Phonological neighbourhood effects in Italian speech production: Evidence from healthy and neurologically impaired populations.

In two speech production studies conducted in Italian, we investigated the impact of phonological neighbourhood properties such as the neighbourhood density and the mean frequency of the neighbours on speech processing. Two populations of healthy (Study 1) and neurologically impaired (Study 2) individuals were tested. We employed multi-regression methods to analyse naming latencies in Study 1 and accuracy rates in Study 2 while controlling for various psycholinguistic predictors. In Study 1, pictures with words from high-density neighbourhoods were named faster than those from low-density neighbourhoods. Additionally, words with high-frequency neighbours were named faster in Study 1 and yielded higher accuracy rates in Study 2. The results suggest facilitatory effects of both the phonological neighbourhood density and frequency neighbourhood variables. Furthermore, we observed interactions between these two phonological neighbourhood variables and name agreement and repetition. Specifically, the facilitation effect was more pronounced for pictures with lower name agreement and during the initial presentation of the pictures. These findings are discussed in the context of previous literature and within the framework of interactive models of speech production.

Rule Perseveration during Task-Switching in Brain Tumor: A Severe Form of Task-Setting Impairment.

It has been proposed that at least two distinct processes are engaged during task-switching: reconfiguration of the currently relevant task-set and interference resolution arising from the competing task-set. Whereas in healthy individuals the two are difficult to disentangle, their disruption is thought to cause different impairments in brain-damaged patients. Yet, the observed deficits are inconsistent across studies and do not allow drawing conclusions regarding their independence. Forty-one brain tumor patients were tested on a task-switching paradigm. We compared their performance between switch and repeat trials (switch cost) to assess rule reconfiguration, and between trials requiring the same response (congruent) and a different response for the two tasks (incongruent) to assess interference control. In line with previous studies, we found the greatest proportion of errors on incongruent trials, suggesting an interference control impairment. However, a closer look at the distribution of errors between two task rules revealed a rule perseveration impairment: Patients with high error rate on incongruent trials often applied only one task rule throughout the task and less frequently switched to the alternative one. Multivariate lesion-symptom mapping analysis unveiled the relationship between lesions localized in left orbitofrontal and posterior subcortical regions and perseveration scores, measured as absolute difference in accuracy between two task rules. This finding points to a more severe task-setting impairment, not reflected as a mere switching deficit, but instead as a difficulty in creating multiple stable task representations, in line with recent accounts of OFC functions suggesting its critical role in representing task states.

Time reference in nonfluent and fluent aphasia: a cross-linguistic test of the PAst DIscourse LInking Hypothesis.

Recent studies by Bastiaanse and colleagues found that time reference is selectively impaired in people with nonfluent agrammatic aphasia, with reference to the past being more difficult to process than reference to the present or to the future. To account for this dissociation, they formulated the PAst DIscourse LInking Hypothesis (PADILIH), which posits that past reference is more demanding than present/future reference because it involves discourse linking. There is some evidence that this hypothesis can be applied to people with fluent aphasia as well. However, the existing evidence for the PADILIH is contradictory, and most of it has been provided by employing a test that predominantly taps retrieval processes, leaving largely unexplored the underlying ability to encode time reference-related prephonological features. Within a cross-linguistic approach, this study tests the PADILIH by means of a sentence completion task that 'equally' taps encoding and retrieval abilities. This study also investigates if the PADILIH's scope can be extended to fluent aphasia. Greek- and Italian-speaking individuals with aphasia participated in the study. The Greek group consisted of both individuals with nonfluent agrammatic aphasia and individuals with fluent aphasia, who also presented signs of agrammatism. The Italian group consisted of individuals with agrammatic nonfluent aphasia only. The two Greek subgroups performed similarly. Neither language group of participants with aphasia exhibited a pattern of performance consistent with the predictions of the PADILIH. However, a double dissociation observed within the Greek group suggests a hypothesis that may reconcile the present results with the PADILIH.

Intraoperative functional mapping of calculation in parietal surgery. New insights and clinical implications.

BACKGROUND: Parietal areas play a crucial role in calculation processing. The purpose of this study is to report our experience in the assessment of calculation processing during awake surgery in parietal areas, focusing on clinical implications and new insights provided by this approach. METHODS: We retrospectively reviewed clinical and surgical data of 13 patients who underwent parietal surgery with calculation mapping. Cortical and sub-cortical areas (in 13 and five patients, respectively) involved in single-digit multiplications and additions were identified using bipolar electro-stimulation. RESULTS: Cortical stimulation data showed that the inferior parietal lobule and the intraparietal sulcus were specifically related to calculation in all cases, regardless of the side (100% of cases, in both sides). Conversely, the superior parietal lobule was inconstantly involved in calculation processing (40% of cases in the left and 75% in the right side), whereas the somatosensory area was never involved. Sub-cortical stimulation was able to detect functional areas for calculation in all patients: in 90% of cases the sub-cortical sites positive for calculation were in close anatomical connection with the cortical sites mapping for the same function. The intraoperative preservation (-or damaging-) of functional sites correlated with the absence (- or occurrence-) of post-operative calculation processing impairment. CONCLUSIONS: Our findings support the specificity of the reported technique in the intraoperative identification of sites functional for calculation. Our data show the bilateral involvement of parietal cortex, especially of the inferior lobule, in calculation processing. Furthermore, our study suggests the existence of a sub-cortical pathway specific for calculation, whose better understanding might be crucial for the clinical outcome of patients.

5-aminolevulinic acid (5-ALA) fluorescence guided surgery of high-grade gliomas in eloquent areas assisted by functional mapping. Our experience and review of the literature.

BACKGROUND: Only few data are available on the specific topic of 5-aminolevulinic acid (5-ALA) guided surgery of high-grade gliomas (HGG) located in eloquent areas. Studies focusing specifically on the post-operative clinical outcome of such patients are yet not available, and it has not been so far explored whether such approach could be more suitable for some particular subgroups of patients. METHODS: Patients affected by HGG in eloquent areas who underwent surgery assisted by 5-ALA fluorescence and intra-operative monitoring were prospectively recruited in our Department between June 2011 and August 2012. Resection rate was reported as complete resection of enhancing tumor (CRET), gross total resection (GTR) >98 % and GTR > 90 %. Clinical outcome was evaluated at 7, 30, and 90 days after surgery. RESULTS: Thirty-one patients were enrolled. Resection was complete (CRET) in 74 % of patients. Tumor removal was stopped to avoid neurological impairment in 26 % of cases. GTR > 98 % and GTR > 90 % was achieved in 93 % and 100 % of cases, respectively. First surgery and awake surgery had a CRET rate of 80 % and 83 %, respectively. Even though at the first-week assessment 64 % of patients presented neurological impairment, there was a 3 % rate of severe morbidity at the 90th day assessment. Newly diagnosed patients had a significantly lower morbidity (0 %) and post-operative higher median KPS. Both pre-operative neurological condition and improvement after corticosteroids resulted significantly predictive of post-operative functional outcome. CONCLUSIONS: 5-ALA surgery assisted by functional mapping makes high HGG resection in eloquent areas feasible , through a reasonable rate of late morbidity. This emerges even more remarkably for selected patients.

The Oxford cognitive screen (OCS) as an acute predictor of long-term functional outcome in a prospective sample of stroke patients.

The Oxford Cognitive Screen (OCS) was developed to measure cognitive impairment in stroke. Here, we test if the OCS administered acutely in stroke patients provides useful information in predicting long-term functional outcome. A group of first-time stroke patients (n = 74) underwent an acute behavioral assessment comprising the OCS and the NIHSS within one-week post-stroke. Functional outcome was evaluated using the Stroke Impact Scale 3.0 (SIS 3.0) and the Geriatric Depression Scale (GDS) at 6 and 12-months post-stroke. We compared the predictive ability of the OCS and NIHSS, separately or in combination, to predict different domains of behavioral impairment at a chronic evaluation. The OCS accounted for 61% of variance of SIS physical domain, 61% of memory domain, 79% of language domain, 70% of participation domain and 70% of recovery domain. The OCS accounted for a greater percentage of outcome variance than demographics and NIHSS. The most informative predictive model included the combination of demographics, OCS and NIHSS data. The OCS, performed early after stroke, is a strong independent predictor of long-term functional outcome and significantly improves the prediction of outcome when considered alongside the NIHSS and demographics.

Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants.

Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.

A registry for Dravet syndrome: The Italian experience.

OBJECTIVES: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. METHODS: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. RESULTS: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0-9) while at last follow-up was 11 years (IQR 5-18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). SIGNIFICANCE: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes.

Presurgical predictors of early cognitive outcome after brain tumor resection in glioma patients.

Gliomas are commonly characterized by neurocognitive deficits that strongly impact patients' and caregivers' quality of life. Surgical resection is the mainstay of therapy, and it can also cause cognitive impairment. An important clinical problem is whether patients who undergo surgery will show post-surgical cognitive impairment above and beyond that present before surgery. The relevant rognostic factors are largely unknown. This study aims to quantify the cognitive impairment in glioma patients 1-week after surgery and to compare different pre-surgical information (i.e., cognitive performance, tumor volume, grading, and lesion topography) towards predicting early post-surgical cognitive outcome. We retrospectively recruited a sample of N = 47 patients affected by high-grade and low-grade glioma undergoing brain surgery for tumor resection. Cognitive performance was assessed before and immediately after (∼1 week) surgery with an extensive neurocognitive battery. Multivariate linear regression models highlighted the combination of predictors that best explained post-surgical cognitive impairment. The impact of surgery on cognitive functioning was relatively small (i.e., 85% of test scores across the whole sample indicated no decline), and pre-operative cognitive performance was the main predictor of early post-surgical cognitive outcome above and beyond information from tumor topography and volume. In fact, structural lesion information did not significantly improve the accuracy of prediction made from cognitive data before surgery. Our findings suggest that post-surgery neurocognitive deficits are only partially explained by preoperative brain damage. The present results suggest the possibility to make reliable, individualized, and clinically relevant predictions from relatively easy-to-obtain information.

Progressive macrographia for block letter writing: A case study.

"Macrographia", a relatively rare symptom generally following cerebellar diseases, consists of an abnormally large handwriting. The case reported in the present investigation shows several outstanding features. First, it is of the progressive variety, letters increase in size as one goes through the word towards the lower-right portion of space. Moreover, it is limited to one allographic variety, that is, block letters. This phenomenon is previously unreported, all allographic varieties being usually equally affected. Finally, no prominent cerebellar or basal ganglia abnormality could be demonstrated with structural MRI or PET. From a cognitive point of view, a peculiar combination of spatial attention, executive function and working memory deficits is proposed to account for the progressive misalignment and elongation of individual letters when specifically writing in block prints. From an anatomical perspective, the pattern of multifocal lesions, encompassing multiple cortical areas in both hemispheres and the corpus callosum, may support this multi-componential interpretation of the reported phenomenon.

Two dissociable semantic mechanisms predict naming errors and their responsive brain sites in awake surgery. DO80 revisited.

How do we choose words, and what affects the selection of a specific term? Naming tests such as the DO80 are frequently used to assess language function during brain mapping in awake surgery. The present study aimed to explore whether specific semantic errors become more probable under the stimulation of specific brain areas. Moreover, it meant to determine whether specific semantic characteristics of the items may evoke specific types of error. A corpus-based qualitative semantic analysis of the DO80 items, and the emitted naming errors to those items during direct cortical electrostimulation (DCE) revealed that the number of hyperonyms (i.e. 'vehicle' for car') of an item predicted the emission of a synonym ('automobile' for 'car'). This association occurred mainly in frontal tumor patients, which was corroborated by behavior to lesion analyses. In contrast, the emission of co-hyponyms was associated with tumors located in temporal areas. These two behavior-lesion associations thus dissociated, and were also dependent on item semantic characteristics. Co-hyponym errors might generate from the disruption in a temporal semantic-to-lexical process, and the production of synonyms could be the result of an impairment in a frontal lexical-selection mechanism. A hypothesis on the lexical selection mechanisms exerted by the inferior frontal gyrus is proposed. Crucially, the present data suggest the need for more restrictive naming tasks, with items conditioned by tumor location.

Immunomodulation With Azathioprine Therapy in Rasmussen Syndrome: A Multimodal Evaluation.

OBJECTIVE: To verify safety and efficacy of the corticosteroid-sparing drug azathioprine (AZA) in Rasmussen syndrome (RS), we retrospectively analyzed a cohort of patients with RS recruited in a single pediatric neuroscience center. METHODS: We compared outcomes in 30 patients with RS who received AZA with 23 patients who were not treated with this drug. We used a multimodal approach to correlate therapy with clinical features (seizures, epilepsia partialis continua [EPC], hemiparesis) and neuroimaging markers of progressive brain atrophy. RESULTS: AZA was well tolerated; only 1 patient discontinued treatment due to pancytopenia. In 27 of 30 patients receiving AZA, all of whom were corticosteroid responders, corticosteroid therapy could be weaned or reduced without worsening of seizures in 89%. Patients receiving AZA had a lower prevalence of EPC (42% vs 67% in controls) and hemiparesis (64% vs 92%, respectively). Cox regression showed for the AZA group compared to controls a delayed time to (1) EPC (≈2 years, exp[B] = 0.295, 95% confidence interval [CI] 0.108-0.807; p = 0.017), (2) hemiparesis (≈1 year, exp[B] = 0.315, 95% CI 0.137-0.724; p = 0.007), and (3) surgery (≈2 years, exp[B] = 2.068, 95% CI 1.012-4.227; p = 0.046). However, there were no group differences in cognitive decline over time (IQ change per year) or in hemispheric gray matter atrophy on serial MRI scans. CONCLUSION: AZA treatment appears to slow clinical progression of RS in steroid responders; this will give the greatest advantage in patients in the early stages of the disease in whom surgical decision-making may require further time. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for pediatric patients with RS AZA is well tolerated and slows hemiparesis and appearance of EPC.

A low-dimensional structure of neurological impairment in stroke.

Neurological deficits following stroke are traditionally described as syndromes related to damage of a specific area or vascular territory. Recent studies indicate that, at the population level, post-stroke neurological impairments cluster in three sets of correlated deficits across different behavioural domains. To examine the reproducibility and specificity of this structure, we prospectively studied first-time stroke patients (n = 237) using a bedside, clinically applicable, neuropsychological assessment and compared the behavioural and anatomical results with those obtained from a different prospective cohort studied with an extensive neuropsychological battery. The behavioural assessment at 1-week post-stroke included the Oxford Cognitive Screen and the National Institutes of Health Stroke Scale. A principal component analysis was used to reduce variables and describe behavioural variance across patients. Lesions were manually segmented on structural scans. The relationship between anatomy and behaviour was analysed using multivariate regression models. Three principal components explained ≈50% of the behavioural variance across subjects. PC1 loaded on language, calculation, praxis, right side neglect and memory deficits; PC2 loaded on left motor, visual and spatial neglect deficits; PC3 loaded on right motor deficits. These components matched those obtained with a more extensive battery. The underlying lesion anatomy was also similar. Neurological deficits following stroke are correlated in a low-dimensional structure of impairment, related neither to the damage of a specific area or vascular territory. Rather they reflect widespread network impairment caused by focal lesions. These factors showed consistency across different populations, neurobehavioural batteries and, most importantly, can be described using a combination of clinically applicable batteries (National Institutes of Health Stroke Scale and Oxford Cognitive Screen). They represent robust behavioural biomarkers for future stroke population studies.

Acquired neurogenic foreign accent syndrome after right-hemisphere lesion with left cerebellar diaschisis: A longitudinal study.

Patients affected by acquired neurogenic foreign accent syndrome (ANFAS) start speaking with a new accent that resembles that of a foreign language. ANFAS has been reported following left-hemisphere damage, but it is extremely rare after right-hemisphere damage. We described KKE, a right-hemisphere-damaged patient. His cognitive functions were largely intact and he was not aphasic. Nonetheless, KKE showed a marked foreing accent which was mainly judged as Slavic. Positron emission tomography revealed left cerebellar diaschisis, even if the cerebellum did not appear lesioned, on MRI scans. Remarkably, KKE still showed ANFAS three years after lesion onset. We propose that this very rare variant of ANFAS, after right-hemisphere lesion, can be due to the damage of a complex cerebral network involving supra- and infra-tentorial structures.

Focal left prefrontal lesions and cognitive impairment: A multivariate lesion-symptom mapping approach.

Despite network studies of the human brain have brought consistent evidence of brain regions with diverse functional roles, the neuropsychological approach has mainly focused on the functional specialization of individual brain regions. Relatively few neuropsychological studies try to understand whether the severity of cognitive impairment across multiple cognitive abilities can be related to focal brain injuries. Here we approached this issue by applying a latent variable modeling of the severity of cognitive impairment in brain tumor patients, followed by multivariate lesion-symptom methods identifying brain regions critically involved in multiple cognitive abilities. We observed that lesions in confined left lateral prefrontal areas including the inferior frontal junction produced the most severe cognitive deficits, above and beyond tumor histology. Our findings support the recently suggested integrated albeit modular view of brain functional organization, according to which specific brain regions are highly involved across different sub-networks and subserve a vast range of cognitive abilities. Defining such brain regions is relevant not only theoretically but also clinically, since it may facilitate tailored tumor resections and improve cognitive surgical outcomes.

Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and macrocephaly.

PURPOSE: Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. METHODS: We use family-based whole-exome sequencing to identify candidate variants. RESULTS: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. CONCLUSION: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.

Addressing the selective role of distinct prefrontal areas in response suppression: A study with brain tumor patients.

The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies.