A cellular resolution atlas of Broca's area.

Brain cells are arranged in laminar, nuclear, or columnar structures, spanning a range of scales. Here, we construct a reliable cell census in the frontal lobe of human cerebral cortex at micrometer resolution in a magnetic resonance imaging (MRI)-referenced system using innovative imaging and analysis methodologies. MRI establishes a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries. Cell counting is obtained with a digital stereological approach on the 3D reconstruction at cellular resolution from a custom-made inverted confocal light-sheet fluorescence microscope (LSFM). Mesoscale optical coherence tomography enables the registration of the distorted histological cell typing obtained with LSFM to the MRI-based atlas coordinate system. The outcome is an integrated high-resolution cellular census of Broca's area in a human postmortem specimen, within a whole-brain reference space atlas.

Quantitative and histologically validated measures of the entorhinal subfields in ex vivo MRI.

Neuroimaging studies have routinely used hippocampal volume as a measure of Alzheimer's disease severity, but hippocampal changes occur too late in the disease process for potential therapies to be effective. The entorhinal cortex is one of the first cortical areas affected by Alzheimer's disease; its neurons are especially vulnerable to neurofibrillary tangles. Entorhinal atrophy also relates to the conversion from non-clinical to clinical Alzheimer's disease. In neuroimaging, the human entorhinal cortex has so far mostly been considered in its entirety or divided into a medial and a lateral region. Cytoarchitectonic differences provide the opportunity for subfield parcellation. We investigated the entorhinal cortex on a subfield-specific level-at a critical time point of Alzheimer's disease progression. While MRI allows multidimensional quantitative measurements, only histology provides enough accuracy to determine subfield boundaries-the pre-requisite for quantitative measurements within the entorhinal cortex. This study used histological data to validate ultra-high-resolution 7 Tesla ex vivo MRI and create entorhinal subfield parcellations in a total of 10 pre-clinical Alzheimer's disease and normal control cases. Using ex vivo MRI, eight entorhinal subfields (olfactory, rostral, medial intermediate, intermediate, lateral rostral, lateral caudal, caudal, and caudal limiting) were characterized for cortical thickness, volume, and pial surface area. Our data indicated no influence of sex, or Braak and Braak staging on volume, cortical thickness, or pial surface area. The volume and pial surface area for mean whole entorhinal cortex were 1131 ± 55.72 mm3 and 429 ± 22.6 mm2 (mean ± SEM), respectively. The subfield volume percentages relative to the entire entorhinal cortex were olfactory: 18.73 ± 1.82%, rostral: 14.06 ± 0.63%, lateral rostral: 14.81 ± 1.22%, medial intermediate: 6.72 ± 0.72%, intermediate: 23.36 ± 1.85%, lateral caudal: 5.42 ± 0.33%, caudal: 10.99 ± 1.02%, and caudal limiting: 5.91 ± 0.40% (all mean ± SEM). Olfactory and intermediate subfield revealed the most extensive intra-individual variability (cross-subject variance) in volume and pial surface area. This study provides validated measures. It maps individuality and demonstrates human variability in the entorhinal cortex, providing a baseline for approaches in individualized medicine. Taken together, this study serves as a ground-truth validation study for future in vivo comparisons and treatments.

Safety Considerations for Cerebellar Theta Burst Stimulation.

PURPOSE: The cerebellum is an intricate neural structure that orchestrates various cognitive and behavioral functions. In recent years, there has been an increasing interest in neuromodulation of the cerebellum with transcranial magnetic stimulation (TMS) for therapeutic and basic science applications. Theta burst stimulation (TBS) is an efficient and powerful TMS protocol that is able to induce longer-lasting effects with shorter stimulation times compared with traditional TMS. Parameters for cerebellar TBS are traditionally framed in the bounds of TBS to the cerebral cortex, even when the 2 have distinct histologic, anatomical, and functional characteristics. Tolerability limits have not been systematically explored in the literature for this specific application. Therefore, we aimed to determine the stimulation parameters that have been used for cerebellar. TBS to date and evaluate adverse events and adverse effects related to stimulation parameters. METHODS: We used PubMed to perform a critical review of the literature based on a systematic review of original research studies published between September 2008 and November 2019 that reported on cerebellar TBS. We recovered information from these publications and communication with authors about the stimulation parameters used and the occurrence of adverse events. FINDINGS: We identified 61 research articles on interventions of TBS to the cerebellum. These articles described 3176 active sessions of cerebellar TBS in 1203 individuals, including healthy participants and patients with various neurologic conditions, including brain injuries. Some studies used substantial doses (eg, pulse intensity and number of pulses) in short periods. No serious adverse events were reported. The specific number of patients who experienced adverse events was established for 48 studies. The risk of an adverse event in this population (n = 885) was 4.1%. Adverse events consisted mostly of discomfort attributable to involuntary muscle contractions. Authors used a variety of methods for calculating stimulation dosages, ranging from the long-established reference of electromyography of a hand muscle to techniques that atone for some of the differences between cerebrum and cerebellum. IMPLICATIONS: No serious adverse events have been reported for cerebellar TBS. There is no substantial evidence of a tolerable maximal-efficacy stimulation dose in humans. There is no assurance of equivalence in the translation of cortical excitability and stimulation intensities from the cerebral cortex to cerebellar regions. Further research for the stimulation dose in cerebellar TBS is warranted, along with consistent report of adverse events. © 2020 Elsevier HS Journals, Inc.

Probabilistic Template of the Lateral Parabrachial Nucleus, Medial Parabrachial Nucleus, Vestibular Nuclei Complex, and Medullary Viscero-Sensory-Motor Nuclei Complex in Living Humans From 7 Tesla MRI.

The lateral parabrachial nucleus, medial parabrachial nucleus, vestibular nuclei complex, and medullary viscero-sensory-motor (VSM) nuclei complex (the latter including among others the solitary nucleus, vagus nerve nucleus, and hypoglossal nucleus) are anatomically and functionally connected brainstem gray matter structures that convey signals across multiple modalities between the brain and the spinal cord to regulate vital bodily functions. It is remarkably difficult to precisely extrapolate the location of these nuclei from ex vivo atlases to conventional 3 Tesla in vivo images; thus, a probabilistic brainstem template in stereotaxic neuroimaging space in living humans is needed. We delineated these nuclei using single-subject high contrast 1.1 mm isotropic resolution 7 Tesla MRI images. After precise coregistration of nuclei labels to stereotaxic space, we generated a probabilistic template of their anatomical locations. Finally, we validated the nuclei labels in the template by assessing their inter-rater agreement, consistency across subjects and volumes. We also performed a preliminary comparison of their location and microstructural properties to histologic sections of a postmortem human brainstem specimen. In future, the resulting probabilistic template of these brainstem nuclei in stereotaxic space may assist researchers and clinicians in evaluating autonomic, vestibular and VSM nuclei structure, function and connectivity in living humans using conventional 3 Tesla MRI scanners.