Introduction

Dispositional anxiety is a stable personality trait with biological underpinnings [1] that is a risk factor for numerous psychiatric disorders, including anxiety disorders, depression, and substance use [2–4]. Understanding individual differences in brain structure associated with this personality trait has the potential to advance understanding of the etiology of these burdensome disorders.

Previous research has shown that trait anxiety and anxiety-related traits are associated with variation in cortical volume and thickness of regions implicated in anxiety-related processes. For instance, trait anxiety and neuroticism have both been linked to reduced thickness in the orbitofrontal cortex [1,5,6]. Behavioral inhibition, a construct similar to trait anxiety, has been associated with decreased gray matter volume in the medial orbitofrontal cortices and the precuneus [7]. The orbitofrontal cortex is important for various cognitive and emotional processes that are thought to be impaired in anxiety, such as extinction learning [8]. Additionally, both the orbitofrontal cortex and precuneus have been identified as nodes in the default mode network (DMN), a neural network involved in self-referential or self-focused attentional processing [9–11]. This network is particularly relevant for internalizing disorders such as anxiety and depression, as DMN dysfunction may be a core neural substrate of pathological self-focused thought, such as rumination or worry [12–14].

As these studies indicate, trait anxiety is associated with abnormalities in cortical volume and thickness; however, to our knowledge no one has assessed the relationship between trait anxiety and cortical folding or gyrification. The process of gyrification begins in the second trimester in utero [15,16], and is thought to be largely complete by the third trimester [17]. Gyrification has been posited to reflect underlying structural connectivity because cortical folding allows for more efficient network wiring as surface area expands in the rapidly developing brain [18]. Initially, theories of gyrification argued the ratio of folding to surface area (the gyrification index) [19] remains relatively constant after the first few years of life, and therefore should primarily reflect early developmental, and genetic influences [17]. However, more recent evidence has pointed to developmental changes in gyrification throughout adolescence and adulthood [16,20–22]. Additionally, monozygotic twins have differences in gyrification patterns, suggesting a greater role for environmental factors influencing gyrification, more so than measures of cortical volume [23,24]. This is particularly true within more superficial sulci [25]. Therefore, differences in gyrification patterns may arise across a larger window of development than previously thought. Importantly, gyrification has been linked to measures of cortical connectivity, both functional [26] and structural [27]. Thus, abnormal cortical folding may provide insight into variation in cortical connectivity that may arise during cortical development.

Aberrant gyrification has been linked to various psychiatric disorders such as schizophrenia [28,29] and autism [30,31]. Abnormal morphology may, therefore, represent a disruption in neurodevelopment that puts one at risk for these and other disorders. Of most relevance for the current study, investigations across clinical samples of anxiety and depression in adults have revealed gyrification abnormalities in the precuneus and posterior cingulate, another key node in the posterior DMN [32–34]. Additionally, there is some evidence suggesting that gyrification abnormalities are linked to dysfunction in this network. Nixon and colleagues [33] found that individuals with depression displayed hypogyrification in the precuneus, as well as increased task-based functional connectivity between the precuneus and anterior nodes of the DMN. Since the DMN is thought to subserve self-focused thought, excessive connectivity may reflect pathological self-focus such as worry [13,14]. Thus, research in this area suggests that there may be a link between gyrification and DMN dysfunction in internalizing disorders that may reflect a vulnerability to developing an anxiety or depressive disorder.

The aim of the current study was to investigate abnormalities in cortical folding that may be associated with trait anxiety, a core risk factor for some of the most prevalent forms of psychopathology, including anxiety disorders, depression, and substance use. Examining gyrification alongside trait anxiety may provide us with important clues about structural differences that arise during neurodevelopment that are associated with this important risk factor. We used a three-dimensional measurement of gyrification, the local gyrification index (LGI) [35], to assess differences in gyrification as a function of trait anxiety.

Materials and Methods

Results

The vertex-wise analysis revealed a negative correlation between trait anxiety and LGI in the precuneus in the left hemisphere (cluster size = 2608.73 mm², 5940 vertices, cluster corrected p = .003; Fig 1). There were no regions where LGI was positively associated with trait anxiety, and there was no moderating effect of sex. There was no relationship between anxiety and gyrification in the right hemisphere.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Fig 1. Decreased precuneus gyrification is associated with trait anxiety.

(A) Inflated and pial surface maps of the left hemisphere demonstrating decreased gyrification in the precuneus as a function of trait anxiety. Images on the left depict the medial view of the left hemisphere. Images on the right are a view from the top of the right hemisphere and are tilted 30 degrees to provide a better angle for viewing the cluster extent. (B) Scatterplot of the correlation between trait anxiety and average LGI within the precuneus cluster.

https://doi.org/10.1371/journal.pone.0149434.g001

We conducted follow up analyses to better understand how other features of the cortical surface may be related to or explain differences in gyrification in the precuneus. Specifically, we correlated average surface area and cortical thickness with average LGI within the significant precuneus cluster. Controlling for the effects of sex and age, we found that surface area was positively associated with LGI (r = 0.204, p = 0.032; Fig 2A). Additionally, we found that cortical thickness was negatively correlated with LGI (r = -0.253, p = 0.007; Fig 2B). The relationships between these measurements and gyrification are consistent with previous findings [20,21]. To determine whether differences in surface area and cortical thickness accounted for the relationship between LGI and trait anxiety, we assessed the relationship between average precuneus LGI and trait anxiety with average surface area and cortical thickness added as covariates (in addition to age and sex). We found that even after controlling for variance in surface area and cortical thickness, there was still a negative association between trait anxiety and LGI (r = -0.315, p = 0.001; Fig 2C).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Fig 2. Correlations between LGI and other cortical measurements.

(A) Scatterplot of the correlation between total surface area and average LGI within the precuneus. (B) Scatterplot demonstrating a negative correlation between average cortical thickness and average LGI within the precuneus. (C) Scatterplot demonstrating the correlation between trait anxiety and LGI when controlling for both cortical surface area and thickness.

https://doi.org/10.1371/journal.pone.0149434.g002

Discussion

In the current study, we investigated differences in cortical gyrification associated with dispositional anxiety. We found that there was less gyrification in the left precuneus as dispositional anxiety increased. Although both cortical thickness and surface area were associated with gyrification, the relationship between precuneus gyrification and trait anxiety remained significant when controlling for these other cortical measurements. These findings suggest that there may be differences that arise during neurodevelopmental in the precuneus in those with dispositional anxiety, though longitudinal replication is warranted. Since theoretical [43] and empirical work [26,27,33] have linked gyrification to underlying cortical connectivity, these aberrations in cortical morphology may be indicative of abnormalities in connectivity between the precuneus and corresponding networks.

Functionally, the precuneus is involved in broad attentional and memory processes, as well as self-reflection and self-focused thinking [44], and is a key node in the DMN [9–11]. Studies of anxiety and anxiety disorders have found abnormalities in both activation and functional connectivity of the DMN [45]. Increased DMN activation has been also been linked to subjective reports of worry [13,14]. Additionally, several studies have found that in healthy individuals, precuneus activation is negatively correlated with activation of the amygdala [46,47]. Moreover, connectivity between these regions has also shown to be altered in social anxiety [48], panic disorder [49] and in youths with generalized anxiety disorder [50]. Thus, the precuneus may play a modulatory role in affective processing, which is disrupted in anxiety [7,47]. The current findings raise the possibility that structural abnormalities in the precuneus may underlie some of the functional abnormalities previously observed in anxiety in this region and related circuitry.

Our findings are consistent with previous studies showing precuneus structural abnormalities in anxiety-related personality dimensions and LGI-specific precuneus findings in clinical populations. Both behavioral inhibition [7] and harm avoidance, [51] have been associated with decreased precuneus gray matter volume. This relationship has also been detected in trait anxiety, but did not survive correction for multiple comparisons [52]. Additionally, although this is the first study to assess gyrification within dispositional anxiety, our findings are consistent with previous studies examining gyrification in clinical samples of anxiety and depression. Yoon and colleagues [32] demonstrated that hypogyrification in the precuneus was associated with greater severity of symptoms in panic disorder, and Zhang and colleagues found precuneus/posterior cingulate cortex (PCC) hypogyrifaction in individuals with depression. Nixon and colleagues [33] replicated the finding of decreased precuneus gyrification in depression and further showed that this hypogyrification was associated with hyper-connectivity between the precuneus and the dorsal lateral prefrontal cortex. Their findings are consistent with the hypothesis that morphological abnormalities may reflect altered functional connectivity. The present study extends these previous findings by suggesting that abnormalities in precuneus cortical folding across these disorders may in part be due to the presence of these abnormalities in dispositional anxiety, a core risk factor that is common to these emotional disorders [2–4].

As posited above, the current findings may provide insight into the development of trait anxiety by demonstrating a structural correlate that may arise during neurodevelopment. Although earlier theories posit that the degree of brain gyrification takes place primarily in utero and then stays constant through childhood and beyond [16,17], recent evidence has suggested that there are developmental changes in gyrification throughout the lifespan [16,20–22]. Since the age of onset for various anxiety disorders ranges from early childhood to adulthood [53], it is hard to definitely understand when these cortical differences occur without assessing changes longitudinally. Additionally, the current study can only infer that these patterns may represent abnormalities in neurodevelopment, for we did not assess cortical changes across development or between individuals of different ages. However, structural abnormalities in the precuneus and posterior cingulate have been identified in pediatric samples, with anxious youths showing gray matter volume abnormalities [54,55], supporting the possibility that the current LGI findings represent aberrations in early neurodevelopment.

We also investigated how other aspects of cortical structure correlated with LGI in the precuneus in order to provide a broader picture of the cortical surface and better understand how these measurements are related to each other. Consistent with previous research [20,21], surface area had a positive relationship with LGI while cortical thickness had a negative relationship. While LGI was associated with thickness and surface area, these variables did not fully account for the relationship between LGI and anxiety. Since other cortical structural measures could not fully explain the relationship between LGI and trait anxiety, it is possible that other structural factors are influencing this relationship. For instance, certain theories of gyrification have emphasized the role of white matter tension [43] or white matter constraints [56] in the development of gyrification. Therefore, it is possible that the current findings reflect underlying differences in white matter strength. Further research on gyrification may be useful in understanding the association between gyrification abnormalities and the structural connectivity of broader neural networks in this population.

Conclusions

In conclusion, we found differences in cortical gyrification associated with trait anxiety that could not be explained by surface area or thickness within a key DMN node. These findings are consistent with findings in clinical populations, highlighting the possibility that differences in local parietal connectivity are associated with a personality dimension that is a key risk factor for many of the most common forms of psychopathology. Although we did not investigate connectivity directly, future research may shed light on whether these structural differences are linked to disruptions in network connectivity. This structural aberration may in turn contribute to the emotional difficulties evident in high trait anxiety through influences on a primary node of the DMN subserving self-referential and self-conscious thought.