Quantification of gray matter changes in the cerebral cortex after isolated cerebellar damage: a voxel-based morphometry study

There is growing evidence based on behavioral and functional imaging studies about the cerebellar involvement in the modulation of cognitive functions. However, it still remains to be clarified how the cerebellum interacts with brain regions sub-serving different cognitive domains. In this study we used magnetic resonance imaging (MRI) and voxel based morphometry (VBM) to investigate changes of cerebral gray matter (GM) density in 15 patients with a focal cerebellar damage (CD) compared to 15 healthy controls. T2-weighted scans and T1-weighted volumes were collected from each subject. With the exception of the cerebellar lesion, none of the patients showed any additional brain MRI abnormality. T1-volumes were analyzed by voxel-based morphometry. Consistent with their neuropsychological abnormalities, patients with right-CD compared to controls showed a reduction of GM density mainly involving the left frontal, parietal and temporal lobes. Conversely, patients with left-CD did not show any significant neuropsychological or cerebral GM abnormality. The present study indicates that specific GM changes may be detected in patients with isolated CD and cognitive dysfunction. We discuss the findings in terms of cerebellar influence on the neuronal networks involved in higher level functions of the association cortex.     

Structural correlates of cognitive domains in normal aging with diffusion tensor imaging

The involvement of brain structures in specific cognitive functions is not straightforward. In order to characterize the brain micro-structural correlates of cognitive domains, 52 healthy subjects, age 25–82 years, completed a computerized neuropsychological battery and were scanned using magnetic resonance diffusion tensor imaging. Factor analysis of 44 different cognitive scores was performed, isolating three cognitive domains—executive function, information processing speed and memory. Partial correlation was conducted between DTI parameters and each of the three cognitive domains controlling for age and motor function. Regions showing significant correlations with cognitive domains are domain-specific and are consistent with previous knowledge. While executive function was correlated with diffusion tensor imaging (DTI) parameters in frontal white matter and in the superior longitudinal fasciculus, information processing speed was correlated with DTI parameters in the cingulum, corona radiata, inferior longitudinal fasciculus, parietal white matter and in the thalamus. Memory performance was correlated with DTI measures in temporal and frontal gray matter and white matter regions, including the cingulate cortex and the parahippocampus. Thus, inter-subject variability in cognitive performance and tissue morphology, as expressed by diffusion tensor magnetic resonance imaging, can be used to relate tissue microstructure with cognitive performance and to provide information to corroborate other functional localization techniques.     

Effect of the XbaI polymorphism of estrogen receptor alpha on postmenopausal gray matter

The frequent polymorphism XbaI (A351G) in the estrogen receptor alpha (ERalpha) gene has been associated with some postmenopausal pathologies' risk such as Alzheimer's disease (AD) or cognitive decline. In the present study, we explored whether the XbaI polymorphism leads to different gray matter volumes using voxel-based morphometry (VBM) on 20 magnetic resonance images of healthy postmenopausal women. Subjects carrying the less common XbaI/X allele were contrasted to non-carriers in groups well balanced by relevant confounding variables. The XbaI/X allele carriers displayed clusters ranging from 9 to 28% of tissue reductions in the cerebellar (cluster size, z, stereotactic coordinates: 16 mm(3); 3.17; 14, -94, -38) and cerebral cortex, in particular in the occipital lobe (272 mm(3); 3.76; -38,-68,-16), in the middle frontal gyrus (192 mm(3); 3.71; 38, 12, 38) and in the middle temporal gyrus, while the opposite comparison was negative. The XbaI/X allele in ERalpha gene is associated to smaller gray matter volumes of the cerebral and cerebellar cortex. This allele might increase the susceptibility for senile neurodegenerative conditions, being associated to smaller cerebral reserve.     

Inspiratory loading elicits aberrant fMRI signal changes in obstructive sleep apnea

We hypothesized that neural processes mediating deficient sensory and autonomic regulatory mechanisms in obstructive sleep apnea (OSA) would be revealed by responses to inspiratory loading in brain regions regulating sensory and motor control. Functional magnetic resonance imaging (fMRI) signals and physiologic changes were assessed during baseline and inspiratory loading in 7 OSA patients and 11 controls, all male and medication-free. Heart rate increases to inspiratory loading began earlier and load pressures were achieved later in OSA patients. Comparable fMRI changes emerged in multiple brain regions in both groups, including limbic, cerebellar, midbrain, and primary motor cortex. However, in OSA subjects, altered signals appeared in primary sensory thalamus and sensory cortex, supplementary motor cortex, cerebellar cortex and deep nuclei, cingulate, medial temporal, and insular cortices, right hippocampus, and midbrain. Signal delays occurred in basal ganglia. We conclude that areas mediating sensory and autonomic processes, and motor timing, are affected in OSA; many of these areas overlap regions of previously demonstrated gray matter loss.     

Executive Function and Theory of Mind in 2 Year Olds: A Family Affair?

This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.     

Obstructive sleep apnea: Brain hemodynamics,structure, and function

This paper summarizes a review of articles that have explored the relationship between obstructive sleep apnea (OSA ), brain infractions, and cognitive dysfunction. The anomalies in brain hemodynamics, brain atrophy, and cognitive dysfunction resulting from OSA are reviewed. The effectiveness of continuous positive airway pressure (CPAP ) treatment on the reversibility of structural and neurobehavioral deficits is also presented. The articles were selected based on a systematic search on PubMed and Medline databases using the key words “sleep apnea, OSA , hypoxia, sleep fragmentation, cerebral hemodynamics, metabolism, brain structure, cognition, memory, quality of life, neuropsychological deficits, and CPAP treatment.” The review suggests that OSA ‐mediated brain hemodynamics and brain atrophy are concomitant with cognitive dysfunction. It is concluded that OSA results in cerebral hemodynamic instability, hypoxia, and sleep fragmentation which appear to be the major contributing factors to the brain structural changes and cognitive deficits. Furthermore, the reviewed studies indicate that CPAP treatment may partially reverse or diminish the adverse effects of OSA on the brain structure and function. Additional investigations are urgently needed to elucidate the underlying mechanisms of the effects of OSA on the brain and the efficacy of CPAP therapy for brain protection.     

Gray matter deficits and resting-state abnormalities in abstinent heroin-dependent individuals

Previous neuroimaging studies have demonstrated both structural and functional damages in heroin-dependent individuals. However, few studies investigated gray matter deficits and abnormal resting-state networks together in heroin-dependent individuals. In the present study, voxel-based morphometry (VBM) was used to identify brain regions with gray matter density reduction. Resting-state fMRI connectivity analysis was employed to assess potential functional abnormalities during resting-state. All clinical significances were investigated by examining their association with duration of heroin use. Compared with healthy subjects, heroin-dependent individuals showed significant reduction in gray matter density in the right dorsolateral prefrontal cortex (DLPFC) and a decrease in resting-state functional connectivity between the right DLPFC and left inferior parietal lobe (IPL). The gray matter density of the right DLPFC and its resting-state functional connectivity with the left IPL both showed significantly negative correlation with duration of heroin use, which were likely to be related to the functional impairments in decision-making and cognitive control exhibited by heroin-dependent individuals. Our findings demonstrated that long heroin dependence impairs the right DLPFC in heroin-dependent individuals, including structural deficits and resting-state functional impairments.     

Gray matter reduction associated with psychopathology and cognitive dysfunction in unipolar depression: a voxel-based morphometry study

BACKGROUND: Functional neuroimaging studies on both cognitive processing and psychopathology in patients with major depression have reported several functionally aberrant brain areas within limbic-cortical circuits. However, less is known about the relationship between psychopathology, cognitive deficits and regional volume alterations in this patient population. METHODS: By means of voxel-based morphometry (VBM) and a standardized neuropsychological test battery, we examined 15 patients meeting DSM-IV criteria for major depression disorder and 14 healthy controls in order to investigate the relationship between affective symptoms, cognitive deficits and structural abnormalities. RESULTS: Patients with depression showed reduced gray matter concentration (GMC) in the left inferior temporal cortex (BA 20), the right orbitofrontal (BA 11) and the dorsolateral prefrontal cortex (BA 46). Reduced gray matter volume (GMV) was found in the left hippocampal gyrus, the cingulate gyrus (BA 24/32) and the thalamus. Structure-cognition correlation analyses revealed that decreased GMC of the right medial and inferior frontal gyrus was associated with both depressive psychopathology and worse executive performance as measured by the Wisconsin Card Sorting Test (WCST). Furthermore, depressive psychopathology and worse performance during the WCST were associated with decreased GMV of the hippocampus. Decreased GMV of the cingulate cortex was associated with worse executive performance. LIMITATIONS: Moderate illness severity, medication effects, and the relatively small patient sample size should be taken into consideration when reviewing the implications of these results. CONCLUSIONS: The volumetric results indicate that regional abnormalities in gray matter volume and concentration may be associated with both psychopathological changes and cognitive deficits in depression.     

女性抑郁症病人脑灰质容量改变的研究

目的:比较女性抑郁病人与正常对照组的大脑灰质容量。方法:采用优化的基于像素的形态测量学方法(VBM)对15名未服药的抑郁症女性患者与15名条件匹配的正常志愿者脑灰质容量进行了对比研究。结果:与正常对照组相比,抑郁病人的左侧额中回眶部、左侧额下回三角部、左侧旁中央小叶、右侧辅助运动区、右侧顶上叶的灰质容量减低。结论:女性抑郁病人大脑灰质容量存在异常。     

Interactions of cognitive reserve with regional brain anatomy and brain function during a working memory task in healthy elders

Cognitive reserve (CR) defines the capacity of the adult brain to cope with pathology in order to minimize symptomatology. Relevant lifetime social, cognitive and leisure activities represent measurable proxies of cognitive CR but its underlying structural and functional brain mechanisms remain poorly understood. We investigated the relationship between CR and regional gray matter volumes and brain activity (fMRI) during a working memory task in a sample of healthy elders. Participants with higher CR had larger gray matter volumes in frontal and parietal regions. Conversely, a negative correlation was observed between CR and fMRI signal in the right inferior frontal cortex, suggesting increased neural efficiency for higher CR individuals. This latter association however disappeared after adjusting for gray matter images in a voxel-based manner. Altogether, present results may reflect both general and specific anatomofunctional correlates of CR in the healthy elders. Thus, whereas heteromodal anterior and posterior gray matter regions correspond to passive (i.e. morphological) correlates of CR unrelated to functional brain activation during this particular cognitive task, the right inferior frontal area reveals interactions between active and passive components of CR related to the cognitive functions tested in the fMRI study.     

Psychological functioning,brain morphology,and functional neuroimaging in Klinefelter syndrome

Klinefelter syndrome (KS; 47,XXY) impacts neurodevelopment and is associated with an increased risk of cognitive, psychological and social impairments, although significant heterogeneity in the neurodevelopmental profile is seen. KS is characterized by a specific cognitive profile with predominantly verbal deficits, preserved function in non‐verbal and visuo‐spatial domains, executive dysfunction and social impairments, and by an increased vulnerability toward psychiatric disorders. The neurobiological underpinnings of the observed neuropsychological profile have not been established. A distinct pattern of both global and regional brain volumetric differences has been demonstrated in addition to preliminary findings of functional brain alterations related to auditory, motor, language and social processing. When present, the combination of cognitive, psychological and social challenges has the potential to negatively affect quality of life. This review intends to provide information and insight to the neuropsychological outcome and brain correlates of KS. Possible clinical intervention and future directions of research will be discussed.     

Age-related decrease of functional connectivity additional to gray matter atrophy in a network for movement initiation

Healthy aging is accompanied by a decrease in cognitive and motor capacities. In a network associated with movement initiation, we investigated age-related changes of functional connectivity (FC) as well as regional atrophy in a sample of 232 healthy subjects (age range 18–85 years). To this end, voxel-based morphometry and whole-brain resting-state FC were analyzed for the supplementary motor area (SMA), anterior midcingulate cortex (aMCC) and bilateral striatum (Str). To assess the specificity of age-related effects, bilateral primary sensorimotor cortex (S1/M1) closely associated with motor execution was used as control seeds. All regions showed strong reduction of gray matter volume with age. Corrected for this regional atrophy, the FC analysis revealed an age × seed interaction for each of the bilateral Str nodes against S1/M1 with consistent age-related decrease in FC with bilateral caudate nucleus and anterior putamen. Specific age-dependent FC decline of SMA was found in bilateral central insula and the adjacent frontal operculum. aMCC showed exclusive age-related decoupling from the anterior cingulate motor area. The present study demonstrates network as well as node-specific age-dependent FC decline of the SMA and aMCC to highly integrative cortical areas involved in cognitive motor control. FC decrease in addition to gray matter atrophy within the Str may provide a substrate for the declining motor control in elderly. Finally, age-related FC changes in both the network for movement initiation as well as the network for motor execution are not explained by regional atrophy in the healthy aging brain.     

Neuroanatomical correlates of aging, cardiopulmonary fitness level, and education

Fitness and education may protect against cognitive impairments in aging. They may also counteract age-related structural changes within the brain. Here we analyzed volumetric differences in cerebrospinal fluid and gray and white matter, along with neuropsychological data, in adults differing in age, fitness, and education. Cognitive performance was correlated with fitness and education. Voxel-based morphometry was used for a whole-brain analysis of structural magnetic resonance images. We found age-related losses in gray and white matter in medial-temporal, parietal, and frontal areas. As in previous work, fitness within the old correlated with preserved gray matter in the same areas. In contrast, higher education predicted preserved white matter in inferior frontal areas. These data suggest that fitness and education may both be predictive of preserved cognitive function in aging through separable effects on brain structure.     

Voxel-based morphometry of disgust proneness

This voxel-based morphometry study investigated whether the personality trait disgust proneness is associated with gray matter volume (GMV) of distinct brain regions implicated in disgust processing. We analyzed brain structural data from 99 healthy women, who had rated their tendency to experience disgust for different disgust domains (offensive food, death, poor hygiene, decay, and body secretions). Food-related disgust proneness was positively correlated with insula volume. The disgust domains decay and death showed negative correlations with GMV of the dorsomedial and the dorsolateral prefrontal cortex (DMPFC, DLPFC). Our data implicate that only core disgust shows an association with the GMV of the gustatory cortex, whereas the reactivity to other disgust areas is linked with cognitive control areas.     

Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia

Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD.     

Longitudinal brain volumetric changes during one year in non-elderly healthy adults: a voxel-based morphometry study

Previous cross-sectional magnetic resonance imaging (MRI) studies of healthy aging in young adults have indicated the presence of significant inverse correlations between age and gray matter volumes, although not homogeneously across all brain regions. However, such cross-sectional studies have important limitations and there is a scarcity of detailed longitudinal MRI studies with repeated measures obtained in the same individuals in order to investigate regional gray matter changes during short periods of time in non-elderly healthy adults. In the present study, 52 healthy young adults aged 18 to 50 years (27 males and 25 females) were followed with repeated MRI acquisitions over approximately 15 months. Gray matter volumes were compared between the two times using voxel-based morphometry, with the prediction that volume changes would be detectable in the frontal lobe, temporal neocortex and hippocampus. Voxel-wise analyses showed significant (P < 0.05, family-wise error corrected) relative volume reductions of gray matter in two small foci located in the right orbitofrontal cortex and left hippocampus. Separate comparisons for males and females showed bilateral gray matter relative reductions in the orbitofrontal cortex over time only in males. We conclude that, in non-elderly healthy adults, subtle gray matter volume alterations are detectable after short periods of time. This underscores the dynamic nature of gray matter changes in the brain during adult life, with regional volume reductions being detectable in brain regions that are relevant to cognitive and emotional processes.     

Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels?

This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.     

Brain atrophy associated with baseline and longitudinal measures of cognition

The overall goal was to identify patterns of brain atrophy associated with cognitive impairment and future cognitive decline in non-demented elders. Seventy-one participants were studied with structural MRI and neuropsychological testing at baseline and 1-year follow-up. Deformation-based morphometry was used to examine the relationship between regional baseline brain tissue volume with baseline and longitudinal measures of delayed verbal memory, semantic memory, and executive function. Smaller right hippocampal and entorhinal cortex (ERC) volumes at baseline were associated with worse delayed verbal memory performance at baseline while smaller left ERC volume was associated with greater longitudinal decline. Smaller left superior temporal cortex at baseline was associated with worse semantic memory at baseline, while smaller left temporal white and gray matter volumes were associated with greater semantic memory decline. Increased CSF and smaller frontal lobe volumes were associated with impaired executive function at baseline and greater longitudinal executive decline. These findings suggest that baseline volumes of prefrontal and temporal regions may underlie continuing cognitive decline due to aging, pathology, or both in non-demented elderly individuals.     

The relationship between brain morphometry and neuropsychological performance in alcohol dependence

The aim of this study was to explore local brain atrophy of patients with alcohol dependence using a voxel-based analysis of magnetic resonance images and to investigate the relationship of those atrophic regions with drinking history and neuropsychological performances. Statistical parametric mapping was applied for the global and regional comparison of segmented gray matter and white matter images from 20 patients with alcohol dependence and with those from 20 controls. The Rey auditory-verbal learning test, Rey-Osterrieth complex figure test, Stroop test, trail-making test, and Wisconsin card sorting test were conducted as neuropsychological evaluations. There was a significant decrease in both gray matter and white matter globally in alcohol dependence. Bilateral parahippocampal white matter areas were reduced in particular. Perseverative responses and perseverative errors in the Wisconsin card sorting test had significant correlation with the decrease of gray matter decrease including the left superior temporal gyri and right postcentral region. The psychological performance measures correlated with gray matter rather than white matter, whereas right temporal white matter correlated with drinking amount for last 4 weeks. This may imply that alcohol consumption in heavy amounts damages both gray matter and white matter, and gray matter atrophy mainly leads to cognitive impairment, whereas white matter is related to drinking history.     

Longitudinal MRI brain volume changes over one year in children with mucopolysaccharidosis types IIIA and IIIB

ObjectiveTo quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB).MethodsIn order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer.ResultsOf the 25 subjects enrolled with MPS III, 17 children (4 females, 13 males) completed at least one MRI with interpretable volumetric data. The ages ranged from 2.8 to 13.7 years old (average 7.2 years old) at enrollment, including 8 with MPS IIIA and 9 with MPS IIIB. At baseline, individuals with MPS III demonstrated reduced cerebral white matter and corpus callosum volumes, but greater volumes of the lateral ventricles, cerebellar cortex, and cerebellar white matter compared to controls. Among the 13 individuals with MPS III with two interpretable MRIs, there were annualized losses or plateaus in supratentorial brain tissue volumes (cerebral cortex ?42.10 ± 18.52 cm³/year [mean ± SD], cerebral white matter ?4.37 ± 11.82 cm³/year, subcortical gray matter ?6.54 ± 3.63 cm³/year, corpus callosum ?0.18 ± 0.62 cm³/yr) and in cerebellar cortex (?0.49 ± 12.57 cm³/year), with a compensatory increase in lateral ventricular volume (7.17 ± 6.79 cm³/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen.ConclusionsLoss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.