Visual Working Memory in Health and Disease

The ability of the nervous system to retain, manipulate and use visual information which is no longer present in the external environment contributes to intelligent behaviour. A new approach to studying visual working memory has led to re-evaluation of the nature of its limitations in keeping with a finite memory resource which is flexibly distributed across space according to attentional priority. Using a novel behavioural paradigm to study visual working memory precision for sequentially presented items, I demonstrate how the resolution with which healthy subjects recall simple objects changes dynamically with each new item in the sequence. Stochastic modelling of the distribution of responses suggested that memory for earlier objects in the sequence was especially prone to failure in integration of visual features, such as orientation and colour, into complete objects. Next, I examined how memory precision was affected by attentional selection according to the relative behavioural relevance of objects in a sequence, and explored the limitations in this filtering process and their relationship with performance on standard measures of memory and intelligence. The role of updating of non-spatial visual working memory across time was then examined in patients with visual neglect following right hemisphere stroke, revealing a profound non-spatial impairment in WM and its voluntary attentional control in neglect, when compared to stroke patients without neglect and healthy control subjects. Lesion analysis identified separable neural correlates of these deficits. Dopaminergic activity in the prefrontal cortex and basal ganglia has a pivotal and complex role in mediating and controlling working memory and attentional processes. In a randomised, double-blind, placebo controlled study, employing a replicated ABA N-of-1 randomised design, I tested the hypothesis that the dopamine agonist rotigotine improves visual neglect following right-hemisphere stroke. Rotigotine was associated with significant improvement in visual search, an effect that appears to have been mediated by an enhancement of selective, goal-directed attention. The medial temporal lobe (MTL) has an established role in supporting long-term memory processes, but its involvement in working memory has been debated recently. I studied visual working memory for sequentially presentated objects in four patients with MTL lesions and found that short-term memory can be compromised in such individuals. Overall, this thesis explores how visual working memory is updated dynamically across time according to attentional priority in health, how these processes are affected in patients with visual neglect following right hemisphere stroke and in those with medial temporal lesions, and how a dopamine agonist might ameliorate visual neglect by modulating selective attention. The thesis concludes with a brief discussion suggesting further research directions

Dynamic Updating of Working Memory Resources for Visual Objects

Recent neurophysiological and imaging studies have investigated how neural representations underlying working memory (WM) are dynamically updated for objects presented sequentially. Although such studies implicate information encoded in oscillatory activity across distributed brain networks, interpretation of findings depends crucially on the underlying conceptual model of how memory resources are distributed.Here, we quantify the fidelity of human memory for sequences of colored stimuli of different orientation. The precision with which each orientation was recalled declined with increases in total memory load, but also depended on when in the sequence it appeared. When one item was prioritized, its recall was enhanced, but with corresponding decrements in precision for other objects. Comparison with the same number of items presented simultaneously revealed an additional performance cost for sequential display that could not be explained by temporal decay. Memory precision was lower for sequential compared with simultaneous presentation, even when each item in the sequence was presented at a different location.Importantly, stochastic modeling established this cost for sequential display was due to misbinding object features (color and orientation). These results support the view that WM resources can be dynamically and flexibly updated as new items have to be stored, but redistribution of resources with the addition of new items is associated with misbinding object features, providing important constraints and a framework for interpreting neural data

Pathological slow-wave activity and impaired working memory binding in post-traumatic amnesia

Associative binding is key to normal memory function and is transiently disrupted during periods of post-traumatic amnesia (PTA) following traumatic brain injury (TBI). Electrophysiological abnormalities including low-frequency activity are common following TBI. Here, we investigate associative memory binding during PTA and test the hypothesis that misbinding is caused by pathological slowing of brain activity disrupting cortical communication. Thirty acute moderate-severe TBI patients (25 males; 5 females) and 26 healthy controls (20 males; 6 females) were tested with a precision working memory paradigm requiring the association of object and location information. Electrophysiological effects of TBI were assessed using resting-state EEG in a subsample of 17 patients and 21 controls. PTA patients showed abnormalities in working memory function and made significantly more misbinding errors than patients who were not in PTA and controls. The distribution of localisation responses was abnormally biased by the locations of non-target items for patients in PTA suggesting a specific impairment of object and location binding. Slow wave activity was increased following TBI. Increases in the delta-alpha ratio indicative of an increase in low-frequency power specifically correlated with binding impairment in working memory. Connectivity changes in TBI did not correlate with binding impairment. Working memory and electrophysiological abnormalities normalised at six-month follow-up. These results show that patients in PTA show high rates of misbinding that are associated with a pathological shift towards lower frequency oscillations

Abnormal dorsal attention network activation in memory impairment after traumatic brain injury

Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injurypatients we examined whether: i) impairments in memory encoding are associated with abnormal brain activation in these networks; ii) whether changes in this brain activity predict subsequent memory retrieval; and iii) whether abnormal white matter integrity underpinningfunctional networks is associated with impaired subsequent memory. 35 patients with moderate-severetraumatic brain injury aged 23-65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy controls underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network.Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal change between patients with and without memory impairment, suggesting that memory encoding mechanisms could be fundamentally altered in this population. We demonstrate a clear relationship between functional networks activated during encoding and underlying abnormalities within the structural connectome in patients with memory impairment. We suggest that encoding failures in this group are likely due to failed control of goal-directed attentional resources

CD8+ encephalitis: a severe but treatable HIV-related acute encephalopathy

Rapidly progressive encephalopathy in an HIV-positive patient presents a major diagnostic and management challenge. CD8+ encephalitis is a severe but treatable form of HIV-related acute encephalopathy, characterised by diffuse perivascular and intraparenchymal CD8+ lymphocytic infiltration. It can occur in patients who are apparently stable on antiretroviral treatment and probably results from viral escape into the central nervous system. Treatment, including high-dose corticosteroids, can give an excellent neurological outcome, even in people with severe encephalopathy and a very poor initial neurological status. We report a woman with CD8+ encephalitis, with a normal CD4 count and undetectable serum viral load, who made a good recovery despite the severity of her presentation

In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1–42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI

A two-stage search of visual working memory:investigating speed in the change-detection paradigm

A popular procedure for investigating working memory processes has been the visual change-detection procedure. Models of performance in that procedure, however, tend to be based on performance accuracy and to treat working memory search as a one-step process, in which memory representations are compared to a test probe to determine if a match is present. To gain a clearer understanding of how search of these representations operate in the change-detection task, we examined reaction time in two experiments, with a single-item probe either located centrally or at the location of an array item. Contrary to current models of visual working memory capacity, our data point to a two-stage search process: a fast first step to check for the novelty of the probe and, in the absence of such novelty, a second, slower step to search exhaustively for a match between the test probe and a memory representation. In addition to these results, we found that participants tended not to use location information provided by the probe that theoretically could have abbreviated the search process. We suggest some basic revisions of current models of processing in this type of visual working memory task

Combining tractography and cortical measures to test system-specific hypotheses in multiple sclerosis

The objective was to test three motor system-specific hypotheses in multiple sclerosis patients: (i) corticospinal tract and primary motor cortex imaging measures differ between multiple sclerosis patients and controls; (ii) in patients, these measures correlate with disability; (iii) in patients, corticospinal tract measures correlate with measures of the ipsilateral primary motor cortex

From micro‐ to macro‐structures in multiple sclerosis: what is the added value of diffusion imaging

Diffusion imaging has been instrumental in understanding damage to the central nervous system as a result of its sensitivity to microstructural changes. Clinical applications of diffusion imaging have grown exponentially over the past couple of decades in many neurological and neurodegenerative diseases, such as multiple sclerosis (MS). For several reasons, MS has been extensively researched using advanced neuroimaging techniques, which makes it an ‘example disease’ to illustrate the potential of diffusion imaging for clinical applications. In addition, MS pathology is characterized by several key processes competing with each other, such as inflammation, demyelination, remyelination, gliosis and axonal loss, enabling the specificity of diffusion to be challenged. In this review, we describe how diffusion imaging can be exploited to investigate micro‐, meso‐ and macro‐scale properties of the brain structure and discuss how they are affected by different pathological substrates. Conclusions from the literature are that larger studies are needed to confirm the exciting results from initial investigations before current trends in diffusion imaging can be translated to the neurology clinic. Also, for a comprehensive understanding of pathological processes, it is essential to take a multiple‐level approach, in which information at the micro‐, meso‐ and macroscopic scales is fully integrated