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Reciprocal interactions between the human thalamus and periaqueductal gray may be important for pain perception.
Pain perception can be altered by activity in the periaqueductal gray (PAG). The PAG can decrease the incoming nociceptive signals at the level of the spinal dorsal horn, but it is not clear whether the PAG can also affect the sensory thalamus, ventral posterolateral and ventral posteromedial thalamic nuclei, to modulate pain. However, the PAG and the thalamus have direct connections with each other; so we postulated that the PAG may also modulate pain by inhibiting the sensory nuclei in the thalamus, and that these may also reciprocally influence the PAG. Here, by analyzing the local field potentials recorded from the sensory thalamus and the PAG in chronic pain patients with deep brain stimulation electrodes, we show that PAG stimulation inhibited the sensory thalamus with decreasing thalamic delta, theta, alpha and beta power, and sensory thalamus stimulation excited the PAG with increasing PAG delta and theta power. We demonstrate that the PAG and the sensory thalamus interact reciprocally at short latency, which may be related to pain modulation.
A cross-linguistic evaluation of script-specific effects on fMRI lateralization in late second language readers.
Behavioral and neuroimaging studies have provided evidence that reading is strongly left lateralized, and the degree of this pattern of functional lateralization can be indicative of reading competence. However, it remains unclear whether functional lateralization differs between the first (L1) and second (L2) languages in bilingual L2 readers. This question is particularly important when the particular script, or orthography, learned by the L2 readers is markedly different from their L1 script. In this study, we quantified functional lateralization in brain regions involved in visual word recognition for participants' L1 and L2 scripts, with a particular focus on the effects of L1-L2 script differences in the visual complexity and orthographic depth of the script. Two different groups of late L2 learners participated in an fMRI experiment using a visual one-back matching task: L1 readers of Japanese who learnt to read alphabetic English and L1 readers of English who learnt to read both Japanese syllabic Kana and logographic Kanji. The results showed weaker leftward lateralization in the posterior lateral occipital complex (pLOC) for logographic Kanji compared with syllabic and alphabetic scripts in both L1 and L2 readers of Kanji. When both L1 and L2 scripts were non-logographic, where symbols are mapped onto sounds, functional lateralization did not significantly differ between L1 and L2 scripts in any region, in any group. Our findings indicate that weaker leftward lateralization for logographic reading reflects greater requirement of the right hemisphere for processing visually complex logographic Kanji symbols, irrespective of whether Kanji is the readers' L1 or L2, rather than characterizing additional cognitive efforts of L2 readers. Finally, brain-behavior analysis revealed that functional lateralization for L2 visual word processing predicted L2 reading competency.
Multisensory integration and attention in developmental dyslexia
Summary Developmental dyslexia affects 5%-10% of the population [1], resulting in poor spelling and reading skills. While there are well-documented differences in the way dyslexics process low-level visual [2, 3] and auditory [4, 5] stimuli, it is mostly unknown whether there are similar differences in audiovisual multisensory processes. Here, we investigated audiovisual integration using the redundant target effect (RTE) paradigm. Some conditions demonstrating audiovisual integration appear to depend upon magnocellular pathways [6], and dyslexia has been associated with deficits in this pathway [7]; so, we postulated that developmental dyslexics ("dyslexics" hereafter) would show differences in audiovisual integration compared with controls. Reaction times (RTs) to multisensory stimuli were compared with predictions from Miller's race model [8, 9]. Dyslexics showed difficulty shifting their attention between modalities; but such "sluggish attention shifting" (SAS) [10] appeared only when dyslexics shifted their attention from the visual to the auditory modality. These results suggest that dyslexics distribute their crossmodal attention resources differently from controls, causing different patterns in multisensory responses compared to controls. From this, we propose that dyslexia training programs should take into account the asymmetric shifts of crossmodal attention. © 2014 Elsevier Ltd.
Multisensory integration and attention in developmental dyslexia.
Developmental dyslexia affects 5%-10% of the population, resulting in poor spelling and reading skills. While there are well-documented differences in the way dyslexics process low-level visual and auditory stimuli, it is mostly unknown whether there are similar differences in audiovisual multisensory processes. Here, we investigated audiovisual integration using the redundant target effect (RTE) paradigm. Some conditions demonstrating audiovisual integration appear to depend upon magnocellular pathways, and dyslexia has been associated with deficits in this pathway; so, we postulated that developmental dyslexics ("dyslexics" hereafter) would show differences in audiovisual integration compared with controls. Reaction times (RTs) to multisensory stimuli were compared with predictions from Miller's race model. Dyslexics showed difficulty shifting their attention between modalities; but such "sluggish attention shifting" (SAS) appeared only when dyslexics shifted their attention from the visual to the auditory modality. These results suggest that dyslexics distribute their crossmodal attention resources differently from controls, causing different patterns in multisensory responses compared to controls. From this, we propose that dyslexia training programs should take into account the asymmetric shifts of crossmodal attention.
Application of a null-beamformer to source localisation in MEG data of deep brain stimulation.
In this paper, we present an analysis of magnetoencephalography (MEG) signals from a patient with whole-body chronic pain in order to investigate changes in neural activity induced by DBS. The patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). Using MEG to reconstruct the neural activity of interest is challenging because of interference to the signal from the DBS device. We demonstrate that a null-beamformer can be used to localise neural activity despite artefacts caused by the presence of DBS electrodes and stimulus pulses. We subsequently verified the accuracy of our source localisation by correlating the predicted DBS electrode positions with their actual positions, previously identified using anatomical imaging. We also demonstrated increased activity in pain-related regions including the pre-supplementary motor area, brainstem periaqueductal gray and medial prefrontal areas when the patient was in pain compared to when the patient experienced pain relief.
Resting tremor classification and detection in Parkinson's disease patients
© 2014 Elsevier Ltd. All rights reserved. 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.
Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia.
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 < 1 × 10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10-8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10-8) and with all the cognitive traits tested (p = 3.07 × 10-8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-5-10-7]) and negatively associated with ADHD PRS (p ~ [10-8-10-17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
Advances in Dyslexia Genetics-New Insights Into the Role of Brain Asymmetries.
Dyslexia is a common condition affecting up to 10% school-aged children. There is strong evidence that genetics plays an important role in dyslexia and is expected to be complex in nature. Few specific susceptibility factors have been identified so far, but their functional characterization has provided novel insights into the biology of dyslexia. In particular, they point to an unexpected role of candidate genes for dyslexia in the biology of cilia, cellular organelles required in many processes including the establishment of left-right asymmetries early in development. This observation has brought back into the spotlight the old idea of a link between dyslexia and handedness. Yet much of the genetics contributing to dyslexia remains unexplained. The lack of biological markers, clear diagnostic criteria, and homogeneous assessment strategies are just some of the factors preventing the collection of the cohorts powered enough for large-scale genetic studies. While the technology and methods to generate and handle large-scale data have reached unprecedented potential, the main challenge remains in establishing universal guidelines to collect suitable phenotype information across independent studies. These difficulties reflect the complex nature of dyslexia which is highly heterogeneous and often co-occurs with other neurodevelopmental disorders.
Discovery and replication of gene influences on brain structure using LASSO regression
We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2.We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8±2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain. © 2012 Kohannim, Hibar, Stein, Jahanshad, Hua, Rajagopalan, Toga, Jack, Weiner, de Zubicaray, McMahon, Hansell, Martin, Wright, Thompson.
Voxelwise genome-wide association study (vGWAS).
The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age+/-s.d.: 75.52+/-6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure.
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.
The Reading Networks and Dyslexia
This chapter provides an overview of the reading networks and their implications for our understanding of developmental dyslexia. In particular, it focuses on the sublexical lettersound conversion and the lexical direct visual-semantic routes for reading that rely greatly on accurate visual input. It proposes that the visual magnocellular system is crucial for this processing.
Magnocellular Based Visual Motion Training Improves Reading in Persian.
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.
Identifying rhythms of subthalamic neural oscillations in time-frequency domain.
We aimed to identify neural oscillations in the time-frequency representation of local field potentials recorded from the subthalamic nucleus. The time-frequency representation was normalised over the global mean and standard deviation global normalisation, or against the baseline period at each frequency, local normalisation. The cross-correlation between beta and gamma oscillations was enhanced by global normalisation. Furthermore, voluntary movement related amplitude changes in the gamma band and frequency modulation in the beta band were revealed by local normalisation. Thus global or local normalisation of time-frequency representation provides a reliable and effective way to identify oscillatory rhythms in subthalamic neural activity by reducing noise and increasing frequency discrimination. It can be used to enhance the detection of obscure or hidden neural oscillations and improve the sensitivity of post-hoc analysis.
What is Developmental Dyslexia?
Until the 1950s, developmental dyslexia was defined as a hereditary visual disability, selectively affecting reading without compromising oral or non-verbal reasoning skills. This changed radically after the development of the phonological theory of dyslexia; this not only ruled out any role for visual processing in its aetiology, but it also cast doubt on the use of discrepancy between reading and reasoning skills as a criterion for diagnosing it. Here I argue that this theory is set at too high a cognitive level to be explanatory; we need to understand the pathophysiological visual and auditory mechanisms that cause children's phonological problems. I discuss how the 'magnocellular theory' attempts to do this in terms of slowed and error prone temporal processing which leads to dyslexics' defective visual and auditory sequencing when attempting to read. I attempt to deal with the criticisms of this theory and show how it leads to a number of successful ways of helping dyslexic children to overcome their reading difficulties.
The current status of the magnocellular theory of developmental dyslexia.
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.
The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.
We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.