Michelle N. Servaas

The biological and psychological basis of neuroticism: Current status and future directions

Neuroticism (N) is believed to reflect a stable disposition involving specific biological and psychological mechanisms that produce its robust association with psychopathology. The nature of these mechanisms remains unclear, however. Based on an extensive review of published evidence, we argue that three interesting leads are emerging. First, N may reflect individual differences in brain circuits involved in perception of and cognitive control over negative stimuli. More specifically, reduced connectivity between the left amygdala and ACC may impair extinction of the amygdala response to anxiety-eliciting stimuli. Second, the neural evidence matches the psychological findings, which associate N with a negative bias in attention, interpretation and recall of information, increased reactivity, and ineffective coping, and is consistent with findings of decreased cardiovascular flexibility. Third, current studies suggest that HPA-axis influences mood independently of N. Strong claims on Ns biological basis, however, are not yet justified due to inconsistencies and lack of replication which are in part due to methodological limitations and Ns heterogeneity. We discuss potential methodological improvements and substantive directions for future research.

Neural correlates of alexithymia: A meta-analysis of emotion processing studies

Alexithymia is a personality trait characterized by difficulties in the experience and cognitive processing of emotions. It is considered a risk factor for a range of psychiatric and neurological disorders. Functional neuroimaging studies investigating the neural correlates of alexithymia have reported inconsistent results. To integrate previous findings, we conducted a parametric coordinate-based meta-analysis including fifteen neuroimaging studies on emotion processing in alexithymia. During the processing of negative emotional stimuli, alexithymia was associated with a diminished response of the amygdala, suggesting decreased attention to such stimuli. Negative stimuli additionally elicited decreased activation in supplementary motor and premotor brain areas and in the dorsomedial prefrontal cortex, possibly underlying poor empathic abilities and difficulties in emotion regulation associated with alexithymia. Positive stimuli elicited decreased activation in the right insula and precuneus, suggesting reduced emotional awareness in alexithymia regarding positive affect. Independent of valence, higher (presumably compensatory) activation was found in the dorsal anterior cingulate possibly indicating increased cognitive demand. These results suggest valence-specific as well as valence-independent effects of alexithymia on the neural processing of emotions.

Filling the Gap: Relationship Between the Serotonin-Transporter-Linked Polymorphic Region and Amygdala Activation

The alleged association between the serotonin-transporter-linked polymorphic region (5-HTTLPR) and amygdala activation forms a cornerstone of the common view that carrying the short allele of this polymorphism is a potential risk factor for affective disorders. The authors of a recent meta-analysis showed that this association is statistically significant (Hedges’s g = 0.35) but warned that estimates might be distorted because of publication bias. Here, we report a replication study of this relationship in 120 participants. We failed to find an association of 5-HTTLPR variation with amygdala activation during a widely used emotional-face-matching paradigm. Moreover, when we conducted a meta-analysis that included unpublished studies and data from the current study, the pooled meta-analytic effect size was no longer significant (g = 0.20, p = .06). These findings cast doubt on previously reported substantial effects, suggesting that the 5-HTTLPR–amygdala association is either much smaller than previously thought, conditional on other factors, or nonexistent.

Neuroticism and the Brain: A Quantitative Meta-analysis of Neuroimaging Studies Investigating Emotion Processing

Neuroticism is a robust personality trait that constitutes a risk factor for mood disorders. Neuroimaging findings related to neuroticism have been inconsistent across studies and hardly integrated in order to construct a model of the underlying neural correlates of neuroticism. The aim of the current meta-analysis was to provide a quantitative summary of the literature, using a parametric coordinate-based meta-analysis (PCM) approach. Data were pooled for emotion processing tasks investigating the contrasts (negative>neutral) and (positive>neutral) to identify brain regions that are consistently associated with neuroticism across studies. Significant negative and positive correlations with neuroticism were found only for the contrast (negative>neutral) after multiple comparisons correction. Differences in brain activation were found to be associated with neuroticism during fear learning, anticipation of aversive stimuli and the processing and regulation of emotion. The relationship between neuroticism and these three psychological processes and their corresponding neural correlates is discussed. Furthermore, the meta-analytic findings are incorporated into a general model of emotion processing in neuroticism.

The Neural Correlates of Worry in Association with Individual Differences in Neuroticism

The tendency to worry is a facet of neuroticism that has been shown to mediate the relationship between neuroticism and symptoms of depression and anxiety. The aim of the current study was to investigate the neural correlates of state worry in association with neuroticism. One‐hundred twenty participants were selected from an initially recruited sample of 240 women based on their neuroticism score. First, participants completed a questionnaire to assess the excessiveness and uncontrollability of pathological worry. Second, we measured brain activation with functional magnetic resonance imaging (fMRI) while participants were randomly presented with 12 worry‐inducing sentences and 12 neutral sentences in a mood induction paradigm. Individuals scoring higher on neuroticism reported to worry more in daily life and to have generated more worry‐related thoughts after the presentation of a worry‐inducing sentence. Furthermore, imaging results showed the involvement of default mode and emotional brain areas during worry, previously associated with self‐related processing and emotion regulation. Specifically, cortical midline structures and the anterior insula showed more activation during worry, when individuals indicated to have generated more worry‐related thoughts. Activation in the retrosplenial and visual cortex was decreased in individuals scoring higher on neuroticism during worry, possibly suggesting reduced autobiographical specificity and visual mental imagery. In the literature, both these processes have been related to the cognitive avoidance of emotional distress. Excessive worry features in a number of emotional disorders and results from studies that elucidate its neural basis may help explain how and why neuroticism contributes to vulnerability for psychopathology. Hum Brain Mapp 35:4303–4315, 2014.

Connectomics and neuroticism: an altered functional network organization

The personality trait neuroticism is a potent risk marker for psychopathology. Although the neurobiological basis remains unclear, studies have suggested that alterations in connectivity may underlie it. Therefore, the aim of the current study was to shed more light on the functional network organization in neuroticism. To this end, we applied graph theory on resting-state functional magnetic resonance imaging (fMRI) data in 120 women selected based on their neuroticism score. Binary and weighted brain-wide graphs were constructed to examine changes in the functional network structure and functional connectivity strength. Furthermore, graphs were partitioned into modules to specifically investigate connectivity within and between functional subnetworks related to emotion processing and cognitive control. Subsequently, complex network measures (ie, efficiency and modularity) were calculated on the brain-wide graphs and modules, and correlated with neuroticism scores. Compared with low neurotic individuals, high neurotic individuals exhibited a whole-brain network structure resembling more that of a random network and had overall weaker functional connections. Furthermore, in these high neurotic individuals, functional subnetworks could be delineated less clearly and the majority of these subnetworks showed lower efficiency, while the affective subnetwork showed higher efficiency. In addition, the cingulo-operculum subnetwork demonstrated more ties with other functional subnetworks in association with neuroticism. In conclusion, the ‘neurotic brain’ has a less than optimal functional network organization and shows signs of functional disconnectivity. Moreover, in high compared with low neurotic individuals, emotion and salience subnetworks have a more prominent role in the information exchange, while sensory(-motor) and cognitive control subnetworks have a less prominent role.

The Effect of Criticism on Functional Brain Connectivity and Associations with Neuroticism

Neuroticism is a robust personality trait that constitutes a risk factor for psychopathology, especially anxiety disorders and depression. High neurotic individuals tend to be more self-critical and are overly sensitive to criticism by others. Hence, we used a novel resting-state paradigm to investigate the effect of criticism on functional brain connectivity and associations with neuroticism. Forty-eight participants completed the NEO Personality Inventory Revised (NEO-PI-R) to assess neuroticism. Next, we recorded resting state functional magnetic resonance imaging (rsfMRI) during two sessions. We manipulated the second session before scanning by presenting three standardized critical remarks through headphones, in which the subject was urged to please lie still in the scanner. A seed-based functional connectivity method and subsequent clustering were used to analyse the resting state data. Based on the reviewed literature related to criticism, we selected brain regions associated with self-reflective processing and stress-regulation as regions of interest. The findings showed enhanced functional connectivity between the clustered seed regions and brain areas involved in emotion processing and social cognition during the processing of criticism. Concurrently, functional connectivity was reduced between these clusters and brain structures related to the default mode network and higher-order cognitive control. Furthermore, individuals scoring higher on neuroticism showed altered functional connectivity between the clustered seed regions and brain areas involved in the appraisal, expression and regulation of negative emotions. These results may suggest that the criticized person is attempting to understand the beliefs, perceptions and feelings of the critic in order to facilitate flexible and adaptive social behavior. Furthermore, multiple aspects of emotion processing were found to be affected in individuals scoring higher on neuroticism during the processing of criticism, which may increase their sensitivity to negative social-evaluation.

Personalized Network Modeling in Psychopathology: The Importance of Contemporaneous and Temporal Connections

Recent literature has introduced (a) the network perspective to psychology and (b) collection of time series data to capture symptom fluctuations and other time varying factors in daily life. Combining these trends allows for the estimation of intraindividual network structures. We argue that these networks can be directly applied in clinical research and practice as hypothesis generating structures. Two networks can be computed: a temporal network, in which one investigates if symptoms (or other relevant variables) predict one another over time, and a contemporaneous network, in which one investigates if symptoms predict one another in the same window of measurement. The contemporaneous network is a partial correlation network, which is emerging in the analysis of cross-sectional data but is not yet utilized in the analysis of time series data. We explain the importance of partial correlation networks and exemplify the network structures on time series data of a psychiatric patient.

Lower dorsal striatum activation in association with neuroticism during the acceptance of unfair offers

Unfair treatment may evoke more negative emotions in individuals scoring higher on neuroticism, thereby possibly impacting their decision-making in these situations. To investigate the neural basis of social decision-making in these individuals, we examined interpersonal reactions to unfairness in the Ultimatum Game (UG). We measured brain activation with fMRI in 120 participants selected based on their neuroticism score, while they made decisions to accept or reject proposals that were either fair or unfair. The anterior insula and anterior cingulate cortex were more activated during the processing of unfair offers, consistent with prior UG studies. Furthermore, we found more activation in parietal and temporal regions for the two most common decisions (fair accept and unfair reject), involving areas related to perceptual decision-making. Conversely, during the decision to accept unfair offers, individuals recruited more frontal regions previously associated with decision-making and the implementation of reappraisal in the UG. High compared to low neurotic individuals did not show differential activation patterns during the proposal of unfair offers; however, they did show lower activation in the right dorsal striatum (putamen) during the acceptance of unfair offers. This brain region has been involved in the formation of stimulus–action–reward associations and motivation/arousal. In conclusion, the findings suggest that both high and low neurotic individuals recruit brain regions signaling social norm violations in response to unfair offers. However, when it comes to decision-making, it seems that neural circuitry related to reward and motivation is altered in individuals scoring higher on neuroticism, when accepting an unfair offer.

Vulnerability for new episodes in recurrent major depressive disorder: protocol for the longitudinal DELTA-neuroimaging cohort study

Introduction Major depressive disorder (MDD) is widely prevalent and severely disabling, mainly due to its recurrent nature. A better understanding of the mechanisms underlying MDD-recurrence may help to identify high-risk patients and to improve the preventive treatment they need. MDD-recurrence has been considered from various levels of perspective including symptomatology, affective neuropsychology, brain circuitry and endocrinology/metabolism. However, MDD-recurrence understanding is limited, because these perspectives have been studied mainly in isolation, cross-sectionally in depressed patients. Therefore, we aim at improving MDD-recurrence understanding by studying these four selected perspectives in combination and prospectively during remission. Methods and analysis In a cohort design, we will include 60 remitted, unipolar, unmedicated, recurrent MDD-participants (35–65 years) with ≥2 MDD-episodes. At baseline, we will compare the MDD-participants with 40 matched controls. Subsequently, we will follow-up the MDD-participants for 2.5 years while monitoring recurrences. We will invite participants with a recurrence to repeat baseline measurements, together with matched remitted MDD-participants. Measurements include questionnaires, sad mood-induction, lifestyle/diet, 3 T structural (T1-weighted and diffusion tensor imaging) and blood-oxygen-level-dependent functional MRI (fMRI) and MR-spectroscopy. fMRI focusses on resting state, reward/aversive-related learning and emotion regulation. With affective neuropsychological tasks we will test emotional processing. Moreover, we will assess endocrinology (salivary hypothalamic-pituitary-adrenal-axis cortisol and dehydroepiandrosterone-sulfate) and metabolism (metabolomics including polyunsaturated fatty acids), and store blood for, for example, inflammation analyses, genomics and proteomics. Finally, we will perform repeated momentary daily assessments using experience sampling methods at baseline. We will integrate measures to test: (1) differences between MDD-participants and controls; (2) associations of baseline measures with retro/prospective recurrence-rates; and (3) repeated measures changes during follow-up recurrence. This data set will allow us to study different predictors of recurrence in combination. Ethics and dissemination The local ethics committee approved this study (AMC-METC-Nr.:11/050). We will submit results for publication in peer-reviewed journals and presentation at (inter)national scientific meetings. Trial registration number NTR3768.