineate individual WM subprocesses in 10 euthymic BD patients and 10 control subjects. RESULTS: Patients exhibited attenuated patterns of activity, predominantly in frontal brain regions, across all WM components. CONCLUSIONS: Based on the attenuated activity observed in the patients, the clinical deficits in WM found in BD may reflect broad fronto-cortico-limbic dysfunction that is not confined to any single WM component. This is important in understanding the pathophysiology of BD and for future studies on executive functions in patients with this illness.

Regional gray matter changes in bipolar disorder: a voxel-based morphometric study.

OBJECTIVE: To investigate structural abnormalities in bipolar disorder (BD) using optimized voxel-based morphometry (VBM) in closely matched patients and controls, and to examine the relationship of clinical features with regional gray matter (GM) volumes. METHODS: Twenty-four patients (six male) aged 19-59 years (mean=38.21 years, SD=11.04 years) with DSM-IV bipolar I disorder were compared with 25 control subjects, matched on age, sex, and years of education. VBM analyses were conducted on high-resolution T1-weighted brain magnetic resonance imaging to detect regional GM volume differences between groups, ensuring statistical correlation for age, sex and total intracranial volumes. Within the patient groups, regional GM changes were also investigated. RESULTS: Compared to controls, BD patients had increased GM volume in left parahippocampal gyrus and decreased GM volume in left middle temporal gyrus. Family history, psychotic symptoms and lithium status were associated with regional GM abnormalities in BD patients. CONCLUSIONS: This study presents evidence of gray matter volume abnormalities in adults with bipolar I disorder. Regional variation in relation to clinical factors suggests a neurobiological basis for clinical heterogeneity and posits the possibility of trait deficits.

Neuropsychological deficits and functional impairment in bipolar depression, hypomania and euthymia.

OBJECTIVE: To examine whether patients with bipolar disorder (BD) have subtle neuropsychological deficits that manifest clinically as cognitive and functional compromise, and this study attempted to determine the pattern of such cognitive deficits and their functional impact across all three phases of BD. We hypothesised that euthymia does not equate with normal neuropsychological function and that each phase has a characteristic pattern of deficits, with disturbance in attention and memory being common across all phases of the illness: (i) bipolar depression - psychomotor slowing and impairment of memory; (ii) hypomania by frontal-executive deficits and (iii) euthymia - a mild disturbance of attention, memory and executive function. METHODS: Twenty-five patients with a diagnosis of bipolar I disorder underwent neuropsychological testing over a period of 30 months in the natural course of their illness while hypomanic and/or depressed and/or euthymic. The results from these assessments were compared with findings from neuropsychological tests conducted on 25 healthy controls matched for age, sex, education and handedness. RESULTS: Initial analyses revealed modest impairment in executive functioning, memory and attention in both hypomanic and depressed bipolar patients, with additional fine motor skills impairment in the latter. Memory deficits, also noted in euthymic patients, were non-significant after controlling for confounding variables, although bipolar depressed patients remained significantly impaired on tests of verbal recall. Bipolar depressed and hypomanic patients differed with respect to the nature of their memory impairment. Depressed patients were more impaired as compared with euthymic patients on tests of verbal recall and fine motor skills. Psychosocial functioning was impaired across all three patient groups, but only in depressed and hypomanic patients did this correlate significantly with neuropsychological performance. CONCLUSIONS: The mood-state-related cognitive deficits in both bipolar depression and hypomania compromise psychosocial function when patients are unwell. In euthymic patients, subtle impairments in attention and memory suggest that an absence of symptoms does not necessarily equate to 'recovery'. The possibility of persistent cognitive deficits in BD is an issue of profound clinical and research interest that warrants further investigation; however, future research needs to adopt more sophisticated neuropsychological probes that are able to better define state and trait deficits and determine their functional impact.

Increased anterior cingulate cortex volume in bipolar I disorder.

OBJECTIVE: Functional neuroimaging studies have implicated the anterior cingulate cortex (ACC) in the pathophysiology of bipolar disorder (BD), but findings from volumetric studies have been less consistent, therefore the purpose of the present study was to further investigate the existence of volumetric abnormalities in the ACC cortex of individuals with BD. In addition to methodological inconsistencies many previous studies have been lacking robustness clinically with respect to characterizing bipolar patients and comparison subjects. Hence, the present study matched the groups closely across a number of demographic parameters. METHODS: Using magnetic resonance imaging, ACC volumes of 24 bipolar patients were compared to 24 gender-, age-, and education-matched control subjects, and these findings were further investigated in relation to both illness and treatment factors. RESULTS: A significantly larger (26%) right ACC in bipolar patients than control subjects was seen, and this difference was not associated with a history of psychosis, familiality, or lithium treatment, after controlling for potential confounds. Patients reporting fewer affective episodes did, however, have significantly larger ACC volumes than controls, suggesting ACC volumetric changes early in the course of BD. CONCLUSIONS: An increase in the size of the ACC may have important implications for the neurobiology of BD. It is suggested that attempts to control affective instability during the early stages of the illness necessitates greater ACC mediation via its role in conflict resolution and hence this is reflected in the increased size of the ACC early in the course of the illness.

Is a lack of disgust something to fear? A functional magnetic resonance imaging facial emotion recognition study in euthymic bipolar disorder patients.

OBJECTIVES: To determine the neural responses invoked in the recognition of facial fear and disgust in euthymic bipolar patients as compared with healthy subjects. METHODS: This study examined 10 female euthymic bipolar patients, and 10 suitably matched healthy subjects using functional magnetic resonance imaging (fMRI) while subjects were engaged in an explicit facial emotion recognition task involving fear, disgust and neutral expressions. The activation paradigm involved nominating the facial expression using specified response keys. Behavioural data were collected and analysed and both within-group (Fear versus Neutral; Disgust versus Neutral) and random-effects between-group analyses were performed on fMRI data using BrainVoyager (Brain Innovations, Maastricht, the Netherlands). RESULTS: Patients were equally accurate in identifying facial expressions as healthy subjects but were slower to respond, especially with respect to fear and disgust. Responses to fear and disgust (within-group analyses) resulted in activation of anticipated brain regions such as amygdala and insula, respectively. However, between-group random effects analysis revealed differential responses to both disgust and fear in both healthy subjects and euthymic bipolar patients such that euthymic bipolar patients responded largely to fear and healthy subjects responded more so to disgust. This partitioning of responsiveness was reflected by differential activation involving the hippocampus and amygdala. CONCLUSIONS: Greater responsiveness to fear with hippocampal activation in patients perhaps reflects recollection of traumatic events associated with past experiences of illness or simply the use of a more mnemonic (hippocampal) as opposed to affective (amygdala) approach when performing the task. It is possible that in bipolar disorder, prefrontal-subcortical network dysfunction that relegates neural processing to limbic regions is impaired and that clinically euthymic bipolar patients, although able to accurately and effectively identify emotions such as fear and disgust, are limited in their ability to interpret their salience. The implications of these findings are discussed.

Cognitive compromise in bipolar disorder with chronic cannabis use: cause or consequence?

This article briefly reviews the neuropsychological deficits associated with bipolar disorder and examines how substance abuse, in particular chronic cannabis use, may contribute to these. The focus of the article is cannabis, owing to its popularity in patients with bipolar disorder, although many studies focus on its use in conjunction with other substances. The findings are contextualized within bipolar disorder, examining functional outcome.

Cerebrovascular autoregulation as a neuroimaging tool.

Functional transcranial Doppler (fTCD) sonography provides a high temporal resolution measure of blood flow and has over the years proved to be a valuable tool in the clinical evaluation of patients with cerebrovascular disorders. More recently, due to advances in physics and computing, it has become possible to derive indices of cerebrovascular autoregulation (CA) as well as cerebrovascular pressure reactivity (CR), using non-invasive techniques. These indices provide a dynamic representation of the brain's regulatory blood flow mechanisms not only in pathological states but also in health. However, whilst the temporal resolution of these regulatory indices is very good, spatially, the localization of brain regions remains very poor, thus limiting its brain mapping capacity. Functional MRI, on the contrary, is a brain-imaging technique that operates on similar blood flow principles; however, unlike fTCD, it provides high spatial resolution. Because both fTCD and fMRI determine blood flow-dependant imaging parameters, the coupling of fTCD with fMRI may provide greater insight into brain function by virtue of the combined enhanced temporal and spatial resolution that each technique affords. This review summarizes the fTCD technique with particular emphasis on the CA and CR indices and their relationship in traumatic brain injury as well as in health.

An emotional Stroop functional MRI study of euthymic bipolar disorder.

OBJECTIVE: To identify the brain regions associated with emotional processing in euthymic bipolar patients. METHODS: The study examined 12 euthymic bipolar patients using functional magnetic resonance imaging (fMRI) while performing an emotional Stroop (eStroop) task. The task comprised emotionally valent and neutral words presented in alternating blocks that was designed to implicitly induce affect. In conjunction with fMRI, galvanic skin responses (GSR) were measured to monitor arousal. RESULTS: Euthymic bipolar patients had diminished activation in response to the affective stimuli in both cortical and subcortical brain regions when compared with healthy subjects. In particular, patients had less activation in the left ventral prefrontal cortex suggesting a potential trait deficit. Patients were slower to react than healthy controls, but did not differ with respect to accuracy. CONCLUSIONS: Euthymic bipolar patients are perhaps constrained in their ability to engage affective processing. Diminished ventral prefrontal cortex activation corroborates previous reports of a potential trait deficit, suggesting that 'all is not well in euthymia', although the effects of medication cannot be overlooked.

A matter of motion or an emotional matter? Management of depression in Parkinson's disease.

Depression is one of the most frequent comorbidities occurring in Parkinson's disease, affecting up to 50% of patients. Depression is associated with severe negative symptoms and has been shown to contribute to an increased rate of decline of both cognitive and motor function, profoundly impacting on the patient's quality of life. The symptoms of depression overlap with the motor features of Parkinson's disease, making detection difficult. Moreover, the lack of specialized screening tools means that depression remains undiagnosed and untreated in a high percentage of patients. However, depression in Parkinson's disease, when identified early, can be effectively treated with a variety of antidepressant medications, improving quality of life and preserving daily function. The focus of this review is to provide an overview of current knowledge regarding depression in Parkinson's disease, followed by a practical discussion addressing the issues of the detection, diagnosis and treatment.

Bipolar disorder: it's all in your mind? The neuropsychological profile of a biological disorder.

OBJECTIVE: To compare and contrast the neuropsychological profile of the 3 phases of bipolar disorder (BD) to achieve a better definition of BD and to identify potential state and trait deficits. METHODS: We conducted a search for English-language papers published in journals from 1965 onward, using the following terms in Medline and Embase: neuropsychology or neuropsychological and BD, depression, mania, and euthymia. We scrutinized suitable subheadings and retrieved familiar papers and literature. RESULTS: We initially identified more than 100 articles and then excluded reviews and papers that did not directly administer neuropsychological tests. This left 27 papers, which we further examined and the findings of which we tabulated and discussed. Cognitive and executive functioning deficits were found, including set-shifting, verbal fluency, planning, attention, and memory. CONCLUSIONS: The neuropsychological deficits found in bipolar depression, mania or hypomania, and euthymia provide important insights into the pathophysiology of BD and may, in future studies, form the basis of clinically meaningful subtypes.

Cognitive generation of affect in hypomania: an fMRI study.

OBJECTIVE: To identify the brain regions associated with the cognitive generation of affect in hypomanic bipolar patients. METHODS: The study examined 10 hypomanic female subjects with bipolar affective disorder, and 10 age- and sex-matched comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned-pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (a) negative and reference, (b) positive and reference and (c) positive and negative captioned-pictures. RESULTS: The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal cortex. Activation in patients involved additional subcortical regions namely the caudate and thalamus. CONCLUSIONS: This preliminary study suggests that hypomanic patients recruit additional subcortical limbic systems for emotional evaluation when advanced prefrontal cortical processing is no longer sufficient. The differential patterns of activation inform us about bipolar disorder and may have potential diagnostic and therapeutic significance.

Cognitive generation of affect in bipolar depression: an fMRI study.

Individuals with bipolar disorder manifest the full spectrum of emotions ranging from depression to mania. In attempting to understand the functional substrates of mood we attempted to identify brain regions associated with the cognitive generation of affect in bipolar depressed patients. We therefore examined ten depressed female subjects with bipolar affective disorder, and ten age-matched and sex-matched healthy comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (experiment 1) negative and reference; (experiment 2) positive and reference and (experiment 3) positive and negative captioned pictures. The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal and anterior cingulate cortices. The activation in patients, when compared with healthy subjects, involved additional subcortical regions, in particular the amygdala, thalamus, hypothalamus and medial globus pallidus. Patients and comparison subjects displayed differential sensitivity to affective change with negative (experiment 1) and positive (experiment 2) affect induction producing converse patterns of activation. We conclude that bipolar depressed patients perhaps recruit additional subcortical limbic systems for emotional evaluation and this may reflect state-related or trait-related dysfunction. The differential patterns of activation inform us about bipolar depression and have potential diagnostic and therapeutic significance.