Brain structural and functional correlates of resilience to Bipolar Disorder

Background: Resilient adaptation can be construed in different ways, but as used here it refers to adaptive brain responses associated with avoidance of psychopathology despite expressed genetic predisposition to Bipolar Disorder (BD). Although family history of BD is associated with elevated risk of affective morbidity a significant proportion of first-degree relatives remain free of psychopathology. Examination of brain structure and function in these individuals may inform on adaptive responses that pre-empt disease expression. Methods: Data presented here are derived from the Vulnerability to Bipolar Disorders Study (VIBES) which includes BD patients, asymptomatic relatives and controls. Participants underwent extensive investigations including brain structural (sMRI) and functional magnetic resonance imaging (fMRI). We present results from sMRI voxel-based-morphometry and from conventional and connectivity analyses of fMRI data obtained during the Stroop Colour Word Test (SCWT), a task of cognitive control during conflict resolution. All analyses were implemented using Statistical Parametric Mapping software version 5 (SPM5). Resilience in relatives was operationalized as the lifetime absence of clinical-range symptoms. Results: Resilient relatives of BD patients expressed structural, functional, and connectivity changes reflecting the effect of genetic risk on the brain. These included increased insular volume, decreased activation within the posterior and inferior parietal regions involved in selective attention during the SCWT, and reduced fronto-insular and fronto-cingulate connectivity. Resilience was associated with increased cerebellar vermal volume and enhanced functional coupling between the dorsal and the ventral prefrontal cortex during the SCWT. Conclusions: Our findings suggests the presence of biological mechanisms associated with resilient adaptation of brain networks and pave the way for the identification of outcome-specific trajectories given a bipolar genotype

Relating constructs of attention and working memory to social withdrawal in Alzheimer's disease and schizophrenia: issues regarding paradigm selection

Central nervous system diseases are not currently diagnosed based on knowledge of biological mechanisms underlying their symptoms. Greater understanding may be offered through an agnostic approach to traditional disease categories, where learning more about shared biological mechanisms across conditions could potentially reclassify sub-groups of patients to allow realisation of more effective treatments. This review represents the output of the collaborative group "PRISM", tasked with considering assay choices for assessment of attention and working memory in a transdiagnostic cohort of Alzheimer's disease and schizophrenia patients exhibiting symptomatic spectra of social withdrawal. A multidimensional analysis of this nature has not been previously attempted. Nominated assays (continuous performance test III, attention network test, digit symbol substitution, N-back, complex span, spatial navigation in a virtual environment) reflected a necessary compromise between the need for broad assessment of the neuropsychological constructs in question with several pragmatic criteria: patient burden, compatibility with neurophysiologic measures and availability of preclinical homologues

Psychobiological correlates of distress in pregnancy

Thesis (PhD (Psychiatry))--University of Stellenbosch, 2011.ENGLISH ABSTRACT: Pregnancy is often accompanied by distressing psychological symptoms such as anxiety. These symptoms may result from changes in cognitive-affective processing, which in turn reflect hormonal changes during this time. However, findings on associations between psychological distress, cognitive-affective changes and hormones have been inconsistent. Furthermore, few studies have investigated the neural circuitry underlying distress and cognitive-affective processing in pregnancy. The prefrontal cortex (PFC) plays a specific role in regulating emotion. Determining the relationship between these changes in cognitive-affective processing and in prefrontal circuitry is important, given the high prevalence of depressive and anxiety disorders in pregnancy. The overall objective of this study was to investigate distressing psychological symptoms and their association with cognitive-affective processes and neurobiological changes over the course of pregnancy. Pregnant women with low risk singleton pregnancies were recruited from Midwife Obstetric Units in the Western Cape. Non-pregnant healthy controls were also recruited from the same demographic area. Distress levels were assessed using the K-10, Spielberger State -Trait Inventory, and Perceived Stress Scale. Subjectively experienced cognitive ability was asked about. Objective cognitive ability was assessed using standardized neuropsychological tests. Selective attention to threat such as fear and anger was assessed using a Facial Stroop Task. Neural circuitry was assessed using Near-Infrared Spectroscopy while viewing dynamic emotional facial expressions of threat (Emotion Recognition Task). Glucocorticoid (cortisol) and gonadal hormonal levels (estrogen, progesterone, and testosterone) were also determined at each trimester of pregnancy. Associations between distressing psychological symptoms, cognitive-affective processes and neurobiology were assessed using standard statistical methods. The main findings to emerge from this research were that, 1. pregnant women had significantly higher trait anxiety at trimester 2, compared to trimester 1 of pregnancy; 2. compared to non-pregnant women, pregnant women paid significantly more attention to fearful faces across trimesters, suggesting altered cognitive-affective processing in pregnancy compared to non-pregnancy; 3. pregnant women demonstrated significantly increased PFC activation in response to fearful and angry faces (all trimesters) that was particularly evident at trimester 2; 4. the PFC activation was, across trimesters, significantly correlated with distress and selective attention to threat; and 5. the PFC activation was, across trimesters, also significantly associated with increased glucocorticoid and gonadal hormone levels. The main findings of this study are consistent with previous literature insofar as distress has previously been associated with altered cognitive-affective processing and prefrontal cortex activation, but extend it by showing that emotional regulation is altered in pregnancy compared to the non-pregnant state. These data provide an important insight into distressing psychological symptoms and their associations with cognitive-affective processes, and changes in neural circuitry and in hormone levels in pregnancy. These findings are also the first to show that structures involved in emotional processing (e.g. the PFC) also play a role in the regulation of affect in pregnancy. Future research should explore the causal mechanisms underlying altered emotional regulation in pregnancy, and include pregnant women that are clinically depressed or anxious as comparison subjects.AFRIKAANSE OPSOMMING: Swangerskap word dikwels geassosieër met stres-veroorsakende sielkundige simptome soos angstigheid. Hierdie simptome mag die gevolg wees van veranderinge in kognitief-affektiewe prosessering, wat op sy beurt mag dui op hormonale veranderinge. Bevindinge oor assosiasies tussen sielkundige stres, kognitief-affektiewe prosessering en hormone is tot dusver onbeslis. Voorts was min studies gerig op die neurologiese meganika onderliggend aan stres en kognitief-affektiewe prosessering tydens swangerskap. Die prefrontale korteks (PFK) het 'n spesifieke rol in die regulering van emosie. Die bepaling van spesifieke assosiasies tussen veranderinge in kognitief-affektiewe prosessering en in prefrontale regulering is belangrik, gegewe die hoë voorkoms van toestande soos depressie en angssteurings tydens swangerskap. Die doel met hierdie studie was 'n ondersoek na assosiasies tussen stres-veroorsakende sielkundige simptome, kognitief-affektiewe prosesse en neurobiologie tydens swangerskap. Swanger vroue met lae risiko enkel-swangerskappe is gewerf by klinieke in Wes-Kaapland. Gesonde nie-swanger vroue is uit dieselfde omgewing gewerf as kontroles. Angs-vlakke is geevalueer met behulp van die K-10; die Spielberger State-Trait Inventory en die Perceived Stress Scale. Vrae is tydens ondersoeke gevra oor subjektief-ervaarde kognitiewe vermoë. Voorts is kognitiewe vermoë geëvalueer met behulp van gestandardiseerde neurosielkundige toetse. Hierbenewens is selektiewe aandag aan bedreigende gesigte wat vrees en woede toon, geëvalueer met behulp van 'n Facial Stroop Task. Neurologiese funksie is geëvalueer met gebruik van Na-Infrarooi Spektroskopie terwyl dinamiese bedreigende emosionele gesigsuitdrukkings vertoon is (Emotion Recognition Task). Gluko-kortikoïed (kortisol) en geslagshormoonvlakke (estrogeen, progesteroon, en testosteroon) is gemeet tydens elke trimester. Verwantskappe tussen stresvolle simptome, kognitief-affektiewe prosessering en neurobiologie is geëvalueer met standaard statistiese metodes. Die hoofbevindinge het op die volgende gedui: 1. swanger vroue het betekenisvolle hoër trait angs-vlakke getoon in trimester 2, vergeleke met trimester 1; 2. vergeleke met nie-swanger vroue, het swanger vroue beduidend meer aandag geskenk aan angstige gesigsuitdrukkings tydens elke trimester wat mag dui op veranderde kognitief-affektiewe prosessering tydens swangerskap vergeleke met nie-swangerskap; 3. swanger vroue het beduidend hoër PFK aktivering getoon teenoor angstige en kwaai gesigte in alle trimesters, maar veral in trimester 2; 4. swanger vroue se PFK aktivering het, in alle trimesters, beduidend gekorreleer het met stres-vlakke en selektiewe aandag teenoor bedreigende stimuli; en 5. swanger vroue se PFK aktivering het, in alle trimesters, ook 'n beduidende verwantskap getoon met verhoogde gluko-kortikoïed en geslagshormoonvlakke. Die hoofbevindinge in hierdie studie stem ooreen met vorige literatuur wat aangedui het dat daar 'n verband is tussen stres en veranderinge in kognitief-affektiewe prosessering en in prefrontale korteks aktivering, maar dui verder op veranderinge in emosionele regulering tydens swangerskap vergeleke met nie-swangerskap. Die data bied 'n belangrike insig in stres-veroorsakende sielkundige simptome; hul verwantskap met kognitief-affektiewe prosesse; veranderinge in neurologiese netwerke; en veranderinge in hormoonvlakke tydens swangerskap. Sover bekend is dit ook die eerste keer bevind dat strukture wat betrokke is by emosionele prosessering (bv. die PFK), ook betrokke is in die regulering van emosie tydens swangerskap. Dit is belangrik dat toekomstige navorsing die onderliggende meganismes wat veranderinge in emosionele regulering teweeg bring, ondersoek. Verdere ondersoek om hierdie veranderinge in swanger depressie-lyers of diegene met angssteurings te vergelyk is ook van belang

Impact Of Adverse Childhood Experiences On Behavioral And Neural Markers Of Executive Function In Menopausal Women

Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Indicators of risk for executive function difficulties at menopause are lacking, as is a mechanistic understanding of how loss of estradiol unmasks this vulnerability. We hypothesized that adverse childhood experiences (ACE) increase the risk of executive dysfunction during menopause via alterations in monoaminergic neurotransmission. To test this hypothesis, we evaluated the effect of ACE on subjective and objective measures of executive function as well as executive activation, functional connectivity, and neurochemistry. We used tryptophan depletion (TD) and lisdexamfetamine (LDX) to probe serotonergic and catecholaminergic function, respectively. High ACE women endorsed greater symptoms of executive dysfunction and performed worse on tasks probing sustained attention and working memory. These negative ACE effects were partially mediated by anxiety and depressive symptoms. ACE moderated the impact of TD on DLPFC activation in hypogonadal women such that TD increased activation in high ACE participants but decreased activation in low ACE participants. Importantly, treatment with estradiol attenuated the effects of both ACE and TD. ACE similarly moderated the impact of TD on within-network connectivity. While ACE was associated with lower within-network connectivity regardless of depletion condition, TD increased connectivity in the high ACE group but had no effect on connectivity in the low ACE group. ACE also moderated response to LDX. In the high ACE group, LDX (vs placebo) increased activation in the insula and reduced symptoms related to difficulty with organization and activation for work. In contrast, response to LDX was not significantly different from placebo in the low ACE group. These results have several clinical and mechanistic implications. First, they highlight that addressing concurrent mood changes is a critical step in treating menopause-induced executive difficulties. Second, this work suggests that early life adversity has latent impacts on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause. Third, they indicate that early adversity may have lasting effects on catecholaminergic neurotransmission and may moderate response to stimulant medications. Together, they emphasize the importance of considering ACE when treating executive difficulties with pharmacologic agents during menopause