Characterization of brain functional connectivity in treatment-resistant depression
Introduction
Major depression is one of the most common psychiatric diseases associated with other medical and mental illnesses. The prevalence of major depressive disorder (MDD) is considerable; ~4.7% of the world's population (Ferrari et al., 2013). Approximately, one-third of MDD patients do not respond to common therapies, known as treatment-resistant depression (TRD) patients (Berlim and Turecki, 2007; Dandekar et al., 2018; Daskalakis and Sun, 2017). Recently, deep-brain stimulation (DBS) has been developed and used to treat TRD (Lozano et al., 2008; Kennedy et al., 2011). The brain regions suggested for DBS treatment are inclusive of the subcallosal cingulate gyrus (SCG) (Lozano et al., 2008; Puigdemont et al., 2012) ventral caudate (VCa) (Malone et al., 2009), inferior thalamic peduncle (ITP) (Jiménez et al., 2005), lateral habenula (LHb) (Sartorius and Henn, 2007; Hoyer et al., 2012), and nucleus accumbens (NAc) (Bewernick et al., 2010). The therapeutic responses to stimulation in each of these brain regions were observed only in 50–60% of TRD subjects (Bewernick et al., 2012; Lozano et al., 2008). These findings may suggest that the success of DBS therapy can be associated with alterations in the structural and functional connections among DBS targets, which is subject-dependent and has remained a major clinical challenge.
Based on the literature, brain structural and functional connectivity (FC) between the DBS regions and other major areas are typically affected by depression. Increased FC between the striatum and dorsolateral prefrontal cortex (He et al., 2019; Vasic et al., 2015), LHb with key brainstem structures (i.e., ventral tegmental area, substantia nigra, pons) as well as the anterior and posterior cingulate cortices, precuneus, thalamus, and sensorimotor cortex. (Ely et al., 2016) have been reported in TRD patients. In contrast, a decreased hypothalamic FC with SCG was observed in these patients (Sudheimer et al., 2015). Thus, it was expected that a suitable stimulation of a DBS target should modulate the abnormal activities in the network of various DBS targets. NAc-DBS reduced abnormal hyperactivity of SCG and orbital frontal cortex (OFC) in TRD (Bewernick et al., 2010). Similar network alterations were obtained by SCG-DBS, which improved the hypoactivity of NAc (Lozano et al., 2008; Kennedy et al., 2011). Interestingly, SCG hyperactivity was also modulated by VCa-DBS. These studies have shown that DBS targets are connected and functionally related. However, the literature demonstrated that these connections are subjective and treatment success depends on the personalized refinement of DBS, particularly a precise selection of DBS target for each TRD patient. In this regard, Accolla et al. (2016) found stronger connectivity of SCG to the medial prefrontal cortex (mPFC) in TRD subjects treated with SCG-DBS compared to those who were non-responders (Accolla et al., 2016). Similarly, another study showed structural connections from SCG to the medial frontal cortex, rostral and dorsal cingulate cortex, and subcortical nuclei in all DBS responders, while these connections were not consistently observed in non-responders (Riva-Posse et al., 2014). Therefore, approximately 40% of patients did not respond appropriately to DBS probably due to a lack of structural and functional connectivity between the different DBS areas in the brain networks (Accolla et al., 2016; Fox et al., 2014; Padmanabhan et al., 2019; Riva-Posse et al., 2014). This indicates that the evaluation of brain structural and FC can be used as a suitable tool to address the clinical challenge of determining the appropriate DBS brain region for each patient. Also, the reflection of the neuronal activity of a brain region is directly related to the cerebral blood flow (CBF) in that region, which can be measured by functional neuroimaging techniques such as PET and arterial spin labeling (ASL) (He et al., 2019). Earlier studies have shown that FC has a metabolic basis that is coupled with CBF and the rate of metabolism. Thus, a brain region with greater FC has a higher metabolism rate (Soddu et al., 2016; Riedl et al., 2014; Li et al., 2012). Therefore, in this study, we used functional magnetic imaging (fMRI) to extract FC between brain regions based on the blood‑oxygen-level-dependent (BOLD) signal at rest.
Graph-theoretical network analysis is an appropriate method that allows to determine the organization of brain connectivity, to characterize the topological properties of brain networks, and to examine the complexity of brain networks globally and locally. Globally, the general properties of the whole brain are examined; whereas, in the nodal or local networks, the graph features are calculated for specific regions of the brain (Wang et al., 2010; Bullmore and Sporns, 2009).
Several metrics are developed to measure the ‘centrality’ of a brain network, including the clustering coefficient, nodal degree centrality, betweenness centrality, node neighbor's degree, and closeness centrality (Bullmore and Sporns, 2009). These features have been used to investigate specific changes in the topological properties of the brain graph. Among them, nodal degree is the most popular measure of centrality since it is directly related to functional connectivity, in contrast to other measures that provide redundant information (Oldham et al., 2019; Bullmore and Sporns, 2009). Furthermore, nodal degree is shown to have a high correlation with other centrality metrics (Oldham et al., 2019; Rueda et al., 2017). Nodal degree is expressed as ‘degree’ throughout the manuscript. For the sake of sensitivity, the degree can be measured locally considering merely the nodes of desired networks. Given that degree quantifies FC, it can be concluded that a brain region with a greater degree has a greater CBF rate and metabolism, and as a result higher neuronal activity.
Importantly, earlier studies reported hemispheric asymmetry for the emotional process (Canli, 1999; Alves et al., 2008). There is also indirect evidence suggesting that the underlying mechanisms of TRD might be different between males and females. This may explain the greater prevalence of TRD among females (Kuehner, 2017; Albert, 2015). Overall, the information about gender and brain lateralization dependence of brain abnormal activities in TRD subjects is limited, ambiguous, and controversial.
We aimed to use the degree to compare the FC of five target brain regions of DBS, as stated above, between both brain hemispheres of females and males in both the TRD and control subjects. We expected the outcomes to improve our understanding of the mechanisms underlying TRD. In particular, we expect the degree along with other major clinical measures to assist with more accurate decision-making in determining the precise target brain region for DBS treatment in each TRD patient.
Section snippets
Subjects and clinical assessments
Thirty-one individuals with TRD and twenty-nine healthy control (HC) subjects were examined. Table 1 summarizes the demographic and clinical characteristics of both groups. All TRD subjects had: at least two trials with anti-depressants from different pharmacological classes (adequate in terms of dosage, duration, and compliance) that failed to produce a significant clinical improvement in TRD subjects. The severity of TRD was evaluated using the 17-item Hamilton Depression Rating Scale
Brain FC: differences in degree values between the TRD and HC groups
To evaluate the effects of brain lateralization on FC, the degree value was calculated for both brain hemispheres in both females and males in the TRD and HC groups throughout the result section; Fig. 2, Fig. 4, Fig. 5, Fig. 6.
Fig. 2 shows the comparison of the degree values of DBS target regions between the HC and TRD groups, using the non-parametric permutation test. Dark-blue points present the difference in degree values between the healthy and TRD groups (TRD-HC), which lie within the
Discussion
We aimed to examine the FC of the target brain regions for DBS in TRD patients. We used the graph theory to measure the degree parameter to characterize the FC of these regions. Our results showed that compared to the HC subjects, the TRD group had a significant difference in degree in the left and right VCa, left LHb, and left ITP regions. Our findings also emphasized the fact that changes in the FC of different regions varied considerably among TRD patients, which makes it difficult to
Limitations and future directions
Using degree measures, we identified abnormal systematic changes in DBS target regions. Out of five DBS target areas, only three areas showed a statistically significant difference between the HC and TRD groups. This could be mainly due to high intersubject variability in degree changes in TRD patients. Furthermore, our results showed that FC (degree) was strongly dependent on gender as well as brain hemispheres. Although these findings were statistically significant, the power was relatively
Clinical significance
Mental disorders, whether based on brain structural changes or not, are usually associated with brain functional changes. Most clinical diagnoses and therapies are based on clinical evaluations, which are both qualitative and strongly dependent on the skills of the specialist, and can lead to increased error in diagnosis and sometimes misinterpretation of therapeutic interventions. Quantitative and objective methods are essential for accurate diagnosis and careful examination of the treatment
Data availability statement
Data can be made available upon reasonable request.
Funding
This work was supported by the Tehran University of Medical Sciences (TUMS) grant [TUMS-95-04-30-33505].
Declaration of competing interest
All authors declare that has no conflict of interest.
Acknowledgement
We thank the contribution of the Iranian National Brain Mapping Laboratory (NBML).
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2023, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :The CAU, part of the striatum, is closely associated with pleasure deficits and psychomotor retardation and plays an important role in the reward network (Friedman, 1994; Bora et al., 2012). Previous studies found that the FC of the ventral caudate nucleus and hypothalamus was significantly increased in TRD patients compared to the HC group, suggesting that this may be an important target for deep brain stimulation (Amiri et al., 2021). Another study found abnormal activation of BOLD signaling between the bilateral DLPFC and the right CAU in patients with long-term grief disorder (Bryant et al., 2021).