Relationship breakdown are associated with changes in resting-state whole-brain dynamics

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During a person’s life, the experience of a stressful life event can lead to the development of depressive symptoms, even in a non-clinical population.

For example, a relationship breakup is a fairly common event and is a powerful risk factor for quality of life, in addition to increasing the risk of a major depressive disorder.

Resting-state neuroimaging studies have increasingly identified abnormal whole-brain communication in patients with depression, but it is currently unclear whether depressive symptoms in individuals without a clinical diagnosis have reliable neural underpinnings.

Therefore, not enough attention has been paid to and not enough reliable neurological data are available concerning the symptoms of depression that some individuals may present at some time in their life without a clinical diagnosis, having been exposed to a stressful situation.

Research published in the advanced online edition of the journal NeuroImage: Clinical on 26 May studies whether individual differences in the severity of depressive symptoms following the breakdown of a relationship are associated to changes in resting-state whole-brain dynamics.

A study by Sonsoles Alonso Martínez, conducted under the supervision of Gustavo Deco, an ICREA research professor with the Department of Information and Communication Technologies (DTIC) and director of the Center for Brain and Cognition (CBC) at UPF, and co-author of the work, along with members of research centres at the European universities of Groningen (Netherlands), Oxford (UK), Aarhus (Denmark) and Minho (Braga, Portugal). Deco has contributed especially to the study methodology.

“In this study, we set out to investigate the dynamical complexity of the brain at rest by applying the intrinsic ignition framework to a dataset of 69 participants with varying degrees of depressive symptoms following a relationship breakup.

We hypothesized that greater levels of self-reported depressive symptoms are associated with reduced global integration and reduced spatiotemporal variability in the functional organization of the brain”, upholds Gustavo Deco, co-author of the study.

Intrinsic ignition analysis, proposed by Deco and Kringelbach (2017), both co-authors of the study, allows characterizing the degree of integration in the brain that results from spontaneous events arising over time.

These events reveal the ability of a given region to start the propagation of neural activity (i.e., ignition) to other regions eliciting varying degrees of integration in the brain. In turn, integration reflects the capacity of the brain to become interconnected and exchange information.

“We investigated whether the severity of depressive symptoms in non-clinical individuals was associated with changes in the dynamical complexity of the brain at rest”, the authors state. At the global level, ignition and ignition variability can be averaged across all brain regions to produce a global measure of integration and temporal variability, respectively. Temporal variability indicates the degree of dynamic flexibility, also referred to as metastability.

This is a diagram from the study
Calculation of ignition-based measures of dynamical complexity. These intrinsic ignition events reflect the capability of a given brain region to start the propagation of neuronal activity to other regions in the brain. Image is credited to UPF.

The results of the study revealed that the severity of depressive symptoms was associated with deficits in the brain’s ability to integrate and process information globally over time.

In addition, the researchers found that the majority of depressive symptoms were associated with reduced spatial diversity (i.e., hierarchy) and reduced temporal variability (i.e., metastability) in the functional organization of the brain.

Given the growing evidence that demonstrates altered resting-state dynamics across neuropsychiatric disorders, “our results in a nonclinical (yet vulnerable) population sample suggest the merit of investigating brain rigidity, understood as less complex brain dynamics, as a potential risk marker for mental health problems”, the study authors conclude.


Romantic love, a very old topic, has been recorded in the poetry, songs, stories, myths, and legends of human civilization for 1000s of years (Jankowiak and Fischer, 1992; Baumeister et al., 1993).

It has been regarded as the inspiration for some of the most extraordinary achievements of mankind (Bartels and Zeki, 2000), and plays an important role in human survival, reproduction, development, and evolution (Fisher, 1998).

Within the last century, romantic love has also become a topic of interest for scientists. Psychologists, for example, define romantic love as a motivational state associated with a desire to enter or maintain a close relationship with a specific other person (Aron and Aron, 1991; Cacioppo et al., 2012; Diamond and Dickenson, 2012). Love has also been shown to play a role in mediating reward and goal-directed motivation (Cacioppo et al., 2012; Diamond and Dickenson, 2012).

It can alter cognition and behavior, such as promoting intensely focused attention on the preferred individual, accompanied by euphoria, craving, obsession, compulsion, distortion of reality, emotional dependence, personality changes, and risk-taking (Peele and Brodsky, 1975; Clark and Mills, 1979). Romantic love is thus a complex sentiment, involving emotional, cognitive, and behavioral components (Sternberg, 1986; Hazan and Shaver, 1987).

In recent years, researchers have devoted increasing attention to the neurobiological substrates and neurological processes of romantic love. Bartels and Zeki (2000) published the first functional magnetic resonance imaging (fMRI) study investigating the brain of a person looking at a photograph of someone whom they love.

Many other researchers have further studied the pattern of brain activity of those who are in love using similar tasks (Bartels and Zeki, 2000, 2004; Aron et al., 2005; Ortigue et al., 2007; Acevedo and Aron, 2009; Fisher et al., 2010; Xu et al., 2011).

Reviews of these studies conclude that love is accompanied by significantly increased activation in brain regions such as the ventral tegmental area (VTA), medial insula, anterior cingulate cortex (ACC), hippocampus, nucleus accumbens (NAC), caudate nucleus, and hypothalamus. At the same time, deactivations can be found in the amygdala, prefrontal cortex (PFC), temporal poles, and temporo-parietal junction (TPJ; Zeki, 2007; de Boer et al., 2012; Diamond and Dickenson, 2012; Tarlaci, 2012).

Cacioppo et al. (2012) have suggested that romantic love-related brain regions can be divided into subcortical and cortical brain networks where the former mediates reward, motivation, and emotion regulation, and the latter mainly supports social cognition, attention, memory, mental associations, and self-representation.

However, it remains unclear whether romantic love also affects the functional architecture of the brain. After Biswal et al. (1995) proposed that functional connectivity (FC) can be studied using resting state functional magnetic resonance imaging (rsfMRI), Raichle et al. (2001) proposed the use of rsfMRI for investigating the brain when no specific task is pursued.

Compared to task-fMRI, rsfMRI is a tool for exploring the intrinsic functional architecture of the brain (Fox and Raichle, 2007; Van Den Heuvel and Hulshoff Pol, 2010; Chou et al., 2012; Lee et al., 2013). This approach helps avoid potential confounds and limitations encountered in task-based approaches (e.g., practice, ceiling or floor effects, or differential performance levels; Di Martino et al., 2008). RsfMRI thus provides promising opportunities for investigating the functional topology of the brain and has been widely used to study differences between populations, too (Fox and Raichle, 2007; Van Den Heuvel and Hulshoff Pol, 2010).

Most rsfMRI studies have adopted FC to examine the correlations and dynamics between brain networks. FC is defined as the correlation of spontaneous blood oxygen level-dependent (BOLD) signals between spatially remote regions (Aertsen et al., 1989; Friston et al., 1993). This measure describes the relationship between neuronal activation patterns of anatomically separated brain regions and networks (Van Den Heuvel and Hulshoff Pol, 2010).

FC has been widely used to study clinical populations such as schizophrenia (Lynall et al., 2010), Parkinson’s disease (Stoffers et al., 2008), autism spectrum disorder (Koshino et al., 2008), depression (Greicius et al., 2007), and substance abuse and dependence (Liu et al., 2010). However, FC provides little information about local features of spontaneous brain activity observed in individual regions.

In contrast, Regional Homogeneity (ReHo) is a local measurement of FC, defined as the temporary similarity between a given voxel and its neighbors (Zang et al., 2004). In this method, Kendall’s coefficient of concordance (KCC) (Zang et al., 2004) is used to measure the correlation between the time series of a given voxel and its nearest neighbor voxels in a voxel-wise way.

ReHo is a validated measure of brain functioning, measuring the synchronized oscillatory activity in the cerebral cortex that is essential for spatiotemporal coordination and integration of activity in anatomically distributed but functionally related neural elements (Van Rooy et al., 2005).

Neuronal synchronization is also hypothesized to underlie the efficient organization of information processing in the brain (Buzsáki and Draguhn, 2004), facilitating the coordination and organization of information processing across several spatial and temporal ranges (Fox et al., 2005).

In the past years, ReHo has been used to study a variety of populations including patients suffering from schizophrenia (Liu et al., 2006), Parkinson’s disease (Wu et al., 2009), autism spectrum disorder (Paakki et al., 2010; Shukla et al., 2010), and depression (Yao et al., 2009).

Given that romantic love is a motivational state (Aron and Aron, 1991; Cacioppo et al., 2012; Diamond and Dickenson, 2012) and that there are many specific psychological and behavioral changes in romantic lovers (such as intensely focused attention on a preferred individual, obsession, and risk-taking; Peele and Brodsky, 1975; Clark and Mills, 1979) as well as facilitation of cognitive behavior (Bianchi-Demicheli et al., 2006; Ortigue et al., 2007), it is not strange to assume that being in love may affect the underlying functional architecture structure of the involved brain regions. In the present study, we computed both ReHo and FC from rsfMRI data to investigate these proposed alterations in functional brain architecture in romantic lovers.

DISCUSSION
Although previous task-fMRI studies have preliminarily identified romantic love-related brain networks (Aron et al., 2005; Fisher et al., 2010; Xu et al., 2011), it remained unclear whether romantic love can affect the functional architecture of the brain. In the present study, we computed both ReHo and FC using rsfMRI data across three groups of participants (LG, “in-love” group who were currently intensely in love; ELG, “ended-love” group who recently ended a romantic relationship and were not currently in love; and SG, “single” group who had never fallen in love with anyone).

ReHo analysis results showed significantly increased ReHo of the left dACC in the in-love group (LG > SG, LG > ELG). Furthermore, the ReHo of the left dACC was positively correlated with the length of time in love in the LG, and was negatively correlated with lovelorn duration in the ELG, suggesting that the ReHo of the left dACC may be closely related to the state of falling in love.

At the same time, the ReHo of the bilateral caudate nucleus was significantly decreased in ELG (ELG < SG, ELG < LG), and was positively correlated with lovelorn duration in the ELG, suggesting that ReHo of the caudate nucleus may be closely related to the effects of ending a love relationship.

Results of FC showed that the lover group had significantly increased FC (LG > SG, LG > ELG) within the reward, motivation, and emotion regulation brain network (including the dACC, caudate nucleus, NAC, and insula) as well as in the social cognition network (including the TPJ, PCC, mPFC, precuneus, and inferior parietal lobe). C

omparable to the ReHo analysis results (in the left dACC), FCs in both networks were significantly positively correlated with the length of time in love in the LG, as well as negatively correlated with lovelorn duration in the ELG, suggesting that falling in love may also be associated with increased connectivity within certain brain networks.

ROMANTIC LOVE AND THE REWARD, MOTIVATION AND EMOTION REGULATION NETWORK
The ACC, caudate nucleus, amygdala, NAC, and insula are core components of the brain systems that play an important role in the processing of sensory and emotional information, reward, and motivational processes (Mogenson et al., 1980).

In the present study, we found significant increased FC in the LG (LG > SG, LG > ELG) between the ACC, caudate nucleus, amygdala, NAC, and insula. This may imply that romantic love may change the function of the reward, motivation, and emotion regulation brain network.

The dACC plays a key role in monitoring conflict through information processing, and compensatory adjustments in cognitive control (Botvinick et al., 2004). In fact, some researchers have found increased activation in the ACC individuals with greater social insight and maturity (Lane et al., 1998; Bush et al., 1999).

Bartels and Zeki (2000) suggested that the dACC is implicated in states of happiness, interoception (i.e., attention to one’s own emotional state), and also in social interactions that involve assessing one’s own and other people’s emotions and states of mind. For example, Aron et al. (2005) found that length of time in love is positively correlated with dACC activation when watching photographs of a romantic partner.

The caudate nucleus is highly innervated by dopaminergic neurons that originate mainly from the VTA and substantia nigra pars compacta (SNc). The caudate nucleus is associated with reward detection, expectation, representation of goals, and integration of sensory inputs (Aron et al., 2005; Lauwereyns, 2006).

The amygdala is mainly responsible for processing information related to fear, sadness and aggression, and mediating emotional learning (Dalgleish, 2004). Activation level in the amygdala has been shown to decrease when participants view photos of their sweetheart (Bartels and Zeki, 2000, 2004; Aron et al., 2005; Xu et al., 2011).

Furthermore, the NAC, a brain area coinciding with cortical areas rich in dopamine and oxytocin receptors, is an important part of the reward pathway that plays a central role in the visual perception of pleasant stimuli (Aharon et al., 2001; Sabatinelli et al., 2007). It is involved in both natural and abnormal reward processes (Breiter et al., 2001; Knutson et al., 2005; Baler and Volkow, 2006; Knutson and Wimmer, 2007; Cooper and Knutson, 2008).

Within the context of love, the recruitment of the NAC is therefore consistent with notions of romantic love as ‘a desire for union with another’ (Hatfield and Rapson, 1993; Acevedo et al., 2012).

The insula has been ascribed a role in representing subjective feelings, attention, cognitive choices, intentions, time perception, awareness of sensations, movements (Farrer and Frith, 2002; Critchley et al., 2004; Tsakiris et al., 2007), the visual image of the self (Devue et al., 2007), subjective expectations (Seymour et al., 2004; Preuschoff et al., 2008), and the trustworthiness of other individuals (Craig, 2002). Studies of romantic love report that the activity in the insula is increased when participants view their romantic partner’s picture (Bartels and Zeki, 2004; Ortigue et al., 2007; Fisher et al., 2010).

Previous research has demonstrated that spatially remote brain regions do not function independently, but rather, interact with one another during cognitive processing. For example, when individuals engage in a reinforcement learning paradigm relating to judging the positive or negative value of visual stimuli both the amygdala and the NAC are involved in signal processing, which is then passed on to the insula (Reynolds and Zahm, 2005; Paulus and Stein, 2006).

Unconditioned and conditioned sexual incentive cues are also known to be processed in the caudate nucleus, which expects, detects, and represents the reward values of the external stimulus, and outputs them to the insula (Cacioppo et al., 2012).

The control of a goal-directed behavior will involve both the insula, representing awareness, and the ACC, representing the control of directed effort (Craig, 2009). Thus, increased FC between these regions in a group of lovers may be the result of frequent efforts to monitor their own emotional state, as well as their lovers’ emotional state, monitoring conflicts while adjusting cognitive strategies in order to resolve conflicts so as to maintain their romantic relationship.

ROMANTIC LOVE AND THE SOCIAL COGNITION NETWORK
Our findings show that the LG had significantly increased FC compared to the SG and ELG between the TPJ seed and vMPFC, and dMPFC; and between the PCC seed and inferior parietal, MPFC, precuneus, and temporal lobe. Moreover, FC was significantly positively related to the length of time in love in the LG. These regions are part of a social cognition network, which contains brain areas activated during social interaction and areas involved in general cognition and attention. Regions activated during social interaction include the TPJ, vMPFC, and dMPFC.

This network has been consistently associated with social, moral and ‘theory of mind’ tasks (the ability to determine other people’s emotions and intentions) (Frith and Frith, 1999; Brunet et al., 2000; Gallagher and Frith, 2003), and has been associated with social trustworthiness (Winston et al., 2002), facial expressions (Winston et al., 2002), moral judgment (Greene and Haidt, 2002; Moll et al., 2002), and attention to one’s own emotions (Lane et al., 1997; Gusnard et al., 2001). Brain regions generally involved in social cognition include the PCC and inferior parietal and middle temporal cortices, which play a role in cognitive attention, and short-and long-term memory (Beauregard et al., 1998; Maddock, 1999; Cabeza and Nyberg, 2000; Buckner et al., 2008).

DOPAMINE, OXYTOCIN, VASOPRESSIN, AND ROMANTIC LOVE
Our results show increased FC between subcortical regions in lovers (between the caudate nucleus, NAC, amygdala, and insula), areas closely related to the mesolimbic dopaminergic system.

The mesolimbic dopaminergic system is suggested to be a mechanism by which humans and other mammals enact behaviors that maintain and protect their pair-bonds (Winslow et al., 1993; Sue Carter et al., 1995; Wang et al., 1997; Aragona et al., 2003). Dopamine has also been shown to play an important role in the romantic love of humans (Acevedo et al., 2012).

The VTA is centrally placed in a wider motivational/reward network associated with behaviors necessary for survival (Camara et al., 2009). It is considered a central platform for pleasurable feelings and pair-bonding (Ortigue et al., 2010). The NAC has been implicated in the interaction between the neurotransmitter dopamine and the neuropeptide oxytocin (Liu and Wang, 2003).

Both oxytocin and vasopressin have been shown to be crucially involved in romantic love and bonding (Kendrick, 2000; Fisher et al., 2006; Gonzaga et al., 2006). Oxytocin is released during sexual activity and mating, and may be the neurochemical mechanism for the anxiolytic effect of mating (Waldherr and Neumann, 2007).

Recently, Rilling et al. (2012) suggested that both oxytocin and vasopressin were associated with increased FC between amygdala and the anterior insula, possibly enhancing the amygdala’s ability to elicit visceralsomatic markers in order to guide decision-making. The increased FC observed between subcortical regions in lovers may therefore reflect the neurophysiological interaction between oxytocin, dopamine, and/or vasopressin while in a state of love.

EFFECT OF LOVELORN STATE ON BRAIN NETWORKS
Although we did not intentionally investigate the effect of lovelorn in the present study, we found that ReHo of the bilateral caudate nucleus was significantly decreased in the ELG (ELG < SG, ELG < LG) and was also correlated with the lovelorn duration of time since breakup of romantic relationship in the ELG (not correlated with the length of time in love in the LG).

As discussed before, the caudate nucleus is associated with detection of reward, expectation, representation of goals, and integration of sensory input (Aron et al., 2005; Lauwereyns, 2006).

Deep brain stimulation of the caudate nucleus has been shown to improve symptoms of anxiety disorder and major depression (Aouizerate et al., 2004). Neurochemical studies have demonstrated that these effects may be mediated by non-selective corticotropic-releasing systems.

Being in a relationship has been associated with elevated CRF mRNA in the bed nucleus of the stria terminalis in nerve fibers originating from the amygdal (Bosch et al., 2008). Therefore, the caudate nucleus may be very important for relieving symptoms of anxiety and depression. An elevated FC between regions involved in the anxiety-relief system after breaking up may be a sign of recovery.


Source:
UPF Barcelona

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