Cognitive decline in thrombotic thrombocytopenic purpura survivors: The role of white matter health as assessed by MRI.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition caused by severe ADAMTS13 deficiency, leading to platelet aggregation and thrombosis. Despite treatment, patients are prone to cognitive impairment and depression. We investigated brain changes in iTTP patients during remission using advanced magnetic resonance imaging (MRI) techniques, correlating these changes with mood and neurocognitive tests. Twenty iTTP patients in remission (30 days post-haematological remission) were compared with six healthy controls. MRI scans, including standard and specialized sequences, were conducted to assess white matter health. Increased T1 relaxation times were found in the cingulate cortex (p < 0.05), and elevated T2 relaxation times were observed in the cingulate cortex, frontal, parietal and temporal lobes (p < 0.05). Pathological changes in these areas are correlated with impaired cognitive and depressive scores in concentration, short-term memory and verbal memory. This study highlights persistent white matter damage in iTTP patients, potentially contributing to depression and cognitive impairment. Key regions affected include the frontal lobe and cingulate cortex. These findings have significant implications for the acute and long-term management of iTTP, suggesting a need for re-evaluation of treatment approaches during both active phases and remission. Further research is warranted to enhance our understanding of these complexities.

EEG and behavioural correlates of mild sleep deprivation and vigilance.

OBJECTIVE: The current study investigated the behavioral, cognitive, and electrophysiological impact of mild (only a few hours) and acute (one night) sleep loss via simultaneously recorded behavioural and physiological measures of vigilance. METHODS: Participants (N = 23) came into the lab for two testing days where their brain activity and vigilance were recorded and assessed. The night before the testing session, participants either slept from 12am to 9am (Normally Rested), or from 1am to 6am (Sleep Restriction). RESULTS: Vigilance was reduced and sleepiness was increased in the Sleep Restricted vs. Normally Rested condition, and this was exacerbated over the course of performing the vigilance task. As well, sleep restriction resulted in more intense alpha bursts. Lastly, EEG spectral power differed in Sleep Restricted vs. Normally Rested conditions as sleep onset progressed, particularly for frequencies reflecting arousal (e.g., delta, alpha, beta). CONCLUSIONS: The findings of this study suggest that only one night of mild sleep loss significantly increases sleepiness and, importantly, reduces vigilance. In addition, this sleep loss has a clear impact on the physiology of the brain in ways that reflect reduced arousal. SIGNIFICANCE: Understanding the neural correlates and cognitive processes associated with loss of sleep may lead to important advancements in identifying and preventing deleterious or potentially dangerous, sleep-related lapses in vigilance.

Clinical and advanced neurophysiology in the prognostic and diagnostic evaluation of disorders of consciousness: review of an IFCN-endorsed expert group.

The analysis of spontaneous EEG activity and evoked potentialsis a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). Thepast few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury,opening up the prospect that new concepts and tools may be available at the bedside. This paper provides a comprehensive, critical overview of bothconsolidated and investigational electrophysiological techniquesfor the prognostic and diagnostic assessment of DoC.We describe conventional clinical EEG approaches, then focus on evoked and event-related potentials, and finally we analyze the potential of novel research findings. In doing so, we (i) draw a distinction between acute, prolonged and chronic phases of DoC, (ii) attempt to relate both clinical and research findings to the underlying neuronal processes and (iii) discuss technical and conceptual caveats.The primary aim of this narrative review is to bridge the gap between standard and emerging electrophysiological measures for the detection and prediction of recovery of consciousness. The ultimate scope is to provide a reference and common ground for academic researchers active in the field of neurophysiology and clinicians engaged in intensive care unit and rehabilitation.

Examining the relationship between measures of autistic traits and neural synchrony during movies in children with and without autism.

Children who have been diagnosed with autism spectrum disorder (ASD) often show a marked deficit in measures of social cognition. In autistic adults, measures of social cognition have been shown to relate to differences in brain synchronization (as measured by fMRI) when individuals are processing naturalistic stimuli, such as movies. However, whether children who differ in their degree of autistic traits, with or without a diagnosis of ASD, differ in their neural responses to movies has not yet been investigated. In the current study, neural synchrony, measured using fMRI, was examined in three groups of children aged 7 to 12, who differed with respect to scores on a measure of autistic traits associated with social impairment and whether or not they had been diagnosed with ASD. While watching the movie 'Despicable Me', those diagnosed with ASD had significantly less neural synchrony in areas that have been previously shown to be associated with social cognition (e.g. areas related to 'theory of mind'), and plot following (e.g. the lateral prefrontal cortex), than those who did not have an ASD diagnosis. In contrast, two groups who differed in their degree of autistic traits, but did not have a diagnosis of ASD, showed no significant differences in neural synchrony across the whole brain. These results shed some light on how autistic traits may contribute to an individual's conscious experience of the world, and how, for children with ASD, that experience may differ markedly from that of those without ASD.

Sleep preferentially enhances memory for a cognitive strategy but not the implicit motor skills used to acquire it.

Sleep is known to be beneficial to the strengthening of two distinct forms of procedural memory: memory for novel, cognitively simple series of motor movements, and memory for novel, cognitively complex strategies required to solve problems. However, these two types of memory are intertwined, since learning a new cognitive procedural strategy occurs through practice, and thereby also requires the execution of a series of simple motor movements. As a result, it is unclear whether the benefit of sleep results from the enhancement of the cognitive strategy, or the motor skills required to execute the solution. To disentangle the role of sleep in these aspects of procedural memory, we employed two tasks: (1) the Tower of Hanoi (ToH), and, (2) a modified version of the ToH, akin to an implicit Motor Sequence Learning (MSL) task. The MSL task involved the identical series of motor movements as the ToH, but without access to the information necessary to execute the task according to the underlying cognitive procedural strategy. Participants (n = 28) were trained on the 3-disk ToH, then retested on 5-disk versions of both ToH and MSL tasks. Half (n = 15) were trained and immediately tested at 8 PM and retested at 8 AM after a night of sleep. They were retested again at 8 PM after a day of wake (PM-AM-PM condition). The other half (n = 13) were trained and immediately tested at 8 AM, retested at 8 PM after a day of wake, and retested again at 8 AM after a night of sleep (AM-PM-AM condition). ToH performance only improved following a period of sleep. There was no benefit of sleep to implicit MSL. Our results show that sleep, but not wake, allowed individuals to extrapolate what was learned on a simpler 3-disk version of the task to the larger 5-disk problem, which included new elements to which they had not yet been exposed. Here, we isolate the specific role sleep plays for cognitive procedural memory: sleep benefits the cognitive strategy, rather than strengthening implicitly acquired motor sequences required to learn and execute the underlying strategy itself.

Human consciousness is supported by dynamic complex patterns of brain signal coordination.

Adopting the framework of brain dynamics as a cornerstone of human consciousness, we determined whether dynamic signal coordination provides specific and generalizable patterns pertaining to conscious and unconscious states after brain damage. A dynamic pattern of coordinated and anticoordinated functional magnetic resonance imaging signals characterized healthy individuals and minimally conscious patients. The brains of unresponsive patients showed primarily a pattern of low interareal phase coherence mainly mediated by structural connectivity, and had smaller chances to transition between patterns. The complex pattern was further corroborated in patients with covert cognition, who could perform neuroimaging mental imagery tasks, validating this pattern's implication in consciousness. Anesthesia increased the probability of the less complex pattern to equal levels, validating its implication in unconsciousness. Our results establish that consciousness rests on the brain's ability to sustain rich brain dynamics and pave the way for determining specific and generalizable fingerprints of conscious and unconscious states.

Correction to: Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States.

The original article [1] contains an error affecting the actigraphy time-stamps throughout the article, particularly in Table 1.

Brain-computer interfaces for patients with disorders of consciousness.

The disorders of consciousness refer to clinical conditions that follow a severe head injury. Patients diagnosed as in a vegetative state lack awareness, while patients diagnosed as in a minimally conscious state retain fluctuating awareness. However, it is a challenge to accurately diagnose these disorders with clinical assessments of behavior. To improve diagnostic accuracy, neuroimaging-based approaches have been developed to detect the presence or absence of awareness in patients who lack overt responsiveness. For the small subset of patients who retain awareness, brain-computer interfaces could serve as tools for communication and environmental control. Here we review the existing literature concerning the sensory and cognitive abilities of patients with disorders of consciousness with respect to existing brain-computer interface designs. We highlight the challenges of device development for this special population and address some of the most promising approaches for future investigations.

Highlighting the structure-function relationship of the brain with the Ising model and graph theory.

With the advent of neuroimaging techniques, it becomes feasible to explore the structure-function relationships in the brain. When the brain is not involved in any cognitive task or stimulated by any external output, it preserves important activities which follow well-defined spatial distribution patterns. Understanding the self-organization of the brain from its anatomical structure, it has been recently suggested to model the observed functional pattern from the structure of white matter fiber bundles. Different models which study synchronization (e.g., the Kuramoto model) or global dynamics (e.g., the Ising model) have shown success in capturing fundamental properties of the brain. In particular, these models can explain the competition between modularity and specialization and the need for integration in the brain. Graphing the functional and structural brain organization supports the model and can also highlight the strategy used to process and organize large amount of information traveling between the different modules. How the flow of information can be prevented or partially destroyed in pathological states, like in severe brain injured patients with disorders of consciousness or by pharmacological induction like in anaesthesia, will also help us to better understand how global or integrated behavior can emerge from local and modular interactions.

Putative cortical dopamine levels affect cortical recruitment during planning.

Planning, the decomposition of an ultimate goal into a number of sub-goals is critically dependent upon fronto-striatal dopamine (DA) levels. Here, we examined the extent to which the val158met polymorphism in the catechol O-methyltransferase (COMT) gene, which is thought to primarily alter cortical DA levels, affects performance and fronto-parietal activity during a planning task (Tower of London). COMT genotype was found to modulate activity in the left superior posterior parietal cortex (SPC) during planning, relative to subtracting, trials. Specifically, left SPC blood oxygenation level-dependent (BOLD) response was reduced in groups with putatively low or high cortical DA levels (COMT homozygotes) relative to those with intermediate cortical DA levels (COMT heterozygotes). These set of results are argued to occur either due to differences in neuronal processing in planning (and perhaps subtracting) caused by the COMT genotype and/or the cognitively heterogeneous nature of the TOL, which allows different cognitive strategies to be used whilst producing indistinguishable behavioural performance in healthy adults. The implications of this result for our understanding of COMT's effect on cognition in health and disease are discussed.

Prefrontal dopamine levels determine the balance between cognitive stability and flexibility.

A key mechanism by which the prefrontal cortex (PFC) supports goal-oriented behaviors is attentional set formation: the formation and maintenance of an attentional bias toward relevant features. It has previously been proposed that a common single nucleotide polymorphism (val158met) in the gene that codes for the catechol O-methyltransferase (COMT) enzyme may affect an individual's ability to form and maintain an attentional set by modulating PFC dopamine (DA) levels. Here, we present data from a functional magnetic resonance imaging study that investigated the effect of this polymorphism on the tendency for older adults to display set-like behavior, and we compare these results to preexisting data from Parkinson's Disease (PD) patients. Our results demonstrate that putatively different levels of PFC DA predict both attentional set formation and right dorsolateral PFC (DLPFC) activation. More specifically, while for PD patients, val homozygotes showed heightened DLPFC activation and increased set-like behavior, for healthy older adults, the opposite pattern of results was observed. This interaction between COMT genotype and PD accords well with previous studies that have shown an excess of DA in the PFC in early PD patients and, furthermore, supports the hypothesis that there is an inverted-U shaped functional relationship between PFC DA levels and attentional set formation.

Relationship between etiology and covert cognition in the minimally conscious state.

OBJECTIVES: Functional neuroimaging has shown that the absence of externally observable signs of consciousness and cognition in severely brain-injured patients does not necessarily indicate the true absence of such abilities. However, relative to traumatic brain injury, nontraumatic injury is known to be associated with a reduced likelihood of regaining overtly measurable levels of consciousness. We investigated the relationships between etiology and both overt and covert cognitive abilities in a group of patients in the minimally conscious state (MCS). METHODS: Twenty-three MCS patients (15 traumatic and 8 nontraumatic) completed a motor imagery EEG task in which they were required to imagine movements of their right-hand and toes to command. When successfully performed, these imagined movements appear as distinct sensorimotor modulations, which can be used to determine the presence of reliable command-following. The utility of this task has been demonstrated previously in a group of vegetative state patients. RESULTS: Consistent and robust responses to command were observed in the EEG of 22% of the MCS patients (5 of 23). Etiology had a significant impact on the ability to successfully complete this task, with 33% of traumatic patients (5 of 15) returning positive EEG outcomes compared with none of the nontraumatic patients (0 of 8). CONCLUSIONS: The overt behavioral signs of awareness (measured with the Coma Recovery Scale-Revised) exhibited by nontraumatic MCS patients appear to be an accurate reflection of their covert cognitive abilities. In contrast, one-third of a group of traumatically injured patients in the MCS possess a range of high-level cognitive faculties that are not evident from their overt behavior.

Dynamic causal modelling of effective connectivity from fMRI: are results reproducible and sensitive to Parkinson's disease and its treatment?

Dynamic causal modelling (DCM) of functional magnetic resonance imaging (fMRI) data offers new insights into the pathophysiology of neurological disease and mechanisms of effective therapies. Current applications can be used both to identify the most likely functional brain network underlying observed data and estimate the networks' connectivity parameters. We examined the reproducibility of DCM in healthy subjects (young 18-48 years, n=27; old 50-80 years, n=15) in the context of action selection. We then examined the effects of Parkinson's disease (50-78 years, Hoehn and Yahr stage 1-2.5, n=16) and dopaminergic therapy. Forty-eight models were compared, for each of 90 sessions from 58 subjects. Model-evidences clustered according to sets of structurally similar models, with high correlations over two sessions in healthy older subjects. The same model was identified as most likely in healthy controls on both sessions and in medicated patients. In this most likely network model, the selection of action was associated with enhanced coupling between prefrontal cortex and the pre-supplementary motor area. However, the parameters for intrinsic connectivity and contextual modulation in this model were poorly correlated across sessions. A different model was identified in patients with Parkinson's disease after medication withdrawal. In "off" patients, action selection was associated with enhanced connectivity from prefrontal to lateral premotor cortex. This accords with independent evidence of a dopamine-dependent functional disconnection of the SMA in Parkinson's disease. Together, these results suggest that DCM model selection is robust and sensitive enough to study clinical populations and their pharmacological treatment. For critical inferences, model selection may be sufficient. However, caution is required when comparing groups or drug effects in terms of the connectivity parameter estimates, if there are significant posterior covariances among parameters.

The val158met COMT polymorphism's effect on atrophy in healthy aging and Parkinson's disease.

We investigated whether the val(158)met functional polymorphism of catechol-o-methyltransferase influenced age-related changes in grey matter density and volume, both in healthy individuals (n=80, ages 18-79) and those with Parkinson's disease (n=50). Global grey matter volumes and voxelwise estimates of grey matter volume and density were determined from structural magnetic resonance images at 3T. Male and female ValVal homozygotes (low prefrontal cortical dopamine) had more grey matter in early adulthood, but this difference disappeared with increasing age. The insula and ventral prefrontal cortex had higher grey matter volume in younger, but not older, ValVal homozygotes. Conversely, the dominant premotor cortex revealed genotypic differences in grey matter density in later life. There were no global or local interactions between Parkinson's disease and COMT val(158)met genotype on morphometry. Since the val(158)met polymorphism is associated with differences in cortical dopamine metabolism, our data suggest a role for dopamine in cortical development followed by differential vulnerability to cortical atrophy across the adult life span.

A multimodal approach to the assessment of patients with disorders of consciousness.

Unlike other neurological conditions, the heterogeneous pathology linked to disorders of consciousness currently excludes a distinction between the vegetative and minimally conscious states based upon pathological presentation. The clinical assessment is therefore made on the basis of the patient's clinical history and exhibited behaviour. This creates a particular challenge for the clinician who has to decide whether a certain behaviour, which might be inconsistent or incomplete, reflects a conscious or an unconscious process. In an alarmingly high number of cases, identified during clinical audit, this decision process has been shown to be particularly fallible. The behavioural assessment is not only highly subjective, but also dependent upon the ability of the patient to move or speak; it is the only way someone can demonstrate they are aware. To address this problem we propose a multimodal approach, which integrates objective tools, such as electrophysiology and functional brain imaging, with traditional behavioural scales. Together this approach informs the clinical decision process and resolves many of the dilemmas faced by clinicians interpreting solely behavioural indices. This approach not only provides objective information regarding the integrity of residual cognitive function, but also removes the dependency on the patient to move or speak by using specially designed paradigms that do not require a motor output in order to reveal awareness of self or environment. To demonstrate this approach we describe the case of BW, who sustained a traumatic brain injury seven months prior to investigation. BW was admitted to a five-day assessment programme, which implemented our multimodal approach. On behavioural assessment BW demonstrated evidence of orientation and visual pursuit. However, he showed no response to written or verbal command, despite holding command cards and scanning text. Electrophysiology confirmed that he retained a preserved neural axis supporting vision and hearing, and suggested some evidence that he was able to create a basic memory trace. A hierarchical fMRI auditory paradigm suggested he was able to perceive sound and speech, but revealed no evidence of speech comprehension or ability to respond to command. This was corroborated in the visual modality using a hierarchical paradigm demonstrating that he was able to perceive motion, objects and faces, but retained no evidence of being able to respond to command. We briefly review work by other teams advocating the use of brain imaging and electrophysiology and discuss the steps that are now required in order to create an international standard for the assessment of persons with impaired consciousness after brain injury.

Towards the routine use of brain imaging to aid the clinical diagnosis of disorders of consciousness.

Clinical audits have highlighted the many challenges and dilemmas faced by clinicians assessing persons with disorders of consciousness (vegetative state and minimally conscious state). The diagnostic decision-making process is highly subjective, dependent upon the skills of the examiner and invariably dictated by the patients' ability to move or speak. Whilst a considerable amount has been learnt since Jennett and Plum coined the term 'vegetative state', the assessment process remains largely unchanged; conducted at the bedside, using behavioural assessment tools, which are susceptible to environmental and physiological factors. This has created a situation where the rate of misdiagnosis is unacceptably high (up to 43%). In order to address these problems, various functional brain imaging paradigms, which do not rely upon the patient's ability to move or speak, have been proposed as a source of additional information to inform the diagnostic decision making process. Although accumulated evidence from brain imaging, particularly functional magnetic resonance imaging (fMRI), has been encouraging, the empirical evidence is still based on relatively small numbers of patients. It remains unclear whether brain imaging is capable of informing the diagnosis beyond the behavioural assessment and whether brain imaging has any prognostic utility. In this study, we describe the functional brain imaging findings from a group of 41 patients with disorders of consciousness, who undertook a hierarchical speech processing task. We found, contrary to the clinical impression of a specialist team using behavioural assessment tools, that two patients referred to the study with a diagnosis of vegetative state did in fact demonstrate neural correlates of speech comprehension when assessed using functional brain imaging. These fMRI findings were found to have no association with the patient's behavioural presentation at the time of investigation and thus provided additional diagnostic information beyond the traditional clinical assessment. Notably, the utility of brain imaging was further underlined by the finding that the level of auditory processing revealed by functional brain imaging, correlated strongly (rs = 0.81, P < 0.001) with the patient's subsequent behavioural recovery, 6 months after the scan, suggesting that brain imaging may also provide valuable prognostic information. Although further evidence is required before consensus statements can be made regarding the use of brain imaging in clinical decision making for disorders of consciousness, the results from this study clearly highlight the potential of imaging to inform the diagnostic decision-making process for persons with disorders of consciousness.

The neural basis of effective memory therapy in a patient with limbic encephalitis.

BACKGROUND: An fMRI study is described in which a postencephalitic woman with amnesia used a wearable camera which takes photographs passively, without user intervention, to record and review recent autobiographical events. "SenseCam" generates hundreds of images which can subsequently be reviewed quickly or one by one. RESULTS: Memory for a significant event was improved substantially when tested after 4.5 weeks, if the patient viewed SenseCam images of the event every 2 days for 3 weeks. In contrast, after only 3.5 weeks, her memory was at chance levels for a similarly significant event which was reviewed equally often, but using a written diary. During the fMRI scan, the patient viewed images of these two events, plus images of an unrehearsed event and images from a novel "control" event that she had never experienced. There was no difference in behavioural responses or in activation when the unrehearsed and novel conditions were compared. Relative to the written-rehearsed condition, successful recognition of the images in the SenseCam-rehearsed condition was associated with activation of frontal and posterior cortical regions associated with normal episodic memory. CONCLUSION: SenseCam images may provide powerful cues that trigger the recall and consolidation of stored but inaccessible memories.

Parkinson's disease and dopaminergic therapy--differential effects on movement, reward and cognition.

Cognitive deficits are very common in Parkinson's disease particularly for 'executive functions' associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative 'on' and 'off' states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1-4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico-striato-thalamo-cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.

Rule-selection and action-selection have a shared neuroanatomical basis in the human prefrontal and parietal cortex.

The human capacity for voluntary action is one of the major contributors to our success as a species. In addition to choosing actions themselves, we can also voluntarily choose behavioral codes or sets of rules that can guide future responses to events. Such rules have been proposed to be superordinate to actions in a cognitive hierarchy and mediated by distinct brain regions. We used event-related functional magnetic resonance imaging to study novel tasks of rule-based and voluntary action. We show that the voluntary selection of rules to govern future responses to events is associated with activation of similar regions of prefrontal and parietal cortex as the voluntary selection of an action itself. The results are discussed in terms of hierarchical models and the adaptive coding potential of prefrontal neurons and their contribution to a global workspace for nonautomatic tasks. These tasks include the choices we make about our behavior.