Modulating perceptual complexity and load reveals degradation of the visual working memory network in ageing

Previous neuroimaging studies have reported a posterior to anterior shift of activation in ageing (PASA). Here, we explore the nature of this shift by modulating load (1,2 or 3 items) and perceptual complexity in two variants of a visual working memory task (VWM): a ‘simple’ color and a ‘complex’ shape change detection task. Functional near-infrared spectroscopy (fNIRS) was used to record changes in activation in younger (N=24) and older adults (N=24). Older adults exhibited PASA by showing lesser activation in the posterior cortex and greater activation in the anterior cortex when compared to younger adults. Further, they showed reduced accuracy at loads 2 and 3 for the simple task and across all loads for the complex task. Activation in the posterior and anterior cortices was modulated differently for younger and older adults. In older adults, increasing load in the simple task was accompanied by decreasing activation in the posterior cortex and lack of modulation in the anterior cortex, suggesting the inability to encode and/or maintain representations without much aid from higher-order centers. In the complex task, older adults recruited verbal working memory areas in the posterior cortex, suggesting that they used adaptive strategies such as labelling the shape stimuli. This was accompanied by reduced activation in the anterior cortex reflecting the inability to exert top-down modulation to typical VWM areas in the posterior cortex to improve behavioral performance

Determinants of age-related brain iron accumulation and links to neurocognitive functions

Iron is crucial for development and normal functioning of the brain. With increasing age, it accumulates in the cells and can cause irreparable damage, affecting both the structure and function of the brain. Despite these findings, the factors which influence iron accumulates and the longitudinal effects of iron are still poorly understood. This doctoral thesis aimed to explore what influences brain iron accumulation in normal aging, and how this accumulation impacts molecular, and functional properties of the brain, and working-memory. Study I investigated if iron accumulation in striatum and DLPFC affected working memory change in normal aging, and if this accumulation and relationship to performance varied based on availability of dopamine, specified by COMT genotype status. We found that iron accumulated in both striatum and DLPFC. Greater iron accumulation in DLPFC was related to more deleterious change in working-memory performance. In addition, iron accumulation was amplified in older adults with presumably lowest levels of dopamine. These individuals were also driving the link between changes in iron and working-memory performance. Study II investigated if iron was linked to dopamine receptor availability and whether this association affected working memory. The study revealed that more iron was related to lower receptor availability in DLPFC and that this, coupled together with older age, contributed to reduced brain activity during a working-memory task. Additionally, the reduction in brain activity was in turn related to poorer task performance. Study III assessed (1) if brain iron content and accumulation were related to longitudinal changes in in brain activity during working-memory performance in normal aging, (2) potential association with glutamate, and (3) whether glutamate mitigated iron-brain activity relationship. In this study, we found that younger adults with initial elevated iron down-regulated more brain activity over a 3-year period, while performing the task. The results also showed a potential age-dependent relationship between iron and glutamate, such that younger adults with elevated iron content had more glutamate in DLPFC. Study IV explored biological and lifestyle factors that might influence iron accumulation in normal aging. Here, blood iron markers, physical activity, diet, and cardiovascular health significantly influenced brain iron content and accumulation. Furthermore, the associations between these factors and brain iron were influenced by age, highlighting the complexity of these relationships. Collectively, our studies show that age-related brain iron accumulation can be influenced by a number of factors, both modifiable and non-modifiable, such as lifestyle choices and genetic predisposition respectively. The potential to attenuate the accumulation of brain iron is essential, as we have also shown that iron can have deleterious effects on brain function and cognition older age. Finally, the links between iron and the dopaminergic system could partially explain age-related alterations, such as diminished receptor availability. Understanding the role of neurotransmitters on attenuating iron accumulation can pave the way for tailoring interventions in neurodegenerative disorders

The relation among aging, dopamine-regulating genes, and neurocognition

When people are getting old, they often feel increasingly harder to concentrate, and become slower and more inflexible during tasks that involve focused attention, information maintenance in the face of distractions, and when fast switching according to changing goals is required. These cognitive functions are collectively referred to as working memory (WM). Both cross-sectional and longitudinal studies have reported WM impairment in aging. Moreover, aging is accompanied by alterations in brain structure, brain function, and dopaminergic neurotransmission. This thesis sought to link WM to brain structure, brain function, and dopamine (DA)-related genes in large samples of younger and older adults. The chief aims were to provide neural and genetic evidence to increase our understanding of the mechanisms of age-related deficits in WM. The DRD2/ANKK1-Taq1A polymorphism has been associated with DA D2 receptor densities in caudate. In study I, we investigated the effects of this polymorphism on grey-matter (GM) volume in striatum in older adults, and examined whether the genetic effect interacts with age. Results showed that the A allele of the DRD2/ANKK1-Taq1A polymorphism was associated with smaller GM volume in caudate and this effect was only observed in older adults (>72 years). The DRD2-C957T polymorphism has been linked to DA D2 receptor densities in both striatum and extrastriatal areas, such as in prefrontal cortex (PFC). In study II, we investigated the genetic effects of two DRD2 polymorphisms on WM functioning and examined how these effects may interact with adult age. In comparing younger and older adults, we found that the old had lower caudate activity in a highly demanding WM task. In addition, there were single and joint genetic effects of the two DRD2 polymorphisms on WM performance and frontostriatal brain activity. The genetic effects on brain function were observed in older, but not in younger adults, suggesting magnified genetic effects in aging. In study III, we related white-matter integrity with WM performance in a large sample across a wide age range. Results demonstrated that WM was associated with white-matter integrity in multiple tracts, indicating that WM functioning relies on global structural connections among multiple brain regions. Moreover, white-matter integrity could partially account for the age-related difference in WM. The COMT-Val158Met polymorphism has been associated with PFC DA levels. In this study, we found genetic effects of COMT on white-matter microstructure, suggesting a relation between dopaminergic function and white-matter integrity. In study IV, we investigated changes of white-matter integrity and WM performance using longitudinal data. We found that white-matter integrity declined across 10 years in the whole sample (25-80 years) and the decline was greater for older than for younger adults, reflecting a non-linear relation between age and white matter. More importantly, we found change – change associations of white-matter integrity and WM performance in several tracts including genu and body of corpus callosum and superior longitudinal fasciculus, suggesting that impaired WM performance in aging might reflect age-related decrease of white-matter integrity in these tracts. Collectively, these studies demonstrate age-related differences and changes in brain structure and brain function associated with impaired WM performance in aging. The findings support and extend previous work on the roles of DA in WM functioning and brain integrity in aging, and contribute to our understanding of neural and genetic correlates of WM, and how these are affected in aging

Early adversity in rural India impacts the brain networks underlying visual working memory

There is a growing need to understand the global impact of poverty on early brain and behavioural development, particularly with regard to key cognitive processes that emerge in early development. Although the impact of adversity on brain development can trap children in an intergenerational cycle of poverty, the massive potential for brain plasticity is also a source of hope: reliable, accessible, culturally-agnostic methods to assess early brain development in low resource settings might be used to measure the impact of early adversity, identify infants for timely intervention, and guide the development and monitor the effectiveness of early interventions. Visual working memory (VWM) is an early marker of cognitive capacity that has been assessed reliably in early infancy and is predictive of later academic achievement in Western countries. Here, we localized the functional brain networks that underlie VWM in early development in rural India using a portable neuroimaging system, and we assessed the impact of adversity on these brain networks. We recorded functional brain activity as young children aged 18-207 weeks performed a visual working memory task. Brain imaging results revealed localized activation in the frontal cortex, replicating findings from a midwestern US sample. Critically, children from families with low maternal education and income showed weaker brain activity and poorer distractor suppression in canonical working memory areas in the left frontal cortex. Implications of this work are far-reaching: it is now cost-effective to localize functional brain networks in early development in low-resource settings, paving the way for novel intervention and assessment methods

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

A fNIRS investigation of speech planning and execution in adults who stutter

Our study aimed to determine the neural correlates of speech planning and execution in adults who stutter (AWS). Fifteen AWS and 15 controls (CON) completed two tasks that either manipulated speech planning or execution processing loads. Functional near-infrared spectroscopy (fNIRS) was used to measure changes in blood flow concentrations during each task, thus providing an indirect measure of neural activity. An image-based reconstruction technique was used to analyze the results and facilitate their interpretation in the context of previous functional neuroimaging studies of AWS that used positron emission tomography (PET) or functional magnetic resonance imaging (fMRI). For planning, we compared neural activity associated with high versus low planning load in AWS and CON. For execution, we compared the neural activity associated with overt versus covert naming in AWS and CON. Broadly, group level effects corroborate previous PET/fMRI findings including under-activation in lefthemisphere perisylvian speech-language networks and over-activation in righthemisphere homologues. Increased planning load revealed atypical left-hemisphere activation in AWS, whereas increased execution load yielded atypical right frontotemporo-parietal and bilateral motor activation in AWS. Our results add to the limited literature differentiating speech planning versus execution processes in AWS

Investigating the neural mechanisms underlying auditory and audio-visual perception in younger and older adults

This thesis aimed to address questions in two distinct areas of research in ageing and cognitive neuroscience. Firstly, given that the pre-stimulus state of cortical oscillations had been shown to predict behavioural and neural responses, we addressed the question of whether pre-stimulus oscillatory mechanisms change or remain consistent in the ageing brain. Secondly, previous research had shown that Audio-visual (AV) speech influences the amplitude and latency of evoked activity. Our research addressed the questions of whether/how AV enhancement and visual predictability of AV speech is represented in evoked activity in noisy listening conditions, and whether such Electroencephalographic (EEG) signatures remain stable with age. In Chapter 3 we investigated the consistency of how pre-stimulus activity influences auditory frequency discrimination performance in young and older participants. In both groups the power of pre-stimulus activity influenced the encoding of sensory evidence reflected by early evoked components, while the phase influenced choice formation in later-activated EEG components. Importantly, for the early EEG components we did not find evidence for a systematic difference in the time scales of the perceptually relevant pre-stimulus activity. In the later-activated EEG component we found a trend for perceptually relevant rhythmic activity to arise from slower frequencies in the ageing brain. At the same time our data replicate previous findings of a significant age-related slowing of Auditory Evoked Potential (AEP) latency, modulations of AEP amplitudes, and a flattening of the spectral profile of EEG activity. In Chapter 4, we investigated the consistency of behaviour and evoked activity underlying AV speech integration in a speech-in-noise discrimination task in younger and older adults. Behaviourally, younger and older adults performed comparably. Performance was greater for Audio-visually informative (AVinf) speech compared to Auditory-only informative (AOinf) speech across groups and noise levels, and was poorer at low noise levels. AV enhancement was greater in high noise levels, across all participants, and older adults derived greater AV enhancement compared to younger adults (an effect that was consistent across noise levels). In terms of visual predictability, we found that word discrimination performance was greater for target words with non-labial initial phonemes (assumed least visually predictive), compared to labial initial phonemes (assumed most visually predictive). Furthermore, we found that AV enhancement was greater for labial initial phonemes, compared to non-labial initial phonemes, and this was consistent across age groups.Neurally, we found that AV enhancement is represented by a centro-parietal P3-like activity in older adults and an N4-like fronto-central activity in younger adults, but found that this activity did not correlate with behavioural AV enhancement. Our results point to distinct patterns of late evoked activity underlying AV enhancement between younger and older adults, possibly representing distinct cognitive (memory) strategies in predicting upcoming target stimuli. At the same time our data replicate previous findings of a significant age-related slowing of AEP latency, modulations of AEP amplitudes, and a flattening of the spectral profile of EEG activity. In Chapter 5 we investigated the consistency of evoked activity underlying the visual predictability of AV speech. We found that visual predictability was reflected by late fronto-central negativity in older adults, but not in younger adults. However, we did not find evidence of an interaction between visual predictability and AV enhancement in terms of evoked activity, raising further questions about how visual predictability of speech is represented the brain’s electrophysiology. Our results point to distinct patterns of late evoked activity underlying visual predictability of visual speech, again possibly reflecting differential strategies in predictive coding. In summary, the results of this thesis demonstrate that pre-stimulus mechanisms in auditory pitch perception remain consistent in the younger and older adult brain, while spectral dynamics change with age. Our results also replicate previous work demonstrating age-related delays in peak latency, and changes in peak amplitude, of early auditory evoked activity. And lastly, we demonstrate that differences in the EEG signatures of AV enhancement between younger and older adults emerge in late evoked activity, and that visual predictability of speech is represented in late evoked activity only in older adults

Hearing in dementia: defining deficits and assessing impact

The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain and are therefore predicted to damage hearing function early and profoundly. Here I present evidence for this proposition, based on structural and functional features of auditory brain organisation that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between ‘peripheral’ and ‘central’ hearing dysfunction, and recently characterised auditory signatures of canonical neurodegenerative dementias (Alzheimer’s disease and frontotemporal dementia). In chapter 3, I examine pure tone audiometric thresholds in AD and FTD syndromes and explore the functional interplay between the auditory brain and auditory periphery by assessing the contribution of auditory cognitive factors on pure tone detection. In chapter 4, I develop this further by examining the processing of degraded speech signals, leveraging the increased importance of top-down integrative and predictive mechanisms on resolving impoverished bottom-up sensory encoding. In chapter 5, I use a more discrete test of phonological processing to focus in on a specific brain region that is an early target in logopenic aphasia, to explore the potential of auditory cognitive tests as disease specific functional biomarkers. Finally, in chapter 6, I use auditory symptom questionnaires to capture real-world hearing in daily life amongst patients with dementia as well as their carers and measure how this correlates with audiometric performance and degraded speech processing. I call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory ‘cognitive stress tests’ and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticity

Physical and Mental Coordination in the Elderly: A Causal Role for the Cerebellum?

The mechanisms underlying the progressive changes in tissues and organs that characterise normal ageing remain unclear. The cerebellum is known to play a major role in motor function, but recent research suggests it plays an equivalent role in cognition. Working with the hypothesis that cortico-cerebellar loops ensure smooth and coordinated activity in both domains, this thesis investigates the possible role of the cerebellum in normal ageing and in interventions to improve function, seeking to contribute to both theoretical and applied approaches to ageing. Study one investigated relationships between motor and cognitive function using raw data from a national normative sample of adults aged 16 to 75, employing a test battery assessing motor and cognitive skills. Differences between age groups were demonstrated in some tests of complex processing speed, working memory and executive function, with suggestive evidence that senescence in tests is reflected in tests sensitive to cerebellar function. Study two refined the battery, while including further measures of motor and memory performance to investigate linkages between cognitive and cerebellar function. Using a sample of 256 older adults, results were variable but provided evidence that pegboard performance could act as a predictor of some cognitive functions. Study three investigated a proactive intervention for healthy older adults designed to improve cerebellar function, and therefore balance and executive function. This involved an 8-10 week self-administered, internet-based coordinative exercise intervention using a ‘cerebellar challenge’ suite of graded activities. Performance on a basket of tests was assessed before and after, and also compared with performance changes in a no-intervention control group. Significantly greater benefits for the intervention group than the controls were found for balance physical coordination and controlled information processing. Overall, these studies support current research indicating cerebellar contribution to both cognitive and motor problems arising in old age, and present evidence that non-verbal memory and controlled speeded information problems may be alleviated through targeted activities affecting cerebellar function improving postural stability and physical coordination

The Role of Working Memory Load in Distractor Suppression

The well-established Load Theory of Attention and Cognitive Control (Load Theory) has sparked research over two decades. There are two integral components of Load Theory, i.e. ‘cognitive load’ and ‘perceptual load’ with the former concept receiving less attention in the literature. The core assumptions of Load Theory, with an emphasis on ‘cognitive load’,have been systematically investigated in this thesis using electroencephalography (EEG) and transcranial magnetic stimulation(TMS). The current research uncovered robust working memory (WM) effects in the healthy youngeradult populationwhich partially supported Load Theory. Experiment 1 revealed that the WM load effect on distractor processing increases when more items were held in WM but can plateau at a certain set-size(i.e.,3 items). In Experiment 2, the direction of distractor interference was inconsistent across the behavioural measures of reaction times and error rates, with the latter in support of Load Theory. In contrast, therewas strong electrophysiological evidence (i.e.,the N2pc and Pd components) for increased susceptibility to peripheral distractors under low WM load conditions (remembering one item). The behavioural effects of Experiments1and 2 which partially supported Load Theory, were not replicated with a TMS protocol (Experiment 3). There were significant effects, partially supporting Load Theory, when the spatial position of distractor and a subsequent target item was considered. Altogether, the findings have contributed to a clearer understanding of WM load effects, especially in terms of the attentional processes involved in distractor processing within a single-task setting. The results have provided recommendations of factors which were omitted in Load Theory such as the distinction of functions (updating and shifting) rather than positing a general executive load. This understanding can inform future research specifically targeting visual processing, WM and selective attention processes which can be extrapolated to everyday situations where attention to detail is crucial