Alterations in effective connectivity anchored on the insula in major depressive disorder
Introduction
With a lifetime prevalence of approximately 1 in 10 individuals, Major Depressive Disorder (MDD) is the most costly of brain disorders (Sobocki et al., 2006) and has been highlighted as the 2nd most disabling condition for its impact on quality of life (Murray and Lopez, 1997) with a high degree of association with suicide rates (Cavanagh et al., 2003). In the last decade, important progress has been made in understanding the neural basis of depression, and key brain networks have been identified to play a role in generating the diverse symptoms of depression.
A prominent neural network model for MDD proposed by Mayberg et al. (1999) suggests that depression is characterized by a disruption in the limbic–cortical network. Using PET, it has been shown that in healthy individuals, activity is decreased in the limbic and paralimbic structures over the cortical, while in depression, this pattern is reversed with overactivity of limbic regions and decreases in dorsal cortical regions (Mayberg et al., 1999). To offer support for this model, Hamilton et al. (2011a) have recently documented increased excitation within the limbic and paralimbic structures (e.g. the hippocampus), and increased inhibition of cortical structures (e.g. dorsomedial prefrontal cortex (DMPFC) and cuneus/posterior cingulate) by the commonly implicated ventral anterior cingulate cortex (vACC). A region in the DMPFC, termed the ‘dorsal nexus’, has also shown to possess abnormally increased connectivity with the three major networks (i.e. cognitive control, affective, default mode) in MDD (Sheline et al., 2010). This ‘hot-wiring’ pattern results in widespread information processing imbalance across the brain, which is thought to underlie the complex symptoms and cognitive deficits observed in MDD.
An additional structure that has garnered increased attention as a key contributor to the pathophysiology of MDD is the anterior insula. The anterior insula shares extensive and widespread anatomical connections to cortical and limbic regions and plays a crucial role in the coordination between the cognitive control and default mode network (Menon and Uddin, 2010). The rich connectivity of the anterior insula to both sensory processing regions (visual, auditory cortices and thalamus) and the so-called self-processing multimodal regions (prefrontal and anterior temporal) suggests a unique role for anterior insula in the ordered or hierarchical information processing, presumed to include bottom-up (sensory to multimodal) and top-down (multimodal to sensory) reciprocal influences. Given the insula׳s posited role in functions related to emotional processing, in addition to its connections to limbic regions, it seems reasonable that the diverse symptoms of MDD may be associated with impaired functioning of this region. Indeed, the functional activity and connectivity of the insula have been shown to be perturbed in several studies of patients with depression (Busatto, 2013, Hamilton et al., 2012, Hamilton et al., 2011b, Sliz and Hayley, 2012, Sprengelmeyer et al., 2011). For example, the activity of the right fronto-insular network was attenuated in patients with depression, and this was associated with greater levels of maladaptive rumination (Hamilton et al., 2011b). Studies of regional homogeneity, which measures local connectivity, have also shown reductions in the right insula, which correlated positively with anxiety and hopelessness (Yao et al., 2009). Similar patterns were also observed in first-degree relatives of MDD patients, suggesting that insular dysfunction represents a crucial vulnerability marker for depression (Liu et al., 2010).
Functional changes have also been reported in the insula following various treatments for MDD. Regional cerebral blood flow of the insula was reduced following repetitive transcranial magnetic stimulation (rTMS) treatment, which also correlated with treatment efficacy (Kito et al., 2011). Other studies have also revealed reductions in insula activity with antidepressant treatment (Delaveau et al., 2011, Fitzgerald et al., 2008). In a recent PET study, the right anterior insula (rAI) was localized as a crucial region for differentiating MDD patients who are responsive to CBT or antidepressants (McGrath et al., 2013). Hypometabolism of the rAI predicted response to CBT, while hypermetabolism predicted a patient to respond to antidepressants. Therefore, the insula offers great promise as a target region for treatment of MDD, where its modulation will have widespread effects on the connectivity of networks that are disrupted in MDD. Studying the directed influence (effective connectivity) of the insula on other structures implicated in depression is crucial for our understanding of the neural circuitry of depression.
We therefore sought to investigate the effect of depression on the effective connectivity of the rAI with the rest of the brain. We employed Granger causality analysis (GCA) on resting-state functional magnetic resonance imaging (fMRI) data to investigate whether positive or negative influences of the rAI on the rest of the brain differ in patients with current major depression. We anticipated a reduction in the connectivity of the fronto-insula network in MDD patients, as well as more widespread abnormalities in connectivity between the rAI and limbic and cortical regions. It is important to note that while Granger-causality allows directional inferences to be made on the basis of temporal precedence observed within the limits of the sparse resolution offered by fMRI, the inferences do not provide conclusive evidence on underlying neural state shifts.
Section snippets
Participants
Sixteen patients and 16 healthy controls were recruited from Shanghai Mental Health Centre and Shanghai Huashan Hospital. The MDD group consisted of 9 females and 7 males, aged 26–45 years (mean 34.43±6.72 years) and received 6–17 years (mean 15.63±1.99 years) education. All patients were first-onset MDD and drug-naïve (no current or past exposure to antidepressants) with illness duration between 3.6 and 14.57 weeks (mean 8.01±4.19). Patients were included in the study if they met DSM-IV
Right anterior insula seed
In the entire sample of both patients and healthy controls, the one-sample t test revealed four large clusters to be positively influenced by the rAI (uncorrected p<0.0005, k=100). The rAI was also negatively influenced by two large clusters (uncorrected p<0.0005, k=100). One-sample t test results are presented in Table 2. Two-sample t tests revealed a significant difference in the causal outflow from the rAI to left DMPFC (−24 20 58) showing a significant positive influence in controls, while
Discussion
Using an effective connectivity approach for the first time to study the interaction of anterior insula with rest of the brain in depression, we have identified an extended frontolimbic circuitry with aberrant connectivity. This circuitry extends from sensory processing regions (cuneus), through subcortical centers (thalamus, caudate), to paralimbic salience processing regions (insula, ACC, hippocampus and striatum) and heteromodal prefrontal sites (DMPFC). Several regions from this extended
Conclusion
In summary, the present study highlights a key role played by the insula in the large-scale network-level abnormalities seen in depression. By demonstrating the importance of both sensory and prefrontal influences on limbic circuits in depression, our results shift the focus from spatially restricted, sparsely connected brain network models to an abnormality in an extended (presumably hierarchical) insula-centered processing deficit in depression. This provides a novel hypothesis for
Role of funding source
Funding for this study was provided by National Natural Science Foundation of China (91232719), the “12th Five-year Plan” of National Key Technologies R&D Program (2012BAI01B04), National Key Clinical Disciplines at Shanghai Mental Health Center (OMA-MH 2011-873), Grants YG2012MS11, STCSM134119a6200, GWHW201208. These grants had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for
Contributors
Author SJI undertook data analyses and wrote the first draft of the manuscript. Author YRF designed and supervised the study. Author KJ supervised the study. Author EBL prepared the data for processing. Author PFL supervised parts of the data analysis and contributed to interpretation of results. Author DHP collected all of the data and analyzed the clinical characteristics. Author LP developed the hypothesis, supervised the data analysis, interpreted the results and helped draft the
Conflict of interest
SJI, YF, KJ and EBL report no potential conflicts of interest in relation to this work.
PFL has received institutional grant support from the Medical Research Council (G0601442 and MR/J01186X/1) and the Dr. Hadwen Trust (PI: Peter Morriss); and receives book royalties from the Royal College of Psychiatrists. DHP is supported by the Science Fund of Shanghai Jiao Tong University (YG2012MS11), Fund of Science and Technology Commission of Shanghai Municipality (134119a6200), Overseas Talent Project
Acknowledgments
Dr. Peng and Dr. Palaniyappan contributed equally to this work.
References (38)
- et al.
Reduced dopamine turnover in the basal ganglia of depressed suicides
Brain Res.
(1997) - et al.
Brain effects of antidepressants in major depression: a meta-analysis of emotional processing studies
J. Affect. Disord.
(2011) - et al.
New targets for rTMS in depression: a review of convergent evidence
Brain Stimul.: Basic Transl. Clin. Res. Neuromodul.
(2013) - et al.
DEM: a variational treatment of dynamic systems
NeuroImage
(2008) - et al.
Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination
Biol. Psychiatry
(2011) - et al.
Decreased regional homogeneity in insula and cerebellum: a resting-state fMRI study in patients with major depression and subjects at high risk for major depression
Psychiatry Res.
(2010) - et al.
Alternative projections of mortality and disability by cause 1990–2020: global burden of disease study
Lancet
(1997) - et al.
Neural primacy of the salience processing system in schizophrenia
Neuron
(2013) - et al.
Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion
NeuroImage
(2012) - et al.
The effect of intra- and inter-subject variability of hemodynamic responses on group level Granger causality analyses
NeuroImage
(2011)
Network modelling methods for FMRI
NeuroImage
The insular cortex and the neuroanatomy of major depression
J. Affect. Disord.
A blind deconvolution approach to recover effective connectivity brain networks from resting state fMRI data
Med. Image Anal.
Regional homogeneity in depression and its relationship with separate depressive symptom clusters: a resting-state fMRI study
J. Affect. Disord.
Functional connectivity in the motor cortex of resting human brain using echo-planar mri
Magn. Reson. Med.
Structural and functional neuroimaging studies in major depressive disorder with psychotic features: a critical review
Schizophr. Bull.
Psychological autopsy studies of suicide: a systematic review
Psychol. Med.
DPARSF: a MATLAB toolbox for “Pipeline” data analysis of resting-state fMRI
Front. Syst. Neurosci.
A functional anatomical study of unipolar depression
J. Neurosci.
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