The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety

“Descriptive statistics for self-report measures are as follows: STAI-S, 32.85 7.03; STAI-T, 37.15 8.25; BDI, 3.40 3.97.”

“Handedness Inventory (Oldfield, 1971).”

“Diffusionweighted images were preprocessed using the Diffusion Toolbox and FSL software of the Oxford Centre for Functional MRI of the Brain (Smith et al., 2004).”

“mented in AlphaSim within AFNI software (Cox, 1996).”

“To generate spatially normalized individual FA images, each individual image was aligned into Montreal Neurological Institute (MNI)-152 standard space using nonlinear registration (Rueckert et al., 1999).”

“Voxels with FA values 0.2 were removed before statistical analyses, and an additional white matter mask derived from the Wake Forest University Pick Atlas (Maldjian et al., 2003) was applied to the images to ensure the results were attributable to white matter.”

“A popular scale that measures the degree of anisotropy is fractional anisotropy (FA), which is thought to be modulated by the degree of myelination, axonal membrane thickness and diameter, and/or amount of parallel organization of axons (Basser and Pierpaoli, 1996; Beaulieu, 2002).”

“Second, other studies showing an inverse relationship between the amygdala and vmPFC involved clinically pathological groups (Rauch et al., 2000; Shin et al., 2005; Etkin and Wager, 2007).”

“…this circuit in adolescents (Burghy et al., 2012; Herringa et al., 2013) as well as studies showing an association between higher levels of anxiety and reduced resting-state functional and structural connectivity in adults (M. J. Kim, Gee, Loucks, Davis, & Whalen, 2011; M. J. Kim & Whalen, 2009).”

“These include structural alterations in the uncinate fasciculus, which connects the amygdala and PFC [37], in the pulvinar [38] and in the amygdala itself [39].”

“…consistently associated with anxiety at the functional level (Frings, Schulze-Bonhage, Spreer, & Wagner, 2009; Hahn et al., 2011; Haas et al., 2007; Kim & Whalen, 2009; Phan et al., 2006; Rauch, Shin, & Wright, 2003), structural studies offer mixed results, which might be partly expected from the…”

“…functional-anatomical dissociation between bottom-up and top-down amygdala-FPl connectivity might also help to clarify the heterogeneity of previous findings concerning the relation between amygdala-prefrontal connectivity and state-anxiety measures (Kim and Whalen, 2009; Clewett et al., 2014).”

“matter tract connecting the amygdala and the ventral prefrontal cortex; greater white matter microstructure of the uncinate fasciculus predicted reduced amygdalar activation (Kim and Whalen, 2009; Swartz et al., 2014).”

“…& Raichle, 2001), more recent studies suggest that the structural and functional connectivity between these two regions is a better predictor of these outcomes than the activity of either region alone (M. J. Kim, Gee, Loucks, Davis, & Whalen, 2011; M. J. Kim & Whalen, 2009; Pezawas et al., 2005).”

“Furthermore, it has been suggested that in order to stop the generation of anxious states the strength of amygdala–mPFC functional connectivity during rest represents efficient crosstalk between these brain regions [16,17].”

“The level of anxiety was associated with the structural integrity of connections between amygdala and prefrontal cortex (PFC) and insula [Baur et al., 2013; Clewett et al., 2014; Kim and Whalen, 2009].”

“…disorder, social phobia, and trait anxiety [MacMillan et al., 2003; Pezawas et al., 2005; BarrosLoscertales et al., 2006; Etkin et al., 2009, 2010; Kim and Whalen, 2009; Spampinato et al., 2009; Cremers et al., 2010; Baur et al., 2011; Blackmon et al., 2011; Kim et al., 2011; Baur et al., 2012;…”

“Using DTI, Kim and Whalen (2009) observed that a stronger structural integrity in a pathway linking the amygdala and vmPFC also predicted lower anxiety levels.”

“, 2004) and altered structural and functional connectivity between the mPFC and amygdala (Kim and Whalen, 2009; Kim et al., 2011).”

“…regarding laterality is equivocal and requires future research, as our findings differentially implicated both right and left amygdala, while previous research has emphasized either left [Kim and Whalen, 2009], or bilateral [Westlye et al., 2011] amygdala structural connections in trait anxiety.”

“To isolate neural responses to emotional expressions and to compare activity for Fear and Surprise, we used the Neutral trials associated with each particular run as a baseline in all of our analyses involving facial expressions, as in previous work (Kim et al., 2003; Kim and Whalen, 2009).”

“A large body of human and animal studies indicates the existence of reciprocal connections linking these regions, via direct and indirect (polysynaptic) pathways (Eichenbaum, 2017; Kim and Whalen, 2009; € Ongür and Price, 2000; Preston and Eichenbaum, 2013; Saunders et al., 1988; Simons and Spiers, 2003).”

“associated with reduced structural integrity in amygdalaprefrontal pathways (assessed using diffusion tensor imaging; Kim and Whalen, 2009) and reduced (negative) functional connectivity between prefrontal cortex and amygdala during threat processing (Monk et al, 2008; for discussion of dysfunction in additional struc…”

“…psychiatric populations and individuals with drug addiction have suggested that impaired emotion and impulse control may result from a structural uncoupling between the PFC and subcortical brain areas (e.g., Crews & Boettiger, 2009; Kim & Whalen, 2009), leading to impairments of top-down control.”

“Structural changes in this area, which is critically implicated in cognition and emotion (Ochsner and Gross, 2005; DeRubeis et al., 2008; Kim and Whalen, 2009), have been shown to include dendritic debranching and hypertrophy, cell proliferation and synaptic remodeling (Davidson and McEwen, 2012)…”

“…is an important caveat for trait neuroticism, which might have different neural features at the higher ranges, as some studies have shown the opposite relationship between amygdala–vmPFC in individuals with diagnosed psychopathology associated with high levels of neuroticism (Kim & Whalen, 2009).”

“Only recently, studies have started to look at associations between trait anxiety and white matter fibers within the insular network as well (Kim and Whalen, 2009; Baur et al., 2013).”

“Furthermore, integrity of white matter fibers connecting the amygdala to the prefrontal cortex is found to be related to individual differences in amygdala responsivity (21, 22).”

“Indeed, individual differences in mPFC-amygdala connectivity are related to variability in trait anxiety in humans (Kim & Whalen, 2009) and a genetic variant common to both mice and humans influences extinction learning (Soliman et al., 2010).”

“Prior studies show that younger adult has positive correlation between white matter integrity and fMRI activation in adjacent gray matter regions (Toosy et al., 2004; Forstmann et al., 2008; Kim and Whalen, 2009; Van Eimeren et al., 2010) or partially adjacent gray matter region (Koch et al., 2010).”

“In fact, recent studies have shown that the structural and functional connectivity between these regions is a more robust predictor of emotional response than the activity of each region separately (Kim et al., 2011; Kim and Whalen, 2009).”

“However, the results in the field seem ambiguous: some studies found that a lack of adequate amygdalar projections to prefrontal regions may be responsible for trait anxiety [27, 28], while other studies correlated the same phenomenon with major depression [14].”

“…given that DTI studies have suggested that the structural integrity of this pathway is negatively correlated with trait anxiety levels (Kim and Whalen, 2009; Baur et al., 2012; Modi et al., 2013), subthreshold posttraumatic stress disorder and hyperarousal symptoms (Costanzo et al., 2016),…”

“Resilience is marked by increased connectivity between prefrontal regulatory regions and the amgydala (Davidson & McEwen, 2012; Kim & Whalen, 2009).”

“regions in the context of processing threat that is modulated by 5-HT signaling [1,2,6,14,38,39].”

“…amygdala as critically implicated in anxiety, emerging evidence highlight the amygdala-medial prefrontal circuitry as particularly involved in the behavioural and cognitive effects of anxiety (Blackmon et al., 2011; Eden et al., 2015; Kim & Whalen, 2009; Kim et al., 2011; Taylor & Whalen, 2015).”

“This tract is involved in emotional regulation (Von Der Heide, Skipper, Klobusicky, & Olson, 2013) and anxious temperament (Baur, Hänggi, & Jäncke, 2012; Kim & Whalen, 2009).”

“To this end, we investigated the relationship between IFG -signatures and the integrity of the major prefrontal-limbic white matter pathway previously implicated in anxiety disorders (Kim and Whalen, 2009; Westlye et al., 2011; Hettema et al., 2012): the uncinate fasciculus (UF).”

“Changes in connectivity within the prefrontal and anterior cingulate cortexes and the amygdala have been correlated with anxiety [78,114,115].”

“Additionally, anxious individuals have lower pathway strength, which has been shown to be associated with lower levels of trait anxiety (Kim & Whalen, 2009) and decreased functional coupling between the ventromedial prefrontal cortex and the amygdala (Pezawas et al., 2005).”

“…al., 2010) is particularly interesting at the light of our findings because interactions between amygdala and vmPFC in the context of depression have been suggested by several functional (Lee et al., 2007; Kim and Whalen, 2009) and structural (Cremers et al., 2011; Singh et al., 2013) MRI studies.”

“For example, Kim and Whalen (2009) found that amygdala reactivity to fearful faces correlated with the structural integrity of a white matter pathway connecting amygdala to the ventral MPFC.”

“Findings from the present study were consistent with multimodal imaging studies which found that the structural integrity of large white matter structures, such as the uncinate fasciculus, were associated with amygdala reactivity (Hein et al., 2018; Kim and Whalen, 2009; Swartz et al., 2014).”

“Specifically, the strength of the connection between the vmPFC and the amygdala, as measured using diffusion tensor imaging, predicts levels of self-reported trait anxiety, such that weaker connections are seen in more anxious individuals [104].”

“Neuroimaging studies in humans have reported an association between bidirectional amygdala-prefrontal connections and anxiety (41,42), but rodent studies suggest this communication can enhance and diminish responses to threatening environmental”

“Consistent with this imbalance, diffusion tensor imaging reveals that connections between amygdala and ventral medial prefrontal cortex are weakened in anxiety (Kim & Whalen, 2009 ).”

“Finally, structural integrity in the amygdala-prefrontal pathway (measured using diffusion tensor imaging) is negatively correlated with trait levels of anxiety (Kim & Whalen, 2009).”

“Trait anxiety correlates inversely with the structural integrity of the vmPCF-amygdala pathway, suggesting an anatomical basis for heightened reactivity and impaired emotional regulation in anxiety (Kim and Wallen, 2009).”

“Structurally, the integrity of white matter tracts between the amygdala and the PFC has been shown to predict individual differences in trait anxiety (Kim and Whalen, 2009).”

“Following this logic, aberrant structural or functional connectivity of amygdala-prefrontal may prompt the inefficient down-regulation of anxiety responses (Banks et al., 2007; Kim and Whalen, 2009; Phan et al., 2009).”

“Adults with high levels of anxiety have been found to have decreased structural connectivity between prefrontal areas and limbic regions (Kim et al., 2011; Kim & Whalen, 2009).”

“Statistics on standard diffusion measures (i.e., fractional anisotropy [FA], axial diffusivity [AD], radial diffusivity, and mean diffusivity) are then extracted from the estimated posterior pathway distribution.”

“It is noteworthy that previous neuroimaging studies have reported associations between FA and internalizing symptoms among older, healthy participants (Kim & Whalen, 2009; Westlye et al., 2011).”

“Kim andWhalen (13) showed a negative correlation between trait anxiety scores and mean FA values of the identified amygdala– ventromedial PFC pathway.”

“Moreover, the reciprocal mPFC-amygdala circuit has been shown to play a vital role in emotion regulation, memory, and stress response [31, 32, 51].”

“Recent studies also found that HA was associatedwith local structural integrity indexed by fractional anisotropy as well as mean and radial diffusivity within most main white matter fibers in the brain (Kim and Whalen, 2009; Westlye et al., 2011).”

“A lack of coupling between these regions with development to help provides that the downregulation may lead to symptoms and ultimately diagnosis of anxiety.”

“…connectivity between amygdala and medial parts of the prefrontal cortex (Heinz et al. 2005; Pezawas et al. 2005; Pacheco et al. 2009), with consequences for psychopathology (Pezawas et al. 2005), trait anxiety (Kim and Whalen 2009), as well as for aspects of decision-making (Roiser et al.”

“Diffusion tensor imaging findings suggest that reduced integrity of white matter tracts (as indexed by fractional anisotrophy) that link the amygdala to vmPFC in humans may indeed be associated with trait vulnerability to anxiety (Kim & Whalen, 2009).”

“Density of white matter connections between these areas is inversely correlated with severity of anxiety symptoms (Kim and Whalen, 2009).”

“In addition, individual differences in the structural integrity of vPFC-amygdala pathway can predict trait anxiety with higher pathway strength associated with lower anxiety (Kim and Whalen, 2009).”

“For example, some studies have found an association between trait anxiety and the structural integrity of an amygdala-ventromedial prefrontal cortex pathway [20], the uncinate fasciculus [21,22], and tracts in the left temporal lobe [23].”

“For instance, studies in trait anxiety (Kim and Whalen 2009), generalized anxiety disorder (Tromp et al.”

“…Bipolar Disorder and Social Phobia, as well as correlated with trait anxiety (Baur et al., 2011; Baur, Hanggi, & Jancke, 2012; Kawashima et al., 2009; M. J. Kim & Whalen, 2009; McIntosh et al., 2008; Phan et al., 2009; Price et al., 2008; S. F. Taylor & Liberzon, 2007; A. Zhang et al., 2012).”

“Recent studies, however, suggest that variation in the amygdala volume and its anatomical coupling to medial prefrontal cortex also relate to individual differences in negative affect [Holmes et al., 2012; Kim and Whalen, 2009].”

“A passive viewing paradigm that has been shown to reliably elicit amygdala activity to facial expressions of emotion was adapted for the current study (Kim and Whalen, 2009; for meta-analysis and review, see Costafreda et al., 2008).”

“Notably, trait anxiety predicted individual differences in the structural integrity of the amygdala prefrontal pathway in a human investigation [45].”

“…have been associated with structural abnormalities in the UF, showing, for instance, an inverse relationship between UF volume and trait anxiety (Kim and Whalen, 2009; Baur et al., 2012) and weakened UF white matter structural integrity in MDD (de Kwaasteniet et al., 2013), particularly…”

“In adults, FA values within this white matter region relate to amygdala activation to threatening faces (Kim and Whalen 2009) and prefrontal cortex-amygdala connectivity during an emotion processing task (Tromp et al. 2012), consistent with the hypothesis that increased myelination of white matter…”

“These latter findings re consistent with studies showing that fear regulatory ircuitry is functionally compromised in anxious individals (Kim and Whalen, 2009).”

“…in social/emotional stimuli processing, some cross-sectional DTI studies found reduced WM organisation in adults with heightened trait anxiety (Kim and Whalen, 2009), social phobia (Baur et al., 2011a,b; Phan et al., 2009), and temperamental disposition to anticipation of harm (Westlye et…”

“Neuroimaging studies have also identified an association between functional and structural indices of this corticolimbic circuit and personality measures associated with anxiety [25–30].”

“Thinner cortical thickness in the right medial orbitofrontal cortex (Kuhn et al. 2011) and weaker structural integrity between the amygdala and the ventromedial PFC, as demonstrated using diffusion tensor imaging (Kim and Whalen 2009), may correspond to higher trait anxiety.”

“For human studies, Kim et al. used diffusion tensor imaging and found a stronger structural connection linking the amygdala and mPFC which could predict the level of individual anxiety (Kim & Whalen, 2009).”

“…(Andolina & Borreca, 2017; Gee et al., 2014; Li et al., 2017), in which the amygdala plays a key role in the activation of the stress response (Kim & Whalen, 2009; Kim et al., 2011; Nutt & Malizia, 2004; Ressler, 2010; Roozendaal et al., 2009; Shin et al., 2006), while the PFC regulates and…”