ReviewA systematic review of resting-state functional-MRI studies in major depression
Introduction
Disturbances of mood and affect are among the most prevalent of all behavioural disorders. Major Depression (MD) is especially common, occurring in about 15% of the population. A 2008 report from the World Health Organisation (WHO) indicated that MD was the foremost contributor to the global burden of disease, as measured by years of health lost to disability (Daly, 2009). MD is a recurrent disorder, affecting adolescents and adults alike. However, despite its prevalence the mechanisms that underpin the disorder remain poorly understood. The diagnosis of a major depressive episode is based not only on the presence of a persistent negative mood state but also on a range of associated disturbances including attention, motivation, psychomotor speed, as well as sleep, appetite and libido. The involvement across such a broad range of functional domains stands as a testament to the disorder's complexity and may, in part, explain the observed variability across imaging studies. To date, the most consistent findings in MD include decreased frontal lobe function (primarily involving the medial prefrontal cortex; MPFC) and increased limbic system activity (including the amygdala). To a lesser extent, abnormalities have also been reported in paralimbic (cingulate) and subcortical (thalamus) structures but as distinct from most of the lesion literature, imaging studies describe bilateral rather than left-lateralization abnormalities. The identified neural substrates and their associated networks are highly connected via feedback loops with complementary networks primarily responsible for identifying non-emotional aspects of information, which include the MPFC (Gallagher and Chiba, 1996). It has been postulated that MD may evolve from a failure in the coordinated interaction between these cortico-limbic pathways. Within this theoretical framework, the dorsal compartment, which includes the neocortical and superior limbic elements, is postulated to regulate attention and cognitive features of depression (such as apathy and impaired attention) and the ventral compartment, composed of the limbic, paralimbic and subcortical regions is hypothesised to mediate vegetative and somatic aspects of the illness (including sleep, appetite and endocrine disturbances). Within this dorsal-ventral segregation, the MPFC and the amygdala are considered the critical neural substrates in the modulation of mood and together form the primary emotion specific neural network.
The past decade has seen significant advances in neuroimaging techniques allowing the non-invasive investigation of the brain's functional domains. With the aid of these sophisticated brain-imaging techniques, it is possible to study these domains in greater detail and glean their interrelationships. One such technique is functional magnetic resonance imaging (fMRI), which is an established imaging modality specific for studying brain activity and neuronal network connectivity. Its utility lies with contrasting functional differences between healthy control populations and patients with a variety of psychiatric conditions including schizophrenia, bipolar disorder (BD) and MD to name a few. To date, the vast majority of fMRI studies have employed stimulus driven paradigms where the imaging signal is time-locked to cognitive or sensorimotor tasks. These studies have primarily focused on interpreting the activation of different brain regions that are stimulated by task performance. More recently in the case of MD, there is a confluence of evidence that suggests depressive symptoms may evolve as a consequence of aberrations within discrete brain networks (rather than in isolated brain regions), which modulate function. To this end, fMRI has more recently been employed in a “stimulus-free” manner such as in the case of resting-state fMRI, to investigate changes in brain networks and their connectivity. Resting-state fMRI is a relatively new modality that potentially overcomes several key limitations of task-stimulated fMRI studies. Typically, resting-state fMRI is conducted while the subject is in a continuous state of rest (e.g. lying still with eyes closed). This allows the inclusion of subjects, suffering from a severe episode of the psychiatric condition, who may be incapable of performing cognitive tasks at a satisfactory level (Greicius, 2008). An important advantage of this is that a more direct comparison can be made between groups, including differences between patient groups of different conditions as well as subjects at varying stages of disease severity and development (Fox and Raichle, 2007).
Presently, the literature on resting state fMRI studies on MD points to a lack of consistency in the approaches to data collection, analysis and, subsequently, interpretation of the findings. As a consequence, this has led to a number of contradictory findings and the lack of an overall consensus on the interpretation of these changes. The aim of this review was to examine the methods and results of the currently available resting-state fMRI studies on MD and to discuss the relevant themes and future considerations.
Section snippets
Methods
A search for papers published in English was conducted via MedLine, Embase, PsycINFO, OvidSP, and ScienceDirect using terms composed of varying combinations of the following keywords: resting state, depression, MRI, affective, and default-mode. A total of 21 articles met the criteria as being resting-state fMRI studies in MD. Of these, 5 articles were excluded for the following reasons (the study): (i) did not use subjects who had been diagnosed with MD; (ii) used subjects with remitted
Methods of resting-state fMRI analysis
In the study of MD, resting-state fMRI is a relatively new approach that has been gaining momentum in recent years. There are a number of different strategies that can be adopted when conducting resting-state fMRI studies. Two of the most popular approaches are termed region-of-interest (ROI) analysis (Fox and Raichle, 2007) and independent component analysis (ICA) (Greicius et al., 2007). In a ROI analysis, a seed region is selected a priori and the subsequent functional connectivity map is
Discussion
The use of resting-state fMRI in MD research is relatively new, however, the number of published studies continues to steadily increase, signifying an intensifying interest in the technique among researchers. The literature thus far has uncovered a wide array of brain regions that exhibit group differences between depressed subjects and healthy controls. Therefore, the perceived value and importance of resting-state fMRI research in MD are likely to continue to grow. Neuroimaging studies of MD
Conclusion
Resting-state fMRI is a valuable neuroimaging modality for studying MD. Numerous research groups have pursued this avenue with promising results, and interest is still growing. The current evidence largely suggests abnormal resting functional connectivity in the cortico-limbic MRC and the DMN to be contributing to the pathophysiology of MD. Continued efforts to study resting-state fMRI in MD, in conjunction with other neuroimaging modalities, will advance our understanding of the involvement of
Role of funding source
The sources of funding for this study have not influenced the outcomes of the review not placed any restrictions on the reporting of the results or preparation of the manuscript.
Conflict of interest
The authors of this manuscript do not have any conflicts of interests to disclose.
Acknowledgements
This work was funded by an NHMRC program grant (566529) and NHMRC Australia fellowship awarded to Professor Hickie (511921).
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