Brain

Neuroimaging genomic studies of autism spectrum disorder and schizophrenia have mainly adopted a ‘top-down’ approach, beginning with the behavioural diagnosis, and moving down to intermediate brain phenotypes and underlying genetic factors. Advances in imaging and genomics have been successfully applied to increasingly large case-control studies. As opposed to diagnostic-first approaches, the bottom-up strategy begins at the level of molecular factors enabling the study of mechanisms related to biological risk, irrespective of diagnoses or clinical manifestations. The latter strategy has emerged from questions raised by top-down studies: why are mutations and brain phenotypes over-represented in individuals with a psychiatric diagnosis? Are they related to core symptoms of the disease or to comorbidities? Why are mutations and brain phenotypes associated with several psychiatric diagnoses? Do they impact a single dimension contributing to all diagnoses? In this review, we aimed at summarizing imaging genomic findings in autism and schizophrenia as well as neuropsychiatric variants associated with these conditions. Top-down studies of autism and schizophrenia identified patterns of neuroimaging alterations with small effect-sizes and an extreme polygenic architecture. Genomic variants and neuroimaging patterns are shared across diagnostic categories suggesting pleiotropic mechanisms at the molecular and brain network levels. Although the field is gaining traction; characterizing increasingly reproducible results, it is unlikely that top-down approaches alone will be able to disentangle mechanisms involved in autism or schizophrenia. In stark contrast with top-down approaches, bottom-up studies showed that the effect-sizes of high-risk neuropsychiatric mutations are equally large for neuroimaging and behavioural traits. Low specificity has been perplexing with studies showing that broad classes of genomic variants affect a similar range of behavioural and cognitive dimensions, which may be consistent with the highly polygenic architecture of psychiatric conditions. The surprisingly discordant effect sizes observed between genetic and diagnostic first approaches underscore the necessity to decompose the heterogeneity hindering case-control studies in idiopathic conditions. We propose a systematic investigation across a broad spectrum of neuropsychiatric variants to identify putative latent dimensions underlying idiopathic conditions. Gene expression data on temporal, spatial and cell type organization in the brain have also considerable potential for parsing the mechanisms contributing to these dimensions’ phenotypes. While large neuroimaging genomic datasets are now available in unselected populations, there is an urgent need for data on individuals with a range of psychiatric symptoms and high-risk genomic variants. Such efforts together with more standardized methods will improve mechanistically informed predictive modelling for diagnosis and clinical outcomes.

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The extracellular matrix as modifier of neuroinflammation and remyelination in multiple sclerosis

Samira Ghorbani, V Wee Yong

doi : 10.1093/brain/awab059

Brain, Volume 144, Issue 7, July 2021, Pages 1958–1973

Remyelination failure contributes to axonal loss and progression of disability in multiple sclerosis. The failed repair process could be due to ongoing toxic neuroinflammation and to an inhibitory lesion microenvironment that prevents recruitment and/or differentiation of oligodendrocyte progenitor cells into myelin-forming oligodendrocytes. The extracellular matrix molecules deposited into lesions provide both an altered microenvironment that inhibits oligodendrocyte progenitor cells, and a fuel that exacerbates inflammatory responses within lesions. In this review, we discuss the extracellular matrix and where its molecules are normally distributed in an uninjured adult brain, specifically at the basement membranes of cerebral vessels, in perineuronal nets that surround the soma of certain populations of neurons, and in interstitial matrix between neural cells. We then highlight the deposition of different extracellular matrix members in multiple sclerosis lesions, including chondroitin sulphate proteoglycans, collagens, laminins, fibronectin, fibrinogen, thrombospondin and others. We consider reasons behind changes in extracellular matrix components in multiple sclerosis lesions, mainly due to deposition by cells such as reactive astrocytes and microglia/macrophages. We next discuss the consequences of an altered extracellular matrix in multiple sclerosis lesions. Besides impairing oligodendrocyte recruitment, many of the extracellular matrix components elevated in multiple sclerosis lesions are pro-inflammatory and they enhance inflammatory processes through several mechanisms. However, molecules such as thrombospondin-1 may counter inflammatory processes, and laminins appear to favour repair. Overall, we emphasize the crosstalk between the extracellular matrix, immune responses and remyelination in modulating lesions for recovery or worsening. Finally, we review potential therapeutic approaches to target extracellular matrix components to reduce detrimental neuroinflammation and to promote recruitment and maturation of oligodendrocyte lineage cells to enhance remyelination.

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Deep grey matter injury in multiple sclerosis: a NAIMS consensus statement

Daniel Ontaneda, Praneeta C Raza, Kedar R Mahajan, Douglas L Arnold, Michael G Dwyer, Susan A Gauthier, Douglas N Greve, Daniel M Harrison, Roland G Henry, David K B Li, Caterina Mainero, Wayne Moore, Sridar Narayanan, Jiwon Oh, Raihaan Patel, Daniel Pelletier, Alexander Rauscher, William D Rooney, Nancy L Sicotte, Roger Tam, Daniel S Reich, Christina J Azevedo, the North American Imaging in Multiple Sclerosis Cooperative (NAIMS)

doi : 10.1093/brain/awab132

Brain, Volume 144, Issue 7, July 2021, Pages 1974–1984

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.

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Aberrant cytoplasmic intron retention is a blueprint for RNA binding protein mislocalization in VCP-related amyotrophic lateral sclerosis

Giulia E Tyzack, Jacob Neeves, Hamish Crerar, Pierre Klein, Oliver Ziff, Doaa M Taha, Raphaëlle Luisier, Nicholas M Luscombe, Rickie Patani

doi : 10.1093/brain/awab078

Brain, Volume 144, Issue 7, July 2021, Pages 1985–1993

We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks of amyotrophic lateral sclerosis (ALS). However, the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep sequencing of nuclear and cytoplasmic fractions of human induced pluripotent stem cells undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins. Remarkably, TDP-43, SFPQ and FUS—RNA binding proteins known for nuclear-to-cytoplasmic mislocalization in ALS—abundantly and specifically bind to this aberrant cytoplasmic pool of IRTs. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets.

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A randomized clinical trial of plasticity-based cognitive training in mild traumatic brain injury

Henry W Mahncke, Joseph DeGutis, Harvey Levin, Mary R Newsome, Morris D Bell, Chad Grills, Louis M French, Katherine W Sullivan, Sarah-Jane Kim, Annika Rose, Catherine Stasio, Michael M Merzenich

doi : 10.1093/brain/awab202

Brain, Volume 144, Issue 7, July 2021, Pages 1994–2008

Clinical practice guidelines support cognitive rehabilitation for people with a history of mild traumatic brain injury (mTBI) and cognitive impairment, but no class I randomized clinical trials have evaluated the efficacy of self-administered computerized cognitive training. The goal of this study was to evaluate the efficacy of a self-administered computerized plasticity-based cognitive training programmes in primarily military/veteran participants with a history of mTBI and cognitive impairment. A multisite randomized double-blind clinical trial of a behavioural intervention with an active control was conducted from September 2013 to February 2017 including assessments at baseline, post-training, and after a 3-month follow-up period. Participants self-administered cognitive training (experimental and active control) programmes at home, remotely supervised by a healthcare coach, with an intended training schedule of 5?days per week, 1?h per day, for 13?weeks. Participants (149 contacted, 83 intent-to-treat) were confirmed to have a history of mTBI (mean of 7.2?years post-injury) through medical history/clinician interview and persistent cognitive impairment through neuropsychological testing and/or quantitative participant reported measure. The experimental intervention was a brain plasticity-based computerized cognitive training programme targeting speed/accuracy of information processing, and the active control was composed of computer games. The primary cognitive function measure was a composite of nine standardized neuropsychological assessments, and the primary directly observed functional measure a timed instrumental activities of daily living assessment. Secondary outcome measures included participant-reported assessments of cognitive and mental health. The treatment group showed an improvement in the composite cognitive measure significantly larger than that of the active control group at both the post-training [+6.9 points, confidence interval (CI) +1.0 to +12.7, P?=?0.025, d?=?0.555] and the follow-up visit (+7.4 points, CI +0.6 to +14.3, P?=?0.039, d?=?0.591). Both large and small cognitive function improvements were seen twice as frequently in the treatment group than in the active control group. No significant between-group effects were seen on other measures, including the directly-observed functional and symptom measures. Statistically equivalent improvements in both groups were seen in depressive and cognitive symptoms.

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Huntington’s disease-specific mis-splicing unveils key effector genes and altered splicing factors

Ainara Elorza, Yamile M?rquez, Jorge R Cabrera, José Luis S?nchez-Trincado, Mar?a Santos-Galindo, Iv? H Hern?ndez, Sara Pic?, Juan I D?az-Hern?ndez, Ram?n Garc?a-Escudero, Manuel Irimia, José J Lucas

doi : 10.1093/brain/awab087

Brain, Volume 144, Issue 7, July 2021, Pages 2009–2023

Correction of mis-splicing events is a growing therapeutic approach for neurological diseases such as spinal muscular atrophy or neuronal ceroid lipofuscinosis 7, which are caused by splicing-affecting mutations. Mis-spliced effector genes that do not harbour mutations are also good candidate therapeutic targets in diseases with more complex aetiologies such as cancer, autism, muscular dystrophies or neurodegenerative diseases. Next-generation RNA sequencing (RNA-seq) has boosted investigation of global mis-splicing in diseased tissue to identify such key pathogenic mis-spliced genes. Nevertheless, while analysis of tumour or dystrophic muscle biopsies can be informative on early stage pathogenic mis-splicing, for neurodegenerative diseases, these analyses are intrinsically hampered by neuronal loss and neuroinflammation in post-mortem brains. To infer splicing alterations relevant to Huntington’s disease pathogenesis, here we performed intersect-RNA-seq analyses of human post-mortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis are not yet present. Together with a human/mouse parallel motif scan analysis, this approach allowed us to identify the shared mis-splicing signature triggered by the Huntington’s disease-causing mutation in both species and to infer upstream deregulated splicing factors. Moreover, we identified a plethora of downstream neurodegeneration-linked mis-spliced effector genes that—together with the deregulated splicing factors—become new possible therapeutic targets. In summary, here we report pathogenic global mis-splicing in Huntington’s disease striatum captured by our new intersect-RNA-seq approach that can be readily applied to other neurodegenerative diseases for which bona fide animal models are available.

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Reactive microglia enhance the transmission of exosomal ?-synuclein via toll-like receptor 2

Yun Xia, Guoxin Zhang, Liang Kou, Sijia Yin, Chao Han, Junjie Hu, Fang Wan, Yadi Sun, Jiawei Wu, Yunna Li, Jinsha Huang, Nian Xiong, Zhentao Zhang, Tao Wang

doi : 10.1093/brain/awab122

Brain, Volume 144, Issue 7, July 2021, Pages 2024–2037

Increasing evidence suggests that microglial activation is strongly linked to the initiation and progression of Parkinson’s disease. Cell-to-cell propagation of ?-synuclein pathology is a highlighted feature of Parkinson’s disease, and the focus of such research has been primarily on neurons. However, recent studies as well as the data contained herein suggest that microglia, the primary phagocytes in the brain, play a direct role in the spread of ?-synuclein pathology. Recent data revealed that plasma exosomes derived from Parkinson’s disease patients (PD-EXO) carry pathological ?-synuclein and target microglia preferentially. Hence, PD-EXO are likely a key tool for investigating the role of microglia in ?-synuclein transmission. We showed that intrastriatal injection of PD-EXO resulted in the propagation of exosomal ?-synuclein from microglia to neurons following microglia activation. Toll-like receptor 2 (TLR2) in microglia was activated by exosomal ?-synuclein and acted as a crucial mediator of PD-EXO-induced microglial activation. Additionally, partial microglia depletion resulted in a significant decrease of exogenous ?-synuclein in the substantia nigra. Furthermore, exosomal ?-synuclein internalization was initiated by binding to TLR2 of microglia. Excessive ?-synuclein phagocytosis may induce the inflammatory responses of microglia and provide the seed for microglia-to-neuron transmission. Consistently, TLR2 silencing in microglia mitigated ?-synuclein pathology in vivo. Overall, the present data support the idea that the interaction of exosomal ?-synuclein and microglial TLR2 contribute to excessive ?-synuclein phagocytosis and microglial activation, which lead to the further propagation and spread of ?-synuclein pathology, thereby highlighting the pivotal roles of reactive microglia in ?-synuclein transmission.

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The latitude gradient for multiple sclerosis prevalence is established in the early life course

Clive E Sabel, John F Pearson, Deborah F Mason, Ernest Willoughby, David A Abernethy, Bruce V Taylor

doi : 10.1093/brain/awab104

Brain, Volume 144, Issue 7, July 2021, Pages 2038–2046

The strongest epidemiological clue that the environment at the population level has a significant impact on the risk of developing multiple sclerosis is the well established, and in many instances, increasing latitudinal gradient of prevalence, incidence and mortality globally, with prevalence increasing by up to 10-fold between the equator and 60° north and south. The drivers of this gradient are thought to be environmental with latitude seen as a proxy for ultraviolet radiation and thus vitamin D production; however, other factors may also play a role. Several important questions remain unanswered, particularly when in the life course is the gradient established, does lifetime migration mitigate or exacerbate previously reported latitude gradients at location of diagnosis, and do factors such as sex or multiple sclerosis disease phenotype influence the timing or significance of the gradient? Utilizing lifetime residence calendars collected as part of the New Zealand National Multiple Sclerosis Prevalence Study, we constructed lifetime latitudinal gradients for multiple sclerosis from birth to prevalence day in 2006 taking into account migration internally and externally and then analysed by sex and multiple sclerosis clinical course phenotype. Of 2917 individuals living in New Zealand on prevalence day, 7 March 2006, with multiple sclerosis, 2127 completed the life course questionnaire and of these, 1587 were born in New Zealand. All cohorts and sub-cohorts were representative of the overall multiple sclerosis population in New Zealand on prevalence day. We found that the prevalence gradient was present at birth and was, in fact, stronger than at census day, and the slope of the gradient persisted until the age of 12 before gradually declining. We found that internal and external migration into New Zealand had little, if any, effect on the gradient except to decrease the significance of the gradient somewhat. Finally, we found as we had reported previously, that the lifetime prevalence gradients were largely driven by females with relapse onset multiple sclerosis. These findings confirm for the first time the importance of early life environmental exposures in the risk of multiple sclerosis indicating strongly that exposures as early as in utero and at birth drive the latitudinal gradient. Consequently, prevention studies should be focused on high-risk individuals and populations from the earliest possible time points especially, when appropriate, on females.

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CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease

Gregory P Williams, Aubrey M Schonhoff, Asta Jurkuvenaite, Nicole J Gallups, David G Standaert, Ashley S Harms

doi : 10.1093/brain/awab103

Brain, Volume 144, Issue 7, July 2021, Pages 2047–2059

?-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation of the innate and adaptive immune system. This immune activation includes microgliosis, increased inflammatory cytokines, and the infiltration of T cells into the CNS. More recently, peripherally circulating CD4 and CD8 T cells derived from individuals with Parkinson’s disease have been shown to produce Th1/Th2 cytokines in response to ?-synuclein, suggesting there may be a chronic memory T cell response present in Parkinson’s disease. To understand the potential effects of these ?-syn associated T cell responses we used an ?-synuclein overexpression mouse model, T cell-deficient mice, and a combination of immunohistochemistry and flow cytometry. In this study, we found that ?-synuclein overexpression in the midbrain of mice leads to the upregulation of the major histocompatibility complex II (MHCII) protein on CNS myeloid cells as well as the infiltration of IFN? producing CD4 and CD8 T cells into the CNS. Interestingly, genetic deletion of TCR? or CD4, as well as the use of the immunosuppressive drug fingolimod, were able to reduce the CNS myeloid MHCII response to ?-synuclein. Furthermore, we observed that CD4-deficient mice were protected from the dopaminergic cell loss observed due to ?-syn overexpression. These results suggest that T cell responses associated with ?-synuclein pathology may be damaging to key areas of the CNS in Parkinson’s disease and that targeting these T cell responses could be an avenue for disease modifying treatments.

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Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy

Lauren E Bleakley, Chaseley E McKenzie, Ming S Soh, Ian C Forster, Paulo Pinares-Garcia, Alicia Sedo, Anirudh Kathirvel, Leonid Churilov, Nikola Jancovski, Snezana Maljevic, Samuel F Berkovic, Ingrid E Scheffer, Steven Petrou, Bina Santoro, Christopher A Reid

doi : 10.1093/brain/awab145

Brain, Volume 144, Issue 7, July 2021, Pages 2060–2073

Pathogenic variants in HCN1 are associated with developmental and epileptic encephalopathies. The recurrent de novo HCN1 M305L pathogenic variant is associated with severe developmental impairment and drug-resistant epilepsy. We engineered the homologue Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse to explore the disease mechanism underlying an HCN1 developmental and epileptic encephalopathy. The Hcn1M294L mouse recapitulated the phenotypic features of patients with the HCN1 M305L variant, including spontaneous seizures and a learning deficit. Active epileptiform spiking on the electrocorticogram and morphological markers typical of rodent seizure models were observed in the Hcn1M294L mouse. Lamotrigine exacerbated seizures and increased spiking, whereas sodium valproate reduced spiking, mirroring drug responses reported in a patient with this variant. Functional analysis in Xenopus laevis oocytes and layer V somatosensory cortical pyramidal neurons in ex vivo tissue revealed a loss of voltage dependence for the disease variant resulting in a constitutively open channel that allowed for cation ‘leak’ at depolarized membrane potentials. Consequently, Hcn1M294L layer V somatosensory cortical pyramidal neurons were significantly depolarized at rest. These neurons adapted through a depolarizing shift in action potential threshold. Despite this compensation, layer V somatosensory cortical pyramidal neurons fired action potentials more readily from rest. A similar depolarized resting potential and left-shift in rheobase was observed for CA1 hippocampal pyramidal neurons. The Hcn1M294L mouse provides insight into the pathological mechanisms underlying hyperexcitability in HCN1 developmental and epileptic encephalopathy, as well as being a preclinical model with strong construct and face validity, on which potential treatments can be tested.

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Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures

Anastasia Brodovskaya, Shinnosuke Shiono, Jaideep Kapur

doi : 10.1093/brain/awab119

Brain, Volume 144, Issue 7, July 2021, Pages 2074–2091

There are no detailed descriptions of neuronal circuit active during frontal lobe motor seizures. Using activity reporter mice, local field potential recordings, tissue clearing, viral tracing, and super-resolution microscopy, we found neuronal activation after focal motor to bilateral tonic-clonic seizures in the striatum, globus pallidus externus, subthalamic nucleus, substantia nigra pars reticulata and neurons of the indirect pathway. Seizures preferentially activated dopamine D2 receptor-expressing neurons over D1 in the striatum, which have different projections. Furthermore, the D2 receptor agonist infused into the striatum exerted an anticonvulsant effect. Seizures activate structures via short and long latency loops, and anatomical connections of the seizure focus determine the seizure circuit. These studies, for the first time, show activation of neurons in the striatum, globus pallidus, subthalamic nucleus, and substantia nigra during frontal lobe motor seizures on the cellular level, revealing a complex neuronal activation circuit subject to modulation by the basal ganglia.

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CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders

Yousra El Ghaleb, Pauline E Schneeberger, Monica L Fern?ndez-Quintero, Stefanie M Geisler, Simone Pelizzari, Abeltje M Polstra, Johanna M van Hagen, Jonas Denecke, Marta Campiglio, Klaus R Liedl, Cathy A Stevens, Richard E Person, Stefan Rentas, Eric D Marsh, Laura K Conlin, Petronel Tuluc, Kerstin Kutsche, Bernhard E Flucher

doi : 10.1093/brain/awab101

Brain, Volume 144, Issue 7, July 2021, Pages 2092–2106

T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Here, we examined four heterozygous missense variants in CACNA1I, encoding the Cav3.3 channel, in patients with variable neurodevelopmental phenotypes. The p.(Ile860Met) variant, affecting a residue in the putative channel gate at the cytoplasmic end of the IIS6 segment, was identified in three family members with variable cognitive impairment. The de novo p.(Ile860Asn) variant, changing the same amino acid residue, was detected in a patient with severe developmental delay and seizures. In two additional individuals with global developmental delay, hypotonia, and epilepsy, the variants p.(Ile1306Thr) and p.(Met1425Ile), substituting residues at the cytoplasmic ends of IIIS5 and IIIS6, respectively, were found. Because structure modelling indicated that the amino acid substitutions differentially affect the mobility of the channel gate, we analysed possible effects on Cav3.3 channel function using patch-clamp analysis in HEK293T cells. The mutations resulted in slowed kinetics of current activation, inactivation, and deactivation, and in hyperpolarizing shifts of the voltage-dependence of activation and inactivation, with Cav3.3-I860N showing the strongest and Cav3.3-I860M the weakest effect. Structure modelling suggests that by introducing stabilizing hydrogen bonds the mutations slow the kinetics of the channel gate and cause the gain-of-function effect in Cav3.3 channels. The gating defects left-shifted and increased the window currents, resulting in increased calcium influx during repetitive action potentials and even at resting membrane potentials. Thus, calcium toxicity in neurons expressing the Cav3.3 variants is one likely cause of the neurodevelopmental phenotype. Computer modelling of thalamic reticular nuclei neurons indicated that the altered gating properties of the Cav3.3 disease variants lower the threshold and increase the duration and frequency of action potential firing. Expressing the Cav3.3-I860N/M mutants in mouse chromaffin cells shifted the mode of firing from low-threshold spikes and rebound burst firing with wild-type Cav3.3 to slow oscillations with Cav3.3-I860N and an intermediate firing mode with Cav3.3-I860M, respectively. Such neuronal hyper-excitability could explain seizures in the patient with the p.(Ile860Asn) mutation. Thus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy.

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The structural connectome and motor recovery after stroke: predicting natural recovery

Philipp J Koch, Chang-Hyun Park, Gabriel Girard, Elena Beanato, Philip Egger, Giorgia Giulia Evangelista, Jungsoo Lee, Maximilian J Wessel, Takuya Morishita, Giacomo Koch, Jean-Philippe Thiran, Adrian G Guggisberg, Charlotte Rosso, Yun-Hee Kim, Friedhelm C Hummel

doi : 10.1093/brain/awab082

Brain, Volume 144, Issue 7, July 2021, Pages 2107–2119

Stroke patients vary considerably in terms of outcomes: some patients present ‘natural’ recovery proportional to their initial impairment (fitters), while others do not (non-fitters). Thus, a key challenge in stroke rehabilitation is to identify individual recovery potential to make personalized decisions for neuro-rehabilitation, obviating the ‘one-size-fits-all’ approach. This goal requires (i) the prediction of individual courses of recovery in the acute stage; and (ii) an understanding of underlying neuronal network mechanisms. ‘Natural’ recovery is especially variable in severely impaired patients, underscoring the special clinical importance of prediction for this subgroup. Fractional anisotropy connectomes based on individual tractography of 92 patients were analysed 2?weeks after stroke (TA) and their changes to 3?months after stroke (TC ? TA). Motor impairment was assessed using the Fugl-Meyer Upper Extremity (FMUE) scale. Support vector machine classifiers were trained to separate patients with natural recovery from patients without natural recovery based on their whole-brain structural connectomes and to define their respective underlying network patterns, focusing on severely impaired patients (FMUE?<?20). Prediction accuracies were cross-validated internally, in one independent dataset and generalized in two independent datasets. The initial connectome 2?weeks after stroke was capable of segregating fitters from non-fitters, most importantly among severely impaired patients (TA: accuracy?=?0.92, precision?=?0.93). Secondary analyses studying recovery-relevant network characteristics based on the selected features revealed (i) relevant differences between networks contributing to recovery at 2?weeks and network changes over time (TC ? TA); and (ii) network properties specific to severely impaired patients. Important features included the parietofrontal motor network including the intraparietal sulcus, premotor and primary motor cortices and beyond them also attentional, somatosensory or multimodal areas (e.g. the insula), strongly underscoring the importance of whole-brain connectome analyses for better predicting and understanding recovery from stroke. Computational approaches based on structural connectomes allowed the individual prediction of natural recovery 2 weeks after stroke onset, especially in the difficult to predict group of severely impaired patients, and identified the relevant underlying neuronal networks. This information will permit patients to be stratified into different recovery groups in clinical settings and will pave the way towards personalized precision neurorehabilitative treatment.

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A Bayesian optimization approach for rapidly mapping residual network function in stroke

Romy Lorenz, Michelle Johal, Frederic Dick, Adam Hampshire, Robert Leech, Fatemeh Geranmayeh

doi : 10.1093/brain/awab109

Brain, Volume 144, Issue 7, July 2021, Pages 2120–2134

Post-stroke cognitive and linguistic impairments are debilitating conditions, with limited therapeutic options. Domain-general brain networks play an important role in stroke recovery and characterizing their residual function with functional MRI has the potential to yield biomarkers capable of guiding patient-specific rehabilitation. However, this is challenging as such detailed characterization requires testing patients on multitudes of cognitive tasks in the scanner, rendering experimental sessions unfeasibly lengthy. Thus, the current status quo in clinical neuroimaging research involves testing patients on a very limited number of tasks, in the hope that it will reveal a useful neuroimaging biomarker for the whole cohort. Given the great heterogeneity among stroke patients and the volume of possible tasks this approach is unsustainable. Advancing task-based functional MRI biomarker discovery requires a paradigm shift in order to be able to swiftly characterize residual network activity in individual patients using a diverse range of cognitive tasks. Here, we overcome this problem by leveraging neuroadaptive Bayesian optimization, an approach combining real-time functional MRI with machine-learning, by intelligently searching across many tasks, this approach rapidly maps out patient-specific profiles of residual domain-general network function. We used this technique in a cross-sectional study with 11 left-hemispheric stroke patients with chronic aphasia (four female, age ± standard deviation: 59?±?10.9?years) and 14 healthy, age-matched control subjects (eight female, age ± standard deviation: 55.6?±?6.8?years). To assess intra-subject reliability of the functional profiles obtained, we conducted two independent runs per subject, for which the algorithm was entirely reinitialized. Our results demonstrate that this technique is both feasible and robust, yielding reliable patient-specific functional profiles. Moreover, we show that group-level results are not representative of patient-specific results. Whereas controls have highly similar profiles, patients show idiosyncratic profiles of network abnormalities that are associated with behavioural performance. In summary, our study highlights the importance of moving beyond traditional ‘one-size-fits-all’ approaches where patients are treated as one group and single tasks are used. Our approach can be extended to diverse brain networks and combined with brain stimulation or other therapeutics, thereby opening new avenues for precision medicine targeting a diverse range of neurological and psychiatric conditions.

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GABAergic cortical network physiology in frontotemporal lobar degeneration

Natalie E Adams, Laura E Hughes, Matthew A Rouse, Holly N Phillips, Alexander D Shaw, Alexander G Murley, Thomas E Cope, W Richard Bevan-Jones, Luca Passamonti, Duncan Street, Negin Holland, David Nesbitt, Karl Friston, James B Rowe

doi : 10.1093/brain/awab097

Brain, Volume 144, Issue 7, July 2021, Pages 2135–2145

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as ?-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10?mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

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Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer’s disease pathology in aged squirrel monkeys

Akash G Patel, Pramod N Nehete, Sara R Krivoshik, Xuewei Pei, Elizabeth L Cho, Bharti P Nehete, Margish D Ramani, Yongzhao Shao, Lawrence E Williams, Thomas Wisniewski, Henrieta Scholtzova

doi : 10.1093/brain/awab129

Brain, Volume 144, Issue 7, July 2021, Pages 2146–2165

Alzheimer’s disease is the most common cause of dementia and the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The failure rate of clinical trials is very high, in part due to the premature translation of successful results in transgenic mouse models to patients. Extensive evidence suggests that dysregulation of innate immunity and microglia/macrophages plays a key role in Alzheimer’s disease pathogenesis. Activated resident microglia and peripheral macrophages can display protective or detrimental phenotypes depending on the stimulus and environment. Toll-like receptors (TLRs) are a family of innate immune regulators known to play an important role in governing the phenotypic status of microglia. We have shown in multiple transgenic Alzheimer’s disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-?, tau pathology, and cerebral amyloid angiopathy (CAA) while promoting cognitive benefits. In the current study we have used a non-human primate model of sporadic Alzheimer’s disease pathology that develops extensive CAA—elderly squirrel monkeys. The major complications in current immunotherapeutic trials for Alzheimer’s disease are amyloid-related imaging abnormalities, which are linked to the presence and extent of CAA; hence, the prominence of CAA in elderly squirrel monkeys makes them a valuable model for studying the safety of the CpG ODN-based concept of immunomodulation. We demonstrate that long-term use of Class B CpG ODN 2006 induces a favourable degree of innate immunity stimulation without producing excessive or sustained inflammation, resulting in efficient amelioration of both CAA and tau Alzheimer’s disease-related pathologies in association with behavioural improvements and in the absence of microhaemorrhages in aged elderly squirrel monkeys. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. The present evidence together with our earlier, extensive preclinical research, validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach, increasing the likelihood of CpG ODN therapeutic efficacy in future clinical trials.

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To what degree is late life cognitive decline driven by age-related neuropathologies?

Patricia A Boyle, Tianhao Wang, Lei Yu, Robert S Wilson, Robert Dawe, Konstantinos Arfanakis, Julie A Schneider, David A Bennett

doi : 10.1093/brain/awab092

Brain, Volume 144, Issue 7, July 2021, Pages 2166–2175

The ageing brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer’s disease, infarcts, and Lewy bodies, account for ?40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline [e.g. limbic predominant age-related TDP-43 encephalopathy (LATE-NC), hippocampal sclerosis, other cerebrovascular conditions]. We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. Deceased participants (n?=?1164) from two longitudinal clinical-pathological studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathological examinations provided 11 pathological indices, including markers of Alzheimer’s disease, non- Alzheimer’s disease neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathological indices with global cognitive decline, and random change point models examined the relation of the pathological indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = ?0.101, SE = 0.003, P?<?0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, P?<?0.001). When considered separately, 10 of 11 pathological indices were associated with faster decline and accounted for between 2% and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathological indices together accounted for 43% of the variation in decline; Alzheimer’s disease-related indices accounted for 30–36% of the variation, non-Alzheimer’s disease neurodegenerative indices 4–10%, and cerebrovascular indices 3–8%. Finally, the 11 pathological indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive ageing and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.

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Segregation of functional networks is associated with cognitive resilience in Alzheimer’s disease

Michael Ewers, Ying Luan, Lukas Frontzkowski, Julia Neitzel, Anna Rubinski, Martin Dichgans, Jason Hassenstab, Brian A Gordon, Jasmeer P Chhatwal, Johannes Levin, Peter Schofield, Tammie L S Benzinger, John C Morris, Alison Goate, Celeste M Karch, Anne M Fagan, Eric McDade, Ricardo Allegri, Sarah Berman, Helena Chui, Carlos Cruchaga, Marty Farlow, Neill Graff-Radford, Mathias Jucker, Jae-Hong Lee, Ralph N Martins, Hiroshi Mori, Richard Perrin, Chengjie Xiong, Martin Rossor, Nick C Fox, Antoinette O’Connor, Stephen Salloway, Adrian Danek, Katharina Buerger, Randall J Bateman, Christian Habeck, Yaakov Stern, Nicolai Franzmeier, for the Alzheimer’s Disease Neuroimaging Initiative and the Dominantly Inherited Alzheimer Network

doi : 10.1093/brain/awab112

Brain, Volume 144, Issue 7, July 2021, Pages 2176–2185

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer’s disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain’s connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer’s disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer’s disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer’s disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer’s disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer’s sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer’s disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P?=?0.007). Similarly, for patients with sporadic Alzheimer’s disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P?=?0.001) and episodic memory (P?=?0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer’s disease.

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Comorbid neuropathological diagnoses in early versus late-onset Alzheimer’s disease

Salvatore Spina, Renaud La Joie, Cathrine Petersen, Amber L Nolan, Deion Cuevas, Celica Cosme, Mackenzie Hepker, Ji-Hye Hwang, Zachary A Miller, Eric J Huang, Anna M Karydas, Harli Grant, Adam L Boxer, Maria Luisa Gorno-Tempini, Howard J Rosen, Joel H Kramer, Bruce L Miller, William W Seeley, Gil D Rabinovici, Lea T Grinberg

doi : 10.1093/brain/awab099

Brain, Volume 144, Issue 7, July 2021, Pages 2186–2198

Co-pathologies play an important role in the expression of the Alzheimer’s disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer’s disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer’s disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer’s disease (median age of onset = 55?years, 44 females) and 48 with late-onset Alzheimer’s disease (median age of onset = 73?years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer’s disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer’s disease pathological diagnosis in 98% of patients with early-onset Alzheimer’s disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer’s disease (median?=?2 versus 3, Mann-Whitney Z?=?3.00, P?=?0.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer’s disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P?=?0.33; Lewy body disease: 49% versus 42%, P?=?0.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer’s disease (22% versus 6%, P?=?0.02). In contrast, LATE (35% versus 8%, P?<?0.001), hippocampal sclerosis (15% versus 3%, P?=?0.02), argyrophilic grain disease (58% versus 41%, P?=?0.052), and vascular brain injury (65% versus 39%, P?=?0.004) were more common in late than in early onset Alzheimer’s disease, respectively. The number of co-pathologies predicted worse cognitive performance at the time of death on Mini-Mental State Examination [1.4 points/pathology (95% confidence interval, CI ?2.5 to ?0.2) and Clinical Dementia Rating-Sum of Boxes (1.15 point/pathology, 95% CI 0.45 to 1.84)], across early and late onset cohorts. The effect of sex on the number of co-pathologies was not significant (P?=?0.17). Prevalence of at least one APOE ?4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of co-pathologies (+0.40, 95% CI 0.01 to 0.79, P?=?0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to males, controlling for age of onset, APOE ?4, and disease duration. Our findings suggest that non-Alzheimer’s disease pathological diagnoses play an important role in the clinical phenotype of early onset Alzheimer’s disease with potentially significant implications for clinical practice and clinical trials design.

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The Developing Human Connectome Project: typical and disrupted perinatal functional connectivity

Michael Eyre, Sean P Fitzgibbon, Judit Ciarrusta, Lucilio Cordero-Grande, Anthony N Price, Tanya Poppe, Andreas Schuh, Emer Hughes, Camilla O’Keeffe, Jakki Brandon, Daniel Cromb, Katy Vecchiato, Jesper Andersson, Eugene P Duff, Serena J Counsell, Stephen M Smith, Daniel Rueckert, Joseph V Hajnal, Tomoki Arichi, Jonathan O’Muircheartaigh, Dafnis Batalle, A David Edwards

doi : 10.1093/brain/awab118

Brain, Volume 144, Issue 7, July 2021, Pages 2199–2213

The Developing Human Connectome Project is an Open Science project that provides the first large sample of neonatal functional MRI data with high temporal and spatial resolution. These data enable mapping of intrinsic functional connectivity between spatially distributed brain regions under normal and adverse perinatal circumstances, offering a framework to study the ontogeny of large-scale brain organization in humans. Here, we characterize in unprecedented detail the maturation and integrity of resting state networks (RSNs) at term-equivalent age in 337 infants (including 65 born preterm). First, we applied group independent component analysis to define 11 RSNs in term-born infants scanned at 43.5–44.5?weeks postmenstrual age (PMA). Adult-like topography was observed in RSNs encompassing primary sensorimotor, visual and auditory cortices. Among six higher-order, association RSNs, analogues of the adult networks for language and ocular control were identified, but a complete default mode network precursor was not. Next, we regressed the subject-level datasets from an independent cohort of infants scanned at 37–43.5?weeks PMA against the group-level RSNs to test for the effects of age, sex and preterm birth. Brain mapping in term-born infants revealed areas of positive association with age across four of six association RSNs, indicating active maturation in functional connectivity from 37 to 43.5?weeks PMA. Female infants showed increased connectivity in inferotemporal regions of the visual association network. Preterm birth was associated with striking impairments of functional connectivity across all RSNs in a dose-dependent manner; conversely, connectivity of the superior parietal lobules within the lateral motor network was abnormally increased in preterm infants, suggesting a possible mechanism for specific difficulties such as developmental coordination disorder, which occur frequently in preterm children. Overall, we found a robust, modular, symmetrical functional brain organization at normal term age. A complete set of adult-equivalent primary RSNs is already instated, alongside emerging connectivity in immature association RSNs, consistent with a primary-to-higher order ontogenetic sequence of brain development. The early developmental disruption imposed by preterm birth is associated with extensive alterations in functional connectivity.

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Cardiovascular brain impulses in Alzheimer’s disease

Zal?n Rajna, Heli Mattila, Niko Huotari, Timo Tuovinen, Johanna Krüger, Sebastian C Holst, Vesa Korhonen, Anne M Remes, Tapio Sepp?nen, Jürgen Hennig, Maiken Nedergaard, Vesa Kiviniemi

doi : 10.1093/brain/awab144

Brain, Volume 144, Issue 7, July 2021, Pages 2214–2226

Accumulation of amyloid-? is a key neuropathological feature in brain of Alzheimer’s disease patients. Alterations in cerebral haemodynamics, such as arterial impulse propagation driving the (peri)vascular CSF flux, predict future Alzheimer’s disease progression. We now present a non-invasive method to quantify the three-dimensional propagation of cardiovascular impulses in human brain using ultrafast 10?Hz magnetic resonance encephalography. This technique revealed spatio-temporal abnormalities in impulse propagation in Alzheimer’s disease. The arrival latency and propagation speed both differed in patients with Alzheimer’s disease. Our mapping of arterial territories revealed Alzheimer’s disease-specific modifications, including reversed impulse propagation around the hippocampi and in parietal cortical areas. The findings imply that pervasive abnormality in (peri)vascular CSF impulse propagation compromises vascular impulse propagation and subsequently glymphatic brain clearance of amyloid-? in Alzheimer’s disease.

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Broca’s area: why was neurosurgery neglected for so long when seeking to re-establish the scientific truth?

Emmanuel Mandonnet, Hugues Duffau

doi : 10.1093/brain/awab195

Brain, Volume 144, Issue 7, July 2021, Page e60

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Where is the speech production area? Evidence from direct cortical electrical stimulation mapping

Zehao Zhao, Yan Liu, Jie Zhang, Junfeng Lu, Jinsong Wu

doi : 10.1093/brain/awab178

Brain, Volume 144, Issue 7, July 2021, Page e61

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Reply: Broca’s area: why was neurosurgery neglected for so long when seeking to re-establish the scientific truth? and Where is the speech production area? Evidence from direct cortical electrical stimulation mapping

Diego L Lorca-Puls, Andrea Gajardo-Vidal, David W Green, Cathy J Price

doi : 10.1093/brain/awab177

Brain, Volume 144, Issue 7, July 2021, Page e62

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Erratum to: The development and convergence of co-pathologies in Alzheimer’s disease

doi : 10.1093/brain/awab158

Brain, Volume 144, Issue 7, July 2021, Page e63

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Erratum to: A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement

Adriana P Rebelo, Andrea Cortese, Amit Abraham, Yael Eshed-Eisenbach, Gal Shner, Anna Vainshtein, Elena Buglo, Vladimir Camarena, Gabriel Gaidosh, Ramin Shiekhattar, Lisa Abreu, Steve Courel, Dennis K Burns, Yunhong Bai, Chelsea Bacon, Shawna M E Feely, Diana Castro, Elior Peles, Mary M Reilly, Michael E Shy, Stephan Zuchner

doi : 10.1093/brain/awab181

Brain, Volume 144, Issue 7, July 2021, Page e64

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