Over-activity in a single brain region called the subgenual anterior cingulate cortex (sgACC) underlies several key symptoms of mood and anxiety disorders, but an antidepressant only successfully treats some of the symptoms.
A new study, published today in the journal Nature Communications, suggests that sgACC is a crucial region in depression and anxiety, and targeted treatment based on a patient’s symptoms could lead to better outcomes.
Depression is a debilitating disorder affecting hundreds of millions of people worldwide, but people experience it differently.
Some mainly have symptoms of elevated negative emotion like guilt and anxiety; some have a loss of ability to experience pleasure (called anhedonia); and others a mix of the two.
Research at the University of Cambridge has found that increased activity in sgACC – a key part of the emotional brain- could underlie increased negative emotion, reduced pleasure and a higher risk of heart disease in depressed and anxious people.
More revealing still is the discovery that these symptoms differ in their sensitivity to treatment with an antidepressant, despite being caused by the same change in brain activity.
Using marmosets, a type of non-human primate, the team of researchers infused tiny concentrations of an excitatory drug into sgACC to over-activate it.
Marmosets are used because their brains share important similarities with those of humans and it is possible to manipulate brain regions to understand causal effects.
The researchers found that sgACC over-activity increases heart rate, elevates cortisol levels and exaggerates animals’ responsiveness to threat, mirroring the stress-related symptoms of depression and anxiety.
“We found that over-activity in sgACC promotes the body’s ‘fight-or-flight’ rather than ‘rest-and-digest’ response, by activating the cardiovascular system and elevating threat responses,” said Dr. Laith Alexander, one of the study’s first authors from the University of Cambridge’s Department of Physiology, Development and Neuroscience.
“This builds on our earlier work showing that over-activity also reduces anticipation and motivation for rewards, mirroring the loss of ability to experience pleasure seen in depression.”
To explore threat and anxiety processing, the researchers trained marmosets to associate a tone with the presence of a rubber snake, an imminent threat which marmosets find innately stressful. Once marmosets learnt this, the researchers ‘extinguished’ the association by presenting the tone without the snake.
They wanted to measure how quickly the marmosets could dampen down and ‘regulate’ their fear response.
“By over-activating sgACC, marmosets stayed fearful for longer as measured by both their behaviour and blood pressure, showing that in stressful situations their emotion regulation was disrupted,” said Alexander.
Similarly, when the marmosets were confronted with a more uncertain threat in the form of an unfamiliar human, they appeared more anxious following over-activation of sgACC.
“The marmosets were much more wary of an unfamiliar person following over-activation of this key brain region – keeping their distance and displaying vigilance behaviours,” said Dr. Christian Wood, one of the lead authors of the study and senior postdoctoral scientist in Cambridge’s Department of Physiology, Development and Neuroscience.
The researchers used brain imaging to explore other brain regions affected by sgACC over-activity during threat. Over-activation of sgACC increased activity within the amygdala and hypothalamus, two key parts of the brain’s stress network.
By contrast, it reduced activity in parts of the lateral prefrontal cortex—a region important in regulating emotional responses and shown to be underactive in depression.
“The brain regions we identified as being affected during threat processing differed from those we’ve previously shown are affected during reward processing,” said Professor Angela Roberts in the University of Cambridge’s Department of Physiology, Development and Neuroscience, who led the study.
“This is key, because the distinct brain networks might explain the differential sensitivity of threat-related and reward-related symptoms to treatment.”
The researchers have previously shown that ketamine – which has rapidly acting antidepressant properties – can ameliorate anhedonia-like symptoms.
But they found that it could not improve the elevated anxiety-like responses the marmosets displayed towards the human intruder following sgACC over-activation.
“We have definitive evidence for the differential sensitivity of different symptom clusters to treatment – on the one hand, anhedonia-like behaviour was reversed by ketamine; on the other, anxiety-like behaviours were not,” Professor Roberts explained.
“Our research shows that the sgACC may sit at the head and the heart of the matter when it comes to symptoms and treatment of depression and anxiety.”
The multifunctional protein CD38 (Cluster of Differentiation 38) contributes to individual differences in social cognition and behavior, which may result from CD38’s regulation of oxytocin secretion (Jin et al., 2007). The majority of human research associating CD38 genetic variation and social phenotypes has focused on two genetic variants of interest, rs3796863 (located in intron 7 on chromosome 4p15; Malavasi et al., 2008), and rs6449182 (located in a regulatory region in intron 1; Ferrero et al., 1999).
Compared to individuals with the rs3796863 CC genotype, A-allele carriers have been associated with enhanced social sensitivity in the form of increased parental sensitivity (Feldman et al., 2012), higher levels of empathy and altruism (Liu et al., 2017), and decreased risk of social impairments and autism spectrum disorders (Lerer et al., 2010; Munesue et al., 2010). Individuals carrying the A-allele have shown greater CD38 gene expression (Lerer et al., 2010) and higher levels of unextracted plasma oxytocin (Feldman et al., 2012) in comparison to individuals with the CC genotype.
However, contrary to previous results demonstrating beneficial socioemotional outcomes associated with the rs3796863 A-allele, our research group found that among individuals who experienced higher levels of interpersonal stress, A-allele carriers had higher levels of social anxiety and depression over a 6-year period compared to those with the CC genotype (Tabak et al., 2016).
As research on oxytocin (and related genes such as CD38), has progressed, paradoxical results such as these have led to the hypothesis that oxytocin enhances sensitivity to positive or negative social stimuli (Olff et al., 2013; Shamay-Tsoory and Abu-Akel, 2015).
Work focusing on oxytocin system genes has shown that variants associated with enhanced social sensitivity may contribute to positive or negative outcomes depending on relevant environmental factors and individual differences (Tabak, 2013). For example, several studies focused on variation in the oxytocin receptor gene polymorphism rs53576 have found that G-allele carriers who experienced childhood maltreatment were at greater risk for mental health concerns (Bradley et al., 2011; McQuaid et al., 2013; Andreou et al., 2018), even though the majority of research examining this SNP has found the G-allele to be beneficial or protective.
Further research focusing on variations in oxytocin system genes has shown that alleles previously associated with beneficial social outcomes may also be related to psychopathology when accounting for relevant moderators (Kushner et al., 2018). Together, studies such as these demonstrate that variation in oxytocin system genes, including CD38, may contribute to enhanced levels of social sensitivity, which can exacerbate the effects of environmental stressors that contribute to the development and maintenance of psychopathology (Tabak, 2013).
This is particularly relevant because positive associations between oxytocin and human social processes have often overshadowed evidence of the potential role of oxytocin in the development of psychopathology (McQuaid et al., 2014).
In the present study, we sought to build on our previous findings (Tabak et al., 2016) by investigating the underlying mechanisms that connect CD38, social sensitivity, and psychopathology. To examine this question, we focused on how CD38 genetic variation moderated a neural circuit that includes regions that have been associated with hyperactivation in both depression and social anxiety; specifically, we examined connectivity between the subgenual anterior cingulate cortex (sgACC) and the amygdala.
A host of neuroimaging research has focused on the sgACC and amygdala in depressed individuals (for review see Ressler and Mayberg, 2007). There is evidence of heightened activation in the amygdala and sgACC in individuals with depression when viewing negative stimuli, and post-treatment decreases in depression symptoms have been associated with decreased activation in these regions (Ressler and Mayberg, 2007).
Studies have also confirmed connectivity between the amygdala and sgACC (Stein et al., 2007) and this neural circuit has important relevance for emotion dysregulation, a prominent characteristic of mood disorders (Joormann and Vanderlind, 2014). Findings have shown greater positive amygdala-sgACC functional connectivity in depressed adolescents during resting-state (Connolly et al., 2013) and while processing fearful facial stimuli (Ho et al., 2014) compared to healthy controls. Similar results have emerged in relatives of individuals diagnosed with major depressive disorder (Wackerhagen et al., 2017).
Studies of individuals with social anxiety disorder have also found increased amygdala activation during emotional face processing (Ball et al., 2012) and when viewing negative (e.g. fearful or threatening) stimuli compared to healthy controls (Freitas-Ferrari et al., 2010; Gentili et al., 2016).
In addition, meta-analytic effects for increased activation in the sgACC have been found in individuals with social anxiety disorder (Gentili et al., 2016). Thus, there is evidence for amygdala and sgACC hyperactivation in both depression and social anxiety disorder, and evidence for altered functional connectivity between these regions in depression.
Elevated levels of neuroticism are a risk factor for depression and anxiety, including social anxiety (Kotov et al., 2010). Therefore, neuroticism is often examined as a trait level individual difference that is positively associated with current levels of anxiety and depression, as well as potentially higher future levels of psychopathology.
Neuroticism is also associated with more negative responses to stress, increased reactivity to threatening stimuli (Barlow et al., 2014), and heightened activation in the amygdala and sgACC (Haas et al., 2007). Given the relationship between neuroticism, psychopathology, and threat reactivity, it is important to note that a meta-analysis of neuroimaging studies examining neuroticism and emotion processing did not find an association between neuroticism and amygdala activation (Servaas et al., 2013).
Rather, findings from Servaas et al. (2013) suggest that the role of neuroticism in amygdala activation appears to be related to altered connectivity between the amygdala and frontal regions that result in emotion dysregulation (Servaas et al., 2013). Indeed, Cremers et al. (2010) found more inverse functional connectivity in the left amygdala and anterior cingulate cortex among individuals with higher levels of neuroticism when viewing negative stimuli.
Previous work by Pezawas et al. (2005) also found that inverse connectivity between the amygdala and sgACC was associated with increased harm avoidance (a construct highly correlated with neuroticism that has been associated with affective disorder symptomology; Jylhä and Isometsä, 2006) in short allele carriers in the 5-HTTLPR polymorphism.
In sum, previous findings suggest that higher levels of neuroticism and altered connectivity between the amygdala and sgACC may represent a common neurobiological mechanism underlying the development of social anxiety disorder and major depression.
In the present study, based on the associations between CD38 genetic variation and affective reactivity (Sauer et al., 2012), social anxiety, and depression (Tabak et al., 2016), we examined the relationship between amygdala-sgACC connectivity and neuroticism in individuals with varying levels of social anxiety and depression.
Using an a priori seed-based approach, we used psychophysiological interaction (PPI) analysis to investigate whether CD38 moderates the relationship between neuroticism and amygdala-sgACC connectivity. We hypothesized that higher levels of neuroticism would be related to positive connectivity in this neural circuit in individuals with genotypes (i.e. the rs3796863 A-allele) that have been associated previously with enhanced social sensitivity.
We also examined variation in a second CD38 SNP, rs6449182, since there is evidence that this polymorphism is functional and the G allele is associated with increased CD38 expression (Jamroziak et al., 2009; Polzonetti et al., 2012; but see Riebold et al., 2011)
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033443/
More information: Nature Communications (2020). DOI: 10.1038/s41467-020-19167-0