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

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

COPYRIGHT 2007 Canadian Medical Association

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.

Objectif : On commence a reconnaitre que le trouble bipolaire (TB) est une maladie caracterisee par des deficits neurocognitifs dont beaucoup ne disparaissent pas au retablissement. Les deficits qui touchent la memoire de travail (MT) en particulier semblent importants. La MT comprend des processus biologiques separes temporalement mettant en cause la retention en ligne et la manipulation d'information. Les etudes anterieures de neuro-imagerie n'ont pas cherche a analyser les contributions individuelles de la MT et a examiner des sous-processus de la MT dans un cas de TB euthymique. Dans cette etude, nous nous sommes penches sur les composantes encodage, retard et reponse de la MT afin d'identifier les substrats neuraux et les contributions respectives au deficit de la MT que l'on retrouve dans des cas de TB. Methodes : Nous avons utilise l'imagerie par resonnance magnetique fonctionnelle reliee a un evenement et une tache MT parametrisee, comportant trois conditions de charge, afin de delimiter des sous-processus individuels de la MT chez 10 patients atteints d'un TB euthymique et 10 sujets temoins. Resultats : Les patients ont montre des tendances attenuees d'activite, principalement dans les regions frontales du cerveau, dans toutes les composantes de la MT. Conclusions : Compte tenu de l'attenuation de l'activite observee chez les patients, les deficits cliniques de la MT que l'on constate dans les cas de TB peuvent refleter un dysfonctionnement frontocorticolimbique general qui n'est pas confine a une seule composante de la MT. Cette constatation est importante si l'on veut comprendre la pathophysiologie du TB et pour des etudes futures des fonctions d'execution chez les patients atteints de cette maladie.

Introduction

Bipolar disorder (BD) is a complex mental illness characterized by acute shifts in a person's mood, energy and ability to function. In BD, symptoms of depression and hypomania are more severe than the normal "ups and downs" experienced by healthy individuals, and episodes of apparent remission are deceptive, because impairments persist even while the patient is apparently well. (1-3) Traditionally, BD has been regarded as a disorder of mood and, as a consequence, initial studies focused on structural abnormalities in limbic-thalamocortical networks, which are known to subserve mood. Collectively, the prefrontal cortex, medial temporal lobe and subcortical structures have been targeted and structural abnormalities identified in each of these regions. (4-7) More recently, neuroimaging studies using positron emission tomography (PET) and single photon emission computed tomography (SPECT) have identified a wide range of metabolic dysfunctions involving the prefrontal cortex, cingulate, and temporal and parietal cortices. (8) Moreover, functional MRI (fMRI) studies have highlighted functional aberrations at various locations along limbic-thalamocortical circuits. (2,9-14) While the search for the precise structure-function relation underpinning the pathophysiology of BD has concentrated on mood-related circuits, it has been assumed that cognitive processes are unaffected and remain largely intact. Consequently, cognitive processes such as working memory (WM) have received far less attention than mood. This is surprising, given that many of the identified abnormalities occur in brain regions that clearly subserve functions other than emotional regulation. In BD, neurocognitive deficits have been identified3 that do not resolve during euthymia, (15) and deficits in WM in particular appear extensive. (16,17)

Working memory

The term "working memory" refers to a complex set of biological processes involved in the on-line retention and manipulation of information, (18) used by organisms to guide behaviour and successfully interact with the environment. WM plays a crucial role in many cognitive functions, such as spatial processing, reasoning, planning and language comprehension. Consequently, impairments in WM have a profound impact on cognition. Several studies have reported that dysfunctions in WM are the underlying cause of cognitive impairments observed in conditions such as schizophrenia, (19) unipolar depression (20) and Parkinson's disease. (21) It has been postulated that WM is not a unitary process but, instead, is composed of 3 independent components that operate dynamically. (18) According to this model, WM comprises a visuospatial sketchpad and phonological loop that stores and manipulates visuospatial and verbal information together with a central executive that regulates attention processes and controls information entry and the retention and release of memory from the visuospatial sketchpad and phonological loop. The precise neurobiological substrates of WM have yet to be elucidated. Results of recent neuroimaging studies lend tentative support for this 3-component model with the implication of such regions as the prefrontal cortex, (22) parietal cortex (23) and anterior cingulate. (24)

BD imaging studies

To date, only 2 WM fMRI studies have been conducted on patients with euthymic BD. (25,26) The first study (25) employed a 2-back WM task incorporated in a block design with 0-back as the baseline condition. The study reported that patients performed significantly worse than control subjects, with respect to the baseline condition 0-back. Despite performing poorly, patients showed qualitatively greater activation foci, compared with control subjects, across the entire brain; this pattern of activation persisted between group comparisons with healthy control subjects. The results from this study are counterintuitive, because poor performance would normally be associated with reduced activation, especially in regions associated with the WM. However, the paradigm employed in this study (2-back block design) did not draw on the load-capacity characteristics of the WM. The second study (26) used 2 separate WM paradigms, the 2-back (block design) and the Sternberg Task (parametric design), in an attempt to dissociate the central executive from the phonological loop. The authors reported no significant between-group differences in reaction time performance in either of the tasks. In direct contrast to the previous (25) study, the authors reported significantly decreased bilateral frontal, temporal and parietal activations for the BD group during the 2-back task, but no between-group differences were found during the Sternberg Task. The authors did not, however, adequately distinguish individual WM subprocesses; thus these findings may not be representative. Studies using the Sternberg Task reported reliable activations in frontal, parietal and subcortical areas. (27,28) However, to accurately elucidate the brain regions involved by such WM tasks, it is necessary to disentangle the contributions of subprocesses such as encode, delay and response execution, because each of these may preferentially engage separate brain regions. Although studies (25,26) have explored WM deficits in patients with BD using traditional n-back and Sternberg memory tasks, these studies that have used block-design paradigms...