Mapping the basal ganglia alterations in children chronically exposed to manganese

abstract: Chronic manganese (Mn) exposure is associated with neuromotor and neurocognitive deficits, but the exact mechanism of Mn neurotoxicity is still unclear. With the advent of magnetic resonance imaging (MRI), in-vivo analysis of brain structures has become possible. Among different sub-cortical structures, the basal ganglia (BG) has been investigated as a putative anatomical biomarker in MR-based studies of Mn toxicity. However, previous investigations have yielded inconsistent results in terms of regional MR signal intensity changes. These discrepancies may be due to the subtlety of brain alterations caused by Mn toxicity, coupled to analysis techniques that lack the requisite detection power. Here, based on brain MRI, we apply a 3D surface-based morphometry method on 3 bilateral basal ganglia structures in school-age children chronically exposed to Mn through drinking water to investigate the effect of Mn exposure on brain anatomy. Our method successfully pinpointed significant enlargement of many areas of the basal ganglia structures, preferentially affecting the putamen. Moreover, these areas showed significant correlations with fine motor performance, indicating a possible link between altered basal ganglia neurodevelopment and declined motor performance in high Mn exposed children.The final version of this article, as published in Scientific Reports, can be viewed online at: https://www.nature.com/articles/srep4180

Measuring intellectual ability in cerebral palsy: The comparison of three tests and their neuroimaging correlates

Standard intelligence scales require both verbal and manipulative responses, making it difficult to use in cerebral palsy and leading to underestimate their actual performance. This study aims to compare three intelligence tests suitable for the heterogeneity of cerebral palsy in order to identify which one(s) could be more appropriate to use. Forty-four subjects with bilateral dyskinetic cerebral palsy (26 male, mean age 23 years) conducted the Raven's Coloured Progressive Matrices (RCPM), the Peabody Picture Vocabulary Test -3rd (PPVT-III) and the Wechsler Nonverbal Scale of Ability (WNV). Furthermore, a comprehensive neuropsychological battery and magnetic resonance imaging were assessed. The results show that PPVT-III gives limited information on cognitive performance and brain correlates, getting lower intelligence quotient scores. The WNV provides similar outcomes as RCPM, but cases with severe motor impairment were unable to perform it. Finally, the RCPM gives more comprehensive information on cognitive performance, comprising not only visual but also verbal functions. It is also sensitive to the structural state of the brain, being related to basal ganglia, thalamus and white matter areas such as superior longitudinal fasciculus. So, the RCPM may be considered a standardized easy-to-administer tool with great potential in both clinical and research fields of bilateral cerebral palsy

Whole-Brain Structural Connectivity in Dyskinetic Cerebral Palsy and Its Association With Motor and Cognitive Function

Dyskinetic cerebral palsy (CP) has long been associated with basal ganglia and thalamus lesions. Recent evidence further points at white matter (WM) damage. This study aims to identify altered WM pathways in dyskinetic CP from a standardized, connectome-based approach, and to assess structure-function relationship in WM pathways for clinical outcomes. Individual connectome maps of 25 subjects with dyskinetic CP and 24 healthy controls were obtained combining a structural parcellation scheme with whole-brain deterministic tractography. Graph theoretical metrics and the network-based statistic were applied to compare groups and to correlate WM state with motor and cognitive performance. Results showed a widespread reduction of WM volume in CP subjects compared to controls and a more localized decrease in degree (number of links per node) and fractional anisotropy (FA), comprising parieto-occipital regions and the hippocampus. However, supramarginal gyrus showed a significantly higher degree. At the network level, CP subjects showed a bilateral pathway with reduced FA, comprising sensorimotor, intraparietal and fronto-parietal connections. Gross and fine motor functions correlated with FA in a pathway comprising the sensorimotor system, but gross motor also correlated with prefrontal, temporal and occipital connections. Intelligence correlated with FA in a network with fronto-striatal and parieto-frontal connections, and visuoperception was related to right occipital connections. These findings demonstrate a disruption in structural brain connectivity in dyskinetic CP, revealing general involvement of posterior brain regions with relative preservation of prefrontal areas. We identified pathways in which WM integrity is related to clinical features, including but not limited to the sensorimotor system

Brain Activation Time-Locked to Sleep Spindles Associated With Human Cognitive Abilities

Simultaneous electroencephalography and functional magnetic resonance imaging (EEG–fMRI) studies have revealed brain activations time-locked to spindles. Yet, the functional significance of these spindle-related brain activations is not understood. EEG studies have shown that inter-individual differences in the electrophysiological characteristics of spindles (e.g., density, amplitude, duration) are highly correlated with “Reasoning” abilities (i.e., “fluid intelligence”; problem solving skills, the ability to employ logic, identify complex patterns), but not short-term memory (STM) or verbal abilities. Spindle-dependent reactivation of brain areas recruited during new learning suggests night-to-night variations reflect offline memory processing. However, the functional significance of stable, trait-like inter-individual differences in brain activations recruited during spindle events is unknown. Using EEG–fMRI sleep recordings, we found that a subset of brain activations time-locked to spindles were specifically related to Reasoning abilities but were unrelated to STM or verbal abilities. Thus, suggesting that individuals with higher fluid intelligence have greater activation of brain regions recruited during spontaneous spindle events. This may serve as a first step to further understand the function of sleep spindles and the brain activity which supports the capacity for Reasoning

Shape of the basal ganglia in preadolescent children is associated with cognitive performance.

Current studies support the belief that high levels of performance and intellectual abilities are associated with increased brain size or volume. With few exceptions, this conclusion is restricted to studies of post-adolescent subjects and to cerebral cortex. There is evidence that "bigger is better" may not pertain to children and further, that there are areas of the brain in which larger structures are associated with cognitive deficits. In 50 preadolescent children (21 girls) a structural survey of the brain (VBM) was conducted to determine and locate areas in which gray matter volume was associated with poor cognitive performance. Only increased gray matter volume in particular areas of the basal ganglia and specifically the putamen was significantly associated with poor performance on tests of memory, response speed and a general marker and subtests of intelligence. Based on the VBM findings, volumetric analysis of basal ganglia structures was performed using FSL/FIRST. However, no significant changes in total volume of putamen or other basal ganglia structures were detected with this analysis. The disagreement between measures of localized gray matter differences and volumetric analysis suggested that there might be local regional deformity rather than widespread volumetric changes of the putamen. Surface analysis with FSL/FIRST demonstrated that bilateral outward deformation of the putamen, but especially the left, was associated with poor performance on several cognitive tests. Expansion of the globus pallidus and caudate nucleus also was associated with poor performance. Moreover a significant association was detected between a reliable test of language-free intelligence and topographically distinct outward and inward deformation of the putamen. Expansion and contraction of the putamen as a predictor of intelligence may explain why this association was not observed with measures of total volume. These results suggest that deformity is a sensitive measure of function, and that distortion of the basal ganglia may be a neurophenotype for risk of developmental impairment

Shape of the basal ganglia in preadolescent children is associated with cognitive performance.

Current studies support the belief that high levels of performance and intellectual abilities are associated with increased brain size or volume. With few exceptions, this conclusion is restricted to studies of post-adolescent subjects and to cerebral cortex. There is evidence that "bigger is better" may not pertain to children and further, that there are areas of the brain in which larger structures are associated with cognitive deficits. In 50 preadolescent children (21 girls) a structural survey of the brain (VBM) was conducted to determine and locate areas in which gray matter volume was associated with poor cognitive performance. Only increased gray matter volume in particular areas of the basal ganglia and specifically the putamen was significantly associated with poor performance on tests of memory, response speed and a general marker and subtests of intelligence. Based on the VBM findings, volumetric analysis of basal ganglia structures was performed using FSL/FIRST. However, no significant changes in total volume of putamen or other basal ganglia structures were detected with this analysis. The disagreement between measures of localized gray matter differences and volumetric analysis suggested that there might be local regional deformity rather than widespread volumetric changes of the putamen. Surface analysis with FSL/FIRST demonstrated that bilateral outward deformation of the putamen, but especially the left, was associated with poor performance on several cognitive tests. Expansion of the globus pallidus and caudate nucleus also was associated with poor performance. Moreover a significant association was detected between a reliable test of language-free intelligence and topographically distinct outward and inward deformation of the putamen. Expansion and contraction of the putamen as a predictor of intelligence may explain why this association was not observed with measures of total volume. These results suggest that deformity is a sensitive measure of function, and that distortion of the basal ganglia may be a neurophenotype for risk of developmental impairment

Prenatal maternal health and child brain structure: Implications for non-verbal ability and optimizing subcortical segmentation

Brain development starts in utero, and the fetal brain can already be affected by the environment, including chemical exposures and maternal health characteristics. These factors range from exposures to large quantities of teratogens (such as alcohol) to variations in the behaviors and characteristics of healthy individuals (such as age, diet, and subclinical levels of depressive and anxiety symptoms), which can nonetheless have long-lasting adverse effects. In this thesis, we reviewed the literature on the effects of prenatal exposures on human neurodevelopment, as well as cognitive, behavioral, and health outcomes. In Study I we found that prenatal exposures are often reported poorly in infant neuroimaging studies and gave recommendations for reporting in future studies. In Study II, we examined which early life factors predicted cortical structure in 5-year-olds. The results from Study II were utilized to make an informed decision regarding confounders in future studies in the 5-year-old neuroimaging sample of the FinnBrain Birth Cohort study. In Study III, we explored the cortical structural correlates of non-verbal ability in 5-year-olds. The findings were generally in line with prior results from adult and adolescent studies, with the important addition of a positive association between gray matter volume and surface area in the right medial occipital region and non-verbal ability as well as visual abstract reasoning ability. Finally, in Study IV, we compared the results from two common segmentation tools, FSL-FIRST and FreeSurfer, against manual segmentation in the hippocampus and subcortical structures. Overall, the agreement with manual segmentation was good, although results were suboptimal for the hippocampus, amygdala, and nucleus accumbens, and careful visual quality control is still recommended. This thesis summarized different perinatal factors affecting the developing brain, and ensured the high quality of our neuroimaging data. This foundational work, together with the multidisciplinary, longitudinal data collection in the FinnBrain Birth Cohort study, can be used to discover how environmental factors affect brain development.Äidin raskausajan terveys ja lapsen aivojen rakenne: yhteydet ei-kielellisiin taitoihin ja subkortikaalisen segmentaation optimointi Aivojen kehitys alkaa kohdussa ja jatkuu läpi elämän. Jo sikiöaikana aivot ovat alttiina ympäristön vaikutuksille, ml. kemialliset altisteet sekä äidin terveyteen liittyvät tekijät. Nämä altisteet vaihtelevat suurista annoksista teratogeeneille (esim. alkoholille) eroihin terveiden yksilöiden ominaisuuksissa ja toiminnassa (esim. ikä, ruokavalio sekä vähäiset masennus- ja ahdistusoireet ilman mielenterveyshäiriön diagnoosia), joilla voi kuitenkin olla kauaskantoisia seuraamuksia. Tässä väitöskirjassa teemme katsauksen raskaudenaikaisten altisteiden vaikutuksista yksilön kehitykseen sekä siihen liittyviin muutoksiin aivoissa. Tutkimuksessa I toteamme, että raskaudenaikaiset altisteet kuvataan usein puutteellisesti vauvojen aivokuvantamista koskevissa tutkimuksissa ja annamme suosituksia raportoinnista. Tutkimuksessa II tutkimme varhaisten altisteiden yhteyksiä 5-vuotiaiden aivojen rakenteeseen. Tämän tutkimuksen tulokset ohjasivat kontrolloitavien muuttujien valintaa. Tutkimuksessa III tutkimme aivokuoren rakenteen yhteyksiä ei-kielelliseen kognitiiviseen kyvykkyyteen 5-vuotiailla. Tulokset olivat pitkälti linjassa aiempien, vanhemmilla osallistujilla tehtyjen tutkimusten kanssa. Uutena tuloksena löysimme yhteyden oikean takaraivolohkon mediaalisen osan tilavuuden ja pinta-alan olevan yhteydessä ei-kielelliseen kyvykkyyteen sekä erityisesti näönvaraiseen päättelyyn. Tutkimuksessa IV vertailimme kahta yleistä segmentointityökalua (FreeSurfer ja FSL-FIRST) käsin tehtyyn segmentaatioon hippokampuksessa ja aivokuoren alaisissa tumakkeissa. Tulokset vaihtelivat paljon rakenteesta riippuen. Huolellista laadunvarmistusta aivoalueiden koon määrityksen yhteydessä suositellaan vahvasti. Tämä väitöskirja antaa kokonaisvaltaisen ymmärryksen aivoihin vaikuttavista varhaisen elämän altisteista. Yhdessä korkealaatuisen aivokuvantamisdatamme sekä muun FinnBrain-syntymäkohortissa kerättävän aineiston kanssa tätä tietoa voidaan hyödyntää useissa tulevissa aivojen kehitystä selvittävissä tutkimuksissa

Examining the Relationships Among Motor, Cognitive, and Mental Health Outcomes after Pediatric Arterial Ischemic Stroke

Pediatric arterial ischemic stroke (AIS) is an important cause of neurological disability in children with motor, cognitive, and behavioural sequelae. Motor impairments are one of the most common adverse outcomes after pediatric AIS, yet little is known about the impact of motor functioning on neuropsychological functioning. This dissertation consists of three studies examining relationships between motor functioning and neuropsychological outcomes after pediatric AIS. Study 1 examined relationships between motor functioning assessed with the Pediatric Stroke Outcome Measure at two timepoints and intellectual abilities. Results showed that motor functioning assessed during early recovery was associated with aspects of intellectual functioning, whereas later motor functioning was not. Different patterns of associations between motor functioning and intellectual abilities were observed in perinatal and childhood AIS groups. Features associated with poor motor outcome were combined cortical+subcortical lesions, hemiparesis, seizures, and utilizing rehabilitation services. Studies 2 and 3 focused on children with acquired dystonia, a movement disorder characterized by involuntary muscle contractions, after AIS involving subcortical regions. Study 2 compared symptoms of anxiety and depression between children with subcortical AIS, with and without dystonia, as well as associations among motor functioning and cognitive and mental health outcomes. Results supported the presence of greater levels of symptoms of anxiety and depression in children with post-stroke dystonia. There were no significant associations between motor and neuropsychological outcomes in the dystonia group, whereas motor and cognitive outcomes were associated in the no dystonia group. Study 3 examined whether there were differences in infarct characteristics on acute neuroimaging between children with and without dystonia and subcortical AIS. There was a significantly higher proportion of children with dystonia with lesions involving the putamen, caudate nucleus, and anterior limb of the internal capsule. More children with dystonia had severe cortical involvement and infarct volumes were significantly larger. Regression analyses showed involvement of the putamen significantly predicted dystonia and intellectual outcome. Overall, results support an association between motor and neuropsychological functioning after pediatric AIS that may be related to maladaptive neural reorganization involving cortico-subcortical networks. Clinical implications and suggestions for future research are discussed

Examining the Relationships Among Motor, Cognitive, and Mental Health Outcomes after Pediatric Arterial Ischemic Stroke

Pediatric arterial ischemic stroke (AIS) is an important cause of neurological disability in children with motor, cognitive, and behavioural sequelae. Motor impairments are one of the most common adverse outcomes after pediatric AIS, yet little is known about the impact of motor functioning on neuropsychological functioning. This dissertation consists of three studies examining relationships between motor functioning and neuropsychological outcomes after pediatric AIS. Study 1 examined relationships between motor functioning assessed with the Pediatric Stroke Outcome Measure at two timepoints and intellectual abilities. Results showed that motor functioning assessed during early recovery was associated with aspects of intellectual functioning, whereas later motor functioning was not. Different patterns of associations between motor functioning and intellectual abilities were observed in perinatal and childhood AIS groups. Features associated with poor motor outcome were combined cortical+subcortical lesions, hemiparesis, seizures, and utilizing rehabilitation services. Studies 2 and 3 focused on children with acquired dystonia, a movement disorder characterized by involuntary muscle contractions, after AIS involving subcortical regions. Study 2 compared symptoms of anxiety and depression between children with subcortical AIS, with and without dystonia, as well as associations among motor functioning and cognitive and mental health outcomes. Results supported the presence of greater levels of symptoms of anxiety and depression in children with post-stroke dystonia. There were no significant associations between motor and neuropsychological outcomes in the dystonia group, whereas motor and cognitive outcomes were associated in the no dystonia group. Study 3 examined whether there were differences in infarct characteristics on acute neuroimaging between children with and without dystonia and subcortical AIS. There was a significantly higher proportion of children with dystonia with lesions involving the putamen, caudate nucleus, and anterior limb of the internal capsule. More children with dystonia had severe cortical involvement and infarct volumes were significantly larger. Regression analyses showed involvement of the putamen significantly predicted dystonia and intellectual outcome. Overall, results support an association between motor and neuropsychological functioning after pediatric AIS that may be related to maladaptive neural reorganization involving cortico-subcortical networks. Clinical implications and suggestions for future research are discussed