Neuropsychological Genotype-Phenotype in Patients with Williams Syndrome with Atypical Deletions: A Systematic Review.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a microdeletion in the q11.23 region of chromosome 7. Recent case series reports and clinical case studies have suggested that the cognitive, behavioral, emotional, and social profile in WS could depend on the genes involved in the deletion. The objective of this systematic review was to analyze and synthesize the variability of the cognitive and behavioral profile of WS with atypical deletion and its probable relationship with the affected genes. The medical subject headings searched were "Williams syndrome," "genotype," "phenotype," "cognitive profile," and "atypical deletion." The studies included were in English or Spanish, with children and adults, and published between January 2000 and October 2022. Twenty-three studies are reported. The characteristics of the participants, the genes involved, the neuropsychological domains and instruments, and the prevalence of the WS cognitive profile criteria were used for the genotype-phenotype analysis. The genes with a major impact on the cognitive profile of WS were (a) LIMK1 and those belonging to the GTF2I family, the former with a greater influence on visuospatial abilities; (b) GTF2IRD1 and GTF2I, which have an impact on intellectual capacity as well as on visuospatial and social skills; (c) FZD9, BAZ1B, STX1A, and CLIP2, which influence the cognitive profile if other genes are also effected; and (d) GTF2IRD2, which is related to the severity of the effect on visuospatial and social skills, producing a behavioral phenotype like that of the autism spectrum. The review revealed four neuropsychological phenotypes, depending on the genes involved, and established the need for more comprehensive study of the neuropsychological profile of these patients. Based on the results found, we propose a model for the investigation of and clinical approach to the WS neuropsychological phenotype.

Cognitive, Behavioral, and Adaptive Profiles in Williams Syndrome With and Without Loss of GTF2IRD2.

Williams syndrome (WS) is a neurodevelopmental disorder that results from a heterozygous microdeletion on chromosome 7q11.23. Most of the time, the affected region contains ~1.5 Mb of sequence encoding approximately 24 genes. Some 5-8% of patients with WS have a deletion exceeding 1.8 Mb, thereby affecting two additional genes, including GTF2IRD2. Currently, there is no consensus regarding the implications of GTF2IRD2 loss for the neuropsychological phenotype of WS patients. OBJECTIVES: The present study aimed to identify the role of GTF2IRD2 in the cognitive, behavioral, and adaptive profile of WS patients. METHODS: Twelve patients diagnosed with WS participated, four with GTF2IRD2 deletion (atypical WS group), and eight without this deletion (typical WS group). The age range of both groups was 7-18 years old. Each patient's 7q11.23 deletion scope was determined by chromosomal microarray analysis. Cognitive, behavioral, and adaptive abilities were assessed with a battery of neuropsychological tests. RESULTS: Compared with the typical WS group, the atypical WS patients with GTF2IRD2 deletion had more impaired visuospatial abilities and more significant behavioral problems, mainly related to the construct of social cognition. CONCLUSIONS: These findings provide new evidence regarding the influence of the GTF2IRD2 gene on the severity of behavioral symptoms of WS related to social cognition and certain visuospatial abilities. (JINS, 2018, 24, 896-904).

Neuropsychological intervention in attention and visuospatial skills in two patients with Williams syndrome with different types of genetic deletion.

Williams Syndrome (WS) is a neurodevelopmental disorder with a distinctive physical, cognitive, and behavioral profile caused by a microdeletion in the q11.23 region of chromosome 7. The neuropsychological profile of WS is characterized by intellectual disability, hypersociability, and deficits, especially in attention and visuospatial skills. Our objective was to assess the effectiveness of a neuropsychological intervention program in attention and visuospatial skills in two patients with WS (aged 7 and 13 years old) with different types of deletion (1.5 and 1.8 Mb). Cognitive, behavioral, and adaptive abilities were evaluated through various neuropsychological tests and scales; the neuropsychological intervention program was subsequently applied, and we assessed its effectiveness. Both patients initially presented significant deficits in attention and visuospatial skills. After the program, we found improvements in attention and visuospatial skills. In addition, both patients had significant clinical advances and changes in adaptive behaviors (social and self-care). These findings suggest that this intervention program could improve attention processes, visuospatial skills, and some aspects of adaptive behavior in patients with WS, regardless of deletion size. Although the sample was small, limiting the generalizability of the results, we believe this program could be a helpful resource for professionals working with individuals with WS.

Cognitive and executive functions in ADHD.

INTRODUCTION: Some studies have reported that attention-deficit/hyperactivity disorder (ADHD) children show alterations in different cognitive functions. Recently, a deficiency in the executive functions (EF) is proposed as the cause underlying all of these symptoms. However discrepancies exist about these findings. OBJECTIVE: Assessment of cognitive and executive functions of subjects with both ADHD hyperactive-impulsive type and combined type, in order to reveal their neuropsychological characteristics and analyze if those functions are related to hyperactive-impulsive behavior. METHOD: Neuropsychological Battery, Stroop test, Wisconsin Card Sorting test and London Tower test were applied to 51 children between 7 and 12 years old (25 controls and 26 ADHD). RESULTS: ADHD children showed worst performance in sustained attention, rapid serial naming of figures and colors, comprehension of written instructions, word dictation, number comparison, arithmetical problems, visual working memory, long term memory and the scores of WCST. Variables related to hyperactivity-impulsivity were: errors and decreased velocity in rapid serial naming of colors and figures, comprehension of written instructions, arithmetical problems and the scores of total errors, perseverating errors and perseverating responses of WCST. CONCLUSION: ADHD children show a great variety of cognitive deficiencies and had deficit only in some domains of executive functions. These deficiencies could explain to some extent the hyperactive and impulsive behavior.

Verbal intelligence and leisure activities are associated with cognitive performance and resting-state electroencephalogram.

Cognitive reserve (CR) is the adaptability of cognitive processes that helps to explain differences in the susceptibility of cognitive or daily functions to resist the onslaught of brain-related injury or the normal aging process. The underlying brain mechanisms of CR studied through electroencephalogram (EEG) are scarcely reported. To our knowledge, few studies have considered a combination of exclusively dynamic proxy measures of CR. We evaluated the association of CR with cognition and resting-state EEG in older adults using three of the most frequently used dynamic proxy measures of CR: verbal intelligence, leisure activities, and physical activities. Multiple linear regression analyses with the CR proxies as independent variables and cognitive performance and the absolute power (AP) on six resting-state EEG components (beta, alpha1, alpha2, gamma, theta, and delta) as outcomes were performed. Eighty-eight healthy older adults aged 60-77 (58 female) were selected from previous study data. Verbal intelligence was a significant positive predictor of perceptual organization, working memory, processing speed, executive functions, and central delta power. Leisure activities were a significant positive predictor of posterior alpha2 power. The dynamic proxy variables of CR are differently associated with cognitive performance and resting-state EEG. Implementing leisure activities and tasks to increase vocabulary may promote better cognitive performance through compensation or neural efficiency mechanisms.

Syntactic Gender Agreement Processing on Direct-Object Clitics by Spanish-Speaking Children with Developmental Language Disorder: Evidence from ERP.

Children with developmental language disorder (DLD) have a psycholinguistic profile evincing multiple syntactic processing impairments. Spanish-speaking children with DLD struggle with gender agreement on clitics; however, the existing evidence comes from offline, elicitation tasks. In the current study, we sought to determine whether converging evidence of this deficit can be found. In particular, we use the real-time processing technique of event-related brain potentials (ERP) with direct-object clitic pronouns in Spanish-speaking children with DLD. Our participants include 15 six-year-old Mexican Spanish-speaking children with DLD and 19 typically developing, age-matched (TD) children. Auditory sentences that matched or did not match the gender features of antecedents represented in pictures were employed as stimuli in a visual-auditory gender agreement task. Gender-agreement violations were associated with an enhanced anterior negativity between 250 and 500 ms post-target onset in the TD children group. In contrast, children with DLD showed no such effect. This absence of the left anterior negativity (LAN) effect suggests weaker lexical representation of morphosyntactic gender features and/or non-adult-like morphosyntactic gender feature checking for the DLD children. We discuss the relevance of these findings for theoretical accounts of DLD. Our findings may contribute to a better understanding of syntactic agreement processing and language disorders.

Frontal functional connectivity and disease duration interactively predict cognitive decline in Parkinson's disease.

OBJECTIVE: Cognitive decline does not always follow a predictable course in Parkinson's disease (PD), with some patients remaining stable while others meet criteria for dementia from early stages. Functional connectivity has been proposed as a good correlate of cognitive decline in PD, although it has not been explored whether the association between this connectivity and cognitive ability is influenced by disease duration, which was our objective. METHODS: We included 30 patients with PD and 15 healthy controls (HC). Six cognitive domains were estimated based on neuropsychological assessment. Phase-based connectivity at frontal and posterior cortical regions was estimated from a resting EEG. RESULTS: The PD group showed significant impairment for the executive, visuospatial, and language domains compared with HC. Increased connectivity at frontal regions was also found in the PD group. Frontal delta and theta connectivity negatively influenced general cognition and visuospatial performance, but this association was moderated by disease duration, with increased connectivity predicting worse performance after 8 years of disease duration. CONCLUSION: Subtle neurophysiological changes underlie cognitive decline along PD progression, especially around a decade after motor symptoms onset. SIGNIFICANCE: Connectivity of EEG slow waves at frontal regions might be used as a predictor of cognitive decline in PD.

An Exploration of Social Cognition in Children with Different Degrees of Genetic Deletion in Williams Syndrome.

An explanation for the social dysfunction observed in Williams syndrome may be deficits in social cognition. This study explored aspects of social cognition in children with Williams syndrome with different genotypes. The 12 participants included one with a 1.1 Mb deletion that retained the GTF2IRD1, GTF2I, and GTF2IRD2 genes, seven with a 1.5 Mb deletion that preserved the GTF2IRD2 gene, and four with a 1.8 Mb deletion with loss of all three genes. The participant retaining all three genes was found to have better performance on social judgment and first-order theory of mind tasks than the group with loss of all three genes. These results may reflect the influence of the GTF2I gene family on social cognition in Williams syndrome.

Poor working memory performance in healthy elderly adults with electroencephalographic risk of cognitive decline affects syntactic processing.

OBJECTIVE: To examine the effects of working memory (WM) load and gender agreement on sentence processing as a function of the electroencephalographic risk (i.e., abnormally high values of theta absolute power) of cognitive decline in older adults. METHODS: Event-related potentials (ERPs) were collected from Spanish speakers (22 older adults belonged to the Risk group, mean age = 67.7 years; 22 older adults belonged to the Control group, mean age = 65.2 years) while reading sentences to detect grammatical errors. Sentences varied with regard to (1) the gender agreement of the noun and adjective, where gender of the adjective either agreed or disagreed with the noun, and (2) WM load (i.e., the number of words between the noun and adjective in the sentence). RESULTS: The Risk group showed a lower percentage of correct answers and longer reaction times than the Control group. The Risk group also showed a different pattern of ERP components, which was characterized by smaller amplitude and longer latency of the P600a component under high WM load conditions. CONCLUSION: The findings suggest that the Risk group shows difficulties integrating information associated with the previous sentence context. SIGNIFICANCE: The electroencephalographic risk factor of cognitive decline might be not only a predictor of but also an indicator of current decline.

Auditory mismatch detection, distraction, and attentional reorientation (MMN-P3a-RON) in neurological and psychiatric disorders: A review.

Involuntary attention allows for the detection and processing of novel and potentially relevant stimuli that lie outside of cognitive focus. These processes comprise change detection in sensory contexts, automatic orientation toward this change, and the selection of adaptive responses, including reorientation to the original goal in cases when the detected change is not relevant for task demands. These processes have been studied using the Event-Related Potential (ERP) technique and have been associated to the Mismatch Negativity (MMN), the P3a, and the Reorienting Negativity (RON) electrophysiological components, respectively. This has allowed for the objective evaluation of the impact of different neuropsychiatric pathologies on involuntary attention. Additionally, these ERP have been proposed as alternative measures for the early detection of disease and the tracking of its progression. The objective of this review was to integrate the results reported to date about MMN, P3a, and RON in different neurological and psychiatric disorders. We included experimental studies with clinical populations that reported at least two of these three components in the same experimental paradigm. Overall, involuntary attention seems to reflect the state of cognitive integrity in different pathologies in adults. However, if the main goal for these ERP is to consider them as biomarkers, more research about their pathophysiological specificity in each disorder is needed, as well as improvement in the general experimental conditions under which these components are elicited. Nevertheless, these ERP represent a valuable neurophysiological tool for early detection and follow-up of diverse clinical populations.

Effects of Age and Working Memory Load on Syntactic Processing: An Event-Related Potential Study.

Cognitive changes in aging include working memory (WM) decline, which may hamper language comprehension. An increase in WM demands in older adults would probably provoke a poorer sentence processing performance in this age group. A way to increase the WM load is to separate two lexical units in an agreement relation (i.e., adjective and noun), in a given sentence. To test this hypothesis, event-related potentials (ERPs) were collected from Spanish speakers (30 older adults, mean age = 66.06 years old; and 30 young adults, mean age = 25.7 years old) who read sentences to detect grammatical errors. The sentences varied with regard to (1) the gender agreement of the noun and adjective, where the gender of the adjective either agreed or disagreed with the noun, and (2) the WM load (i.e., the number of words between the noun and adjective in the sentence). No significant behavioral differences between groups were observed in the accuracy of the response, but older adults showed longer reaction times regardless of WM load condition. Compared with young participants, older adults showed a different pattern of ERP components characterized by smaller amplitudes of LAN, P600a, and P600b effects when the WM load was increased. A smaller LAN effect probably reflects greater difficulties in processing the morpho-syntactic features of the sentence, while smaller P600a and P600b effects could be related to difficulties in recovering and mapping all sentence constituents. We concluded that the ERP pattern in older adults showed subtle problems in syntactic processing when the WM load was increased, which was not sufficient to affect response accuracy but was only observed to result in a longer reaction time.

Semantic Processing Impairment in Patients with Temporal Lobe Epilepsy.

The impairment in episodic memory system is the best-known cognitive deficit in patients with temporal lobe epilepsy (TLE). Recent studies have shown evidence of semantic disorders, but they have been less studied than episodic memory. The semantic dysfunction in TLE has various cognitive manifestations, such as the presence of language disorders characterized by defects in naming, verbal fluency, or remote semantic information retrieval, which affects the ability of patients to interact with their surroundings. This paper is a review of recent research about the consequences of TLE on semantic processing, considering neuropsychological, electrophysiological, and neuroimaging findings, as well as the functional role of the hippocampus in semantic processing. The evidence from these studies shows disturbance of semantic memory in patients with TLE and supports the theory of declarative memory of the hippocampus. Functional neuroimaging studies show an inefficient compensatory functional reorganization of semantic networks and electrophysiological studies show a lack of N400 effect that could indicate that the deficit in semantic processing in patients with TLE could be due to a failure in the mechanisms of automatic access to lexicon.

Event-related brain potentials during a semantic priming task in children with learning disabilities not otherwise specified.

Learning disabilities (LDs) are the most common psychiatric disorders in children. LDs are classified either as "Specific" or "Learning Disorder Not Otherwise Specified". An important hypothesis suggests a failure in general domain process (i.e., attention) that explains global academic deficiencies. The aim of this study was to evaluate event-related potential (ERP) patterns of LD Not Otherwise Specified children with respect to a control group. Forty-one children (8-10.6 years old) participated and performed a semantic judgment priming task while ERPs were recorded. Twenty-one LD children had significantly lower scores in all academic skills (reading, writing and arithmetic) than twenty controls. Different ERP patterns were observed for each group. Control group showed smaller amplitudes of an anterior P200 for unrelated than related word pairs. This P200 effect was followed by a significant early N400a effect (greater amplitudes for unrelated than related word pairs; 350-550 ms) with a right topographical distribution. By contrast, LD Not Otherwise Specified group did not show a P200 effect or a significant N400a effect. This evidence suggests that LD Not Otherwise Specified children might be deficient in reading, writing and arithmetic domains because of their sluggish shifting of attention to process the incoming information.

Visuospatial working memory in toddlers with a history of periventricular Leukomalacia: an EEG narrow-band power analysis.

BACKGROUND: Periventricular Leukomalacia (PVL) affects white matter, but grey matter injuries have also been reported, particularly in the dorsomedial nucleus and the cortex. Both structures have been related to working memory (WM) processes. The aim of this study was to compare behavioral performances and EEG power spectra during a visuospatial working memory task (VSWMT) of toddlers with a history of PVL and healthy toddlers. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, comparative study of WM was conducted in toddlers with a history of PVL and healthy toddlers. The task responses and the EEG narrow-band power spectra during a VSWMT were compared in both groups. The EEG absolute power was analyzed during the following three conditions: baseline, attention and WM retention. The number of correct responses was higher in the healthy group (20.5 ± 5.0) compared to the PVL group (16.1 ± 3.9) (p = 0.04). The healthy group had absolute power EEG increases (p ≤ 0.05) during WM compared to the attention condition in the bilateral frontal and right temporal, parietal and occipital regions in frequencies ranging from 1.17 to 2.34 Hz and in the right temporal, parietal and occipital regions in frequencies ranging from 14.06 to 15.23 Hz. In contrast, the PVL group had absolute power increases (p ≤ 0.05) in the bilateral fronto-parietal, left central and occipital regions in frequencies that ranged from 1.17 to 3.52 Hz and in the bilateral frontal and right temporal regions in frequencies ranging from 9.37 to 19.14 Hz. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that PVL toddlers have visuospatial WM deficits and a very different pattern of absolute power increases compared to a healthy group of toddlers, with greater absolute power in the low frequency range and widespread neuronal networks in the WM retention phase.

Phonological processing in Parkinson's disease: a neuropsychological assessment.

Patients with Parkinson's disease (PD) have cognitive deficits that cause functional impairments across several domains, including language. There is experimental evidence that basal ganglia and frontostriatal circuits are implicated in phonological processing, which leads to the hypothesis that a dysfunction of these circuits could be expressed behaviorally as phonological deficiencies in patients with PD. Using neuropsychological assessments, the present study aimed to explore the phonological processing abilities of patients in the initial stages of PD while controlling for other cognitive processes. The results showed lower scores in patients with PD on phonological tests with respect to a control group and these differences were independent of processes such as attention/working memory, long-term memory, thinking, and verbal language comprehension. However, there was an association between phonological skills and reading comprehension abilities. This finding implies a specific phonological deficit in terms of word reading.

Involuntary attention impairment in early Parkinson's disease: an event-related potential study.

Dopaminergic nigro-striatal depletion interferes with the detection of novel stimuli. This suggests that Parkinson's disease (PD) may generate from the initial stages a failure in involuntary attention (IA), which can be studied through the distraction potential, composed by the mismatch negativity (MMN), the P3a and the reorientation negativity (RON). This study analyzed IA using event-related potentials (ERPs) in patients with early PD with and without dopaminergic replacement therapy. Twenty-five medicated, and 17 non-medicated patients with early PD were studied, as well as 20 healthy control subjects. All subjects performed an auditory distraction task while a digital EEG was being recorded. The distraction potential was obtained by averaging methodology. Each wave was analyzed with a Repeated Measures ANOVA test. The MMN was obtained in all subjects and no significant differences in mean amplitude were found among the groups. There was a main effect of group for the amplitude of P3a (F(2,59)=4.8, p=0.01, ɛ=0.411), with a significant lower amplitude in the medicated group compared to the control group (MD=-1.03, p=0.003). RON also showed a main effect of group (F(2,59)=4.8, p=0.01, ɛ=0.467), with significantly lower amplitudes in non-medicated patients with respect to both the control and medicated groups (MD=1.19, p=0.01, MD=1.27, p=0.005, respectively). There were no significant differences in the latencies of any of the waves among the groups. The main finding of this study was the reduction in the IA in early PD. Reorientation of attention (RON) showed a dopaminergic modulation in these patients. These results represent the basis for future in depth studies on the involvement of IA in executive impairments in PD.

Event-related potentials findings differ between children and adults during arithmetic-fact retrieval.

Some cognitive abilities of arithmetical calculation depend on retrieval of arithmetic facts from long-term memory. Arithmetic-fact retrieval has been studied in adults through Event-Related Potentials (ERP) experiments. Such information in children, however, has been scarce. It has been reported that from the age of 9 years, children employ a memory retrieval strategy for solving simple multiplication problems. The present study compared arithmetical-fact retrieval in children and adults while they were being subjected to ERP recording. The subjects were asked to make judgments about solutions to simple multiplication problems. Both groups of participants displayed the so-called arithmetic N400 effect for incorrect solutions relative to correct solutions. Adults showed a posterior N400 effect, while children showed a widely distributed N400 effect. Children displayed a larger amplitude and longer latency arithmetic N400 component than adults; this observation could be due to children exerting greater effort involving more widespread cortical activation than adults to solve the experimental problems. The Late Positive Component (LPC), which follows the arithmetic N400 and has been described previously in adult subjects, was observed in the present adult subjects, but was present in children only for correct solutions. These results may indicate that, relative to adults, children showed slower memory retrieval and a different pattern of a verification mechanism for correct and incorrect solutions.

Poor reading skills may involve a failure to focus attention.

A source localization analysis was carried out to provide brain functional and structural assessments of individuals with poor reading skills. Standardized low-resolution brain electromagnetic tomography was used to locate sources of P2 and P3 event-related potential components in normal readers and in poor reader children performing a cued continuous performance task. Cue-elicited P2 sources in the right superior parietal gyrus were smaller in 37 poor readers than in 40 normal readers. Poor readers showed a higher P3 activation in response to a false target in frontal and frontorbital regions than normal readers. These results suggest that reading disabilities may be attributed to failures in attentional focalization for incoming stimuli.