Language function in childhood idiopathic epilepsy syndromes.

PURPOSE: To examine the impact of diverse syndromes of focal and generalized epilepsy on language function in children with new and recent onset epilepsy. Of special interest was the degree of shared language abnormality across epilepsy syndromes and the unique effects associated with specific epilepsy syndromes. METHODS: Participants were 136 youth with new or recent-onset (diagnosis within past 12 months) epilepsy and 107 healthy first-degree cousin controls. The participants with epilepsy included 20 with Temporal Lobe Epilepsy (TLE; M age = 12.99  years, SD = 3.11), 41 with Benign Epilepsy with Centrotemporal Spikes (BECTS; M age = 10.32, SD = 1.67), 42 with Juvenile Myoclonic Epilepsy (JME; M age = 14.85, SD = 2.75) and 33 with absence epilepsy (M age = 10.55, SD = 2.76). All children were administered a comprehensive test battery which included multiple measures of language and language-dependent abilities (i.e., verbal intelligence, vocabulary, verbal reasoning, object naming, reception word recognition, word reading, spelling, lexical and semantic fluency, verbal list learning and delayed verbal memory). Test scores were adjusted for age and gender and analyzed via MANCOVA. RESULTS: Language abnormalities were found in all epilepsy patient groups. The most broadly affected children were those with TLE and absence epilepsy, whose performance differed significantly from controls on 8 of 11 and 9 of 11 tests respectively. Although children with JME and BECTS were less affected, significant differences from controls were found on 4 of 11 tests each. While each group had a unique profile of language deficits, commonalities were apparent across both idiopathic generalized and localization-related diagnostic categories. DISCUSSION: The localization related and generalized idiopathic childhood epilepsies examined here were associated with impact on diverse language abilities early in the course of the disorder.

Cognitive development: gaming your way out of dyslexia?

A recent study found that dyslexic children trained on action video games show significant improvements on basic measures of both attention and reading ability, suggesting future directions for the study of dyslexia intervention paradigms.

Thalamofrontal neurodevelopment in new-onset pediatric idiopathic generalized epilepsy.

BACKGROUND: Quantitative MRI techniques have demonstrated thalamocortical abnormalities in idiopathic generalized epilepsy (IGE). However, there are few studies examining IGE early in its course and the neurodevelopmental course of this region is not adequately defined. OBJECTIVE: We examined the 2-year developmental course of the thalamus and frontal lobes in pediatric new-onset IGE (i.e., within 12 months of diagnosis). METHODS: We performed whole-brain MRI in 22 patients with new-onset IGE and 36 age-matched healthy controls. MRI was repeated 24 months after baseline MRI. Quantitative volumetrics were used to examine thalamic and frontal lobe volumes. RESULTS: The IGE group showed significant differences in thalamic volume within 1 year of seizure onset (baseline) and went on to show thalamic volume loss at a significantly faster rate than healthy control children over the 2-year interval. The control group also showed a significantly greater increase in frontal white matter expansion than the IGE group. In contrast, frontal lobe gray matter volume differences were moderate at baseline and persisted over time, indicating similar developmental trajectories with differences early in the disease process that are maintained. CONCLUSIONS: Brain tissue abnormalities in thalamic and frontal regions can be identified very early in the course of IGE and an abnormal trajectory of growth continues over a 2-year interval.

Semantic memory activation in individuals at risk for developing Alzheimer disease.

OBJECTIVE: To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE epsilon4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names. METHODS: Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no epsilon4 allele (control [CON]); 2) family history, no epsilon4 allele (FH); and 3) family history and epsilon4 allele (FH+epsilon4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). RESULTS: Cognitively intact older adults with AD risk factors (FH and FH+epsilon4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+epsilon4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. CONCLUSIONS: Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.

Semantic memory activation in amnestic mild cognitive impairment.

Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65-85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE epsilon4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame--Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.

Genotype differences in cognitive functioning in Noonan syndrome.

Noonan syndrome (NS) is an autosomal-dominant genetic disorder associated with highly variable features, including heart disease, short stature, minor facial anomalies and learning disabilities. Recent gene discoveries have laid the groundwork for exploring whether variability in the NS phenotype is related to differences at the genetic level. In this study, we examine the influence of both genotype and nongenotypic factors on cognitive functioning. Data are presented from 65 individuals with NS (ages 4-18) who were evaluated using standardized measures of intellectual functioning. The cohort included 33 individuals with PTPN11 mutations, 6 individuals with SOS1 mutations, 1 individual with a BRAF mutation and 25 participants with negative, incomplete or no genetic testing. Results indicate that genotype differences may account for some of the variation in cognitive ability in NS. Whereas cognitive impairments were common among individuals with PTPN11 mutations and those with unknown mutations, all of the individuals with SOS1 mutations exhibited verbal and nonverbal cognitive skills in the average range or higher. Participants with N308D and N308S mutations in PTPN11 also showed no (or mild) cognitive delays. Additional influences such as hearing loss, motor dexterity and parental education levels accounted for significant variability in cognitive outcomes. Severity of cardiac disease was not related to cognitive functioning. Our results suggest that some NS-causing mutations have a more marked impact on cognitive skills than others.

Modulation of the semantic system by word imageability.

A prevailing neurobiological theory of semantic memory proposes that part of our knowledge about concrete, highly imageable concepts is stored in the form of sensory-motor representations. While this theory predicts differential activation of the semantic system by concrete and abstract words, previous functional imaging studies employing this contrast have provided relatively little supporting evidence. We acquired event-related functional magnetic resonance imaging (fMRI) data while participants performed a semantic similarity judgment task on a large number of concrete and abstract noun triads. Task difficulty was manipulated by varying the degree to which the words in the triad were similar in meaning. Concrete nouns, relative to abstract nouns, produced greater activation in a bilateral network of multimodal and heteromodal association areas, including ventral and medial temporal, posterior-inferior parietal, dorsal prefrontal, and posterior cingulate cortex. In contrast, abstract nouns produced greater activation almost exclusively in the left hemisphere in superior temporal and inferior frontal cortex. Increasing task difficulty modulated activation mainly in attention, working memory, and response monitoring systems, with almost no effect on areas that were modulated by imageability. These data provide critical support for the hypothesis that concrete, imageable concepts activate perceptually based representations not available to abstract concepts. In contrast, processing abstract concepts makes greater demands on left perisylvian phonological and lexical retrieval systems. The findings are compatible with dual coding theory and less consistent with single-code models of conceptual representation. The lack of overlap between imageability and task difficulty effects suggests that once the neural representation of a concept is activated, further maintenance and manipulation of that information in working memory does not further increase neural activation in the conceptual store.

Cerebellar atrophy in temporal lobe epilepsy affects procedural memory.

The authors examined a cognitive function mediated by the cerebellum, classical eyeblink conditioning, and its relationship to cerebellar volume in healthy controls (n = 59) and temporal lobe epilepsy subjects (n = 77). Controls demonstrated better conditioning, larger cerebellar volumes, and an association between conditioning and cerebellar volume that was not observed in epilepsy patients. These findings provide support for the hypothesis that cerebellar atrophy in epilepsy affects procedural memory.

The nature and course of neuropsychological morbidity in chronic temporal lobe epilepsy.

OBJECTIVE: To characterize the nature and degree of cognitive morbidity in patients with chronic temporal lobe epilepsy compared with healthy control subjects, determine the association between the duration of epilepsy and cognitive morbidity, and ascertain whether there are factors that moderate the association between duration of disorder and cognitive impairment. METHODS: Temporal lobe epilepsy (n = 96) and healthy control (n = 82) subjects were assessed with a comprehensive neuropsychological battery. Test performances were adjusted for age, gender, and education and transformed to a common metric (z scores). Analyses included group comparisons and correlations of duration of epilepsy with cognitive morbidity. RESULTS: Patients with temporal lobe epilepsy exhibited not only worse memory function (p < 0.05) but worse performance across measures of intelligence, language, executive function, and motor speed (p < 0.05). Chronicity of epilepsy was related to worsening mental status (r = 0.42, p < 0.001). This relationship was particularly evident among those individuals with less (r = 0.58, p < 0.001) compared with more (r = 0.25, NS) cerebral reserve, operationally defined by years of formal education. CONCLUSIONS: Neuropsychological morbidity in chronic temporal lobe epilepsy is widespread in nature despite a focal epileptic process. Cross-sectional analyses demonstrate that increasing duration of epilepsy is associated with worsening mental status. Individuals with less educational attainment (low cerebral reserve) exhibit especially poor cognitive function in association with chronicity of epilepsy.

Object naming and semantic knowledge in temporal lobe epilepsy.

Object-naming impairment is common among temporal lobe epilepsy (TLE) patients, but other aspects of semantic memory have received limited attention in this population. This study examined object-naming ability and depth of semantic knowledge in healthy controls (n = 29) and patients with early onset TLE (n = 21). After administration of the Boston Naming Test (BNT), the authors asked participants to provide detailed definitions of 6 BNT objects. The TLE group demonstrated a significant deficit relative to controls in both object-naming ability and semantic knowledge for the target objects, even after controlling for IQ. In a multiple regression analysis that included other neuropsychological test scores as independent variables, the semantic knowledge score was the only significant predictor of patients' object-naming performance. Thus, at the group level, early onset TLE patients have a semantic knowledge deficit that contributes to dysnomia.

How psychological science informs the teaching of reading.

This monograph discusses research, theory, and practice relevant to how children learn to read English. After an initial overview of writing systems, the discussion summarizes research from developmental psychology on children's language competency when they enter school and on the nature of early reading development. Subsequent sections review theories of learning to read, the characteristics of children who do not learn to read (i.e., who have developmental dyslexia), research from cognitive psychology and cognitive neuroscience on skilled reading, and connectionist models of learning to read. The implications of the research findings for learning to read and teaching reading are discussed. Next, the primary methods used to teach reading (phonics and whole language) are summarized. The final section reviews laboratory and classroom studies on teaching reading. From these different sources of evidence, two inescapable conclusions emerge: (a) Mastering the alphabetic principle (that written symbols are associated with phonemes) is essential to becoming proficient in the skill of reading, and (b) methods that teach this principle directly are more effective than those that do not (especially for children who are at risk in some way for having difficulty learning to read). Using whole-language activities to supplement phonics instruction does help make reading fun and meaningful for children, but ultimately, phonics instruction is critically important because it helps beginning readers understand the alphabetic principle and learn new words. Thus, elementary-school teachers who make the alphabetic principle explicit are most effective in helping their students become skilled, independent readers.

Memory outcome after left anterior temporal lobectomy in patients with expected and reversed Wada memory asymmetry scores.

PURPOSE: The ideal candidate for anterior temporal lobectomy surgery shows a Wada memory asymmetry (WMA) score characterized by better memory performance in the hemisphere contralateral to the seizure focus relative to the ipsilateral (surgical) hemisphere. However, some surgical candidates show a reversed WMA or better Wada memory performance in the hemisphere of surgical interest relative to the hemisphere contralateral to the seizure focus. To date, no data are available contrasting memory and seizure outcome for these two Wada groups. The present study compared memory and seizure outcome after left anterior temporal lobectomy (L-ATL) in patients showing expected and reversed WMA scores, and also examined the relationship of the individual hemisphere Wada memory scores for predicting verbal memory outcome after L-ATL. METHODS: We compared 6-month postoperative verbal memory change scores and seizure outcome in L-ATL patients with either an expected (n=12) or reversed WMA (n=9) pattern on Wada memory testing. RESULTS: L-ATL patients showing a reversed WMA score had a poorer verbal memory outcome and poorer seizure control after surgery compared with patients showing a WMA score in the expected direction. CONCLUSIONS: L-ATL patients with a reversed WMA score have a greater risk for memory morbidity and poorer seizure outcome than do patients with a WMA score in the expected direction. The WMA score was the best predictor of memory outcome after L-ATL. When the WMA score is not considered, both individual Wada hemisphere scores (contralateral and ipsilateral) provided significant and independent contribution to predicting postoperative verbal memory functioning. These findings are discussed in the context of the functional reserve and hippocampal adequacy models of memory change after temporal lobectomy.

Are there orthographic impairments in phonological dyslexia?

Two hypotheses have been advanced concerning the basis of acquired phonological dyslexia. According to the dual-route model, the pattern derives from impaired grapheme-phoneme conversion. According to the phonological impairment hypothesis, it derives from impaired representation and use of phonology. Effects of graphemic complexity and visual similarity observed in studies by Howard and Best (1996), orthographic effects on phoneme counting (Berndt, Haendiges, Mitchum, & Wayland, 1996), and data from patient LB (Derouesne & Beauvois, 1985) have been taken as evidence for an orthographic impairment in phonological dyslexia and therefore against the impaired phonology hypothesis (Coltheart, 1996). We present a computational simulation, results of two behavioral studies, and a critical analysis of the MJ and LB data, which suggest that the "orthographic" deficits in such patients arise from phonological impairments that interact with orthographic properties of stimuli.

Interactions of alcuronium, TMB-8, and other allosteric ligands with muscarinic acetylcholine receptors: studies with chimeric receptors.

A series of ligands that allosterically modulate the binding of classical ligands to muscarinic receptors was evaluated at wild-type and chimeric receptors. All of the ligands studied had highest affinity toward the M(2) subtype and lowest affinity toward the M(5) subtype. The chimeric receptors were mostly M(5) sequence; the amount of M(2) sequence ranged from about 6 to just under 30%. Alcuronium and TMB-8 had much higher affinity for the chimeric receptor that included the M(2) second outer loop of the receptor plus flanking regions of TM4 and TM5 than for any of the other chimeric receptors (the affinities of which remained similar to that of the M(5) subtype). However, this chimera retained the negative cooperativity between alcuronium and the classical antagonist N-methylscopolamine that is characteristic of M(5) (these ligands are positively cooperative at M(2)). Verapamil, tetrahydroaminoacridine, and d-tubocurarine were also sensitive to that chimeric substitution, although verapamil and tetrahydroaminoacridine had even higher affinity for a chimera with M(2) sequence in TM7. None of these ligands shared gallamine's sensitivity to a region of the third outer loop, but studies in which obidoxime reversed the allosteric effects of gallamine and other ligands suggested that they nevertheless compete for a common site. In summary, although the present data are consistent with previous studies that have suggested that allosteric ligands bind to the outermost regions of muscarinic receptors, it appears that different allosteric ligands may derive subtype selectivity from different regions of the receptor.

Site-directed mutagenesis implicates a threonine residue in TM6 in the subtype selectivities of UH-AH 37 and pirenzepine at muscarinic receptors.

The structural basis for the selectivity of the antagonist UH-AH 37 at human muscarinic acetylcholine receptors was investigated by expressing mutant receptors in COS-7 cells. Previous studies have demonstrated that the interaction between UH-AH 37 and [(3)H]N-methylscopolamine in equilibrium assays is competitive and that the high affinity of UH-AH 37 for the M(5) subtype, compared to M(2), is due to an epitope in the sixth transmembrane domain (TM6) or the third outer loop of the receptor. By mutating each nonconserved residue in this region of M(2) and M(5) to its counterpart in the other receptor, we identified a threonine residue in the middle of TM6 uniquely responsible for the higher affinity of the M(5) receptor (M(1), M(3), and M(4) receptors also carry a threonine at that location and also have high affinity for UH-AH 37). The mutant receptor in which the corresponding alanine of the M(2) receptor was replaced by threonine, M(2)(401)ala --> thr, expressed enhanced affinity for pirenzepine as well as for UH-AH 37. The chick M(2) receptor, which expresses anomalously high affinity for pirenzepine, differs from its mammalian counterparts by the presence of a threonine at this position. Affinities of AF-DX 116 and 4-DAMP, as well as the allosteric potency of UH-AH 37, were not sensitive to the M(2)(401) ala --> thr mutation.

Verbal working memory in HIV-seropositive drug users.

Recent evidence suggests that HIV-seropositive drug users are impaired on tasks of visuospatial working memory compared with drug users seronegative for HIV. In the current study we evaluated the performance of 30 HIV-seropositive male drug users and 30 risk-matched seronegative controls on two measures of verbal working memory, the Listening Span and the verbal Self Ordered Pointing Task. Impaired working memory performance was significantly more common among HIV-seropositive persons compared to controls, with the highest incidence of deficit among symptomatic participants. These findings indicate that working memory deficits in persons with HIV are not domain-specific and can be demonstrated reliably in drug users.

Language deficits in dyslexic children: speech perception, phonology, and morphology.

We investigated the relationship between dyslexia and three aspects of language: speech perception, phonology, and morphology. Reading and language tasks were administered to dyslexics aged 8-9 years and to two normal reader groups (age-matched and reading-level matched). Three dyslexic groups were identified: phonological dyslexics (PD), developmentally language impaired (LI), and globally delayed (delay-type dyslexics). The LI and PD groups exhibited similar patterns of reading impairment, attributed to low phonological skills. However, only the LI group showed clear speech perception deficits, suggesting that such deficits affect only a subset of dyslexics. Results also indicated phonological impairments in children whose speech perception was normal. Both the LI and the PD groups showed inflectional morphology difficulties, with the impairment being more severe in the LI group. The delay group's reading and language skills closely matched those of younger normal readers, suggesting these children had a general delay in reading and language skills, rather than a specific phonological impairment. The results are discussed in terms of models of word recognition and dyslexia.

Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression.

The purpose of this article is to review the topic of interictal psychiatric comorbidity among adult patients with chronic epilepsy, focusing specifically on those studies that have used contemporary psychiatric nosology. Five specific issues are addressed: (a) the risk and predominant type(s) of psychiatric comorbidity in chronic epilepsy, (b) adequacy of recognition and treatment of psychiatric comorbidity, (c) the additional burdens that comorbid psychiatric disorders impose upon patients with chronic epilepsy, (d) the etiology of these disorders, and (e) strategies for treatment. Current appreciation for these issues in epilepsy is contrasted to related fields (e.g., primary care, psychiatry, and epidemiology), where considerable attention has been devoted to the identification, consequences, and treatment of psychiatric comorbidity. The issue of psychiatric comorbidity in epilepsy is reviewed with the aim of identifying a clinical and research agenda that will advance understanding of at least one important psychiatric condition associated with epilepsy-namely, major depression.

Preoperative FDG-PET temporal lobe hypometabolism and verbal memory after temporal lobectomy.

OBJECTIVE: To examine the relationship of preoperative fluorodeoxyglucose (FDG)-PET asymmetry in temporal lobe metabolism and memory outcome after anterior temporal lobectomy (ATL). METHODS: In a university-based epilepsy surgery center, 60 ATL patients (27 left, 33 right) were divided into two groups: no/mild (n = 21) or moderate/ severe (n = 39) asymmetry in temporal lobe hypometabolism as determined by FDG-PET. All patients were nonretarded, at least 18 years of age, left-hemisphere speech dominant, without MRI abnormalities other than hippocampal atrophy, and with unilateral temporal lobe origin of intractable complex partial seizures. Neuropsychological measures of intelligence and verbal and visual memory function were assessed preoperatively and 6 months postoperatively. RESULTS: Left ATL patients with no/mild asymmetry in FDG-PET temporal lobe metabolism exhibited significantly greater verbal memory decline compared with left ATL patients with moderate/severe hypometabolism. There was no significant relationship between PET asymmetry and pre- to postsurgical IQ change. No significant relationship was observed between extent of PET hypometabolism and memory outcome for right ATL patients. CONCLUSIONS: FDG-PET asymmetry can be added to the preoperative clinical markers that appear useful in predicting verbal memory decline after left ATL.