Mechanisms in social anxiety disorder in the context of early developmental trauma : an imaging, neurocognitive and genetics study

David, Rosenstein (2015-12)

Thesis (PhD)--Stellenbosch University, 2016.

Thesis

ENGLISH SUMMARY : The contribution of early developmental trauma (EDT) to the neurobiological mechanisms of social anxiety disorder (SAD) is poorly understood. A cross sectional study was conducted to examine the effects of EDT on the pathophysiological mechanisms in SAD. The study assessed three groups: SAD with EDT, SAD without EDT and healthy controls matched for age, gender, ethnicity, education and handedness. We conducted neurocognitive testing, DNA sequencing from whole blood, structural magnetic resonance imaging and proton magnetic resonance imaging. Bayesian statistical analyses were conducted, as the philosophical and theoretical underpinnings of Bayesian statistical methods account for many of the limitations inherent in traditional statistical methods. Bayesian statistical analysis was also used due to the limitations presented by the data in this study. The SAD with EDT group had a smaller left caudate nucleus compared with the SAD without EDT group and smaller left and right anterior cingulate cortex and left thalamus compared with controls. The SAD with EDT group had higher inositol (Ins) and lower N-Acetylaspartate (NAA) concentrations in the amygdala compared with controls, and higher concentrations of Glutamine (Gln) and Glutamate (Glu) compared with controls. In contrast, the SAD without EDT group only had higher concentrations of Glu and Gln relative to controls. Further the SAD with EDT group had neurocognitive difficulties compared with controls spanning domains such as verbal immediate and delayed memory recall, executive functioning and fine motor functioning. The SAD without EDT group only demonstrated difficulties of immediate and delayed verbal memory compared with controls. Heterozygous (TG) carriers of the TPH2 gene had higher total social anxiety scores and higher scores on the social fear and avoidance subscales than homozygous (GG) carriers. In addition individuals who carried at least one C allele of the RGS2 gene, compared with homozygous GG carriers, had higher concentrations of NAA and Ins; both metabolites are indicative of neuronal integrity. A number of correlations were observed between neurocognitive test findings and specific structural grey matter volumetric abnormalities, mainly in the SAD with EDT group. In the SAD with EDT group fine motor dexterity in the dominant hand was negatively correlated with the left caudate nucleus. In the SAD with EDT group executive functioning represented by non-perseverative errors negatively correlated with the right amygdala and conceptual level responses correlated positively with the right amygdala. No significant correlations were found in fine motor performance in the non-dominant hand and grey matter volumes. In the SAD without EDT group immediate memory recall was positively correlated with the left ACC and delayed verbal memory was positively correlated with the right ACC. In conclusion this study provides novel insights into the mechanisms of SAD within the context of EDT compared with SAD without EDT and healthy controls. A number of limbic circuitry volume differences, neurocognitive performance difficulties and more profuse dysregulated neurometabolism of the left amygdala characterizes individuals with SAD and EDT compared to individuals with SAD without EDT, demonstrating the additional influence of EDT on the pathophysiology of SAD.

AFRIKAANSE OPSOMMING : Vroee Ontwikkelings Trauma (VOT) se bydrae tot die neurobiologiese meganismes van Sosiale Angs Versteuring (SAV) is onduidelik. ‘n Deursnit studie is gedoen om die effek van VOT op die patofisiologiese meganismes van SAV te ondersoek. Drie groepe is ondersoek: SAV met VOT, SAV sonder VOT en ‘n gesonde kontrole groep, wat ooreenstem met die ondersoek groepe op grond van ouderdom, geslag, etnisiteit, opleiding en hand voorkeur. Neurokognitiewe toetse, deoksiribonukleiensuur (DNS) volgorde bepaling vanuit heelbloed, strukturele magnetiese resonans beelding en proton magnetiese resonans beelding is gedoen. Bayes statistiese analise is gedoen, omdat die filosofiese en teoretiese grondslag van Bayes se statistiese metodes baie van die beperkings van tradisionele statistiese metodes in ag neem. Dit is ook gebruik as gevolg van die beperkings wat die data van hierdie spesifieke studie te vore gebring het. Die SAV met VOT groep het ‘n kleiner linker kaudaat kern in vergelyking met die SAV sonder VOT groep en ‘n kleiner linker en regter anterior singulaat korteks (ASK) en linker talamus wanneer hulle met die kontrole groep vergelyk word. Die SAV met VOT groep het ook laer Inositol (Ins) en N-Asetielaspartaat (NAA) vlakke en hoer konsentrasies van Glutamien (Gln) en Glutamaat (Glu) in die amigdala as hulle vergelyk word met die kontrole groep. In teenstelling daarmee het die SAV sonder VOT groep slegs hoer konsentrasies van Gln en Glu getoon relatief tot die kontrole groep. Verder het die SAV met VOT groep neurokognitiewe disfunksie in verbale onmiddellike en vertraagde geheue herroeping, uitvoerende funksionering en fyn motor funksionering in vergelyking met die kontrole groep. Die SAV sonder VOT groep het slegs gebreke in onmiddellike en vertraagde geheue herroeping getoon in vergelyking met die kontrole groep. Heterosigotiese (TG) draers van die TPH2 geen het hoer totale sosiale angs tellings en hoer tellings op sosiale vrees en vermyding subskale as homosigotiese (GG) draers. Daar is ook gevind dat individue wat ten minste een C alleel dra van die RGS2 geen, wanneer hulle vergelyk word met homosigotiese GG draers, hoer vlakke NAA en Ins het. Altwee hierdie metaboliete gee ‘n aanduiding van neuronale integriteit. Verskeie korrelasies is gevind tussen neurokognitiewe toets bevindings en spesifieke grysstof volumetriese abnormaliteite, waarvan die meeste in die SAV met VOT groep is. In die SAV met VOT groep het fyn motor vaardigheid met die dominante hand negatief korreleer met die linker kaudaat kern. In die SAV met VOT groep het uitvoerende funksionering, verteenwoordig deur nie-aanhoudende foute, negatief korreleer met die regter amigdala en begrips vlak antwoorde positief korreleer met die regter amigdala. Geen betekenisvolle korrelasies is gevind in fyn motor werkverrigting met die nondominante hand en grysstof volumes nie. In die SAV sonder VOT groep het onmiddellike geheue herroeping positief korreleer met die linker ASK en vertraagde verbale geheue het positief korreleer met die regter ASK. Ten slotte, die studie het nuwe bevindinge voorsien in die meganismes van SAV in die konteks van VOT in vergelyking met SAV sonder VOT en gesonde kontroles. Individue met SAV en VOT word gekarakteriseer deur verskeie limbiese baanwerk volume verskille, neurokognitiewe werksverrigting moeilikhede en erger ontwrigte neurometabolisme in die linker amigdala as hulle vergelyk word met individue met SAV sonder VOT. Dit demonstreer die bykomende effek van VOT op die patofisiologie van SAV.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/97705
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