White matter integrity deficits in prefrontal–amygdala pathways in Williams syndrome

Abstract

Williams syndrome is a neurodevelopmental disorder associated with significant non-social fears. Consistent with this elevated non-social fear, individuals with Williams syndrome have an abnormally elevated amygdala response when viewing threatening non-social stimuli. In typically-developing individuals, amygdala activity is inhibited through dense, reciprocal white matter connections with the prefrontal cortex. Neuroimaging studies suggest a functional uncoupling of normal prefrontal–amygdala inhibition in individuals with Williams syndrome, which might underlie both the extreme amygdala activity and non-social fears. This functional uncoupling might be caused by structural deficits in underlying white matter pathways; however, prefrontal–amygdala white matter deficits have yet to be explored in Williams syndrome. We used diffusion tensor imaging to investigate prefrontal–amygdala white matter integrity differences in individuals with Williams syndrome and typically-developing controls with high levels of non-social fear. White matter pathways between the amygdala and several prefrontal regions were isolated using probabilistic tractography. Within each pathway, we tested for between-group differences in three measures of white matter integrity: fractional anisotropy (FA), radial diffusivity (RD), and parallel diffusivity (λ₁). Individuals with Williams syndrome had lower FA, compared to controls, in several of the prefrontal–amygdala pathways investigated, indicating a reduction in white matter integrity. Lower FA in Williams syndrome was explained by significantly higher RD, with no differences in λ₁, suggestive of lower fiber density or axon myelination in prefrontal–amygdala pathways. These results suggest that deficits in the structural integrity of prefrontal–amygdala white matter pathways might underlie the increased amygdala activity and extreme non-social fears observed in Williams syndrome.

Introduction

Williams syndrome (OMIM#194050) is a rare neurodevelopmental disorder caused by a microdeletion of about 25 genes on chromosome 7 (band 7q11.23) (Ewart et al., 1993). Individuals with Williams syndrome (WS) are socially fearless and disinhibited (Doyle et al., 2004, Dykens, 2003, Gosch and Pankau, 1994), yet intriguingly, have unusually high levels of non-social fears (Dykens, 2003, Klein-Tasman and Mervis, 2003, Leyfer et al., 2006, Stinton et al., 2010). These non-social fears increase in severity with age (Davies et al., 1998, Dykens, 2003) and result in intense anticipatory anxiety which significantly impairs daily functioning (Dykens, 2003). Accordingly, around 50% of individuals with WS have a comorbid diagnosis of specific phobia (Leyfer et al., 2009, Leyfer et al., 2006), compared to an estimated specific phobia prevalence of 4–9% in the general population (American Psychiatric Association, 1994, Kessler et al., 2005). Given significant clinical impairment, it is imperative to understand the unique neurobiology which underlies elevated non-social fear in individuals with WS.

The amygdala – a small subcortical structure involved in threat detection and fear processing (Aggleton, 2000) – is involved in abnormal fear processing in individuals with WS (Bellugi et al., 1999, Reiss et al., 2004). When viewing threatening non-social scenes, individuals with WS exhibit elevated amygdala activity compared to typically-developing controls (Meyer-Lindenberg et al., 2005, Munoz et al., 2010). Interestingly, this increased amygdala activity appears to be above and beyond what can be accounted for by normal fear processing; individuals with WS exhibit elevated amygdala activity in response to threatening non-social scenes even when compared to controls matched for a level of non-social fear (Thornton-Wells et al., 2011). This amygdala hyperactivity suggests a difference in neural processing in individuals with WS that is unique to WS as a disorder and that cannot be accounted for by a high trait level of non-social fear. Despite this extreme amygdala response to threatening non-social stimuli, individuals with WS do not have chronically elevated amygdala activity to all types of stimuli (Meyer-Lindenberg et al., 2005, Thornton-Wells et al., 2011), indicating that amygdala hyperactivity in response to threatening non-social stimuli is not simply due to global functional impairment of the amygdala. Instead, amygdala hyperactivity in WS might result from a lack of cortical inhibitory control within the context of non-social threat.

Amygdala hyperactivity may result from a failure of the orbitofrontal cortex (OFC) to properly inhibit amygdala responses during non-social fear processing. The OFC sends dense axonal projections to the amygdala (Stefanacci and Amaral, 2002) which synapse within primarily GABAergic nuclei (Ghashghaei and Barbas, 2002), suggesting an inhibitory role for OFC inputs. In agreement with anatomical evidence, previous neuroimaging studies have demonstrated that the OFC plays a role in top-down regulation of amygdala response and emotional reactivity in typically-developing individuals (Indovina et al., 2011, Ochsner et al., 2004, Phan et al., 2005). In individuals with WS, normal OFC inhibition of the amygdala is disrupted (Meyer-Lindenberg et al., 2005). These findings suggest circuit-level impairment of normal OFC-amygdala inhibition in the context of non-social fear processing, which may result in amygdala hyperactivity in individuals with WS.

Another prefrontal cortex region, the subgenual anterior cingulate cortex (sgACC), may also inhibit amygdala responses (Pezawas et al., 2005). The sgACC receives dense structural projections from the amygdala (Freedman et al., 2000) and is implicated as a key neural substrate underlying anxiety and negative emotions (Drevets et al., 1997, Liotti et al., 2000, Ongur et al., 1998). Dysfunction in the sgACC might contribute to pathological fear processes; for example, individuals at high risk for development of anxiety disorders have increased amygdala activity in response to fearful stimuli (Hariri et al., 2002, Hariri et al., 2005), decreased sgACC volume (Pezawas et al., 2005), and decreased functional coupling between sgACC and the amygdala (Pezawas et al., 2005). Although the function of the sgACC has not been specifically explored in WS, two previous structural studies have demonstrated significantly lower gray matter density in the sgACC region in individuals with WS compared to controls (Campbell et al., 2009, Chiang et al., 2007). Given the role of the sgACC in anxiety, decreased gray matter density in the sgACC region in WS provides intriguing evidence that disrupted sgACC-amygdala interaction might contribute to abnormal amygdala hyperactivity in non-social fear contexts.

While converging lines of evidence point toward a functional disconnect in normal prefrontal–amygdala inhibition during non-social fear processing in WS, the underlying structural mechanisms remain unclear. One potential mechanism is reduced structural integrity of the axons which form prefrontal–amygdala inhibitory pathways. Individuals with WS show marked abnormalities in widespread white matter pathways (Hoeft et al., 2007, Marenco et al., 2007). While some white matter abnormalities observed in WS have been specifically associated with discrete neurocognitive impairments (Hoeft et al., 2007), to date, no studies have directly investigated whether structural integrity deficits in prefrontal–amygdala white matter pathways might contribute to abnormal non-social fear processing in WS.

In the present study, we used diffusion tensor imaging (DTI) to investigate prefrontal–amygdala white matter integrity in individuals with WS relative to controls. To isolate structural deficits unique to WS and not due to high non-social fear, we targeted a control group that was also high in non-social fear but did not have WS. We hypothesized that individuals with WS, compared to controls, would show structural abnormalities in white matter pathways between prefrontal inhibitory control regions, including the OFC and sgACC, and the amygdala.