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\"In the 1860s and 1870s, leading neurologists used animal experimentation to establish that discrete sections of the brain regulate specific mental and physical functions. These discoveries had immediate medical benefits: David Ferrier's detailed cortical maps, for example, saved lives by helping surgeons locate brain tumors and haemorrhages without first opening up the skull. These experiments both incited controversy and stimulated creative thought, because they challenged the possibility of an extra-corporeal soul. This book examines the cultural impact of neurological experiments on late Victorian Gothic romances by Robert Louis Stevenson, Bram Stoker, H. G. Wells and others. Novels like Dracula and Jekyll and Hyde expressed the deep-seated fears and visionary possibilities suggested by cerebral localization research and offered a corrective to the linearity and objectivity of late Victorian neurology\"-- Provided by publisher.

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases 1 . Tau assemblies seem to spread through specific neural networks in each disease 2 , with short filaments having the greatest seeding activity 3 . The abundance of tau inclusions strongly correlates with disease symptoms 4 . Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau) 1 . In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions 5 , with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations 6 , 7 . Such conformers may give rise to different neuropathological phenotypes 8 , 9 , reminiscent of prion strains 10 . However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau 11 . Here we determine the structures of tau filaments from patients with Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer’s disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick’s disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer’s disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers. The structures of tau filaments from patients with the neurodegenerative disorder Pick’s disease show that the filament fold is different from that of the tau filaments found in Alzheimer’s disease.

Paroxysmal sympathetic hyperexcitation (PSH) refers to a clinical syndrome characterized by a sudden increase in sympathetic excitability caused by severe brain injury. This study aims to investigate the effectiveness and practicality of combining transcranial direct current stimulation (tDCS) with medication to treat PSH and employ non-linear electroencephalography (EEG) to assess changes in cortical activation post-intervention. 40 PSH patients were randomly assigned to receive either active tDCS or sham tDCS treatment over an 8-week period. The tDCS stimulation targeted the prefrontal area, left frontal-temporal-parietal cortex, right frontal-temporal-parietal cortex, and left dorsolateral prefrontal cortex. Both patient groups also underwent medication and other conventional therapies. The Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM), Coma Recovery Scale-Revised (CRS-R), medication dosage, and approximate entropy (ApEn) index were assessed before and after treatment. The active tDCS group exhibited more substantial improvements in changes of PSH-AM, changes of CRS-R, and medication reduction ratios compared to the sham tDCS group after the treatment. After treatment and during follow-up, a significantly greater number of patients in the active tDCS group demonstrated clinically important differences compared to the sham tDCS group. The active tDCS group showed significantly higher ApEn indices in the less affected frontal lobe compared to the control group. No significant differences in ApEn indices were noted in the sham tDCS group before and after treatment. Regression analysis revealed that the group (active tDCS/sham tDCS) was the primary factor associated with improving PSH-AM. Therefore, we believe that in patients with PSH, combining tDCS with medication therapy demonstrated superior clinical efficacy compared to medication therapy alone. Electrophysiological results also indicated enhanced cortical excitability. Therefore, this single-center pilot study suggests that multi-target, multi-session tDCS combined with medication may be an effective treatment protocol for PSH.

Transcranial direct current stimulation (tDCS) can improve cognitive function. However, it is not clear how high-definition tDCS (HD-tDCS) regulates the cognitive function and its neural mechanism, especially in individuals with mild cognitive impairment (MCI). This study aimed to examine whether HD-tDCS can modulate cognitive function in individuals with MCI and to determine whether the potential variety is related to spontaneous brain activity changes recorded by resting-state functional magnetic resonance imaging (rs-fMRI). Forty-three individuals with MCI were randomly assigned to receive either 10 HD-tDCS sessions or 10 sham sessions to the left dorsolateral prefrontal cortex (L-DLPFC). The fractional amplitude of low-frequency fluctuation (fALFF) and the regional homogeneity (ReHo) was computed using rs-fMRI data from all participants. The results showed that the fALFF and ReHo values changed in multiple areas following HD-tDCS. Brain regions with significant decreases in fALFF values include the Insula R, Precuneus R, Thalamus L, and Parietal Sup R, while the Temporal Inf R, Fusiform L, Occipital Sup L, Calcarine R, and Angular R showed significantly increased in their fALFF values. The brain regions with significant increases in ReHo values include the Temporal Inf R, Putamen L, Frontal Mid L, Precentral R, Frontal Sup Medial L, Frontal Sup R, and Precentral L. We found that HD-tDCS can alter the intensity and synchrony of brain activity, and our results indicate that fALFF and ReHo analysis are sensitive indicators for the detection of HD-tDCS during spontaneous brain activity. Interestingly, HD-tDCS increases the ReHo values of multiple brain regions, which may be related to the underlying mechanism of its clinical effects, these may also be related to a potential compensation mechanism involving the mobilization of more regions to complete a function following a functional decline.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Restoring motor function after stroke necessitates involvement of numerous cognitive systems. However, the impact of damage to motor and cognitive network organization on recovery is not well understood. To discover correlates of successful recovery, we explored imaging characteristics in chronic stroke subjects by combining noninvasive brain stimulation and fMRI. Twenty stroke survivors (6 months or more after stroke) were randomly assigned to a single session of transcranial direct current stimulation (tDCS) or sham during image acquisition. Twenty healthy subjects were included as controls. tDCS was limited to 10 min at 2 mA to serve as a mode of network modulation rather than therapeutic delivery. Fugl-Meyer Assessments (FMA) revealed significant motor improvement in the chronic stroke group receiving active stimulation (p = 0.0005). Motor changes in this group were correlated in a data-driven fashion with imaging features, including functional connectivity (FC), surface-based morphometry, electric field modeling and network topology, focusing on relevant regions of interest. We observed stimulation-related changes in FC in supplementary motor (p = 0.0029), inferior frontal gyrus (p = 0.0058), and temporo-occipital (p = 0.0095) areas, though these were not directly related to motor improvement. The feature most strongly associated with FMA improvement in the chronic stroke cohort was graph topology of the dorsal attention network (DAN), one of the regions surveyed and one with direct connections to each of the areas with FC changes. Chronic stroke subjects with a greater degree of motor improvement had lower signal transmission cost through the DAN (p = 0.029). While the study was limited by a small stroke cohort with moderate severity and variable lesion location, these results nevertheless suggest a top-down role for higher order areas such as attention in helping to orchestrate the stroke recovery process.

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy—a class of disorders in which the tau protein forms insoluble inclusions in the brain—that is characterized by motor and cognitive disturbances 1 – 3 . The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls 4 , 5 , and genome-wide association studies have identified additional risk factors 6 . By histology, astrocytic plaques are diagnostic of CBD 7 , 8 ; by SDS–PAGE, so too are detergent-insoluble, 37 kDa fragments of tau 9 . Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease 10 , CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats 11 – 15 . This distinguishes such ‘4R’ tauopathies from Pick’s disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments) 16 . Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer’s disease, Pick’s disease and CTE 17 – 19 . The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4. Cyro-electron microscopy of tau filaments from people with corticobasal degeneration reveals a previously unseen four-layered fold, distinct from the filament structures seen in Alzheimer’s disease, Pick’s disease and chronic traumatic encephalopathy.

The combination of repeated behavioral training with transcranial direct current stimulation (tDCS) holds promise to exert beneficial effects on brain function beyond the trained task. However, little is known about the underlying mechanisms. We performed a monocenter, single-blind randomized, placebo-controlled trial comparing cognitive training to concurrent anodal tDCS (target intervention) with cognitive training to concurrent sham tDCS (control intervention), registered at ClinicalTrial.gov (Identifier NCT03838211). The primary outcome (performance in trained task) and secondary behavioral outcomes (performance on transfer tasks) were reported elsewhere. Here, underlying mechanisms were addressed by pre-specified analyses of multimodal magnetic resonance imaging before and after a three-week executive function training with prefrontal anodal tDCS in 48 older adults. Results demonstrate that training combined with active tDCS modulated prefrontal white matter microstructure which predicted individual transfer task performance gain. Training-plus-tDCS also resulted in microstructural grey matter alterations at the stimulation site, and increased prefrontal functional connectivity. We provide insight into the mechanisms underlying neuromodulatory interventions, suggesting tDCS-induced changes in fiber organization and myelin formation, glia-related and synaptic processes in the target region, and synchronization within targeted functional networks. These findings advance the mechanistic understanding of neural tDCS effects, thereby contributing to more targeted neural network modulation in future experimental and translation tDCS applications. The neural mechanisms underlying the beneficial effects of behavioural training in combination with transcranial direct current stimulation (tDCS) are not well understood. Here, the authors combine cognitive training with tDCS, showing a modulation of prefrontal white and grey matter microstructure, and increased prefrontal functional connectivity.

Background Children and young people (CYP) with moderate/severe acquired brain injury (ABI) often have problems with chronic cognitive fatigue. Methylphenidate, a controlled drug, and cognitive behavioural therapy have been used to manage fatigue, but their effects are not fully established, and they are not widely available. Transcranial direct current stimulation (tDCS) is a non‐invasive brain stimulation technique that has shown promise for managing fatigue in adults with neurological conditions. However, no studies have used tDCS to manage fatigue in CYP with ABI nor have involved patients to co‐create the intervention or research protocol. Objective To co‐create a trial protocol for a study examining the feasibility of using tDCS as an intervention to manage fatigue in CYP with ABI and provide proof‐of‐concept for its efficacy through patient public involvement and engagement (PPIE). Design Our co‐creation approach encompassed three key stages: co‐define, co‐design, and co‐refine to actively bring stakeholders together. The co‐define phase consisted of discussing end‐users' experiences and needs related to fatigue. We then co‐designed an intervention protocol to address fatigue using tDCS. The final phase invited stakeholder feedback to co‐refine the tDCS intervention, ensuring it was acceptable and sustainable. Setting and Participants Stakeholders (n = 42) included CYP with ABI and their parents as well as members of an established young persons' advisory group. Stakeholders participated in in‐person, online and hybrid focus groups, 1:1 meetings, and surveys, over five stages. Results We followed the Medical Research Council guidelines for intervention development and used design thinking approaches to co‐create the tDCS intervention. This process led to the development of a study protocol where tDCS is delivered at home rather than in the hospital and to monitor sessions remotely via an online platform. The treatment duration was extended to 4 weeks to maximise the likelihood of detecting beneficial effects. Stakeholder contribution also led to the inclusion of children with neurodiversity and to making the research more accessible for everyone. Discussion and Conclusions PPIE members were involved in co‐defining the problem, co‐designing the intervention, determining treatment parameters, selecting efficacy outcome measures, identifying barriers to adherence, developing mitigating strategies, and co‐producing and reviewing the research study protocol. This ongoing stakeholder involvement shaped the co‐creation process, balancing idealistic approaches with feasible steps. Our protocol considered implementation barriers from the start and balanced scientific needs with patient and family priorities. The PPIE members will continue to be involved in conducting the study and designing qualitative work, reinforcing their ongoing engagement. Patient or Public Contribution To develop this study protocol, the PPIE members were actively involved in defining the problem, creating the intervention, determining treatment parameters, selecting the relevant outcome measures, identifying barriers to adherence, developing mitigating strategies, reviewing the research study protocol and writing the manuscript.

An increasing amount of recent research has focused on the multisensory and neural bases of the bodily self. This pre‐reflective form of self is considered as multifaceted, incorporating phenomenal components, such as self location, body ownership, first‐person perspective, agency, and the perceptual body image. Direct electrical brain stimulation (EBS) during presurgical evaluation of epilepsy and brain tumor resection is a unique method to causally relate specific brain areas to the various phenomenal components of the bodily self. We conducted a systematic review of the literature describing altered phenomenal experience of the bodily self evoked by EBS. We included 42 articles and analyzed self reports from 221 patients. Three‐dimensional density maps of EBS revealed that stimulation in the middle cingulum, inferior parietal lobule, supplementary motor area, posterior insula, hippocampal complex/amygdala, and precuneus most consistently altered one or several components of the bodily self. In addition, we found that only EBS in the parietal cortex induced disturbances of all five components of the bodily self considered in this review article. These findings inform current neuroscientific models of the bodily self. We searched for the brain areas causally underpinning the bodily self using electrical brain stimulation (EBS). EBS of six brain areas most consistently altered the bodily self across studies (middle cingulum, inferior parietal lobule, supplementary motor area, posterior insula, hippocampal complex/amygdala, and precuneus). Only EBS in the parietal cortex induced disturbances of all components of the bodily self (self location, body ownership, first‐person perspective, agency, and the perceptual body image).