Neural and cognitive mechanisms underpinning novel treatments for depression

Depression is a prevalent and debilitating psychiatric condition. However, currently available pharmacological treatments are ineffective for almost a third of all depressed patients. Moreover, even when effective, standard treatments suffer from substantial therapeutic lag, often taking weeks-to-months to reach maximum efficacy. Thus, the need for faster acting treatments for depression is high. Evidence of novel glutamatergic pharmacological and brain stimulation antidepressant treatments has been reported. However, it is unknown how exactly these treatments, namely transcranial direct current stimulation and ketamine, work at either the biological or cognitive level. The aim of this thesis was to provide a cognitive and systems level biological explanation for the efficacy of these treatments on two important symptoms of depression, anhedonia and cognitive control. Following a general introductory chapter, the first experimental chapter explores the effect of tDCS on cognitive control in healthy volunteers. The second experimental chapter explores the reliability of 7 Tesla (T) proton magnetic resonance spectroscopy (1HMRS) as a technique to quantify glutamate and glutamine levels in the healthy human brain. The third experimental chapter explores the relationship between levels of glutamatergic metabolites, one purported mechanism to which ketamine and tDCS elicit their antidepressant response, and anhedonia in medication-free depressed patients and healthy individuals at baseline and following ketamine and placebo. The fifth and final experimental chapter explores whether ketamine alters the behaviour and neural activity underlying cognitive control in patients with depression. The results suggest that tDCS may induce improvements in cognition in healthy volunteers and that ketamine may improve levels of anhedonia and mood, but not cognition, in depressed patients. Surprisingly, a decrease in 7T 1H-MRS measured glutamine, but not glutamate, levels was found post-ketamine; moreover, baseline levels of glutamine, but not glutamate, were associated with the antidepressant and anti-anhedonic response to ketamine. The final chapter discusses the experimental results in light of cognitive and neural mechanisms thought to underpin depression and its treatment

Cultivating Water Literacy in STEM Education: Undergraduates’ Socio-Scientific Reasoning about Socio-Hydrologic Issues

Water-literate individuals effectively reason about the hydrologic concepts that underlie socio-hydrological issues (SHI), but functional water literacy also requires concomitant reasoning about the societal, non-hydrological aspects of SHI. Therefore, this study explored the potential for the socio-scientific reasoning construct (SSR), which includes consideration of the complexity of issues, the perspectives of stakeholders involved, the need for ongoing inquiry, skepticism about information sources, and the affordances of science toward the resolution of the issue, to aid undergraduates in acquiring such reasoning skills. In this fixed, embedded mixed methods study (N = 91), we found SHI to hold great potential as meaningful contexts for the development of water literacy, and that SSR is a viable and useful construct for better understanding undergraduates’ reasoning about the hydrological and non-hydrological aspects of SHI. The breadth of reasoning sources to which participants referred and the depth of the SSR they exhibited in justifying those sources varied within and between the dimensions of SSR. A number of participants’ SSR was highly limited. Implications for operationalizing, measuring, and describing undergraduate students’ SSR, as well as for supporting its development for use in research and the classroom, are discussed

Aggregatibacter actinomycetemcomitans leukotoxin induces cytosol acidification in LFA-1 expressing immune cells

Studies have suggested that Aggregatibacter actinomycetemcomitans leukotoxin (LtxA) kills human lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18)-bearing immune cells through a lysosomal-mediated mechanism. Lysosomes are membrane-bound cellular organelles that contain an array of acid hydrolases that are capable of breaking down biomolecules. The lysosomal membrane bilayer confines the pH-sensitive enzymes within an optimal acidic (pH 4.8) environment thereby protecting the slightly basic cytosol (pH 6.8-7.5). In the current study, we have probed the effect of LtxA-induced cytolysis on lysosomal integrity in two different K562 erythroleukemia cell lines. K562-puro/LFA-1 cells were stably transfected with CD11a and CD18 cDNA to express LFA-1 on the cell surface while K562-puro, which does not express LFA-1, served as a control. Following treatment with 100 ng ml-1 LtxA cells were analyzed by live cell imaging in conjunction with time-lapse confocal microscopy and by flow cytometry. Using a pH-sensitive indicator (pHrodo®) we demonstrated that the toxin causes a decrease in the intracellular pH in K562-puro/LFA-1 cells that is noticeable within the first 15 min of treatment. This process correlated with the disappearance of lysosomes in the cytosol as determined by both acridine orange and LysoTracker® Red DND-99 staining. These changes were not observed in K562-puro cells or when heat inactivated toxin was added to K562-puro/LFA-1. Our results suggest that LtxA induces lysosomal damage, cytosol acidification, which is followed by cell death in K562-puro/LFA-1 cells. © 2016 John Wiley & Sons A/S

The neural basis of hot and cold cognition in depressed patients, unaffected relatives, and low -risk healthy controls: An fMRI investigation

BACKGROUND: Modern cognitive neuropsychological models of depression posit that negatively biased emotional (“hot”) processing confers risk for depression, while preserved executive function (“cold”) cognition promotes resilience. METHODS: We compared neural responses during hot and cold cognitive tasks in 99 individuals: those at familial risk for depression (N = 30 unaffected first-degree relatives of depressed individuals) and those currently experiencing a major depressive episode (N = 39 unmedicated depressed patients) with low-risk healthy controls (N = 30). Primary analyses assessed neural activation on two functional magnetic resonance imaging tasks previously associated with depression: dorsolateral prefrontal cortex (DLPFC) responsivity during the n-back working memory task; and amygdala and subgenual anterior cingulate cortex (sgACC) responsivity during incidental emotional face processing. RESULTS: Depressed patients exhibited significantly attenuated working memory-related DLPFC activation, compared to low-risk controls and unaffected relatives; unaffected relatives did not differ from low-risk controls. We did not observe a complementary pattern during emotion processing. However, we found preliminary support that greater DLPFC activation was associated with lower amygdala response during emotion processing. LIMITATIONS: These findings require confirmation in a longitudinal study to observe each individual's risk of developing depression; without this, we cannot identify the true risk level of the first-degree relative or low-risk control group. CONCLUSIONS: These findings have implications for understanding the neural mechanisms of risk and resilience in depression: they are consistent with the suggestion that preserved executive function might confer resilience to developing depression in first-degree relatives of depressed patients

Harnessing electric potential: DLPFC tDCS induces widespread brain perfusion changes.

A commentary on widespread modulation of cerebral perfusion induced during and after transcranial direct current stimulation applied to the left dorsolateral prefrontal corte

Perception of a need to change weight in individuals living with and beyond breast, prostate and colorectal cancer: a cross-sectional survey

PURPOSE: People living with and beyond cancer (LWBC) are advised to achieve a body mass index (BMI) within the healthy range (≥ 18.5 and < 25). Not perceiving a need for weight change may be a barrier to achieving a healthy weight. This study aimed to explore factors associated with perceived need for weight change among people LWBC. METHODS: Adults diagnosed with breast, prostate, or colorectal cancer were recruited through National Health Service sites in Essex and London. Participants (N = 5835) completed the ‘Health and Lifestyle After Cancer’ survey, which included a question on perceived need to change weight. Associations between perceived need for weight change and BMI, and perceived need for weight change and health and demographic variables, were analyzed using chi-square tests and logistic regression, respectively. RESULTS: The proportion of participants perceiving a need to lose weight differed according to BMI category: healthy weight (23%), overweight (64%), obese (85%) (P < 0.001). Having overweight or obesity but not perceiving a need to lose weight was associated with being older, male, non-white, not married or cohabiting, and having cancer that had spread, no formal qualifications, no comorbidities, and having received chemotherapy. CONCLUSIONS: Perceived need to lose weight is prevalent among people LWBC with obesity and overweight. This group may be interested in weight management support. Demographic and health factors were associated with having obesity or overweight but not perceiving a need to lose weight. IMPLICATIONS FOR CANCER SURVIVORS: Weight loss interventions for people LWBC are needed. A subset of people LWBC with overweight and obesity may need additional information or motivators to engage with weight management

The impact of induced anxiety on affective response inhibition

Studying the effects of experimentally induced anxiety in healthy volunteers may increase our understanding of the mechanisms underpinning anxiety disorders. Experimentally induced stress (via threat of unpredictable shock) improves accuracy at withholding a response on the sustained attention to response task (SART), and in separate studies improves accuracy to classify fearful faces, creating an affective bias. Integrating these findings, participants at two public science engagement events (n = 46, n = 55) were recruited to explore the effects of experimentally induced stress on an affective version of the SART. We hypothesized that we would see an improved accuracy at withholding a response to affectively congruent stimuli (i.e. increased accuracy at withholding a response to fearful 'no-go' distractors) under threat of shock. Induced anxiety slowed reaction time, and at the second event quicker responses were made to fearful stimuli. However, we did not observe improved inhibition overall during induced anxiety, and there was no evidence to suggest an interaction between induced anxiety and stimulus valence on response accuracy. Indeed Bayesian analysis provided decisive evidence against this hypothesis. We suggest that the presence of emotional stimuli might make the safe condition more anxiogenic, reducing the differential between conditions and knocking out any threat-potentiated improvement