Real-time quantification of in vivo cerebrospinal fluid velocity using the functional magnetic resonance imaging inflow effect.

In vivo estimation of cerebrospinal fluid (CSF) velocity is crucial for understanding the glymphatic system and its potential role in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Current cardiac or respiratory-gated approaches, such as 4D flow magnetic resonance imaging (MRI), cannot capture CSF movement in real time because of limited temporal resolution and, in addition, deteriorate in accuracy at low fluid velocities. Other techniques like real-time phase-contrast-MRI or time-spatial labeling inversion pulse are not limited by temporal averaging but have limited availability, even in research settings. This study aims to quantify the inflow effect of dynamic CSF motion on functional MRI (fMRI) for in vivo, real-time measurement of CSF flow velocity. We considered linear and nonlinear models of velocity waveforms and empirically fit them to fMRI data from a controlled flow experiment. To assess the utility of this methodology in human data, CSF flow velocities were computed from fMRI data acquired in eight healthy volunteers. Breath-holding regimens were used to amplify CSF flow oscillations. Our experimental flow study revealed that CSF velocity is nonlinearly related to inflow effect-mediated signal increase and well estimated using an extension of a previous nonlinear framework. Using this relationship, we recovered velocity from in vivo fMRI signal, demonstrating the potential of our approach for estimating CSF flow velocity in the human brain. This novel method could serve as an alternative approach to quantifying slow flow velocities in real time, such as CSF flow in the ventricular system, thereby providing valuable insights into the glymphatic system's function and its implications for neurological disorders.

Brain network hypersensitivity underlies pain crises in sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

CO2 as an engine for neurofluid flow: Exploring the coupling between vascular reactivity, brain clearance, and changes in tissue properties.

The brain relies on an effective clearance mechanism to remove metabolic waste products for the maintenance of homeostasis. Recent studies have focused on elucidating the forces that drive the motion of cerebrospinal fluid (CSF), responsible for removal of these waste products. We demonstrate that vascular responses evoked using controlled manipulations of partial pressure of carbon dioxide (PaCO2) levels, serve as an endogenous driver of CSF clearance from the brain. To demonstrate this, we retrospectively surveyed our database, which consists of brain metastases patients from whom blood oxygen level-dependent (BOLD) images were acquired during targeted hypercapnic and hyperoxic respiratory challenges. We observed a correlation between CSF inflow signal around the fourth ventricle and CO2-induced changes in cerebral blood volume. By contrast, no inflow signal was observed in response to the nonvasoactive hyperoxic stimulus, validating our measurements. Moreover, our results establish a link between the rate of the hemodynamic response (to elevated PaCO2) and peritumoral edema load, which we suspect may affect CSF flow, consequently having implications for brain clearance. Our expanded perspective on the factors involved in neurofluid flow underscores the importance of considering both cerebrovascular responses, as well as the brain mechanical properties, when evaluating CSF dynamics in the context of disease processes.

Paravascular fluid dynamics reveal arterial stiffness assessed using dynamic diffusion-weighted imaging.

Paravascular cerebrospinal fluid (pCSF) surrounding the cerebral arteries within the glymphatic system is pulsatile and moves in synchrony with the pressure waves of the vessel wall. Whether such pulsatile pCSF can infer pulse wave propagation-a property tightly related to arterial stiffness-is unknown and has never been explored. Our recently developed imaging technique, dynamic diffusion-weighted imaging (dynDWI), captures the pulsatile pCSF dynamics in vivo and can explore this question. In this work, we evaluated the time shifts between pCSF waves and finger pulse waves, where pCSF waves were measured by dynDWI and finger pulse waves were measured by the scanner's built-in finger pulse oximeter. We hypothesized that the time shifts reflect brain-finger pulse wave travel time and are sensitive to arterial stiffness. We applied the framework to 36 participants aged 18-82 years to study the age effect of travel time, as well as its associations with cognitive function within the older participants (N = 15, age > 60 years). Our results revealed a strong and consistent correlation between pCSF pulse and finger pulse (mean CorrCoeff = 0.66), supporting arterial pulsation as a major driver for pCSF dynamics. The time delay between pCSF and finger pulses (TimeDelay) was significantly lower (i.e., faster pulse propagation) with advanced age (Pearson's r = -0.44, p = 0.007). Shorter TimeDelay was further associated with worse cognitive function in the older participants. Overall, our study demonstrated pCSF as a viable pathway for measuring intracranial pulses and encouraged future studies to investigate its relevance with cerebrovascular functions.

Effects of clamping end-tidal CO2 on neurofluidic low-frequency oscillations.

In recent years, low-frequency oscillations (LFOs) (0.01-0.1 Hz) have been a subject of interest in resting-state functional magnetic resonance imaging research. They are believed to have many possible driving mechanisms, from both regional and global sources. Internal fluctuations in the partial pressure of CO2 (PCO2) has long been thought of as one of these major driving forces, but its exact contributions compared with other mechanisms have yet to be fully understood. This study examined the effects of end-tidal PCO2 (PetCO2) oscillations on LF cerebral hemodynamics and cerebrospinal fluid (CSF) dynamics under "clamped PetCO2" and "free-breathing" conditions. Under clamped PetCO2, a participant's PetCO2 levels were fixed to their baseline average, whereas PetCO2 was not controlled in free breathing. Under clamped PetCO2, the fractional amplitude of hemodynamic LFOs in the occipital and sensorimotor cortex and temporal lobes were found to be significantly reduced. Additionally, the fractional amplitude of CSF LFOs, measured at the fourth ventricle, was found to be reduced by almost one-half. However, the spatiotemporal distributions of blood and CSF delay times, as measured by cross-correlation in the LF domain, were not significantly altered between conditions. This study demonstrates that, while PCO2 oscillations significantly mediate LFOs, especially those observed in the CSF, other mechanisms are able to maintain LFOs, with high correlation, even in their absence.

Real-time Quantification of in vivo cerebrospinal fluid velocity using fMRI inflow effect.

In vivo estimation of cerebrospinal fluid (CSF) velocity is crucial for understanding the glymphatic system and its potential role in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Current cardiac or respiratory gated approaches, such as 4D flow MRI, cannot capture CSF movement in real time due to limited temporal resolution and in addition deteriorate in accuracy at low fluid velocities. Other techniques like real-time PC-MRI or time-spatial labeling inversion pulse are not limited by temporal averaging but have limited availability even in research settings. This study aims to quantify the inflow effect of dynamic CSF motion on functional magnetic resonance imaging (fMRI) for in vivo, real-time measurement of CSF flow velocity. We considered linear and nonlinear models of velocity waveforms and empirically fit them to fMRI data from a controlled flow experiment. To assess the utility of this methodology in human data, CSF flow velocities were computed from fMRI data acquired in eight healthy volunteers. Breath holding regimens were used to amplify CSF flow oscillations. Our experimental flow study revealed that CSF velocity is nonlinearly related to inflow effect-mediated signal increase and well estimated using an extension of a previous nonlinear framework. Using this relationship, we recovered velocity from in vivo fMRI signal, demonstrating the potential of our approach for estimating CSF flow velocity in the human brain. This novel method could serve as an alternative approach to quantifying slow flow velocities in real time, such as CSF flow in the ventricular system, thereby providing valuable insights into the glymphatic system's function and its implications for neurological disorders.

Brain network hypersensitivity underlies pain crises in sickle cell disease.

Sickle cell disease (SCD) is a genetic disorder causing blood vessel blockages and painful Vaso-occlusive crises (VOCs). VOCs, characterized by severe pain due to blocked blood flow, are recurrent and unpredictable, posing challenges for preventive strategies. In this study we propose explosive synchronization (ES), a phenomenon characterized by abrupt brain network phase transitions, as a novel approach to address this challenge. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) and VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited significantly lower alpha wave frequency than controls. SCD patients under painful pressure stimulation showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, patients who had a higher frequency of VOCs in the preceding 12 months presented with stronger FDA. The timing of VOC occurrence relative to EEG recordings was significantly associated to FDA. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Stronger FDA correlated with higher responsivity and complexity in our model. Simulation under noisy environment showed that higher FDA could be linked to increased occurrence frequency of crisis. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

Neurofluid coupling during sleep and wake states.

BACKGROUND: In clinical populations, the movement of cerebrospinal fluid (CSF) during sleep is a growing area of research with potential mechanistic connections in both neurodegenerative (e.g., Alzheimer's Disease) and neurodevelopmental disorders. However, we know relatively little about the processes that influence CSF movement. To inform clinical intervention targets this study assesses the coupling between (a) real-time CSF movement, (b) neuronal-driven movement, and (c) non-neuronal systemic physiology driven movement. METHODS: This study included eight young, healthy volunteers, with concurrently acquired neurofluid dynamics using functional Magnetic Resonance Imaging (MRI), neural activity using Electroencephalography (EEG), and non-neuronal systemic physiology with peripheral functional Near-Infrared Spectroscopy (fNIRS). Neuronal and non-neuronal drivers were assessed temporally; wherein, EEG measured slow wave activity that preceded CSF movement was considered neuronally driven. Similarly, slow wave oscillations (assessed via fNIRS) that coupled with CSF movement were considered non-neuronal systemic physiology driven. RESULTS AND CONCLUSIONS: Our results document neural contributions to CSF movement were only present during light NREM sleep but low-frequency non-neuronal oscillations were strongly coupled with CSF movement in all assessed states - awake, NREM-1, NREM-2. The clinical/research implications of these findings are two-fold. First, neuronal-driven oscillations contribute to CSF movement outside of deep sleep (NREM-3); therefore, interventions aimed at increasing CSF movement may yield meaningful increases with the promotion of NREM sleep more generally - a focus on NREM S3 may not be needed. Second, non-neuronal systemic oscillations contribute across wake and sleep stages; therefore, interventions may increase CSF movement by manipulating systemic physiology.

Age-dependent neurovascular coupling characteristics in children and adults during general anesthesia.

General anesthesia is an indispensable procedure in clinical practice. Anesthetic drugs induce dramatic changes in neuronal activity and cerebral metabolism. However, the age-related changes in neurophysiology and hemodynamics during general anesthesia remain unclear. Therefore, the objective of this study was to explore the neurovascular coupling between neurophysiology and hemodynamics in children and adults during general anesthesia. We analyzed frontal electroencephalogram (EEG) and functional near-infrared spectroscopy (fNIRS) signals recorded from children (6-12 years old, n = 17) and adults (18-60 years old, n = 25) during propofol-induced and sevoflurane-maintained general anesthesia. The neurovascular coupling was evaluated in wakefulness, maintenance of a surgical state of anesthesia (MOSSA), and recovery by using correlation, coherence and Granger-causality (GC) between the EEG indices [EEG power in different bands and permutation entropy (PE)], and hemodynamic responses the oxyhemoglobin (Δ[HbO]) and deoxy-hemoglobin (Δ[Hb]) from fNIRS in the frequency band in 0.01-0.1 Hz. The PE and Δ[Hb] performed well in distinguishing the anesthesia state (p > 0.001). The correlation between PE and Δ[Hb] was higher than those of other indices in the two age groups. The coherence significantly increased during MOSSA (p < 0.05) compared with wakefulness, and the coherences between theta, alpha and gamma, and hemodynamic activities of children are significantly stronger than that of adults' bands. The GC from neuronal activities to hemodynamic responses decreased during MOSSA, and can better distinguish anesthesia state in adults. Propofol-induced and sevoflurane-maintained combination exhibited age-dependent neuronal activities, hemodynamics, and neurovascular coupling, which suggests the need for separate rules for children's and adults' brain states monitoring during general anesthesia.

mHealth hyperspectral learning for instantaneous spatiospectral imaging of hemodynamics.

Hyperspectral imaging acquires data in both the spatial and frequency domains to offer abundant physical or biological information. However, conventional hyperspectral imaging has intrinsic limitations of bulky instruments, slow data acquisition rate, and spatiospectral trade-off. Here we introduce hyperspectral learning for snapshot hyperspectral imaging in which sampled hyperspectral data in a small subarea are incorporated into a learning algorithm to recover the hypercube. Hyperspectral learning exploits the idea that a photograph is more than merely a picture and contains detailed spectral information. A small sampling of hyperspectral data enables spectrally informed learning to recover a hypercube from a red-green-blue (RGB) image without complete hyperspectral measurements. Hyperspectral learning is capable of recovering full spectroscopic resolution in the hypercube, comparable to high spectral resolutions of scientific spectrometers. Hyperspectral learning also enables ultrafast dynamic imaging, leveraging ultraslow video recording in an off-the-shelf smartphone, given that a video comprises a time series of multiple RGB images. To demonstrate its versatility, an experimental model of vascular development is used to extract hemodynamic parameters via statistical and deep learning approaches. Subsequently, the hemodynamics of peripheral microcirculation is assessed at an ultrafast temporal resolution up to a millisecond, using a conventional smartphone camera. This spectrally informed learning method is analogous to compressed sensing; however, it further allows for reliable hypercube recovery and key feature extractions with a transparent learning algorithm. This learning-powered snapshot hyperspectral imaging method yields high spectral and temporal resolutions and eliminates the spatiospectral trade-off, offering simple hardware requirements and potential applications of various machine learning techniques.

Using carpet plots to analyze blood transit times in the brain during hypercapnic challenge magnetic resonance imaging.

Blood arrival time and blood transit time are useful metrics in characterizing hemodynamic behaviors in the brain. Functional magnetic resonance imaging in combination with a hypercapnic challenge has been proposed as a non-invasive imaging tool to determine blood arrival time and replace dynamic susceptibility contrast (DSC) magnetic resonance imaging, a current gold-standard imaging tool with the downsides of invasiveness and limited repeatability. Using a hypercapnic challenge, blood arrival times can be computed by cross-correlating the administered CO2 signal with the fMRI signal, which increases during elevated CO2 due to vasodilation. However, whole-brain transit times derived from this method can be significantly longer than the known cerebral transit time for healthy subjects (nearing 20 s vs. the expected 5-6 s). To address this unrealistic measurement, we here propose a novel carpet plot-based method to compute improved blood transit times derived from hypercapnic blood oxygen level dependent fMRI, demonstrating that the method reduces estimated blood transit times to an average of 5.32 s. We also investigate the use of hypercapnic fMRI with cross-correlation to compute the venous blood arrival times in healthy subjects and compare the computed delay maps with DSC-MRI time to peak maps using the structural similarity index measure (SSIM). The strongest delay differences between the two methods, indicated by low structural similarity index measure, were found in areas of deep white matter and the periventricular region. SSIM measures throughout the remainder of the brain reflected a similar arrival sequence derived from the two methods despite the exaggerated spread of voxel delays computed using CO2 fMRI.

Whole body measurements using near-infrared spectroscopy in a rat spinal cord contusion injury model.

Background: Spinal cord injuries cause great damage to the central nervous system as well as the peripheral vasculature. While treatments for spinal cord injury typically focus on the spine itself, improvements in the function of the peripheral vasculature after spinal cord injury have shown to improve overall neurological recovery.Objective: This study focused on the use of near-infrared spectroscopy (NIRS) as a mode to monitor cerebral and peripheral vascular condition non-invasively during the recovery process.Design: Animal research study.Methods: Rats underwent spinal contusion or sham injury and relative concentrations of de-/oxyhemoglobin (Δ[HbO]/Δ[Hb]) over time were measured over the cerebral, spinal, and pedal regions via NIRS. Correlational relationships across the body were determined. Rats received 1 NIRS measurement before injury and 3 after injury: 4, 7, and 14 days post.Results: Correlational relationships between signals across the body, between animals with and without spinal cord injury, indicate that NIRS was able to detect patterns of vascular change in the spine and the periphery occurring secondary to spinal cord injury and evolving during subsequent recovery. Additionally, NIRS determined an overall correlational decrease within the central nervous system, between spinal and cerebral measurements.Conclusion: NIRS was able to closely reflect physiologic changes in the rat during recovery, demonstrating a promising method to monitor whole body hemodynamics after spinal cord injury.

Optical imaging and spectroscopy for the study of the human brain: status report.

This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions.

Human CSF movement influenced by vascular low frequency oscillations and respiration.

Cerebrospinal fluid (CSF) movement through the pathways within the central nervous system is of high significance for maintaining normal brain health and function. Low frequency hemodynamics and respiration have been shown to drive CSF in humans independently. Here, we hypothesize that CSF movement may be driven simultaneously (and in synchrony) by both mechanisms and study their independent and coupled effects on CSF movement using novel neck fMRI scans. Caudad CSF movement at the fourth ventricle and hemodynamics of the major neck blood vessels (internal carotid arteries and internal jugular veins) was measured from 11 young, healthy volunteers using novel neck fMRI scans with simultaneous measurement of respiration. Two distinct models of CSF movement (1. Low-frequency hemodynamics and 2. Respiration) and possible coupling between them were investigated. We show that the dynamics of brain fluids can be assessed from the neck by studying the interrelationships between major neck blood vessels and the CSF movement in the fourth ventricle. We also demonstrate that there exists a cross-frequency coupling between these two separable mechanisms. The human CSF system can respond to multiple coupled physiological forces at the same time. This information may help inform the pathological mechanisms behind CSF movement-related disorders.

Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)

Cerebrospinal fluid (CSF) in the paravascular spaces of the surface arteries (sPVS) is a vital pathway in brain waste clearance. Arterial pulsations may be the driving force of the paravascular flow, but its pulsatile pattern remains poorly characterized, and no clinically practical method for measuring its dynamics in the human brain is available. In this work, we introduce an imaging and quantification framework for in-vivo non-invasive assessment of pulsatile fluid dynamics in the sPVS. It used dynamic Diffusion-Weighted Imaging (dDWI) at a lower b-values of 150s/mm2 and retrospective gating to detect the slow flow of CSF while suppressing the fast flow of adjacent arterial blood. The waveform of CSF flow over a cardiac cycle was revealed by synchronizing the measurements with the heartbeat. A data-driven approach was developed to identify sPVS and allow automatic quantification of the whole-brain fluid waveforms. We applied dDWI to twenty-five participants aged 18-82 y/o. Results demonstrated that the fluid waveforms across the brain showed an explicit cardiac-cycle dependency, in good agreement with the vascular pumping hypothesis. Furthermore, the shape of the CSF waveforms closely resembled the pressure waveforms of the artery wall, suggesting that CSF dynamics is tightly related to artery wall mechanics. Finally, the CSF waveforms in aging participants revealed a strong age effect, with a significantly wider systolic peak observed in the older relative to younger participants. The peak widening may be associated with compromised vascular compliance and vessel wall stiffening in the older brain. Overall, the results demonstrate the feasibility, reproducibility, and sensitivity of dDWI for detecting sPVS fluid dynamics of the human brain. Our preliminary data suggest age-related alterations of the paravascular pumping. With an acquisition time of under six minutes, dDWI can be readily applied to study fluid dynamics in normal physiological conditions and cerebrovascular/neurodegenerative diseases.

Spatial complexity method for tracking brain development and degeneration using functional near-infrared spectroscopy.

Brain complexity analysis using functional near-infrared spectroscopy (fNIRS) has attracted attention as a biomarker for evaluating brain development and degeneration processes. However, most methods have focused on the temporal scale without capturing the spatial complexity. In this study, we propose a spatial time-delay entropy (STDE) method as the spatial complexity measure based on the time-delay measure between two oxy-hemoglobin (Δ[HbO]) or two deoxy-hemoglobin (Δ[Hb]) oscillations within the 0.01-0.1 Hz frequency band. To do this, we analyze fNIRS signals recorded from infants in their sleeping state, children, adults, and healthy seniors in their resting states. We also evaluate the effects of various noise to STDE calculations and STDE's performance in distinguishing various developmental age groups. Lastly, we compare the results with the normalized global spatial complexity (NGSC) and sample entropy (SampEn) measures. Among these measures, STDEHbO (STDE based on Δ[HbO] oscillations) performs best. The STDE value increases with age throughout childhood (p < 0.001), and then decreases in adults and healthy seniors in the 0.01-0.1 Hz frequency band. This trajectory correlates with cerebrovascular development and degeneration. These findings demonstrate that STDE can be used as a new tool for tracking cerebrovascular development and degeneration across a lifespan based on the fNIRS resting-state measurements.

Coupling between cerebrovascular oscillations and CSF flow fluctuations during wakefulness: An fMRI study.

It is commonly believed that cerebrospinal fluid (CSF) movement is facilitated by blood vessel wall movements (i.e., hemodynamic oscillations) in the brain. A coherent pattern of low frequency hemodynamic oscillations and CSF movement was recently found during non-rapid eye movement (NREM) sleep via functional MRI. This finding raises other fundamental questions: 1) the explanation of coupling between hemodynamic oscillations and CSF movement from fMRI signals; 2) the existence of the coupling during wakefulness; 3) the direction of CSF movement. In this resting state fMRI study, we proposed a mechanical model to explain the coupling between hemodynamics and CSF movement through the lens of fMRI. Time delays between CSF movement and global hemodynamics were calculated. The observed delays between hemodynamics and CSF movement match those predicted by the model. Moreover, by conducting separate fMRI scans of the brain and neck, we confirmed the low frequency CSF movement at the fourth ventricle is bidirectional. Our finding also demonstrates that CSF movement is facilitated by changes in cerebral blood volume mainly in the low frequency range, even when the individual is awake.

Monitoring anesthesia using simultaneous functional Near Infrared Spectroscopy and Electroencephalography.

OBJECTIVE: This study aims to understand the neural and hemodynamic responses during general anesthesia in order to develop a comprehensive multimodal anesthesia depth monitor using simultaneous functional Near Infrared Spectroscopy (fNIRS) and Electroencephalogram (EEG). METHODS: 37 adults and 17 children were monitored with simultaneous fNIRS and EEG, during the complete general anesthesia process. The coupling of fNIRS signals with neuronal signals (EEG) was calculated. Measures of complexity (sample entropy) and phase difference were also quantified from fNIRS signals to identify unique fNIRS based biomarkers of general anesthesia. RESULTS: A significant decrease in the complexity and power of fNIRS signals characterize the anesthesia maintenance phase. Furthermore, responses to anesthesia vary between adults and children in terms of neurovascular coupling and frontal EEG alpha power. CONCLUSIONS: This study shows that fNIRS signals could reliably quantify the underlying neuronal activity under general anesthesia and clearly distinguish the different phases throughout the procedure in adults and children (with less accuracy). SIGNIFICANCE: A multimodal approach incorporating the specific differences between age groups, provides a reliable measure of anesthesia depth.

Development of brain atlases for early-to-middle adolescent collision-sport athletes.

Human brains develop across the life span and largely vary in morphology. Adolescent collision-sport athletes undergo repetitive head impacts over years of practices and competitions, and therefore may exhibit a neuroanatomical trajectory different from healthy adolescents in general. However, an unbiased brain atlas targeting these individuals does not exist. Although standardized brain atlases facilitate spatial normalization and voxel-wise analysis at the group level, when the underlying neuroanatomy does not represent the study population, greater biases and errors can be introduced during spatial normalization, confounding subsequent voxel-wise analysis and statistical findings. In this work, targeting early-to-middle adolescent (EMA, ages 13-19) collision-sport athletes, we developed population-specific brain atlases that include templates (T1-weighted and diffusion tensor magnetic resonance imaging) and semantic labels (cortical and white matter parcellations). Compared to standardized adult or age-appropriate templates, our templates better characterized the neuroanatomy of the EMA collision-sport athletes, reduced biases introduced during spatial normalization, and exhibited higher sensitivity in diffusion tensor imaging analysis. In summary, these results suggest the population-specific brain atlases are more appropriate towards reproducible and meaningful statistical results, which better clarify mechanisms of traumatic brain injury and monitor brain health for EMA collision-sport athletes.