Search

The use of spoken and written language is a capacity that is unique to humans. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The relevant genetic architecture is complex, heterogeneous, and multifactorial, and yet to be investigated with well-powered studies. Here, we present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, with total sample sizes ranging from 13,633 to 33,959 participants aged 5-26 years (12,411 to 27,180 for those with European ancestry, defined by principal component analyses). We identified a genome-wide significant association with word reading (rs11208009, p=1.098 × 10−8) independent of known loci associated with intelligence or educational attainment. All five reading-/language-related traits had robust SNP-heritability estimates (0.13–0.26), and genetic correlations between them were modest to high. Using genomic structural equation modelling, we found evidence for a shared genetic factor explaining the majority of variation in word and nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS was performed to jointly analyse word and nonword reading, spelling, and phoneme awareness, maximizing power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with cortical surface area of the banks of the left superior temporal sulcus, a brain region with known links to processing of spoken and written language. Analysis of evolutionary annotations on the lineage that led to modern humans showed enriched heritability in regions depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of these uniquely human traits.

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson’s disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = −0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

SP is funded by the Royal Society. This work was supported by an Action Medical Research Action/The Chief Scientist Office (CSO), Scotland grant (GN2614) and a Cunningham Trust grant to SP and SJP. Support to the analysis was provided by the St Andrews Bioinformatics Unit funded by the Wellcome Trust [grant 105621/Z/14/Z]. Assessment of the Aston cohort was supported by funding from The Waterloo Foundation to JBT and SP [797–1720]. Analysis of the discovery pedigree was supported by the University of Kansas grant (NIH:NIDCD 5 R01 DC001803). Analysis of the York cohort was funded by Wellcome Trust Programme Grant 082036/B/07/Z. DFN is currently supported by Oxford Brookes University funds, the Leverhulme Trust and the British Academy. This work was, in part, completed while DFN was at the Wellcome Trust Centre for Human Genetics, Oxford as an MRC Career Development Fellow (G1000569/1). We would like to thank the members of all teams who collected the data and the families who participated. At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared to cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum p = 0.002 for nonword reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level. Publisher PDF

Research has shown improved reading following visual magnocellular training in individuals with dyslexia. Many studies have demonstrated how the magnocellular pathway controls visual spatial attention. Therefore, we have investigated the relationship between magnocellular pathway and visual spatial attention deficits in dyslexia in order to better understand how magnocellular-based interventions may help children to learn to read. Magnocellular function, visual spatial attention, and reading abilities of thirty elementary school students with dyslexia, aged between 8 and 10, were measured. The experimental group received magnocellular-based visual motion training for 12 sessions, while the control group received neutral sessions. All tests were repeated at the end of the training and after 1 month. The magnocellular functioning, visual spatial attention, and reading abilities of the experimental group improved significantly compared to the controls. Additionally, improvement in reaction time of invalid conditions predicted improvements in saccadic eye movements. We conclude that visual magnocellular training improved saccadic eye movement control, visual spatial orientation, and reading ability.

Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen–posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting., Raghu et al. report that the majority of variation in outcomes following pallidal DBS for cervical dystonia can be explained by electrode location and structural connectivity. Individual differences in the primary motor cortex–putamen–internal pallidal limb of the direct pathway offer the prospect of a personalized approach.

(1) Background—the magnocellular hypothesis proposes that impaired development of the visual timing systems in the brain that are mediated by magnocellular (M-) neurons is a major cause of dyslexia. Their function can now be assessed quite easily by analysing averaged visually evoked event-related potentials (VERPs) in the electroencephalogram (EEG). Such analysis might provide a useful, objective biomarker for diagnosing developmental dyslexia. (2) Methods—in adult dyslexics and normally reading controls, we recorded steady state VERPs, and their frequency content was computed using the fast Fourier transform. The visual stimulus was a black and white checker board whose checks reversed contrast every 100 ms. M- cells respond to this stimulus mainly at 10 Hz, whereas parvocells (P-) do so at 5 Hz. Left and right visual hemifields were stimulated separately in some subjects to see if there were latency differences between the M- inputs to the right vs. left hemispheres, and these were compared with the subjects’ handedness. (3) Results—Controls demonstrated a larger 10 Hz than 5 Hz fundamental peak in the spectra, whereas the dyslexics showed the reverse pattern. The ratio of subjects’ 10/5 Hz amplitudes predicted their reading ability. The latency of the 10 Hz peak was shorter during left than during right hemifield stimulation, and shorter in controls than in dyslexics. The latter correlated weakly with their handedness. (4) Conclusion—Steady state visual ERPs may conveniently be used to identify developmental dyslexia. However, due to the limited numbers of subjects in each sub-study, these results need confirmation.

Funding: AG and TFMA were supported by the Munich Cluster for Systems Neurology (SyNergy). AG 535 was supported by Fondazione Umberto Veronesi. SP is a Royal Society University Research fellow. BMM, CF, BSP and SEF are supported by the Max Planck Society. AW, BM and HK were funded by the Fraunhofer Society and the Max Planck Society within the ‘Pakt für Forschung und Innovation’. HK was also supported by LIFE – Leipzig Research Center for Civilization Diseases funded by means of the European Union; the European Regional Development Fund (ERDF); and the Free State of Saxony within the excellence initiative. FR is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-17-EURE-542 0017 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696). TFMA was supported by the BMBF through the DIFUTURE consortium of the Medical Informatics Initiative Germany (grant 01ZZ1804A) and by the European Union’s Horizon 2020 Research and Innovation Programme (grant MultipleMS, EU RIA 733161). Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p

The phonological theory of dyslexia makes it difficult to distinguish developmental dyslexia from social causes of reading failure, because, whatever their cause, all poor readers seem to have similar phonological problems. In order to understand why children with dyslexia fail, we need to understand the physiological mechanisms that underlie their failure to acquire phonological skills. An important cause is probably impaired development of the brain’s rapid temporal processing systems; these are required for sequencing accurately the order of the sounds and letters in a word. Such temporal, “transient”, processing is probably carried out in all parts of the brain primarily by a distinct set of “magnocellular” neurones, and the development of these has been found to be impaired in many people with dyslexia. Therefore measuring poor readers’ auditory and temporal processing skills should enable dyslexia to be reliably distinguished from other causes of phonological deficits.

The visual magnocellular system is thought to play a crucial role in learning to read. Here therefore, we examined whether magnocellular based training could improve reading in children with visual reading problems. The participants were 24 male primary school students aged between 9–11 (Mean = 9.76, SD = 0.59) with specific reading difficulty. Experimental and control groups were matched for age, sex, educational level, IQ, reading abilities (measured by APRA), magnocellular performance as assessed by a random dot kinematogram (RDK) paradigm and recordings of their saccadic eye movements. The experimental group received twelve magnocellular based visual motion training sessions, twice a week over 6 weeks. During the same period, the control group played a video game with the help of a practitioner. All measures were made just prior to the training and were repeated at the 6th, 12th training session and one month later. The experimental group showed significant improvements in magnocellular function, visual errors and reading accuracy during the course of intervention. Follow-up assessment confirmed that these effects persisted one month later. Impaired magnocellular functioning appeared to be an important cause of poor reading in Persian. Hence magnocellular based training could help many children with specific reading difficulties. Also testing magnocellular function could be used as screening tool for detecting dyslexia before a child begins to fail at school.

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p, Translational Psychiatry, 9 (1), ISSN:2158-3188

Developmental dyslexia (DD) is one of the most prevalent learning disorders among children and is characterized by deficits in different cognitive skills, including reading, spelling, short term memory and others. To help unravel the genetic basis of these skills, we conducted a Genome Wide Association Study (GWAS), including nine cohorts of reading-impaired and typically developing children of European ancestry, recruited across different countries (N=2,562-3,468).We observed a genome-wide significant effect (p−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2 withinMIR924HG (micro-RNA 924 host gene;p= 4.73×10−9), and a suggestive association on 8q12.3 withinNKAIN3(encoding a cation transporter;p= 2.25 ×10−8). RAN represents one of the best universal predictors of reading fluency across orthographies and linkage to RAN has been previously reported withinCELF4(18q12.2), a gene highly expressed in the fetal brain which is co-expressed withNKAIN3and predicted to be a target ofMIR924. These findings suggest new candidate DD susceptibility genes and provide insights into the genetics and neurobiology of dyslexia.

Parkinson is a neurodegenerative disease, in which tremor is the main symptom. This paper investigates the use of different classification methods to identify tremors experienced by Parkinsonian patients. Some previous research has focussed tremor analysis on external body signals (e.g., electromyography, accelerometer signals, etc.). Our advantage is that we have access to sub-cortical data, which facilitates the applicability of the obtained results into real medical devices since we are dealing with brain signals directly. Local field potentials (LFP) were recorded in the subthalamic nucleus of 7 Parkinsonian patients through the implanted electrodes of a deep brain stimulation (DBS) device prior to its internalization. Measured LFP signals were preprocessed by means of splinting, down sampling, filtering, normalization and rectification. Then, feature extraction was conducted through a multi-level decomposition via a wavelet transform. Finally, artificial intelligence techniques were applied to feature selection, clustering of tremor types, and tremor detection. The key contribution of this paper is to present initial results which indicate, to a high degree of certainty, that there appear to be two distinct subgroups of patients within the group-1 of patients according to the Consensus Statement of the Movement Disorder Society on Tremor. Such results may well lead to different resultant treatments for the patients involved, depending on how their tremor has been classified. Moreover, we propose a new approach for demand driven stimulation, in which tremor detection is also based on the subtype of tremor the patient has. Applying this knowledge to the tremor detection problem, it can be concluded that the results improve when patient clustering is applied prior to detection.

Some people doubt that the concept of developmental dyslexia (DD) is useful at all because the phonological weaknesses seen in DD cannot be distinguished from those found in every person with poor reading skills, whatever their cause. Here I argue that true DD is characterised by poor temporal processing, hence impaired visual and auditory sequencing, that is caused by impaired development of transient/magnocellular (M-) systems throughout the brain. These deficits can be measured in order to distinguish the causes of the phonological weaknesses in DD from those causing similar deficits in other types of poor reading. Importantly this knowledge can be exploited to develop effective improvements in treatment. The evidence for impaired visual magnocellular function in many, if not all, people with dyslexia is now overwhelming; it is supported not only by psychophysical tests of M- function, but also by electrophysiological, eye movement, attentional, imaging, interventional and genetic findings. Analogously, auditory temporal processing is mediated by auditory transient, 'magnocellular', processing systems, and evidence is accumulating persuasively that this system is also impaired in dyslexics. I briefly introduce the idea that 'motor magnocellular systems' may also be impaired in dyslexia, then consider genetic, immunological and nutritional factors that interact to cause the impaired magnocellular phenotype. I then discuss why the dyslexic phenotype is so common by speculating about what strengths it might confer that would maintain the responsible genes in the human genome.

When language is processed, brain activity occurs not only in the classic ‘language areas’ such as Broca’s area, but also in areas which control movement. Our systems of understanding, including higher level cognition, are rooted in bodily awareness which needs to be developed as a precursor to intellectual reasoning. Cognition is embodied, and this concept may offer a radical new way of improving school education by improving children’s systems of physical understanding. A new classroom physical intervention, called Move4words, based on embodied cognition, was developed for pupils aged 7–13 years and trialled with 348 typical pupils in 10 mainstream UK schools. Three pilot controlled trials showed significant improvements in academic performance, particularly for struggling pupils performing in the lowest 20 percent. Effect sizes were large for the lowest achievers: Hedges’ g = 0.86 for national examinations at age 11 (KS2 SATs) and g = 1.24 for progress through National Curriculum Levels in reading, writing and maths. Performance gains were maintained for at least 1 year after the end of the intervention.

Emerging evidence of the high variability in the cognitive skills and deficits associated with reading achievement and dysfunction promotes both a more dimensional view of the risk factors involved, and the importance of discriminating between trajectories of impairment. Here we examined reading and component orthographic and phonological skills alongside measures of cognitive ability and auditory and visual sensory processing in a large group of primary school children between the ages of 7 and 12 years. We identified clusters of children with pseudoword or exception word reading scores at the 10th percentile or below relative to their age group, and a group with poor skills on both tasks. Compared to age-matched and reading-level controls, groups of children with more impaired exception word reading were best described by a trajectory of developmental delay, whereas readers with more impaired pseudoword reading or combined deficits corresponded more with a pattern of atypical development. Sensory processing deficits clustered within both of the groups with putative atypical development: auditory discrimination deficits with poor phonological awareness skills; impairments of visual motion processing in readers with broader and more severe patterns of reading and cognitive impairments. Sensory deficits have been variably associated with developmental impairments of literacy and language; these results suggest that such deficits are also likely to cluster in children with particular patterns of reading difficulty. © 2012 Elsevier Ltd.

OBJECTIVE: Recent research has provided evidence for a genetically mediated association between language or reading-related cognitive deficits and impaired motor coordination. Other studies have identified relationships between lateralization of hand skill and cognitive abilities. With a large sample, the authors aimed to investigate genetic relationships between measures of reading-related cognition, hand motor skill, and hand skill lateralization. METHOD: The authors applied univariate and bivariate correlation and familiality analyses to a range of measures. They also performed genomewide linkage analysis of hand motor skill in a subgroup of 195 sibling pairs. RESULTS: Hand motor skill was significantly familial (maximum heritability=41%), as were reading-related measures. Hand motor skill was weakly but significantly correlated with reading-related measures, such as nonword reading and irregular word reading. However, these correlations were not significantly familial in nature, and the authors did not observe linkage of hand motor skill to any chromosomal regions implicated in susceptibility to dyslexia. Lateralization of hand skill was not correlated with reading or cognitive ability. CONCLUSIONS: The authors confirmed a relationship between lower motor ability and poor reading performance. However, the genetic effects on motor skill and reading ability appeared to be largely or wholly distinct, suggesting that the correlation between these traits may have arisen from environmental influences. Finally, the authors found no evidence that reading disability and/or low general cognitive ability were associated with ambidexterity. Correction for Francks et al., Am J Psychiatry 160 (11) In the November issue of the Journal, there was an error in the article by Clyde Francks, D.Phil., et al. titled "Familial and Genetic Effects on Motor Coordination, Laterality, and Reading-Related Cognition" (Am J Psychiatry 2003; 160:1970–1977). The content of Tables 3 and 4 was switched, although the table titles and footnotes are correct.

Children with developmental dyslexia struggle to learn to read and spell despite adequate intelligence and educational opportunity. Several lines of research are attempting to establish the neurobiological basis of dyslexia, and low-level sensory and motor deficits have been found in dyslexic populations; furthermore, behavioural and imaging data point to cerebellar dysfunction in dyslexia. To investigate this, normal readers (n=19) and children with developmental dyslexia (n=16) were asked to perform various cognitive, literacy, and balancing tasks. Children balanced on the left or right foot, with eyes open or closed, for a period of 10 s during which their movements were recorded with a motion-tracking system. Dyslexic children were less stable than the control children in both eyes-open conditions (left foot P=0.02, right foot P=0.012). While there were no group differences during the eyes-closed conditions, the dyslexic children dropped a foot to correct balance significantly more often than control children (P

Dr. Henry Hans Heinz Schmidek (b. 10th September 1937) died suddenly in Oxford on 26th October 2008 after myocardial infarction. British neurosurgery and Oxford will be the poorer because he had pl...

Despite that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favored intervention for patients with medically intractable dystonia, the pathophysiological mechanisms of dystonia are largely unclear. In eight patients with primary dystonia who were treated with bilateral chronic pallidal stimulation, we correlated symptom-related electromyogram (EMG) activity of the most affected muscles with the local field potentials (LFPs) recorded from the globus pallidus electrodes. In 5 dystonic patients with mobile involuntary movements, rhythmic EMG bursts in the contralateral muscles were coherent with the oscillations in the pallidal LFPs at the burst frequency. In contrast, no significant coherence was seen between EMG and LFPs either for the sustained activity separated out from the compound EMGs in those 5 cases, or in the EMGs in 3 other cases without mobile involuntary movements and rhythmic EMG bursts. In comparison with the resting condition, in both active and passive movements, significant modulation in the GPi LFPs was seen in the range of 8-16 Hz. The finding of significant coherence between GPi oscillations and rhythmic EMG bursts but not sustained tonic EMG activity suggests that the synchronized pallidal activity may be directly related to the rhythmic involuntary movements. In contrast, the sustained hypertonic muscle activity may be represented by less synchronized activity in the pallidum. Thus, the pallidum may play different roles in generating different components of the dystonic symptom complex.

Objective To differentiate physiological from harmonic components in coherence analysis of the tremor-related neural and muscular signals by comparing power, cross-power and coherence spectra. Methods Influences of waveform, burst-width and additional noise on generating harmonic peaks in the power, cross-power and coherence spectra were studied using simulated signals. The local field potentials (LFPs) of the subthalamic nucleus (STN) and the EMGs of the contralateral forearm muscles in PD patients with rest tremor were analysed. Results (1) Waveform had significant effect on generating harmonics; (2) noise significantly decreased the coherence values in a frequency-dependent fashion; and (3) cross-spectrum showed high resistance to harmonics. Among six examples of paired LFP–EMG signals, significant coherence appeared at the tremor frequency only, both the tremor and double tremor frequencies and the double-tremor frequency only. Conclusions In coherence analysis of neural and muscular signals, distortion in waveform generates significant harmonic peaks in the coherence spectra and the coherence values of both physiological and harmonic components are modulated by extra noise or non-tremor related activity. Significance The physiological or harmonic nature of a coherence peak at the double tremor frequency may be differentiated when the coherence spectra are compared with the power and in particular the cross-power spectra.

The development of reading skills may depend to a certain extent on the development of basic visual perception. The magnocellular theory of developmental dyslexia assumes that deficits in the magnocellular pathway, indicated by less sensitivity in perceiving dynamic sensory stimuli, are responsible for a proportion of reading difficulties experienced by dyslexics. Using a task that measures coherent motion detection threshold, this study examined the relationship between dynamic visual perception and reading development in Chinese children. Experiment 1 compared the performance of 27 dyslexics and their age- and IQ-matched controls in the coherent motion detection task and in a static pattern perception task. Results showed that only in the former task did the dyslexics have a significantly higher threshold than the controls, suggesting that Chinese dyslexics, like some of their Western counterparts, may have deficits in magnocellular pathway. Experiment 2 examined whether dynamic visual processing affects specific cognitive processes in reading. One hundred fifth-grade children were tested on visual perception and reading-related tasks. Regression analyses found that the motion detection threshold accounted for 11% and 12%, respectively, variance in the speed of orthographic similarity judgment and in the accuracy of picture naming after IQ and vocabulary size were controlled. The static pattern detection threshold could not account for any variance. It is concluded that reading development in Chinese depends to a certain extent on the development of dynamic visual perception and its underlying neural pathway and that the impact of visual development can be specifically related to orthographic processing in reading Chinese.

Cluster headache (CH) is a debilitating neurovascular condition characterized by severe unilateral periorbital head pain. Deep brain stimulation of the posterior hypothalamus has shown potential in alleviating CH in its most severe, chronic form. During surgical implantation of stimulating macroelectrodes for cluster head pain, one of our patients suffered a CH attack. During the attack local field potentials displayed a significant increase in power of approximately 20 Hz. To the authors' knowledge, this is the first recorded account of neuronal activity observed during a cluster attack. Our results both support and extend the current literature, which has long implicated hypothalamic activation as key to CH generation, predominantly through indirect haemodynamic neuroimaging techniques. Our findings reveal a potential locus in CH neurogenesis and a potential rationale for efficacious stimulator titration. © 2009 Blackwell Publishing Ltd.

Motor cortex stimulation is increasingly reported in the literature as a surgical option for the alleviation of neuropathic pain. The authors review the published literature and present their results including those demonstrated in a randomized controlled trial that confirmed the efficacy of the procedure. Patient selection and prediction of outcomes, however, remain difficult issues.

The aim of this preliminary study was to examine the developing cognitive profiles of children with cerebellar tumours in a consecutive series of clinical patients. MRI and longitudinal intellectual profiles were obtained on seven children (two females, five males; mean age 3 years at diagnosis; mean age 7 years at first assessment). Tumours in three of the children were astrocytomas; of the remaining tumours, two were medulloblastomas, one low-grade glioma, and one ependymoma. In right-handed children, we observed an association between greater damage to right cerebellar structures and a plateauing in verbal and/or literacy skills. In contrast, greater damage to left cerebellar structures was associated with delayed or impaired non-verbal/spatial skills. Long-term cognitive development of the children studied tentatively supports a role for the cerebellum in learning/development. These findings suggest that lateralized cerebellar damage may selectively impair the development of cognitive functions subserved by the contralateral cerebral hemisphere and, in addition, that all children with cerebellar lesions in early childhood should routinely undergo long-term monitoring of their intellectual development.

PURPOSE: Visual disturbances that make it difficult to read text are often termed "visual stress". Coloured filters in spectacles may help some children overcome reading problems that are often caused by visual stress. It has been suggested that for optimal effect each child requires an individually prescribed colour for each eye, as determined in systems such as the "Harris Foundation" coloured filters. Alternatively, it has been argued that only blue or yellow filters, as used in the "Dyslexia Research Trust" (DRT) filter system, are necessary to affect the underlying physiology. METHOD: A randomised, double blind trial with 73 delayed readers, was undertaken to compare changes in reading and spelling as well as irregular and non-word reading skills after 3 months of wearing either the Harris or the DRT filters. RESULTS: Reading improved significantly after wearing either type of filter (t = -8.4, p

The accuracy of saccades directed towards the remembered positions of targets in left (LVF) or right (RVF) visual hemifield was measured. The majority of right-handed subjects were found to be more accurate at directing their gaze to locations in the LVF than in the RVF, suggessting that the right hemisphere is superior to the left in oculomotor control. Even after completion of a corrective saccade following the primary saccade, subjects systematically undershot target direction and overshot target depth, suggesting that visual feedback normally plays an important role in the fine guidance of gaze after the completion of a primary saccade.

OBJECTIVES: To compare action tremor (AT) during manual tracking in normal subjects and patients with multiple sclerosis with tremor (MS-tremor group) and without tremor (MS-no tremor group), and to differentiate tremor occurring predominantly around the distal joint from that involving the proximal joints of the arm. METHODS: Subjects performed both a visually guided ramp tracking task using wrist flexion/extension and a whole arm circle tracking task using shoulder movement. Action tremor at the wrist or shoulder was computed as the SD of the tracking velocity. The ratio of wrist:arm tremor was then calculated to differentiate distal from proximal tremor in the tested arm. Frequency spectra of the records were also examined. RESULTS: During wrist tracking, AT in patients with multiple sclerosis contained a major frequency component at 4-5 Hz; the frequency was slightly lower during whole arm tracking. The ratio of wrist:arm tremor was significantly higher in the MS-tremor group. Of 12 tested arms, eight had tremor significantly weighted towards the distal joint, only one towards the proximal joint, and three had a ratio inside the control range. CONCLUSIONS: AT in the arms of patients with multiple sclerosis can be effectively differentiated into proximal or distal using these two different tracking tasks. Despite the variability of the effects of multiple sclerosis, most of the AT was distal rather than proximal in this group of patients. Possibly conduction block along the corticocerebellocortical pathways caused this distal tremor.

The effect of stereotactic lesional surgery for the treatment of tremor in multiple sclerosis was examined in a prospective case-controlled study. Surgery was not undertaken in 33 patients (72% of 46 cases referred for stereotactic surgery), two of whom died within 4 months of referral. Twenty-four multiple sclerosis patients were included in the study; 13 underwent surgery and were matched against 11 controls on the basis of age, sex, expanded disability system scores (EDSS) and disease duration. Assessments were carried out at baseline/preoperatively, and then 3 and 12 months later; these included accelerometric and clinical ratings of tremor, spirography, handwriting, a finger-tapping test, nine-hole peg test, tremor-related disability, general neurological examination, Barthel Activities of Daily Living (ADL) Index of general disability, EDSS, a 0-4 ataxia scale, Mini-Mental State (MMS) examination, speech and swallowing assessments and grip strength. Postoperative MRI scans demonstrated that tremor could be attenuated by lesions centred on the thalamus in seven cases, on the zona incerta in five cases and in the subthalamic nucleus in one case. Two patients developed hemiparesis and in two cases epilepsy recurred. Two surgical patients and one control patient died between the 3 and 6 months assessments. Both groups had a significant deterioration in EDSS but not Barthel ADL Index scores at 1 year, but the difference between the groups was not significant. Similarly, no differences between the groups' rates of deterioration of speech or swallowing or MMS were found. Significant improvements in contralateral upper limb postural (P2) and kinetic tremors, spiral scores and head tremor were detected at 3 and 12 months after surgery (but not handwriting or nine-hole peg test performance). Tremor-related disability and finger-tapping speed were also significantly better 12 months after surgery, the latter having significantly worsened for the control group. A 3 Hz 'filter' for postural (P2) upper limb tremor was detected by accelerometry/spectral analysis above which tremor was always abolished and at or below which some residual tremor invariably remained. Criteria for selecting multiple sclerosis patients for this form of surgery are discussed.

Family and twin studies consistently demonstrate a significant role for genetic factors in the aetiology of the reading disorder dyslexia. However, dyslexia is complex at both the genetic and phenotypic levels, and currently the nature of the core deficit or deficits remains uncertain. Traditional approaches for mapping disease genes, originally developed for single-gene disorders, have limited success when there is not a simple relationship between genotype and phenotype. Recent advances in high-throughput genotyping technology and quantitative statistical methods have made a new approach to identifying genes involved in complex disorders possible. The method involves assessing the genetic similarity of many sibling pairs along the lengths of all their chromosomes and attempting to correlate this similarity with that of their phenotypic scores. We are adopting this approach in an ongoing genome-wide search for genes involved in dyslexia susceptibility, and have already successfully applied the method by replicating results from previous studies suggesting that a quantitative trait locus at 6p21.3 influences reading disability.

97 UN CO RR EC T I have known and admired David ever since he was an undergraduate at Balliol College, Oxford. I was also terrified and slightly jealous of him. He was so effortlessly, self-confidently and obviously brilliant that lesser, self-doubting, mortals such as myself were greatly in awe of him. But he was never arrogant or unpleasant, so one could not dislike him. Everyone agrees that despite his fantastic intelligence, knowledge and originality he was always charming, always smiling and always polite. In fact I’d heard of David even before he came up to Balliol because my cousin was at Kings College School, Wimbledon and warned me of this genius going to do medicine at Oxford at about the same time as I was. His father, a Methodist minister, had transferred to Wimbledon from Bolton where David had been born and attended Queen Elizabeth’s Grammar School. But I didn’t really get to know him until 1963 by which time he’d won his congratulatory First and obtained a Prize Fellowship at Magdalen College, Oxford, where Hugh Sinclair’s theory that many modern ills, from arterial disease to schizophrenia, are due to deficiency of essential fatty acids was to influence his work greatly in the future. But at that time he was working with George Gordon in the Oxford University Laboratory of Physiology, recording from nerve cells processing cutaneous sensory signals. I was then working on the control of respiration with John Widdecombe in the same laboratory and we used to discuss all sorts of things in the Common Room. Then we both went on to clinical school, he to St. Mary’s, me to St. Thomas’s, and our paths didn’t really cross again until many years later through a shared interest in neurodevelopmental problems. What attracted me enormously about David was his unflagging enthusiasm for new ideas and his fearlessly unconventional opinions on almost everything. There were a number of recurrent themes to our conversations: science as the new religion, the inability of Reductionism to solve any worthwhile problems, the shortcomings of pharmaceutical research, particularly in dealing with psychiatric disorders and the failings of peer review. In

Lesioning or chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius results in abolition of tremor in the contralateral limbs in Parkinson's disease (PD) and also in essential tremor. Recently, chronic DBS of the subthalamic nucleus has also proved to be very effective in reducing contralateral limb tremor in PD. These targets have been less effective in controlling the complex limb tremor often seen in multiple sclerosis (MS). Consequently, other targets have been sought in cases of MS with tremor. We describe a patient with MS with disabling proximal and distal involuntary arm movements in whom we were able to obtain sustained control of contralateral arm tremor and achieve functional improvement of the affected arm by chronic DBS of the region of the zona incerta. We also highlight the important role played by local field potentials recorded from the brain, with simultaneous recording of corresponding EMGs, in target localisation. © 2002 Harcourt Publishers Ltd.

Chronic deep brain stimulation (DBS) of the periventricular gray (PVG) has been used for the treatment of chronic central pain for decades. In recent years motor cortex stimulation (MCS) has largely supplanted DBS in the surgical management of intractable neuropathic pain of central origin. However, MCS provides satisfactory pain relief in about 50-75% of cases, a range comparable to that reported for DBS (none of the reports are in placebo-controlled studies and hence the further need for caution in evaluating and comparing these results). Our experience also suggests that there is still a role for DBS in the control of central pain. Here we present a series of eight consecutive cases of intractable chronic pain of central origin treated with PVG DBS with an average follow-up of 9 months. In each case, two electrodes were implanted in the PVG and the ventroposterolateral thalamic nucleus, respectively, under guidance of corneal topography/magnetic resonance imaging image fusion. The PVG was stimulated in the frequency range of 2-100 Hz in alert patients while pain was assessed using the McGill-Melzack visual analogue scale. In addition, local field potentials (FPs) were recorded from the sensory thalamus during PVG stimulation. Maximum pain relief was obtained with 5-35 Hz stimulation while 50-100 Hz made the pain worse. This suggests that pain suppression was frequency dependent. Interestingly, we detected low frequency thalamic FPs at 0.2-0.4 Hz closely associated with the pain. During 5-35 Hz PVG stimulation the amplitude of this potential was significantly reduced and this was associated with marked pain relief. At the higher frequencies (50-100 Hz), however, there was no reduction in the FPs and no pain suppression. We have found an interesting and consistent correlation between thalamic electrical activity and chronic pain. This low frequency potential may provide an objective index for quantifying chronic pain, and may hold further clues to the mechanism of action of PVG stimulation. It may be possible to use the presence of these slow FPs and the effect of trial PVG DBS on both the clinical status and the FPs to predict the probable success of future pain control in individual patients.

To study the modulated electrical potential specifically related to the electrode-brain interface (EBI) in deep brain stimulation (DBS) under physiological condition, we quantitatively identified the physiologically modulated electrode potentials by decomposing the local field potentials (LFPs) recorded from 11 patients (18 electrodes in four different brain regions) who underwent DBS, and correlated them with simultaneously recorded physiological signals of blood pressure (BP) and respiration. Results showed that electrode potentials were modulated by BP and respiration and could be detected as a specific component of the compound LFP signals with a mean (+/-S.D.) amplitude of 6.9+/-1.7 microV. The detection rate and amplitude of the modulated electrode potentials were independent from brain regions and neurological disorders. The current approach can be used to study the changes in properties of the EBI under physiological condition and to investigate the effects of the EBI on the 'crossing' current of either the neural signals to be recorded or the electrical pulses for neurostimulation.

Selection of students for places at universities mainly depends on GCSE grades and predictions of A-level grades, both of which tend to favour applicants from independent schools. We have therefore developed a new type of test that would measure candidates' 'deep learning' approach since this assesses the motivation and creative thinking that we look for in university students. We recruited 526 applicants to Oxford University and gave them a short commentary test and a learning style questionnaire. Specific deep learning approach questions correlated with results in the new test, and both predicted whether the candidate subsequently obtained a place at Oxford. Furthermore high scores on one open-ended commentary question, demanding arguments in favour of a case, produced a greater than 70% chance of obtaining a first class degree at the end of their course irrespective of the candidates' type of school attended or GCSE scores. Candidates from State schools scored as well as those from Independent schools in both tests. Thus our test seemed to index candidates' potential to succeed at a highly selective university, and might usefully be added to current selection procedures for such universities. © 2008 Springer Science+Business Media B.V.

This study aimed to find out whether preoperative diffusion tensor imaging (DTI) and probabilistic tractography could help with surgical planning for deep brain stimulation in the periaqueductal/periventricular grey area (PAG/PVG) in a patient with lower leg stump pain. A preoperative DTI was obtained from the patient, who then received DBS surgery in the PAG/PVG area with good pain relief. The postoperative MRI scan showing electrode placement was used to calculate four seed areas to represent the contacts on the Medtronic 3387® electrode. Probabilistic tractography was then performed from the pre-operative DTI image. Tracts were seen to connect to many areas within the pain network from the four different contacts. These initial findings suggest that preoperative DTI scanning and probabilistic tractography may be able to assist surgical planning in the future.

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is a novel neurosurgical therapy developed to address symptoms of gait freezing and postural instability in Parkinson's disease and related disorders. Here we summarise our non-human primate investigations of relevance to our surgical targeting of the PPN and relate the primate research to initial clinical experience of PPN DBS. © Springer-Verlag 2010.

BACKGROUND: Developmental dyslexia is a neurodevelopmental learning disability characterised by unexpectedly poor reading and unknown aetiology. One hypothesis proposes excessive platelet activating factor, a potent vasodilator, as a contributor, implying that there should be a negative association between dyslexia and high blood pressure (HBP). Since both conditions have a partial genetic basis, this association may be apparent at the familial level. AIMS: To test this prediction in dyslexic and non-dyslexic children. METHODS: Individuals and families with (HBP+) and without (HBP-) a family history of HBP were compared. RESULTS: Proportionately fewer dyslexics (49/112) than controls (11/12) were HBP+. Families with multiple, all dyslexic children were less likely to be HBP+ (7/16) than those with a non-dyslexic child (11/11). Within families, mean child scores on reading were higher in the HBP+ group (mean 44.3, SE 0.95) than in the HBP- group (mean 40.3, SE 0.87). CONCLUSION: HBP+ family history is associated with better performance on reading. The prediction of a negative association between dyslexic status and familial high blood pressure is therefore confirmed.

The mechanisms by which neural signals are encoded to produce conscious sensations remain a central question in neuroscience. Invasive recordings from human brain structures in vivo give us the opportunity to study neural correlates of these sensations. Pain is a sensation fundamental to survival and its subjective nature in the clinical setting makes it difficult to quantify. It remains without direct objective neuronal correlates. Here we describe an 8–14 Hz, spindle-shaped neural signal present in both the sensory thalamus and periaqueductal gray area (PAG) in humans that directly correlates to the subjective reporting of pain intensity. Local field potentials (LFPs) recorded by deep brain macroelectrodes reveal the ensemble activity of neuronal groups in particular brain regions.1 The oscillatory amplitude of such ensembles is proportionate to the degree of synchrony with which they oscillate.2 Properties of oscillations including their synchrony, frequency, and corresponding power spectra vary both between brain structures and dynamically, depending upon the activity performed.3 ### Methods. Twelve patients (11 male, 1 female) underwent deep brain stimulation for treatment of chronic neuropathic pain. Etiology was as follows; poststroke pain (4), phantom limb pain (3), facial pain of various causes (4), and brachial plexus injury (1). Nuclei targeted were periaqueductal gray (PAG) alone in 3 patients, ventroposterolateral/medial nucleus of the thalamus (VPL/VPM) in 6 patients, and both in 3 patients. This was decided upon based on clinical grounds (in general, sensory thalamus was avoided if the patient had had a thalamic stroke). Three patients …

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common surgical therapy for Parkinson' s disease (PD). DBS of the pedunculopontine nucleus (PPN) is emerging as a promising surgical therapy for PD as well. In order to better characterize these nuclei in humans, we determined the anatomical connections of the PPN and STN and the topography of these connections using probabilistic diffusion tractography. Diffusion tractography was carried out in eight healthy adult subjects using diffusion data acquired at 1.5 T MRI (60 directions, b=1000 s/mm(2), 2 x 2 x 2 mm(3) voxels). The major connections that we identified from single seed voxels within STN or PPN were present in at least half the subjects and the topography of these connections within a 36-voxel region surrounding the initial seed voxel was then examined. Both the PPN and STN showed connections with the cortex, basal ganglia, cerebellum, and down the spinal cord, largely matching connections demonstrated in primates. The topography of motor and associative brain areas in the human STN was strikingly similar to that shown in animals. PPN Topography has not been extensively demonstrated in animals, but we showed significant topography of cortical and subcortical connections in the human PPN. In addition to demonstrating the usefulness of PDT in determining the connections and topography of small grey matter structures in vivo, these results allow for inference of optimal DBS target locations and add to our understanding of the role of these nuclei in PD.

There is growing evidence to support the use of motor cortex stimulation (MCS) in the management of patients with chronic neuropathic pain. A prospective audit of ten patients using a modified staged technique for motor cortex implantation provides further evidence for the analgesic effectiveness of this technique. Ten patients suffering from phantom limb pain (n=3), post stroke pain (n=5), post traumatic neuralgia secondary to gunshot injury to the brain stem (n=1) and brachyalgia secondary to neuro-fibromatosis (n=150% pain relief) and long-term benefit in 4/5 of patients who initially responded to intermittent cortical stimulation (longest follow up 31 months after implantation). Of those patients who benefited two had post stroke pain, two phantom limb pain and one post-traumatic neuralgia. We conclude that motor cortex stimulation is an effective analgesic intervention in some patients with chronic neuropathic pain, but it is difficult if not impossible to predict those patients who may respond to treatment prior to implantation. Randomised controlled trials are now urgently needed to test the effectiveness of motor cortex stimulation under double-blind conditions.

Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P > 0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P < 0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

There is now much evidence that the visual magnocellular system in many dyslexics is slightly less sensitive than in controls. We were surprised therefore by the conclusion of Amitay et al . (2002) that the dyslexics in their study did not suffer from a magnocellular visual deficit, when actually their results seem to provide quite strong evidence that their dyslexics did have such a deficit. Their opposite conclusion seems to have resulted from their strong assumptions about how M impairments should be manifested in a dyslexic population and from the way in which they scaled dyslexic performance. They assume that a magnocellular deficit should produce a totally consistent pattern of results across a variety of different tasks designed to assess magnocellular functioning, and that any variability implies that no magnocellular deficit exists. This is unwarranted because a mild magnocellular deficit could be obscured by measurement ‘noise’ which may lead to inconsistent performance. We can estimate from their table 2 the power of their study to detect differences (Amitay et al ., …

Practice makes perfect, but the neural substrates of trial-to-trial learning in motor tasks remain unclear. There is some evidence that the basal ganglia process feedback-related information to modify learning in essentially cognitive tasks 1, 2, 3 and 4, but the evidence that these key motor structures are involved in offline feedback-related improvement of performance in motor tasks is paradoxically limited. Lesion studies in adult zebra finches suggest that the avian basal ganglia are involved in the transmission or production of an error signal during song 5, 6 and 7. However, patients with Huntington's disease, in which there is prominent basal ganglia dysfunction, are not impaired in error-dependent modulation of future trial performance [8]. By directly recording from the subthalamic nucleus in patients with Parkinson's disease, we demonstrate that this nucleus processes error in trial performance at short latency. Local evoked activity is greatest in response to smallest errors and influences the programming of subsequent movements. Accordingly, motor parameters are least likely to change after the greatest evoked responses so that accurately performed trials tend to precede other accurate trials. This relationship is disrupted by electrical stimulation of the nucleus at high frequency. Thus, the human subthalamic nucleus is involved in feedback-based learning.