Iatrogenic Alzheimer's disease in recipients of cadaveric pituitary-derived growth hormone.

Alzheimer's disease (AD) is characterized pathologically by amyloid-beta (Aß) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aß as the root cause of AD. We previously reported human transmission of Aß pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt-Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aß seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aß can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aß assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.

When do bursts matter in the primary motor cortex? Investigating changes in the intermittencies of beta rhythms associated with movement states.

Brain activity exhibits significant temporal structure that is not well captured in the power spectrum. Recently, attention has shifted to characterising the properties of intermittencies in rhythmic neural activity (i.e. bursts), yet the mechanisms that regulate them are unknown. Here, we present evidence from electrocorticography recordings made over the motor cortex to show that the statistics of bursts, such as duration or amplitude, in the beta frequency (14-30 Hz) band, significantly aid the classification of motor states such as rest, movement preparation, execution, and imagery. These features reflect nonlinearities not detectable in the power spectrum, with states increasing in nonlinearity from movement execution to preparation to rest. Further, we show using a computational model of the cortical microcircuit, constrained to account for burst features, that modulations of laminar specific inhibitory interneurons are responsible for the temporal organisation of activity. Finally, we show that the temporal characteristics of spontaneous activity can be used to infer the balance of cortical integration between incoming sensory information and endogenous activity. Critically, we contribute to the understanding of how transient brain rhythms may underwrite cortical processing, which in turn, could inform novel approaches for brain state classification, and modulation with novel brain-computer interfaces.

A simple intervention for disorders of consciousness- is there a light at the end of the tunnel?

Sleep is a physiological state necessary for memory processing, learning and brain plasticity. Patients with disorders of consciousness (DOC) show none or minimal sign of awareness of themselves or their environment but appear to have sleep-wake cycles. The aim of our study was to assess baseline circadian rhythms and sleep in patients with DOC; to optimize circadian rhythm using an intervention combining blue light, melatonin and caffeine, and to identify the impact of this intervention on brain function using event related potentials. We evaluated baseline circadian rhythms and sleep in 17 patients with DOC with 24-h polysomnography (PSG) and 4-hourly saliva melatonin measurements for 48 h. Ten of the 17 patients (5 female, age 30-71) were then treated for 5 weeks with melatonin each night and blue light and caffeine treatment in the mornings. Behavioral assessment of arousal and awareness [Coma recovery scale-revised (CRS-R)], 24-h polysomnography and 4-hourly saliva melatonin measurements, oddball mismatch negativity (MMN) and subject's own name (SON) experiments were performed twice at baseline and following intervention. Baseline sleep was abnormal in all patients. Cosinor analysis of saliva melatonin results revealed that averaged baseline % rhythmicity was low (M: 31%, Range: 13-66.4%, SD: 18.4). However, increase in % Melatonin Rhythm following intervention was statistically significant (p = 0.012). 7 patients showed improvement of CRS-R scores with intervention and this was statistically significant (p = 0.034). All the patients who had improvement of clinical scores also had statistically significant improvement of neurophysiological responses on MMN and SON experiments at group level (p = 0.001). Our study shows that sleep and circadian rhythms are severely deranged in DOC but optimization is possible with melatonin, caffeine and blue light treatment. Clinical and physiological parameters improved with this simple and inexpensive intervention. Optimization of sleep and circadian rhythms should be integrated into rehabilitation programs for people with DOC.

Classical infratentorial superficial siderosis of the central nervous system: pathophysiology, clinical features and management.

The term superficial siderosis (SS) is derived from the Greek word 'sideros', meaning iron. It includes two subtypes, distinguished by their anatomical distribution, causes and clinical features: 'classical' infratentorial SS (iSS, which sometimes also affects supratentorial regions) and cortical SS (cSS, which affects only supratentorial regions). This paper considers iSS, a potentially disabling disorder usually associated with very slow persistent or intermittent subarachnoid bleeding from a dural defect, and characterised by progressive hearing and vestibular impairment, ataxia, myelopathy and cognitive dysfunction. The causal dural defect-most often spinal but sometimes in the posterior fossa-typically follows trauma or neurosurgery occurring decades before diagnosis. Increasing recognition of iSS with paramagnetic-sensitive MRI is leading to an unmet clinical need. Given the diagnostic challenges and complex neurological impairments in iSS, we have developed a multidisciplinary approach involving key teams. We discuss pathophysiology, diagnosis and management of iSS, including a proposed clinical care pathway.

Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon.

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aß) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)-attributed to the transmission of Aß seeds-have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.

Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit.

Synchronization of neural oscillations is thought to facilitate communication in the brain. Neurodegenerative pathologies such as Parkinson's disease (PD) can result in synaptic reorganization of the motor circuit, leading to altered neuronal dynamics and impaired neural communication. Treatments for PD aim to restore network function via pharmacological means such as dopamine replacement, or by suppressing pathological oscillations with deep brain stimulation. We tested the hypothesis that brain stimulation can operate beyond a simple "reversible lesion" effect to augment network communication. Specifically, we examined the modulation of beta band (14-30 Hz) activity, a known biomarker of motor deficits and potential control signal for stimulation in Parkinson's. To do this we setup a neural mass model of population activity within the cortico-basal ganglia-thalamic (CBGT) circuit with parameters that were constrained to yield spectral features comparable to those in experimental Parkinsonism. We modulated the connectivity of two major pathways known to be disrupted in PD and constructed statistical summaries of the spectra and functional connectivity of the resulting spontaneous activity. These were then used to assess the network-wide outcomes of closed-loop stimulation delivered to motor cortex and phase locked to subthalamic beta activity. Our results demonstrate that the spatial pattern of beta synchrony is dependent upon the strength of inputs to the STN. Precisely timed stimulation has the capacity to recover network states, with stimulation phase inducing activity with distinct spectral and spatial properties. These results provide a theoretical basis for the design of the next-generation brain stimulators that aim to restore neural communication in disease.

Dynamics of cortical and corticomuscular connectivity during planning and execution of visually guided steps in humans.

The cortical mechanisms underlying the act of taking a step-including planning, execution, and modification-are not well understood. We hypothesized that oscillatory communication in a parieto-frontal and corticomuscular network is involved in the neural control of visually guided steps. We addressed this hypothesis using source reconstruction and lagged coherence analysis of electroencephalographic and electromyographic recordings during visually guided stepping and 2 control tasks that aimed to investigate processes involved in (i) preparing and taking a step and (ii) adjusting a step based on visual information. Steps were divided into planning, initiation, and execution phases. Taking a step was characterized by an upregulation of beta/gamma coherence within the parieto-frontal network during planning followed by a downregulation of alpha and beta/gamma coherence during initiation and execution. Step modification was characterized by bidirectional modulations of alpha and beta/gamma coherence in the parieto-frontal network during the phases leading up to step execution. Corticomuscular coherence did not exhibit task-related effects. We suggest that these task-related modulations indicate that the brain makes use of communication through coherence in the context of large-scale, whole-body movements, reflecting a process of flexibly fine-tuning inter-regional communication to achieve precision control during human stepping.

Inference of brain networks with approximate Bayesian computation - assessing face validity with an example application in Parkinsonism.

This paper describes and validates a novel framework using the Approximate Bayesian Computation (ABC) algorithm for parameter estimation and model selection in models of mesoscale brain network activity. We provide a proof of principle, first pass validation of this framework using a set of neural mass models of the cortico-basal ganglia thalamic circuit inverted upon spectral features from experimental, in vivo recordings. This optimization scheme relaxes an assumption of fixed-form posteriors (i.e. the Laplace approximation) taken in previous approaches to inverse modelling of spectral features. This enables the exploration of model dynamics beyond that approximated from local linearity assumptions and so fit to explicit, numerical solutions of the underlying non-linear system of equations. In this first paper, we establish a face validation of the optimization procedures in terms of: (i) the ability to approximate posterior densities over parameters that are plausible given the known causes of the data; (ii) the ability of the model comparison procedures to yield posterior model probabilities that can identify the model structure known to generate the data; and (iii) the robustness of these procedures to local minima in the face of different starting conditions. Finally, as an illustrative application we show (iv) that model comparison can yield plausible conclusions given the known neurobiology of the cortico-basal ganglia-thalamic circuit in Parkinsonism. These results lay the groundwork for future studies utilizing highly nonlinear or brittle models that can explain time dependant dynamics, such as oscillatory bursts, in terms of the underlying neural circuits.

Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

Measuring directed functional connectivity using non-parametric directionality analysis: Validation and comparison with non-parametric Granger Causality.

BACKGROUND: 'Non-parametric directionality' (NPD) is a novel method for estimation of directed functional connectivity (dFC) in neural data. The method has previously been verified in its ability to recover causal interactions in simulated spiking networks in Halliday et al. (2015). METHODS: This work presents a validation of NPD in continuous neural recordings (e.g. local field potentials). Specifically, we use autoregressive models to simulate time delayed correlations between neural signals. We then test for the accurate recovery of networks in the face of several confounds typically encountered in empirical data. We examine the effects of NPD under varying: a) signal-to-noise ratios, b) asymmetries in signal strength, c) instantaneous mixing, d) common drive, e) data length, and f) parallel/convergent signal routing. We also apply NPD to data from a patient who underwent simultaneous magnetoencephalography and deep brain recording. RESULTS: We demonstrate that NPD can accurately recover directed functional connectivity from simulations with known patterns of connectivity. The performance of the NPD measure is compared with non-parametric estimators of Granger causality (NPG), a well-established methodology for model-free estimation of dFC. A series of simulations investigating synthetically imposed confounds demonstrate that NPD provides estimates of connectivity that are equivalent to NPG, albeit with an increased sensitivity to data length. However, we provide evidence that: i) NPD is less sensitive than NPG to degradation by noise; ii) NPD is more robust to the generation of false positive identification of connectivity resulting from SNR asymmetries; iii) NPD is more robust to corruption via moderate amounts of instantaneous signal mixing. CONCLUSIONS: The results in this paper highlight that to be practically applied to neural data, connectivity metrics should not only be accurate in their recovery of causal networks but also resistant to the confounding effects often encountered in experimental recordings of multimodal data. Taken together, these findings position NPD at the state-of-the-art with respect to the estimation of directed functional connectivity in neuroimaging.

Triple dissociation of attention and decision computations across prefrontal cortex.

Naturalistic decision-making typically involves sequential deployment of attention to choice alternatives to gather information before a decision is made. Attention filters how information enters decision circuits, thus implying that attentional control may shape how decision computations unfold. We recorded neuronal activity from three subregions of the prefrontal cortex (PFC) while monkeys performed an attention-guided decision-making task. From the first saccade to decision-relevant information, a triple dissociation of decision- and attention-related computations emerged in parallel across PFC subregions. During subsequent saccades, orbitofrontal cortex activity reflected the value comparison between currently and previously attended information. In contrast, the anterior cingulate cortex carried several signals reflecting belief updating in light of newly attended information, the integration of evidence to a decision bound and an emerging plan for what action to choose. Our findings show how anatomically dissociable PFC representations evolve during attention-guided information search, supporting computations critical for value-guided choice.

Patients with a severe prolonged Disorder of Consciousness can show classical EEG responses to their own name compared with others' names.

Patients in Vegetative State (VS), also known as Unresponsive Wakefulness State (UWS) are deemed to be unaware of themselves or their environment. This is different from patients diagnosed with Minimally Conscious state (MCS), who can have intermittent awareness. In both states, there is a severe impairment of consciousness; these disorders are referred to as disorders of consciousness (DOC) and if the state is prolonged, pDOC. There is growing evidence that some patients who are behaviourally in VS/UWS can show neural activation to environmental stimuli and that this response can be detected using functional brain imaging (fMRI/PET) and electroencephalography (EEG). Recently, it has also been suggested that a more reliable detection of brain responsiveness and hence a more reliable differentiation between VS/UWS and MCS requires person-centred and person-specific stimuli, such as the subject's own name stimulus. In this study we obtained event related potential data (ERP) from 12 healthy subjects and 16 patients in pDOC, five of whom were in the VS/UWS and 11 in the Minimally Conscious State (MCS). We used as the ERP stimuli the subjects' own name, others' names and reversed other names. We performed a sensor level analysis using Statistical Parametric Mapping (SPM) software. Using this paradigm in 4 DOC patients (3 in MCS, and 1 in VS/UWS) we detected a statistically significant difference in EEG response to their own name versus other peoples' names with ERP latencies (~300 ms and ~700 ms post stimuli). Some of these differences were similar to those found in a control group of healthy subjects. This study shows the feasibility of using self-relevant stimuli such as a subject's own name for assessment of brain function in pDOC patients. This neurophysiological test is suitable for bed-side/hospital based assessment of pDOC patients. As it does not require sophisticated scanning equipment it can feasibly be used within a hospital or care setting to help professionals tailor medical and psycho-social management for patients.

Sensitivity and Specificity of the ECAS in Parkinson's Disease and Progressive Supranuclear Palsy.

Disentangling Parkinson's disease (PD) and progressive supranuclear palsy (PSP) may be a diagnostic challenge. Cognitive signs may be useful, but existing screens are often insufficiently sensitive or unsuitable for assessing people with motor disorders. We investigated whether the newly developed ECAS, designed to be used with people with even severe motor disability, was sensitive to the cognitive impairment seen in PD and PSP and able to distinguish between these two disorders. Thirty patients with PD, 11 patients with PSP, and 40 healthy controls were assessed using the ECAS, as well as an extensive neuropsychological assessment. The ECAS detected cognitive impairment in 30% of the PD patients, all of whom fulfilled the diagnostic criteria for mild cognitive impairment. The ECAS was also able to detect cognitive impairment in PSP patients, with 81.8% of patients performing in the impaired range. The ECAS total score distinguished between the patients with PSP and healthy controls with high sensitivity (91.0) and specificity (86.8). Importantly, the ECAS was also able to distinguish between the two syndromes, with the measures of verbal fluency offering high sensitivity (82.0) and specificity (80.0). In sum, the ECAS is a quick, simple, and inexpensive test that can be used to support the differential diagnosis of PSP.

Propagation of beta/gamma rhythms in the cortico-basal ganglia circuits of the parkinsonian rat.

Much of the motor impairment associated with Parkinson's disease is thought to arise from pathological activity in the networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in parkinsonism, we investigated changes to the directed connectivity in BG networks following dopamine depletion. We recorded local field potentials (LFPs) in the cortex and basal ganglia of rats rendered parkinsonian by injection of 6-hydroxydopamine (6-OHDA) and in dopamine-intact controls. We performed systematic analyses of the networks using a novel tool for estimation of directed interactions (nonparametric directionality, NPD). We used a "conditioned" version of the NPD analysis that reveals the dependence of the correlation between two signals on a third reference signal. We find evidence of the dopamine dependency of both low-beta (14-20 Hz) and high-beta/low-gamma (20-40 Hz) directed network interactions. Notably, 6-OHDA lesions were associated with enhancement of the cortical "hyperdirect" connection to the subthalamic nucleus (STN) and its feedback to the cortex and striatum. We find that pathological beta synchronization resulting from 6-OHDA lesioning is widely distributed across the network and cannot be located to any individual structure. Furthermore, we provide evidence that high-beta/gamma oscillations propagate through the striatum in a pathway that is independent of STN. Rhythms at high beta/gamma show susceptibility to conditioning that indicates a hierarchical organization compared with those at low beta. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in parkinsonism. NEW & NOTEWORTHY We present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aim of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinson's disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a "short-circuiting" of the network that gives rise to the conditions from which pathological synchronization may arise.

Late recovery of awareness in prolonged disorders of consciousness -a cross-sectional cohort study.

PURPOSE: To detect any improvement of awareness in prolonged disorders of consciousness in the long term. METHODS: A total of 34 patients with prolonged disorders of consciousness (27 vegetative state and seven minimally conscious state; 16 males; aged 21-73) were included in the study. All patients were initially diagnosed with vegetative/minimally conscious state on admission to our specialist neurological rehabilitation unit. Re-assessment was performed 2-16 years later using Coma Recovery Scale-Revised. RESULTS: Although remaining severely disabled, 32% of the patients showed late improvement of awareness evidenced with development of non-reflexive responses such as reproducible command following and localization behaviors. Most of the late recoveries occurred in patients with subarachnoid hemorrhage (5/11, 45.5%). The ages of patients within the late recovery group (Mean = 45, SD = 11.4) and non-recovery group (Mean = 43, SD = 15.5) were not statistically different (p = 0.76). CONCLUSIONS: This study shows that late improvements in awareness are not exceptional in non-traumatic prolonged disorders of consciousness cases. It highlights the importance of long-term follow up of patients with prolonged disorders of consciousness, regardless of the etiology, age, and time passed since the brain injury. Long-term follow up will help clinicians to identify patients who may benefit from further assessment and rehabilitation. Although only one patient achieved recovery of function, recovery of awareness may have important ethical implications especially where withdrawal of artificial nutrition and hydration is considered. Implications for rehabilitation Long-term regular follow-up of people with prolonged disorders of consciousness is important. Albeit with poor functional outcomes late recovery of awareness is possible in both traumatic and non-traumatic prolonged disorders of consciousness cases. Recovery of awareness has significant clinical and ethical implications especially where withdrawal of artificial nutrition and hydration is considered.

The Crossed Flexor Plantar Response in Patients with Klippel-Feil Syndrome.

The plantar reflex is one of most important and widely tested components of the neurological examination. We describe 3 subjects with Klippel-Feil syndrome and mirror movements where unilateral cutaneous stimulation of the foot leads to flexor plantar responses in both feet. We discuss the evidence which suggests that this "crossed flexor" plantar response reveals a transcortical pathway for the flexor plantar response.