Children with autism exhibit a host of motor disorders including poor coordination, poor tool use and delayed learning of complex motor skills like riding a tricycle. Theory suggests that one of the crucial steps in motor learning is the ability to form internal models: to predict the sensory consequences of motor commands and learn from errors to improve performance on the next attempt. The cerebellum appears to be an important site for acquisition of internal models, and indeed the development of the cerebellum is abnormal in autism. Here, we examined autistic children on a range of tasks that required a change in the motor output in response to a change in the environment. We first considered a prism adaptation task in which the visual map of the environment was shifted. The children were asked to throw balls to visual targets with and without the prism goggles. We next considered a reaching task that required moving the handle of a novel tool (a robotic arm). The tool either imposed forces on the hand or displaced the cursor associated with the handle position. In all tasks, the children with autism adapted their motor output by forming a predictive internal model, as exhibited through after-effects. Surprisingly, the rates of acquisition and washout were indistinguishable from normally developing children. Therefore, the mechanisms of acquisition and adaptation of internal models in self-generated movements appeared normal in autism. Sparing of adaptation suggests that alternative mechanisms contribute to impaired motor skill development in autism. Furthermore, the findings may have therapeutic implications, highlighting a reliable mechanism by which children with autism can most effectively alter their behaviour.
reach adaptation; prism adaptation; motor control; autism
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
comorbidity; depression; epilepsy; hippocampus; serotonin
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioral and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naïve animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioral equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
Comorbidity; depression; epilepsy; hippocampus; serotonin
Children with autism exhibit a host of motor disorders including poor coordination, poor tool use, and delayed learning of complex motor skills like riding a tricycle. Theory suggests that one of the crucial steps in motor learning is the ability to form internal models: to predict the sensory consequences of motor commands and learn from errors to improve performance on the next attempt. The cerebellum appears to be an important site for acquisition of internal models, and indeed the development of the cerebellum is abnormal in autism. Here, we examined autistic children on a range of tasks that required a change in the motor output in response to a change in the environment. We first considered a prism adaptation task in which the visual map of the environment was shifted. The children were asked to throw balls to visual targets with and without the prism goggles. We next considered a reaching task that required moving the handle of a novel tool (a robotic arm). The tool either imposed forces on the hand or displaced the cursor associated with the handle position. In all tasks, the children with autism adapted their motor output by forming a predictive internal model, as exhibited through after-effects. Surprisingly, the rates of acquisition and washout were indistinguishable from normally developing children. Therefore, the mechanisms of acquisition and adaptation of internal models in self-generated movements appeared normal in autism. Sparing of adaptation suggests that alternative mechanisms contribute to impaired motor skill development in autism. Furthermore, the findings may have therapeutic implications, highlighting a reliable mechanism by which children with autism can most effectively alter their behavior.
reach adaptation; prism adaptation; motor control; autism
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ∼40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis–frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis–frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6–7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7–2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ∼60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.
amyotrophic lateral sclerosis; familial ALS, C9ORF72 gene; phenotype–genotype correlation
In searching for persistent seizure-induced alterations in brain function that might be causally related to epilepsy, presynaptic transmitter release has relatively been neglected. To measure directly the long-term effects of pilocarpine-induced status epilepticus on vesicular release and recycling in hippocampal mossy fibre presynaptic boutons, we used (i) two-photon imaging of FM1-43 vesicular release in rat hippocampal slices; and (ii) transgenic mice expressing the genetically encoded pH-sensitive fluorescent reporter synaptopHluorin preferentially at glutamatergic synapses. In this study we found that, 1–2 months after pilocarpine-induced status epilepticus, there were significant increases in mossy fibre bouton size, faster rates of action potential-driven vesicular release and endocytosis. We also analysed the ultrastructure of rat mossy fibre boutons using transmission electron microscopy. Pilocarpine-induced status epilepticus led to a significant increase in the number of release sites, active zone length, postsynaptic density area and number of vesicles in the readily releasable and recycling pools, all correlated with increased release probability. Our data show that presynaptic release machinery is persistently altered in structure and function by status epilepticus, which could contribute to the development of the chronic epileptic state and may represent a potential new target for antiepileptic therapies.
epilepsy; neurotransmitter release; hippocampus; synaptic vesicle recycling; mossy fibre terminals
Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34–74 years) and disease duration (mean = 5.3, range = 1–16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia–amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with Mr 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.
frontotemporal dementia; frontotemporal lobar degeneration; amyotrophic lateral sclerosis; C9ORF72, TDP-43
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients’ clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients’ delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.
frontotemporal lobar degeneration; clinical characteristics; motor neuron disease; psychosis; neuropathology
Failure to develop normal language comprehension is an early warning sign of autism, but the neural mechanisms underlying this signature deficit are unknown. This is because of an almost complete absence of functional studies of the autistic brain during early development. Using functional magnetic resonance imaging, we previously observed a trend for abnormally lateralized temporal responses to language (i.e. greater activation on the right, rather than the expected left) in a small sample (n = 12) of sleeping 2–3 year olds with autism in contrast to typically developing children, a finding also reported in autistic adults and adolescents. It was unclear, however, if findings of atypical laterality would be observed in a larger sample, and at even earlier ages in autism, such as around the first birthday. Answers to these questions would provide the foundation for understanding how neurofunctional defects of autism unfold, and provide a foundation for studies using patterns of brain activation as a functional early biomarker of autism. To begin to examine these issues, a prospective, cross-sectional design was used in which brain activity was measured in a large sample of toddlers (n = 80) during the presentation of a bedtime story during natural sleep. Forty toddlers with autism spectrum disorder and 40 typically developing toddlers ranging in age between 12–48 months participated. Any toddler with autism who participated in the imaging experiment prior to final diagnosis was tracked and diagnoses confirmed at a later age. Results indicated that at-risk toddlers later diagnosed as autistic display deficient left hemisphere response to speech sounds and have abnormally right-lateralized temporal cortex response to language; this defect worsens with age, becoming most severe in autistic 3- and 4-year-olds. Typically developing children show opposite developmental trends with a tendency towards greater temporal cortex response with increasing age and maintenance of left-lateralized activation with age. We have now demonstrated lateralized abnormalities of temporal cortex processing of language in autism across two separate samples, including a large sample of young infants who later are diagnosed with autism, suggesting that this pattern may reflect a fundamental early neural developmental pathology in autism.
autism; language; functional magnetic resonance imaging; sleep; temporal cortex
Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.
amyotrophic lateral sclerosis; C9ORF72; dementia; neurodegeneration
The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.
Alzheimer's disease; tauopathy; acetylation; post-translational modification; tau
Distortions in time perception and timed performance are presented by a number of different neurological and psychiatric conditions (e.g. Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder and autism). As a consequence, the primary focus of this review is on factors that define or produce systematic changes in the attention, clock, memory and decision stages of temporal processing as originally defined by Scalar Expectancy Theory. These findings are used to evaluate the Striatal Beat Frequency Theory, which is a neurobiological model of interval timing based upon the coincidence detection of oscillatory processes in corticostriatal circuits that can be mapped onto the stages of information processing proposed by Scalar Timing Theory.
time perception; timing; striatum; frontal lobe; Parkinson's disease
The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P < 0.05, family-wise whole-brain corrected). Group × task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P < 0.05, family-wise small-volume correction). These data show a cortical–subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both conditions.
psychogenic movement disorder; fixed dystonia; DYT1 gene; functional imaging; motor; cerebellum; basal ganglia; dorsolateral prefrontal cortex; attention
Loss of the Merlin tumour suppressor causes abnormal de-differentiation and proliferation of Schwann cells and formation of schwannoma tumours in patients with neurofibromatosis type 2. Within the mature peripheral nerve the normal development, differentiation and maintenance of myelinating and non-myelinating Schwann cells is regulated by a network of transcription factors that include SOX10, OCT6 (now known as POU3F1), NFATC4 and KROX20 (also known as Egr2). We have examined for the first time how their regulation of Schwann cell development is disrupted in primary human schwannoma cells. We find that induction of both KROX20 and OCT6 is impaired, whereas enforced expression of KROX20 drives both myelin gene expression and cell cycle arrest in Merlin-null cells. Importantly, we show that human schwannoma cells have reduced expression of SOX10 protein and messenger RNA. Analysis of mouse SOX10-null Schwann cells shows they display many of the characteristics of human schwannoma cells, including increased expression of platelet derived growth factor receptor beta (PDGFRB) messenger RNA and protein, enhanced proliferation, increased focal adhesions and schwannoma-like morphology. Correspondingly, reintroduction of SOX10 into human Merlin-null cells restores the ability of these cells to induce KROX20 and myelin protein zero (MPZ), localizes NFATC4 to the nucleus, reduces cell proliferation and suppresses PDGFRB expression. Thus, we propose that loss of the SOX10 protein, which is vital for normal Schwann cell development, is also key to the pathology of Merlin-null schwannoma tumours.
Schwann; merlin; SOX10; KROX20; schwannoma
Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation.
congenital myasthenic syndrome; ALG2; ALG14; mutation; N-linked glycosylation
Movement disorders of basal ganglia origin may arise from abnormalities in synchronized oscillatory activity in a network that includes the basal ganglia, thalamus and motor cortices. In humans, much has been learned from the study of basal ganglia local field potentials recorded from temporarily externalized deep brain stimulator electrodes. These studies have led to the theory that Parkinson's disease has characteristic alterations in the beta frequency band (13–30 Hz) in the basal ganglia–thalamocortical network. However, different disorders have rarely been compared using recordings in the same structure under the same behavioural conditions, limiting straightforward assessment of current hypotheses. To address this, we utilized subdural electrocorticography to study cortical oscillations in the three most common movement disorders: Parkinson's disease, primary dystonia and essential tremor. We recorded local field potentials from the arm area of primary motor and sensory cortices in 31 subjects using strip electrodes placed temporarily during routine surgery for deep brain stimulator placement. We show that: (i) primary motor cortex broadband gamma power is increased in Parkinson's disease compared with the other conditions, both at rest and during a movement task; (ii) primary motor cortex high beta (20–30 Hz) power is increased in Parkinson's disease during the ‘stop’ phase of a movement task; (iii) the alpha–beta peaks in the motor and sensory cortical power spectra occur at higher frequencies in Parkinson's disease than in the other two disorders; and (iv) patients with dystonia have impaired movement-related beta band desynchronization in primary motor and sensory cortices. The findings support the emerging hypothesis that disease states reflect abnormalities in synchronized oscillatory activity. This is the first study of sensorimotor cortex local field potentials in the three most common movement disorders.
Parkinson's disease; dystonia; essential tremor; electrocorticography; primary motor cortex
Adult brain connectivity is shaped by the balance of sensory inputs in early life. In the case of pain pathways, it is less clear whether nociceptive inputs in infancy can have a lasting influence upon central pain processing and adult pain sensitivity. Here, we show that adult pain responses in the rat are ‘primed’ by tissue injury in the neonatal period. Rats that experience hind-paw incision injury at 3 days of age, display an increased magnitude and duration of hyperalgesia following incision in adulthood when compared with those with no early life pain experience. This priming of spinal reflex sensitivity was measured by both reductions in behavioural withdrawal thresholds and increased flexor muscle electromyographic responses to graded suprathreshold hind-paw stimuli in the 4 weeks following adult incision. Prior neonatal injury also ‘primed’ the spinal microglial response to adult injury, resulting in an increased intensity, spatial distribution and duration of ionized calcium-binding adaptor molecule-1-positive microglial reactivity in the dorsal horn. Intrathecal minocycline at the time of adult injury selectively prevented both the hyperalgesia and early microglial reactivity associated with prior neonatal injury. The enhanced neuroimmune response seen in neonatally primed animals could also be demonstrated in the absence of peripheral tissue injury by direct electrical stimulation of tibial nerve fibres, confirming that centrally mediated mechanisms contribute to these long-term effects. These data suggest that early life injury may predispose individuals to enhanced sensitivity to painful events.
pain; development; neuron–glia interaction; microglia; sensory processing
Chronic pain is a frequent component of many neurological disorders, affecting 20–40% of patients for many primary neurological diseases. These diseases result from a wide range of pathophysiologies including traumatic injury to the central nervous system, neurodegeneration and neuroinflammation, and exploring the aetiology of pain in these disorders is an opportunity to achieve new insight into pain processing. Whether pain originates in the central or peripheral nervous system, it frequently becomes centralized through maladaptive responses within the central nervous system that can profoundly alter brain systems and thereby behaviour (e.g. depression). Chronic pain should thus be considered a brain disease in which alterations in neural networks affect multiple aspects of brain function, structure and chemistry. The study and treatment of this disease is greatly complicated by the lack of objective measures for either the symptoms or the underlying mechanisms of chronic pain. In pain associated with neurological disease, it is sometimes difficult to obtain even a subjective evaluation of pain, as is the case for patients in a vegetative state or end-stage Alzheimer's disease. It is critical that neurologists become more involved in chronic pain treatment and research (already significant in the fields of migraine and peripheral neuropathies). To achieve this goal, greater efforts are needed to enhance training for neurologists in pain treatment and promote greater interest in the field. This review describes examples of pain in different neurological diseases including primary neurological pain conditions, discusses the therapeutic potential of brain-targeted therapies and highlights the need for objective measures of pain.
brain imaging; Parkinson's disease; complex regional pain syndrome; migraine; brain trauma
Post-mortem ganglion cell dropout has been observed in multiple sclerosis; however, longitudinal in vivo assessment of retinal neuronal layers following acute optic neuritis remains largely unexplored. Peripapillary retinal nerve fibre layer thickness, measured by optical coherence tomography, has been proposed as an outcome measure in studies of neuroprotective agents in multiple sclerosis, yet potential swelling during the acute stages of optic neuritis may confound baseline measurements. The objective of this study was to ascertain whether patients with multiple sclerosis or neuromyelitis optica develop retinal neuronal layer pathology following acute optic neuritis, and to systematically characterize such changes in vivo over time. Spectral domain optical coherence tomography imaging, including automated retinal layer segmentation, was performed serially in 20 participants during the acute phase of optic neuritis, and again 3 and 6 months later. Imaging was performed cross-sectionally in 98 multiple sclerosis participants, 22 neuromyelitis optica participants and 72 healthy controls. Neuronal thinning was observed in the ganglion cell layer of eyes affected by acute optic neuritis 3 and 6 months after onset (P < 0.001). Baseline ganglion cell layer thicknesses did not demonstrate swelling when compared with contralateral unaffected eyes, whereas peripapillary retinal nerve fibre layer oedema was observed in affected eyes (P = 0.008) and subsequently thinned over the course of this study. Ganglion cell layer thickness was lower in both participants with multiple sclerosis and participants with neuromyelitis optica, with and without a history of optic neuritis, when compared with healthy controls (P < 0.001) and correlated with visual function. Of all patient groups investigated, those with neuromyelitis optica and a history of optic neuritis exhibited the greatest reduction in ganglion cell layer thickness. Results from our in vivo longitudinal study demonstrate retinal neuronal layer thinning following acute optic neuritis, corroborating the hypothesis that axonal injury may cause neuronal pathology in multiple sclerosis. Further, these data provide evidence of subclinical disease activity, in both participants with multiple sclerosis and with neuromyelitis optica without a history of optic neuritis, a disease in which subclinical disease activity has not been widely appreciated. No pathology was seen in the inner or outer nuclear layers of eyes with optic neuritis, suggesting that retrograde degeneration after optic neuritis may not extend into the deeper retinal layers. The subsequent thinning of the ganglion cell layer following acute optic neuritis, in the absence of evidence of baseline swelling, suggests the potential utility of quantitative optical coherence tomography retinal layer segmentation to monitor neuroprotective effects of novel agents in therapeutic trials.
optical coherence tomography; retinal segmentation; optic neuritis; multiple sclerosis; demyelinating disease; neuro-ophthalmology
Chronic stroke patients with heterogeneous lesions, but no direct damage to the primary sensorimotor cortex, are capable of longitudinally acquiring the ability to modulate sensorimotor rhythms using grasping imagery of the affected hand. Volitional modulation of neural activity can be used to drive grasping functions of the paralyzed hand through a brain–computer interface. The neural substrates underlying this skill are not known. Here, we investigated the impact of individual patient's lesion pathology on functional and structural network integrity related to this volitional skill. Magnetoencephalography data acquired throughout training was used to derive functional networks. Structural network models and local estimates of extralesional white matter microstructure were constructed using T1-weighted and diffusion-weighted magnetic resonance imaging data. We employed a graph theoretical approach to characterize emergent properties of distributed interactions between nodal brain regions of these networks. We report that interindividual variability in patients’ lesions led to differential impairment of functional and structural network characteristics related to successful post-training sensorimotor rhythm modulation skill. Patients displaying greater magnetoencephalography global cost-efficiency, a measure of information integration within the distributed functional network, achieved greater levels of skill. Analysis of lesion damage to structural network connectivity revealed that the impact on nodal betweenness centrality of the ipsilesional primary motor cortex, a measure that characterizes the importance of a brain region for integrating visuomotor information between frontal and parietal cortical regions and related thalamic nuclei, correlated with skill. Edge betweenness centrality, an analogous measure, which assesses the role of specific white matter fibre pathways in network integration, showed a similar relationship between skill and a portion of the ipsilesional superior longitudinal fascicle connecting premotor and posterior parietal visuomotor regions known to be crucially involved in normal grasping behaviour. Finally, estimated white matter microstructure integrity in regions of the contralesional superior longitudinal fascicle adjacent to primary sensorimotor and posterior parietal cortex, as well as grey matter volume co-localized to these specific regions, positively correlated with sensorimotor rhythm modulation leading to successful brain–computer interface control. Thus, volitional modulation of ipsilesional neural activity leading to control of paralyzed hand grasping function through a brain–computer interface after longitudinal training relies on structural and functional connectivity in both ipsilesional and contralesional parietofrontal pathways involved in visuomotor information processing. Extant integrity of this structural network may serve as a future predictor of response to longitudinal therapeutic interventions geared towards training sensorimotor rhythms in the lesioned brain, secondarily improving grasping function through brain–computer interface applications.
motor learning; skill; stroke; rehabilitation; brain–computer interface; imagery
Converging evidence from neuroimaging studies and computational modelling suggests an organization of language in a dual dorsal–ventral brain network: a dorsal stream connects temporoparietal with frontal premotor regions through the superior longitudinal and arcuate fasciculus and integrates sensorimotor processing, e.g. in repetition of speech. A ventral stream connects temporal and prefrontal regions via the extreme capsule and mediates meaning, e.g. in auditory comprehension. The aim of our study was to test, in a large sample of 100 aphasic stroke patients, how well acute impairments of repetition and comprehension correlate with lesions of either the dorsal or ventral stream. We combined voxelwise lesion-behaviour mapping with the dorsal and ventral white matter fibre tracts determined by probabilistic fibre tracking in our previous study in healthy subjects. We found that repetition impairments were mainly associated with lesions located in the posterior temporoparietal region with a statistical lesion maximum in the periventricular white matter in projection of the dorsal superior longitudinal and arcuate fasciculus. In contrast, lesions associated with comprehension deficits were found more ventral-anterior in the temporoprefrontal region with a statistical lesion maximum between the insular cortex and the putamen in projection of the ventral extreme capsule. Individual lesion overlap with the dorsal fibre tract showed a significant negative correlation with repetition performance, whereas lesion overlap with the ventral fibre tract revealed a significant negative correlation with comprehension performance. To summarize, our results from patients with acute stroke lesions support the claim that language is organized along two segregated dorsal–ventral streams. Particularly, this is the first lesion study demonstrating that task performance on auditory comprehension measures requires an interaction between temporal and prefrontal brain regions via the ventral extreme capsule pathway.
stroke; voxelwise lesion-behaviour mapping; extreme capsule; superior longitudinal fascicle; arcuate fascicle
Transplanted neural stem/precursor cells possess peculiar therapeutic plasticity and can simultaneously instruct several therapeutic mechanisms in addition to cell replacement. Here, we interrogated the therapeutic plasticity of neural stem/precursor cells after their focal implantation in the severely contused spinal cord. We injected syngeneic neural stem/precursor cells at the proximal and distal ends of the contused mouse spinal cord and analysed locomotor functions and relevant secondary pathological events in the mice, cell fate of transplanted neural stem/precursor cells, and gene expression and inflammatory cell infiltration at the injured site. We used two different doses of neural stem/precursor cells and two treatment schedules, either subacute (7 days) or early chronic (21 days) neural stem/precursor cell transplantation after the induction of experimental thoracic severe spinal cord injury. Only the subacute transplant of neural stem/precursor cells enhanced the recovery of locomotor functions of mice with spinal cord injury. Transplanted neural stem/precursor cells survived undifferentiated at the level of the peri-lesion environment and established contacts with endogenous phagocytes via cellular–junctional coupling. This was associated with significant modulation of the expression levels of important inflammatory cell transcripts in vivo. Transplanted neural stem/precursor cells skewed the inflammatory cell infiltrate at the injured site by reducing the proportion of ‘classically-activated’ (M1-like) macrophages, while promoting the healing of the injured cord. We here identify a precise window of opportunity for the treatment of complex spinal cord injuries with therapeutically plastic somatic stem cells, and suggest that neural stem/precursor cells have the ability to re-programme the local inflammatory cell microenvironment from a ‘hostile’ to an ‘instructive’ role, thus facilitating the healing or regeneration past the lesion.
neural stem cells; spinal cord injury; cell transplantation; macrophages; immune regulation; tissue healing