Biology subjects

Mandelli, M. L.

Publications and source records attributed to Mandelli, M. L..

5 recordsLinked to original sources

bioRxiv2025

Data-driven Cognitive Clusters in Persistent Developmental Dyslexia

Developmental dyslexia is a neurodevelopmental condition characterized by persistent reading difficulties despite adequate intelligence and educational opportunities. The cognitive underpinnings of dyslexia remain incompletely understood. Although multiple causal pathways have been proposed, there is a gap in studies that can reliably identify dyslexia subtypes based on comprehensive evaluations that go beyond measures of reading and phonology. We employed one of the largest detailed samples of children with developmental dyslexia resistant to intervention, consisting of 147 extensively phenotyped school-age children aged 7-14 years who were recruited from specialized schools for students with learning differences. We implemented data-driven analyses leveraging a comprehensive neuropsychological assessment to delineate cognitive subdomains and characterize the heterogeneity in the sample. Hierarchical clustering of 24 cognitive measures aided in constructing a framework to subsequently interpret emerging clusters. Four clusters emerged, predominantly associated with: Processing Speed & Executive Function, Visuospatial & Mathematical Reasoning, Phonological Manipulation, and Verbal Short-term Memory & Word Retrieval. Subsequent latent profile analysis identified two distinct dyslexia profiles: one characterized by marked difficulties in executive functioning and processing speed, and another displaying impairments primarily in verbal short-term memory and word retrieval relative to the other profile. Importantly, both profiles exhibited comparable severity of persistent reading difficulties despite their divergent cognitive profiles. These findings show that phenotypically similar reading impairments can arise from distinct underlying cognitive factors, emphasizing the role of comprehensive neuropsychological evaluation in developing tailored interventions for affected children.

neuroscience↗

bioRxiv2024

Parallel Encoding of Speech in Human Frontal and Temporal Lobes

Models of speech perception are centered around a hierarchy in which auditory representations in the thalamus propagate to primary auditory cortex, then to the lateral temporal cortex, and finally through dorsal and ventral pathways to sites in the frontal lobe. However, evidence for short latency speech responses and low-level spectrotemporal representations in frontal cortex raises the question of whether speech-evoked activity in frontal cortex strictly reflects downstream processing from lateral temporal cortex or whether there are direct parallel pathways from the thalamus or primary auditory cortex to the frontal lobe that supplement the traditional hierarchical architecture. Here, we used high-density direct cortical recordings, high-resolution diffusion tractography, and hemodynamic functional connectivity to evaluate for evidence of direct parallel inputs to frontal cortex from low-level areas. We found that neural populations in the frontal lobe show speech-evoked responses that are synchronous or occur earlier than responses in the lateral temporal cortex. These short latency frontal lobe neural populations encode spectrotemporal speech content indistinguishable from spectrotemporal encoding patterns observed in the lateral temporal lobe, suggesting parallel auditory speech representations reaching temporal and frontal cortex simultaneously. This is further supported by white matter tractography and functional connectivity patterns that connect the auditory nucleus of the thalamus (medial geniculate body) and the primary auditory cortex to the frontal lobe. Together, these results support the existence of a robust pathway of parallel inputs from low-level auditory areas to frontal lobe targets and illustrate long-range parallel architecture that works alongside the classical hierarchical speech network model.

neuroscience↗

bioRxiv2023

Atrophy-driven functional network collapse in neurodegenerative disease

Cognitive and behavioral deficits in Alzheimers disease (AD) and frontotemporal dementia (FTD) result from brain atrophy and altered functional connectivity. However, it is unclear how atrophy relates to functional connectivity disruptions across dementia subtypes and stages. We addressed this question using structural and functional MRI from 221 patients with AD (n=82), behavioral variant FTD (n=41), corticobasal syndrome (n=27), nonfluent (n=34) and semantic (n=37) variant primary progressive aphasia, and 100 cognitively normal individuals. Using partial least squares regression, we identified three principal structure-function components. The first component showed overall atrophy correlating with primary cortical hypo-connectivity and subcortical/association cortical hyper-connectivity. Components two and three linked focal syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores predicted global and domain-specific cognitive deficits. Anatomically, functional connectivity changes reflected alterations in specific brain activity gradients. Eigenmode analysis identified temporal phase and amplitude collapse as an explanation for atrophy-driven functional connectivity changes.

neuroscience↗

bioRxiv2023

Anatomical and behavioral correlates of auditory perception in developmental dyslexia

Developmental dyslexia is typically associated with difficulties in basic auditory processing and in manipulating speech sounds. However, the neuroanatomical correlates of auditory difficulties in developmental dyslexia (DD) and their contribution to individual clinical phenotypes are still unknown. Recent intracranial electrocorticography findings associated processing of sound amplitude rises and speech sounds with posterior and middle superior temporal gyrus (STG), respectively. We hypothesize that regional STG anatomy will relate to specific auditory abilities in DD, and that auditory processing abilities will relate to behavioral difficulties with speech and reading. One hundred and ten children (78 DD, 32 typically developing, age 7-15 years) completed amplitude rise time and speech in noise discrimination tasks. They also underwent a battery of cognitive tests. Anatomical MRI scans were used to identify regions in which local cortical gyrification complexity correlated with auditory behavior. Behaviorally, amplitude rise time but not speech in noise performance was impaired in DD. Neurally, amplitude rise time and speech in noise performance correlated with gyrification in posterior and middle STG, respectively. Furthermore, amplitude rise time significantly contributed to reading impairments in DD, while speech in noise only explained variance in phonological awareness. Finally, amplitude rise time and speech in noise performance were not correlated, and each task was correlated with distinct neuropsychological measures, emphasizing their unique contributions to DD. Overall, we provide a direct link between the neurodevelopment of the left STG and individual variability in auditory processing abilities in neurotypical and dyslexic populations.

neuroscience↗

bioRxiv2019

Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP-43-C pathology

Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, these patients are described with different terms, such as semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. ATL atrophy presents with various degrees of lateralization, with right-sided cases considered rarer even though estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a medial-to-lateral gradient. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Taken together, our findings indicate that incipient right predominant ATL atrophy is common in TDP-43-C pathology, and that distribution of damage within the ATLs appears to be the same in left- and right- sided variants. Thus, regardless of differences in clinical phenotype and atrophy lateralization, both temporal variants of FTD should be viewed as a spectrum presentation of the same disease. Highlights Anterior temporal lobe (ATL) degeneration is most often caused by FTLD-TDP type C pathology Cases can present with predominantly left (60%) or right (40%) ATL atrophy Within ATLs, medial regions are more vulnerable than lateral ones The observed spectrum of clinical phenotypes is driven by atrophy lateralization Left and right temporal variants of FTD should be considered the same disease

neuroscience↗