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).”

“Disruptions in its developmental trajectory are likely to alter thresholds to emotional information and contribute to psychopathology, particularly, anxiety (Tottenham and Sheridan 2010; Kim and Whalen 2009).”

“…Copyright © 2011 the authors 0270-6474/11/3110937-11$15.00/0 Frontal lobe white matter connections are commonly implicated as underdeveloped in psychiatric disorders including schizophrenia (Kubicki et al., 2007), mood disorders (Heng et al., 2010), and anxiety (Kim and Whalen, 2009).”

“Using DTI, it was demonstrated that the structural integrity of an amygdala–vmPFC pathway was compromised in the participants who exhibited high trait anxiety [10].”

“…viscerolimbic affective and self-relevance network (with connections to amygdala, insula, and nucleus accumbens) and a dorsally mediated cognitive network (with connections to dorsolateral PFC and hippocampus; Kim & Whalen, 2009; Schmitz & Johnson, 2006; Price, Carmichael, & Drevets, 1996).”

“1; Thiebaut de Schotten et al., 2012), there are differences (Croxson et al., 2005).”

“Human neuroimaging studies in adults have revealed both structural (Kim and Whalen, 2009) and functional (Kim et al.”

“Structural integrity of his vmPFC–amygdala pathway is inversely correlated with trait nxiety (27), suggesting that anatomically compromised inhibitory function contributes to heightened reactivity and impaired emotion regulation in anxiety.”

“In healthy populations, the amygdala and vmPFC show inverse activity (Phelps, et al., 2004), which might be mediated by the integrity of the white matter tracts between them (Kim, et al., 2009).”

“Connectivity between the amygdala and pre- and orbitofrontal regions was decreased in one study in highly anxious healthy subjects (Kim and Whalen, 2009).”

“Structural imaging showed that OFC–amygdala white matter tracts predict trait anxiety in healthy subjects (Kim and Whalen, 2009).”

“Strength of white matter tracts connecting these regions may also be inversely associated with anxious symptoms in adults 17 , suggesting evidence of disruptions in structural, as well as functional, connectivity.”

“, 2007), anxiety (Kim and Whalen, 2009), schizophrenia (Callicott et al.”

“This is not unreasonable as individual differences in structural connectivity can predict trait anxiety and can be related to attention deficits (17, 18) and individual differences in resting-state functional MRI (fMRI) measures may relate to various behavioral differences, including impulsivity (19–22).”

“Both animal and human studies support the idea that the amygdala and the mPFC are structurally as well as functionally connected (Kim and Whalen, 2009; Thayer, 2006).”

“However, even within a single disorder, results are conflicting, some reporting hypoconnectivity while others find hyper-connectivity(8;40;48;49).”

“uncinate fasciculus in healthy control subjects (24), suggesting a relation between frontolimbic activity and structural connectivity.”

“Examples include emotional go/no-go tasks (inhibition of prepotent responses are tested in the presence of emotionally distracting cues) (37), emotional oddball tasks (the ability to respond to an infrequent target is assessed in the setting of a disturbing cue) (38), emotional distractor tasks (threatrelated distract…”

“This model has been supported by numerous studies (Clewett et al., 2014; Kim and Whalen, 2009; Prater et al., 2013), though other studies report increased connectivity between the AN and ECN in anxiety disorders relative to healthy controls (HC) (Etkin et al., 2009; Kim et al., 2014).”

“The CeA and interconnected amygdala nuclei also regulate unconditioned anxiety (Killcross et al., 1997), but in contrast to the BNST, play a clear role in conditioned fear-associated memories (Amano et al., 2010; Kim and Whalen, 2009; Miller and Urcelay, 2007; Tasan et al., 2010; Tye et al., 2011).”

“, 2012), and white matter connectivity and microstructure (Bjørnebekk et al., 2011; Cohen et al., 2009; Jung et al., 2010a, 2010b; Kim and Whalen, 2009; Taddei et al., 2012; Takeuchi et al., 2010; Volpe et al., 2008; Westlye et al., 2011; Xu and Potenza, 2012).”

“While the lPFC is thought to support cognitive control process [90], the mPFC has reciprocal connections with brain regions involved in emotional processing (amygdala), memory (hippocampus) and higher-order”

“This pathway, not commonly outlined in human atlases, is located within the basal forebrain sweeping dorsally from the amygdala and traveling ventrally to the pallidal complex (Kim and Whalen, 2009).”

“In addition, nicotine dependence has been associated with increased odds of anxiety disorders (OR: 2.2 for men, 2.6 for women) (Breslau et al. 1991).”

“…that in both task-related and resting tate studies as well as in trait anxiety the top-down regulation by he PFC of the amygdala is diminished (Kim and Whalen, 2009; Kim t al., 2011a, 2011b; Davidson and McEwen, 2012; Urry et al., 2006). im et al. (2011a) for example demonstrated negatively…”

“Investigating the structural integrity of the amygdala–prefrontal pathway with diffusion tensor imaging, Kim and Whalen (2009) found evidence for an inverse correlation with participants’ trait anxiety levels.”

“Several studies have looked for a relationship between white-matter integrity as assessed by diffusion tensor imaging and personality factors (Cohen, Schoene-Bake, Elger, & Weber, 2009; Kim & Whalen, 2009; Westlye, Bjørnebekk, Grydeland, Fjell, & Walhovd, 2011; Xu & Potenza, 2012).”

“Such interactions may be important in anxiety disorders and regulation of fear responses more broadly (Etkin et al., 2010; Kim and Whalen, 2009; Urry et al., 2006).”

“In particular, FA within this white matter region has been shown to relate to amygdala activation to fearful faces (Kim & Whalen, 2009), and functional connectivity between the anterior cingulate cortex and amygdala during emotion processing (Tromp et al., 2012).”

“The wider importance of our findings is that ideas such that amygdala-prefrontal connections influence associative learning (Cohen et al., 2008) and distinct aspects of emotional processes (Kim and Whalen, 2009) can now be tested more rigorously.”

“Finally, in line with assuming that stronger interactions between PFC and amygdala reflect stronger control over negative emotions, stronger PFC-amygdala connectivity has been shown to be associated with lower trait anxiety in healthy individuals (Kim and Whalen, 2009).”

“Importantly, projections to the nuclei of the amygdala reported in Ebeling and von Cramon (1992) refers to the entorhinal cortex and should not be mistaken for the amygdala proper as is often done (Schmahmann and Pandya, 2006; Kim and Whalen, 2009).”

“This is consistent with previous studies showing attenuation of UF fiber integrity in patients with GAD (Hettema et al., 2012; Tromp et al., 2012), in patients with generalized social anxiety disorder (Phan et al., 2009), and in nonclinical trait-anxious individuals (Kim and Whalen, 2009).”

“Such disruptions in structural and/or functional connectivity were interpreted as implying poor communication between brain regions, resulting in deficient information exchange [Kim and Whalen, 2009].”

“Decreased structural and functional connectivity between pgACC and amygdala also predicts trait [Kim and Whalen, 2009; Pezawas et al., 2005], state [Kim et al.”

“Human Amygdala-mPFC Connections As described earlier, strong structural (Kim & Whalen, 2009) and functional connections (Etkin, Prater, Hoeft, Menon, & Schatzberg, 2010; Hare, et al., 2008; Kim, et al., 2004; Pezawas, et al., 2005; Roy, et al., 2009) exist between the amygdala and the mPFC in…”

“Specifically, altered frontoamygdala connectivity has been observed in anxiety (Kim and Whalen, 2009; Roy et al., 2013), depression (Tang et al., 2013) and post-traumatic stress disorder (PTSD; Edwards et al., 2013, Stevens et al., 2013, Brown et al., 2014).”

“Although the uncinate fasciculus is sometimes proposed as a critical pathway for anxiety (Kim and Whalen, 2009), our results suggest that other, more complex modulatory pathways contribute to PTSD, which is in line with other research implicating the limbic-thalamo-cortical pathway (Lanius et al.,…”

“In addition, the strength of the amygdala—vmPFC pathway, as expressed by structural integrity (measured with diffusion tensor imaging, DTI) is lower in individuals with high trait anxiety (Kim and Whalen, 2009).”

“Data by Kim and Whalen (2009) support the idea that anxiety is associated with ineffective top-down inhibition.”

“The precise functions of the UF remain unclear but may involve mediating emotion regulation and social cognitive processes [39].”

“A growing body of neuroimaging studies links white matter (WM) measures to anxiety-related psychological processes [1-4].”

“Previous DTI and functional MR imaging studies have shown associations between trait anxiety and connectivity of the amygdala and other corticolimbic regions, including the sACC and ventromedial prefrontal circuitry.(26,27,29,72) Furthermore, generalized social anxiety disorder is associated with reduced FA in the unc…”

“Importantly, Kim and Whalen (2009) noted that the relationship between anxiety and amygdala reactivity has typically been found in studies that have used unconsciously presented and/or unattended facial stimuli.”

“In support of this, high structural integrity of the amygdala-ventromedial prefrontal cortex white matter tracts is associated with low anxiety levels (11).”

“Disruptions of the amygdala– vmPFC circuitry are centrally involved in the maintenance of anxiety symptoms (Kim and Whalen, 2009; Kim et al., 2011).”

“…brain regions have been associated with general anxiety disorder [Cha et al., 2016; Tromp et al., 2012] while structural connectivity of amygdala with prefrontal cortex as well as more complex cortical networks can predict trait anxiety in humans [Greening and Mitchell, 2015; Kim and Whalen, 2009].”

“A rich body of human and rodent literature has identified robust structural and functional connections between the amygdala and PFC during the developmental period (Bouwmeester et al., 2002a,b; Kim and Whalen, 2009; Gee et al., 2013a,b).”

“Impaired down-regulation of anxiety is associated with the diminished integrity of amygdala-prefrontal tracts (Banks et al., 2007; Kim and Whalen, 2009; Phan et al., 2009).”

“…(AMG) -vmPPFC pathway, identified through regression of the L AMG fMRI signal (increased when viewing fearful vs. neutral faces) on the FA maps (Kim and Whalen, 2009); this tract is thought to represent a shorter, multisynaptic pathway between AMG and ventral forebrain, compared to uncinate…”

“Finally, our results show strong overlapwith DW-MRI-derived pathways between the amygdala and the anterior cingulate cortex (JohansenBerg et al., 2008) as well as the OFC (Kim & Whalen, 2009).”

“Anatomical alterations of the amygdala-prefrontal network have been repeatedly reported in anxiety disorders [105] and SAD in particular [44].”

“The current study focuses on linking trait anxiety at the individual level with the SN. Trait anxiety is often used as an index of vulnerability to anxiety disorders (Kim and Whalen, 2009; Indovina et al., 2011).”

“…coursed medially through ventral striatal regions, consistent with findings from previous probabilistic tractography studies (Croxson et al., 2005; Kim and Whalen, 2009; Clewett et al., 2014; see Figure 4B for a single subject map identified using deterministic tractography for illustration…”

“…2005; Roiser et al., 2009) and anatomical studies (Pacheco et al., 2009) of patients or healthy subjects reporting S allele effects on amygdala–mPFC coupling, which has been related to trait anxiety via functional connectivity (Pezawas et al., 2005) and fractional anisotropy (Kim and Whalen, 2009).”

“In healthy populations, the amygdala and vmPFC showed inverse patterns of activity during the performance of such tasks (Phelps et al., 2004; Hare et al., 2008), which might be mediated by the integrity of the white matter tracts between them (Kim and Whalen, 2009).”

“We wanted to explore in the CW group whether we would find similar results using similar analysis methods (Kim and Whalen, 2009).”

“Given the results of related previous studies (Kim and Whalen, 2009; Phan et al., 2009), which for the first time investigated associations between FA and anxiety, we expected that reduced rather than increased FA would be a characteristic of abnormal WM architecture in anxious individuals.”

“This claim is supported by a recent study that found that stronger vmPFC-amygdala connectivity predicted lower anxiety levels (Kim and Whalen, 2009; Kim et al., 2011).”

“Finally, we assessed for relapse-related differences in neurocognitive measures of executive control, emotional decision making and trait measures of stress reactivity previously associated with medial prefrontal to amygdala coupling (51, 63) as well as measures of cocaine craving and obsessive-compulsive cocaine use.”

“A recent study of diffusion tensor imaging showed that the structural integrity of the pathway between the amygdala and vmPFC was inversely correlated with trait anxiety levels across subjects (Kim and Whalen, 2009).”

“Moreover, the posterior cingulate is linked to the processing of pain (Nielsen et al., 2005). As high-trait anxiety has been reported to be associated with higher pain experiences than in humans with low-trait anxiety (Tang and Gibson, 2005), this could explain the positive correlation between FA values of the hippoca…”