Browsing by Author "van Honk, Jack"

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    An investigation of amygdala and hippocampal subregions and their relation to ageing in anxiety and related disorders
    (2024) Ntwatwa, Ziphozihle; Ipser, Jonathan; Groenewold, Nynke; Stein, Dan; van Honk, Jack
    Background Obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD) are debilitating disorders that are associated with (inconsistent) evidence of hippocampal and amygdala volumetric abnormalities. In addition, both OCD and SAD are associated with accentuated biological aging, as indexed by cellular and molecular markers. Nevertheless, little is known about brain aging in OCD and SAD, or the extent to which inconsistencies in hippocampal and amygdala volume findings in these disorders may be due to the differential effect of age on the subfields from which these structures are composed. Accordingly, this dissertation set out to characterise differences in hippocampal and amygdala subfield volumes between healthy controls (HCs) and participants with OCD and SAD in large-scale MRI datasets and relate these to whole and regional brain aging. Methods Hippocampal and amygdala subfield volumes and brain age estimates were derived from T1 weighted MRI images from the OCD Brain Imaging Consortium (De Wit et al., 2014) and the European and South African Research Network in Anxiety Disorders (Bas-Hoogendam et al., 2017). Subfield volumes were segmented using an automated segmentation algorithm from Freesurfer (v6.0). The brain age analysis was performed by using a previously trained machine learning algorithm that provides brain age estimates for the whole brain, as well as for regions of interest (occipital, frontal, temporal, parietal, cingulate, insula, or cerebellar–subcortical features) (Kaufmann et al., 2019). Differences in relative brain age (brain predicted age difference; brain-PAD) were calculated by subtracting chronological age from the predicted brain age. Between-group differences (diagnosis vs HCs) in volumetric and brain-PAD estimates were assessed using a mixed-effects (d) model adjusted for several covariates. Subgroup analyses were performed to determine the association of the main findings with clinical characteristics. Finally, unique associations between subfield volumes and whole brain age were estimated using partial correlation analysis. Results There was no evidence for a difference in subfield volumes between individuals with OCD and HCs. However, we found that psychotropic medication use was associated with significantly smaller hippocampal dentate gyrus (d=-0.26, pFDR=0.042), molecular layer (d=-0.29, pFDR=0.042) and larger lateral (d=0.23, pFDR=0.049) and basal (d=0.25, pFDR=0.049) amygdala subfields than HCs. Individuals with OCD without psychotropic medication use had significantly smaller hippocampal CA1 (d=-0.28, pFDR=0.016) compared to HCs. No association was found for symptom severity. In contrast to the findings for OCD, individuals with SAD demonstrated significantly smaller basal (d= 0.32, pFDR=0.022), accessory basal (d=-0.42, pFDR=0.005) and corticoamygdaloid transition area (d=0.37, pFDR=0.014) amygdala subfields overall compared to HCs, and larger hippocampal CA3 (d=0.34, pFDR=0.024), CA4 (d=0.44, pFDR= 0.007), dentate gyrus (d=0.35, pFDR= 0.022) and molecular layer (d=0.28, pFDR=0.033). In addition, individuals with SAD without comorbid anxiety disorder had smaller lateral amygdala and hippocampal amygdala transition area, compared to HCs. No association was found for psychotropic medication use and symptom severity. Individuals with OCD (n=375) had significantly higher whole brain-PAD (+1.6 years, pFDR=0.006, d=0.20) compared to HCs (n=335), but no differences were observed in the regional models. The effect on whole brain brain-PAD estimates was largely driven by psychotropic medication use as higher relative brain age was evident in individuals with OCD with psychotropic medication use (+2.98 years, d=0.38, p <0.001) compared to HCs, but not in individuals without psychotropic medication use (+0.57 years, d=0.07, p =0.374) compared to HCs. No association was found for symptom severity. Partial correlation analysis found a significant negative association between hippocampal and amygdala volume and whole brain PAD in the OCD group (R=-0.224, p=0.00001), but not in the HC group (R=0.081, p=0.138), specifically the lateral nucleus (R=-0.18), CAT(R=-0.13), hippocampal fimbria (R=0.17), and hippocampal fissure (R=0.17) were significant in OCD. Individuals with SAD (n=107) had significantly higher whole brain-PAD (+2.5 years, d=0.33, pFDR=0.010) compared to HCs (n=137), and significantly higher regional brain-PAD in the temporal (+3.80 years, d=0.37, pFDR=0.008,), parietal (+3.57 years, d=0.38, pFDR=0.008), occipital (+3.26 years, d = 0.33, pFDR=0.010), and frontal regions (+2.97 years, d=0.33, pFDR=0.010,) compared to HCs. Brain PAD was higher in SAD without comorbid anxiety disorder, without MDD, and without psychotropic medication use. No association was found for symptom severity. There was no partial correlation between subfields and brain age. Discussion & Conclusion The evidence presented in the thesis suggests that 1) differences in subfield volumes between OCD and HCs were influenced by psychotropic medication use, which is consistent with previous studies that suggest that psychotropic medication status is a strong confounder for subcortical brain volumes observed in OCD, 2) differences in subfield volumes between SAD and HCs were observed in the areas associated with sensory information processing and these differences were partially influenced by psychiatric comorbidity, 3) both OCD and SAD were associated with accentuated brain aging with differential patterns in the whole and regional brain, dependent on clinical characteristics, and 4) only OCD relative brain age was associated with subfield volumes. It is unclear whether our findings in OCD and SAD reflect an adaptive response or are a pre-existing risk factor to these disorders, or both. Future longitudinal analysis is required to investigate whether the observed differences in subfield volume and brain age remain over time.
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    In the eye of the beholder: Reduced threat-bias and increased gaze-imitation towards reward in relation to trait anger
    (Public Library of Science, 2012) Terburg, David; Aarts, Henk; Putman, Peter; van Honk, Jack
    The gaze of a fearful face silently signals a potential threat's location, while the happy-gaze communicates the location of impending reward. Imitating such gaze-shifts is an automatic form of social interaction that promotes survival of individual and group. Evidence from gaze-cueing studies suggests that covert allocation of attention to another individual's gaze-direction is facilitated when threat is communicated and further enhanced by trait anxiety. We used novel eye-tracking techniques to assess whether dynamic fearful and happy facial expressions actually facilitate automatic gaze-imitation. We show that this actual gaze-imitation effect is stronger when threat is signaled, but not further enhanced by trait anxiety. Instead, trait anger predicts facilitated gaze-imitation to reward, and to reward compared to threat. These results agree with an increasing body of evidence on trait anger sensitivity to reward.
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    Paradoxical facilitation of working memory after basolateral amygdala damage
    (Public Library of Science, 2012) Morgan, Barak; Terburg, David; Thornton, Helena B; Stein, Dan J; van Honk, Jack
    Working memory is a vital cognitive capacity without which meaningful thinking and logical reasoning would be impossible. Working memory is integrally dependent upon prefrontal cortex and it has been suggested that voluntary control of working memory, enabling sustained emotion inhibition, was the crucial step in the evolution of modern humans. Consistent with this, recent fMRI studies suggest that working memory performance depends upon the capacity of prefrontal cortex to suppress bottom-up amygdala signals during emotional arousal. However fMRI is not well-suited to definitively resolve questions of causality. Moreover, the amygdala is neither structurally or functionally homogenous and fMRI studies do not resolve which amygdala sub-regions interfere with working memory. Lesion studies on the other hand can contribute unique causal evidence on aspects of brain-behaviour phenomena fMRI cannot "see". To address these questions we investigated working memory performance in three adult female subjects with bilateral basolateral amygdala calcification consequent to Urbach-Wiethe Disease and ten healthy controls. Amygdala lesion extent and functionality was determined by structural and functional MRI methods. Working memory performance was assessed using the Wechsler Adult Intelligence Scale-III digit span forward task. State and trait anxiety measures to control for possible emotional differences between patient and control groups were administered. Structural MRI showed bilateral selective basolateral amygdala damage in the three Urbach-Wiethe Disease subjects and fMRI confirmed intact functionality in the remaining amygdala sub-regions. The three Urbach-Wiethe Disease subjects showed significant working memory facilitation relative to controls. Control measures showed no group anxiety differences. Results are provisionally interpreted in terms of a 'cooperation through competition' networks model that may account for the observed paradoxical functional facilitation effect.
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    Testosterone administration increases the size of womens' peripersonal space: An embodied index of social dominance
    (2019) Masson, Catherine Jane; Solms, Mark; van Honk, Jack
    Peripersonal space (PPS) is the space immediately surrounding the body, encoded by a specific frontoparietal network of multimodal neurons. Stimuli in PPS are represented in a body-part centred manner in terms of possibilities for action, and PPS representations function to facilitate defensive and/or approaching responses to stimuli. The size of PPS differs between individuals and contexts, with physical and psychological factors having a determining role on the size of PPS. For these reasons, PPS has been conceptualised as ‘the space of the bodily self'. In this study we investigated whether the dominance enhancing effects of testosterone may reflect in changes of the representation of PPS. We conducted a double-blind placebo-controlled within-subjects testosterone administration study in women (N=19) where participants performed a multisensory-integration task (a commonly used measure of PPS) while facing an unknown confederate. Results indicated that in comparison to placebo, the administration of testosterone caused a significant enlargement of participants' PPS, suggesting that testosterone caused participants to reflexively appropriate a larger space as their own. This effect was particularly pronounced in participants with higher trait anxiety, converging with other research which has shown that the dominance enhancing effects of testosterone administration can be particularly effective in anxious individuals. Results also indicated a multisensory-facilitation effect around the confederate, which was constant across testosterone and placebo conditions – confirming that the effect of testosterone was self-specific. The PPS boundary gradient was unchanged by testosterone. These findings suggest that an enlarged PPS may provide an embodied index of social dominance. Further, because PPS representations function to support approaching and/or defensive responses to the environment, an enlarged PPS due to raised testosterone may support the enhanced approach behaviour and vigilance to threat known to be conferred by testosterone.