The flexibly ordered brain

I investigate the human brain systems involved in the cognitive control of behaviour. Using novel cognitive paradigms and brain imaging, I identify brain systems that support the flexible structuring of behaviour. I then observe how these systems are implicated in patients with depression as they respond to psilocybin therapy. In the first of three experiments, I observe the changes in healthy adult brain activation that are associated with task-switching. This demonstrated that remapping rules introduces a switching-cost to response speed and activates the multiple-demand (MD) network. Critically, switching-costs and MD activation were greater when the rules being remapped were of an abstract and higher-order nature. Going deeper, in the second experiment, I investigate how healthy adult brains mitigate switching-costs by structuring behaviour into efficient routines. I observe that learning to optimise and structure behaviour covaries with changes in MD and default mode network (DMN) activation alongside increases in between-network connectivity. These concurrent behavioural and neural adaptations imply that cognitive demand is minimised when behavioural routines are structured. Indeed, these mechanisms are known to have broad roles in flexibly adapting behaviour and, subsequently, they have been implicated in disorders such as depression. Using these insights, in the third experiment, I examine the neural basis of the treatment response to psilocybin in patients with depression. In two clinical trials, I find that treatment response covaried with global increases in between-network connectivity. Converging functional cartography measures indicated that this global shift in network organisation related to increased dynamic flexibility and integration of the MD and DMN. Together, the findings in this thesis indicate that a ‘flexibly ordered brain’, the adaptive sequencing of neurocognitive states, is a necessary feature of well-being and for successfully navigating the demands of daily life.Open Acces

Shift invariant preduals of ℓ₁(ℤ)

The Banach space ℓ<sub>1</sub>(ℤ) admits many non-isomorphic preduals, for example, C(K) for any compact countable space K, along with many more exotic Banach spaces. In this paper, we impose an extra condition: the predual must make the bilateral shift on ℓ<sub>1</sub>(ℤ) weak<sup>*</sup>-continuous. This is equivalent to making the natural convolution multiplication on ℓ<sub>1</sub>(ℤ) separately weak*-continuous and so turning ℓ<sub>1</sub>(ℤ) into a dual Banach algebra. We call such preduals <i>shift-invariant</i>. It is known that the only shift-invariant predual arising from the standard duality between C<sub>0</sub>(K) (for countable locally compact K) and ℓ<sub>1</sub>(ℤ) is c<sub>0</sub>(ℤ). We provide an explicit construction of an uncountable family of distinct preduals which do make the bilateral shift weak<sup>*</sup>-continuous. Using Szlenk index arguments, we show that merely as Banach spaces, these are all isomorphic to c<sub>0</sub>. We then build some theory to study such preduals, showing that they arise from certain semigroup compactifications of ℤ. This allows us to produce a large number of other examples, including non-isometric preduals, and preduals which are not Banach space isomorphic to c<sub>0</sub>

White matter tract integrity in treatment-resistant gambling disorder

Background Gambling disorder is a relatively common psychiatric disorder recently re-classified within the DSM-5 under the category of ‘substance-related and addictive disorders’. Aims To compare white matter integrity in patients with gambling disorder with healthy controls; to explore relationships between white matter integrity and disease severity in gambling disorder. Method In total, 16 participants with treatment-resistant gambling disorder and 15 healthy controls underwent magnetic resonance imaging (MRI). White matter integrity was analysed using tract-based spatial statistics. Results Gambling disorder was associated with reduced fractional anisotropy in the corpus callosum and superior longitudinal fasciculus. Fractional anisotropy in distributed white matter tracts elsewhere correlated positively with disease severity. Conclusions Reduced corpus callosum fractional anisotropy is suggestive of disorganised/damaged tracts in patients with gambling disorder, and this may represent a trait/vulnerability marker for the disorder. Future research should explore these measures in a larger sample, ideally incorporating a range of imaging markers (for example functional MRI) and enrolling unaffected first-degree relatives of patients.This research was supported by a grant from the National Center for Responsible Gaming to Dr. Grant, and by a grant from the Academy of Medical Sciences to Dr. Chamberlain (UK). Dr. Grant has received research grants from NIMH, National Center for Responsible Gaming, and Forest and Roche Pharmaceuticals Dr. Grant receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the Journal of Gambling Studies and has received royalties from Oxford University Press, American Psychiatric Publishing, Inc., Norton Press, and McGraw Hill. Dr. Chamberlain consults for Cambridge Cognition. Mr. Odlaug has received a research grant from the Trichotillomania Learning Center, consults for H. Lundbeck A/S, and has received royalties from Oxford University Press. Mr. Leppink and Ms. Derbyshire report no conflicts of interest.This is the author accepted manuscript. The final version is available from the Royal College of Psychiatrists via http://dx.doi.org/10.1192/bjp.bp.115.16550

White matter tract integrity in treatment-resistant gambling disorder.

BACKGROUND: Gambling disorder is a relatively common psychiatric disorder recently re-classified within the DSM-5 under the category of 'substance-related and addictive disorders'. AIMS: To compare white matter integrity in patients with gambling disorder with healthy controls; to explore relationships between white matter integrity and disease severity in gambling disorder. METHOD: In total, 16 participants with treatment-resistant gambling disorder and 15 healthy controls underwent magnetic resonance imaging (MRI). White matter integrity was analysed using tract-based spatial statistics. RESULTS: Gambling disorder was associated with reduced fractional anisotropy in the corpus callosum and superior longitudinal fasciculus. Fractional anisotropy in distributed white matter tracts elsewhere correlated positively with disease severity. CONCLUSIONS: Reduced corpus callosum fractional anisotropy is suggestive of disorganised/damaged tracts in patients with gambling disorder, and this may represent a trait/vulnerability marker for the disorder. Future research should explore these measures in a larger sample, ideally incorporating a range of imaging markers (for example functional MRI) and enrolling unaffected first-degree relatives of patients.This research was supported by a grant from the National Center for Responsible Gaming to Dr. Grant, and by a grant from the Academy of Medical Sciences to Dr. Chamberlain (UK). Dr. Grant has received research grants from NIMH, National Center for Responsible Gaming, and Forest and Roche Pharmaceuticals Dr. Grant receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the Journal of Gambling Studies and has received royalties from Oxford University Press, American Psychiatric Publishing, Inc., Norton Press, and McGraw Hill. Dr. Chamberlain consults for Cambridge Cognition. Mr. Odlaug has received a research grant from the Trichotillomania Learning Center, consults for H. Lundbeck A/S, and has received royalties from Oxford University Press. Mr. Leppink and Ms. Derbyshire report no conflicts of interest.This is the author accepted manuscript. The final version is available from the Royal College of Psychiatrists via http://dx.doi.org/10.1192/bjp.bp.115.16550

Predicting clinical diagnosis in Huntington's disease: An imaging polymarker.

OBJECTIVE: Huntington's disease (HD) gene carriers can be identified before clinical diagnosis; however, statistical models for predicting when overt motor symptoms will manifest are too imprecise to be useful at the level of the individual. Perfecting this prediction is integral to the search for disease modifying therapies. This study aimed to identify an imaging marker capable of reliably predicting real-life clinical diagnosis in HD. METHOD: A multivariate machine learning approach was applied to resting-state and structural magnetic resonance imaging scans from 19 premanifest HD gene carriers (preHD, 8 of whom developed clinical disease in the 5 years postscanning) and 21 healthy controls. A classification model was developed using cross-group comparisons between preHD and controls, and within the preHD group in relation to "estimated" and "actual" proximity to disease onset. Imaging measures were modeled individually, and combined, and permutation modeling robustly tested classification accuracy. RESULTS: Classification performance for preHDs versus controls was greatest when all measures were combined. The resulting polymarker predicted converters with high accuracy, including those who were not expected to manifest in that time scale based on the currently adopted statistical models. INTERPRETATION: We propose that a holistic multivariate machine learning treatment of brain abnormalities in the premanifest phase can be used to accurately identify those patients within 5 years of developing motor features of HD, with implications for prognostication and preclinical trials. Ann Neurol 2018;83:532-543.SLM is funded by a National Institute for Health Research (NIHR) Translational Research Collaboration for Rare Diseases fellowship. This research has been funded/supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. RAB is funded by the NIHR Cambridge Biomedical Research Centre and the Cambridge University NHS Foundation Trust. RED is employed on an EC Marie-Curie CIG, awarded to AH, SJT, EJ and RS receive funding from a Wellcome Collaborative Award (200181/Z/15/Z

Dissociable effects of age and Parkinson’s disease on instruction-based learning

The cognitive deficits associated with Parkinson’s disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson’s disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson’s disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson’s might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson’s Disease. Seventeen participants with Parkinson’s disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson’s group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson’s show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease.

BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. OBJECTIVES: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. METHODS: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. RESULTS: At baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. CONCLUSIONS: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression

Nutrient enrichment diminishes plant diversity and density, and alters long-term ecological trajectories, in a biodiverse forest restoration

Nutrient enrichment can negatively affect natural plant communities and result in the loss of species diversity and productivity. Despite this, fertiliser (especially phosphorus) is typically applied to restore highly biodiverse communities. Long-term effects of nutrient addition to restored plant communities, particularly those adapted to inherently low nutrient soils, have received little attention. We report results of a large-scale 20-year field experiment established in West Australian jarrah forest restored after bauxite mining Three P-application rates were applied (0, 80 and 120 kg ha−1) once at the beginning of the experiment, and plant communities monitored after 1, 6, 13 and 20 years. One year after the onset of restoration, native plant species richness and plant density was highest at 80 and 120 kg P ha−1. Subsequently, native species richness, plant density, and the richness and density of seeder and slow-growing resprouter species were highest without fertilisation, establishing the negative impact of P enrichment on plant community and ecosystem development in P impoverished soils. Total plant cover was similar for all P treatments across the chronosequence which, when combined with higher stem densities at zero P, suggests zero P favoured smaller, slower growing species. Applied-P initially favoured weeds and ephemerals and, while these species declined over time, other species were lost from these plots. The similarity of the restored communities to unmined reference jarrah forest increased over time and was consistently highest at in the absence of P fertiliser. Jarrah forest restoration is assumed to follow the initial floristic model of plant succession. However, we question this assumption and instead suggest that successional outcomes are contingent on P fertilisation rather than initial floristics per se. Applied P retarded recruitment of resprouter species that were present at zero P, debunking the assumption under IFM that these species do not disperse to restored areas. Consequently, based on the most comprehensive long-term study of P-fertilisation in the context of restoration of P-impoverished ecosystems yet reported, we propose that P limitation is important for the recreation of species diversity in inherently P impoverished forests. These results highlight the necessity of long-term experiments for understanding forest successional dynamics and implications for restoration practices

Predicting responses to psychedelics: a prospective study

Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points included N= 654, N= 535, N= 379, N= 315, and N= 212 respectively. Psychological well-being was increased two weeks after a psychedelic experience and remained at this level after four weeks. This increase was larger for individuals who scored higher for a ‘mystical-type experience’, and smaller for those who scored higher for ‘challenging experience’. Having ‘clear intentions’ for the experience was conducive to mystical-type experiences. Having a positive ‘set’, as well as having the experience with intentions related to ‘recreation’, were both found to decrease the likelihood of having a challenging experience. The trait ‘absorption’ and higher drug doses promoted both mystical-type and challenging experiences. When comparing different types of variables, traits variables seemed to explain most variance in the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding crucial clinical decisions about whether, when, where and how to dose with a psychedelic, thus helping to reduce risks while maximising potential benefits in an evidence-based manner

Phosphorus supply affects seedling growth of mycorrhizal but not cluster-root forming jarrah-forest species

Aims Fertiliser is often used to kick-start ecological restoration despite growing evidence of the potentially negative impacts on plant diversity. Jarrah (Eucalyptus marginata) forest species growing on nutrient (especially phosphorus) impoverished soils in southwestern Australia have a suite of adaptations for phosphorus (P) acquisition, including the formation of cluster roots, and associations with mycorrhizal fungi. Here we investigated how escalating P supply, along with a stoichiometric adjustment of nitrogen (N) supply, impacted the growth and nutrition of a wide range of jarrah forest seedlings. Methods In a pot experiment, we measured seedling biomass and nutritional responses of 12 jarrah forest species to a gradient of P supply in relation to N supply, and for the mycorrhizal species, inoculation with arbuscular mycorrhizal fungi. Results Three cluster-root forming species did not respond to increasing P, probably because they were reliant on seed P. Generally, mycorrhizal species showed a positive biomass response to increasing P when N was available. Mycorrhizas benefited seedling growth at low P (9 mg P added per kg of jarrah forest soil) when N was also available, and were parasitic to seedling growth at high P (243 mg P/ kg soil) without additional N. Conclusions These results highlight importance of P and N supply in determining the nature of the symbiosis between plants and mycorrhizal fungi. Since P supply has the potential to reduce plant growth, for a range of species, our results suggest careful consideration of fertiliser amounts for ecological restoration of ecosystems adapted to nutrient poor soils