GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

[Fatigue after acquired brain injury and its impact on socio-professional reintegration]. / La fatigue chez le patient cérébrolésé et son impact sur la réinsertion socioprofessionnelle.

Patients with acquired brain injury often suffer from pathological fatigue that differs from "normal" fatigue in that it appears more quickly and during non-demanding tasks, and recovery is not complete despite rest. It limits physical and cognitive activities, interferes with rehabilitation and return to work. The underlying mechanisms are poorly understood but appear to involve dysfunction of brain interactions. Current management combining physical reconditioning, cognitive compensatory strategies, and treatment of associated factors often leads to significant clinical improvement and promotes socio-professional reintegration. However, the effect remains insufficient in some patients, which underlines the importance of developing new therapeutic approaches based on a better understanding of the underlying neuronal deficits.

Les patients cérébrolésés présentent souvent une fatigue pathologique qui diffère de la fatigue « normale ¼, car elle apparaît plus rapidement, lors de tâches peu exigeantes, et ne disparaît pas complètement avec le repos. Elle limite les activités physiques et cognitives,et interfère avec la réadaptation et la reprise du travail. Les mécanismes sous-jacents, peu connus, semblent impliquer une altération des interactions cérébrales. La prise en charge actuelle combine reconditionnement physique, apprentissage de stratégies de compensation et traitement des facteurs associés ; cela favorise souvent l'amélioration clinique et la réinsertion socioprofessionnelle. L'effet reste cependant insuffisant chez certains patients, d'où l'importance de développer des thérapies se basant sur une meilleure compréhension des déficits neuronaux sous-jacents.

Neurosensory stimulation outdoors enhances cognition recovery in cognitive motor dissociation: A prospective crossover study.

BACKGROUND: Neurosensory stimulation is effective in enhancing the recovery process of severely brain-injured patients with disorders of consciousness. Multisensory environments are found in nature, recognized as beneficial to many medical conditions. Recent advances detected covert cognition in patients behaviorally categorized as un- or minimally responsive; a state described as cognitive motor dissociation (CMD). OBJECTIVE: To determine effectiveness of a neurosensory stimulation approach enhanced by outdoor therapy, in the early phases of recovery in patients presenting with CMD. METHODS: A prospective non-randomized crossover study was performed. A two-phase neurosensory procedure combined identical individually goal assessed indoor and outdoor protocols. All sessions were video-recorded and observations rated offline. The frequency of volitional behavior was measured using a behavioral grid. RESULTS: Fifteen patients participated in this study. The outdoor group patients had statistically significant higher number of intentional behaviors than the indoor group on seven features of the grid. Additionally, for all items assessed, total amount of behaviors in the outdoor condition where higher than those in the indoor condition. CONCLUSIONS: Although preliminary, this study provides robust evidence supporting the effectiveness and appropriateness of an outdoor neurosensory intervention in patients with covert cognition, to improve adaptive goal-oriented behavior. This may be a step towards helping to restore functional interactive communication.

Motor behavior unmasks residual cognition in disorders of consciousness.

Disorders of consciousness (DOC) are a common consequence of severe brain injuries, and clinical evaluation is critical to provide a correct diagnosis and prognosis. The revised Motor Behavior Tool (MBT-r) is a clinical complementary tool aiming to identify subtle motor behaviors that might reflect residual cognition in DOC. In this prospective study including 30 DOC patients in the early stage after brain injury, we show that the revised MBT-r has an excellent inter-rater agreement and has the ability to identify a subgroup of patients, underestimated by the Coma Recovery Scale-Revised, showing residual cognition and a subsequent recovery of consciousness. ANN NEUROL 2019;85:443-447.

Hemodynamic Changes May Indicate Vessel Wall Injury After Stent Retrieval Thrombectomy for Acute Stroke.

BACKGROUND AND PURPOSE: Stent retrievers have revolutionized endovascular treatment of acute ischemic stroke (AIS). Animal studies showed that mechanical thrombectomy (MT) may cause endothelial injury and intimal layer edema. Using transcranial color-coded duplex-sonography (TCCS) we observed postprocedural hemodynamic changes in the treated vessel. METHODS: We studied AIS patients with large intracranial artery occlusion in whom MT with stent retrievers was performed. Only those with complete recanalization (modified TICI-2b or 3) as assessed by postprocedural digital subtraction angiography (DSA) and in whom early control TCCS was performed were retained. Patients treated with intra-arterial thrombolysis or stenting were excluded. RESULTS: In 31 patients treated within a time period of 4 years (29 with middle cerebral artery [MCA] and 2 with basilar artery [BA] occlusion), postacute stroke brain-DSA confirmed complete recanalization without residual stenosis or vasospasm. However, in 27 (17 men, mean age 66.3 years) of them TCCS (mean 3.4 days after MT) showed very segmental acceleration of blood flow velocities in the affected arteries (MCA maximum peak systolic velocity [PSVmax] at least >35% as compared to the contralateral side at the same depth; BA PSVmax >40% as compared to velocities at different depths of the same vessel). None showed clinical deterioration. TCCS follow-up (mean 20 days) showed normalization in 14 of 16 cases. CONCLUSION: Our TCCS study provides preliminary evidence of focal acceleration of blood flow velocities after MT. Without residual stenosis or vasospasm, this may be a sign of endothelial layer disruption/intimal injury. Further studies are needed to confirm our results.

The role of parieto-temporal connectivity in pure neglect dyslexia.

The initial stages of reading are characterised by parallel and effortless access to letters constituting a word. Neglect dyslexia is an acquired reading disorder characterised by omission or substitution of the initial or the final letters of words. Rarely, the disorder appears in a'pure' form that is, without other signs of spatial neglect. Neglect dyslexia is linked to damage involving the inferior parietal lobe and regions of the temporal lobe, but the precise anatomical basis of the pure form of the disorder is unknown. Here, we show that pure neglect dyslexia is associated with decreased structural connectivity between the inferior parietal and lateral temporal lobe. We examined patient DM, who following bilateral occipito-parietal damage presented left neglect dyslexia together with right visual field loss, but no signs of spatial neglect. DM's reading errors were affected by word length and were much more frequent for pseudowords than for existing words. Most errors were omissions or substitutions of the first or second letter, and the spatial distribution of errors was similar for stimuli presented left or right of fixation. The brain lesions of DM comprised the inferior and superior parietal lobule as well as the cuneus and precuneus of the left hemisphere, and the angular gyrus and lateral occipital cortex of the right hemisphere. Diffusion tensor imaging revealed bilateral decrease of fibre tracts connecting the inferior parietal lobule with the superior and middle temporal cortex. These findings suggest that parieto-temporal connections play a significant role for the deployment of attention within words during reading.

Outcome Prediction of Consciousness Disorders in the Acute Stage Based on a Complementary Motor Behavioural Tool.

INTRODUCTION: Attaining an accurate diagnosis in the acute phase for severely brain-damaged patients presenting Disorders of Consciousness (DOC) is crucial for prognostic validity; such a diagnosis determines further medical management, in terms of therapeutic choices and end-of-life decisions. However, DOC evaluation based on validated scales, such as the Revised Coma Recovery Scale (CRS-R), can lead to an underestimation of consciousness and to frequent misdiagnoses particularly in cases of cognitive motor dissociation due to other aetiologies. The purpose of this study is to determine the clinical signs that lead to a more accurate consciousness assessment allowing more reliable outcome prediction. METHODS: From the Unit of Acute Neurorehabilitation (University Hospital, Lausanne, Switzerland) between 2011 and 2014, we enrolled 33 DOC patients with a DOC diagnosis according to the CRS-R that had been established within 28 days of brain damage. The first CRS-R assessment established the initial diagnosis of Unresponsive Wakefulness Syndrome (UWS) in 20 patients and a Minimally Consciousness State (MCS) in the remaining13 patients. We clinically evaluated the patients over time using the CRS-R scale and concurrently from the beginning with complementary clinical items of a new observational Motor Behaviour Tool (MBT). Primary endpoint was outcome at unit discharge distinguishing two main classes of patients (DOC patients having emerged from DOC and those remaining in DOC) and 6 subclasses detailing the outcome of UWS and MCS patients, respectively. Based on CRS-R and MBT scores assessed separately and jointly, statistical testing was performed in the acute phase using a non-parametric Mann-Whitney U test; longitudinal CRS-R data were modelled with a Generalized Linear Model. RESULTS: Fifty-five per cent of the UWS patients and 77% of the MCS patients had emerged from DOC. First, statistical prediction of the first CRS-R scores did not permit outcome differentiation between classes; longitudinal regression modelling of the CRS-R data identified distinct outcome evolution, but not earlier than 19 days. Second, the MBT yielded a significant outcome predictability in the acute phase (p<0.02, sensitivity>0.81). Third, a statistical comparison of the CRS-R subscales weighted by MBT became significantly predictive for DOC outcome (p<0.02). DISCUSSION: The association of MBT and CRS-R scoring improves significantly the evaluation of consciousness and the predictability of outcome in the acute phase. Subtle motor behaviour assessment provides accurate insight into the amount and the content of consciousness even in the case of cognitive motor dissociation.

From disorders of consciousness to early neurorehabilitation using assistive technologies in patients with severe brain damage.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on the latest challenges addressed by neurorehabilitation initiated very early after the brain damage, such as dealing with disorders of consciousness in terms of diagnosis, prognosis and rehabilitative treatment, or determining best timing for first rehabilitative intervention, best therapeutic approaches and best modalities. RECENT FINDINGS: Early management of patients with severe brain damage requires a multidisciplinary rehabilitative approach that encompasses clinical skills in various fields, standard therapies, and assistive technologies.Despite a high rate of misdiagnosis and poor outcome prediction in disorders of consciousness, the observation of subtle motor signs may be a promising way to reach accurate diagnosis and better outcome prediction. Neurosensory stimulation remains the current treatment to promote emergence from disorders of consciousness.Early timing of neurological rehabilitation is definitively efficient, but a safety period should be respected. Some standard therapies and assistive technologies have demonstrated explicit evidence in neurological recovery and high treatment dose is needed to emphasize the therapeutic effect, but several controversies persist in treatment evidence. SUMMARY: Current advancements have provided growing evidence for early neurorehabilitation, which should be definitively applied, but further studies are explicitly needed to diminish persistent controversies in the field.

Two intrinsic coupling types for resting-state integration in the human brain.

Recent findings indicate that synchronous neural activity at rest influences human performance in subsequent tasks. Synchronization can occur in form of phase coupling or amplitude correlation. It is unknown whether these coupling types have differing behavioral significance at rest. To address this, we performed resting-state electroencephalography (EEG) and source connectivity analysis in several populations of healthy subjects and patients with brain lesions. We systematically compared different types and frequencies of neural synchronization and investigated their association with behavioral performance in verbal and spatial attention tasks. Behavioral performance could be consistently predicted by two distinct resting-state coupling patterns: (1) amplitude envelope correlation of beta activity between homologous areas of both hemispheres, (2) lagged phase synchronization in EEG alpha activity between a brain area and the entire cortex. A disruption of these coupling patterns was also associated with neurological deficits in patients with stroke lesions. This suggests the existence of two distinct network systems responsible for resting-state integration. Lagged phase synchronization in the alpha band is associated with global interaction across networks while amplitude envelope correlation seems to be behaviorally relevant for interactions within networks and between hemispheres. These two coupling types may therefore provide complementary insights on brain physiology and pathology.

Neural Correlate of Anterograde Amnesia in Wernicke-Korsakoff Syndrome.

The neural correlate of anterograde amnesia in Wernicke-Korsakoff syndrome (WKS) is still debated. While the capacity to learn new information has been associated with integrity of the medial temporal lobe (MTL), previous studies indicated that the WKS is associated with diencephalic lesions, mainly in the mammillary bodies and anterior or dorsomedial thalamic nuclei. The present study tested the hypothesis that amnesia in WKS is associated with a disrupted neural circuit between diencephalic and hippocampal structures. High-density evoked potentials were recorded in four severely amnesic patients with chronic WKS, in five patients with chronic alcoholism without WKS, and in ten age matched controls. Participants performed a continuous recognition task of pictures previously shown to induce a left medial temporal lobe dependent positive potential between 250 and 350 ms. In addition, the integrity of the fornix was assessed using diffusion tensor imaging (DTI). WKS, but not alcoholic patients without WKS, showed absence of the early, left MTL dependent positive potential following immediate picture repetitions. DTI indicated disruption of the fornix, which connects diencephalic and hippocampal structures. The findings support an interpretation of anterograde amnesia in WKS as a consequence of a disconnection between diencephalic and MTL structures with deficient contribution of the MTL to rapid consolidation.

Isolated prospective confabulation in Wernicke-Korsakoff syndrome: a case for reality filtering.

A 57-year-old man suffered severe amnesia and disorientation, accompanied by content-specific confabulation, due to an alcoholic Wernicke-Korsakoff syndrome. For months, he was deeply concerned about a single obligation that he thought he had to respond to, but which he had already assumed 20 years previously. This monothematic, prospective confabulation was associated with failures of reality filtering as previously documented in behaviorally spontaneous confabulation and disorientation: the patient failed to suppress the interference of currently irrelevant memories and to abandon anticipations that were no longer valid (impaired extinction capacity). Magnetic resonance imaging showed damage to the mamillary bodies and the dorsomedial thalamic nucleus. Positron emission tomography (FDG-PET) showed extended orbitofrontal hypometabolism. We suggest that isolated prospective confabulation shares the core feature (acts and thoughts based on currently irrelevant memory), mechanism (failure of reality filtering), and anatomical basis (orbitofrontal dysfunction) with behaviorally spontaneous confabulations.

Modulation of environmental reduplicative paramnesia by perceptual experience.

Environmental reduplicative paramnesia (ERP) is characterized by the involuntary attribution of a false identity to a place. ERP has rarely been examined experimentally; its mechanisms therefore remain speculative. Here, we describe a patient with extended traumatic right fronto-temporal damage and severe persistent ERP, in whom we were able to modulate ERP by exposing him to various typical landmarks of the town where he was hospitalized. When landmarks were ambiguous as regards location (e.g., unknown buildings), the patient erroneously localized himself in his hometown, which was more than two thousand kilometers away. In contrast, when he visited distinct landmarks of the place where he actually resided, his ERP was immediately corrected, and spatial orientation was restored. These findings indicate that ERP may be temporarily modifiable through perception of unequivocal topographic information.

EEG alpha band synchrony predicts cognitive and motor performance in patients with ischemic stroke.

Functional brain networks are known to be affected by focal brain lesions. However, the clinical relevance of these changes remains unclear. This study assesses resting-state functional connectivity (FC) with electroencephalography (EEG) and relates observed topography of FC to cognitive and motor deficits in patients three months after ischemic stroke. Twenty patients (mean age 61.3 years, range 37-80, 9 females) and nineteen age-matched healthy participants (mean age 66.7 years, range 36-88, 13 females) underwent a ten-minute EEG-resting state examination. The neural oscillations at each grey matter voxel were reconstructed using an adaptive spatial filter and imaginary component of coherence (IC) was calculated as an index of FC. Maps representing mean connectivity value at each voxel were correlated with the clinical data. Compared to healthy controls, alpha band IC of stroke patients was locally reduced in brain regions critical to observed behavioral deficits. A voxel-wise Pearson correlation of clinical performances with FC yielded maps of the neural structures implicated in motor, language, and executive function. This correlation was again specific to alpha band coherence. Ischemic lesions decrease the synchrony of alpha band oscillations between affected brain regions and the rest of the brain. This decrease is linearly related to cognitive and motor deficits observed in the patients.

The impact of denoising on independent component analysis of functional magnetic resonance imaging data.

Independent component analysis (ICA) is a suitable method for decomposing functional magnetic resonance imaging (fMRI) activity into spatially independent patterns. Practice has revealed that low-pass filtering prior to ICA may improve ICA results by reducing noise and possibly by increasing source smoothness, which may enhance source independence; however, it eliminates useful information in high frequency features and it amplifies low signal fluctuations leading to independence loss. On the other hand, high-pass filtering may increase the independence by preserving spatial information, but its denoising properties are weak. Thus, such filtering strategies did not lead to simultaneous enhancements in independence and noise reduction; therefore, band-pass filtering or more sophisticated filtering methods are expected to be more appropriate. We used advanced wavelet filtering procedures, such as wavelet-based methods relying upon hard and soft coefficient thresholding and non-stationary Gaussian modelling based on geometrical prior information, to denoise artificial and real fMRI data. We compared the performance of these methods with the performance of traditional Gaussian smoothing techniques. First, we demonstrated both analytically and empirically the consistent performance increase of spatial filtering prior to ICA using spatial correlation and statistical sensitivity as quality measures. Second, all filtering methods were computationally efficient. Finally, denoising using low-pass filters was needed to improve ICA, suggesting that noise reduction may have a more significant effect on the component independence than the preservation of information contained within high frequencies.

The behavioral significance of coherent resting-state oscillations after stroke.

Stroke lesions induce not only loss of local neural function, but disruptions in spatially distributed areas. However, it is unknown whether they affect the synchrony of electrical oscillations in neural networks and if changes in network coherence are associated with neurological deficits. This study assessed these questions in a population of patients with subacute, unilateral, ischemic stroke. Spontaneous cortical oscillations were reconstructed from high-resolution electroencephalograms (EEG) with adaptive spatial filters. Maps of functional connectivity (FC) between brain areas were created and correlated with patient performance in motor and cognitive scores. In comparison to age matched healthy controls, stroke patients showed a selective disruption of FC in the alpha frequency range. The spatial distribution of alpha band FC reflected the pattern of motor and cognitive deficits of the individual patient: network nodes that participate normally in the affected functions showed local decreases in FC with the rest of the brain. Interregional FC in the alpha band, but not in delta, theta, or beta frequencies, was highly correlated with motor and cognitive performance. In contrast, FC between contralesional areas and the rest of the brain was negatively associated with patient performance. Alpha oscillation synchrony at rest is a unique and specific marker of network function and linearly associated with behavioral performance. Maps of alpha synchrony computed from a single resting-state EEG recording provide a robust and convenient window into the functionality and organization of cortical networks with numerous potential applications.