While at Temple he spearheaded a novel therapeutic approach from proof of concept to drug design and synthesis. Bruce is awarded and teaching experienced in medical pharmacology. Marcos has over 29 years experience in biostatistics, clinical and regulatory affairs and deep relationships at the FDA.
Michele has over 15 years of experience in clinical and product development. She was instrumental in bringing a novel diagnostic product to the worldwide market for women at risk for preterm delivery. In addition, she has experience managing community-based intervention trials. Michele received a B. Clair is a veteran medical device executive with more than 30 years of experience in medical product development both for major device manufacturers and start-up companies. He has held positions and directed programs at nearly twenty companies including; QinetiQ former Foster-Miller, Inc.
Auditory Brainstem Response Evaluation. How Boston Children's approaches ABR Your child will be seen by members of our Diagnostic Audiology Program , which specializes in all aspects of infant and child hearing loss, from psychological effects to technological assistance. Related Conditions and Treatments.
The investigators, led by Hannah Kinney, MD, a neuropathologist at Boston Children's, have shown over the past two decades that infants who die suddenly, unexpectedly and without explanation—whose deaths are generally attributed to sudden infant death syndrome SIDS —have differences in brainstem chemistry that set them apart from infants dying of other causes.
These abnormalities impair brainstem circuits that help control breathing, heart rate, blood pressure and temperature control during sleep, and, the researchers believe, prevent sleeping babies from rousing when they rebreathe too much carbon dioxide due to inadequate ventilation or become overheated from overbundling. At the same time, epidemiologic studies have shown that infants dying suddenly and unexpectedly are often found in unsafe sleep environments, such as sleeping face down with their face in the pillow, or sleeping with another person in the bed.
In the new study, Kinney and colleagues asked if these infants are truly normal. Thus, the brainstem is critical for a complete understanding of brain structure-function relationships. We expect our anatomical analysis to be of use to neuroanatomists as well as clinical and basic neuroscientists. Early students of neuroanatomy who macrodissected the human brain provided gross, approximate descriptions of the brainstem as a whole and its component parts, namely the midbrain, pons and medulla e.
Microscopic studies of the human brainstem have provided comprehensive descriptions of this structure since the early s. A historical review of these aspects of the human brainstem has been provided by Olszewski and Baxter and can be highlighted briefly as follows. The classical work of Ziehen has provided extensive descriptions of cyto- and myelo-architecture of fiber pathways in the brainstem.
Subsequent cytoarchitectonic studies have provided additional detail and more refined visualization with the use of photomicrographs Gagel and Bodechtel, ; Stern, ; Crosby and Woodburne, ; Riley, More recently, the atlases of Paxinos and Huang and Tona et al.
It should be noted that the Paxinos and Huang atlas provides unprecedented detail and coverage of not only nuclei but also fiber tracts in the human brainstem—almost twice the number of fiber pathways compared to other atlases.
Given that in the present study we needed to simplify and adapt the brainstem nuclear and fiber tract analysis to the neuroimaging data under analysis, we used primarily the Tona et al.
The results of the analyses were also consistent with Naidich et al. Finally, for didactic purposes we have displayed the human brainstem gray and white matter structures in six classical axial planes, namely, through the rostral and caudal midbrain, rostral and caudal pons, rostral and caudal medulla, as generally accepted in neuroanatomy following, for example, the Nolte textbook Nolte and Angevine, ; Nolte, ; Nolte et al.
With the advent of MRI, there have been several studies addressing the in vivo and non-invasive visualization of the gray and white matter of the human brainstem Salamon et al. MRI-based morphometry has examined the morphological and volumetric characterization of the brainstem since the early s Filipek et al.
Although the gross nature of these investigations precluded their addressing the fine architecture of the brainstem, these early morphological studies indicated the great potential of neuroimaging to visualize this structure in vivo and non-invasively. Pioneering morphometric studies with structural imaging measured the major components of the brainstem, namely the midbrain, pons, and medulla, and were used to localize functional activation of specific cranial nerve nuclei in combination with task-specific fMRI acquisitions e.
Moreover, using dMRI tractography, several fiber tract connections have been identified and delineated in the brainstem. Although most studies have addressed principally major motor and sensory connections such as the corticospinal tract e. In the context of an increasing body of information in the anatomical brainstem imaging field, to our knowledge the present study takes a step forward in identifying and delineating the greatest number of nuclear structures to date.
This was achieved principally because of the high spatial resolution, and the very high signal quality of the dataset we analyzed. Importantly, the anatomical analysis was done by expert neuroanatomists using 3D Slicer segmentation and visualization tools.
Finally, comparisons of the delineated nuclear structures were done with guidance from classical brainstem textbooks and atlases portraying the precise cytoarchitecture and topography of the human brainstem nuclei. The present analysis represents an advancement concerning traditional histological atlases, given the volumetric nature of our data and our ability to use MRI at a micron resolution.
Furthermore, histological slices often have physical artifacts and geometric distortions e. The inherent 3D nature of MRI reduces tissue distortions, leading to more accurate representations in MR-based atlases. Moreover, in vivo histology is not possible; thus, relating histological atlases to in vivo imaging can be problematic.
In contrast, MRI is the primary modality for structural brain imaging, and MR-based atlases appear to be more appropriate and easier to register, and thus to inform more accurately in vivo MR-based studies or interventions. By delineating the structural parts of the brainstem, we have provided a viable means of visualizing in 3D the different cranial nerve systems, conduit systems, and integrative systems.
This is a useful method for illustrating and understanding brainstem anatomy for basic neuroscientists as well as neurologists, psychiatrists, and neurosurgeons. As a result of this endeavor, 3D visualizations in the publicly available platform of 3D Slicer allow the student of the brainstem to use the atlas provided herein readily and relatively simply as a learning and teaching tool for this highly complex domain of neuroanatomy.
Brainstem functions can be generally categorized in a didactic, simplistic manner as conduit, cranial nerve, and integrative. The topographic arrangement of the brainstem with the spinal cord, cerebellum, and cerebrum makes it a natural route of passage for the numerous fiber tracts interconnecting these structures, thus justifying its role as a conduit of fibers of passage. In this study, we labeled 22 and delineated 16 of these fiber pathways, as shown in Table 1 and Figures 1 , 3.
It should be noted, however, that fibers of passage may also course through the nuclei of the midbrain, pons, and medulla. Although three of the cranial nerves , namely olfactory cranial nerve I , optic cranial nerve II , and accessory cranial nerve XI , do not project primarily or directly to the brainstem, the other nine are anatomically associated with the brainstem.
As such, the main associated functions are sensory, i. The most intriguing and least explored role of the brainstem relates to its integrative functions.
Briefly, several integrative functions take place at the level of the midbrain, pons and medulla, dealing with regulation of consciousness and arousal Moruzzi and Magoun, ; Solms and Turnbull, ; Edlow et al.
A critical role in integrative functions is served by the reticular formation, as reflected structurally by its diffuse pattern of connectivity with several other parts of the brain. Furthermore, cell groups that are sources of major neurotransmission systems in the brain are localized in the brainstem, namely the substantia nigra and ventral tegmental area VTA; dopamine , locus coeruleus noradrenaline , raphe nuclei serotonin and reticular formation acetylcholine; e.
All structures involved in the aforementioned functions were identified in the present study. It should be noted that the reticular formation and periaqueductal gray were labeled as single regions of interest, given the limitations in spatial resolution and contrast characteristics of our dataset for visualizing individual cell groups. Alterations of brainstem structure have been and remain a current matter of relevance in neurological and neurosurgical clinical practice.
Lesions of the brainstem such as embolic or hemorrhagic strokes and tumors can affect the conduit, cranial nerve, and integrative functions of the brainstem. This is of particular note given the therapeutic interventions that can be applied using deep brain stimulation DBS for neuromodulation. Anatomical visualization of such structures and circuits is of clinical relevance given the therapeutic potential of neuromodulation of the brainstem Fridman and Schiff, Neurochemical modulation of neurotransmitter systems arising in brainstem nuclei is of interest in neuropsychiatric practice given the involvement of transmitters in a variety of syndromes.
More specifically, selective serotonin reuptake inhibitors SSRIs and selective norepinephrine reuptake inhibitors SNRIs are routinely used as antidepressants due to their ability to enhance the levels of these neurotransmitters, whereas dopamine antagonists have potent antipsychotic effects by blocking dopamine receptors e.
Given the quality of the imaging dataset used herein, a cogent way of viewing limitations is by comparing these data with histological observations at the microscopic level. A critical student of neuroanatomy always has as the gold standard of analysis a microscopic level of explanation.
Neuroimaging is still a few steps away, perhaps by a factor of 10 in spatial resolution, from reaching this level of visualization, although it seems this is rapidly approaching. In this study, we were able to delineate 25 nuclear masses and 16 fiber pathways in the human brainstem using a micron spatial resolution in a postmortem human brainstem. This is still far from the detail provided by microscopic histological examination, where brainstem nuclei and fiber tracts have been identified and delineated using such techniques.
It should be noted that in the present study the reticular formation was delineated as a region of interest by the exclusion of other structures and guided by histological atlases; the reticular formation per se could not be visualized with certainty using the current imaging methods.
This limitation also applies to the description of the systems, such as the vestibuloocular system, which has more connections than were visualized in the current dataset. We recognize as well that certain boundaries of the ROIs segmented in this investigation may change as the state of MRI technology and neuroanatomical knowledge grows. We will publish updates in an on-line repository as the present structural borders may be modified as we receive feedback. Future studies using combined high-resolution MRI datasets with their histological sections for comparison Makris et al.
These approaches will also permit a formal evaluation of the variability in volume and extent of regions of the human brainstem. To date, such variability in the human brainstem has been incompletely studied Andrew and Watkins, ; Afshar, ; Blood et al.
As MRI technology advances it is expected that higher resolution datasets than the one used in the present study will become available. Thus, histological analyses should be done in these samples as well in a co-registered fashion with the MRI datasets for precise and valid comparisons.
In addition to the greater level of structural detail that these types of comparison will produce, they are also expected to generate a more complete description of brainstem systems. Using a high-resolution MRI postmortem dataset of the human brainstem and the 3D Slicer platform set of tools for image analysis, we were able to identify and delineate a large number of nuclear masses, the largest so far to our knowledge.
Also, we identified and delineated most of the sizeable brainstem white matter fiber tracts of conduit and interconnecting nature. NM wrote the first draft of the manuscript, which was read and revised by all the authors.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Afshar, F. Aggarwal, M. Feasibility of creating a high-resolution 3D diffusion tensor imaging based atlas of the human brainstem: a case study at NeuroImage 74, — Andrew, J. Baltimore, MD: Williams and Wilkins. Google Scholar. Angevine, J. Baizer, J.
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