A Proposed Human Structural Brain Connectivity Matrix in the Center for Morphometric Analysis Harvard-Oxford Atlas Framework: A Historical Perspective and Future Direction for Enhancing the Precision of Human Structural Connectivity with a Novel Neuroanatomical Typology.

A complete structural definition of the human nervous system must include delineation of its wiring diagram (e.g., Swanson LW. Brain architecture: understanding the basic plan, 2012). The complete formulation of the human brain circuit diagram (BCD [Front Neuroanat. 2020;14:18]) has been hampered by an inability to determine connections in their entirety (i.e., not only pathway stems but also origins and terminations). From a structural point of view, a neuroanatomic formulation of the BCD should include the origins and terminations of each fiber tract as well as the topographic course of the fiber tract in three dimensions. Classic neuroanatomical studies have provided trajectory information for pathway stems and their speculative origins and terminations [Dejerine J and Dejerine-Klumpke A. Anatomie des Centres Nerveux, 1901; Dejerine J and Dejerine-Klumpke A. Anatomie des Centres Nerveux: Méthodes générales d'étude-embryologie-histogénèse et histologie. Anatomie du cerveau, 1895; Ludwig E and Klingler J. Atlas cerebri humani, 1956; Makris N. Delineation of human association fiber pathways using histologic and magnetic resonance methodologies; 1999; Neuroimage. 1999 Jan;9(1):18-45]. We have summarized these studies previously [Neuroimage. 1999 Jan;9(1):18-45] and present them here in a macroscale-level human cerebral structural connectivity matrix. A matrix in the present context is an organizational construct that embodies anatomical knowledge about cortical areas and their connections. This is represented in relation to parcellation units according to the Harvard-Oxford Atlas neuroanatomical framework established by the Center for Morphometric Analysis at Massachusetts General Hospital in the early 2000s, which is based on the MRI volumetrics paradigm of Dr. Verne Caviness and colleagues [Brain Dev. 1999 Jul;21(5):289-95]. This is a classic connectional matrix based mainly on data predating the advent of DTI tractography, which we refer to as the "pre-DTI era" human structural connectivity matrix. In addition, we present representative examples that incorporate validated structural connectivity information from nonhuman primates and more recent information on human structural connectivity emerging from DTI tractography studies. We refer to this as the "DTI era" human structural connectivity matrix. This newer matrix represents a work in progress and is necessarily incomplete due to the lack of validated human connectivity findings on origins and terminations as well as pathway stems. Importantly, we use a neuroanatomical typology to characterize different types of connections in the human brain, which is critical for organizing the matrices and the prospective database. Although substantial in detail, the present matrices may be assumed to be only partially complete because the sources of data relating to human fiber system organization are limited largely to inferences from gross dissections of anatomic specimens or extrapolations of pathway tracing information from nonhuman primate experiments [Front Neuroanat. 2020;14:18, Front Neuroanat. 2022;16:1035420, and Brain Imaging Behav. 2021;15(3):1589-1621]. These matrices, which embody a systematic description of cerebral connectivity, can be used in cognitive and clinical studies in neuroscience and, importantly, to guide research efforts for further elucidating, validating, and completing the human BCD [Front Neuroanat. 2020;14:18].

Optical coherence tomography in diagnosis of inflammatory scalp disorders.

BACKGROUND: The common inflammatory scalp disorders share similar clinical manifestations, and patient work up require invasive, undesirable diagnostic procedures like biopsy to ensure correct diagnosis. Optical coherence tomography (OCT) is a non-invasive high-resolution imaging modality that has found a valuable tool to assist in the diagnose and evaluation of different skin diseases. OBJECTIVES: To describe the structural and vascular dynamic OCT (D-OCT) findings of inflammatory scalp disorders including scalp psoriasis, seborrhoeic dermatitis and contact dermatitis and to compare trichoscopy and OCT features. METHODS: Subjects with diagnosis of seborrhoeic dermatitis, psoriasis or contact dermatitis were enrolled in this study. OCT scans were taken on involved scalp, and the same scalp regions were evaluated by trichoscopy and compared with healthy scalp. RESULTS: A total of fourteen subjects (two healthy controls, four seborrhoeic dermatitis, five psoriasis and three contact dermatitis) participated. D-OCT imaging of vascular pattern in healthy scalp and the inflammatory scalp disorders were described. D-OCT images could enhance the clinician's ability to distinguish psoriasis from seborrhoeic dermatitis by objectively detect and assess red loop density. In scalp contact dermatitis, the vessels of the deep plexus were more dilated and fewer in number than those found in seborrhoeic dermatitis. CONCLUSION: Dynamic OCT provides information that more clearly elucidates changes at the level of the superficial and deep plexuses without invasively interfering with superficial structures. In the context of inflammatory scalp disorders, this is useful to discern disorders with overlapping symptoms and minimize the use of invasive biopsies to diagnose.

Intoxication From Accidental Marijuana Ingestion in Pediatric Patients: What May Lie Ahead.

Marijuana is the most commonly used illicit drug. In young children, there are relatively few reports in the literature of acute marijuana intoxication. Here, we describe the case of a previously healthy 2-year-old girl who presented with clinical seizures. A urine toxicology screen showed elevated levels of tetrahydrocannabinol. The source of the drug was not identified. After a short stay in the hospital, the patient fully recovered with only supportive measures. In this report, we also summarize all domestic and international cases of marijuana intoxication in children younger than 6 years, in conjunction with the number of exposures in children of similar age identified by the US National Poison Data System. This report highlights what is becoming a more common problem. As cannabis continues to be decriminalized across the United States with its increasingly diverse modes of delivery, the potential for accidental exposure in infants and young children also rises. Clinicians should now routinely consider marijuana intoxication in children who present with acute neurological abnormalities.

Optical coherence tomography for the investigation of frontal fibrosing alopecia.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a cicatricial alopecia that affects the frontotemporal hairline, eyebrows and body hair. OCT is a non-invasive imaging technique useful in understanding skin architecture and vascularization. OBJECTIVE: To describe structural and vascular findings in FFA using OCT. METHODS: This was a case-control study conducted from the months of December 2016-February 2017. The study was IRB approved and conducted at the University of Miami Hospital outpatient dermatology hair and nail clinic in Miami, FL. Four patients with biopsy proven FFA, and three healthy age and sex-matched controls participated. OCT scans were taken on cicatricial alopecic band, inflammatory hairline, eyebrow, uninvolved scalp, facial papules, glabellar red dots and arm. The same body regions were evaluated in controls. RESULTS: Patients and controls were women aged 42-66. Results reveal epidermal thickness is increased in the inflammatory hairline (0.13 mm) and decreased in the alopecic band (0.08 mm) compared to controls (0.10 mm). Attenuation coefficient increased the inflammatory hairline and decreased in the alopecic band compared to controls. Vascular flow in the alopecic band is decreased compared to inflammatory scalp and controls in the superficial levels, but increased at deeper levels as compared to controls. Inflammatory tissue is consistently more vascular at all levels (P < 0.01). Vascular flows in each stage are significantly different than one another (P < 0.01). CONCLUSIONS: Increased vascular flow of the deep plexus in cicatricial stages can be a consequence of superficial tissue ischaemia or fibrosis. It is difficult to establish if the increased flow in the inflammatory stage is due to neovascularization as seen in other ischaemic diseases or is the result of the inflammatory response. OCT may be a useful non-invasive tool in imaging FFA. Not only can the technology assist in monitoring disease activity in a non-invasive manner, but it may elucidate new pathophysiologic findings.

Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison.

Reversible cerebral vasoconstriction syndromes (RCVS) and primary angiitis of the central nervous system (PACNS) are invariably considered in the differential diagnosis of new cerebral arteriopathies. However, prompt and accurate diagnosis remains challenging. Here we compared the features of 159 RCVS to 47 PACNS patients and developed criteria for prompt bedside diagnosis. Recurrent thunderclap headache (TCH), and single TCH combined with either normal neuroimaging, border zone infarcts, or vasogenic edema, have 100% positive predictive value for diagnosing RCVS or RCVS-spectrum disorders. In patients without TCH and positive angiography, neuroimaging can discriminate RCVS (no lesion) from PACNS (deep/brainstem infarcts). Ann Neurol 2016;79:882-894.

Network localization of neurological symptoms from focal brain lesions.

A traditional and widely used approach for linking neurological symptoms to specific brain regions involves identifying overlap in lesion location across patients with similar symptoms, termed lesion mapping. This approach is powerful and broadly applicable, but has limitations when symptoms do not localize to a single region or stem from dysfunction in regions connected to the lesion site rather than the site itself. A newer approach sensitive to such network effects involves functional neuroimaging of patients, but this requires specialized brain scans beyond routine clinical data, making it less versatile and difficult to apply when symptoms are rare or transient. In this article we show that the traditional approach to lesion mapping can be expanded to incorporate network effects into symptom localization without the need for specialized neuroimaging of patients. Our approach involves three steps: (i) transferring the three-dimensional volume of a brain lesion onto a reference brain; (ii) assessing the intrinsic functional connectivity of the lesion volume with the rest of the brain using normative connectome data; and (iii) overlapping lesion-associated networks to identify regions common to a clinical syndrome. We first tested our approach in peduncular hallucinosis, a syndrome of visual hallucinations following subcortical lesions long hypothesized to be due to network effects on extrastriate visual cortex. While the lesions themselves were heterogeneously distributed with little overlap in lesion location, 22 of 23 lesions were negatively correlated with extrastriate visual cortex. This network overlap was specific compared to other subcortical lesions (P < 10(-5)) and relative to other cortical regions (P < 0.01). Next, we tested for generalizability of our technique by applying it to three additional lesion syndromes: central post-stroke pain, auditory hallucinosis, and subcortical aphasia. In each syndrome, heterogeneous lesions that themselves had little overlap showed significant network overlap in cortical areas previously implicated in symptom expression (P < 10(-4)). These results suggest that (i) heterogeneous lesions producing similar symptoms share functional connectivity to specific brain regions involved in symptom expression; and (ii) publically available human connectome data can be used to incorporate these network effects into traditional lesion mapping approaches. Because the current technique requires no specialized imaging of patients it may prove a versatile and broadly applicable approach for localizing neurological symptoms in the setting of brain lesions.

Non-invasive subcutaneous fat reduction: a review.

The risks, financial costs and lengthy downtime associated with surgical procedures for fat reduction have led to the development of a number of non-invasive techniques. Non-invasive body contouring now represents the fastest growing area of aesthetic medicine. There are currently four leading non-invasive techniques for reducing localized subcutaneous adipose tissue: low-level laser therapy (LLLT), cryolipolysis, radio frequency (RF) and high-intensity focused ultrasound (HIFU). To review and compare leading techniques and clinical outcomes of non-invasive subcutaneous fat reduction. The terms 'non-invasive', 'low-level laser', 'cryolipolysis', 'ultrasound' and 'radio frequency' were combined with 'lipolysis', 'fat reduction' or 'body contour' during separate searches in the PubMed database. We identified 31 studies (27 prospective clinical studies and four retrospective chart reviews) with a total of 2937 patients that had been treated with LLLT (n = 1114), cryolipolysis (n = 706), HIFU (n = 843) or RF (n = 116) or other techniques (n = 158) for fat reduction or body contouring. A majority of these patients experienced significant and satisfying results without any serious adverse effects. The studies investigating these devices have all varied in treatment regimen, body locations, follow-up times or outcome operationalization. Each technique differs in offered advantages and severity of adverse effects. However, multiple non-invasive devices are safe and effective for circumferential reduction in local fat tissue by 2 cm or more across the abdomen, hips and thighs. Results are consistent and reproducible for each device and none are associated with any serious or permanent adverse effects.

Regional infant brain development: an MRI-based morphometric analysis in 3 to 13 month olds.

Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants' whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders.

Effects of parasitic sex-ratio distorters on host genetic structure in the Armadillidium vulgare-Wolbachia association.

In the pill bug Armadillidium vulgare (Crustacea, Oniscidea), Wolbachia facilitates its spread through vertical transmission via the eggs by inducing feminization of genetic males. The spread of feminizing Wolbachia within and across populations is therefore expected to influence mitochondrial DNA (mtDNA) genetic structure by hitchhiking. To test this hypothesis, we analysed nuclear and mtDNA genetic structure, and Wolbachia prevalence in 13 populations of the pill bug host. Wolbachia prevalence (ranging from 0% to 100% of sampled females) was highly variable among populations. All three Wolbachia strains previously observed in A. vulgare were present (wVulC, wVulM and wVulP) with wVulC being the most prevalent (nine of 13 populations). The host showed a genetic structure on five microsatellite loci that is compatible with isolation by distance. The strong genetic structure observed on host mtDNA was correlated with Wolbachia prevalence: three mitotypes were in strong linkage disequilibrium with the three strains of Wolbachia. Neutrality tests showed that the mtDNA polymorphism is not neutral, and we thus suggest that this unusual pattern of mtDNA polymorphism found in A. vulgare was due to Wolbachia.

Network analysis: applications for the developing brain.

Development of the human brain follows a complex trajectory of age-specific anatomical and physiological changes. The application of network analysis provides an illuminating perspective on the dynamic interregional and global properties of this intricate and complex system. Here, we provide a critical synopsis of methods of network analysis with a focus on developing brain networks. After discussing basic concepts and approaches to network analysis, we explore the primary events of anatomical cortical development from gestation through adolescence. Upon this framework, we describe early work revealing the evolution of age-specific functional brain networks in normal neurodevelopment. Finally, we review how these relationships can be altered in disease and perhaps even rectified with treatment. While this method of description and inquiry remains in early form, there is already substantial evidence that the application of network models and analysis to understanding normal and abnormal human neural development holds tremendous promise for future discovery.

Regional prefrontal cortex gray matter volumes in youth at familial risk for schizophrenia from the Harvard Adolescent High Risk Study.

BACKGROUND: Regional prefrontal cortex gray matter reductions have been identified in schizophrenia, likely reflecting a combination of genetic vulnerability and disease effects. Few morphometric studies to date have examined regional prefrontal abnormalities in non-psychotic biological relatives who have not passed through the age range of peak risk for onset of psychosis. We conducted a region-of-interest morphometric study of prefrontal subregions in adolescent and young adult relatives of schizophrenia patients. METHODS: Twenty-seven familial high-risk (FHR) first-degree relatives of schizophrenia patients and forty-eight control subjects without a family history of psychosis (ages 13-28) underwent high-resolution magnetic resonance imaging at 1.5Tesla. The prefrontal cortex was parcellated into polar, dorsolateral, ventrolateral, ventromedial and orbital subregions. The Chapman scales measured subpsychotic symptoms. General linear models examined associations of prefrontal subregion volumes with familial risk and subpsychotic symptoms. RESULTS: FHR subjects had significantly reduced bilateral ventromedial prefrontal and frontal pole gray matter volumes compared with controls. Ventromedial volume was significantly negatively correlated with magical ideation and anhedonia scores in FHR subjects. CONCLUSIONS: Selective, regional prefrontal gray matter reductions may differentially mark genetic vulnerability and early symptom processes among non-psychotic young adults at familial risk for schizophrenia.

Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements.

Corpus callosum (CC) area abnormalities have been reported in magnetic resonance imaging (MRI) studies of adults and youths with bipolar disorder (BPD), suggesting interhemispheric communication may be abnormal in BPD and may be present early in the course of illness and affect normal neuromaturation of this structure throughout the lifecycle. Neuroimaging scans from 44 youths with DSM-IV BPD and 22 healthy controls (HC) were analyzed using cross-sectional area measurements and a novel method of volumetric parcellation. Univariate analyses of variance were conducted on CC subregions using both volume and traditional area measurements. Youths with BPD had smaller middle and posterior callosal regions, and reduced typical age-related increases in CC size. The cross-sectional area and novel volumetric methodologies resulted in similar findings. Future longitudinal assessments of CC development would track the evolution of callosal abnormalities in youths with BPD and allow exploration of the functional significance of these findings.

White matter volume abnormalities and associations with symptomatology in schizophrenia.

The cerebral white matter (WM) is critically involved in many bio-behavioral functions impaired in schizophrenia. However, the specific neural systems underlying symptomatology in schizophrenia are not well known. By comparing the volume of all brain fiber systems between chronic patients with DSM-III-R schizophrenia (n=88) and matched healthy community controls (n=40), we found that a set of a priori WM regions of local and distal associative fiber systems was significantly different in patients with schizophrenia. There were significant positive correlations between volumes (larger) in anterior callosal, cingulate and temporal deep WM regions (related to distal connections) with positive symptoms, such as hallucinations, delusions and bizarre behavior, and significant negative correlation between volumes (smaller) in occipital and paralimbic superficial WM (related to local connections) and posterior callosal fiber systems with higher negative symptoms, such as alogia. Furthermore, the temporal sagittal system showed significant rightward asymmetry between patients and controls. These observations suggest a pattern of volume WM alterations associated with symptomatology in schizophrenia that may be related in part to predisposition to schizophrenia.

WebParc: a tool for analysis of the topography and volume of stroke from MRI.

The quantitative assessment of the anatomic consequences of cerebral infarction is critical in the study of the etiology and therapeutic response in patients with stroke. We present here an overview of the operation of "WebParc," a computational system that provides measures of stroke lesion volume and location with respect to canonical forebrain neural systems nomenclature. Using a web-based interface, clinical imaging data can be registered to a template brain that contains a comprehensive set of anatomic structures. Upon delineation of the lesion, we can express the size and localization of the lesion in terms of the regions that are intersected within the template. We demonstrate the application of the system using MRI-based diffusion-weighted imaging and document measures of the validity and reliability of its uses. Intra- and inter-rater reliability is demonstrated, and characterized relative to the various classes of anatomic regions that can be assessed. The WebParc system has been developed to meet criteria of both efficiency and intuitive operator use in the real time analysis of stroke anatomy, so as to be useful in support of clinical care and clinical research studies. This article is an overview of its base-line operation with quantitative anatomic characterization of lesion size and location in terms of stroke distribution within the separate gray and white matter compartments of the brain.

Anterior cingulate volumetric alterations in treatment-naïve adults with ADHD: a pilot study.

OBJECTIVE: We sought to examine preliminary results of brain alterations in anterior cingulate cortex (ACC) in treatment-naïve adults with ADHD. The ACC is a central brain node for the integration of cognitive control and allocation of attention, affect and drive. Thus its anatomical alteration may give rise to impulsivity, hyperactivity and inattention, which are cardinal behavioral manifestations of ADHD. METHOD: Segmentation and parcellation of the ACC was performed on controls (n = 22), treated (n = 13) and treatment-naïve adults with ADHD (n = 13). RESULTS: There was a 21% volume reduction in the left ACC of the treatment-naïve group relative to the control group. Also, there was a 23% volume reduction in the right ACC of the treated group relative to the control group. CONCLUSION: These results raise the possibility that in ADHD there are volumetric deficits persistent into adulthood, that are independent of medical treatment.

Cerebellum, language, and cognition in autism and specific language impairment.

We performed cerebellum segmentation and parcellation on magnetic resonance images from right-handed boys, aged 6-13 years, including 22 boys with autism [16 with language impairment (ALI)], 9 boys with Specific Language Impairment (SLI), and 11 normal controls. Language-impaired groups had reversed asymmetry relative to unimpaired groups in posterior-lateral cerebellar lobule VIIIA (right side larger in unimpaired groups, left side larger in ALI and SLI), contralateral to previous findings in inferior frontal cortex language areas. Lobule VIIA Crus I was smaller in SLI than in ALI. Vermis volume, particularly anterior I-V, was decreased in language-impaired groups. Language performance test scores correlated with lobule VIIIA asymmetry and with anterior vermis volume. These findings suggest ALI and SLI subjects show abnormalities in neurodevelopment of fronto-corticocerebellar circuits that manage motor control and the processing of language, cognition, working memory, and attention.

Neocortical neurogenesis: morphogenetic gradients and beyond.

Each of the five cellular layers of the cerebral neocortex is composed of a specific number of a single predominant 'class' of projection neuron. The projection neuron class is defined by its unique morphology and axonal projections to other areas of the brain. Precursor cell populations lining the embryonic lateral ventricles produce the projection neurons. The mechanisms regulating precursor cell proliferation also regulate total numbers of neurons produced at specific developmental periods and destined to a specific neocortical layer. Because the newborn neurons migrate relatively long distances to reach their final layer destinations, it is often assumed that the mechanisms governing acquisition of neuronal-class-specific characteristics, many of which become evident after neuron production, are independent of the mechanisms governing neuron production. We review evidence that suggests that the two mechanisms might be linked via operations of Notch1 and p27(Kip1), molecules known to regulate precursor cell proliferation and neuron production.

The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York.

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder of white matter resulting from deficiency of galactosylceramide beta-galactosidase (GALC) and the consequent accumulation of galactosylceramide and psychosine. Although most patients present within the first 6 months of life, i.e., the early infantile or "classic" phenotype, others present later in life including in adolescence and adulthood. The only available treatment for infants with early infantile Krabbe disease is hematopoietic cell transplantation (HCT), typically using umbilical cord blood. Although transplanted children are far better neurologically than they would have been had they followed the typical fulminant course of early infantile Krabbe disease, anecdotal reports have surfaced suggesting that the majority of presymptomatic children transplanted for Krabbe disease have developed motor and language deterioration. The cause and extent of the deterioration is unknown at this time. With the advent of universal newborn screening for Krabbe disease in New York State and the projected start of screening in Illinois in 2010, understanding the outcome of treatment becomes of paramount importance. Thus, the purpose of this workshop was to bring together child neurologists, geneticists, neurodevelopmental pediatricians, transplanters, neuroradiologists, neurophysiologists, developmental neurobiologists, neuroscientists, and newborn screeners to review the results of the transplantation experience in humans and animals and, if neurologic deterioration was confirmed, develop possible explanations as to causation. This workshop was the first attempt at a multicenter crossdiscipline evaluation of the results of HCT for Krabbe disease. A broad range of individuals participated, including clinicians, academicians, and authorities from the National Institutes of Health, American College of Medical Genetics, and Department of Health and Human Services.