Faculty Bibliography

The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA≥31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed.

OBJECTIVE:Cerebrovascular reactivity is impaired in patients suffering from obstructive sleep apnea syndrome (OSAS) as demonstrated by transcranial Doppler studies. We use magnetic resonance imaging techniques to investigate the anatomical distribution of cerebrovascular reactivity changes in patients with OSAS, as well as their evolution after therapeutic and sham continuous positive airway pressure (CPAP) treatment. METHODS:Twenty-three men with moderate or severe obstructive sleep apnea were compared to a healthy control group (n=7) using a breath-holding functional magnetic resonance imaging task and the flow-sensitive alternating inversion recovery (FAIR) imaging before and after 2 months of therapeutic (active) or sub-therapeutic (sham) CPAP treatment. RESULTS:Significantly higher cerebrovascular reactivity was found in healthy controls as compared to patients in bilateral cortical and subcortical brain regions. Cerebrovascular reactivity increased with therapeutic CPAP in the thalamus and decreased with sham CPAP in medial frontal regions in OSAS patients. Duration of nocturnal hypoxemia and body mass index negatively correlated with cerebrovascular reactivity, particularly in the medial temporal lobe structures, suggesting a possible pathophysiological mechanism for hippocampal injury. There was no difference in perfusion between patients and control group, and no effect of CPAP or sham-CPAP treatment on perfusion in patients. CONCLUSIONS:Observed cerebrovascular reactivity changes were neither homogeneous throughout the brain nor followed vascular territories, but rather corresponded to underlying neuronal networks, establishing a relationship between cerebrovascular reactivity and surrounding neuronal activity.

PURPOSE/OBJECTIVE:To evaluate the feasibility of performing fetal brain magnetic resonance venography using susceptibility weighted imaging (SWI). MATERIALS AND METHODS/METHODS:After obtaining informed consent, pregnant women in the second and third trimester were imaged using a modified SWI sequence. Fetal SWI acquisition was repeated when fetal or maternal motion was encountered. The median and maximum number of times an SWI sequence was repeated was four and six respectively. All SWI image data were systematically evaluated by a pediatric neuroradiologist for image quality using an ordinal scoring scheme: 1. diagnostic; 2. diagnostic with artifacts; and 3. nondiagnostic. The best score in an individual fetus was used for further statistical analysis. Visibility of venous vasculature was also scored using a dichotomous variable. A subset of SWI data was re-evaluated by the first and independently by a second pediatric neuroradiologist. Kappa coefficients were computed to assess intra-rater and inter-rater reliability. RESULTS:SWI image data from a total of 22 fetuses were analyzed. Median gestational age and interquartile range of the fetuses imaged were 32 (29.9-34.9) weeks. In 68.2% of the cases (n = 15), there was no artifact; 22.7% (n = 5) had minor artifacts and 9.1% (n = 2) of the data was of nondiagnostic quality. Cerebral venous vasculature was visible in 86.4% (n = 19) of the cases. Substantial agreement (Kappa = 0.73; 95% confidence interval 0.44-1.00)) was observed for intra-rater reliability and moderate agreement (Kappa = 0.48; 95% confidence interval 0.19-0.77) was observed for inter-rater reliability. CONCLUSION/CONCLUSIONS:It is feasible to perform fetal brain venography in humans using SWI.

PURPOSE/OBJECTIVE:To evaluate fetal cerebral venous blood oxygenation, Yv, using principles of MR susceptometry. MATERIALS AND METHODS/METHODS:A cohort of 19 pregnant subjects, with a mean gestational age of 31.6 ± 4.7 weeks were imaged using a modified susceptibility-weighted imaging (SWI) sequence. Data quality was first assessed for feasibility of oxygen saturation measurement, and data from five subjects (mean ± std gestational age of 33.7 ± 3.6 weeks) were then chosen for further quantitative analysis. SWI phase in the superior sagittal sinus was used to evaluate oxygen saturation using the principles of MR susceptometry. Systematic error in the measured Y(v) values was studied through simulations. RESULTS:Simulations showed that the systematic error in Yv depended upon the assumed angle of the vessel, θ, relative to the main magnetic field and the error in that vessel angle δθ. For the typical vessel angle of θ = 30° encountered in the fetal data analyzed, a δθ as large as ±20° led to an absolute error, δYv, of less than 11%. The measured mean oxygen saturation across the five fetuses was 66% ± 9.4%. This average cerebral venous blood oxygenation value is in close agreement with values in the published literature. CONCLUSION/CONCLUSIONS:We have reported the first in vivo measurement of human fetal cerebral venous oxygen saturation using MRI.

The vast majority of mental illnesses can be conceptualized as developmental disorders of neural interactions within the connectome, or developmental miswiring. The recent maturation of pediatric in vivo brain imaging is bringing the identification of clinically meaningful brain-based biomarkers of developmental disorders within reach. Even more auspicious is the ability to study the evolving connectome throughout life, beginning in utero, which promises to move the field from topological phenomenology to etiological nosology. Here, we scope advances in pediatric imaging of the brain connectome as the field faces the challenge of unraveling developmental miswiring. We highlight promises while also providing a pragmatic review of the many obstacles ahead that must be overcome to significantly impact public health.

BACKGROUND:Radiation and chemotherapy targeted to the central nervous system (CNS) can cause cognitive impairment, including impaired memory. These memory impairments may be referable to damage to hippocampal structures resulting from CNS treatment. PROCEDURE/METHODS:In the present study, we explored episodic memory and its neuroimaging correlates in 10 adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy and both systemic and intrathecal chemotherapy and 10 controls matched for age and sex, using a subsequent memory paradigm after episodic encoding of visual scenes. RESULTS:We report behavioral, structural, and functional changes in the brains of the adult survivors. They demonstrated poorer recognition memory, hippocampal atrophy, and altered blood oxygenation level-dependent (BOLD) signal in the hippocampus. Whole brain statistical map analysis revealed increased BOLD signal/activation in several brain regions during unsuccessful encoding in ALL survivors, potentially reflecting ineffective neural recruitment. Individual differences in memory performance in ALL participants were related to magnitude of BOLD response in regions associated with successful encoding. CONCLUSIONS:Taken together, these findings describe long term neuroimaging correlates of cognitive dysfunction after childhood exposure to CNS-targeted cancer therapies, suggesting enduring damage to episodic memory systems.

OBJECTIVE:  We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. METHODS:  Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low-frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. RESULTS:  The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). CONCLUSIONS:  Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically important imaging biomarker.

Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.

The organization of the brain is highly plastic in fetal life. Establishment of healthy neural functional systems during the fetal period is essential to normal growth and development. Across the last several decades, remarkable progress has been made in understanding the development of human fetal functional brain systems. This is largely due to advances in imaging methodologies. Fetal neuroimaging began in the 1950-1970's with fetal electroencephalography (EEG) applied during labor. Later, in the 1980's, magnetoencephalography (MEG) emerged as an effective approach for investigating fetal brain function. Most recently, functional magnetic resonance imaging (fMRI) has arisen as an additional powerful approach for examining fetal brain function. This review will discuss major developmental findings from fetal imaging studies such as the maturation of prenatal sensory system functions, functional hemispheric asymmetry, and sensory-driven neurodevelopment. We describe how with improved imaging and analysis techniques, functional imaging of the fetus has the potential to assess the earliest point of neural maturation and provide insight into the patterning and sequence of normal and abnormal brain development.