MRI illuminates abnormalities in the brains of people with depression, potentially opening the door to new and improved treatments for the disorder, according to two studies presented this week at the annual meeting of the Radiological Society of North America (RSNA).
Major depressive disorder (MDD) is one of the most common and debilitating mental disorders worldwide.
Symptoms include feelings of hopelessness, diminished interest in daily activities, and fatigue. Limited understanding of the brain changes associated with MDD hinders the effectiveness of treatments.
“Unfortunately, with current treatments there is a large chance of relapse or recurrence,” said Kenneth T. Wengler, Ph.D., from Columbia University in New York City and co-author of one of the studies. “To develop new, more effective treatments, we must improve our understanding of the disorder.”
Dr. Wengler and colleagues at the Renaissance School of Medicine at Stony Brook University in Stony Brook, N.Y., recently studied connections between MDD and disruptions in the blood-brain barrier (BBB), a network of blood vessels and tissue that protects the brain from foreign substances.
Using a new MRI technique they developed called intrinsic diffusivity encoding of arterial labeled spins (IDEALS), they looked at BBB water permeability, or the movement of water out of the blood vessels and into the brain tissue.
Comparison of results in 14 healthy individuals and 14 MDD patients found that less water moved from inside the blood vessels to outside in the MDD patients, representing disrupted BBB integrity.
This difference was particularly large in two regions of the brain: the amygdala and the hippocampus.
“We observed disruption of the blood-brain barrier in gray matter regions known to be altered in major depressive disorder,” Dr. Wengler said.
“This study helps improve our understanding of the pathophysiology of depression and can open new avenues of treatment for a disorder that affects over 100 million individuals worldwide.”
A second study presented at RSNA 2019 looked at abnormalities in the complex network of connections in the brain known as the connectome for their role in depression.
Previous research has focused on characterizing the connections between different brain regions, but this study, from researchers at the University of North Carolina (UNC) in Chapel Hill, N.C., looked deeper within individual brain regions.
The researchers compared 66 adults with MDD and 66 matched healthy controls during wakeful rest using functional MRI (fMRI) and a newly developed multiscale neural model inversion framework that linked the brain’s microscopic circuitry with its larger-scale interactions.
As part of the study, the researchers were able to assess excitatory or inhibitory influence between neuronal cell groups.
A proper balance between excitation and inhibition is crucial to a well-functioning brain.
Overview of the computational modeling study. MRI is performed to obtain functional MRI (fMRI) and diffusion MRI (dMRI) data of the patient.
Functional connectivity (FC) and structural connectivity (SC) are computed based on fMRI blood-oxygen-level-dependent (BOLD) signals and dfMRI tractography.
The SC and FC information is used as input to the computational model which generates simulated neural activity and corresponding simulated BOLD signals, together with estimates of the intra-regional and inter-regional connectivity parameters.
Predictions about the pathophysiological mechanisms of major depressive disorder (MDD) can then be made by comparing the connectivity parameter estimates of normal control (NC) patients with individuals with MDD. The image is credited to RNSA.
Patients with MDD had abnormal patterns of excitation and inhibition at the dorsal lateral prefrontal cortex, a brain area important to cognitive control functions, including the regulation of the amygdala, a key region embedded deep in the brain for expression of emotion.
It has long been hypothesized that malfunctioning inhibitory control over the amygdala could result in depressive symptoms.
“In our study, we found that excitation and inhibition in the brain regions in control of executive functions and emotional regulation were reduced in patients with MDD,” said study co-author Guoshi Li, Ph.D., from the Image Display, Enhancement and Analysis (IDEA) group at UNC.
“This suggests that control functions in MDD are impaired, which may lead to elevated responses in the amygdala, resulting in increased anxiety and other negative moods.”
In addition, the researchers found that recurrent excitation in the thalamus, an area of the central brain that is also responsible for emotional regulation, was abnormally elevated in patients with MDD.
Dr. Li said the new approach could open the door for a deeper understanding of the mechanisms behind depression.
“Current methods of studying the brain provide a superficial understanding of connectivity,” Dr. Li said.
“This method allows us to identify impaired connectivity within each brain region, making it a potentially more powerful tool to study the neuromechanism of brain disorders and develop more effective diagnosis and treatment.”
Dr. Wengler’s co-authors are Kwan Y. Chen, M.D., Christine DeLorenzo, Ph.D., Mark E. Schweitzer, M.D., Turhan Canli, Ph.D., and Xiang He, Ph.D. The study was funded by Stony Brook University.
Dr. Li’s co-authors are Yujie Liu, M.D., Yanting Zheng, Ph.D., Ye Wu, Ph.D., Pew-Thian Yap, Ph.D., Shijun Qiu, M.D., Han Zhang, Ph.D., and Dinggang Shen, Ph.D. The study was funded by the National Institutes of Health.
Late-life depression (LLD) is one of the most common psychiatric disorders afflicting the growing geriatric population and is associated with cognitive, affective and somatic abnormalities in individuals aged 60 years and older (Blazer, 2003; Fiske et al., 2009; Desseilles et al., 2011; Elliott et al., 2011).
There is evidence to suggest that the severity of depressive symptomatology in LLD is a causal factor associated with neurocognitive decline, even when patients enter the euthymic phase or achieve remission (Paterniti et al., 2002; Bhardwaj et al., 2010; O’Shea et al., 2015; Yao & Meng, 2015).
Recent cross-sectional and longitudinal studies, however, have failed to demonstrate a significant relationship between LLD symptoms and cognitive impairments (Ganguli et al., 2006; Becker et al., 2009).
The discrepancy between these results suggests the presence of underlying mediators related to cognitive functioning in LLD, particularly individual differences in susceptibility to cognitive and functional decline in the context of age-related brain pathology (Barnett et al., 2006; Stern, 2007; O’Shea et al., 2015).
Cognitive reserve (CR) refers to an active process that involves facilitating the flexibility and efficiency of neural networks, to compensate for impairments emerging as a consequence of brain damage or pathology (Stern, 2002, 2007; Stern et al., 2018b).
A growing body of evidence supports the CR-related hypothesis that people with higher CR cope with age- and disease-related neurocognitive changes better than those with lower CR (Steffener & Stern, 2012; Stern, 2012) and, moreover, that levels of CR predict cognitive decline progression in individuals with neurological conditions (Tucker & Stern, 2011; Stern, 2012; Soldan et al., 2015).
For example, Alzheimer’s disease (AD) patients who had more education and demonstrated greater engagement in leisure activities (i.e. higher CR) suffered less neurocognitive decline (Scarmeas & Stern, 2004; Wilson et al., 2013).
By contrast, low CR would operate as a vulnerability factor for increased clinical symptoms of disease and functional limitations (Barnett et al., 2006; Phillips et al., 2008; Meng & D’Arcy, 2012).
These results suggest that CR may act as a protective mechanism by facilitating cognitive performance and decreasing age-related and disease-associated clinical symptoms consequent to brain pathology (Stern, 2007, 2009, 2012).
There is increasing interest in CR’s mode of impacting the relationship between age-related neurological diseases (e.g. AD) and cognitive decline; however, it remains unclear whether CR has analogous effects in the context of psychiatric conditions, especially among the at-risk elderly population (Butters et al., 2000, 2008; Tucker & Stern, 2011; Giogkaraki et al., 2013; Watson & Joyce, 2015; Deschamps, 2018).
Previous behavioral studies have used multiple measures of CR (e.g. educational attainment, occupational complexity and verbal ability) to demonstrate that levels of CR in later life impact the risk of depression (Turner & Lloyd, 1999; Spitznagel et al., 2006; Ladin, 2008). In these researches, higher CR appears to act as a protective factor against the symptoms of psychiatric conditions, including major depressive disorder (Turner & Lloyd, 1999; Barnett et al., 2006; Venezia et al., 2018).
These findings suggest that CR may be encoded more generally, rather than in disorder-specific ways, for the elderly population. Given that CR mechanisms may allow people to cope more effectively with a variety of age- and disease-related forms of cognitive decline and functional changes, it is worth noting that CR is relevant to both the pathological and normal aging process.
Despite the failure of some investigations to demonstrate CR’s positive effects on cognitive performance in individuals with LLD (Bhalla et al., 2005), a recent study reported that reading ability acts as a CR moderator to significantly influence the association between depressive symptoms and executive functioning in individuals with LLD (O’Shea et al., 2015).
Moreover, LLD patients with lower CR showed a greater loss of total brain volume than those with higher CR (O’Shea et al., 2015), suggesting that the protective effects of CR on cognitive functions and brain structure are generally obtained in the context of age-related psychiatric disorders.
Although there is considerable research focusing on the behavioral impacts of CR on age-related psychiatric disorders and on individual differences in cognitive performance, the underlying neural mechanisms in LLD are poorly understood.
Focusing solely on studies reliant on functional magnetic resonance imaging (fMRI) furnishes an opportunity to examine the neural signatures and mechanisms by which CR scaffolds neural function and maintains optimal cognitive performance in the face of aging-associated brain neurodegradation.
The concept of neural compensation is often invoked in fMRI studies in regard to neural mechanisms involved in the response to age- and disease-related brain pathology (Barulli & Stern, 2013; Stern et al., 2018b).
Neural compensation refers to an inter-individual variability in the capacity to compensate for brain pathology by making more efficient use of neural networks and recruiting alternative brain circuits (Park & Reuter-Lorenz, 2009; Grady, 2012; Huang et al., 2012; Stern, 2012; Korsnes & Ulstein, 2014; Cabeza et al., 2018). Evidence from recent functional neuroimaging studies reveals that higher CR was associated with greater activation in task-related brain regions in elderly patients with AD (Scarmeas et al., 2004; Sheline et al., 2006).
Moreover, a recent meta-analysis study indicated that elderly patients with AD and higher CR exhibited greater activation in the anterior cingulate cortex (ACC) during cognitive tasks relative to those with lower CR (Colangeli et al., 2016).
These findings suggest that elderly individuals with higher levels of CR are more capable of recruiting alternative and/or additional brain networks to respond to cognitive changes due to pathological aging, especially within the prefrontal regions (Korsnes & Ulstein, 2014; Scarmeas & Stern, 2004; Stern et al., 2018b).
There is compelling evidence to suggest that CR levels may be linked to the resilience and adaptability of the brain to cope with age- and disease-related cognitive declines. However, it is unclear whether and how CR modulates emotional regulation, measured as the level of depression severity and affective control, and neural mechanisms associated with emotional control in geriatric depression.
This fMRI study investigated whether individual differences in educational attainment and verbal capacity (the most widely used proxies for CR) modified the adverse influence of age-related psychiatric conditions on the severity of depression, cognitive performance and neural processing of emotional-cognitive control in LLD. Specifically, we hypothesized that the known adverse age-related psychiatric symptoms and cognitive impairment would be attenuated among individuals with higher CR who suffer from LLD.
The cognitive and neural processes of emotional-cognitive control were assessed using the emotional Stroop (eStroop) task, which heavily taps into selective attention, inhibition of emotional responses and conflict resolution (Dalgleish & Watts, 1990; Williams et al., 1996; Ben-Haim et al., 2016; Song et al., 2017). Individuals with LLD showed altered emotion-related activities in prefrontal-ACC-insula circuitries, and this has been identified as reflecting aberrant cognitive control mechanisms for processing emotional information (Fales et al., 2008, 2009; Frodl, 2016).
We then predicted that CR would modulate the neural activation patterns of localization involved in cognitive control and emotional awareness during the eStroop task, which involve the dorsolateral prefrontal cortex (DLPFC), ACC and the anterior insula (AI). Given that post-hoc mediation analysis provides a decent way of investigating the role of intermediate variables which play a role in the relationship between two other variables (Na et al., 2017; Fan et al., 2018), we applied this approach to our efforts to identify the associations of clinical and neurological variables which may be interrelated in LLD, CR, depression symptoms and brain function.
Linda Brooks – RSNA
The images are credited to RNSA.
Original Research: The studies will be presented at the 105th Scientific Assembly and Annual Meeting of the Radiological Society of North America-RSNA 2019.