Cognitive effects of aromatase inhibitor therapy in peripubertal boys.

OBJECTIVE: Aromatase inhibitors, blockers of oestrogen biosynthesis, have emerged as a new potential treatment modality for boys with short stature. The cognitive effects of such therapy are unknown. In this study, we explored the effects of aromatase inhibition on cognitive performance in peripubertal boys. DESIGN: Prospective, double-blind, randomised, placebo-controlled clinical study. METHODS: Twenty-eight boys, aged 9.0-14.5 years, with idiopathic short stature were treated with the aromatase inhibitor letrozole (2.5 mg/day) or placebo, for 2 years. During the treatment, the progression of physical signs of puberty and the concentrations of sex hormones were followed up. A selection of cognitive tests, focusing on memory function, was administered to the participants at entry, at 12 months and at 24 months after the start of the treatment. RESULTS: Letrozole effectively inhibited the conversion of androgen to oestrogen, as indicated by high serum testosterone and low serum oestradiol concentrations in letrozole-treated boys who progressed into puberty. In both the groups, there was a gain in performance during the follow-up period in tests of verbal performance, in most of the tests of visuospatial performance and in some tests of verbal memory. No significant differences between the letrozole- and placebo-treated boys in development of cognitive performance were found in any of the tests during the follow-up period. CONCLUSIONS: Our results suggest that blockade of oestrogen biosynthesis with an aromatase inhibitor does not influence cognitive performance in peripubertal males.

Influence of phonological expectations during a phoneme deletion task: evidence from event-related brain potentials.

Several studies have identified a negativity [the phonological mismatch negativity (PMN)] preceding the N400 during auditory sentence comprehension. The present study investigated whether the PMN reflects a prelexical or lexical stage of spoken word recognition. Event-related brain potentials (ERPs) were recorded to investigate phonological processing independently from lexical/semantic influences during a task requiring metalinguistic analysis of speech stimuli. Participants were instructed to omit the initial phoneme from a word ("clap" without the/k/) after which they heard a correct (lap) or incorrect (cap, ap, nose) answer. The PMN (peaking at 270 ms) was largest to incorrect items and did not differentiate between items that shared the same rime and items that were phonologically unrelated to the correct choice. Further, the PMN did not differ between word (cap) and nonword (ap) choices. The P300 was largest to correct items but was also seen to choices that rhymed with the correct answer. It is concluded that the PMN serves as a neural marker for the analysis of acoustic input merging with prelexical phonemic expectations.

Working memory, intelligence and knowledge base in adult persons with intellectual disability.

Previous studies have suggested that performance in working memory (WM) tasks is deficient in all etiologies and at all levels of intellectual disability (ID). Knowledge about WM structure, cognitive processes reflected in WM tasks, or the long-term memory contribution to WM capacity in ID is. however, not satisfactory. In the present study, WM capacity, WM task requirements, as well as effects between WM, skills, knowledge base, and intelligence were explored in two groups with matched fluid intelligence: adult persons with ID and normally developing children aged 3-6 years. The ID Group performed equally well as the children in WM tasks based on familiar semantic information and were significantly better on all measures reflecting skills and knowledge base. The Child Group performed better in phonological and visuo-spatial WM tasks including nonsemantic information, respectively. In particular, it appeared that the groups differed in their WM performance although they were matched for fluid intelligence. We hypothesize that the ID Group depended more on knowledge support from long-terrm memory whereas the Child Group could benefit more from efficient online WM processes.

Working memory in spelling: evidence from backward typing.

Theories of spelling (Margolin, 1984; Nolan & Caramazza, 1983) propose a working memory system for storing order and identity information of letters during the spelling process. Capacity limitations related to the use of such a graphemic buffer were explored. Participants had to type words backwards. Longer pauses between key presses were assumed to signal points at which graphemic buffer contents were refreshed. Five- and six-letter words were divided by a major pause into chunks of two and three letters, partly coinciding with syllables. Articulatory suppression had no effect on performance. Increasing the length of the stimuli to seven to eight letters resulted in major pauses occurring at syllable boundaries, and performance becoming vulnerable to articulatory suppression but not foot tapping. Forward typing resulted in a similar pause pattern. The results suggest that chunks of approximately three letters can be handled at any one time. For short words the task seems to rely on non-phonological modes of coding, whereas longer words appear to require the use of a phonological code, possibly for keeping track of progress through the word.

Working memory and everyday cognition in adults with Down's syndrome.

A number of previous studies have suggested that young people with Down's syndrome (DS) have a specific deficit of the phonological loop component of the working memory. However, there have also been studies which have proposed a specific deficit of the central executive component of working memory and suggested similarities of working memory functioning with patients with Alzheimer's disease. Fifteen middle-aged people with DS were matched for their individual scores of non-verbal intelligence to 15 individuals with mixed aetiology of intellectual disability. A versatile range of tasks was used in order to evaluate the functioning of working memory components. In addition, several everyday cognition skills were assessed. The subjects with DS performed significantly more poorly in all tasks assessing the phonological loop. Performance in other working memory tasks and compound variables representing different working memory components was equal in the groups. In addition, both groups had equal everyday cognition skills. The functioning of the phonological loop seems to be clearly deficient in people with DS. Interestingly, the deficit does not seem to affect the vocabulary or other everyday cognition skills in individuals with DS. No signs of specific deficit of the central executive component of working memory were found.

Phonological aspects of word recognition as revealed by high-resolution spatio-temporal brain mapping.

We describe, for the first time, the use of high-resolution event-related brain potentials (hrERP) to identify the spatio-temporal characteristics of neural systems involved in phonological analysis. Subjects studied a visual word/non-word that was followed by the brief presentation of a prime letter (e.g. House, M) with the instruction to anticipate the word/non-word formed by replacing the word's first letter with the prime letter. After the prime letter, an auditory target word/non-word was presented that either matched/mismatched expectations (e.g., Mouse/Barn). ERPs were recorded to the onset of the auditory targets and scalp topographical maps were derived for the phonological mismatch negativity (PMN). The PMN reflected phonological analysis and examination of the peak topography revealed that the response was characterized by a prominent frontal, right-asymmetrical distribution. Spatial de-blurring (using current source density maps) indicated that the PMN scalp topography resulted primarily from an active left anterior source. The current results provide the initial evidence for the localization of the intra-cranial generator(s) involved in phonological analysis.

Temporal order and processing acuity of visual, auditory, and tactile perception in developmentally dyslexic young adults.

We studied the temporal acuity of 16 developmentally dyslexic young adults in three perceptual modalities. The control group consisted of 16 age- and IQ-matched normal readers. Two methods were used. In the temporal order judgment (TOJ) method, the stimuli were spatially separate fingertip indentations in the tactile system, tone bursts of different pitches in audition, and light flashes in vision. Participants indicated which one of two stimuli appeared first. To test temporal processing acuity (TPA), the same 8-msec nonspeech stimuli were presented as two parallel sequences of three stimulus pulses. Participants indicated, without order judgments, whether the pulses of the two sequences were simultaneous or nonsimultaneous. The dyslexic readers were somewhat inferior to the normal readers in all six temporal acuity tasks on average. Thus, our results agreed with the existence of a pansensory temporal processing deficit associated with dyslexia in a language with shallow orthography (Finnish) and in well-educated adults. The dyslexic and normal readers' temporal acuities overlapped so much, however, that acuity deficits alone would not allow dyslexia diagnoses. It was irrelevant whether or not the acuity task required order judgments. The groups did not differ in the nontemporal aspects of our experiments. Correlations between temporal acuity and reading-related tasks suggested that temporal acuity is associated with phonological awareness.

Working memory structure and intellectual disability.

The working memory of people with intellectual disability has been found to generally lag behind their mental age. However, studies concerning the structure of working memory or its connections to other cognitive functions are rare. The present study employs a versatile battery of tests for the evaluation of working memory structure in adults with intellectual disability of unknown aetiology. In addition, connections between working memory and cognitive skills valid for everyday functioning are evaluated. Working memory performance in the study participants was found to stem from two distinct components which could be regarded to represent phonological and general working memory. General working memory was closely related to intelligence, whereas phonological working memory was not. The subjects in the study group differed in their working memory profiles. These distinct profiles were significantly related to academic skills (e.g. reading, writing and mathematics) and sentence comprehension because the profile of the working memory predicted these abilities even when the intelligence and educational background of the participants was taken into consideration.

Rate of information segregation in developmentally dyslexic children.

Slowed processing of sequential perceptual information is related to developmental dyslexia. We investigated this unimodally and crossmodally in developmentally dyslexic children and controls ages 8-12 years. The participants judged whether two spatially separate trains of brief stimuli, presented at various stimulus onset asynchronies (SOA) in one or two senses, were synchronous or not. The stimulus trains consisted of light flashes in vision, clicks in audition, and indentations of the skin in the tactile sense. The dyslexic readers required longer SOAs than controls for successful performance in all six comparisons. The crossmodal spatiotemporal resolution of the groups differed more than unimodal performance. The dyslexic readers' segregation performance was also less differentiated than that of the controls. Our results show that not only sensory but also polysensory nonverbal information processing is temporally impaired in dyslexic children.

Neurophysiology of fluent and impaired reading: a magnetoencephalographic approach.

This article reviews a series of magnetoencephalographic (MEG) experiments aimed at identifying cortical areas and time windows relevant or even critical for fluent reading. The approach was to compare single-word processing in fluent and dyslexic readers. The activations which differed between the two groups were then studied in more detail to determine their functional roles. In fluent reading, overall visual feature processing occurs about 100 milliseconds (ms) after seeing a word, in the posteromedial extrastriate cortex bilaterally. This activation does not differentiate between letters and symbols. The first reading-specific signal is detected about 150 ms after word onset, when the left inferior occipitotemporal cortex responds preferentially to letter strings. After 200 ms, the left superior temporal cortex, in particular, is engaged in semantic processing of single words and their integration with connected text. While visual feature processing seems to be within normal limits in dyslexic subjects, reading is disrupted during the first 200 ms after seeing a word, at the letter-string specific stage. The subsequent activations are weak and delayed as compared with those in fluent readers. Also presented is a case of deep dyslexia, where the same tools were used to demonstrate that reading comprehension was still subserved by the left hemisphere despite severe damage.

Semantic cortical activation in dyslexic readers.

The combined temporal and spatial resolution of MEG (magnetoencephalography) was used to study whether the same brain areas are similarly engaged in reading comprehension in normal and developmentally dyslexic adults. To extract a semantically sensitive stage of brain activation we manipulated the appropriateness of sentence-ending words to the preceding sentence context. Sentences, presented visually one word at a time, either ended with a word that was (1) expected, (2) semantically appropriate but unexpected, (3) semantically anomalous but sharing the initial letters with the expected word, or (4) both semantically and orthographically inappropriate to the sentence context. In both subject groups all but the highly expected sentence endings evoked strong cortical responses, localized most consistently in the left superior temporal cortex, although additional sources were occasionally found in more posterior parietal and temporal areas and in the right hemisphere. Thus, no significant differences were found in the spatial distribution of brain areas involved in semantic processing between fluent and dyslexic readers. However, both timing and strength of activation clearly differed between the two groups. First, activation sensitivity to word meaning within a sentence context began about 100 msec later in dyslexic than in control subjects. This is likely to result from affected presemantic processing stages in dyslexic readers. Second, the neural responses were significantly weaker in dyslexic than in control subjects, indicating involvement of a smaller or less-synchronous neural population in reading comprehension. Third, in contrast to control subjects, the dyslexic readers showed significantly weaker activation to semantically inappropriate words that began with the same letters as the most expected word than to both orthographically and semantically inappropriate sentence-ending words. Thus, word recognition by the dyslexic group seemed to be qualitatively different: Whereas control subjects perceived words as wholes, dyslexic subjects may have relied on sublexical word recognition and occasionally mistook a correctly beginning word for the one they had expected.

Children's performance on pseudoword repetition depends on auditory trace quality: evidence from event-related potentials.

This study explored the relation between phonological short-term memory and auditory-sensory processing in 7-9-year-old children. Twenty-four participants performed a pseudoword repetition test. The mismatch-negativity (MMN) component of auditory event-related brain potentials was obtained from 9 participants with the highest and 9 participants with the lowest scores on the test. The MMN indexes short-term auditory-sensory memory, including auditory-sensory representations for speech. It was recorded to just perceptible /baga/-/baka/ bisyllabic and easily discriminable 1000/1100-Hz tone contrasts with interstimulus intervals of 350 and 2,000 ms. The high and low repeaters differed significantly in MMN amplitude to speech stimuli at the shorter interstimulus interval. Thus, the accuracy of auditory-sensory processing seems to affect phonological short-term representations in school-age children and therefore may play a role in vocabulary development.

Distinct time courses of word and context comprehension in the left temporal cortex.

The time course and cortical basis of reading comprehension were studied using magnetoencephalography. The cortical structures implicated most consistently with comprehension were located in the immediate vicinity of the left auditory cortex, where final words totally inappropriate to the overall sentence context evoked enduring activation starting approximately 250 ms and lasting up to 600 ms after word onset. Contextually appropriate but unexpected words produced weaker activation which terminated earlier. Highly anticipated words totally failed to activate this area, suggesting that the conceptual network became involved only if unexpected information was detected during the primary word identification process. We propose that the point in time (350 ms after word onset) where the response to appropriate but unexpected endings started to diverge from those to contextually inappropriate endings reflects the boundary between understanding a single word and the meaning of a whole sentence.

Phonological short-term memory and new word learning in children.

Sixty-five 5-year old children participated in 4 experimental tasks of word learning that varied systematically in the amounts of phonological and nonphonological learning required. Measures of the children's performances on 2 measures of phonological memory (digit span and nonword repetition), vocabulary knowledge, and nonverbal ability were also obtained. Learning of the sound structures of new words was significantly, and to some degree independently, associated with aspects of both phonological memory skill and vocabulary knowledge. Learning of pairs of familiar words was linked with current vocabulary knowledge, although not with phonological memory scores. The findings suggest that both existing lexical knowledge and phonological short-term memory play significant roles in the long-term learning of the sounds of new words. The study also provides evidence of both shared and distinct processes contributing to nonword repetition and digit span tasks.

A dissociation between simple and complex span impairment in alcoholics.

We investigated whether the surprisingly good memory performance of alcoholics may result from simple memory performance being spared while performance in complex memory tasks is impaired. Simple word span was contrasted with a complex word span task involving concurrent monitoring and re-organisation of items for recall. To control for disruption of rehearsal in the complex word span task, performance on two additional tasks with disrupted rehearsal but no additional processing components was studied. As hypothesised, the alcoholics showed a deficit in the complex but not the simple word span task. They were also impaired, compared to controls, on both tasks with disrupted rehearsal. The difference between groups remained in the complex span task when scores in simple span and either of the two other tasks were used as covariates. Thus, both executive processes necessary for coping with disrupted rehearsal and additional processes scheduling processing and storage in a complex task may play a role in accounting for working memory deficits found in alcoholics.

Impaired visual word processing in dyslexia revealed with magnetoencephalography.

Dyslexia is most often attributed to phonological impairments, manifested in abnormal activation of the left temporal and temporoparietal cortex in response to auditorily presented language and possibly associated with anomalies in the cytoarchitecture and hemispheric symmetry of the plana temporale. The immediate cortical correlate of the severely impaired reading process has, however, remained obscure. Here we report on the distinct time courses of cortical activation in dyslexic and control subjects during passive viewing of single words, tracked with whole-head magnetoencephalography. A striking difference was found in the left inferior temporo-occipital region where intracranial recordings have recently identified word-specific responses within 200 msec after stimulus onset: controls showed a sharp activation at about 180 msec after word presentation, whereas dyslexics failed to activate this area entirely, or showed a slowly increasing late response. Perception of words as specific units thus seems to be impaired in dyslexics.

Phonology, working memory, and foreign-language learning.

Three tasks were used to predict English learning by Finnish children over a three-year period. In the pseudoword repetition task the pupils had to repeat aloud tape-recorded pseudowords sounding like Finnish or English. In the pseudoword copying task the pupils saw strings of letters resembling Finnish or English words and copied them when they had disappeared from view. When comparing syntactic-semantic structures, the pupils had to find the syntactically matching pairs from two sets of Finnish sentences. Repetition and copying accuracy and the ability to compare syntactic-semantic structures predicted English learning. Intercorrelations between test scores and English and mathematics grades suggest that repetition and copying accuracy were specifically related to language learning. It is concluded that the ability to represent unfamiliar phonological material in working memory underlies the acquisition of new vocabulary items in foreign-language learning.

Oral magnesium reduces ventricular ectopy in digitalised patients with chronic atrial fibrillation.

We have examined the effects of magnesium replacement therapy upon post-exercise heart rate and incidence of ventricular premature beats (VPB) in digitalised patients with AF. In 11 such patients, all of whom had serum magnesium concentrations of less than 0.85 mmol/l, treatment with magnesium glycerophosphate was associated with a significant reduction in number of VPBs (982 v. 416 VPB/24 h). Five patients had a high prevalence of ventricular ectopy (greater than 300 VPB/24 h) and these subjects showed particularly marked decreases in VPBs during magnesium treatment (1998 v. 690 VPB/24 h). Three patients had slightly increased QTc intervals but these did not change during magnesium replacement. No significant changes were seen in the mean post-exercise heart rate although 2 subjects did show falls of 25% or more during magnesium replacement. We conclude that treatment with magnesium glycerophosphate may be associated with a decreased prevalence of ventricular ectopy in some digitalised patients with chronic AF and mild-moderate hypomagnesaemia.

A comparison of digoxin, diltiazem and their combination in the treatment of atrial fibrillation.

Fourteen patients (four females) with chronic atrial fibrillation were entered into a randomized, double-blind crossover study to compare the effects of treatment with diltiazem alone, digoxin alone, and a combination of diltiazem plus digoxin. The dose of digoxin was adjusted so as to achieve serum concentrations within the range 1.3-2.6 nmol l-1 between six and eight hours after dosing. Four patients were withdrawn from the study; three patients experienced side effects while taking diltiazem and one reverted to sinus rhythm while taking digoxin. Among the remaining 10 patients, mean heart rates were significantly lower during treatment with the combination of digoxin and diltiazem than with digoxin alone both at rest, after exercise and during ambulatory ECG monitoring. Post-exercise heart rates were reduced by 15% with combination therapy when compared with digoxin alone (151.9 vs. 128.1 bpm), but there was no evidence that this reduction in ventricular rate was associated with improved exercise tolerance. The results suggest that further reduction of the rapid ventricular rates seen in digitalized patients with AF by the use of diltiazem does not appear to be of benefit in the majority of patients.