White matter integrity deficits in prefrontal–amygdala pathways in Williams syndrome
Highlights
►Individuals with Williams syndrome (WS) have significant non-social fears. ►Threatening non-social images elicit amygdala hyperactivity in individuals with WS. ►Amygdala activity is inhibited by the prefrontal cortex (PFC). ►Individuals with WS have lower white matter integrity in PFC-amygdala pathways. ►PFC-amygdala white matter deficits may contribute to amygdala hyperactivity in WS.
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.
Section snippets
Participants
Eight individuals with Williams syndrome and 10 typically-developing control individuals participated in this study. One control subject was removed from analysis due to excessive motion during the DTI acquisition (excessive motion was defined as translational motion > 4 mm or rotational motion > 3°), resulting in a group of 9 control subjects included in data analysis. Subjects were 19–38 years old (mean = 23 years) and were predominantly Caucasian (88%) and right handed (71%) (Table 1).
WS subjects
Prefrontal–amygdala pathway analysis
To determine whether individuals with WS had decreased white matter integrity in prefrontal–amygdala pathways, we compared FA within tracts identified by probabilistic tractography. Individuals with WS had significantly lower FA in regions of several of the tracts tested (bilateral BA25-to-amygdala, bilateral infOFC-to-amygdala, right medOFC-to-amygdala, and right supOFC-to-amygdala), indicating extensive differences in prefrontal–amygdala white matter integrity. There were no group differences
Discussion
To test for structural differences in prefrontal–amygdala white matter pathways in Williams syndrome (WS), we compared white matter integrity in individuals with WS to typically-developing controls matched for high trait levels of non-social fear. Findings from two analytic methods, probabilistic tractography and Tract-Based Spatial Statistics (TBSS), both demonstrated decreased white matter integrity in prefrontal–amygdala white matter paths in individuals with WS. Because the prefrontal
Acknowledgments
We thank the individuals with Williams syndrome and their families for participating in this study. We thank Elizabeth Roof for research assistance. This research was supported in part by funding from the National Institute of Mental Health NIMH (K01-MH083052 to JUB), NIH Roadmap for Medical Research Postdoctoral Fellowship, Biobehavioral Intervention Training Program (T32 MH75883, TATW), a Hobbs Discovery Grant from the Vanderbilt Kennedy Center, the Vanderbilt Institute for Clinical and
References (62)
The Amygdala
(2000)Diagnostic and Statistical Manual of Mental Disorders, 4 (DSM-IV)
(1994)- et al.
Characterization and propagation of uncertainty in diffusion-weighted MR imaging
Magn. Reson. Med.
(2003) - et al.
Towards the neural basis for hypersociability in a genetic syndrome
Neuroreport
(1999) - et al.
Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders
Arch. Gen. Psychiatry
(1990) - et al.
Brain structural differences associated with the behavioural phenotype in children with Williams syndrome
Brain Res.
(2009) - et al.
3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry
NeuroImage
(2007) - et al.
Stable early maternal report of behavioral inhibition predicts lifetime social anxiety disorder in adolescence
J. Am. Acad. Child Adolesc. Psychiatry
(2009) - et al.
Adults with Williams syndrome. Preliminary study of social, emotional and behavioural difficulties
Br. J. Psychiatry
(1998) - et al.
“Everybody in the world is my friend” hypersociability in young children with Williams syndrome
Am. J. Med. Genet. A
(2004)
Subgenual prefrontal cortex abnormalities in mood disorders
Nature
Anxiety, fears, and phobias in persons with Williams syndrome
Dev. Neuropsychol.
Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps
NeuroImage
Assignment of functional activations to probabilistic cytoarchitectonic areas revisited
NeuroImage
A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data
NeuroImage
Early risk factors and developmental pathways to chronic high inhibition and social anxiety disorder in adolescence
Am. J. Psychiatry
Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome
Nat. Genet.
Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition (SCID-I/P)
Biometrics Research
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
Subcortical projections of area 25 (subgenual cortex) of the macaque monkey
J. Comp. Neurol.
Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey
Neuroscience
Early anxious/withdrawn behaviours predict later internalising disorders
J. Child Psychol. Psychiatry
Social-emotional and behavioral adjustment in children with Williams-Beuren syndrome
Am. J. Med. Genet.
A susceptibility gene for affective disorders and the response of the human amygdala
Arch. Gen. Psychiatry
Serotonin transporter genetic variation and the response of the human amygdala
Science
More is not always better: increased fractional anisotropy of superior longitudinal fasciculus associated with poor visuospatial abilities in Williams syndrome
J. Neurosci.
Tract probability maps in stereotaxic spaces: analyses of white matter anatomy and tract-specific quantification
NeuroImage
Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans
Neuron
A Bayesian framework for global tractography
NeuroImage
Temperamental influences on reactions to unfamiliarity and challenge
Adv. Exp. Med. Biol.
Kaufman Brief Intelligence Test
Cited by (22)
Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes
2022, Biological PsychiatryCitation Excerpt :Increased FA has also been reported in 15q11.2, 16p11.2, and 7q11.23 (Williams syndrome) deletions. In patients with Williams syndrome, findings are heterogeneous across studies (43–47); the most consistent findings are increased FA in the superior longitudinal fasciculus and decreased FA in the posterior limb of the internal capsule. Similar to observations regarding 22q11.2, the 15q11.2 and 16p11.2 CNVs also showed dosage-dependent effects in white matter (26).
Attenuated link between the medial prefrontal cortex and the amygdala in children with autism spectrum disorder: Evidence from effective connectivity within the “social brain”
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :In particular, the prefrontal cortex provides contextual and experiential input into the amygdala to regulate emotional responses triggered by the amygdala, which is then used to interpret social stimuli and prepare behavioral and emotional responses (Adolphs, 2003). Atypical amygdala connectivity has been verified in various disorders with affective and cognitive deficits; abnormal structural integrity of the prefrontal and amygdala pathways was also observed in neuropsychiatric disorders, such as depression, Williams syndrome, and post-traumatic stress disorder (Cullen et al., 2014; Avery et al., 2012; Shin et al., 2006). Compared with the recent studies that individuals with ASD show abnormal frontoamygdala functional connectivity (Rausch et al., 2018; Odriozola et al., 2019), our effective connectivity findings verified and extended prior work to a directed mPFC-amygdala pathway in the social brain that may underlie core social deficits in children with ASD.
Genetics of brain networks and connectivity
2019, Connectomics: Applications to NeuroimagingGenetics of brain networks and connectivity
2018, Connectomics: Applications to NeuroimagingEarly weaning influences short-term synaptic plasticity in the medial prefrontal-anterior basolateral amygdala pathway
2016, Neuroscience ResearchCitation Excerpt :One of these synaptic functions is likely control of trait anxiety as seen in the rodent elevated-plus maze (Ito et al., 2006). Interestingly, human trait anxiety seems to involve the linkage between the amygdala and the prefrontal cortex (Avery et al., 2012; Burghy et al., 2012; Kim and Whalen, 2009). When we comprehensively analyzed for correlations (Table 3), it appeared that the PPF ability of the mPFC–aBLA pathway was involved in other brain functions besides trait anxiety.