Melbourne School of Psychological Sciences - Theses
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ItemReliability and validity of the list learning paradigm and implications for clinical memory assessment( 2017)The free-recall multi-trial paradigm of verbal list learning is conventionally used to detect episodic memory deficits in clinical neuropsychology practice. The widespread use of the test occurs despite evidence of poor precision. The focus of the current thesis was to improve the reliability of the list learning test. The need for improved precision in memory measurement was also addressed in the context of novel methodologies such as computerized testing and diagnostic validity research. Three experimental studies and a brief systematic review with meta-analysis were conducted to achieve a better estimation of verbal memory assessment in clinical practice. In STUDY 1, the reliability of the conventional five-trial structure of the Rey Auditory Verbal Learning Test (RAVLT, Rey 1964; Schmidt, 1996) was modelled. A Quasi-Markov simplex, which is a structural equation auto-regressive model specific to the alternative formulation of the reliability coefficient, was applied to a normative dataset of 398 participants. Model fitting results indicated that long-term memory, corresponding to the learning efficiency trait (Gl) under the Cattell-Horn-Carroll (CHC) model of cognition, was mostly captured by the first two trials of the RAVLT, with subsequent trials adding little to reliability and Gl estimation. Results of STUDY 1 provided the basis for the development of STUDY 2, where the aim was to examine the psychometric quality of an experimental list learning test of multiple lists of two trials only. Two samples of participants were prospectively selected. One sample of n = 119 clinical participants was recruited from the Victorian Comprehensive Epilepsy Program at St Vincent’s Hospital, Melbourne, and a second sample, including n = 89 student participants, was selected from a tertiary education population. The experimental list learning test was administered twice and compared against established and experimental neuropsychological tests. Correlational analyses were performed to obtain reliability and construct validity estimates. Overall, the experimental administration of the list learning test showed better retest-reliability coefficients (rxx = .61 to .79) than the RAVLT (e.g., rxx = .26 to .64; Cairstairs, Myors & Shores, 2012), with moderate-to-large convergent validity correlations with standard tests of long-term memory ability and small-to-moderate discriminant validity correlations with tests of working memory. Despite promising data, the reliability of the experimental word list was still considered inadequate for the purpose of individual clinical assessment. A subsample of the seizure disorders participants (n = 80) and the full sample of student participants (n = 89) took part in an additional assessment (STUDY 3) involving the administration of two computerized memory tests from the CogState Computerized Cognitive Battery. Correlational analyses and calculation of Reliable Change Indices (RCIs) on individual performance were used to interpret results. Similarly to the results in STUDY 2, the CogState subtests showed inadequate retest reliability coefficients (rxx = .49 to .77) for clinical assessment purpose. Small-to-medium construct validity correlations with conventional tests of learning and working memory were also found. Discrepancies in RCIs interpretations were observed when different test parameters and reliabilities were used. In particular, the Within-Subject Standard Deviation (WSD) index was found to substantially increase the rate of Type I error when test reliabilities were low. Finally, the diagnostic validity of the list learning test was addressed in STUDY 4. Results from a brief systematic review and meta-analysis of the California Verbal Learning Test (CVLT, CVLT-II and CVLT-C; Delis, Kramer, Kaplan & Ober, 1987, 2000) were reported. The study reviewed the CVLT sensitivity, specificity and the reporting of confidence intervals across various scores from 25 studies published between 2002 and 2016. A meta-analysis examining the diagnostic accuracy of the score most consistently reported, the forced choice recognition, was also performed. The methodological quality of all 25 studies selected was rated according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2; Whiting et al., 2011) criteria. Results from STUDY 4 indicated moderate-to-high specificity (75% or above) and moderate-to-low sensitivity (75% or below) across all CVLT scores; however, reporting of confidence intervals was missing in all 25 studies reviewed. Calculation of confidence intervals would have altered interpretation of results in the sensitivities of 22 studies (88%) and in the specificities of five studies (20%) due to the considerable uncertainty associated with the wide confidence limits obtained (95% confidence intervals [CI]: 30% to 80%). Meta-analytic results of the CVLT forced choice recognition score indicated optimal specificity (Hedges’ g = 93%, 95% CI: 90% to 94%) but mediocre sensitivity (Hedges’ g = 45%, 95% CI: 38% to 52%). Although the forced choice recognition score may be more accurate for the detection of true positive rates, extremely low sensitivity may produce a high rate of false negatives. In terms of methodological quality, lack of clarity with respect to blinding and use of well-validated reference standard appeared to be the major methodological limitation of most of the studies reviewed. In conclusion, the current thesis highlighted the need for better memory tests to accurately assess verbal episodic memory functions. Irrespective of the structural variation of the list learning test, the list learning psychometrics could not be improved to acceptable standards in a way that is feasible for clinical assessment purposes. Use of word list tests in neuropsychology practice should therefore be discouraged to avoid misleading clinical interpretations. In a similar way, use of the CogState computerized memory measures prior to rigorous independent validation of their psychometrics may lead to incorrect clinical inferences. With regards to the diagnostic validity of the CVLT, reporting of confidence intervals around sensitivity and specificity estimates was ignored and the presence of methodological flaws undermined the true diagnostic utility of the CVLT scores. Overall, adequate knowledge of psychometric theory should become a priority for every clinician interested in selecting the best available testing resource for clinical memory assessment. The current thesis showed that new and more precise memory measures are needed in neuropsychology practice. Clinicians who choose to use tests with low reliabilities need to do so with understanding of the resultant limitations in diagnostic precision.
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ItemCognitive and psychosocial functioning in genetic generalised epilepsy( 2017)Genetic generalised epilepsies (GGE) are a common, but under-studied cluster of epileptic syndromes of predominantly child and adolescent onset. The primary syndromes of GGE are childhood absence epilepsy (CAE), juvenile absence epilepsy(JAE), juvenile myoclonic epilepsy (JME), and genetic generalised epilepsy with generalised tonic-clonic seizures only (GTSCO). Important questions remain regarding: the degree of cognitive and psychopathological comorbidity, particularly in adults and in syndromes other than JME; effects of the disease on cognitive function; and psychopathology and psychosocial wellbeing in these patient groups. This thesis aimed to provide a detailed and quantitative description of cognitive function and psychopathology in GGE, assess the impact of contributing factors including subclinical epileptiform discharges on cognitive and psychopathology outcomes, and to evaluate the relationship between psychopathology and cognition. Methods employed include narrative systematic review, quantitative meta-analysis, and prospective assessment of cognitive and psychosocial functioning of a relatively large sample of people with GGE. Results indicated mild to moderately large reductions across most cognitive factors relative to that of healthy control participants and age-based normative data, with a relative weakness in long-term retrieval and memory function. Short-term memory function was not reduced relative to age-based normative data. Overall cognitive ability and memory function was negatively associated with total duration of epileptiform discharges during a 24-hour period. Approximately 50% of the sample reported elevated symptoms on a measure of psychopathology spanning six symptom types, with depression and anxiety the most common amongst these. Collectively, these findings highlight the need for increased awareness, screening and the provision of services for psychological comorbidities for people with GGE.
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ItemCerebello-cortical and fronto-parietal contributions to working memory function in children born extremely preterm: a diffusion MRI study( 2016)Survivors of extremely preterm birth (<28 weeks’ gestation) and/or extremely low birth weight (<1000 grams) have elevated rates of working memory impairment compared with term-born peers. This impairment may be a core deficit underlying problems experienced by these children in other areas of cognitive, behavioural and academic functioning. Extremely preterm survivors are also at risk of white matter injury and cerebellar injury as a result of neurological disruptions associated with preterm birth. However, it is not yet known whether this injury and developmental disruption to cerebellar white matter connections underlies the working memory deficits seen in this population. It is also unclear whether working memory deficits may be ameliorated through intensive working memory training, and whether white matter microstructural plasticity underlies training gains in working memory capacity. This thesis aimed to examine whether variability in the maturity and microstructural organisation of white matter pathways associated with working memory were related to working memory ability in a group of 7-year-old extremely preterm children. It also aimed to evaluate whether working memory capacity and white matter microstructure were capable of change (functional and neuroplastic change, respectively), in response to the most widely evaluated adaptive working memory training intervention, Cogmed. Sixty participants were recruited from a large cohort of 7-year-old extremely preterm children born in Victoria, Australia. Two white matter pathways in the brain were investigated using probabilistic tractography with diffusion-weighted MRI; the superior longitudinal fasciculus (SLF), a monosynaptic fronto-parietal white matter tract well-recognised for its involvement in working memory function, and the cerebello-thalamo-prefrontal (CTP) pathway, a polysynaptic efferent cerebellar white matter pathway hypothesised to be involved in working memory function. The CTP pathway was further divided into two monosynaptic components; the cerebello-thalamic tract (CT), and the thalamo-prefrontal tract (TP). The diffusion-weighted MRI measures of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were used to assess white matter microstructure. The Cogmed working memory training intervention (5-7 weeks) was administered using a double-blinded, placebo-controlled, randomised control trial. In the adaptive Cogmed intervention, activities became more complex with increasing proficiency of the participant, thereby challenging working memory capacity. In the placebo Cogmed intervention, activities remained at a fixed, low level of difficulty. Working memory capacity and white matter microstructure were assessed at baseline and two-weeks post-intervention using gold-standard measures. The study found that, prior to the intervention, immaturity of microstructural connectivity in cerebello-thalamo-prefrontal and fronto-parietal white matter pathways was related to lower working memory performance. Following the intervention, no significant difference in working memory performance or microstructural white matter maturity was noted in children who undertook adaptive versus placebo training. The novel finding of this thesis is that early disruption to the microstructural development of cerebello-cortical white matter pathways (as a result of extremely preterm birth) may represent a potential neurobiological mechanism underlying working memory dysfunction in this population. Evaluation of these tracts in the perinatal period therefore has the potential to identify children at risk of developing working memory deficits later in life, so that close surveillance or early interventions may be applied. However, Cogmed adaptive (versus placebo) working memory training does not appear to be an effective intervention in improving working memory capacity for school-age extremely preterm children.
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ItemWernicke-Korsakoff syndrome in alcoholic and nonalcoholic patients: clinical and neuropsychological presentation( 2015)Background. Wernicke-Korsakoff syndrome (WKS) is a relatively common neurological disorder due to thiamine deficiency. Approximately 80% of cases with WKS pathology are not diagnosed during life. Untimely diagnosis is associated with poorer patient outcome. WKS most frequently occurs in combination with alcohol use disorder. The relative roles of thiamine deficiency and excessive alcohol consumption in cognitive dysfunction remain unclear. Previous research of WKS in people without alcohol use disorder is limited. Aims. To enhance understanding of nonalcohol-related WKS and WKS in general by demonstrating the presence and variability of the major acute neurological and chronic cognitive symptoms of WKS in cases whether or not related to alcohol. Better understanding and enhanced awareness of the poorly recognised aspects of WKS has clinical and research implications, including for diagnosis and patient management. Methods. The thesis comprises three studies. STUDY ONE was a systematic review of case reports of Wernicke's encephalopathy and WKS in patients without history of alcohol use disorder. Eligible cases totalled 574. Publication dates ranged from 1867 to 2011. Comparisons of patient background and clinical presentation were made with published data on samples comprising, almost exclusively, alcohol-related WKS. STUDY TWO was an analysis of the neuropsychological profiles of nine cases with WKS and alcohol use disorder. One case was recruited prospectively and eight cases were chosen retrospectively on a consecutive basis from a database of patient records. In STUDY THREE, the psychometric test scores of 12 published cases with WKS not related to alcohol were evaluated within the frameworks of the Wechsler and Cattell-Horn-Carroll models of intelligence. Results. STUDY ONE revealed important similarities in clinical presentation between WKS whether or not related to alcohol use disorder. For example, persisting memory impairment was frequently reported in both groups. Several group differences were also identified, such as longer duration of precipitating illness for cases with alcohol-related WKS. STUDY TWO highlighted the variability in neuropsychological profiles in clinical cases with WKS. In contrast to the conventional view of Korsakoff's syndrome, Study Two revealed that a large discrepancy between memory and general intellectual function has poor sensitivity to the detection of chronic WKS. General intellectual function was not always preserved relative to memory function. STUDY THREE found deficits on objective measures of multiple cognitive abilities in published cases of WKS. No case in this small series had a history of alcohol use disorder, therefore the variable range of cognitive deficits could not be attributed to any additional effect of excessive alcohol consumption on the brain. As hypothesised, cognitive profiles included cases with severe, selective memory impairment as well as cases with more generalised cognitive impairment. Conclusions. Consistent with the hypotheses of the thesis, the two primary conclusions were (1) alcohol is not required for any element of WKS, including chronic cognitive impairment and Korsakoff's syndrome, and (2) the range and severity of cognitive deficits in chronic WKS are more variable than is typically appreciated.
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ItemNeurocognitive and psychiatric markers of network disease in epilepsy( 2015)People with epilepsy frequently experience debilitating memory and mood difficulties. Autobiographic memory impairments are a vulnerability factor for developing and maintaining unipolar depression in the psychiatric population, yet despite the wealth of research examining cognition and behaviour in epilepsy, the links between them remain unclear. This thesis aimed to profile the autobiographic memory and mood function of patients with focal epilepsy relative to healthy controls, and characterise how these functions may be interlinked. Three behavioural studies were conducted to achieve these objectives. Participants were prospectively recruited from the Comprehensive Epilepsy Programme at Austin Health, Melbourne, between 2010-2014. The cognitive and psychiatric functioning of 85 adults with chronic focal epilepsy was compared to that of 72 sociodemographically-matched controls largely recruited from the patients’ families (N=157). Gold-standard psychometric measures assessed depressive symptoms and cognitive function. Study One was an initial qualitative exploration of the relationships between cognitive impairment and depression in a form of focal epilepsy not typically linked to memory disorder, to assess the effects of seizures and pathology on those functions. A well-characterised case series of nine patients with frontal lobe epilepsy (FLE) was contrasted to 24 matched controls. Results suggested that FLE can selectively interrupt the integrity of the autobiographic memory/cognitive control networks versus the affective network. Study Two aimed to quantitatively delineate the effects of seizure chronicity on impaired autobiographic memory in a large cohort of patients (n=85) relative to healthy controls (n=72), and the potential links between poor autobiographic recall and mood. This revealed that chronic seizures beginning in childhood dysregulate cognition-related networks important for autobiographic recall, while autobiographic memory impairments in patients with a more recent disease onset are largely linked to depressive symptoms, perhaps reflecting maladaptive psychological adjustment to the onset of epilepsy as an adult. Together, the first two studies show that autobiographic memory difficulties are only related to depression in certain epilepsy syndromes. Finally, Study Three comprised a data-driven investigation into the existence of a cognitive phenotype of depression in epilepsy. Results showed that of the 21 (25%) patients currently meeting criteria for a formal depressive disorder, 15 (71%) had a ‘Cognitive’ phenotype of the disorder, while six (29%) presented with a ‘Somatic’ phenotype. These findings are congruent with phenotypes of depression found in other populations, and suggest that different presentations of depression in epilepsy may uniquely index dysregulation of selected brain networks. Moreover the lack of seizure-related correlates to the Cognitive phenotype discounts the widespread assumption that cognitive and affective network dysfunction in epilepsy is a side-effect of seizures. The results of this thesis suggest that epilepsy can selectively disrupt large-scale brain networks important to cognition and affect, and that behavioural disturbances in people with epilepsy may be primary manifestations of the network disease.
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ItemNeural correlates of attention in the context of prematurity( 2014)This study aimed to examine attention outcomes in a high-risk very preterm (VPT; <30 weeks’ gestational age) and/or very low birth weight (VLBW; <1250 g) children at 7 years, and to assess whether brain abnormality measured by neonatal magnetic resonance imaging (MRI) can predict later adverse outcome within this domain. It also aimed to investigate whether the attention difficulties observed at 7 years were associated with abnormalities in the key white matter pathways associated with attention. A cohort of 198/224 VPT/VLBW children and 70/77 term controls were examined. Neonatal MRI scans performed at term-equivalent age were assessed for white matter, cortical grey matter, deep grey matter, and cerebellar abnormalities. Standardised neuropsychological tests of attention and MRI scans were conducted at 7 years. Diffusion tractography analyses were performed on the key white matter tracts associated with attention (the superior longitudinal fasciculi, the cingulum bundles, and the reticular activating system). At 7 years of age, the VPT/VLBW group performed significantly worse than term controls on all attention outcomes. Associations between higher neonatal brain abnormality scores and adverse attention performances at 7 years were found in the VPT group; in particular, white matter and deep grey matter abnormalities were reasonable predictors of long-term attention outcomes. Findings at 7 years also revealed altered microstructural organisation and reduced tract volume within the proposed attention tracts in the VPT children compared with the term controls and also that, such alterations were related to the adverse attention outcomes in VPT children. Attention is a significant area of concern in VPT/VLBW children. This is the first study to show that neonatal brain pathology may be used to predict, in conjunction with other known risk factors, which children may be at risk of later adverse attention outcomes. This study also highlights the importance of white matter tract integrity for the development of attention abilities in VPT children.
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ItemNeuropsychological characterization of typical and atypical progressive supranuclear palsy and comparison with Parkinson's disease( 2013)This thesis examined the cognitive aspects of patients with progressive supranuclear palsy defined according to the recently proposed phenotypic distinctions (PSP+). 14 patients with PSP-Richardson’s syndrome (PSP-RS), 3 with PSP-Parkinsonism (PSP-P), 4 with PSP-Pure akinesia with gait freezing (PSP-PAGF) and 19 patients with idiopathic Parkinson’s disease (PD) were examined using a comprehensive battery of neuropsychological tests encompassing a wide range of cognitive domains. The results from the current thesis provide clear evidence that the PSP clinical phenotypes can be differentiated by a characteristic pattern and progression of cognitive deficits at a group (PSP+) and at a phenotypic level (PSP-RS, PSP-P, PSP-PAGF). Specifically, the pattern of cognitive deficits most useful in distinguishing between PSP+ and PD were psychomotor slowing and prominent ‘frontal’ executive dysfunction. In addition, longitudinal analyses revealed a differential decline of executive function in patients with PSP+ in comparison to PD. At the phenotypic level, patients with the classic variant of PSP (PSP-RS) could be distinguished from those with the ‘atypical’ phenotypes (PSP-P and PSP-PAGF) by a more severe and extensive pattern of cognitive impairments and longitudinal decline in executive function. These findings were broadly consistent with the reported pathological differences in PSP-RS, PSP-P, and PSP-PAGF. Results from this research confirm the existence of three distinct clinical phenotypes of PSP, which can be differentiated on pathological, clinical and cognitive grounds. In addition, this thesis indicates that neuropsychological assessment may be able to contribute to the in vivo differentiation of the PSP clinical phenotypes in clinical practice.
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ItemCattell-Horn-Carroll model in neuropsychology( 2014)The Cattell-Horn-Carroll (CHC) model is a comprehensive and strongly empirically supported model of cognitive abilities with increasing acceptance in diverse psychological assessment settings. However, there is less evidence directly supporting the generality and utility of the CHC model for diagnostic assessment in clinical populations. Thirty-one high quality datasets involving popular neuropsychological tests were reanalyzed with confirmatory factor analysis. The CHC classifications of neuropsychological tests were supported, and the CHC model fit well across a wide range of clinically relevant populations. One issue of special relevance is the place of executive function in the CHC model, as executive function is seen as central in neuropsychological assessment but is not explicitly represented in the CHC model. As a hypothetical additional factor to the CHC model, general executive function was found to be redundant. For specific executive functions, the literature on the Switching, Inhibition, and Updating executive function model was critically reviewed and the executive function model was explained in terms of the CHC model. The CHC model was supported as a paradigm for diagnostic assessment of cognitive disorders. The results have important implications for theoretical models of cognitive abilities, interpretation of popular clinical tests, and neuropsychological assessment.
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ItemThe neuroendocrine system following preterm birth and its effects on cognitive and brain development at age 7( 2012)Preterm birth is associated with a well-defined pattern of neurodevelopmental impairments which include a range of cognitive deficits, as well as structural brain abnormalities. Further, preterm infants are known to have a transiently altered neuroendocrine system during the first weeks of postnatal life. Although recent studies have focused on characterising long-term neurobehavioural deficits, few have examined potential mechanisms that may, at least partly, explain these poorer outcomes. This study aimed to address this shortcoming by focusing on the postnatal neuroendocrine system and its association with neurodevelopmental outcomes at age 7 in a group of children born very preterm. Postnatal concentrations of three hormones, free thyroxine, cortisol, and growth hormone, were examined using both direct hypothesis testing and exploratory hypothesis-generating approaches. Three direct hypotheses were proposed following review of the literature. Firstly, it was hypothesised that lower postnatal free thyroxine concentrations would be associated with poorer performances on measures of intellect, attention, and visuoperceptual abilities, as well as reductions in grey and white matter volumes at age 7 in children born very preterm. Secondly, it was hypothesised that higher postnatal cortisol concentrations would be associated with poorer performances on tasks of new learning and memory and volumetric reductions in the hippocampi at age 7 in children born very preterm. The final hypothesis predicted that elevated postnatal growth hormone concentrations would be related to deficits in attention and executive functioning and reductions in the prefrontal brain volumes at age 7 in children born very preterm. The current study investigated 83 children born very preterm (gestational age <30 weeks and/or birth weight <1250g), born between June 2002 and December 2003 in Melbourne, Victoria. During the neonatal period, hormone analysis was conducted over eight time points during the first 42 days of life (cord, Day 1, Day 4, Day 7, Day 14, Day 21, Day 28, and Day 42) to characterise the hormone profiles associated with preterm birth. At age 7, the children participated in a cognitive assessment and an MRI scan. A broad neuropsychological battery that assessed six domains of cognition, namely intellect, language, visuoperceptual reasoning, memory, attention and executive functioning, and processing speed, was used to characterise the cognitive profiles of this group of children. MRI imaging analysis was conducted using Freesurfer (v 5.1.0) to obtain cortical and subcortical brain volumes. The results did not confirm the direct hypotheses, although some interesting and novel findings arose. Firstly, elevated free thyroxine concentrations were related to poorer processing speed performances. A similar relationship was observed with elevated cortisol concentrations and decrements in processing speed. Lastly, elevated cortisol concentrations were related to volumetric reductions in subcortical regions, particularly the basal ganglia. Possible explanations for these findings were reviewed, though more research is required to confirm these relationships. Using a critical illness theory of endocrinology, it was concluded that the hormone profile exhibited by this cohort of children born very preterm during the early postnatal period, namely low concentrations of free thyroxine, and elevated concentrations of cortisol and growth hormone, reflected a transient reaction to acute critical illness. Moreover, given the adaptive nature of this acute illness phase, it was concluded that this postnatal hormone profile did not explain the diffuse nature of the neurodevelopmental impairments common to the preterm population.
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ItemNeurodevelopment in children with single-suture craniosynostosis: the early years( 2010)Craniosynostosis is a common developmental disorder characterised by premature, pathological fusion of one or more of the fibrous connections, or sutures, that normally separate the bony plates of the skull during early development. Premature sutural fusion, typically occurring in utero, results in anomalous skull growth, and may have consequences for the developing brain. Most cases of single-suture craniosynostosis (SSC) require surgery, preferentially performed within the first year of life, to release the fused suture and reshape the deformed skull and improve brain growth potential. The exact mechanisms by which brain development is disrupted in SSC are uncertain. Research suggests that children with all forms of SSC are at heightened risk for neuropsychological problems; however, the nature, extent and risk factors (e.g., genetic, environmental, severity of skull deformity) for these disturbances, are yet to be established. The aim of this study was to examine the impact that SSC may have on neurodevelopmental skills during infancy and to use a theory-driven approach to explore the possible contributory factors to developmental progression during infancy. Participants included 30 infants with SSC (16 metopic, 14 sagittal). Participants were assessed on the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III) during early infancy when they were between 5 and 15 months of age. Fifty-three percent (n=16) of these infants were also assessed in late infancy when they were between 17 and 33 months of age and at least six months post-surgical intervention. During both early and late infancy, children with craniosynostosis demonstrated significantly poorer gross motor skills compared to the normative sample, but other skills were in line with normal population expectations. Factors including subtype of craniosynostosis, severity of deformity, social risk and age at surgery, were not shown to be significantly associated with developmental level during early or late infancy. The impact of genetic variables on early development was unclear in the current sample. This study has provided important insights into the functional significance of disruption to typical brain growth in infants with SSC. Findings indicate that SSC is a condition associated with developmental delay during early infancy prior to surgical intervention, with developmental concerns remaining evident post-surgically in late infancy. Findings support recommendations for the close monitoring of the development of these children during early life.