Cognitive functioning in dyskinetic cerebral palsy: Its relation to motor function, communication and epilepsy.

BACKGROUND: Cerebral palsy (CP) is a disorder of motor function often accompanied by cognitive impairment. There is a paucity of research focused on cognition in dyskinetic CP and on the potential effect of related factors. AIM: To describe the cognitive profile in dyskinetic CP and to assess its relationship with motor function and associated impairments. METHOD: Fifty-two subjects with dyskinetic CP (28 males, mean age 24 y 10 mo, SD 13 y) and 52 typically-developing controls (age- and gender-matched) completed a comprehensive neuropsychological assessment. Gross Motor Function Classification System (GMFCS), Communication Function Classification System (CFCS) and epilepsy were recorded. Cognitive performance was compared between control and CP groups, also according different levels of GMFCS. The relationship between cognition, CFCS and epilepsy was examined through partial correlation coefficients, controlling for GMFCS. RESULTS: Dyskinetic CP participants performed worse than controls on all cognitive functions except for verbal memory. Milder cases (GMFCS I) only showed impairment in attention, visuoperception and visual memory. Participants with GMFCS II-III also showed impairment in language-related functions. Severe cases (GMFCS IV-V) showed impairment in intelligence and all specific cognitive functions but verbal memory. CFCS was associated with performance in receptive language functions. Epilepsy was related to performance in intelligence, visuospatial abilities, visual memory, grammar comprehension and learning. CONCLUSION: Cognitive performance in dyskinetic CP varies with the different levels of motor impairment, with more cognitive functions impaired as motor severity increases. This study also demonstrates the relationship between communication and epilepsy and cognitive functioning, even controlling for the effect of motor severity.

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.

The interaction effect between BDNF val66met polymorphism and obesity on executive functions and frontal structure.

The prevalence of obesity is increasing worldwide. Previous research has shown a relationship between obesity and both executive functioning alterations and frontal cortex volume reductions. The Brain Derived Neurotrophic Factor val66met polymorphism, involved in eating behavior, has also been associated with executive functions and prefrontal cortex volume, but to date it has not been studied in relation to obesity. Our aim is to elucidate whether the interaction between the Brain Derived Neurotrophic Factor val66met polymorphism and obesity status influences executive performance and frontal-subcortical brain structure. Sixty-one volunteers, 34 obese and 27 controls, age range 12-40, participated in the study. Participants were assigned to one of two genotype groups (met allele carriers, n = 16, or non-carriers, n = 45). Neuropsychological assessment comprised the Trail Making Test, the Stroop Test and the Wisconsin Card Sorting Test, all tasks that require response inhibition and cognitive flexibility. Subjects underwent magnetic resonance imaging in a Siemens TIM TRIO 3T scanner and images were analyzed using the FreeSurfer software. Analyses of covariance controlling for age and intelligence showed an effect of the obesity-by-genotype interaction on perseverative responses on the Wisconsin Card Sorting Test as well as on precentral and caudal middle frontal cortical thickness: obese met allele carriers showed more perseverations on the Wisconsin Card Sorting Test and lower frontal thickness than obese non-carriers and controls. In conclusion, the Brain Derived Neurotrophic Factor may play an important role in executive functioning and frontal brain structure in obesity.

Does verbal and gestural expression ability predict comprehension ability in cerebral palsy?

Some people with cerebral palsy have motor and associated impairments that may hinder verbal and gestural expression to various extents. This study explores whether the ability to produce verbal or gestural expressions may be related to the comprehension of verbal communications and gestures. The influence of severity of motor impairment, general cognitive performance, and age on comprehension ability was also explored. Forty people with cerebral palsy were assigned to different groups according to their verbal and gestural expression abilities. A neuropsychological assessment of comprehension abilities and general cognitive performance was carried out. Multiple linear regression analysis was applied to identify the possible influence of expression abilities on comprehension abilities and also to detect the possible contribution of severity of motor impairment, general cognitive performance, and age. Results indicate that verbal and gestural comprehension was mainly predicted by general cognitive performance. Severity of motor impairment and age did not contribute to predicting comprehension abilities. Only verbal grammar comprehension was significantly predicted by verbal expression ability. Verbal expression ability may be an important marker for cerebral palsy therapies. In non-ambulant patients with bilateral cerebral palsy, impaired gestural expression should not be taken as an indicator of impaired gestural comprehension.

Frontal cortical thinning and subcortical volume reductions in early adulthood obesity.

Obesity depends on homeostatic and hedonic food intake behavior, mediated by brain plasticity changes in cortical and subcortical structures. The aim of this study was to investigate cortical thickness and subcortical volumes of regions related to food intake behavior in a healthy young adult sample with obesity. Thirty-seven volunteers, 19 with obesity (age=33.7±5.7 (20-39) years body-mass index (BMI)=36.08±5.92 (30.10-49.69)kg/m(2)) and 18 controls (age=32.3±5.9 (21-40) years; BMI=22.54±1.94 (19.53-24.97)kg/m(2)) participated in the study. Patients with neuropsychiatric or biomedical disorders were excluded. We used FreeSurfer software to analyze structural magnetic resonance images (MRI) and obtain global brain measures, cortical thickness and subcortical volume estimations. Finally, correlation analyses were performed for brain structure data and obesity measures. There were no between-group differences in age, gender, intelligence or education. Results showed cortical thickness reductions in obesity in the left superior frontal and right medial orbitofrontal cortex. In addition, the obesity group had lower ventral diencephalon and brainstem volumes than controls, while there were no differences in any other subcortical structure. There were no statistically significant correlations between brain structure and obesity measures. Overall, our work provides evidence of the structural brain characteristics associated with metabolically normal obesity. We found reductions in cortical thickness, ventral diencephalon and brainstem volumes in areas that have been implicated in food intake behavior.

Alterations of the salience network in obesity: a resting-state fMRI study.

Obesity is a major health problem in modern societies. It has been related to abnormal functional organization of brain networks believed to process homeostatic (internal) and/or salience (external) information. This study used resting-state functional magnetic resonance imaging analysis to delineate possible functional changes in brain networks related to obesity. A group of 18 healthy adult participants with obesity were compared with a group of 16 lean participants while performing a resting-state task, with the data being evaluated by independent component analysis. Participants also completed a neuropsychological assessment. Results showed that the functional connectivity strength of the putamen nucleus in the salience network was increased in the obese group. We speculate that this abnormal activation may contribute to overeating through an imbalance between autonomic processing and reward processing of food stimuli. A correlation was also observed in obesity between activation of the putamen nucleus in the salience network and mental slowness, which is consistent with the notion that basal ganglia circuits modulate rapid processing of information.

Dopamine genes (DRD2/ANKK1-TaqA1 and DRD4-7R) and executive function: their interaction with obesity.

Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The 'DRD2/ANKK1-TaqIA A1-allele status' had a significant effect on almost all the executive variables, but no significant 'DRD4 7R-allele status' effects were observed for any of the executive variables analyzed. There was a significant 'group' x 'DRD2/ANKK1-TaqIA A1-allele status' interaction effect on LN and 'group' x 'DRD4 7R-allele status' interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions.

Neural substrates of visual paired associates in young adults with a history of very preterm birth: alterations in fronto-parieto-occipital networks and caudate nucleus.

This study investigated neuronal activation during visuo-perceptual learning processing in adults who were born very preterm (VPT, <33 weeks' gestation). A visual paired associates task was administered during functional magnetic resonance imaging (fMRI) and neuronal activation was compared between 21 VPT-born adults of both sexes and 22 matched controls. The task consisted of 4 conditions (encoding, recognition, same/different discrimination condition (baseline) and a low-level baseline), each containing 8 stimuli pairs. There were no group differences in terms of correctly recognized visual pairs. However, during encoding, VPT-born individuals showed increased BOLD signal response compared to controls in left caudate nucleus, right cuneus (BA 18) and left superior parietal lobule (BA 7), and decreased signal in right inferior frontal gyrus (BA 46). During recognition, VPT-born adults showed increased BOLD signal response compared to controls in right cerebellum and in anterior cingulate gyrus (BA 32) bilaterally. The fMRI data were additionally analyzed controlling for structural differences in the hippocampus bilaterally, where the VPT group showed decreased probability of the absolute amount of grey matter compared to controls. Results of our study suggest that despite good task performance, VPT-born individuals activate different neural networks during mnemonic processing of visuo-perceptual material which may indicate neural compensation for the adult consequences of perinatal brain injury following very preterm birth, as well as maturational delays.

Neuropsychologic impairment in bilateral cerebral palsy.

The lower-than-average cognitive performance of individuals with bilateral cerebral palsy found in previous studies does not always refer to an abnormal performance or clinically significant impairment. We aimed to establish the percentage of persons with bilateral cerebral palsy who present neuropsychologic impairment, and its relationship to perinatal data and motor signs. Forty children, adolescents, and adults (age range, 6-38 years; 15 females and 25 males) with bilateral cerebral palsy were neuropsychologically assessed. Vocabulary was impaired in 85% of participants, language comprehension in 13-48%, visuoperceptual abilities in 60%, visuospatial abilities in 90%, short-term memory in 21-58%, declarative memory in 47-67%, and praxis comprehension in 20%, with executive deficits in 58-74%. Perinatal data (intrauterine growth and birth weight) contributed to explaining memory impairment. Among cerebral palsy subtypes (spastic, mixed, and dyskinetic), forms of impairment differed only in short-term verbal memory. No persons with dyskinetic cerebral palsy experienced impairment in immediate memory or working visual memory. We conclude that visuospatial deficit is the most frequent impairment in people with bilateral cerebral palsy. Moreover, short-term memory impairment seems sensitive to perinatal complications, and differs among bilateral cerebral palsy subtypes.

Patterns of cerebral white matter damage and cognitive impairment in adolescents born very preterm.

There is increasing evidence about the presence of white matter damage in subjects with a history of premature birth, even in those classified as good outcome because of an apparently normal development. Although intellectual performance is within normal limits in premature children it is significantly decreased compared to paired controls. The purpose of this study was to investigate the relationship between a lower performance intelligence quotient and white matter damage in preterm adolescents. The sample comprised 44 adolescents (mean age+/-S.D.: 14.4+/-1.6 years) born before 32 weeks of gestational age and 43 term-born adolescents (14.5+/-2.1 years). Individual voxel-based morphometry analyses demonstrated that 35/44 (80%) preterm subjects had white matter abnormalities. The centrum semiovale and the posterior periventricular regions were the most frequently affected areas. Correlation analysis showed that in preterms the performance intelligence quotient correlated with the whole-brain white matter volume (r=0.32; P=0.036) but not with grey matter volume. Complementary analysis showed that low scores in the Digit Symbol subtest, a measure of processing speed, in the preterm group correlated with reductions in white matter concentration. These results suggest that white matter damage is highly common and that it persists until adolescence. Hence, diffuse white matter loss may be responsible for performance intelligence quotient and processing speed decrements in subjects with very preterm birth.

Proton magnetic resonance spectroscopy reveals medial temporal metabolic abnormalities in adolescents with history of preterm birth.

Prematurity is associated with volumetric reductions in specific brain areas such as the hippocampus and with metabolic changes that can be detected by spectroscopy. Short echo time (35 ms) Proton magnetic resonance spectroscopy (1H MRS) was performed to assess possible medial temporal lobe metabolic abnormalities in 21 adolescents with preterm birth (mean age: 14.8, SD: 1.3) compared with an age-matched control sample (mean age: 14.8, SD: 1.6). 1H MRS spectra were analyzed with linear combination model fitting, obtaining the absolute metabolite concentrations for Creatine (Cr), and myo-inositol (Ins). In addition, the following metabolite sums were measured: total Cho (glycerophospho-choline + phosphocholine), total N-acetyl-aspartate + N-acetyl-aspartylglutamate (NA), and total Glx (glutamate + glutamine). A stereological analysis was performed to calculate hippocampal volume. Absolute Cr, and total NA values were decreased in the preterm group (p = 0.016; p = 0.002, respectively). The preterm also showed a hippocampal reduction (p < 0.0001). Significant relationships were found between gestational age and different metabolites and the hippocampal volume. Moreover, hippocampal volume correlated with brain metabolites in the whole sample. Results demonstrate that prematurity affects medial temporal lobe metabolites, and that the alteration is related to structural changes, suggesting that the cerebral changes persist until adolescence.

Corpus callosum and prefrontal functions in adolescents with history of very preterm birth.

Very preterm (VPT) birth can account for thinning of the corpus callosum and poorer cognitive performance. Research findings about preterm and VPT adolescents usually describe a small posterior corpus callosum, although our research group has also found reductions of the anterior part, specifically the genu. The aim of the present study was to investigate the functional implications of this concrete reduction. Fifty-two VPT adolescents were compared with 52 adolescents born at term; there were no significant differences in age and gender, and socioeconomic status was similar between the groups. All participants underwent a magnetic resonance imaging (MRI) study and assessment of prefrontal functioning and vocabulary. The VPT group showed significant reductions of the genu, isthmus and splenium, as well as a significantly worse performance on category verbal fluency, executive functions, everyday memory and vocabulary. Although several parts of the corpus callosum correlated with some prefrontal functions, the genu was the part which principally explained these correlations. The subtest Vocabulary only correlated with the splenium. The relationship between genu and prefrontal functions and between splenium and vocabulary may be due to the fact that these parts of the corpus callosum connect prefrontal and posterior parietal cortex, respectively. The work presented here provides evidence of specific associations between reductions in the anterior corpus callosum (genu) and lower prefrontal functioning in VPT adolescents.

Growth of the corpus callosum in adolescents born preterm.

OBJECTIVE: To examine the growth of the corpus callosum between adolescence and early adulthood in individuals who were born before 33 weeks' gestation (very preterm [VPT]) and its relation to neuropsychological function. DESIGN: A longitudinal cohort study of VPT individuals born between January 4, 1982, and December 29, 1984, and a term-born comparison group. SETTING: A long-term follow-up study into perinatal predictors of outcome after preterm birth at University College Hospital, London. PARTICIPANTS: A total of 72 VPT and 34 term-born individuals were assessed in adolescence (aged 15 years) and in early adulthood (aged 19 years). Adult assessments took place between June 6, 2002, and October 23, 2004. MAIN EXPOSURE: Birth before 33 weeks' gestation. OUTCOME MEASURE: The cross-sectional area of 4 segments of the corpus callosum, measured on the midsagittal slice of high-resolution structural magnetic resonance images in adolescence and young adulthood. RESULTS: Total corpus callosum size increased in term and VPT groups, but growth was much greater in the VPT group (13.4% in the VPT group vs 3.3% in the term group). There were significant associations between adult performance IQ and growth of anterior (P = .001), midposterior (P = .009), and posterior (P = .009) segments in the VPT group. CONCLUSIONS: The corpus callosum grows dramatically in VPT adolescents, and this growth is associated with neuropsychological outcome. This may represent a delay of a normal maturational process in VPT individuals.

Gestational age at preterm birth in relation to corpus callosum and general cognitive outcome in adolescents.

Prematurity is associated with corpus callosum abnormalities and low general cognitive functioning. The present study explores the specific relationship between gestational age, corpus callosum, and intelligence quotient (IQ) in a sample of preterm-born adolescents. Sixty-four adolescents born at a gestational age of 36 weeks or less were divided into 4 groups attending to their gestational age (GA) (group 1, < or = 27; group 2, 28-30; group 3, 31-33; group 4, 34-36). These individuals were compared with 53 adolescents born at term and of similar age, gender, and sociocultural status. Individuals born at a gestational age of 27 or less (group 1) presented a generalized corpus callosum reduction in the posterior part (posterior midbody, isthmus, and splenium) as well as in the anterior part (anterior midbody and genu), a reduced total white-matter volume, and a low Full-Scale IQ. Group 2 (GA between 28 and 30) also showed a low IQ, but corpus callosum reduction was only found in the splenium, without total white-matter volume reductions. Group 3 (GA between 31 and 33) did not present differences in corpus callosum size or a reduced total white- matter volume, but they showed a low Full-Scale IQ. Group 4 (GA between 34 and 36) did not show a smaller corpus callosum or a lower general cognitive performance. Specific significant correlations were found between corpus callosum subregions and gestational age. These results suggest the importance of gestational age in prematurity in relation to brain structural and functional outcome. Premature babies born at a gestational age of 27 weeks or less are the target group for long-term corpus callosum and white-matter anomalies and for a low IQ.

Corpus callosum size and neuropsychologic impairment in adolescents who were born preterm.

Prematurity is associated with cerebral abnormalities that might account for poorer cognitive performance. The aim of our study was to investigate the correlations between corpus callosum reductions and neuropsychologic performance in adolescents who were born preterm. Twenty-five subjects born before 33 weeks' gestation were compared with 25 subjects born at term and of similar age, gender, and sociocultural status. All subjects underwent magnetic resonance imaging and neuropsychologic examinations. Premature subjects performed worse than controls in global cognitive functioning, verbal memory, and verbal fluency. Corpus callosum measurements showed a global reduction owing mainly to thinning in the splenium, posterior midbody, and genu. Corpus callosum size significantly correlated with gestational age, Wechsler Performance IQ, and memory performance. These results suggest that cerebral growth during infancy does not compensate for corpus callosum reduction and that this reduction reflects neuropsychologic deficit. The cognitive impairment can arise from the paucity of the complex interneuronal connections owing to fiber damage, particularly myelinated fibers.

White matter volume and concentration reductions in adolescents with history of very preterm birth: a voxel-based morphometry study.

Very preterm birth (VPTB) is an important risk factor for white matter (WM) damage. We used voxel-based morphometry (VBM) to examine regional WM brain abnormalities in 50 adolescents with antecedents of very preterm birth (VPTB) without evidence of WM damage on T2-weighted MRI. This group was compared with a group of 50 subjects born at term and matched for age, handedness and socio-cultural status. We also examined the relationship between WM changes and gestational age (GA) and weight (GW) at birth in VPTB subjects. Both modulated and unmodulated VBM analyses showed significant abnormalities in several WM brain regions in the VPTB group, involving all the cerebral lobes. However, density analyses (unmodulated data) mainly identified periventricular damage and the involvement of the longitudinal fascicles while volume analyses (modulated data) detected WM decreases in regions distant from the ventricular system, located at the origin and end of the long fascicles. A significant correlation was found between WM decreases and both GA and GW in various brain regions: the lower the GA and GW, the lower the WM integrity. This study supports the current view that widespread white matter impairment is associated with immature birth.

Correlations of thalamic reductions with verbal fluency impairment in those born prematurely.

Prematurity is associated with reduced brain volume, and the thalamus is among the structures most affected. We used a voxel-based morphometry analysis of gray matter to map regional atrophy in the thalamus in a sample of 30 adolescents with antecedents of very preterm birth. The preterm sample was compared with 30 controls matched by age, sex, handedness and sociocultural status. Individuals with very preterm birth differed from controls in several thalamic nuclei, and semantic and phonetic fluency showed different correlation patterns with brain volume. Semantic fluency achieved significant correlations with more thalamic nuclei than phonetic fluency. These results agree with functional magnetic resonance imaging studies showing that semantic fluency involves more cerebral regions than phonetic fluency.

Hippocampal functional magnetic resonance imaging during a face-name learning task in adolescents with antecedents of prematurity.

Functional magnetic resonance imaging (fMRI) was used to map hippocampal activation during a declarative memory task in a sample of 14 adolescents with antecedents of prematurity (AP). The sample with AP was matched by age, sex and handedness with 14 full-term controls with no history of neurological or psychiatric illness. The target task consisted in learning 16 novel face-name pairs, and the control task involved the examination of two repeated face-name pairs. Stereological methods were also used to quantify hippocampal volumes. In both groups, we observed increased activation in the learning condition compared to the control task in the right fusiform gyrus and the left inferior occipital gyrus, but only premature subjects activated the hippocampus. Group comparison of the activation versus control conditions showed that prematures had greater activity in the right hippocampus than controls during the encoding of the word-face association. Volumetric analyses showed a significant left hippocampal volume loss in adolescents with AP. In addition, we found a significant positive correlation in the premature group between right hippocampal activation and face-name recognition. Functional MRI data also correlated with structural MRI data: right hippocampal activation correlated positively with right hippocampal volume. Our findings are consistent with previous studies of brain plasticity after focal lesions. Left hippocampal tissue loss may be related to an increase in contralateral brain activity, probably reflecting a compensatory mechanism. Our data also suggest that this plasticity is not enough to achieve normal performance.

Hippocampal gray matter reduction associates with memory deficits in adolescents with history of prematurity.

Using optimized voxel-based morphometry (VBM), we compared the relationship between hippocampal and thalamic gray matter loss and memory impairment in 22 adolescents with history of prematurity (HP) and 22 normal controls. We observed significant differences between groups in verbal learning and verbal recognition, but not in visual memory. VBM analysis showed significant left hippocampal and bilateral thalamic reductions in HP subjects. Using stereological methods, we also observed a reduction in hippocampal volume, with left posterior predominance. We found correlations between left hippocampal gray matter reductions (assessed by VBM) and verbal memory (learning and percentage of memory loss) in the premature group. The stereological analysis showed a correlation between verbal learning and the left posterior hippocampus. Our results suggest that left hippocampal tissue loss may be responsible for memory impairment and is probably related to the learning disabilities that HP subjects present during schooling.

Medial temporal MR spectroscopy is related to memory performance in normal adolescent subjects.

In addition to the study of pathological conditions, magnetic resonance spectroscopy can provide useful information about brain-behavior relationships in normal subjects. Recently, there have been reports of correlations between N-acetylaspartate (NAA) values and cognitive functions in normal adults. We tested the possible specific relationship between the NAA/choline (Cho) ratio in the medial temporal lobe and memory performance in normal adolescents. The medial temporal NAA/Cho ratio was unrelated to age, gender and general intelligence but presented a clear correlation with several memory measures. In the regression analysis two memory variables (RAVLT learning and a face-name recognition task) explained 55.6% of NAA/Cho variance. We conclude that NAA values in the medial temporal lobe are related to memory abilities but not to global intelligence in normal adolescent subjects.