Event related potential (ERP) evidence for selective impairment of verbal recollection in abstinent recreational methylenedioxymethamphetamine (“Ecstasy”)/polydrug users

Objectives Ecstasy is a recreational drug whose active ingredient, 3,4-methylenedioxymethamphetamine (MDMA), acts predominantly on the serotonergic system. Although MDMA is known to be neurotoxic in animals, the long-term effects of recreational Ecstasy use in humans remain controversial but one commonly reported consequence is mild cognitive impairment particularly affecting verbal episodic memory. Although event-related potentials (ERPs) have made significant contributions to our understanding of human memory processes, until now they have not been applied to study the long-term effects of Ecstasy. The aim of this study was to examine the effects of past Ecstasy use on recognition memory for both verbal and non-verbal stimuli using ERPs. Methods We compared the ERPs of 15 Ecstasy/polydrug users with those of 14 cannabis users and 13 non-illicit drug users as controls. Results Despite equivalent memory performance, Ecstasy/polydrug users showed an attenuated late positivity over left parietal scalp sites, a component associated with the specific memory process of recollection. Conlusions This effect was only found in the word recognition task which is consistent with evidence that left hemisphere cognitive functions are disproportionately affected by Ecstasy, probably because the serotonergic system is laterally asymmetrical. Experimentally, decreasing central serotonergic activity through acute tryptophan depletion also selectively impairs recollection, and this too suggests the importance of the serotonergic system. Overall, our results suggest that Ecstasy users, who also use a wide range of other drugs, show a durable abnormality in a specific ERP component thought to be associated with recollection.

Lexical and nonlexical processing in developmental dyslexia: a case for different resources and different impairments

In a group of adult dyslexics word reading and, especially, word spelling are predicted more by what we have called lexical learning (tapped by a paired-associate task with pictures and written nonwords) than by phonological skills. Nonword reading and spelling, instead, are not associated with this task but they are predicted by phonological tasks. Consistently, surface and phonological dyslexics show opposite profiles on lexical learning and phonological tasks. The phonological dyslexics are more impaired on the phonological tasks, while the surface dyslexics are equally or more impaired on the lexical learning tasks. Finally, orthographic lexical learning explains more variation in spelling than in reading, and subtyping based on spelling returns more interpretable results than that based on reading. These results suggest that the quality of lexical representations is crucial to adult literacy skills. This is best measured by spelling and best predicted by a task of lexical learning. We hypothesize that lexical learning taps a uniquely human capacity to form new representations by recombining the units of a restricted set.

Localizing the deficit in a case of jargonaphasia

We report the case of a neologistic jargonaphasic and ask whether her target-related and abstruse neologisms are the result of a single deficit, which affects some items more severely than others, or two deficits: one to lexical access and the other to phonological encoding. We analyse both correct/incorrect performance and errors and apply both traditional and formal methods (maximum-likelihood estimation and model selection). All evidence points to a single deficit at the level of phonological encoding. Further characteristics are used to constrain the locus still further. V.S. does not show the type of length effect expected of a memory component, nor the pattern of errors associated with an articulatory deficit. We conclude that her neologistic errors can result from a single deficit at a level of phonological encoding that immediately follows lexical access where segments are represented in terms of their features. We do not conclude, however, that this is the only possible locus that will produce phonological errors in aphasia, or, indeed, jargonaphasia.

Length, lexicality, and articulatory suppression in immediate recall:evidence against the articulatory loop

Influential models of short-term memory have attributed the fact that short words are recalled better than longer words in serial recall (the length effect) to articulatory rehearsal. Crucial for this link is the finding that the length effect disappears under articulatory suppression. We show, instead, that, under suppression, the length effect is abolished or reversed for real words but remains robust for nonwords. The latter finding is demonstrated in a variety of conditions: with lists of three and four nonwords, with nonwords drawn from closed and open sets, with spoken and written presentation, and with written and spoken output. Our interpretation is that the standard length effect derives from the number of phonological units to be retained. The length effect is abolished or reversed under suppression because this condition encourages reliance on lexical-semantic representations. Using these representations, longer words can more easily be reconstructed from degraded phonology than shorter words. © 2005 Elsevier Inc. All rights reserved.

Patterns of phonological errors as a function of a phonological versus an articulatory locus of impairment

WWe present the case of two aphasic patients: one with fluent speech, MM, and one with dysfluent speech, DB. Both patients make similar proportions of phonological errors in speech production and the errors have similar characteristics. A closer analysis, however, shows a number of differences. DB's phonological errors involve, for the most part, simplifications of syllabic structure; they affect consonants more than vowels; and, among vowels, they show effects of sonority/complexity. This error pattern may reflect articulatory difficulties. MM's errors, instead, show little effect of syllable structure, affect vowels at least as much as consonants and, and affect all different vowels to a similar extent. This pattern is consistent with a more central impairment involving the selection of the right phoneme among competing alternatives. We propose that, at this level, vowel selection may be more difficult than consonant selection because vowels belong to a smaller set of repeatedly activated units.

Measuring the influence of similarity on category-specific effects

There is evidence for both advantages and disadvantages in normal recognition of living over nonliving things. This paradox has been attributed to high levels of perceptual similarity within living categories having a different effect on performance in different contexts. However, since living things are intrinsically more similar to each other, previous studies could not determine whether the various category effects were due to perceptual similarity, or to other characteristics of living things. We used novel animal and vehicle stimuli that were matched for similarity to measure the influence of perceptual similarity in different contexts. We found that displaying highly similar objects in blocked sets reduced their perceived similarity, eliminating the detrimental effect on naming performance. Experiment 1 demonstrated a disadvantage for highly similar objects in name learning and name verification using mixed groups of similar and dissimilar animals and vehicles. Experiment 2 demonstrated no disadvantage for the same highly similar objects when they were blocked, e.g., similar animals presented alone. Thus, perceptual similarity, rather than other characteristics particular to living things, is affected by context, and could create apparent category effects under certain testing conditions.

REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.

Does normal processing provide evidence of specialised semantic subsystems?

Category-specific disorders are frequently explained by suggesting that living and non-living things are processed in separate subsystems (e.g. Caramazza & Shelton, 1998). If subsystems exist, there should be benefits for normal processing, beyond the influence of structural similarity. However, no previous study has separated the relative influences of similarity and semantic category. We created novel examples of living and non-living things so category and similarity could be manipulated independently. Pre-tests ensured that our images evoked appropriate semantic information and were matched for familiarity. Participants were trained to associate names with the images and then performed a name-verification task under two levels of time pressure. We found no significant advantage for living things alongside strong effects of similarity. Our results suggest that similarity rather than category is the key determinant of speed and accuracy in normal semantic processing. We discuss the implications of this finding for neuropsychological studies. © 2005 Psychology Press Ltd.

Aspects of tic like behaviour and serotonergic control

Tic-like movements in rodents bear close similarities to those observed in humans both pharmacologically and morphologically. Pharmacologically, tics are modulated by serotonergic and dopaminergic systems and abnormalities of these systems have been reported in Tourette's Syndrome (TS). Therefore, serotonergic and dopaminergic modulation of tics induced by a thyrotrophin-releasing hormone (TRH) analogue were studied as possible models for TS. The TRH analogue MK771 induced a variety of tic like movements in mice; blinking fore-paw-licking and fore-paw-tremor were quantified and serotonergic and dopaminergic modulation was investigated. The selective dopamine D1 receptor antagonists SCH23390 and SCH39166 and dopamine D2 antagonists raclopride and sulpiride had no effect on MK771 induced blinking. The D1 antagonists attenuated fore-paw-tremor and -licking while the D2 antagonists were generally without effect on these behaviours. Ketanserin (5-HT2A/ alpha-1 antagonist) and ritanserin (5-HT2A/2C antagonist) were able to attenuate MK771-induced blinking and ketanserin, mianserin (5-HT2A/2C antagonist) and prazosin (alpha-1 adrenoceptor antagonist) were able to attenuate MK771-induced fore-paw-tremor and -licking. The 5-HT2C/2B antagonist SB200646A was without effect on blinking and fore-paw-licking but dose-dependently potentiated fore-paw-tremor. The 5-HT1A agonists 8-OH DPAT and buspirone attenuated blinking at the lower doses tested but were ineffective at the higher doses; the converse was found for fore-paw-licking and -tremor behaviours.The effects of these ligands appeared to be at a postsynaptic 5-HTlA site since para-chlorophenylalanine was without effect on the manipulation of these behaviours. (S)-W A Y100135 was without effect on MK771-induced behaviours, spontaneous and DOl-induced head shakes. Because kynurenine potentiates head shakes and plasma concentrations are raised in TS patients the effects of kynurenine on the 5-HT2A/2C agonist DOl mediated head shake were established. Kynurenine potentiated the DOl head shake. Attempts were made to correlate serotonergic unit activity with tic like behaviour in cats but this proved unsuccessful. However, the pharmacological understanding of 5-HTlA receptor function has been hampered because of the lack of selective antagonists for this site. For this reason the effects of the novel 5-HTlA antagonists (S)-WA Y- 100135 and WAY -100635 were tested on 5-HT single-unit activity recorded from the dorsal-raphe-nucleus in the behaving cat. Both drugs antagonised the suppression of unit activity caused by 8-0H DPAT. (S)-WA Y-100135 reduced unit activity whereas WAY-100635 increased it. This suggests that WAY-100635 is acting as an antagonist at the 5-HTlA somatodendritic autoreceptor and that (S)W A Y -100135 acts as a partial agonist at this site. Aspects of tic like behaviour and serotonergic control are discussed.

Regulation of mucus secretion by cells isolated from the rat gastric mucosa

     This study was undertaken to further understanding of the mechanisms which regulate mucus secretion by rat stomach cells. Particular objectives were: (i) to develop and use a radiochemical assay to estimate the secretion of mucin by a suspension of gastric mucosal cells in vitro, (ii) to develop and use a solid-phase enzyme immunoassay (EIA) to study the regulation of the release of bulk gastric mucin from the isolated cells and (iii) to compare the results obtained with the two procedures.      Cells were isolated by exposure of gastric mucosa to pronase and EDTA. Cell suspensions were preincubated with D-[6-3H]glucosamine. [3H]-labelled material of high molecular mass released into the incubation medium, was purified by Fast Protein Liquid Chromatography, and appeared to be gastric mucin. Some unidentified [3H]-labelled material of lower molecular mass was also found in the medium. Release of [3H]-labelled high molecular mass material was essentially linearly related to time. Secretin, isoprenaline and carbachol stimulated release of [3H]-labelled high molecular mass material. The half-maximally effective concentrations of secretin and isoprenaline were 2.3nM and 34nM respectively. Histamine, gastrin and epidermal growth factor were without effect.      A rabbit polyclonal antibody was raised by using purified 'native' rat gastric mucin as immunogen. The antibody preparation appeared specific for rat gastric mucin and was used to establish a quantitative solid-phase EIA. Release of bulk mucin was essentially linearly related to time. Phorbol-12-myristate-13-acetate (PMA), forskolin and A23187 dose-dependently stimulated bulk mucin release. Synergistic interactions were observed between PMA and forskolin, and PMA and A23187. Secretin and isoprenaline were confirmed as mucin secretogogues.      In conclusion gastric mucin release was investigated for the first time by using a suspension of gastric mucosal cells. Two different assay procedures were developed. Some pathways and agents responsible for controlling mucin secretion were identified.

Accessibility indices and linked trips: a case study of the elderly

The confusion over the concept of accessibility in transport planning and the deficiencies of existing accessibility indices are examined by developing a conceptual framework of accessibility with a fundamental distinction being drawn between the, often conflicting, theoretical and practical dimensions. The theoretical validity of alternative indices is assessed with reference to the problems and assumptions implicit in defining, measuring, valuing and aggregating the variables and components comprising accessibility. The major deficiencies of existing indices are identified as the inability of indices to take account of the potential to link trips between more than one activity location and the level of assumptions implicit in valuing and aggregating accessibility information. In this context, it is argued that accessibility information is more appropriately expressed on a comparative basis in the form of a profile rather than as a composite single-unit index and that the present confines of accessibility measurement must be extended in line with current developments in disaggregate travel and activity modelling. The sensitivity of accessibility levels to the use of alternative value judgements, alternative forms and levels of aggregation and the inclusion of information on the potential to link trips is examined by undertaking a case study. Accessibility profiles are developed for 23 zones in the London Borough of Hammersmith and Fulham showing the accessibility of the elderly to post offices and grocers. In a practical context, the profiles assist in identifying areas and individuals with relatively poor accessibility. The incidence and nature of linked trip-making and its significance and implications for accessibility measurement are explored further by analysing the results of a survey of the elderly's travel patterns. It is concluded that future accessibility analysis should be undertaken at a disaggregate level, taking account of the potential opportunity available from nonhome as well as home origins.

Model evaluation and case series data

We discuss aggregation of data from neuropsychological patients and the process of evaluating models using data from a series of patients. We argue that aggregation can be misleading but not aggregating can also result in information loss. The basis for combining data needs to be theoretically defined, and the particular method of aggregation depends on the theoretical question and characteristics of the data. We present examples, often drawn from our own research, to illustrate these points. We also argue that statistical models and formal methods of model selection are a useful way to test theoretical accounts using data from several patients in multiple-case studies or case series. Statistical models can often measure fit in a way that explicitly captures what a theory allows; the parameter values that result from model fitting often measure theoretically important dimensions and can lead to more constrained theories or new predictions; and model selection allows the strength of evidence for models to be quantified without forcing this into the artificial binary choice that characterizes hypothesis testing methods. Methods that aggregate and then formally model patient data, however, are not automatically preferred to other methods. Which method is preferred depends on the question to be addressed, characteristics of the data, and practical issues like availability of suitable patients, but case series, multiple-case studies, single-case studies, statistical models, and process models should be complementary methods when guided by theory development.

Reduced attentional capacity, but normal processing speed and shifting of attention in developmental dyslexia: evidence from a serial task

We report the performance of a group of adult dyslexics and matched controls in an array-matching task where two strings of either consonants or symbols are presented side by side and have to be judged to be the same or different. The arrays may differ either in the order or identity of two adjacent characters. This task does not require naming – which has been argued to be the cause of dyslexics’ difficulty in processing visual arrays – but, instead, has a strong serial component as demonstrated by the fact that, in both groups, Reaction times (RTs) increase monotonically with position of a mismatch. The dyslexics are clearly impaired in all conditions and performance in the identity conditions predicts performance across orthographic tasks even after age, performance IQ and phonology are partialled out. Moreover, the shapes of serial position curves are revealing of the underlying impairment. In the dyslexics, RTs increase with position at the same rate as in the controls (lines are parallel) ruling out reduced processing speed or difficulties in shifting attention. Instead, error rates show a catastrophic increase for positions which are either searched later or more subject to interference. These results are consistent with a reduction in the attentional capacity needed in a serial task to bind together identity and positional information. This capacity is best seen as a reduction in the number of spotlights into which attention can be split to process information at different locations rather than as a more generic reduction of resources which would also affect processing the details of single objects.

REST is a hypoxia-responsive transcriptional repressor

Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxiadependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.

The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch

The Raf-1 protein kinase is a major activator of the ERK MAPK pathway, which links signaling by a variety of cell surface receptors to the regulation of cell proliferation, survival, differentiation and migration. Signaling by Raf-1 is regulated by a complex and poorly understood interplay between phosphorylation events and protein-protein interactions. One important mode of Raf-1 regulation involves the phosphorylation-dependent binding of 14-3-3 proteins. Here, we have examined the mechanism whereby the C-terminal 14-3-3 binding site of Raf-1, S621, controls the activation of MEK-ERK signaling. We show that phosphorylation of S621 turns over rapidly and is enriched in the activated pool of endogenous Raf-1. The phosphorylation on this site can be mediated by Raf-1 itself but also by other kinase(s). Mutations that prevent the binding of 14-3-3 proteins to S621 render Raf-1 inactive by specifically disrupting its capacity to bind to ATP, and not by gross conformational alteration as indicated by intact MEK binding. Phosphorylation of S621 correlates with the inhibition of Raf-1 catalytic activity in vitro, but 14-3-3 proteins can completely reverse this inhibition. Our findings suggest that 14-3-3 proteins function as critical cofactors in Raf-1 activation, which induce and maintain the protein in a state that is competent for both ATP binding and MEK phosphorylation.