John Frederick Stein

University of Oxford | OX · Department of Physiology, Anatomy and Genetics

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or lan...

Worldwide, the majority of people prefer using the right hand for most motor tasks. Because of the link between handedness and language hemispheric dominance, handedness has been studied for association with language-related disorders. No clear pattern has emerged from these studies, and inconsistencies have been attributed to small sample sizes, p...

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were...

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 in...

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...

Reading and writing are crucial for many aspects of modern life but up to 1 in 10 children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet no convincing genetic markers have been found due to limited study power. Here, we present a genome-wide association study representing...

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...

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...

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, rapi...

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. Exp...

Deep brain stimulation has already revolutionised the clinical management of treatment-resistant movement disorders and offers novel treatment options for an increasing range of neurological and psychiatric illnesses. In this article, we briefly review the history of deep brain stimulation, particularly focusing on the last 50 years, which have see...

Prof. John Stein, Magdalen College, Oxford, explores how dyslexia works and explains why the condition might be a profound positive when it comes to designing software.

The late 19th neurological concept of dyslexia had 3 crucial elements: selectively poor reading, with unaffected other cognitive skills and a genetic background. The contemporary ‘phonological theory’ has undermined the selectivity criterion because all poor readers, dyslexic or otherwise, have phonological problems. Here I argue that the phonologi...

This is my response to the critique by Blythe et al. of my review ‘What is Developmental Dyslexia?’. In this response, I provide greater detail about the evidence supporting the view that faulty eye movement control can cause dyslexics’ visual reading difficulties and that impaired development of the visual magnocellular system may be the underlyin...

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 readin...

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 characterized by poor temporal processing, hence impaired visual and auditory sequenci...

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...

Dyslexia is a specific impairment in learning to read and has strong heritability. An intronic deletion within the DCDC2 gene, with ~8% frequency in European populations, is increasingly used as a marker for dyslexia in neuroimaging and behavioral studies. At a mechanistic level, this deletion has been proposed to influence sensory processing capac...

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...

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....

Background: Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5-10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association sp...

The security of medical devices is critical to good patient care, especially when the devices are implanted. In light of recent developments in information security, there is reason to be concerned that medical implants are vulnerable to attack. The ability of attackers to exert malicious control over brain implants ("brainjacking") has unique chal...

Background: Multiple oscillations emerging from the same neuronal substrate serve to construct a local oscillatory network. The network usually exhibits complex behaviors of rhythmic, balancing and coupling between the oscillations, and the quantification of these behaviors would provide valuable insight into organization of the local network rela...

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P< 0.5x10−8) 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 biolog...

Background: Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a new treatment for alleviating intractable neuropathic pain. However, it fails to help some patients. The large size of the ACC and the intersubject variability make it difficult to determine the optimal site to position DBS electrodes. The aim of this work was the...

Nutrient deficiencies have been implicated in anti-social behaviour in schoolchildren; hence, correcting them may improve sociability. We therefore tested the effects of vitamin, mineral and n-3 supplementation on behaviour in a 12-week double-blind randomised placebo-controlled trial in typically developing UK adolescents aged 13-16 years (n 196)....

A disturbance of body representation is central to many neurological and psychiatric conditions, but the mechanisms by which body representations are constructed by the brain are not fully understood. We demonstrate a directional disturbance in tactile identification of the toes in healthy humans. Nineteen young adult participants underwent tactile...

Correlating electrical activity within the human brain to movement is essential for developing and refining interventions (e.g. deep brain stimulation (DBS)) to treat central nervous system disorders. It also serves as a basis for next generation brain-machine interfaces (BMIs). This study highlights a new decoding strategy for capturing movement a...

A functioning thalamus is essential for treatment of patients with disorders of consciousness (DOC) using deep brain stimulation (DBS). This work aims to identify the potential biomarkers related to consciousness from the thalamic deep brain local field potentials (LFPs) in DOC patients. The frequency features of central thalamic LFPs were characte...

Background: Meares Irlen Syndrome (MIS), otherwise known as "visual stress", is one condition that can cause difficulties with reading. Aim: This study aimed to compare the effect of two coloured-filter systems on the symptoms of visual stress in children with reading delay. Methods: The study design was a pre-test, post-test, randomized head-...

Nonlinear interaction between neural oscillations may be a biomarker for closed-loop deep brain stimulation (DBS) in Parkinson's disease. Bispectral analysis is an effective tool to detect quadratic phase coupling. In this paper we applied bispectral analysis to local field potentials (LFPs) recorded from Parkinsonism patients' subthalamic nucleus...

Dyslexia is more than just difficulty with translating letters into sounds. Many dyslexics have problems with clearly seeing letters and their order. These difficulties may be caused by abnormal development of their visual “magnocellular” (M) nerve cells; these mediate the ability to rapidly identify letters and their order because they control vis...

Appendix S1: QQ plots and association plots of the top association signals from analysis based on PC1 and IQ-adjusted PC1. Contribution of each dataset to the strength of the association in the PC1 and IQ-adjusted PC1 meta-analysis, for the top association signals.

Appendix S2: SNP-, gene- and pathway-based meta-analysis results from analysis based on PC1 and IQ-adjusted PC1. Test for independent associations within the top associated regions, after conditioning on the most significant local association signal.

Appendix S3: Analyses based on PC1read and IQ-adjusted PC1read (trait loadings on PC1read, Manhattan plots, QQ plots and top associations)

Appendix S4: Genotype calls and QC protocols; correlation patterns of reading and language measures; statistical analyses, commands and parameters.

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a Genome-wide Association Scan (GWAS) meta-analysis using three richly characterised datasets comprising individuals with histories of reading or la...

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. Thi...

We would like to take this opportunity to comment on the recent article by Brasky et al. (1). This study is a case–control study, measuring only associations rather than cause and effect, and it uses inappropriate measures of dietary exposure to omega-3 fatty acids, which show very low consumption levels overall. The abstract concludes by stating,...

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 thi...

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 investiga...

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...

Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia. Genome-wide single nucleotide polymorphis...

Figure S1: Causative mechanisms of the sex chromosome aneuploidies.

Dyslexia is one of the most common childhood disorders with a prevalence of around 5-10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, inclu...

Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728...

In this fMRI study, we examined the cerebral processing associated with second language (L2) reading in different writing systems in late L2 learners. To examine the impacts of cross-linguistic differences between the first language (L1) and L2 on learning to read in L2, we employed a bidirectional approach and compared brain activation during sing...

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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...

Omega 3 fatty acid deficiency is implicated in antisocial behavior; hence correcting deficiencies may improve behavior. The effect of nutrient supplementation was tested in typically developing school children. Pupils (n=196) consumed randomly assigned placebo or active supplements containing omega 3s, vitamins and minerals over 12 week terms. Beha...

The trend of current brain computer interfaces (BCI) seek to establish bi-directional communication with the brain, for instance, recovering motor functions by externally controlling devices and directly stimulating the brain. This will greatly assist paralyzed individuals through bypassing the damaged brain region. The key process of this communic...

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of...

Developmental dyslexia is usually considered to result from a high level cognitive/linguistic deficit. But it is possible that the phonological difficulties that most display may in part be due to impaired auditory perception. This study investigates the ability of adult dyslexics, screened for normal hearing sensitivity, to perform a non-speech au...

Background: The midbrain periaqueductal and periventricular gray (PAVG) region is important for pain and autonomic modulation. We have previously described changes in blood pressure dependent upon dorsal or ventral electrode positioning with PAVG deep brain stimulation (DBS), yet controversy exists about whether DBS acts via endogenous opioid rele...

Background / Purpose: Of the 10% of children who find it unexpectedly difficult to learn to read fluently despite normal intelligence, health and education (developmental dyslexia), many have impaired development of visual magnocellular neurons. This impairs their ability to visually process letters properly. Magnocellular neurons are responsible...

About half of all children with reading problems complain that words and letters appear to blur and move around. This failure to achieve visual stability is probably due to impaired development of visual magnocellular (M-) neurones, which are responsible for the rapid and accurate direction of visual attention and binocular fixation. Although dispu...

: Pain perception can be altered, and it is believed that the periaqueductal gray (PAG) plays an important role in the modulation via the descending pain pathway, exerting the effect on the spinal dorsal horn. However, with findings indicating that the PAG has upward projections to the thalamus, it is reasonable to hypothesize that the PAG can also...

Developmental dyslexia is a genetically based neurobiological syndrome, which is characterized by reading difficulty despite normal or high general intelligence. Even remediated dyslexic readers rarely achieve fast, fluent reading. Some dyslexics also have impairments in attention, short-term memory, sequencing (letters, word sounds, and motor acts...

This paper explores the development of multi-feature classification techniques used to identify tremor-related characteristics in the Parkinsonian patient. Local field potentials were recorded from the subthalamic nucleus and the globus pallidus internus of eight Parkinsonian patients through the implanted electrodes of a Deep brain stimulation (DB...

DefinitionGeneticsReading ModelsM-System, Eye Movements, and ReadingEye FixationLetter OrderVergence ControlThe Visual Magnocellular System in Dyslexics – RetinaLGNVisual CortexV5/MTHigher Visual AreasRemediation of Visual ProblemsAuditory/Phonological Processing?Auditory M-System?CerebellumA General Temporal Processing M-System?The Reading Network...

Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity ind...

A major thrust in brain machine interface (BMI) is to establish a robust, bi-directional direct link between the central nervous system (CNS) and artificial devices (e.g. medical implants, artificial organs, neural stimulators, robotic hands, etc.) for cybernetic interface and treatment of a range of neurodegenerative conditions. Significant effort...

Dyslexia affects about 10% of all children and is a potent cause of loss of self-confidence, personal and family misery, and waste of potential. Although the dominant view is that it is caused by specifically linguistic/phonological weakness, recent research within the field of neuroscience has shown that it is associated with visual processing pro...

Targeting of the motor thalamus for the treatment of tremor has traditionally been achieved by a combination of anatomical atlases and neuroimaging, intraoperative clinical assessment, and physiological recordings. To evaluate whether thalamic nuclei targeted in tremor surgery could be identified by virtue of their differing connections with noninv...