Attention and novelty processing in stroke and Parkinson’s disease

The ventral fronto-parietal network has been considered to play a crucial role in reorienting attention towards significant environmental events, while the dorsal system is thought to be dominant in controlling goal-directed behaviour (Corbetta and Shulman 2002). I begin by reviewing literature which suggests this distinction may not be so clear cut and suggest my own scheme which takes into account this evidence (Singh-Curry and Husain 2009). Specifically, ventral areas, particularly the right inferior parietal lobe (IPL), appear to be activated by tasks involving sustained attention, responding to salient taskrelevant events, detecting novel stimuli and switching between tasks. Accordingly, I hypothesise that the right IPL may play a crucial role in reconfiguring behaviour between a task-engaged state and a more exploratory mode of functioning, which permits the identification of potentially important novel events. The first few chapters of my thesis aimed to test this hypothesis by examining attention deficits in stroke patients with hemispatial neglect, the syndrome which frequently occurs following damage to the right IPL. These patients were shown to have difficulty sustaining attention over time, even when no spatial shifts of attention were required. This deficit in sustained attention was particularly evident for stimuli of lower perceptual salience. More importantly, however, these deficits were found to interact with each other, as well as the direction of spatial attention, suggesting that these functions may be dependent on an interrelated brain network. Consistent with this notion, the results of lesion-symptom analysis indicated that the Right IPL and ventral attention network appears to be crucial in the mediation of all of these processes, including the processing of novel stimuli, supporting my hypothesis. The detection of novel events has also been found to activate the midbrain dopaminergic system (Bunzeck and Duzel 2006), while the principal pathological feature of Parkinson’s disease (PD) is degeneration of these neurons (Hornykiewicz 1998). Although PD is traditionally considered a disorder of movement, more recently it has been recognised that there may be associated cognitive deficits, including disorders of impulse control (Weintraub 2008). At present, however, the factors which predispose some individuals with PD to develop such problems are unclear. Accordingly, in the second part of my thesis, I examined novelty processing and risktaking behaviour in PD in order to identify subgroups which may be particularly vulnerable to developing impulse control problems. In addition to PD patients with impulse control disorders (ICD), those who were classified as akinetic-rigid, as opposed to tremor dominant – without ICD – were found to process novelty more quickly than nonnovel perceptually salient stimuli, unlike tremor dominant PD patients. Novelty seeking was found to be associated with relative preservation of the mesolimbic dopaminergic system in patients without ICD, while increased risk-taking was associated with preservation of the mesolimbic system in ICD patients. Mesolimbic sparing, in addition to the akinetic-rigid motor phenotype of PD may therefore increase susceptibility to impulse control problems in PD

Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease

BACKGROUND: In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population. METHODS: Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals. RESULTS: We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus. CONCLUSIONS: Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease

Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: A Real-world Case Series

Objective To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting. Methods This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined. Results The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6–85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression–free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure. Conclusions Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher. Classification of Evidence This study is rated Class IV because of the uncontrolled, open-label design