Cytoarchitectonic parcellation and functional characterization of four new areas in the caudal parahippocampal cortex

Brain areas at the parahippocampal gyrus of the temporal–occipital transition region are involved in different functions including processing visual–spatial information and episodic memory. Results of neuroimaging experiments have revealed a differentiated functional parcellation of this region, but its microstructural correlates are less well understood. Here we provide probability maps of four new cytoarchitectonic areas, Ph1, Ph2, Ph3 and CoS1 at the parahippocampal gyrus and collateral sulcus. Areas have been identified based on an observer-independent mapping of serial, cell-body stained histological sections of ten human postmortem brains. They have been registered to two standard reference spaces, and superimposed to capture intersubject variability. The comparison of the maps with functional imaging data illustrates the different involvement of the new areas in a variety of functions. Maps are available as part of Julich-Brain atlas and can be used as anatomical references for future studies to better understand relationships between structure and function of the caudal parahippocampal cortex.

Scene Preferences, Aesthetic Appeal, and Curiosity

A gradient of µ-opioid receptors extends from early sensory areas of the cerebral cortex to associative cortex, with the greatest density of receptors in the most anterior associative regions. In 2006, Biederman and Vessel proposed that the hedonic value of perceptual and cognitive experience is a function of activation of this gradient. A desire for opioid activity provided by this gradient renders us infovores, always seeking novel but richly interpretable experiences. Richly interpretable experiences engage the opioid-dense anterior regions of the gradient, while novel experiences engage neural ensembles that have yet to undergo adaptation. Support for this proposal derives from the greater activity elicited in opioid-rich parahippocampal cortex for preferred over nonpreferred scenes, with neural network modeling of visual aesthetic responses suggesting that representations in later stages are more predictive of aesthetic responses, and psychopharmacological experiments that support the potential involvement of endogenous opioids.

Medial Temporal Lobe Subregional Atrophy in Aging and Alzheimer's Disease: A Longitudinal Study

Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.

Novel objects with causal schemas elicit selective responses in tool- and hand-selective lateral occipito-temporal cortex

Tool-selective lateral occipito-temporal cortex (LOTC) responds preferentially to images of tools (hammers, brushes) relative to non-tool objects (clocks, shoes). What drives these responses? Tools have elongated shapes and are more likely to have motor associations, but another essential property is that they exert causal effects on the environment. We tested whether LOTC would respond to novel objects associated with a tool-canonical schema in which their actions cause other events. To do so, we taught male and female human participants about novel objects embedded in animated event sequences, which varied in the temporal order of their events. Causer objects moved prior to the appearance of an environmental event (e.g., stars) while Reactor objects moved after an identical event; objects were matched on shape and motor association. During fMRI, participants viewed still images of these novel objects. We localized tool-selective LOTC and non-tool-selective parahippocampal cortex (PHC) by contrasting neural responses to images of familiar tools and non-tools. We found that LOTC responded more to Causers than Reactors; this effect was absent and weaker in right PHC. We also localized responses to images of hands, which elicit overlapping responses with tools. Across inferior temporal cortex, voxels’ tool and hand selectivity positively predicted a preferential response to Causers, and non-tool selectivity negatively so. We conclude that a causal schema typical of tools is sufficient to drive LOTC, and more generally, that preferential responses to domains across the temporal lobe may reflect the relational event structures typical of those domains.

Incidental reinstatement of faces and scenes in medial temporal lobe subregions during word recognition

During associative retrieval, the brain reinstates neural representations that were present during encoding. The human medial temporal lobe (MTL) with its subregions hippocampus (HC), perirhinal cortex (PRC), and parahippocampal cortex (PHC) plays a central role in neural reinstatement. Previous studies have given compelling evidence for reinstatement in the MTL during explicitly instructed associative retrieval. High-confident recognition may be similarly accompanied by recollection of associated information from the encoding context. It is unclear, however, whether high-confident recognition memory elicits reinstatement in the MTL even in the absence of an explicit instruction to retrieve associated information. Here, we addressed this open question using high-resolution fMRI. Twenty-eight male and female human volunteers engaged in a recognition memory task for words that they had previously encoded together with faces and scenes. Using complementary uni- and multivariate approaches, we show that MTL subregions including the PRC, PHC, and HC differentially reinstate category-specific representations during high-confident word recognition, even though no explicit instruction to retrieve the associated category was given. This constitutes novel evidence that high-confident recognition memory is accompanied by incidental reinstatement of associated category information in MTL subregions, and supports a functional model of the MTL that emphasises content-sensitive representations during both encoding and retrieval.

On the Search for Brain Bifurcation Parameters: Lessons From FMRI Studies on Visual Illusions

Data from three functional magnetic resonance imaging (fMRI) studies that involved in total about 100 participants and showed that the strength of several visual illusions such as the Ebbinghaus, Ponzo, and Muller-Lyer illusions depends on neuroanatomical subject measures such as visual cortex surface area and parahippocampal cortex gray matter volume were evaluated using a dynamical systems perspective to determine brain bifurcation parameters. Bifurcation parameters that involved power laws and captured relational dependencies were fitted separately to the three fMRI studies. The bifurcation parameter hypothesis that states that such parameters show unique quantities and are no longer correlated to structural systems properties was tested. The power law exponents and mean bifurcation parameter values were determined. For all three studies and three illusion types, the bifurcation parameter hypothesis was supported. Accordingly, the constructed parameters characterized the reactions of the participants under the Ebbinghaus, Ponzo, and Muller-Lyer illusions in terms of unique threshold values that no longer depended on neuroanatomical subject measures. Power law exponents in the range from 1 to 7 were found. The fMRI data describing gray matter volume of certain active regions in the parahippocampal cortex showed some interesting relationship between the mean bifurcation parameter values.

Medial Temporal Lobe Contributions to Resting-State Networks

The medial temporal lobe (MTL) is a set of interconnected brain regions that have been shown to play a central role in behavior as well as in neurological disease. Recent studies using resting-state functional Magnetic Resonance Imaging (rsfMRI) have attempted to understand the MTL in terms of its functional connectivity with the rest of the brain. However, the exact characterization of the whole-brain networks that co-activate with the MTL as well as how the various sub-regions of the MTL are associated with these networks remains poorly understood. Here we attempted to advance these issues by exploiting the high spatial-resolution 7T rsfMRI dataset from the Human Connectome Project with a data-driven analysis approach that relied on Independent Component Analysis (ICA) restricted to the MTL. We found that four different well-known resting-state networks co-activated with a unique configuration of MTL subcomponents. Specifically, we found that different sections of the parahippocampal cortex were involved in the default mode, visual and dorsal attention networks, sections of the hippocampus in the somatomotor and default mode networks, and the lateral entorhinal cortex in the dorsal attention network. We replicated this set of results in a validation sample. These results provide new insight into how the MTL and its subcomponents contribute to known resting-state networks. The participation of the MTL in an expanded range of resting-state networks requires a rethink of its presumed role in behavior and disease.

Relaxin-3 Innervation From the Nucleus Incertus to the Parahippocampal Cortex of the Rat

Spatial learning and memory processes depend on anatomical and functional interactions between the hippocampus and the entorhinal cortex. A key neurophysiological component of these processes is hippocampal theta rhythm, which can be driven from subcortical areas including the pontine nucleus incertus (NI). The NI contains the largest population of neurons that produce and presumably release the neuropeptide, relaxin-3, which acts via the Gi/o-protein-coupled receptor, relaxin-family peptide 3 receptor (RXFP3). NI activation induces general arousal including hippocampal theta, and inactivation induces impairment of spatial memory acquisition or retrieval. The primary aim of this study was to map the NI/relaxin-3 innervation of the parahippocampal cortex (PHC), including the medial and lateral entorhinal cortex, endopiriform cortex, perirhinal, postrhinal, and ectorhinal cortex, the amygdalohippocampal transition area and posteromedial cortical amygdala. Retrograde tracer injections were placed in different parts of the medial and lateral entorhinal cortex, which produced prominent retrograde labeling in the ipsilateral NI and some labeling in the contralateral NI. Anterograde tracer injections into the NI and immunostaining for relaxin-3 produced fiber labeling in deep layers of all parahippocampal areas and some dispersed fibers in superficial layers. Double-labeling studies revealed that both hippocampal projecting and calcium-binding protein-positive (presumed GABAergic) neurons received a relaxin-3 NI innervation. Some of these fibers also displayed synaptophysin (Syn) immunoreactivity, consistent with the presence of the peptide at synapses; and relaxin-3-positive fibers containing Syn bouton-like staining were frequently observed in contact with hippocampal-projecting or calcium-binding protein-positive neuronal somata and more distal elements. Finally, in situ hybridization studies revealed that entorhinal neurons in the superficial layers, and to a lesser extent in deep layers, contain RXFP3 mRNA. Together, our data support functional actions of the NI/relaxin-3-parahippocampal innervation on processes related to memory, spatial navigation and contextual analysis.

Extent of parahippocampal ablation is associated with seizure freedom after laser amygdalohippocampotomy

OBJECTIVE The authors aimed to examine the relationship between mesial temporal subregion ablation volume and seizure outcome in a diverse cohort of patients who underwent stereotactic laser amygdalohippocampotomy (SLAH) for mesial temporal lobe epilepsy (MTLE). METHODS Seizure outcomes and pre- and postoperative images were retrospectively reviewed in patients with MTLE who underwent SLAH at a single institution. Mesial temporal subregions and the contrast-enhancing ablation volume were manually segmented. Pre- and postoperative MR images were coregistered to assess anatomical ablation. Postoperative MRI and ablation volumes were also spatially normalized, enabling the assessment of seizure outcome with heat maps. RESULTS Twenty-eight patients with MTLE underwent SLAH, 15 of whom had mesial temporal sclerosis (MTS). The rate of Engel class I outcome at 1 year after SLAH was 39% overall: 47% in patients with MTS and 31% in patients without MTS. The percentage of parahippocampal gyrus (PHG) ablated was higher in patients with an Engel class I outcome (40% vs 25%, p = 0.04). Subregion analysis revealed that extent of ablation in the parahippocampal cortex (35% vs 19%, p = 0.03) and angular bundle (64% vs 43%, p = 0.02) was positively associated with Engel class I outcome. The degree of amygdalohippocampal complex (AHC) ablated was not associated with seizure outcome (p = 0.30). CONCLUSIONS Although the AHC was the described target of SLAH, seizure outcome in this cohort was associated with degree of ablation for the PHG, not the AHC. Complete coverage of both the AHC and PHG is technically challenging, and more work is needed to optimize seizure outcome after SLAH.

Auditory Beat Stimulation Modulates Memory-Related Single-Neuron Activity in the Human Medial Temporal Lobe

Auditory beats are amplitude-modulated signals (monaural beats) or signals that subjectively cause the perception of an amplitude modulation (binaural beats). We investigated the effects of monaural and binaural 5 Hz beat stimulation on neural activity and memory performance in neurosurgical patients performing an associative recognition task. Previously, we had reported that these beat stimulation conditions modulated memory performance in opposite directions. Here, we analyzed data from a patient subgroup, in which microwires were implanted in the amygdala, hippocampus, entorhinal cortex and parahippocampal cortex. We identified neurons responding with firing rate changes to binaural versus monaural 5 Hz beat stimulation. In these neurons, we correlated the differences in firing rates for binaural versus monaural beats to the memory-related differences for remembered versus forgotten items and associations. In the left hemisphere, we detected statistically significant negative correlations between firing rate differences for binaural versus monaural beats and remembered versus forgotten items/associations. Importantly, such negative correlations were also observed between beat stimulation-related firing rate differences in the pre-stimulus window and memory-related firing rate differences in the post-stimulus windows. In line with concepts of homeostatic plasticity, our findings suggest that beat stimulation is linked to memory performance via shifting baseline firing levels.