Deficient Response to Altered Auditory Feedback in Dyslexia.

Although dyslexia is characterized by a deficit in phonological representations, the nature of this deficit is debated. Previously, it was shown that adults with dyslexia respond differently to online manipulations of auditory feedback. In the present study, we found that individual differences in reading and reading-related skills within a group of 30 children (10-13 years old) with dyslexia were associated with the response to altered feedback. The fractional anisotropy of the arcuate fasciculus/superior longitudinal fasciculus was not directly related to the response to altered feedback. This study corroborates that speech perception-production communication is important for phonological representations and reading.

Transition from LDR to HDR brachytherapy for cervical cancer: Evaluation of tumor control, survival, and toxicity.

PURPOSE: In 2012, our institution transitioned from low-dose-rate (LDR) brachytherapy to high dose-rate (HDR) brachytherapy. We report clinical outcomes after brachytherapy for cervical cancer at our institution over a continuous 10-year period. METHODS AND MATERIALS: From 2004 to 2014, 258 women (184 LDR and 74 HDR) were treated with tandem and ovoid brachytherapy in the multidisciplinary management of International Federation of Gynecology and Obstetrics Stages IA-IVB cervical cancer. Clinical and treatment-related prognostic factors including age, stage, smoking status, relevant doses, and toxicity data were recorded. RESULTS: Median followup for the LDR and HDR groups was 46 months and 12 months, respectively. The majority of patients (92%) received external beam radiotherapy as well as concurrent chemotherapy (83%) before the start of brachytherapy. For all stages, the 1-year local control and overall survival (OS) rates were comparable between the LDR and HDR groups (87% vs. 81%, p = 0.12; and 75% vs. 85%, p = 0.16), respectively. Factors associated with OS on multivariate analysis include age, stage, and nodal involvement. On multivariate analysis, severe toxicity (acute or chronic) was higher with HDR than LDR (24% vs. 10%, p = 0.04). Additional prognostic factors associated with increased severe toxicity include former/current smokers and total dose to lymph nodes. CONCLUSIONS: This comparative retrospective analysis of a large cohort of women treated with brachytherapy demonstrates no significant difference in OS or local control between the LDR and HDR. Acute and chronic toxicity increased shortly after the implementation of HDR, highlighting the importance of continued refinement of HDR methods, including integrating advanced imaging.

Understanding jumping to conclusions in patients with persecutory delusions: working memory and intolerance of uncertainty.

BACKGROUND: Persecutory delusions are a key psychotic experience. A reasoning style known as 'jumping to conclusions' (JTC) - limited information gathering before reaching certainty in decision making - has been identified as a contributory factor in the occurrence of delusions. The cognitive processes that underpin JTC need to be determined in order to develop effective interventions for delusions. In the current study two alternative perspectives were tested: that JTC partially results from impairment in information-processing capabilities and that JTC is a motivated strategy to avoid uncertainty. METHOD: A group of 123 patients with persistent persecutory delusions completed assessments of JTC (the 60:40 beads task), IQ, working memory, intolerance of uncertainty, and psychiatric symptoms. Patients showing JTC were compared with patients not showing JTC. RESULTS: A total of 30 (24%) patients with delusions showed JTC. There were no differences between patients who did and did not jump to conclusions in overall psychopathology. Patients who jumped to conclusions had poorer working memory performance, lower IQ, lower intolerance of uncertainty and lower levels of worry. Working memory and worry independently predicted the presence of JTC. CONCLUSIONS: Hasty decision making in patients with delusions may partly arise from difficulties in keeping information in mind. Interventions for JTC are likely to benefit from addressing working memory performance, while in vivo techniques for patients with delusions will benefit from limiting the demands on working memory. The study provides little evidence for a contribution to JTC from top-down motivational beliefs about uncertainty.

Neuroimaging reveals dual routes to reading in simultaneous proficient readers of two orthographies.

Orthographic differences across languages impose differential weighting on distinct component processes, and consequently on different pathways during word-reading tasks. Readers of transparent orthographies such as Italian and Hindi are thought to rely on spelling-to-sound assembly and show increased activation in phonologically tuned areas along the dorsal pathway, whereas reading an opaque orthography such as English is thought to rely more on lexically mediated processing associated with increased activation of semantically tuned regions along the ventral pathway. To test if biliterate Hindi/English readers exhibit orthography-specific reading pathways, we used behavioural measures and functional neuroimaging. Reaction times and activation patterns of monolingual English and Hindi readers were compared to two groups of adult biliterates; 14 simultaneous readers who learnt to read both languages at age 5 and 10 sequential readers who learnt Hindi at 5 and English at 10. Simultaneous, but not sequential readers demonstrated relative activation differences of dorsal and ventral areas in the two languages. Similar to native counterparts, simultaneous readers preferentially activated the left inferior temporal gyrus for English and left inferior parietal lobule (L-IPL) for Hindi, whereas, sequential readers showed higher activation along the L-IPL for reading both languages. We suggest that early simultaneous exposure to reading distinct orthographies results in orthography-specific plasticity that persists through adulthood.

Functional MRI of sentence comprehension in children with dyslexia: beyond word recognition.

Sentence comprehension (SC) studies in typical and impaired readers suggest that reading for meaning involves more extensive brain activation than reading isolated words. Thus far, no reading disability/dyslexia (RD) studies have directly controlled for the word recognition (WR) components of SC tasks, which is central for understanding comprehension processes beyond WR. This experiment compared SC to WR in 29, 9-14 year olds (15 typical and 14 impaired readers). The SC-WR contrast for each group showed activation in left inferior frontal and extrastriate regions, but the RD group showed significantly more activation than Controls in areas associated with linguistic processing (left middle/superior temporal gyri), and attention and response selection (bilateral insula, right cingulate gyrus, right superior frontal gyrus, and right parietal lobe). Further analyses revealed this overactivation was driven by the RD group's response to incongruous sentences. Correlations with out-of-scanner measures showed that better word- and text-level reading fluency was associated with greater left occipitotemporal activation, whereas worse performance on WR, fluency, and comprehension (reading and oral) were associated with greater right hemisphere activation in a variety of areas, including supramarginal and superior temporal gyri. Results provide initial foundations for understanding the neurobiological correlates of higher-level processes associated with reading comprehension.

What makes one person paranoid and another person anxious? The differential prediction of social anxiety and persecutory ideation in an experimental situation.

BACKGROUND: In recent years a close association between anxiety and persecutory ideation has been established, contrary to the traditional division of neurosis and psychosis. Nonetheless, the two experiences are distinct. The aim of this study was to identify factors that distinguish the occurrence of social anxiety and paranoid thoughts in an experimental situation. METHOD: Two hundred non-clinical individuals broadly representative of the UK general population were assessed on a range of psychological factors, experienced a neutral virtual reality social environment, and then completed state measures of paranoia and social anxiety. Clustered bivariate logistic regressions were carried out, testing interactions between potential predictors and the type of reaction in virtual reality. RESULTS: The strongest finding was that the presence of perceptual anomalies increased the risk of paranoid reactions but decreased the risk of social anxiety. Anxiety, depression, worry and interpersonal sensitivity all had similar associations with paranoia and social anxiety. CONCLUSIONS: The study shows that social anxiety and persecutory ideation share many of the same predictive factors. Non-clinical paranoia may be a type of anxious fear. However, perceptual anomalies are a distinct predictor of paranoia. In the context of an individual feeling anxious, the occurrence of odd internal feelings in social situations may lead to delusional ideas through a sense of 'things not seeming right'. The study illustrates the approach of focusing on experiences such as paranoid thinking rather than diagnoses such as schizophrenia.

Differential components of sentence comprehension: beyond single word reading and memory.

A number of studies have used functional neuroimaging to examine the neural mechanisms of sentence comprehension; however, few fMRI studies have examined activation patterns associated with sentence comprehension after accounting for activation attributable to single-word-level tasks important for sentence comprehension. To investigate the patterns of activation associated with sentence comprehension after controlling for single word reading and maintaining single words in memory, 20 unimpaired adult readers completed a block design paradigm which included sentence comprehension, single word reading, and short-term memory (for words) tasks. Results indicated that, regardless of the aspect of sentence comprehension being controlled for, activation was observed in bilateral temporal lobes (left > right) as well as bilateral occipital lobes and middle frontal gyri. Additional findings showed that bilateral superior parietal lobe activation was greatest for short-term memory for words, while left anterior inferior frontal gyri activation (centered around Brodmann's area 47) was greatest for single word reading. Results suggest that temporal cortex (left > right) is a core region important for sentence comprehension beyond the short-term memory and semantic requirements inherent in processing sentences.

Neural correlates of temporal-order judgments versus those of spatial-location: deactivation of hippocampus may facilitate spatial performance.

The retrieval of temporal-order versus spatial-location information was investigated using fMRI. The primary finding in the hippocampus proper, seen in region of interest analyses, was an increase in BOLD signal intensity for temporal retrieval, and a decrease in signal intensity for spatial retrieval, relative to baseline. The negative BOLD signal change with spatial memory processing, while unexpected, is consistent with the recent fMRI literature indicating decreased BOLD can be associated with neuronal activation, and it is argued that the deactivation observed here may facilitate spatial performance. Spatial-location judgments also yielded a stronger (positive) response in the right midfrontal gyrus, while temporal-order judgments (autobiographic condition only) showed greater activity in the left superior temporal gyrus, suggesting greater working memory demands and greater semantization for each judgment type, respectively. Finally, all conditions activated the left midfrontal gyrus, although autobiographic memories showed additional activity in the medial frontal gyrus.

Investigating a simple model of cutaneous wound healing angiogenesis.

A simple model of wound healing angiogenesis is presented, and investigated using numerical and asymptotic techniques. The model captures many key qualitative features of the wound healing angiogenic response, such as the propagation of a structural unit into the wound centre. A detailed perturbative study is pursued, and is shown to capture all features of the model. This enables one to show that the level of the angiogenic response predicted by the model is governed to a good approximation by a small number of parameter groupings. Further investigation leads to predictions concerning how one should select between potential optimal means of stimulating cell proliferation in order to increase the level of the angiogenic response.

Successful thrombolytic therapy of pulmonary embolism associated with urosepsis in an infant.

Childhood pulmonary embolism (PE) is a rare but serious condition marked by hypoxemia, shock, right-sided heart failure, and significant risk for fatality. Recommended treatment options include surgical embolectomy, anticoagulation, and thrombolysis. This report describes the successful use of recombinant tissue plasminogen activator to treat PE associated with urosepsis in a 34-day-old infant and reverse severe hemodynamic compromise. Diagnosis of proximal PE and monitoring its treatment were successfully achieved by echocardiography.

Neurobiological studies of reading and reading disability.

UNLABELLED: Evidence from neuroimaging studies, including our own, suggest that skilled word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system appears to be functionally disrupted in developmental dyslexia. Relative to nonimpaired readers, reading-disabled individuals demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers, the dorsal circuit predominates at first, and in conjunction with premotor systems, is associated with analytic processing necessary for learning to integrate orthographic with phonological and lexical semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word form system, which underlies fluency in word recognition. LEARNING OUTCOMES: As a result of this activity, (1) the participant will learn about a model of lexical processing involving specific cortical regions. (2) The participant will learn about evidence which supports the theory that two dorsal LH systems may be disrupted in developmental dyslexia. (3) The participant will learn that individuals with reading impairment may rely on other regions of the brain to compensate for the disruption of posterior function.

Functional MRI of language processing: dependence on input modality and temporal lobe epilepsy.

PURPOSE: Functional magnetic resonance imaging (MRI) using two language-comprehension tasks was evaluated to determine its ability to lateralize language processing and identify regions that must be spared in surgery. METHODS: Two parallel cognitive language tasks, one using auditory input and the other visual input, were tested in a group of control subjects and in temporal lobe epilepsy patients who were candidates for surgical intervention. The patient studies provide an opportunity to compare functional MRI language localization with that obtained using Wada testing and electrocorticography. All of the patients in this study underwent all three procedures and a battery of neuropsychological testing. Such studies provide an opportunity not only to validate the fMRI findings but also, by comparing the patient results with those obtained in control subjects, to provide insight into the impact of a pathology such as epilepsy on cortical organization or functional patterns of activation. RESULTS: The results reveal both modality-dependent and modality-independent language-processing patterns for visual versus auditory task presentation. The visual language task activated distinct sites in Broca's area, BA (Brodmann area) 44 that were not activated in the auditory language task. The auditory language task strongly activated contralateral right BA22-21 area (homologous to Wernicke's area on the left). Language lateralization scores were significantly stronger for visual than for auditory task presentation. The conjunction of activation from the two different input modalities (modality-independent areas) likely highlights regions that perform more abstract computations (e.g., syntactic or pragmatic processing) in language processing. Modality-specific areas (e.g., right Wernicke, left fusiform gyrus, Broca BA44, supramarginal gyrus), appear to cope with the computations relevant to making contact with these more abstract dimensions. Patients showed recruitment of contralateral homologous language areas (p < 0.005) that was significantly above that found in a normal control group. Extra- and intraoperative cortical stimulations were concordant with the fMRI data in eight of 10 cases. The fMRI lateralization scores were also consistent with the Wada testing in 8/10 patients. CONCLUSIONS: The fMRI results demonstrate that the epileptic brain may be a progressive model for cortical plasticity.

Clinical implications of physiological changes in the aging heart.

Elderly individuals experience a disproportionate burden from cardiovascular disease. Global changes in aging will have a significant impact on the future of medical practice. However, most physicians have little formal training in geriatric medicine and sometimes fail to distinguish disease states from normal aging. Increasingly, it is recognised that a sedentary lifestyle may be responsible for a large fraction of the so-called 'age-related' changes in the cardiovascular system. Nonetheless, well characterised changes do occur in most individuals with aging. Loss of myocytes with subsequent hypertrophy of the remaining cells is usually observed. Calcification involving the conduction and valvular apparatus is seen in most elderly individuals and may predispose to the common arrhythmias of old age. Age-related loss of arterial compliance contributes to isolated systolic hypertension and left ventricular hypertrophy. Despite these changes, for the majority of healthy older adults, cardiac output is well maintained in the basal state through use of the Frank-Starling principle, in the setting of reduced early diastolic filling. Myocardial relaxation is slowed in part due to age-related changes in the sarcoplasmic reticulum Ca2+ ATPase pump. Elevated blood levels of catecholamines contribute to desensitisation to noradrenergic stimulation and this is associated with an age-related decline in maximum achievable heart rate. Changes in the baroreceptor reflex function and decreased sodium conservation may predispose some individuals to orthostatic and postprandial hypotension. The aetiology of cardiovascular aging is under intense study. The most likely mechanisms involve the result of cumulative damage mediated through a variety of insults. Oxidative stress, non-enzymatic glycation, inflammation and changes in cardiovascular gene expression all seem to influence cardiovascular aging. The benefits of exercise continue to be discovered. Endurance-type training has been shown to have a dramatic impact on parameters of cardiovascular aging. Favourable effects are seen in maximum oxygen consumption, diastolic filling, relaxation and arterial stiffness. Some changes such as the maximum heart rate response do not appear to change with conditioning. Pharmacotherapy may afford the opportunity to influence the aging process. Drugs that can reduce age-associated arterial stiffness, cardiac fibrosis and ventricular hypertrophy should prove useful. Antioxidants continue to be a topic of great interest and require more study. Despite some well described changes with aging, most elderly individuals maintain the opportunity for improved cardiovascular function through conditioning. Early recognition and treatment of diseases that are distinguishable from normal aging, including hypertension and atherosclerosis, together with preventive efforts, should reduce the predicted trends in cardiovascular morbidity and mortality among the aged.

The functional neural architecture of components of attention in language-processing tasks.

Using functional magnetic resonance imaging we examined three important dimensions of attentional control (selective attention, divided attention, and executive function) in 25 neurologically normal, right-handed men and women, using tasks involving the perception and processing of printed words, spoken words, or both. In the context of language-processing manipulations: selective attention resulted in increased activation at left hemisphere parietal sites as well as at inferior frontal sites, divided attention resulted in additional increases in activation at these same left hemisphere sites and was also uniquely associated with increased activation of homologous sites in the right hemisphere, and executive function (measured during a complex task requiring sequential decision-making) resulted in increased activation at frontal sites relative to all other conditions. Our findings provide support for the belief that specific functional aspects of attentional control in language processing involve widely distributed but distinctive cortical systems, with mechanisms associated with the control of perceptual selectivity involving primarily parietal and inferior frontal sites and executive function engaging specific sites in frontal cortex.

Network analysis of brain activations in working memory: behavior and age relationships.

Forty-six middle-aged female subjects were scanned using functional Magnetic Resonance Imaging (fMRI) during performance of three distinct stages of a working memory task-encoding, rehearsal, and recognition-for both printed pseudowords and visual forms. An expanse of areas, involving the inferior frontal, parietal, and extrastriate cortex, was active in response to stimuli during both the encoding and recognition periods. Additional increases during memory recognition were seen in right prefrontal regions, replicating a now-common finding [for reviews, see Fletcher et al. (1997) Trends Neurosci 20:213-218; MacLeod et al. (1998) NeuroImage 7:41-48], and broadly supporting the Hemispheric Encoding/Retrieval Asymmetry hypothesis [Tulving et al. (1994) Proc Natl Acad Sci USA 91:2016-2020]. Notably, this asymmetry was not qualified by the type of material being processed. A few sites demonstrated higher activity levels during the rehearsal period, in the absence of any new stimuli, including the medial extrastriate, precuneus, and the medial temporal lobe. Further analyses examined relationships among subjects' brain activations, age, and behavioral scores on working memory tests, acquired outside the scanner. Correlations between brain scores and behavior scores indicated that activations in a number of areas, mainly frontal, were associated with performance. A multivariate analysis, Partial Least Squares [McIntosh et al. (1996) NeuroImage 3:143-157, (1997) Hum Brain Map 5:323-327], was then used to extract component effects from this large set of univariate correlations. Results indicated that better memory performance outside the scanner was associated with higher activity at specific sites within the frontal and, additionally, the medial temporal lobes. Analysis of age effects revealed that younger subjects tended to activate more than older subjects in areas of extrastriate cortex, medial frontal cortex, and the right medial temporal lobe; older subjects tended to activate more than younger subjects in the insular cortex, right inferior temporal lobe, and right inferior frontal gyrus. These results extend recent reports indicating that these regions are specifically involved in the memory impairments seen with aging.

Functional neuroimaging studies of reading and reading disability (developmental dyslexia).

Converging evidence from a number of neuroimaging studies, including our own, suggest that fluent word identification in reading is related to the functional integrity of two consolidated left hemisphere (LH) posterior systems: a dorsal (temporo-parietal) circuit and a ventral (occipito-temporal) circuit. This posterior system is functionally disrupted in developmental dyslexia. Reading disabled readers, relative to nonimpaired readers, demonstrate heightened reliance on both inferior frontal and right hemisphere posterior regions, presumably in compensation for the LH posterior difficulties. We propose a neurobiological account suggesting that for normally developing readers the dorsal circuit predominates at first, and is associated with analytic processing necessary for learning to integrate orthographic features with phonological and lexical-semantic features of printed words. The ventral circuit constitutes a fast, late-developing, word identification system which underlies fluent word recognition in skilled readers.

Investigation of the human hippocampal formation using a randomized event-related paradigm and Z-shimmed functional MRI.

Functional neuroimaging of the hippocampal formation has presented a challenge to neuroscientists because of the small size of the hippocampus proper and its location at the basal level of the brain. Choosing the appropriate control condition for subtraction-based studies has also proved difficult. Event-related experimental designs are a powerful tool in behavioral and electrophysiological studies. Recently, such experimental designs have been applied to functional MR imaging studies but these studies used large intertrial intervals in order to separate the slow blood flow response from temporally adjacent events, severely limiting the number of events that can be presented in a single run. This leads to poor statistical power and restrictions on the design of the experimental paradigm. We present data obtained using a rapidly presented, randomized event-related paradigm, combined with a novel fMRI imaging method designed to improve imaging in basal brain regions. The results demonstrate bilateral activation in the hippocampal formation in identification of novel complex scenes distinct from a learned basis set of complex scenes. Differential activation is obtained in the counter task of identifying a learned target complex scene against a background of novel scenes. The results are also compared with the more conventional block design complex scene paradigms previously reported by others. The block design provides strong posterior activation, likely related more to visual scene processing, whereas the event-related design provides more anterior hippocampal activation with the encoding of novel scenes.

Supracondylar humerus fractures in children. Comparison of operative treatment methods.

A retrospective analysis was performed of 87 children treated operatively for supracondylar humerus fractures by 18 different surgeons during a 6-year period. No patient suffered from compartment syndrome or Volkmann's ischemic contracture. Early postoperative fracture displacement occurred in four (7%) of 60 patients with Type III fractures, and in one (4%) of 23 patients with Type II fractures. Displacement occurred in one (2%) of 52 Type III fractures stabilized with crossed medial and lateral Kirschner wires, whereas displacement occurred in two (28%) of seven Type III fractures stabilized with lateral wires only. Thirty-four patients could be located for long-term followup; complete examination of both upper extremities was performed on these 34 patients at an average of 33 months postoperatively. The long-term results were excellent in 19 (56%), good in seven (21%), fair in one (3%), and poor in seven (21%) patients. Five additional patients were not available for followup at the time of the current study, but had followup of at least 6 months available. Of the 39 patients with followup of at least 6 months, five patients' fractures (13%) healed with coronal plane malalignment greater than 10 degrees which resulted in gunstock deformity. There was no statistically significant relationship between treatment method and gunstock deformity. However, none of the patients with gunstock deformity had compromised activity because of the deformity, and all had full elbow extension and at least 130 degrees elbow flexion.

An event-related neuroimaging study distinguishing form and content in sentence processing.

Two coordinated experiments using functional Magnetic Resonance Imaging (fMRI) investigated whether the brain represents language form (grammatical structure) separately from its meaning content (semantics). While in the scanner, 14 young, unimpaired adults listened to simple sentences that were either nonanomalous or contained a grammatical error (for example, *Trees can grew.), or a semantic anomaly (for example, *Trees can eat.). A same⁄different tone pitch judgment task provided a baseline that isolated brain activity associated with linguistic processing from background activity generated by attention to the task and analysis of the auditory input. Sites selectively activated by sentence processing were found in both hemispheres in inferior frontal, middle, and superior frontal, superior temporal, and temporo-parietal regions. Effects of syntactic and semantic anomalies were differentiated by some nonoverlapping areas of activation: Syntactic anomaly triggered significantly increased activity in and around Broca's area, whereas semantic anomaly activated several other sites anteriorly and posteriorly, among them Wernicke's area. These dissociations occurred when listeners were not required to attend to the anomaly. The results confirm that linguistic operations in sentence processing can be isolated from nonlinguistic operations and support the hypothesis of a specialization for syntactic processing.