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1.  Acquisition of internal models of motor tasks in children with autism 
Brain  2008;131(11):2894-2903.
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.
doi:10.1093/brain/awn226
PMCID: PMC2577807  PMID: 18819989
reach adaptation; prism adaptation; motor control; autism
2.  Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine 
Brain  2008;131(8):2071-2083.
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.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
comorbidity; depression; epilepsy; hippocampus; serotonin
3.  The role of the posterior cingulate cortex in cognition and disease 
Brain  2013;137(1):12-32.
The posterior cingulate cortex is a highly connected and metabolically active brain region. Recent studies suggest it has an important cognitive role, although there is no consensus about what this is. The region is typically discussed as having a unitary function because of a common pattern of relative deactivation observed during attentionally demanding tasks. One influential hypothesis is that the posterior cingulate cortex has a central role in supporting internally-directed cognition. It is a key node in the default mode network and shows increased activity when individuals retrieve autobiographical memories or plan for the future, as well as during unconstrained ‘rest’ when activity in the brain is ‘free-wheeling’. However, other evidence suggests that the region is highly heterogeneous and may play a direct role in regulating the focus of attention. In addition, its activity varies with arousal state and its interactions with other brain networks may be important for conscious awareness. Understanding posterior cingulate cortex function is likely to be of clinical importance. It is well protected against ischaemic stroke, and so there is relatively little neuropsychological data about the consequences of focal lesions. However, in other conditions abnormalities in the region are clearly linked to disease. For example, amyloid deposition and reduced metabolism is seen early in Alzheimer’s disease. Functional neuroimaging studies show abnormalities in a range of neurological and psychiatric disorders including Alzheimer’s disease, schizophrenia, autism, depression and attention deficit hyperactivity disorder, as well as ageing. Our own work has consistently shown abnormal posterior cingulate cortex function following traumatic brain injury, which predicts attentional impairments. Here we review the anatomy and physiology of the region and how it is affected in a range of clinical conditions, before discussing its proposed functions. We synthesize key findings into a novel model of the region’s function (the ‘Arousal, Balance and Breadth of Attention’ model). Dorsal and ventral subcomponents are functionally separated and differences in regional activity are explained by considering: (i) arousal state; (ii) whether attention is focused internally or externally; and (iii) the breadth of attentional focus. The predictions of the model can be tested within the framework of complex dynamic systems theory, and we propose that the dorsal posterior cingulate cortex influences attentional focus by ‘tuning’ whole-brain metastability and so adjusts how stable brain network activity is over time.
doi:10.1093/brain/awt162
PMCID: PMC3891440  PMID: 23869106
posterior cingulate cortex; attention: functional connectivity; default mode network; metastability
4.  Abnormal autonomic and associated brain activities during rest in autism spectrum disorder 
Brain  2014;137(1):153-171.
Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.
doi:10.1093/brain/awt294
PMCID: PMC3891443  PMID: 24424916
autism; autonomic nervous system; emotion; skin conductance; resting state
5.  Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing 
Brain  2013;137(1):255-267.
Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer’s Disease Centre, Nun Study, and National Alzheimer’s Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case–control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P < 0.001). This enables informative evaluation of anatomical regions outside of the hippocampus. To assess the morphology of brain microvasculature far more rigorously than what is possible using semi-quantitative pathological scoring, we applied digital pathological (Aperio ScanScope) methods on a subsample of frontal cortex sections from hippocampal sclerosis of ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0.03), and larger vessel areas (P < 0.03) than controls. Unlike the arterioles, CD34-immunoreactive capillaries had dimensions that were unchanged in cases with hippocampal sclerosis of ageing versus controls. Arteriolosclerosis appears specific to hippocampal sclerosis of ageing brains, because brains with Alzheimer’s disease pathology did not show the same morphological alterations. We conclude that there may be a pathogenetic change in aged human brain arterioles that impacts multiple brain areas and contributes to hippocampal sclerosis of ageing.
doi:10.1093/brain/awt318
PMCID: PMC3891448  PMID: 24271328
TDP-43; NACC; FTLD; SMA; HS-Ageing
6.  PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum 
Brain  2013;137(1):69-77.
Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot–Marie–Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.
doi:10.1093/brain/awt326
PMCID: PMC3891450  PMID: 24355708
ataxia; recessive ataxia; hypogonadism; retinal degeneration; spastic ataxia; early onset ataxia; spasticity; genetics; hereditary spastic paraplegia
7.  Mechanisms of deep brain stimulation for essential tremor 
Brain  2014;137(1):4-6.
doi:10.1093/brain/awt347
PMCID: PMC3891452  PMID: 24424913
8.  Neural mechanisms of discourse comprehension: a human lesion study 
Brain  2013;137(1):277-287.
Discourse comprehension requires language to be interpreted in the context of prior knowledge and experience. Barbey et al. use data from a large sample of focal lesions to argue that discourse comprehension emerges from a distributed network of brain regions that support specific competencies for human intelligence.
Discourse comprehension is a hallmark of human social behaviour and refers to the act of interpreting a written or spoken message by constructing mental representations that integrate incoming language with prior knowledge and experience. Here, we report a human lesion study (n = 145) that investigates the neural mechanisms underlying discourse comprehension (measured by the Discourse Comprehension Test) and systematically examine its relation to a broad range of psychological factors, including psychometric intelligence (measured by the Wechsler Adult Intelligence Scale), emotional intelligence (measured by the Mayer, Salovey, Caruso Emotional Intelligence Test), and personality traits (measured by the Neuroticism-Extraversion-Openness Personality Inventory). Scores obtained from these factors were submitted to voxel-based lesion-symptom mapping to elucidate their neural substrates. Stepwise regression analyses revealed that working memory and extraversion reliably predict individual differences in discourse comprehension: higher working memory scores and lower extraversion levels predict better discourse comprehension performance. Lesion mapping results indicated that these convergent variables depend on a shared network of frontal and parietal regions, including white matter association tracts that bind these areas into a coordinated system. The observed findings motivate an integrative framework for understanding the neural foundations of discourse comprehension, suggesting that core elements of discourse processing emerge from a distributed network of brain regions that support specific competencies for executive and social function.
doi:10.1093/brain/awt312
PMCID: PMC3954106  PMID: 24293267
discourse comprehension; psychometric intelligence; emotional intelligence; personality traits; voxel-based lesion-symptom mapping
9.  Cell number changes in Alzheimer’s disease relate to dementia, not to plaques and tangles 
Brain  2013;136(12):3738-3752.
Alzheimer’s disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-β plaques and neurofibrillary tangles have been implicated either directly as disruptors of neural function, or indirectly by precipitating neuronal death and thus causing a reduction in neuronal number. Alternatively, the initial cognitive decline has been attributed to subtle intracellular events caused by amyloid-β oligomers, resulting in dementia after massive synaptic dysfunction followed by neuronal degeneration and death. To investigate whether Alzheimer’s disease is associated with changes in the absolute cell numbers of ageing brains, we used the isotropic fractionator, a novel technique designed to determine the absolute cellular composition of brain regions. We investigated whether plaques and tangles are associated with neuronal loss, or whether it is dementia that relates to changes of absolute cell composition, by comparing cell numbers in brains of patients severely demented with those of asymptomatic individuals—both groups histopathologically diagnosed as Alzheimer’s—and normal subjects with no pathological signs of the disease. We found a great reduction of neuronal numbers in the hippocampus and cerebral cortex of demented patients with Alzheimer’s disease, but not in asymptomatic subjects with Alzheimer’s disease. We concluded that neuronal loss is associated with dementia and not the presence of plaques and tangles, which may explain why subjects with histopathological features of Alzheimer’s disease can be asymptomatic; and exclude amyloid-β deposits as causes for the reduction of neuronal numbers in the brain. We found an increase of non-neuronal cell numbers in the cerebral cortex and subcortical white matter of demented patients with Alzheimer’s disease when compared with asymptomatic subjects with Alzheimer’s disease and control subjects, suggesting a reactive glial cell response in the former that may be related to the symptoms they present.
doi:10.1093/brain/awt273
PMCID: PMC3859218  PMID: 24136825
ageing; amyloid-β; dementia; neuronal loss; isotropic fractionator
10.  Neural network connectivity differences in children who stutter 
Brain  2013;136(12):3709-3726.
Affecting 1% of the general population, stuttering impairs the normally effortless process of speech production, which requires precise coordination of sequential movement occurring among the articulatory, respiratory, and resonance systems, all within millisecond time scales. Those afflicted experience frequent disfluencies during ongoing speech, often leading to negative psychosocial consequences. The aetiology of stuttering remains unclear; compared to other neurodevelopmental disorders, few studies to date have examined the neural bases of childhood stuttering. Here we report, for the first time, results from functional (resting state functional magnetic resonance imaging) and structural connectivity analyses (probabilistic tractography) of multimodal neuroimaging data examining neural networks in children who stutter. We examined how synchronized brain activity occurring among brain areas associated with speech production, and white matter tracts that interconnect them, differ in young children who stutter (aged 3–9 years) compared with age-matched peers. Results showed that children who stutter have attenuated connectivity in neural networks that support timing of self-paced movement control. The results suggest that auditory-motor and basal ganglia-thalamocortical networks develop differently in stuttering children, which may in turn affect speech planning and execution processes needed to achieve fluent speech motor control. These results provide important initial evidence of neurological differences in the early phases of symptom onset in children who stutter.
doi:10.1093/brain/awt275
PMCID: PMC3859219  PMID: 24131593
stuttering; resting state functional MRI; DTI probabilistic tractography; basal ganglia thalamocortical loop; auditory motor integration
11.  Ictal high frequency oscillations distinguish two types of seizure territories in humans 
Brain  2013;136(12):3796-3808.
High frequency oscillations have been proposed as a clinically useful biomarker of seizure generating sites. We used a unique set of human microelectrode array recordings (four patients, 10 seizures), in which propagating seizure wavefronts could be readily identified, to investigate the basis of ictal high frequency activity at the cortical (subdural) surface. Sustained, repetitive transient increases in high gamma (80–150 Hz) amplitude, phase-locked to the low-frequency (1–25 Hz) ictal rhythm, correlated with strong multi-unit firing bursts synchronized across the core territory of the seizure. These repetitive high frequency oscillations were seen in recordings from subdural electrodes adjacent to the microelectrode array several seconds after seizure onset, following ictal wavefront passage. Conversely, microelectrode recordings demonstrating only low-level, heterogeneous neural firing correlated with a lack of high frequency oscillations in adjacent subdural recording sites, despite the presence of a strong low-frequency signature. Previously, we reported that this pattern indicates a failure of the seizure to invade the area, because of a feedforward inhibitory veto mechanism. Because multi-unit firing rate and high gamma amplitude are closely related, high frequency oscillations can be used as a surrogate marker to distinguish the core seizure territory from the surrounding penumbra. We developed an efficient measure to detect delayed-onset, sustained ictal high frequency oscillations based on cross-frequency coupling between high gamma amplitude and the low-frequency (1–25 Hz) ictal rhythm. When applied to the broader subdural recording, this measure consistently predicted the timing or failure of ictal invasion, and revealed a surprisingly small and slowly spreading seizure core surrounded by a far larger penumbral territory. Our findings thus establish an underlying neural mechanism for delayed-onset, sustained ictal high frequency oscillations, and provide a practical, efficient method for using them to identify the small ictal core regions. Our observations suggest that it may be possible to reduce substantially the extent of cortical resections in epilepsy surgery procedures without compromising seizure control.
doi:10.1093/brain/awt276
PMCID: PMC3859220  PMID: 24176977
epilepsy surgery; seizure localization; human microelectrode recordings; high frequency oscillations
12.  Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis 
Brain  2013;136(12):3766-3774.
Transient attacks of weakness in hypokalaemic periodic paralysis are caused by reduced fibre excitability from paradoxical depolarization of the resting potential in low potassium. Mutations of calcium channel and sodium channel genes have been identified as the underlying molecular defects that cause instability of the resting potential. Despite these scientific advances, therapeutic options remain limited. In a mouse model of hypokalaemic periodic paralysis from a sodium channel mutation (NaV1.4-R669H), we recently showed that inhibition of chloride influx with bumetanide reduced the susceptibility to attacks of weakness, in vitro. The R528H mutation in the calcium channel gene (CACNA1S encoding CaV1.1) is the most common cause of hypokalaemic periodic paralysis. We developed a CaV1.1-R528H knock-in mouse model of hypokalaemic periodic paralysis and show herein that bumetanide protects against both muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo from a glucose plus insulin infusion. This work demonstrates the critical role of the chloride gradient in modulating the susceptibility to ictal weakness and establishes bumetanide as a potential therapy for hypokalaemic periodic paralysis arising from either NaV1.4 or CaV1.1 mutations.
doi:10.1093/brain/awt280
PMCID: PMC3859222  PMID: 24142145
calcium channel; skeletal muscle; NKCC transporter; acetazolamide
13.  Striatal dopaminergic dysfunction at rest and during task performance in writer’s cramp 
Brain  2013;136(12):3645-3658.
Writer’s cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer’s cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously investigated in writer’s cramp. Using positron emission tomography imaging with the D2/D3 antagonist 11C-raclopride, we analysed striatal D2/D3 availability at rest and endogenous dopamine release during sequential finger tapping and speech production tasks in 15 patients with writer’s cramp and 15 matched healthy control subjects. Compared with control subjects, patients had reduced 11C-raclopride binding to D2/D3 receptors at rest in the bilateral striatum, consistent with findings in previous studies. During the tapping task, patients had decreased dopamine release in the left striatum as assessed by reduced change in 11C-raclopride binding compared with control subjects. One cluster of reduced dopamine release in the left putamen during tapping overlapped with a region of reduced 11C-raclopride binding to D2/D3 receptors at rest. During the sentence production task, patients showed increased dopamine release in the left striatum. No overlap between altered dopamine release during speech production and reduced 11C-raclopride binding to D2/D3 receptors at rest was seen. Striatal regions where D2/D3 availability at rest positively correlated with disease duration were lateral and non-overlapping with striatal regions showing reduced D2/D3 receptor availability, except for a cluster in the left nucleus accumbens, which showed a negative correlation with disease duration and overlapped with striatal regions showing reduced D2/D3 availability. Our findings suggest that patients with writer’s cramp may have divergent responses in striatal dopamine release during an asymptomatic motor task involving the dystonic hand and an unrelated asymptomatic task, sentence production. Our voxel-based results also suggest that writer’s cramp may be associated with reduced striatal dopamine release occuring in the setting of reduced D2/D3 receptor availability and raise the possibility that basal ganglia circuits associated with premotor cortices and those associated with primary motor cortex are differentially affected in primary focal dystonias.
doi:10.1093/brain/awt282
PMCID: PMC3859223  PMID: 24148273
dystonia; dopamine; PET; raclopride; striatum
14.  Natural history of pulmonary function in collagen VI-related myopathies 
Brain  2013;136(12):3625-3633.
The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed ‘collagen VI-related myopathies’ and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.
doi:10.1093/brain/awt284
PMCID: PMC3859224  PMID: 24271325
collagen VI-related myopathies; natural history; forced vital capacity; optimization of care; outcome measure
15.  Altered brain activity for phonological manipulation in dyslexic Japanese children 
Brain  2013;136(12):3696-3708.
Because of unique linguistic characteristics, the prevalence rate of developmental dyslexia is relatively low in the Japanese language. Paradoxically, Japanese children have serious difficulty analysing phonological processes when they have dyslexia. Neurobiological deficits in Japanese dyslexia remain unclear and need to be identified, and may lead to better understanding of the commonality and diversity in the disorder among different linguistic systems. The present study investigated brain activity that underlies deficits in phonological awareness in Japanese dyslexic children using functional magnetic resonance imaging. We developed and conducted a phonological manipulation task to extract phonological processing skills and to minimize the influence of auditory working memory on healthy adults, typically developing children, and dyslexic children. Current experiments revealed that several brain regions participated in manipulating the phonological information including left inferior and middle frontal gyrus, left superior temporal gyrus, and bilateral basal ganglia. Moreover, dyslexic children showed altered activity in two brain regions. They showed hyperactivity in the basal ganglia compared with the two other groups, which reflects inefficient phonological processing. Hypoactivity in the left superior temporal gyrus was also found, suggesting difficulty in composing and processing phonological information. The altered brain activity shares similarity with those of dyslexic children in countries speaking alphabetical languages, but disparity also occurs between these two populations. These are initial findings concerning the neurobiological impairments in dyslexic Japanese children.
doi:10.1093/brain/awt248
PMCID: PMC3916739  PMID: 24052613
developmental dyslexia; phonological awareness; functional magnetic resonance imaging; basal ganglia; Japanese language
16.  White matter involvement in sporadic Creutzfeldt-Jakob disease 
Brain  2014;137(12):3339-3354.
Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter abnormality either on T2-weighted or diffusion-weighted images. Widespread reduction in white matter mean diffusivity, however, was apparent visibly on the quantitative attenuation coefficient maps compared to healthy control subjects. Neuropathological analysis showed diffuse astrocytic gliosis and activated microglia in the white matter, rare prion deposition and subtle subcortical microvacuolization, and patchy foci of demyelination with no evident white matter axonal degeneration. Decreased mean diffusivity on attenuation coefficient maps might be associated with astrocytic gliosis. We show for the first time significant global reduced mean diffusivity within the white matter in sporadic Creutzfeldt-Jakob disease, suggesting possible primary involvement of the white matter, rather than changes secondary to neuronal degeneration/loss.
Sporadic Creutzfeldt-Jakob disease (sCJD) is considered primarily a disease of grey matter. However, Caverzasi et al. now show a global decrease in mean diffusivity in white matter. The changes appear to be associated with reactive astrocytic gliosis and activated microglia, and suggest primary involvement of the white matter in sCJD.
doi:10.1093/brain/awu298
PMCID: PMC4240303  PMID: 25367029
DTI; CJD; mean diffusivity; gliosis; microglia
17.  A family affair: brain abnormalities in siblings of patients with schizophrenia 
Brain  2013;136(11):3215-3226.
Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development.
doi:10.1093/brain/awt116
PMCID: PMC3808683  PMID: 23698280
schizophrenia; imaging; grey matter; endophenotype
18.  Handedness and language learning disability differentially distribute in progressive aphasia variants 
Brain  2013;136(11):3461-3473.
Primary progressive aphasia is a neurodegenerative clinical syndrome that presents in adulthood with an isolated, progressive language disorder. Three main clinical/anatomical variants have been described, each associated with distinctive pathology. A high frequency of neurodevelopmental learning disability in primary progressive aphasia has been reported. Because the disorder is heterogeneous with different patterns of cognitive, anatomical and biological involvement, we sought to identify whether learning disability had a predilection for one or more of the primary progressive aphasia subtypes. We screened the University of California San Francisco Memory and Aging Center's primary progressive aphasia cohort (n = 198) for history of language-related learning disability as well as hand preference, which has associations with learning disability. The study included logopenic (n = 48), non-fluent (n = 54) and semantic (n = 96) variant primary progressive aphasias. We investigated whether the presence of learning disability or non-right-handedness was associated with differential effects on demographic, neuropsychological and neuroimaging features of primary progressive aphasia. We showed that a high frequency of learning disability was present only in the logopenic group (χ2 = 15.17, P < 0.001) and (χ2 = 11.51, P < 0.001) compared with semantic and non-fluent populations. In this group, learning disability was associated with earlier onset of disease, more isolated language symptoms, and more focal pattern of left posterior temporoparietal atrophy. Non-right-handedness was instead over-represented in the semantic group, at nearly twice the prevalence of the general population (χ2 = 6.34, P = 0.01). Within semantic variant primary progressive aphasia the right-handed and non-right-handed cohorts appeared homogeneous on imaging, cognitive profile, and structural analysis of brain symmetry. Lastly, the non-fluent group showed no increase in learning disability or non-right-handedness. Logopenic variant primary progressive aphasia and developmental dyslexia both manifest with phonological disturbances and posterior temporal involvement. Learning disability might confer vulnerability of this network to early-onset, focal Alzheimer’s pathology. Left-handedness has been described as a proxy for atypical brain hemispheric lateralization. As non-right-handedness was increased only in the semantic group, anomalous lateralization mechanisms might instead be related to frontotemporal lobar degeneration with abnormal TARDBP. Taken together, this study suggests that neurodevelopmental signatures impart differential trajectories towards neurodegenerative disease.
doi:10.1093/brain/awt242
PMCID: PMC3808687  PMID: 24056533
Alzheimer’s disease; frontotemporal dementia; dementia aphasia; case control study; risk factors in epidemiology
19.  Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study 
Brain  2013;136(11):3242-3251.
Elevated in vivo markers of presynaptic striatal dopamine activity have been a consistent finding in schizophrenia, and include a large effect size elevation in dopamine synthesis capacity. However, it is not known if the dopaminergic dysfunction is limited to the striatal terminals of dopamine neurons, or is also evident in the dopamine neuron cell bodies, which mostly originate in the substantia nigra. The aim of our studies was therefore to determine whether dopamine synthesis capacity is altered in the substantia nigra of people with schizophrenia, and how this relates to symptoms. In a post-mortem study, a semi-quantitative analysis of tyrosine hydroxylase staining was conducted in nigral dopaminergic cells from post-mortem tissue from patients with schizophrenia (n = 12), major depressive disorder (n = 13) and matched control subjects (n = 13). In an in vivo imaging study, nigral and striatal dopaminergic function was measured in patients with schizophrenia (n = 29) and matched healthy control subjects (n = 29) using 18F-dihydroxyphenyl-l-alanine (18F-DOPA) positron emission tomography. In the post-mortem study we found that tyrosine hydroxylase staining was significantly increased in nigral dopaminergic neurons in schizophrenia compared with both control subjects (P < 0.001) and major depressive disorder (P < 0.001). There was no significant difference in tyrosine hydroxylase staining between control subjects and patients with major depressive disorder, indicating that the elevation in schizophrenia is not a non-specific indicator of psychiatric illness. In the in vivo imaging study we found that 18F-dihydroxyphenyl-l-alanine uptake was elevated in both the substantia nigra and in the striatum of patients with schizophrenia (effect sizes = 0.85, P = 0.003 and 1.14, P < 0.0001, respectively) and, in the voxel-based analysis, was elevated in the right nigra (P < 0.05 corrected for family wise-error). Furthermore, nigral 18F-dihydroxyphenyl-l-alanine uptake was positively related with the severity of symptoms (r = 0.39, P = 0.035) in patients. However, whereas nigral and striatal 18F-dihydroxyphenyl-l-alanine uptake were positively related in control subjects (r = 0.63, P < 0.001), this was not the case in patients (r = 0.30, P = 0.11). These findings indicate that elevated dopamine synthesis capacity is seen in the nigral origin of dopamine neurons as well as their striatal terminals in schizophrenia, and is linked to symptom severity in patients.
doi:10.1093/brain/awt264
PMCID: PMC3808688  PMID: 24097339
dopamine; psychosis; depression; substantia nigra; schizophrenia; F-DOPA; dihydroxyphenyl-l-alanine; brain imaging; striatum; tyrosine; post-mortem
20.  Use of quadrupedal step training to re-engage spinal interneuronal networks and improve locomotor function after spinal cord injury 
Brain  2013;136(11):3362-3377.
Can lower limb motor function be improved after a spinal cord lesion by re-engaging functional activity of the upper limbs? We addressed this issue by training the forelimbs in conjunction with the hindlimbs after a thoracic spinal cord hemisection in adult rats. The spinal circuitries were more excitable, and behavioural and electrophysiological analyses showed improved hindlimb function when the forelimbs were engaged simultaneously with the hindlimbs during treadmill step-training as opposed to training only the hindlimbs. Neuronal retrograde labelling demonstrated a greater number of propriospinal labelled neurons above and below the thoracic lesion site in quadrupedally versus bipedally trained rats. The results provide strong evidence that actively engaging the forelimbs improves hindlimb function and that one likely mechanism underlying these effects is the reorganization and re-engagement of rostrocaudal spinal interneuronal networks. For the first time, we provide evidence that the spinal interneuronal networks linking the forelimbs and hindlimbs are amenable to a rehabilitation training paradigm. Identification of this phenomenon provides a strong rationale for proceeding toward preclinical studies for determining whether training paradigms involving upper arm training in concert with lower extremity training can enhance locomotor recovery after neurological damage.
doi:10.1093/brain/awt265
PMCID: PMC3808689  PMID: 24103912
spinal cord hemisection; rats; motor coordination; propriospinal system; quadrupedal locomotion
21.  Damage to the anterior arcuate fasciculus predicts non-fluent speech production in aphasia 
Brain  2013;136(11):3451-3460.
Non-fluent aphasia implies a relatively straightforward neurological condition characterized by limited speech output. However, it is an umbrella term for different underlying impairments affecting speech production. Several studies have sought the critical lesion location that gives rise to non-fluent aphasia. The results have been mixed but typically implicate anterior cortical regions such as Broca’s area, the left anterior insula, and deep white matter regions. To provide a clearer picture of cortical damage in non-fluent aphasia, the current study examined brain damage that negatively influences speech fluency in patients with aphasia. It controlled for some basic speech and language comprehension factors in order to better isolate the contribution of different mechanisms to fluency, or its lack. Cortical damage was related to overall speech fluency, as estimated by clinical judgements using the Western Aphasia Battery speech fluency scale, diadochokinetic rate, rudimentary auditory language comprehension, and executive functioning (scores on a matrix reasoning test) in 64 patients with chronic left hemisphere stroke. A region of interest analysis that included brain regions typically implicated in speech and language processing revealed that non-fluency in aphasia is primarily predicted by damage to the anterior segment of the left arcuate fasciculus. An improved prediction model also included the left uncinate fasciculus, a white matter tract connecting the middle and anterior temporal lobe with frontal lobe regions, including the pars triangularis. Models that controlled for diadochokinetic rate, picture-word recognition, or executive functioning also revealed a strong relationship between anterior segment involvement and speech fluency. Whole brain analyses corroborated the findings from the region of interest analyses. An additional exploratory analysis revealed that involvement of the uncinate fasciculus adjudicated between Broca’s and global aphasia, the two most common kinds of non-fluent aphasia. In summary, the current results suggest that the anterior segment of the left arcuate fasciculus, a white matter tract that lies deep to posterior portions of Broca’s area and the sensory-motor cortex, is a robust predictor of impaired speech fluency in aphasic patients, even when motor speech, lexical processing, and executive functioning are included as co-factors. Simply put, damage to those regions results in non-fluent aphasic speech; when they are undamaged, fluent aphasias result.
doi:10.1093/brain/awt267
PMCID: PMC3808690  PMID: 24131592
aphasia; speech production; non-fluent speech; arcuate fasciculus; uncinate fasciculus
22.  Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome 
Brain  2013;136(11):3441-3450.
We sought to characterize perfusion patterns of progressive multifocal leukoencephalopathy lesions by arterial spin labelling perfusion magnetic resonance imaging and to analyse their association with immune reconstitution inflammatory syndrome, and survival. A total of 22 patients with progressive multifocal leukoencephalopathy underwent a clinical evaluation and magnetic resonance imaging of the brain within 190 days of symptom onset. The presence of immune reconstitution inflammatory syndrome was determined based on clinical and laboratory criteria. Perfusion within progressive multifocal leukoencephalopathy lesions was determined by arterial spin labelling magnetic resonance imaging. We observed intense hyperperfusion within and at the edge of progressive multifocal leukoencephalopathy lesions in a subset of subjects. This hyperperfusion was quantified by measuring the fraction of lesion volume showing perfusion in excess of twice normal appearing grey matter. Hyperperfused lesion fraction was significantly greater in progressive multifocal leukoencephalopathy progressors than in survivors (12.8% versus 3.4% P = 0.02) corresponding to a relative risk of progression for individuals with a hyperperfused lesion fraction ≥ 4.0% of 9.1 (95% confidence interval of 1.4–59.5). The presence of hyperperfusion was inversely related to the occurrence of immune reconstitution inflammatory syndrome at the time of scan (P = 0.03). Indeed, within 3 months after symptom onset, hyperperfusion had a positive predictive value of 88% for absence of immune reconstitution inflammatory syndrome. Arterial spin labelling magnetic resonance imaging recognized regions of elevated perfusion within lesions of progressive multifocal leukoencephalopathy. These regions might represent virologically active areas operating in the absence of an effective adaptive immune response and correspond with a worse prognosis.
doi:10.1093/brain/awt268
PMCID: PMC3808691  PMID: 24088807
progressive multifocal leukoencephalopathy; magnetic resonance imaging; perfusion imaging; neuroinflammation; neuroimmunology
23.  Thalamic cholinergic innervation and postural sensory integration function in Parkinson’s disease 
Brain  2013;136(11):3282-3289.
The pathophysiology of postural instability in Parkinson’s disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson’s disease. Our aim was to investigate the relationship of cholinergic terminal loss in thalamus and cortex, and nigrostriatal dopaminergic denervation, on postural sensory integration function in Parkinson’s disease. We studied 124 subjects with Parkinson’s disease (32 female/92 male; 65.5 ± 7.4 years old; 6.0 ± 4.2 years motor disease duration; modified Hoehn and Yahr mean stage 2.4 ± 0.5) and 25 control subjects (10 female/15 male, 66.8 ± 10.1 years old). All subjects underwent 11C-dihydrotetrabenazine vesicular monoaminergic transporter type 2 and 11C-methylpiperidin-4-yl propionate acetylcholinesterase positron emission tomography and the sensory organization test balance platform protocol. Measures of dopaminergic and cholinergic terminal integrity were obtained, i.e. striatal vesicular monoaminergic transporter type 2 binding (distribution volume ratio) and thalamic and cortical acetylcholinesterase hydrolysis rate per minute (k3), respectively. Total centre of pressure excursion (speed), a measure of total sway, and sway variability were determined for individual sensory organization test conditions. Based on normative data, principal component analysis was performed to reduce postural sensory organization functions to robust factors for regression analysis with the dopaminergic and cholinergic terminal data. Factor analysis demonstrated two factors with eigenvalues >2 that explained 52.2% of the variance, mainly reflecting postural sway during sensory organization test Conditions 1–3 and 5, respectively. Regression analysis of the Conditions 1–3 postural sway-related factor [R2adj = 0.123, F(5,109) = 4.2, P = 0.002] showed that decreased thalamic cholinergic innervation was associated with increased centre of pressure sway speed (β = −0.389, t = −3.4, P = 0.001) while controlling for covariate effects of cognitive capacity and parkinsonian motor impairments. There was no significant effect of cortical cholinergic terminal deficits or striatal dopaminergic terminal deficits. This effect could only be found for the subjects with Parkinson’s disease. We conclude that postural sensory integration function of subjects with Parkinson’s disease is modulated by pedunculopontine nucleus-thalamic but not cortical cholinergic innervation. Impaired integrity of pedunculopontine nucleus cholinergic neurons and their thalamic efferents play a role in postural control in patients with Parkinson’s disease, possibly by participating in integration of multimodal sensory input information.
doi:10.1093/brain/awt247
PMCID: PMC3900870  PMID: 24056537
Parkinson’s disease; pedunculopontine nucleus; postural sensory organization; positron emission tomography; acetylcholine
24.  The expanding spectrum of aetiologies causing retinal microcystic macular change 
Brain  2013;136(11):3212-3214.
doi:10.1093/brain/awt295
PMCID: PMC3900871  PMID: 24131594

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