Could platelet activating factor play a role in developmental dyslexia?

Post-mortem studies by Galaburda and colleagues on the brains of developmental dyslexics found characteristic neuronal abnormalities: ectopias, microgyria, and fewer large-soma cells in sensory thalamus. An association between dyslexia and immune dysfunction has also been proposed. We describe a mechanism which may explain these observations. Platelet-activating factor (PAF) is a pro-inflammatory lipid implicated in neurological disorders. We propose that PAF may also be involved in dyslexia.     

The topical niacin sensitivity test: an inter- and intra-rater reliability study in healthy controls

Topical application of nicotinic acid results in erythema, and in some cases oedema of the skin, supporting a strong relationship between niacin sensitivity and prostaglandin D2. The aim of this study was to examine the inter-rater and intra-rater reliability of a 12-min niacin sensitivity test in healthy adults. Three raters assessed the skin reaction of 12 volunteers, over 3-min intervals across four niacin concentrations (0.1, 0.01, 0.001, and 0.0001), and over six sessions. Inter-rater reliability estimates ranged from 0.85 to 0.97 for the total niacin sensitivity score. Similar inter-rater reliability estimates were found for niacin sensitivity ratings by concentration and time. Intra-rater reliability estimates ranged from 0.63 to 0.93 for the total niacin sensitivity score. These data indicate that the 12-min topical niacin sensitivity test has excellent reliability.     

Increased levels of cytosolic phospholipase A2 in dyslexics

Research findings are increasingly reporting evidence of physiological abnormalities in dyslexia and sites for dyslexia have been identified on three chromosomes. It has been suggested that genetic inheritance may cause phospholipid abnormalities in dyslexia somewhat similar to those found in schizophrenia. A key enzyme in phospholipid metabolism, Type IV, or cytosolic, phospholipase A2 (cPLA2), releases arachidonic acid (AA), a 20-carbon fatty acid, which is the major source of production of prostaglandins and leukotrienes. An entirely new assay, which for the first time has enabled determination of the amount of the enzyme rather than its activity, was used to measure cPLA2 in dyslexic-type adults and controls and the two groups were found to differ significantly, the dyslexic-types having more of the enzyme. A report elsewhere of schizophrenics having even greater amounts of the enzyme suggests that dyslexia may be on a continuum with schizophrenia, as may be other neurodevelopmental disorders - which have also been described as phospholipid spectrum disorders.     

Niacin skin-flush response and electrodermal activity in patients with schizophrenia and healthy controls

Patients with schizophrenia have in different studies shown reduced niacin sensitivity and lower electrodermal activity (EDA) after auditory stimulation. Peripheral mediation of prostaglandins may have a physiological role in both responses. This motivates study of both niacin response and electrodermal responding in the same patients with schizophrenia. Thirty patients with schizophrenia and 17 controls were investigated with EDA and thereafter given 200mg niacin orally with continuous assessment of skin temperature. The patients showed a delayed temperature increase after niacin ingestion (P=0.002) and a higher frequency of electrodermal non-responding (P<0.05). Response/non-response for niacin correlated with EDA response/non-response in the patient group (P=0.009). The niacin test revealed a slower vasodilation reaction in the patients. The association between response patterns for the niacin test and EDA suggests that a common aberration in skin physiology may be of importance for both reactions in schizophrenia.     

The impact of PLA2G4A and PTGS2 gene polymorphisms,and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients

We investigated the etiology of the attenuated niacin skin flush response in schizophrenia patients. Skin response to topical niacin of 0.1 M, 0.01 M, 0.001 M, and 0.0001 M concentrations was rated using method of volumetric niacin response (VNR) and correlated to two functional A/G polymorphisms in genes: phospholipase A2 group IVA (BanI of the PLA2G4A), and rs689466 of the prostaglandin synthase-2 (PTGS2). We further tested the possible correlation between niacin response and fatty acid (FA) content of red blood cells (RBCs). We detected statistically significant but weak impact of both polymorphisms on niacin flush response in schizophrenia patients. The dosage of the G alleles of both polymorphisms was associated with higher VNR values, although each polymorphic variant accounted for only 1% of the overall flush response variability. Regarding FA content, both n?3 and n?6 polyunsaturated FAs (PUFAs) were significantly reduced in the patient group, but an association with niacin sensitivity was not detected.     

Visual function, fatty acids and dyslexia

There is mounting evidence that developmental dyslexia is a neurodevelopmental disorder which involves abnormalities of fatty acid metabolism, particularly with respect to certain long-chain highly unsaturated fatty acids (HUFAs). Psychophysical evidence also strongly suggests that dyslexics may have visual deficits as well as phonological problems. Specifically, these visual deficits appear to be related to the magnocellular pathway, which is specialized for processing fast, rapidly-changing information about the visual scene. It remains unclear how these two aspects of dyslexia - fatty acid processing and visual magnocellular function - could be related. We propose some hypotheses - necessarily speculative, given the paucity of biochemical research in this field to date - which address this question.     

Impaired niacin sensitivity in acute first-episode but not in multi-episode schizophrenia

Niacin (vitamin B3) flushing--a marker of altered prostaglandin signaling--is indirectly linked to the phospholipid-prostaglandin metabolism. Diminished skin flushing was repeatedly found in schizophrenia, but has not been systematically investigated at different stages of disorder as yet. We compared niacin sensitivity of 32 first-episode and 32 multi-episode patients (mainly on stable medication) with age and gender matched healthy controls. Methylnicotinate was applied in three concentrations onto the inner forearm skin. Flush response was assessed in 3 min intervals over 15 min using optical reflection spectroscopy. Whereas first-episode patients showed significantly diminished flush response as compared to controls, comparable differences were not found between multi-episode patients and controls. Comparison of niacin sensitivity at different stages of schizophrenia support the notion of altered prostaglandin signaling primarily at the onset of disorder. Longitudinal studies have to rule out possible long-term effects of neuroleptic medication.     

Reading text increases binocular disparity in dyslexic children

Children with developmental dyslexia show reading impairment compared to their peers, despite being matched on IQ, socio-economic background, and educational opportunities. The neurological and cognitive basis of dyslexia remains a highly debated topic. Proponents of the magnocellular theory, which postulates abnormalities in the M-stream of the visual pathway cause developmental dyslexia, claim that children with dyslexia have deficient binocular coordination, and this is the underlying cause of developmental dyslexia. We measured binocular coordination during reading and a non-linguistic scanning task in three participant groups: adults, typically developing children, and children with dyslexia. A significant increase in fixation disparity was observed for dyslexic children solely when reading. Our study casts serious doubts on the claims of the magnocellular theory. The exclusivity of increased fixation disparity in dyslexics during reading might be a result of the allocation of inadequate attentional and/or cognitive resources to the reading process, or suboptimal linguistic processing per se.     

Developmental dyslexia is characterized by the co-existence of visuospatial and phonological disorders in Chinese children

Developmental dyslexia is a neurological condition that is characterized by severe impairment in reading skill acquisition in people with adequate intelligence and typical schooling [1], [2] and [3]. For English readers, reading impairment is critically associated with a phonological processing disorder [3], [4] and [5], which may co-occur with an orthographic (visual word form) processing deficit [6], but not with a general visual processing dysfunction in most dyslexics [7]. The pathophysiology of dyslexia varies across languages [8]: for instance, unlike English, written Chinese maps visually intricate graphic forms (characters) onto meanings; pronunciation of Chinese characters must be rote memorized. This suggests that, in Chinese, a fine-grained visuospatial analysis must be performed to activate characters' phonology and meaning; consequently, disordered phonological processing may commonly co-exist with abnormal visuospatial processing in Chinese dyslexia. To test this hypothesis, we conducted an fMRI experiment in which 12 Chinese dyslexics, shown previously [9] to exhibit a phonological disorder, performed a physical size judgment measuring visuospatial dimensions. Compared with 12 control subjects, the dyslexics showed weaker activations in left intraparietal sulcus (IPS) mediating visuospatial processing. Analyses of individual dyslexics' performances further suggest that developmental dyslexia in Chinese is commonly associated with the co-existence of a visuospatial deficit and a phonological disorder.     

Brain mechanisms in normal and dyslexic readers

Developmental dyslexics, individuals with an unexplained difficulty reading, have been shown to have deficits in phonological processing -- the awareness of the sound structure of words -- and, in some cases, a more fundamental deficit in rapid auditory processing. In addition, dyslexics show a disruption in white matter connectivity between posterior and frontal regions. These results give continued support for a neurobiological etiology of developmental dyslexia. However, more research will be required to determine the possible causal relationships between these neurobiological disruptions and dyslexia.     

Dyslexia in adults is associated with clinical signs of fatty acid deficiency

Developmental dyslexia is a complex syndrome whose exact cause remains unknown. It has been suggested that a problem with fatty acid metabolism may play a role, particularly in relation to the visual symptoms exhibited by many dyslexics. We explored this possibility using two self-report questionnaires, designed on the basis of clinical experience, to assess (1) clinical signs of fatty acid deficiency; and (2) symptoms associated with dyslexia in known dyslexic and non-dyslexic subjects. Dyslexic signs and symptoms included the auditory-linguistic and spoken language difficulties traditionally associated with the disorder, as well as visual problems (both with reading and more generally) and motor problems. Fatty acid deficiency signs were significantly elevated in dyslexic subjects relative to controls, particularly within males (P<0.001). In addition, the severity of these clinical signs of fatty acid deficiency was strongly correlated with the severity of dyslexic signs and symptoms not only in the visual domain, but also with respect to auditory, linguistic and motor problems. The pattern of relationships differed somewhat between dyslexic and control groups, and sex differences were also observed. Our findings support the hypothesis that fatty acid metabolism may be abnormal in developmental dyslexia, and indicate the need for further studies using more objective measures.     

Relationship between the niacin skin flush response and essential fatty acids in schizophrenia

The skin flush response to niacin is selectively mediated by the release of vasodilatory prostaglandins from the skin. The normal skin flush response to niacin is attenuated in many individuals with schizophrenia (SCZ). This finding suggests abnormal prostaglandin signaling in SCZ. Since prostaglandins are derived from arachidonic acid (AA), the finding of an abnormal skin flush response is consistent with biochemical data suggesting relative depletion of AA, and other essential fatty acids (EFAs), in a substantial portion of people with SCZ. This paper will describe the mechanism of the skin flush response to niacin, and will review evidence that the response to niacin is abnormal in SCZ, that this abnormality is not related to psychotropic medications, and that it may be a marker of the EFA deficiency which has been documented to be present in many patients with SCZ.     

Effects of niacin supplementation and dietary concentrate proportion on body temperature,ruminal pH and milk performance of primiparous dairy cows

The objective of this study was to investigate the effects of niacin and dietary concentrate proportion on body temperature, ruminal pH and milk production of dairy cows. In a 2 × 2 factorial design, 20 primiparous Holstein cows (179 ± 12 days in milk) were assigned to four dietary treatments aimed to receive either 0 or 24 g niacin and 30% (low) or 60% (high) concentrate with the rest being a partial mixed ration (PMR) composed of 60% corn and 40% grass silage (on dry matter basis). Ambient temperature and relative humidity were determined and combined by the calculation of temperature humidity index. Respiration rates, rectal, skin and subcutaneous temperatures were measured. Milk production and composition were determined. Ruminal pH and temperature were recorded at a frequency of 5 min using wireless devices for continuous intra-ruminal measurement (boluses). pH values were corrected for pH sensor drift. The climatic conditions varied considerably but temporarily indicated mild heat stress. Niacin did not affect skin, rectal and subcutaneous temperatures but tended to increase respiration rates. High concentrate reduced skin temperatures at rump, thigh and neck by 0.1–0.3°C. Due to the technical disturbances, not all bolus data could be subjected to statistical evaluation. However, both niacin and high concentrate influenced mean ruminal pH. High concentrate increased the time spent with a pH below 5.6 and ruminal temperatures (0.2–0.3°C). Niacin and high concentrate enhanced milk, protein and lactose yield but reduced milk fat and protein content. Milk fat yield was slightly reduced by high concentrate but increased due to niacin supplementation. In conclusion, niacin did not affect body temperature but stimulated milk performance. High concentrate partially influenced body temperatures and had beneficial effects on milk production.     

Palmar dermatoglyphics of dyslexia

Palmar dermatoglyphic prints were taken of 261 dyslexics (173 males and 88 females) and compared against those of 707 controls (372 males and 335 females). Dyslexics of both sexes were found to exhibit greater complexity in terms of ridge count and pattern location than controls, particularly on the left hand. Specifically, both male and female dyslexics exhibited higher left a-b counts, wider atd angles on both palms, and higher frequencies of pattern in left interdigital area IV. Additionally, male dyslexics also had higher right a-b counts and greater frequency of pattern in the left hypothenar area. Dyslexics of both sexes were also found to have more distally located axial triradii, and investigation of bilateral asymmetry found dyslexics to exhibit more directional asymmetry than controls in the variable of a-b count, with the left value for both groups being greater than the right. It was concluded that the study evidenced strong support for the hypothesis that some causative factor relating to the development of dyslexia is operating during the time period in which dermatoglyphic features are formed. The relevance of these findings in terms of the Geschwind hypothesis and the possible importance of prenatal testosterone are discussed.     

Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results

It has been hypothesised that polyunsaturated fatty acids (PUFA) play an important role in the aetiology of schizophrenia and depression. Evidence supporting this hypothesis for schizophrenia includes abnormal brain phospholipid turnover shown by 31P Magnetic Resonance Spectroscopy, increased levels of phospholipase A2, reduced niacin skin flush response, abnormal electroretinogram, and reduced cell membrane levels of n-3 and n-6 PUFA. In depression, there is strong epidemiological evidence that fish consumption reduces risk of becoming depressed and evidence that cell membrane levels of n-3 PUFA are reduced. Four out of five placebo-controlled double- blind trials of eicosapentaenoic acid (EPA) in the treatment of schizophrenia have given positive findings. In depression, two placebo-controlled trials have shown a strong therapeutic effect of ethyl-EPA added to existing medication. The mode of action of EPA is currently not known, but recent evidence suggests that arachidonic acid (AA) if of particular importance in schizophrenia and that clinical improvement in schizophrenic patients using EPA treatment correlates with changes in AA.     

A Common Left Occipito-Temporal Dysfunction in Developmental Dyslexia and Acquired Letter-By-Letter Reading?

Background

We used fMRI to examine functional brain abnormalities of German-speaking dyslexics who suffer from slow effortful reading but not from a reading accuracy problem. Similar to acquired cases of letter-by-letter reading, the developmental cases exhibited an abnormal strong effect of length (i.e., number of letters) on response time for words and pseudowords.

Results

Corresponding to lesions of left occipito-temporal (OT) regions in acquired cases, we found a dysfunction of this region in our developmental cases who failed to exhibit responsiveness of left OT regions to the length of words and pseudowords. This abnormality in the left OT cortex was accompanied by absent responsiveness to increased sublexical reading demands in phonological inferior frontal gyrus (IFG) regions. Interestingly, there was no abnormality in the left superior temporal cortex which—corresponding to the onological deficit explanation—is considered to be the prime locus of the reading difficulties of developmental dyslexia cases.

Conclusions

The present functional imaging results suggest that developmental dyslexia similar to acquired letter-by-letter reading is due to a primary dysfunction of left OT regions.     

Endophenotype properties of niacin sensitivity as marker of impaired prostaglandin signalling in schizophrenia

BACKGROUND: Disruption of arachidonic acid pathways and prostaglandin signalling has been implicated in the pathophysiology of schizophrenia. AIMS: We intended to study prostaglandin signalling in groups of young schizophrenia patients, first-degree relatives, and healthy controls in order to assess effects of heritability on this biological marker-one important endophenotype criterion. METHOD: Namely, we assessed intensity of methylnicotinate skin flushing using optical reflection spectroscopy. Tests were applied to 19 adolescent first-episode schizophrenia patients, 21 first-degree relatives, and groups of age and gender matched healthy controls. RESULTS: Compared to healthy controls, attenuation of skin flushing at low niacin concentrations was found only in schizophrenia patients, but not in first-degree relatives. CONCLUSION: While our results indicate niacin hyposensitivity as reliable biological marker in schizophrenia, they do not provide clear evidence for its heritability. Particularly, the results in adolescent schizophrenia patients are suggestive for the perception of attenuated niacin flushing as secondary to the pathophysiology at the onset of schizophrenic illness, namely increased oxidative stress, alterations of unspecific immune-response or inflammation-like processes.     

Altered low-γ sampling in auditory cortex accounts for the three main facets of dyslexia

It has recently been conjectured that dyslexia arises from abnormal auditory sampling. What sampling rate is altered and how it affects reading remains unclear. We hypothesized that by impairing phonemic parsing abnormal low-gamma sampling could yield phonemic representations of unusual format and disrupt phonological processing and verbal memory. Using magnetoencephalography and behavioral tests, we show in dyslexic subjects a reduced left-hemisphere bias for phonemic processing, reflected in less entrainment to ≈30?Hz acoustic modulations in left auditory cortex. This deficit correlates with measures of phonological processing and rapid naming. We further observed enhanced cortical entrainment at rates beyond 40?Hz in dyslexics and show that this particularity is associated with a verbal memory deficit. These data suggest that a single auditory anomaly, i.e., phonemic oversampling in left auditory cortex, accounts for three main facets of the linguistic deficit in dyslexia.     

Dyslexia Impairs Speech Recognition but Can Spare Phonological Competence

Dyslexia is associated with numerous deficits to speech processing. Accordingly, a large literature asserts that dyslexics manifest a phonological deficit. Few studies, however, have assessed the phonological grammar of dyslexics, and none has distinguished a phonological deficit from a phonetic impairment. Here, we show that these two sources can be dissociated. Three experiments demonstrate that a group of adult dyslexics studied here is impaired in phonetic discrimination (e.g., ba vs. pa), and their deficit compromises even the basic ability to identify acoustic stimuli as human speech. Remarkably, the ability of these individuals to generalize grammatical phonological rules is intact. Like typical readers, these Hebrew-speaking dyslexics identified ill-formed AAB stems (e.g., titug) as less wordlike than well-formed ABB controls (e.g., gitut), and both groups automatically extended this rule to nonspeech stimuli, irrespective of reading ability. The contrast between the phonetic and phonological capacities of these individuals demonstrates that the algebraic engine that generates phonological patterns is distinct from the phonetic interface that implements them. While dyslexia compromises the phonetic system, certain core aspects of the phonological grammar can be spared.     

Differential Entrainment of Neuroelectric Delta Oscillations in Developmental Dyslexia

Oscillatory entrainment to the speech signal is important for language processing, but has not yet been studied in developmental disorders of language. Developmental dyslexia, a difficulty in acquiring efficient reading skills linked to difficulties with phonology (the sound structure of language), has been associated with behavioural entrainment deficits. It has been proposed that the phonological ‘deficit’ that characterises dyslexia across languages is related to impaired auditory entrainment to speech at lower frequencies via neuroelectric oscillations (<10 Hz, ‘temporal sampling theory’). Impaired entrainment to temporal modulations at lower frequencies would affect the recovery of the prosodic and syllabic structure of speech. Here we investigated event-related oscillatory EEG activity and contingent negative variation (CNV) to auditory rhythmic tone streams delivered at frequencies within the delta band (2 Hz, 1.5 Hz), relevant to sampling stressed syllables in speech. Given prior behavioural entrainment findings at these rates, we predicted functionally atypical entrainment of delta oscillations in dyslexia. Participants performed a rhythmic expectancy task, detecting occasional white noise targets interspersed with tones occurring regularly at rates of 2 Hz or 1.5 Hz. Both groups showed significant entrainment of delta oscillations to the rhythmic stimulus stream, however the strength of inter-trial delta phase coherence (ITC, ‘phase locking’) and the CNV were both significantly weaker in dyslexics, suggestive of weaker entrainment and less preparatory brain activity. Both ITC strength and CNV amplitude were significantly related to individual differences in language processing and reading. Additionally, the instantaneous phase of prestimulus delta oscillation predicted behavioural responding (response time) for control participants only.