Cumulative Blood Pressure Exposure, Basal Ganglia, and Thalamic Morphology in Midlife.

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

Sex-Based Differences in Cortical and Subcortical Development in 436 Individuals Aged 4-54 Years.

Sex-based differences in brain development have long been established in ex vivo studies. Recent in vivo studies using magnetic resonance imaging (MRI) have offered considerable insight into sex-based variations in brain maturation. However, reports of sex-based differences in cortical volumes and thickness are inconsistent. We examined brain maturation in a cross-sectional, single-site cohort of 436 individuals (201 [46%] males) aged 4-54 years (median = 16 years). Cortical thickness, cortical surface area, subcortical surface area, volumes of the cerebral cortex, white matter (WM), cortical and subcortical gray matter (GM), including the thalamic subnuclei, basal ganglia, and hippocampi were calculated using automatic segmentation pipelines. Subcortical structures demonstrated distinct curvilinear trajectories from the cortex, in both volumetric maturation and surface-area expansion in relation to age. Surface-area analysis indicated that dorsal regions of the thalamus, globus pallidus and striatum, regions demonstrating structural connectivity with frontoparietal cortices, exhibited extensive expansion with age, and were inversely related to changes seen in cortical maturation, which contracted with age. Furthermore, surface-area expansion was more robust in males in comparison to females. Age- and sex-related maturational changes may reflect alterations in dendritic and synaptic architecture known to occur during development from early childhood through to mid-adulthood.

Basal ganglia and thalamic tract connectivity in very preterm and full-term children; associations with 7-year neurodevelopment.

BACKGROUND: Altered basal ganglia and thalamic connectivity may be critical for cognitive, motor and behavioural impairments common to very preterm (<32 weeks' gestational age) children. This study aims to (1) compare corticostriatal and thalamocortical tract connectivity between very preterm and term-born children at 7 years of age; (2) explore tract connectivity associations with 7-year neurodevelopmental outcomes, and whether these relationships differed between groups. METHODS: Eighty-three very preterm and 19 term-born (≥37 weeks' gestational age) children underwent structural and diffusion magnetic resonance imaging and had a neuropsychological assessment at 7 years. Corticostriatal and thalamocortical tracts were reconstructed and white matter connectivity was estimated with apparent fibre density. RESULTS: Compared with term-born controls, very preterm children had decreased connectivity in tracts linking the caudate to right motor areas (-10%, p = 0.03) and the thalamus with left motor areas (-5.7%, p = 0.03). Reduced connectivity in corticostriatal and thalamocortical tracts was associated with adverse motor functioning in both groups (p = 0.06). Decreased connectivity of the left caudate and putamen with the lateral prefrontal cortex was associated with lower reading performance for controls (p = 0.06). CONCLUSION: Corticostriatal and thalamocortical tracts are vulnerable to very preterm birth. Poorer connectivity in these tracts may underlie the motor impairments observed in very preterm children.

Differential developmental changes in cortical representations of auditory-vocal stimuli in songbirds.

Procedural skill learning requires iterative comparisons between feedback of self-generated motor output and a goal sensorimotor pattern. In juvenile songbirds, neural representations of both self-generated behaviors (each bird's own immature song) and the goal motor pattern (each bird's adult tutor song) are essential for vocal learning, yet little is known about how these behaviorally relevant stimuli are encoded. We made extracellular recordings during song playback in anesthetized juvenile and adult zebra finches ( Taeniopygia guttata) in adjacent cortical regions RA (robust nucleus of the arcopallium), AId (dorsal intermediate arcopallium), and RA cup, each of which is well situated to integrate auditory-vocal information: RA is a motor cortical region that drives vocal output, AId is an adjoining cortical region whose projections converge with basal ganglia loops for song learning in the dorsal thalamus, and RA cup surrounds RA and receives inputs from primary and secondary auditory cortex. We found strong developmental differences in neural selectivity within RA, but not in AId or RA cup. Juvenile RA neurons were broadly responsive to multiple songs but preferred juvenile over adult vocal sounds; in addition, spiking responses lacked consistent temporal patterning. By adulthood, RA neurons responded most strongly to each bird's own song with precisely timed spiking activity. In contrast, we observed a complete lack of song responsivity in both juvenile and adult AId, even though this region receives song-responsive inputs. A surprisingly large proportion of sites in RA cup of both juveniles and adults did not respond to song playback, and responsive sites showed little evidence of song selectivity. NEW & NOTEWORTHY Motor skill learning entails changes in selectivity for behaviorally relevant stimuli across cortical regions, yet the neural representation of these stimuli remains understudied. We investigated how information important for vocal learning in zebra finches is represented in regions analogous to infragranular layers of motor and auditory cortices during vs. after the developmentally regulated learning period. The results provide insight into how neurons in higher level stages of cortical processing represent stimuli important for motor skill learning.

MRI Differences Associated with Intrauterine Growth Restriction in Preterm Infants.

BACKGROUND: Preterm infants are at risk for neurodevelopmental impairment. Intrauterine growth restriction (IUGR) further increases this risk. Brain imaging studies are often utilized at or near term-equivalent age to determine later prognosis. OBJECTIVE: To evaluate the association between intrauterine growth and regional brain volume on MRI scans performed in preterm infants at or near term-equivalent age. METHODS: This is a retrospective case-control study of 24 infants born at gestational age ≤30 weeks and cared for in a large, inner-city, academic neonatal intensive-care unit from 2012 to 2013. Each IUGR infant was matched with 1-2 appropriate for gestational age (AGA) infants who served as controls. Predischarge MRI scans routinely obtained at ≥36 weeks' adjusted age were analyzed for regional brain volumetric differences. We examined the association between IUGR and thalamic, basal ganglion, and cerebellar brain volumes in these preterm infants. RESULTS: Compared to AGA infants, IUGR infants had a smaller thalamus (7.88 vs. 5.87 mL, p = 0.001) and basal ganglion (8.87 vs. 6.92 mL, p = 0.002) volumes. There was no difference in cerebellar volumes between the two study groups. Linear regression analyses revealed similar trends in the associations between IUGR and brain volumes after adjusting for sex, gestational age at birth, and postconceptual age and weight at MRI. CONCLUSIONS: Thalamus and basal ganglion volumes are reduced in growth-restricted preterm infants. These differences may preferentially impact neurodevelopmental outcomes. Further research is needed to explore these relationships.

The developing human brain: age-related changes in cortical, subcortical, and cerebellar anatomy.

INTRODUCTION: This study is the first to characterize normal development and sex differences across neuroanatomical structures in cortical, subcortical, and cerebellar brain regions in a single large cohort. METHODS: One hundred and ninety-two magnetic resonance images were examined from 96 typically developing females and 96 age-matched typically developing males from 4 to 18 years of age. Image segmentation of the cortex was conducted with CIVET, while that of the cerebellum, hippocampi, thalamus, and basal ganglia were conducted using the MAGeT algorithm. RESULTS: Cortical thickness analysis revealed that most cortical regions decrease linearly, while surface area increases linearly with age. Volume relative to total cerebrum followed a quadratic trend with age, with only the left supramarginal gyrus showing sexual dimorphism. Hippocampal relative volume increased linearly, while the thalamus, caudate, and putamen decreased linearly, and the cerebellum did not change with age. The relative volumes of several subcortical subregions followed inverted U-shaped trends that peaked at ~12 years of age. Many subcortical structures were found to be larger in females than in males, independently of age, while others showed a sex-by-age interaction. CONCLUSION: This study provides a comprehensive assessment of cortical, subcortical, and cerebellar growth patterns during normal development, and draws attention to the role of sex on neuroanatomical maturation throughout childhood and adolescence.

Deep grey matter growth predicts neurodevelopmental outcomes in very preterm children.

We evaluated whether the volume and growth rate of critical brain structures measured by MRI in the first weeks of life following very preterm (<32/40 weeks) birth could predict subsequent neurodevelopmental outcomes at 4 years of age. A significant proportion of children born very prematurely have cognitive deficits, but these problems are often only detected at early school age. Structural T2-weighted magnetic resonance images were acquired in 96 very preterm neonates scanned within 2 weeks of birth and 70 of these at term-equivalent age. An automated 3D image analysis procedure was used to measure the volume of selected brain structures across all scans and time points. At 4 years of age, 53 children returned for neuropsychological assessments evaluating IQ, language and visual motor integration. Associations with maternal education and perinatal measures were also explored. Multiple regression analyses revealed that growth of the caudate and globus pallidus between preterm birth and term-equivalent age predicted visual motor integration scores after controlling for sex and gestational age. Further associations were found between caudate and putamen growth with IQ and language scores. Analyses at either preterm or term-equivalent age only found associations between normalized deep grey matter growth and visual motor integration scores at term-equivalent age. Maternal education levels were associated with measures of IQ and language, but not visual motor integration. Thalamic growth was additionally linked with perinatal measures and presence of white matter lesions. These results highlight deep grey matter growth rates as promising biomarkers of long-term outcomes following very preterm birth, and contribute to our understanding of the brain-behaviour relations in these children.

Performance monitoring in children and adolescents: a review of developmental changes in the error-related negativity and brain maturation.

To realize our goals we continuously adapt our behavior according to internal or external feedback. Errors provide an important source for such feedback and elicit a scalp electrical potential referred to as the error-related negativity (ERN), which is a useful marker for studying typical and atypical development of cognitive control mechanisms involved in performance monitoring. In this review, we survey the available studies on age-related differences in the ERN in children and adolescents. The majority of the studies show that the ERN increases in strength throughout childhood and adolescence, suggesting continued maturation of the neural systems for performance monitoring, but there are still many unresolved questions. We further review recent research in adults that has provided important insights into the neural underpinnings of the ERN and performance monitoring, implicating distributed neural systems than include the dorsal anterior and posterior cingulate cortex, the lateral prefrontal cortex, insula, basal ganglia, thalamus and white matter connections between these regions. Finally, we discuss the possible roles of structural and functional maturation of these brain regions in the development of the ERN. Overall, we argue that future work should use multimodal approaches to give a better understanding of the neurocognitive development of performance monitoring.

Morphology and microstructure of subcortical structures at birth: a large-scale Asian neonatal neuroimaging study.

This paper presents the growth pattern and sexual dimorphism of the thalamus and basal ganglia in a large-scale Asian neonatal cohort using both T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Our study observed a robust growth of the thalamus and basal ganglia (caudate, putamen, globus pallidus, and anterior limb of internal capsule) beyond the overall brain growth in the early postnatal period (36-43 weeks of the gestational age). Additionally, the microstructure of the two structures was integrated as reflected by an increase in fractional anisotropy (FA) and a decrease in axial and radial water diffusivities in the first few weeks of life. Sexual dimorphism was only observed in the whole brain growth and the left thalamic volume but not in the other volumes or DTI measures of the basal ganglia and thalamus at birth. Even though the pattern of sexual dimorphism in the total brain volume is present at birth and persists throughout postnatal brain development, sexual dimorphisms of the basal ganglia and thalamus differ from those found in later stages of brain development, indicating that regionally distinct patterns of postnatal brain development between males and females arise after birth.

Deep gray matter maturation in very preterm neonates: regional variations and pathology-related age-dependent changes in magnetization transfer ratio.

PURPOSE: To elucidate the relationship between gestational age, pathologic findings, and magnetic resonance (MR) imaging measures of tissue maturation-myelination in deep gray matter areas in very preterm neonates imaged at birth. MATERIALS AND METHODS: The study was approved by the research ethics board. Written informed consent was given by the infants' parents. Forty-two preterm neonates (19 boys; median gestational age, 28.7 weeks) with normal-appearing gray matter structures at presentation underwent MR imaging within 2 weeks of birth that included T1- and T2-weighted, magnetization transfer, and T1 relaxometry sequences. Neonates were separated into the following groups: those with normal findings (n = 23), those with white matter injury (WMI) (n = 9), those with grade I germinal matrix hemorrhage (GMH) (n = 3), and those with grade II GMH and WMI (n = 7). Analysis of covariance was used to determine regional effects of age and pathologic findings on magnetization transfer ratio (MTR) and to assess the relationship between MTR and T1. RESULTS: MTR increased linearly with age (P ≤ .0265), with a similar rate of change of 0.32% per week (95% confidence interval [CI]: 0.16, 0.49) in the basal ganglia (BG) and thalami. A lower trend (0.11% per week; 95% CI: -0.05, 0.28) was seen in the pons. Higher MTRs were seen in the thalami and pons than in the BG (P < .05), indicating earlier maturation. Accordingly, higher T1 values were observed in the BG relative to the thalami (P < .0001). Higher MTRs in the BG were observed in the group of neonates with normal findings at presentation than in the group with WMI (P = .02). CONCLUSION: MTR measurements can be used to monitor early myelination in the developing brain and to help detect changes in tissue that are not shown on T1- and T2-weighted MR images.

Mechanisms and time course of vocal learning and consolidation in the adult songbird.

In songbirds, the basal ganglia outflow nucleus LMAN is a cortical analog that is required for several forms of song plasticity and learning. Moreover, in adults, inactivating LMAN can reverse the initial expression of learning driven via aversive reinforcement. In the present study, we investigated how LMAN contributes to both reinforcement-driven learning and a self-driven recovery process in adult Bengalese finches. We first drove changes in the fundamental frequency of targeted song syllables and compared the effects of inactivating LMAN with the effects of interfering with N-methyl-d-aspartate (NMDA) receptor-dependent transmission from LMAN to one of its principal targets, the song premotor nucleus RA. Inactivating LMAN and blocking NMDA receptors in RA caused indistinguishable reversions in the expression of learning, indicating that LMAN contributes to learning through NMDA receptor-mediated glutamatergic transmission to RA. We next assessed how LMAN's role evolves over time by maintaining learned changes to song while periodically inactivating LMAN. The expression of learning consolidated to become LMAN independent over multiple days, indicating that this form of consolidation is not completed over one night, as previously suggested, and instead may occur gradually during singing. Subsequent cessation of reinforcement was followed by a gradual self-driven recovery of original song structure, indicating that consolidation does not correspond with the lasting retention of changes to song. Finally, for self-driven recovery, as for reinforcement-driven learning, LMAN was required for the expression of initial, but not later, changes to song. Our results indicate that NMDA receptor-dependent transmission from LMAN to RA plays an essential role in the initial expression of two distinct forms of vocal learning and that this role gradually wanes over a multiday process of consolidation. The results support an emerging view that cortical-basal ganglia circuits can direct the initial expression of learning via top-down influences on primary motor circuitry.

Infant brain development and vulnerability to later internalizing difficulties: the Generation R study.

OBJECTIVE: Although clinical studies have demonstrated smaller subcortical volumes in structures such as the amygdala, hippocampus, caudate nucleus, and thalamus in adults and adolescents with depressive disorders and anxiety, no study has assessed such structures in babies, long before the development of the disorders. This study examined whether the size of the "gangliothalamic ovoid" (encompassing the basal ganglia and thalamus) assessed during infancy is associated with increased internalizing problems in early childhood. METHOD: Cranial ultrasounds were used to assess gangliothalamic ovoid diameter and ventricular volume at 6 weeks of postnatal age; moreover, head circumference was measured. Outcome data included ratings of internalizing and externalizing problems using the Child Behavior Checklist (reported by mothers and fathers) at 18 and/or 36 months. Analyses were based on a total of 651 children. RESULTS: Smaller gangliothalamic diameter was associated with higher Child Behavior Checklist Internalizing scores at ages 18 and 36 months. Results remained significant after correcting for head circumference and were evident for the DSM-oriented subscales of anxiety problems and affective problems. Total ventricular volume was not consistently associated with Internalizing scores. CONCLUSIONS: Findings associating infant brain measurements with Child Behavior Checklist mother and father reports at two time points are consistent with previous cross-sectional reports of smaller subcortical volumes in depression. Results were not simply reflective of overall brain development, because the pattern held after adjustment for head circumference. This is the first study to point toward a biological vulnerability evident in infancy, involved in the development of internalizing problems in childhood.

Diffusion-tensor MR imaging of gray and white matter development during normal human brain maturation.

BACKGROUND AND PURPOSE: Conventional MR imaging findings of human brain development are thought to result from decreasing water content, increasing macromolecular concentration, and myelination. We use diffusion-tensor MR imaging to test theoretical models that incorporate hypotheses regarding how these maturational processes influence water diffusion in developing gray and white matter. METHODS: Experimental data were derived from diffusion-tensor imaging of 167 participants, ages 31 gestational weeks to 11 postnatal years. An isotropic diffusion model was applied to the gray matter of the basal ganglia and thalamus. A model that assumes changes in the magnitude of diffusion while maintaining cylindrically symmetric anisotropy was applied to the white matter of the corpus callosum and internal capsule. Deviations of the diffusion tensor from the ideal model predictions, due to measurement noise, were estimated by using Monte Carlo simulations. RESULTS: Developing gray matter of the basal ganglia and developing white matter of the internal capsule and corpus callosum largely conformed to theory, with only small departures from model predictions in older children. However, data from the thalamus substantially diverged from predicted values, with progressively larger deviations from the model with increasing participant age. CONCLUSION: Changes in water diffusion during maturation of central gray and white matter structures can largely be explained by theoretical models incorporating simple assumptions regarding the influence of brain water content and myelination, although deviations from theory increase as the brain matures. Diffusion-tensor MR imaging is a powerful method for studying the process of brain development, with both scientific and clinical applications.

A critical maturational period of reduced brain vulnerability to injury. A study of cerebral glucose metabolism in cats.

We have developed a feline cerebral hemispherectomy model as an analog to the surgical procedure used in pediatric intractable epilepsy. Previous work with this model has shown a remarkable plasticity associated with an early period of brain development, which we have defined using morphological, cerebral metabolic and behavioral methods. However, the important functional-metabolic bracketing of this period has not yet been performed. We have conducted the present study to answer questions raised by our previous findings using [14C] 2-deoxy-D-glucose autoradiography but only including animals lesioned at day 10 postnatally (P10) or in adulthood. The questions were; (a) is there any age better than P10 for an optimal metabolic outcome?, and (b) can we determine a cutoff point for the beneficial effects of the young age-at-lesion? Twenty-one adult cats were studied. Seven cats served as intact controls, five received a left hemineodecortication at P30, three at P60, three at P90 and three at P120, respectively. Histological analysis indicated that the extent of the lesion was similar between the age groups. Local glucose metabolic rates (LCMR(glc)) were measured in 50 structures bilaterally and used to calculate overall LCMR(glc) for seven grouped sites within the cerebral cortex, thalamus, basal ganglia, mesencephalic tegmentum (and tectum), limbic system and cerebellum. Results indicated a widespread bilateral depression of LCMR(glc) in all age-at-lesion groups. The depression in overall LCMR(glc) across all structures measured in each hemisphere was significant (P<0.05) for the P120 group relative to intacts for both ipsilateral (left) and contralateral (right) sides of the brain. The ipsilateral thalamus was the region most effected by the injury, with significant losses for all age-at-lesion groups. In addition, while there were widespread depressions for all lesion groups, these losses were significant for the P120 group in five groups of structures ipsilaterally (thalamus, basal ganglia, tectum, limbic system, cerebellum) and in three contralaterally (thalamus, tectum, cerebellum). In contrast, significant depressions for the earlier age-at-lesion groups (P30, P60, P90) were found only in the ipsilateral thalamus and bilaterally in the tectum. These results, together with our previous results for the P10 group, indicate a relative sparing of LCMR(glc) after hemineodecortication during the first 60 days of life, with gradually decreasing plasticity thereafter, such that there is some residual sparing at 90 days of age, and afterwards an almost complete loss of metabolic plasticity, with lesions at P120 producing a dismal outcome. These results complement earlier morphological and behavioral studies and support the concept of a 'Critical Maturational Period' of reduced vulnerability to developmental injury.

A developmental study of the dopamine D2R receptors in the human basal ganglia and thalamus.

The development of the dopamine D2R receptors (D2R) in the human basal ganglia (BG) and thalamus was investigated in 25 normal brains by means of an immunohistochemical method and Western blotting. Immunoreactivity to D2R was detected in the cytoplasm and dendrites of small and large neurons in the BG and thalamus. D2R-positive neurons were clearly observed at 19 weeks of gestation (GW) in the globus pallidus and thalamus, and at 21 GW in the striatum. The number of D2R-positive neurons gradually increased and reached a peak at 27 GW in the globus pallidus, at 39 GW in the thalamus, and at 1 month of age in the striatum. The number of D2R-positive large neurons in the globus pallidus and small neurons in the striatum decreased after 1 year and about 10 years of age, respectively. Western blotting confirmed the specificity of the immunohistochemistry. Our results suggest that the D2R protein begins to be synthesized at an early fetal stage in the BG and thalamus, and the development of D2R is mostly consistent with neuronal maturation in the BG. D2R may play an important role in regulating the neuronal development of the BG. The decrease in D2R-positive neurons may be related to D2R post-transcriptional regulation.

Spatial and temporal patterns of oligodendrocyte differentiation in rat cerebrum and cerebellum.

Oligodendrocytes are largely generated postnatally during mammalian CNS development. We have used a variety of antibodies to label immature neuroectodermal cells and developing oligodendrocytes in several areas of the rat CNS. Antibodies included those to GD3 ganglioside, a characteristic glycolipid of immature cells; carbonic anhydrase (CA), contained primarily in oligodendrocytes; and galactocerebroside and myelin basic protein, myelin components. Several aspects of oligodendrocyte development were examined: changes in shapes of immature cells with respect to time and to location within the brain, the sequential acquisition of the various markers, and possible sites of origin and pathways of precursor cell migration. Our observations suggest that oligodendrocytes in the forebrain and cerebellum arise from cells of the subventricular zone (SVZ) adjacent to the ventricles and migrate into and through nearby white and gray matter. During maturation, there are distinct patterns of morphological changes that correlate with time, locations of the cells in the brain, and acquisition of specific markers.