Lakshmi Yatham

Professor

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Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Executive function deficits in bipolar I disorder: Association with brain structure, illness progression, and antipsychotic medication (2013)

Executive function impairments are a core feature of Bipolar I Disorder (BDI), present not only during acute episodes but also persisting following remission of mood symptoms. Despite advances in knowledge regarding the neural basis of executive functions (EF) in healthy subjects, particularly in regards to the role of the dorsolateral prefrontal cortex (DLPFC) and caudate; research into how changes within these regions contribute to the deficits in BDI is lacking. This thesis explores EF in patients early in the course of illness, examining how impairments evolve with illness progression and how this may relate to neuromorphological changes and naturalistic pharmacological treatment regimes.The first analysis demonstrates that EF is moderate-severely impaired in patients with BDI even following sustained symptomatic recovery from their first manic episode. Both larger caudate size and treatment with a higher relative dose of an antipsychotic drug predicted the severity of deficits. Despite receiving ongoing clinical care, half of patients experienced a subsequent hypo/manic and/or depressive episode within one year. While those who remained well did show significant improvements in EF compared to those whose illness progressed, both patient groups still maintained moderate deficits compared to healthy subjects at follow-up. Although not directly associated with cognitive changes, sustained recovery during this time was also associated with reduced grey matter loss (including the left DLPFC) when compared affective recurrence, even after accounting for other clinical or treatment factors.Maintenance pharmacological treatment with an antipsychotic is commonly used to prevent episode recurrence in BDI. Drugs within this class each show varying affinity to the dopamine D₂ receptor (D₂R), which plays an important modulatory role in DLPFC and caudate function. Differences in D₂R binding have a likely impact on EF, as patients receiving an antipsychotic with high D₂R affinity (risperidone) showed larger impairments when compared to those treated with a low affinity drug (quetiapine) or no antipsychotic.These results demonstrate that illness related structural changes in the DLPFC and caudate are associated with the presence and evolution of executive function deficits in BDI; although the potential confounding effects of antipsychotics which influence functioning in these regions must also be considered.

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Neurobiological Correlates of Overweight and Obesity in People with Bipolar Disorder (2013)

Up to 75% of people with bipolar disorder (BD) are overweight or obese, and these patients suffer more severe psychiatric symptoms than normal-weight patients, including more frequent depressions, more suicide attempts, lower response rates to pharmacotherapy, and greater cognitive impairment. Obesity is a chronic inflammatory condition that damages numerous body organs and is causally linked to the development of diabetes, heart disease, and cancer. BD is fundamentally a brain illness, and this, along with converging evidence from human and animal studies suggesting that the brain is a target organ for obesity-related damage, compelled me to investigate obesity-related neurobiological changes early in BD. I found that at recovery from their first manic episode, there was no difference between BD patients and age- and gender-matched healthy subjects in mean body mass index (BMI) or rates of overweight or obesity. Nonetheless, magnetic resonance imaging (MRI) demonstrated that overweight/obese patients had reduced white matter and temporal lobe volumes compared to normal-weight patients. WM reductions are characteristic of early-stage BD, while temporal lobe reductions are frequently reported later in the illness. These findings thus suggested a testable hypothesis: that the neuropathology of BD is exacerbated with elevated BMI. Subsequent investigations supported this hypothesis. A voxel-based analysis of regional brain volumes revealed that BMI-related volume reductions primarily affected frontal, temporal, and subcortical emotion-generating and –regulating brain areas implicated in BD. Moreover, MR spectroscopy showed that overweight/obese patients had reduced hippocampal N-acetylaspartate concentrations compared to normal-weight patients. Similar findings were not detected in overweight/obese healthy subjects, who had reduced occipital lobe grey matter volume and no neurochemical alterations. These are the first data to establish a relationship between elevated BMI and neurobiological alterations in BD, or any psychiatric illness. They demonstrate that elevated BMI is associated with unique brain changes early in BD that negatively impact regions believed to be vulnerable in the illness. This immediately suggests an explanation for the more severe illness course experienced by obese BD patients, and creates a compelling argument for examining the neurobiological impact of obesity in other mental illnesses with high obesity rates, such as major depressive disorder and schizophrenia.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Quantification of grey matter changes following first episode mania in bipolar I disorder: a systematic review and prospective study (2021)

Background: While there is evidence of widespread grey matter (GM) changes in bipolar I disorder (BD-I), it is unclear how early in the illness such changes emerge. However, to date there has been little systematic examination of longitudinal grey matter changes early during BD-I. We conducted a systematic review to examine the literature regarding GM changes in BD-I patients following the first episode of mania (FEM), in addition to a quantitative analysis of grey matter changes in a prospective cohort of BD-I patients in the first three years of disease.Methods: Following PRISMA guidelines, we conducted a systematic review of studies examining longitudinal changes in GM volume (GMV), cortical thickness and/or surface area in patients with BD-I following FEM. We qualitatively synthesized results regarding baseline differences between BD-I patients and HCs, and longitudinal GM changes in BD-I patients. For the longitudinal study, FEM patients and HCs were recruited and completed structural 3T MRI at pre-determined intervals. Images were analyzed using FreeSurfer’s longitudinal pipeline and linear mixed models used to examine longitudinal changes in cortical thickness, surface area and subcortical volume. Results: Fifteen studies met inclusion criteria for the systematic review, all examining changes in GMV. While results were highly heterogeneous, one replicated finding was decreased anterior cingulate cortex (ACC) volumes in first episode BD-I patients versus HC at baseline, and greater longitudinal ACC volume decrease in patients in the months following FEM. The potential impact of episode recurrence, substance use, age of onset and prior depressive episodes was inconsistently examined.In the longitudinal study, BD-I patients and HCs showed comparable reductions in cortical surface area and subcortical volumes over 3 years. No significant time*group effects were found; BD-I patients had smaller right thalamic volumes versus HCs at year 3 at trend-level significance.Limitations: The literature regarding GM changes early in BD-I is inconsistent. The sample size in our longitudinal study may have been insufficient to detect statistically significant changes. Conclusions: Evidence for longitudinal grey matter changes in the early phases of BD-I is inconsistent. Larger longitudinal studies are needed to fully understand neuroprogression in early BD-I.

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Cognitive functioning in bipolar disorder: the influence of sex (2013)

Following a wave of similar research conducted in samples with schizophrenia, there has been a recent surge of studies investigating sex differences in the phenomenology of bipolar disorder (BD). These studies have almost exclusively focused on sex differences in course and clinical presentation. As compared with male BD patients, women with BD have increased likelihood of experiencing rapid cycling, mixed mania, suicidal ideation, and a medical or psychiatric comorbidity. However, in addition to its characteristic affective disturbance, the phenomenology of BD is associated with significant and persistent cognitive impairment. There is evidence to support that sexual dimorphisms, the basis of sex differences in cognitive functioning, are altered in BD. Additionally, it has been found that healthy patterns of cognitive sex differences are disrupted in schizophrenia, a closely related illness to BD. Despite this evidence, there have been few studies that have investigated the influence of sex on cognitive functioning in BD; the results that are available are both scant and contradictory. In order to clarify whether sex influences cognitive functioning in BD, 66 patients with BD-I disorder and 105 matched healthy controls were tested on a broad battery of neuropychological tests. As patients used in this sample were tested immediately proceeding symptomatic remission from their first-manic episode, this experimental design is poised to assess sex differences in cognitive functioning early in the course of BD. Overall, unlike in schizophrenia, healthy patterns of cognitive sex differences are intact early in the course of BD. To supplement and contextualize the study presented above, a large portion of this thesis is dedicated to providing literature reviews of the following topics: sex differences in the clinical phenomenology of BD, cognitive impairment in BD, sex differences in cognitive impairment and their neurobiological underpinnings in healthy samples.

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