Intrinsic connectivity of left ventrolateral prefrontal cortex predicts individual differences in controlled semantic retrieval.

Control processes allow us to constrain the retrieval of semantic information from long-term memory so that it is appropriate for the task or context. Control demands are influenced by the strength of the target information itself and by the circumstances in which it is retrieved, with more control needed when relatively weak aspects of knowledge are required and after the sustained retrieval of related concepts. To investigate the neurocognitive basis of individual differences in these aspects of semantic control, we used resting-state fMRI to characterise the intrinsic connectivity of left ventrolateral prefrontal cortex (VLPFC), implicated in controlled retrieval, and examined associations on a paced serial semantic task, in which participants were asked to detect category members amongst distractors. This task manipulated both the strength of target associations and the requirement to sustain retrieval within a narrow semantic category over time. We found that individuals with stronger connectivity between VLPFC and medial prefrontal cortex within the default mode network (DMN) showed better retrieval of strong associations (which are thought to be recalled more automatically). Stronger connectivity between the same VLPFC seed and another DMN region in medial parietal cortex was associated with larger declines in retrieval over the course of the category. In contrast, participants with stronger connectivity between VLPFC and cognitive control regions within the ventral attention network (VAN) had better controlled retrieval of weak associations and were better able to sustain their comprehension throughout the category. These effects overlapped in left insular cortex within the VAN, indicating that a common pattern of connectivity is associated with different aspects of controlled semantic retrieval induced by both the structure of long-term knowledge and the sustained retrieval of related information.

Keeping it together: Semantic coherence stabilizes phonological sequences in short-term memory.

Our ability to hold a sequence of speech sounds in mind, in the correct configuration, supports many aspects of communication, but the contribution of conceptual information to this basic phonological capacity remains controversial. Previous research has shown modest and inconsistent benefits of meaning on phonological stability in short-term memory, but these studies were based on sets of unrelated words. Using a novel design, we examined the immediate recall of sentence-like sequences with coherent meaning, alongside both standard word lists and mixed lists containing words and nonwords. We found, and replicated, substantial effects of coherent meaning on phoneme-level accuracy: The phonemes of both words and nonwords within conceptually coherent sequences were more likely to be produced together and in the correct order. Since nonwords do not exist as items in long-term memory, the semantic enhancement of phoneme-level recall for both item types cannot be explained by a lexically based item reconstruction process employed at the point of retrieval ("redintegration"). Instead, our data show, for naturalistic input, that when meaning emerges from the combination of words, the phonological traces that support language are reinforced by a semantic-binding process that has been largely overlooked by past short-term memory research.

Time to turn the other cheek? The influence of left and right poses on perceptions of academic specialisation.

The human face expresses emotion asymmetrically. Whereas the left cheek is more emotionally expressive, the right cheek appears more impassive, hence the appropriate cheek to put forward depends on the circumstance. Nicholls, Clode, Wood, and Wood (1999, Proceedings of the Royal Society (Section B), 266, 1517-1522) demonstrated that people posing for family portraits offer the left cheek, whereas those posing as a Royal Society scientist favour the right. Given that the stereotypical representations of members of different academic disciplines differ markedly in their perceived openness and emotionality (e.g., "serious" scientist vs. "creative" writer), we reasoned that people may use cheek as a cue when determining a model's area of academic interest. Two hundred and nine participants (M=90, F=119) viewed pairs of left and right cheek poses, and made a forced-choice decision indicating which image depicted a Chemistry, Psychology or English student. Half the images were mirror-reversed to control for perceptual and aesthetic biases. Consistent with prediction, participants were more likely to select left cheek images for English students, and right cheek images for Chemistry students, irrespective of image orientation. The results confirm that determining the best cheek to put forward depends on your academic expertise: an impassive right cheek suggests hard science, whereas an emotive left cheek implies the arts. Psychology produced no left or right bias, consistent with its position as a discipline perpetually straddling the boundary between art and science.

rTMS evidence for a dissociation in short-term memory for spoken words and nonwords.

Differing patterns of verbal short-term memory (STM) impairment have provided unique insights into the relationship between STM and broader language function. Lexicality effects (i.e., better recall for words than nonwords) are larger in patients with phonological deficits following left temporoparietal lesions, and smaller in patients with semantic impairment and anterior temporal damage, supporting linguistic accounts of STM. However, interpretation of these patient dissociations are complicated by (i) non-focal damage and (ii) confounding factors and secondary impairments. This study addressed these issues by examining the impact of inhibitory transcranial magnetic stimulation (TMS) on auditory-verbal STM performance in healthy individuals. We compared the effects of TMS to left anterior supramarginal gyrus (SMG) and left anterior middle temporal gyrus (ATL) on STM for lists of nonwords and random words. SMG stimulation disrupted nonword recall, in a pattern analogous to that observed in patients, compatible with a role for this site in processing speech sounds without support from long-term lexical-semantic representations. Stimulation of ATL, a semantic site, disrupted the recall of words but not nonwords. A visual pattern memory task indicated that these effects of TMS were restricted to the verbal domain. These data provide convergent evidence for the conclusions of neuropsychological studies that support linguistic accounts of verbal STM.

Individual differences in verbal short-term memory and reading aloud: Semantic compensation for weak phonological processing across tasks.

According to contemporary accounts, linguistic behavior reflects the interaction of distinct representations supporting word meaning and phonology. However, there is controversy about the extent to which this interaction occurs within task-specific systems, specialized for reading and short-term memory (STM), as opposed to between components that support the full range of linguistic tasks. We examined whether individual differences in the efficiency of phonological processing would relate to the application of lexical-semantic knowledge to support verbal STM, single word reading and repetition. In a sample of 83 participants, we related nonword performance in each task (as a marker of phonological capacity in the absence of meaning) to the effects of word imageability (a lexical-semantic variable). We found stronger reliance on lexical-semantic knowledge in participants with weaker phonological processing. This relationship held across tasks, suggesting that lexical-semantic processing can compensate for phonological weakness which would otherwise give rise to poor performance. Our results are consistent with separable yet interacting primary systems for phonology and semantics, with lexical-semantic knowledge supporting pattern completion within the phonological system in a similar way across STM and reading tasks. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Distinct individual differences in default mode network connectivity relate to off-task thought and text memory during reading.

Often, as we read, we find ourselves thinking about something other than the text; this tendency to mind-wander is linked to poor comprehension and reduced subsequent memory for texts. Contemporary accounts argue that periods of off-task thought are related to the tendency for attention to be decoupled from external input. We used fMRI to understand the neural processes that underpin this phenomenon. First, we found that individuals with poorer text-based memory tend to show reduced recruitment of left middle temporal gyrus in response to orthographic input, within a region located at the intersection of default mode, dorsal attention and frontoparietal networks. Voxels within these networks were taken as seeds in a subsequent resting-state study. The default mode network region (i) had greater connectivity with medial prefrontal cortex, falling within the same network, for individuals with better text-based memory, and (ii) was more decoupled from medial visual regions in participants who mind-wandered more frequently. These findings suggest that stronger intrinsic connectivity within the default mode network is linked to better text processing, while reductions in default mode network coupling to the visual system may underpin individual variation in the tendency for our attention to become disengaged from what we are reading.

Dynamic semantic cognition: Characterising coherent and controlled conceptual retrieval through time using magnetoencephalography and chronometric transcranial magnetic stimulation.

Distinct neural processes are thought to support the retrieval of semantic information that is (i) coherent with strongly-encoded aspects of knowledge, and (ii) non-dominant yet relevant for the current task or context. While the brain regions that support readily coherent and more controlled patterns of semantic retrieval are relatively well-characterised, the temporal dynamics of these processes are not well-understood. This study used magnetoencephalography (MEG) and dual-pulse chronometric transcranial magnetic stimulation (cTMS) in two separate experiments to examine temporal dynamics during the retrieval of strong and weak associations. MEG results revealed a dissociation within left temporal cortex: anterior temporal lobe (ATL) showed greater oscillatory response for strong than weak associations, while posterior middle temporal gyrus (pMTG) showed the reverse pattern. Left inferior frontal gyrus (IFG), a site associated with semantic control and retrieval, showed both patterns at different time points. In the cTMS experiment, stimulation of ATL at ∼150 msec disrupted the efficient retrieval of strong associations, indicating a necessary role for ATL in coherent conceptual activations. Stimulation of pMTG at the onset of the second word disrupted the retrieval of weak associations, suggesting this site may maintain information about semantic context from the first word, allowing efficient engagement of semantic control. Together these studies provide converging evidence for a functional dissociation within the temporal lobe, across both tasks and time.

Newly-acquired words are more phonologically robust in verbal short-term memory when they have associated semantic representations.

Verbal short-term memory (STM) is a crucial cognitive function central to language learning, comprehension and reasoning, yet the processes that underlie this capacity are not fully understood. In particular, although STM primarily draws on a phonological code, interactions between long-term phonological and semantic representations might help to stabilise the phonological trace for words ("semantic binding hypothesis"). This idea was first proposed to explain the frequent phoneme recombination errors made by patients with semantic dementia when recalling words that are no longer fully understood. However, converging evidence in support of semantic binding is scant: it is unusual for studies of healthy participants to examine serial recall at the phoneme level and also it is difficult to separate the contribution of phonological-lexical knowledge from effects of word meaning. We used a new method to disentangle these influences in healthy individuals by training new 'words' with or without associated semantic information. We examined phonological coherence in immediate serial recall (ISR), both immediately and the day after training. Trained items were more likely to be recalled than novel nonwords, confirming the importance of phonological-lexical knowledge, and items with semantic associations were also produced more accurately than those with no meaning, at both time points. For semantically-trained items, there were fewer phoneme ordering and identity errors, and consequently more complete target items were produced in both correct and incorrect list positions. These data show that lexical-semantic knowledge improves the robustness of verbal STM at the sub-item level, even when the effect of phonological familiarity is taken into account.

The Safety of Atomoxetine for the Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Comprehensive Review of Over a Decade of Research.

Atomoxetine is a noradrenergic reuptake inhibitor prescribed for attention-deficit/hyperactivity disorder (ADHD) that first gained approval in the USA in 2002 and has been authorized in 97 countries worldwide. The aim of this paper is to comprehensively review publications that addressed one or more of seven major safety topics relevant to atomoxetine treatment of children and adolescents (aged ≥6 years) diagnosed with ADHD. While the review focuses on children and adolescents, publications in which data from patients aged >18 years and from 6 to 18 years were analyzed in the same dataset were included. Using a predefined search strategy, including agreement of two reviewers when selecting papers, reduced the potential for bias. Using this process, we identified 70 eligible papers (clinical trials, epidemiological studies, and case reports) across the seven topics. We also referred to the European Summary of Product Characteristics (SPC) and US label. We found 15 papers about suicidality, three about aggression/hostility, seven about psychosis/mania, six about seizures, seven about hepatic effects, 29 about cardiovascular effects, and 28 about growth and development. The main findings (i.e., those from the largest and most well-conducted studies/analyses) are as follows. A large register-based study of pediatric and adult patients (6818 received atomoxetine) calculated a hazard ratio of 0.96 for suicide-related events during treatment with atomoxetine, and a meta-analysis of 23 placebo-controlled studies (N = 3883), published in 2014, found no completed suicides and no statistically significant association between atomoxetine and suicidality. The frequency of aggression/hostility was not statistically significantly higher with atomoxetine, e.g., experienced by 1.6 % (N = 21/1308) of atomoxetine-treated patients versus 1.1 % (N = 9/806) of placebo-treated patients in one meta-analysis. Symptoms of psychosis and mania were mainly observed in patients with comorbid bipolar disorder/depression. Based on spontaneous reports, during a 2-year period when 2.233 million adult and pediatric patients were exposed to atomoxetine, the reporting rate for seizures was 8 per 100,000 patients. In the manufacturer's database, atomoxetine was a "probable cause" of three hepatic adverse events (AEs) (all reversible hepatitis), and 133 hepatic AEs had possible confounding factors and were "possibly related" to atomoxetine, during 4 years when atomoxetine exposure had reached about 4.3 million patients. Rare cases of severe liver injury are described in the US label and European SPC; a case requiring liver transplantation is described in the US label. In a comprehensive review of a clinical trials database (N = 8417 received atomoxetine), most pediatric patients experienced modest increases in heart rate and blood pressure, and 8-12 % experienced more pronounced changes (≥20 bpm, ≥15 to 20 mmHg). However, in three long-term analyses (≥2 years), blood pressure was within age norms, and few patients discontinued due to cardiovascular AEs. As described in the European SPC, QT interval prolongation is uncommon, e.g., in an open-label study, 1.4 % of 711 children and adolescents had prolonged QTc intervals (≥450 ms in males, ≥470 ms in females) that were not clinically significant at ≥3 years of treatment with atomoxetine. The European SPC warns about potential QT interval prolongation in patients with a personal or family history, or if atomoxetine is administered with other drugs that potentially affect the QT interval. Decreases in growth (weight and height gain) occurred and were greatest in patients of above average weight and height, but appeared to recover over 2-5 years of atomoxetine treatment. In conclusion, suicidality, aggression/hostility, psychosis, seizures, liver injuries, and prolonged QT interval are uncommon or rare in children and adolescents treated with atomoxetine, based on data from the predefined search and from the European SPC. Overall, the data that we assessed from our search do not suggest that associations exist between atomoxetine and suicidality or seizures. The data also suggest that an association may not exist between atomoxetine and aggression/hostility. While atomoxetine may affect the cardiovascular system, the data suggest these effects are not clinically significant in most patients. Reductions in growth appear to be reversible in the long term.

tDCS to temporoparietal cortex during familiarisation enhances the subsequent phonological coherence of nonwords in immediate serial recall.

Research has shown that direct current stimulation (tDCS) over left temporoparietal cortex - a region implicated in phonological processing - aids new word learning. The locus of this effect remains unclear since (i) experiments have not empirically separated the acquisition of phonological forms from lexical-semantic links and (ii) outcome measures have focused on learnt associations with a referent rather than phonological stability. We tested the hypothesis that left temporoparietal tDCS would strengthen the acquisition of phonological forms, even in the absence of the opportunity to acquire lexical-semantic associations. Participants were familiarised with nonwords paired with (i) photographs of concrete referents or (ii) blurred images where no clear features were visible. Nonword familiarisation proceeded under conditions of anodal tDCS and sham stimulation in different sessions. We examined the impact of these manipulations on the stability of the phonological trace in an immediate serial recall (ISR) task the following day, ensuring that any effects were due to the influence of tDCS on long-term learning and not a direct consequence of short-term changes in neural excitability. We found that only a few exposures to the phonological forms of nonwords were sufficient to enhance nonword ISR overall compared to entirely novel items. Anodal tDCS during familiarisation further enhanced the acquisition of phonological forms, producing a specific reduction in the frequency of phoneme migrations when sequences of nonwords were maintained in verbal short-term memory. More of the phonemes that were recalled were bound together as a whole correct nonword following tDCS. These data show that tDCS to left temporoparietal cortex can facilitate word learning by strengthening the acquisition of long-term phonological forms, irrespective of the availability of a concrete referent, and that the consequences of this learning can be seen beyond the learning task as strengthened phonological coherence in verbal short-term memory.

The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research.

Atomoxetine was first licensed to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in the US in 2002. The aim of this paper is to comprehensively review subsequent publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. We identified 125 eligible papers using a predefined search strategy. Overall, these papers demonstrate that atomoxetine is an effective treatment for the core ADHD symptoms (effect sizes 0.6-1.3, vs. placebo, at 6-18 weeks), and improves functional outcomes and quality of life, in various pediatric populations with ADHD (i.e., males/females, patients with co-morbidities, children/adolescents, and with/without prior exposure to other ADHD medications). Initial responses to atomoxetine may be apparent within 1 week of treatment, but can take longer (median 23 days in a 6-week study; n=72). Responses often build gradually over time, and may not be robust until after 3 months. A pooled analysis of six randomized placebo-controlled trials (n=618) indicated that responses at 4 weeks may predict response at 6-9 weeks, although another pooled analysis of open-label data (n=338) suggests that the probability of a robust response to atomoxetine [≥40% decrease in ADHD-Rating Scale (ADHD-RS) scores] may continue to increase beyond 6-9 weeks. Atomoxetine may demonstrate similar efficacy to methylphenidate, particularly immediate-release methylphenidate, although randomized controlled trials are generally limited by short durations (3-12 weeks). In conclusion, notwithstanding these positive findings, before initiating treatment with atomoxetine, it is important that the clinician sets appropriate expectations for the patient and their family with regard to the likelihood of a gradual response, which often builds over time.

Systematic review of atomoxetine data in childhood and adolescent attention-deficit hyperactivity disorder 2009-2011: focus on clinical efficacy and safety.

BACKGROUND: Clinicians obtain critical prescribing knowledge from clinical papers and review articles. This is the first published systematic review of clinical atomoxetine data covering 2009-2011. OBJECTIVE: We aim to update clinicians on current clinical atomoxetine data with specific reference to time of onset of efficacy and maximal efficacy. These data may allow critical analysis of comparative efficacy between atomoxetine and stimulant medications. METHODS: A formal systematic review of atomoxetine data from January 2009-June 2011 was conducted. The search term used was "atomoxetine" in the English language. The search yielded 747 citations from which 106 are clinical data. This paper includes clinical efficacy and safety data and excludes quality-of-life and review papers. RESULTS: Atomoxetine has an onset of action within 4 weeks (possibly within 1 week in subsequent responders) but requires at least 12 weeks for full response to be demonstrated. Treatment-naïve cohorts (6-12 weeks) report effect sizes of 0.6-1.3. Using minimum 6-week clinical trial criteria, atomoxetine may demonstrate similar efficacy to methylphenidate comparing reduction in core ADHD symptoms in meta-analysis, although the diversity of the data makes interpretation complex. From epidemiological databases, cardiovascular and suicide-related events were similar to those seen in patients taking methylphenidate. CONCLUSIONS: Incremental response time to atomoxetine should be considered in the design of future comparative efficacy trials.

Suicide related events and attention deficit hyperactivity disorder treatments in children and adolescents: a meta-analysis of atomoxetine and methylphenidate comparator clinical trials.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is becoming an increasingly commonly diagnosed and treated childhood illness. Untreated ADHD is recognised as an independent risk factor for suicide-related events and deliberate self-harm and is reported more commonly in these populations. With the treatment of ADHD it is thus crucial to understand further any associations between pharmacological treatments and suicide-related events. Specific data for suicide-related events with stimulants have not been publically reported. Suicidal tendencies are, however, a contraindication to the treatment of patients with methylphenidate. Clinicians and patients may be helped by a meta-analytic comparison of suicide-related events in comparative randomised double-blind atomoxetine and methylphenidate clinical trials. METHODS: Suicide-related events retrospectively mapped to the suicide-related event assessment instrument recommended by the FDA, the Columbia Classification Algorithm for Suicide Assessment (C-CASA), were evaluated in five double-blind placebo controlled comparative studies of atomoxetine and methylphenidate (n = 1024) of 6 to 9 weeks duration. The Mantel-Haenszel risk ratio and Mantel-Haenszel incidence differences have been calculated. RESULTS: In total there were 5 suicide-related events, atomoxetine (ATX) 3/559 and methylphenidate (MPH) 2/465. There were no suicide attempts nor completed suicides. Meta-analysis finds no difference of a difference in risk between ATX and MPH with a Mantel-Haenszel risk ratio of 0.52 (95% CI; 0.06, 4.54). CONCLUSION: In the only reported meta-analysis of comparative suicide-related events between atomoxetine and methylphenidate, no significant evidence of a difference in risk has been found. These data may be informative to clinicians and patients when developing clinical guidelines.

A 12-week nursing support programme for carers of children and adolescents in the UK with attention deficit hyperactivity disorder prescribed atomoxetine.

INTRODUCTION: Patient support programmes are assuming greater importance in the UK in many therapeutic areas, mostly with the aim of improving adherence to medication and many being provided by the pharmaceutical industry. Atomoxetine is a noradrenaline reuptake inhibitor for the treatment of attention deficit hyperactivity disorder that has recently demonstrated incremental efficacy for at least 12 weeks. Issues of adherence may be predicted over this initial period particularly if adverse events are reported. The Strattera Support Service was initiated in 2006 ( funded by Eli Lilly) to provide advice, initially through telephone contact, by trained nurses during the first 12 weeks of atomoxetine therapy and is offered to carers of patients diagnosed with ADHD after atomoxetine has been prescribed. The aim of this pilot service evaluation is to assess discontinuation rates and compare them with historical control data. METHODS: Data from patients in the service who initiated atomoxetine between 1 January 2009 and 31 March 2010 were analysed to provide a pilot service evaluation. Continuation rates of patients in the service who were taking atomoxetine at week 12 were assessed and compared with historical control data. RESULTS: Between 1 January 2009 and 31 March 2010, 346 patients (300 male patients) enrolled in the programme and commenced treatment with atomoxetine. The mean age of patients was 10.5 years. At 12 weeks, 33 (9.5%) patients had discontinued treatment; continuation rates were similar regardless of age and sex. Discontinuation rates of 39% are reported from historical control data. CONCLUSIONS: Preliminary data from a 12-week atomoxetine patient support programme are supportive that discontinuation rates may be lower than historically expected. Further service evaluations of this programme may be required.

Orthographic transparency modulates the grain size of orthographic processing: behavioral and ERP evidence from bilingualism.

Grapheme-to-phoneme mapping regularity is thought to determine the grain size of orthographic information extracted whilst encoding letter strings. Here we tested whether learning to read in two languages differing in their orthographic transparency yields different strategies used for encoding letter-strings as compared to learning to read in one (opaque) language only. Sixteen English monolingual and 16 early Welsh-English bilingual readers undergoing event-related brain potentials (ERPs) recordings were asked to report whether or not a target letter displayed at fixation was present in either a nonword (consonant string) or an English word presented immediately before. Bilinguals and monolinguals showed similar behavioural performance on target detection presented in words and nonwords, suggesting similar orthographic encoding in the two groups. By contrast, the amplitude of ERPs locked to the target letters (P3b, 340-570 ms post target onset, and a late frontal positive component 600-1,000 ms post target onset) were differently modulated by the position of the target letter in words and nonwords between bilinguals and monolinguals. P3b results show that bilinguals who learnt to read simultaneously in an opaque and a transparent orthographies encoded orthographic information presented to the right of fixation more poorly than monolinguals. On the opposite, only monolinguals exhibited a position effect on the late positive component for both words and nonwords, interpreted as a sign of better re-evaluation of their responses. The present study shed light on how orthographic transparency constrains grain size and visual strategies underlying letter-string encoding, and how those constraints are influenced by bilingualism.

Decoding ability makes waves in reading: deficient interactions between attention and phonological analysis in developmental dyslexia.

Whilst there is general consensus that phonological processing is deficient in developmental dyslexia, recent research also implicates visuo-attentional contributions. Capitalising on the P3a wave of event-related potentials as an index of attentional capture, we tested dyslexic and normal readers on a novel variant of a visual oddball task to examine the interplay of orthographic-phonological integration and attentional engagement. Targets were animal words (10% occurrence). Amongst nontarget stimuli were two critical conditions: pseudohomophones of targets (10%) and control pseudohomophones (of fillers; 10%). Pseudohomophones of targets (but not control pseudohomophones) elicited a large P3 wave in normal readers only, revealing a lack of attentional engagement with these phonologically salient stimuli in dyslexic participants. Critically, both groups showed similar early phonological discrimination as indexed by posterior P2 modulations. Furthermore, phonological engagement, as indexed by P3a differences between pseudohomophone conditions, correlated with several measures of reading. Meanwhile, an analogous experiment using coloured shapes instead of orthographic stimuli failed to show group differences between experimental modulations in the P2 or P3 ranges. Overall, our results show that, whilst automatic aspects of phonological processing appear intact in developmental dyslexia, the breakdown in pseudoword reading occurs at a later stage, when attention is oriented to orthographic-phonological information.

A systematic review of the safety information contained within the Summaries of Product Characteristics of medications licensed in the United Kingdom for Attention Deficit Hyperactivity Disorder. how does the safety prescribing advice compare with national guidance?

BACKGROUND: The safety of paediatric medications is paramount and contraindications provide clear pragmatic advice. Further advice may be accessed through Summaries of Product Characteristics (SPCs) and relevant national guidelines. The SPC can be considered the ultimate independent guideline and is regularly updated. In 2008, the authors undertook a systematic review of the SPC contraindications of medications licensed in the United Kingdom (UK) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). At that time, there were fewer contraindications reported in the SPC for atomoxetine than methylphenidate and the specific contraindications varied considerably amongst methylphenidate formulations. In 2009, the European Medicines Agency (EMA) mandated harmonisation of methylphenidate SPCs. Between September and November 2011, there were three changes to the atomoxetine SPC that resulted in revised prescribing information. In addition, Clinical Guidance has also been produced by the National Institute for Health and Clinical Excellence (NICE) (2008), the Scottish Intercollegiate Guidelines Network (SIGN) (2009) and the British National Formulary for Children (BNFC). METHODS: An updated systematic review of the Contraindications sections of the SPCs of all medications currently licensed for treatment of ADHD in the UK was undertaken and independent statements regarding contraindications and relevant warnings and precautions were then compared with UK national guidance with the aim of assessing any disparity and potential areas of confusion for prescribers. RESULTS: As of November 2011, there were seven medications available in the UK for the treatment of ADHD. There are 15 contraindications for most formulations of methylphenidate, 14 for dexamfetamine and 5 for atomoxetine. Significant differences exist between the SPCs and national guidance part due to the ongoing reactive process of amending the former as new information becomes known. In addition, recommendations are made outside UK SPC licensed indications and a significant contraindication for methylphenidate (suicidal behaviours) is missing from both the NICE and SIGN guidelines. Particular disparity exists relating to monitoring for suicidal and psychiatric side effects. The BNFC has not yet been updated in line with the European Union (EU) Directive on methylphenidate; it does not include any contraindications for atomoxetine but describes contraindications for methylphenidate that are no longer in the SPC. CONCLUSION: Clinicians seeking prescribing advice from critical independent sources of data, such as SPCs and national guidelines, may be confused by the disparity that exists. There are major differences between guidelines and SPCs and neither should be referred to in isolation. The SPC represents the most relevant source of safety data to aid prescribing of medications for ADHD as they present the most current safety data in line with increased exposure. National guidelines may need more regular updates.

Electrophysiological cross-language neighborhood density effects in late and early english-welsh bilinguals.

Behavioral studies with proficient late bilinguals have revealed the existence of orthographic neighborhood density (ND) effects across languages when participants read either in their first (L1) or second (L2) language. Words with many cross-language (CL) neighbors have been found to elicit more negative event-related potentials (ERPs) than words with few CL neighbors (Midgley et al., 2008); the effect started earlier, and was larger, for L2 words. Here, 14 late and 14 early English-Welsh bilinguals performed a semantic categorization task on English and Welsh words presented in separate blocks. The pattern of CL activation was different for the two groups of bilinguals. In late bilinguals, words with high CLND elicited more negative ERP amplitudes than words with low CLND starting around 175 ms after word onset and lasting until 500 ms. This effect interacted with language in the 300-500 ms time window. A more complex pattern of early effects was revealed in early bilinguals and there were no effects in the N400 window. These results suggest that CL activation of orthographic neighbors is highly sensitive to the bilinguals' learning experience of the two languages.

Electrophysiological evidence for impaired attentional engagement with phonologically acceptable misspellings in developmental dyslexia.

Event-related potential (ERP) studies of word recognition have provided fundamental insights into the time-course and stages of visual and auditory word form processing in reading. Here, we used ERPs to track the time-course of phonological processing in dyslexic adults and matched controls. Participants engaged in semantic judgments of visually presented high-cloze probability sentences ending either with (a) their best completion word, (b) a homophone of the best completion, (c) a pseudohomophone of the best completion, or (d) an unrelated word, to examine the interplay of phonological and orthographic processing in reading and the stage(s) of processing affected in developmental dyslexia. Early ERP peaks (N1, P2, N2) were modulated in amplitude similarly in the two groups of participants. However, dyslexic readers failed to show the P3a modulation seen in control participants for unexpected homophones and pseudohomophones (i.e., sentence completions that are acceptable phonologically but are misspelt). Furthermore, P3a amplitudes significantly correlated with reaction times in each experimental condition. Our results showed no sign of a deficit in accessing phonological representations during reading, since sentence primes yielded phonological priming effects that did not differ between participant groups in the early phases of processing. On the other hand, we report new evidence for a deficient attentional engagement with orthographically unexpected but phonologically expected words in dyslexia, irrespective of task focus on orthography or phonology. In our view, this result is consistent with deficiency in reading occurring from the point at which attention is oriented to phonological analysis, which may underlie broader difficulties in sublexical decoding.

Reading for sound with dyslexia: evidence for early orthographic and late phonological integration deficits.

Deteriorated phonological representations are widely assumed to be the underlying cause of reading difficulties in developmental dyslexia; however, existing evidence also implicates degraded orthographic processing. Here, we used event-related potentials whilst dyslexic and control adults performed a pseudoword-word priming task requiring deep phonological analysis to examine phonological and orthographic priming, respectively. Pseudowords were manipulated to be homophonic or non-homophonic to a target word and more or less orthographically similar. Since previous ERP research with normal readers has established phonologically driven differences as early as 250 ms from word presentation, degraded phonological representations were expected to reveal reduced phonological priming in dyslexic readers from 250 ms after target word onset. However, phonological priming main effects in both the N2 and P3 ranges were indistinguishable in amplitude between groups. Critically, we found group differences in the N1 range, such that orthographic modulations observed in controls were absent in the dyslexic group. Furthermore, early group differences in phonological priming transpired as interactions with orthographic priming (in P2, N2 and P3 ranges). A group difference in phonological priming did not emerge until the P600 range, in which the dyslexic group showed significantly attenuated priming. As the P600 is classically associated with online monitoring and reanalysis, this pattern of results suggest that during deliberate phonological processing, the phonological deficit in reading may relate more to inefficient monitoring rather than deficient detection. Meanwhile, early differences in perceptual processing of phonological information may be driven by the strength of engagement with orthographic information.