The cover image is based on the Research Article India ink to 3D imaging: The legacy of Dr. Deepak “Dee” N. Pandya and his influence on generations of neuroanatomists by Gene J. Blatt et al., https://doi.org/10.1002/cne.25551.

In this tribute article, we describe the legacy of Dr. Deepak Pandya on neuroanatomy and how he influenced our research. We provide examples of tracing with India ink and how methods have evolved to tracking neurons and their connections with artificial intelligence and whole brain imaging.

Using neuroanatomical investigations in the macaque, Deepak Pandya and his colleagues have established the framework for auditory cortex organization, with subdivisions into core and belt areas. This has aided subsequent neurophysiological and imaging studies in monkeys and humans, and a nomenclature building on Pandya's work has also been adopted by the Human Connectome Project. The foundational work by Pandya and his colleagues is highlighted here in the context of subsequent and ongoing studies on the functional anatomy and physiology of auditory cortex in primates, including humans, and their relevance for understanding cognitive aspects of speech and language.

Illustration of the supratemporal plane after opening of the Sylvian fissure. AI is the primary auditory cortex; AII is association cortex. The dots indicate terminations of transcallosal connections between the two hemispheres. Note that there are connections to medial AI but not to lateral AI. In the anterior-posterior direction, the cells show a tonotopic distribution. The reason for the difference medial-lateral is unknown and was speculated in 1969 to be related to auditory localization in space.

Architectural subdivision of the inferior parietal cortex (IPC) of the capuchin monkey in a 3D reconstruction of the left hemisphere. Five architectural areas are shown: three areas in the IPC convexity (PFG, in red; PG, in blue; and Opt, in brown), and two areas in the IPC operculum (PFop, in purple; and PGop, in green).

Lamination is an important classification criterion for feedforward, feedback, and other cortical connections. Lamination, however, needs to be considered with neuropil and local environments. There is substantial heterogeneity of parent cell types, within and across layers, and substantial heterogeneity of postsynaptic dendritic targets, as these cross the layers.

Medalla et al. quantified the density, laminar distribution, and somatodendritic morphology of inhibitory interneurons expressing one or more of the calcium-binding proteins (CaBPs) (calretinin [CR], calbindin [CB], and/or parvalbumin [PV]) in mouse versus rhesus monkey in two functionally and cytoarchitectonically distinct regions—the primary visual and frontal cortical areas. This study revealed that laminar distribution and dendritic morphology of inhibitory interneurons were largely dependent on CaBP expression. The main species difference was the significantly greater density and proportion of CR+ interneurons and lower extent of CaBP coexpression in monkey compared to mouse cortices. Cluster analyses revealed that the somatodendritic morphology of layer 2–3 inhibitory interneurons is dependent on CaBP and, to a lesser extent, species, but not cortical area. By contrast to pyramidal cells that show highly distinctive area- and species-specific features, the current study found more subtle differences in the distribution and features of interneurons across areas and species. These data yield insight into how nuanced differences in the cytoarchitecture, distribution, and properties of neurons may underlie specializations in cortical regions to confer species- and area-specific functional capacities.

In macaques, connections are more frequent between architectonically similar ventral temporal cortices, in line with the Structural Model, which predicts density and laminar distribution of connections based on cortical type differences between linked areas. Pathways associated with memory in the entorhinal cortex are embedded in the laminar inhibitory microenvironment.

The superior temporal sulcus and middle temporal gyrus region underlies multisensory integration resulting in a key component of the semantic system in the language dominant hemisphere of the human brain

Summary diagram showing the general topography of the M1r CSP found in the present study (b) compared to the topography of the M1c CSP (a) and LPMCd CSP (c) found in our previous studies (Morecraft et al., 2013, 2019) .

The tight overlap of tract-tracing labeling patterns and cytoarchitectonic subareas in the macaque monkey insular cortex supports the notion that the primate insular cortex is highly organized, with separate dysgranular modules possibly integrating interoception with functionally distinct exteroceptive modalities.

Critical to human imaging studies is the localization of cortical areas based on cytoarchitectural analyses. Retrosplenial cortex forms a complex region that is not localized only around the splenium of the corpus callosum as previously thought but it extends rostrally to abut midcingulate cortex in both monkey and human brains. This extension involves anterior and intermediate divisions and we provide a logical nomenclature for divisions of both based on the distribution of neuron-specific nuclear binding protein and intermediate neurofilament antibodies. The graphical image shows the flat map of area distributions and associated designations in human based on location and modifications to Brodmann's original map. Note that flattening distorts cortex caudal to the splenium (Spl). fCas, fundus of the callosal sulcus. For further details see Figure 2.

Based on histologically validated Nissl architecture delineations and tau pathology estimations, Oltmer et al. generated an average entorhinal cortex, provided probability maps, and investigated interindividual variability within the human entorhinal subfields in health and disease.

In this study, we determined the density of posttranslational oligomeric, phosphorylated, and late truncated tau epitopes within medial temporal lobe (MTL) subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment, mild cognitive impairment (MCI), and Alzheimeŕs disease (AD). We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Our results suggest a dual-hit process in NFT formation, with decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal-hippocampal connectome.

This graphic illustrates a coronal section of the human brain and highlights key characteristics of white matter neurons (WMNs). Two classes emerged, subplate and subcortical deep WMNs, which appeared to be neurochemically heterogenous; for example, image (a) demonstrates that there was no chemical overlap between NADPH-d (blue) and MAP-2 (red) positivity. Inspection of morphological features led to (b) the classification of three groups of NADPH-d+ WMNs: (1) unipolar, (2) bipolar, and (3) multipolar—the latter of which was most frequently observed. (c) In cognitively normal par, subplate WMNs were found to be significantly larger than subcortical deep WMNs. (d) NADPH-d+ subcortical neurons also tended to embrace the outer walls of microvessels, suggesting a functional role in vasodilation. Together, these observations provide a landscape for future systematic investigations of this unique cell population. Created with BioRender.com.

A novel subdivision of the bed nucleus of stria terminalis (BST) was identified in monkey, rat, and mouse brains based on the human equivalent. This spindle-shaped small cell subdivision (BSTsc) receives its main inputs from the earlier visual and spatial processing structures and projects to many common target regions as other BST subdivisions do (see the graph). The neurons in the BSTsc mostly expresses excitatory marker genes while those in other BST components mainly contains inhibitory marker genes. The BSTsc is poised to serve as a shortcut bridge directly linking spatial information from the environment to vigilant adaptive internal responses.

The human cortex has a rich fiber structure, as revealed by myelin-staining of histological slices. Myelin also contributes to the image contrast in MRI. Recent advances in MR scanner and imaging technology allowed the acquisition of an ex-vivo data set at an isotropic resolution of 100 µm. We focused on a computational analysis of this data set with the aim of bridging histological knowledge with MRI-based results. As an example, the discrimination between unistriate (visual) cortex and adjacent astriate cortex is shown in the figure.

Key Findings:

• Differences exist in the white matter integrity of the cingulum bundle between participants who are on the dementia continuum.
• White matter integrity of the cingulum is associated with gray matter volume.
• White matter integrity of the cingulum ventral, independent of gray matter volume, may be predictive of memory performance.

Direct information about origins and terminations of cortico-cortical long association fiber pathways in humans is extremely limited. The topographic location and trajectory of cortico-cortical association pathway stems in humans and nonhuman primates is similar (1), but only in nonhuman primates is there complete information on origins and terminations as well as stems. Thus, an extrapolation approach, from nonhuman primate to human (2), is applied in the present report to infer connectivity patterns for the superior fronto-occipital fascicle in the human brain.

Brain magnetic resonance imaging and positron emission tomography following unilateral status epilepticus revealed abnormalities in cerebral association areas and contralateral cerebellar cognitive posterior lobe regions, with sparing of primary sensory and motor areas in cerebral cortex and cerebellum. This unique observation provides confirmation in the human brain of anatomical-functional specialization in cerebrocerebellar circuits.