The corticotopic organization of the human basal forebrain as revealed by regionally selective functional connectivity profiles

The cholinergic basal forebrain (CBF), comprising different groups of cortically projecting cholinergic neurons, plays a crucial role in higher cognitive processes and has been implicated in diverse neuropsychiatric disorders. A distinct corticotopic organization of CBF projections has been revealed in animal studies, but little is known about their organization in the human brain. We explored regional differences in functional connectivity (FC) profiles within the human CBF by applying a clustering approach to resting‐state functional magnetic resonance imaging (rs‐fMRI) data of healthy adult individuals (N = 85; 19–85 years). We further examined effects of age on FC of the identified CBF clusters and assessed the reproducibility of cluster‐specific FC profiles in independent data from healthy older individuals (N = 25; 65–89 years). Results showed that the human CBF is functionally organized into distinct anterior‐medial and posterior‐lateral subdivisions that largely follow anatomically defined boundaries of the medial septum/diagonal band and nucleus basalis Meynert. The anterior‐medial CBF subdivision was characterized by connectivity with the hippocampus and interconnected nodes of an extended medial cortical memory network, whereas the posterior‐lateral subdivision was specifically connected to anterior insula and dorsal anterior cingulate components of a salience/attention network. FC of both CBF subdivisions declined with increasing age, but the overall topography of subregion‐specific FC profiles was reproduced in independent rs‐fMRI data of healthy older individuals acquired in a typical clinical setting. Rs‐fMRI‐based assessments of subregion‐specific CBF function may complement established volumetric approaches for the in vivo study of CBF involvement in neuropsychiatric disorders.     

Delineating functional segregations of the human middle temporal gyrus with resting‐state functional connectivity and coactivation patterns

Although the middle temporal gyrus (MTG) has been parcellated into subregions with distinguished anatomical connectivity patterns, whether the structural topography of MTG can inform functional segregations of this area remains largely unknown. Accumulating evidence suggests that the brain's underlying organization and function can be directly and effectively delineated with resting‐state functional connectivity (RSFC) by identifying putative functional boundaries between cortical areas. Here, RSFC profiles were used to explore functional segregations of the MTG and defined four subregions from anterior to posterior in two independent datasets, which showed a similar pattern with MTG parcellation scheme obtained using anatomical connectivity. The functional segregations of MTG were further supported by whole brain RSFC, coactivation, and specific RFSC, and coactivation mapping. Furthermore, the fingerprint with predefined 10 networks and functional characterizations of each subregion using meta‐analysis also identified functional distinction between subregions. The specific connectivity analysis and functional characterization indicated that the bilateral most anterior subregions mainly participated in social cognition and semantic processing; the ventral middle subregions were involved in social cognition in left hemisphere and auditory processing in right hemisphere; the bilateral ventro‐posterior subregions participated in action observation, whereas the left subregion was also involved in semantic processing; both of the dorsal subregions in superior temporal sulcus were involved in language, social cognition, and auditory processing. Taken together, our findings demonstrated MTG sharing similar structural and functional topographies and provide more detailed information about the functional organization of the MTG, which may facilitate future clinical and cognitive research on this area.     

Inter‐hemispheric connectivity in the fusiform gyrus supports memory consolidation for faces

This study investigated how changes of functional connectivity over time accompany consolidation of face memories. Based on previous research, it was hypothesized that connectivity changes in networks initially active during face perception and face encoding would be associated with individual recognition memory performance. Resting‐state functional connectivity was examined shortly before, shortly after and about 40 min after incidental learning of faces. Memory performance was assessed in a surprise recognition test shortly after the last resting‐state session. Results reveal that memory performance‐related connectivity between the left fusiform face area and other brain areas gradually changed over the course of the experiment. Specifically, the increase in connectivity with the contralateral fusiform gyrus, the hippocampus, the amygdala and the inferior frontal gyrus correlated with recognition memory performance. As the increase in connectivity in the two final resting‐state sessions was associated with memory performance, the present results demonstrate that memory formation is not restricted to the incidental learning phase but continues and increases in the following 40 min. It is discussed that the delayed increase in inter‐hemisphere connectivity between the left and right fusiform gyrus is an indicator for memory formation and consolidation processes.     

Guided saccades modulate object and face-specific activity in the fusiform gyrus

We investigated the influence of saccadic eye movements on the magnitude of functional MRI (fMRI) activation in brain regions known to participate in object and face perception. In separate runs, subjects viewed a static image of a uniform gray field, a face, or a flower. Every 500 ms a small fixation cross made a discrete jump within the image and subjects were required to make a saccade and fixate the cross at its new location. Each run consisted of alternating blocks in which the subject was guided to make small and large saccades. A comparison of large vs. small saccade blocks revealed robust activity in the oculomotor system, particularly within the frontal eye fields (FEF), intraparietal sulcus (IPS), and superior colliculi regardless of the background image. Activity within portions of the ventral occipitotemporal cortex (VOTC) including the lingual and fusiform gyri was also modulated by saccades, but here saccade-related activity was strongly influenced by the background image. Activity within the VOTC was strongest when large saccadic eye movements were made over an image of a face or a flower compared to a uniform gray image. Of most interest was activity in the functionally predefined face-specific region of the fusiform gyrus, where large saccades made over a face increased activity, but where similar large saccades made over a flower or a uniform gray field did not increase activity. These results demonstrate the potentially confounding influence of uncontrolled eye movements for neuroimaging studies of face and object perception.     

Tuning face perception with electrical stimulation of the fusiform gyrus

The fusiform gyrus (FG) is an important node in the face processing network, but knowledge of its causal role in face perception is currently limited. Recent work demonstrated that high frequency stimulation applied to the FG distorts the perception of faces in human subjects (Parvizi et al. [ 2012 ]: J Neurosci 32:14915–14920). However, the timing of this process in the FG relative to stimulus onset and the spatial extent of FG's role in face perception are unknown. Here, we investigate the causal role of the FG in face perception by applying precise, event‐related electrical stimulation (ES) to higher order visual areas including the FG in six human subjects undergoing intracranial monitoring for epilepsy. We compared the effects of single brief (100 μs) electrical pulses to the FG and non‐face‐selective visual areas on the speed and accuracy of detecting distorted faces. Brief ES applied to face‐selective sites did not affect accuracy but significantly increased the reaction time (RT) of detecting face distortions. Importantly, RT was altered only when ES was applied 100ms after visual onset and in face‐selective but not place‐selective sites. Furthermore, ES applied to face‐selective areas decreased the amplitude of visual evoked potentials and high gamma power over this time window. Together, these results suggest that ES of face‐selective regions within a critical time window induces a delay in face perception. These findings support a temporally and spatially specific causal role of face‐selective areas and signify an important link between electrophysiology and behavior in face perception. Hum Brain Mapp 38:2830–2842, 2017. © 2017 Wiley Periodicals, Inc.     

Functional connectivity based parcellation of early visual cortices

Human brain can be divided into multiple brain regions based on anatomical and functional properties. Recent studies showed that resting‐state connectivity can be utilized for parcellating brain regions and identifying their distinctive roles. In this study, we aimed to parcellate the primary and secondary visual cortices (V1 and V2) into several subregions based on functional connectivity and to examine the functional characteristics of each subregion. We used resting‐state data from a research database and also acquired resting‐state data with retinotopy results from a local site. The long‐range connectivity profile and three different algorithms (i.e., K‐means, Gaussian mixture model distribution, and Ward's clustering algorithms) were adopted for the parcellation. We compared the parcellation results within V1 and V2 with the eccentric map in retinotopy. We found that the boundaries between subregions within V1 and V2 were located in the parafovea, indicating that the anterior and posterior subregions within V1 and V2 corresponded to peripheral and central visual field representations, respectively. Next, we computed correlations between each subregion within V1 and V2 and intermediate and high‐order regions in ventral and dorsal visual pathways. We found that the anterior subregions of V1 and V2 were strongly associated with regions in the dorsal stream (V3A and inferior parietal gyrus), whereas the posterior subregions of V1 and V2 were highly related to regions in the ventral stream (V4v and inferior temporal gyrus). Our findings suggest that the anterior and posterior subregions of V1 and V2, parcellated based on functional connectivity, may have distinct functional properties.     

Time course of gamma‐band oscillation associated with face processing in the inferior occipital gyrus and fusiform gyrus: A combined fMRI and MEG study

Debate continues over whether the inferior occipital gyrus (IOG) or the fusiform gyrus (FG) represents the first stage of face processing and what role these brain regions play. We investigated this issue by combining functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in normal adults. Participants passively observed upright and inverted faces and houses. First, we identified the IOG and FG as face‐specific regions using fMRI. We applied beamforming source reconstruction and time–frequency analysis to MEG source signals to reveal the time course of gamma‐band activations in these regions. The results revealed that the right IOG showed higher gamma‐band activation in response to upright faces than to upright houses at 100 ms from the stimulus onset. Subsequently, the right FG showed greater gamma‐band response to upright faces versus upright houses at around 170 ms. The gamma‐band activation in the right IOG and right FG was larger in response to inverted faces than to upright faces at the later time window. These results suggest that (1) the gamma‐band activities occurs rapidly first in the IOG and next in the FG and (2) the gamma‐band activity in the right IOG at later time stages is involved in configuration processing for faces. Hum Brain Mapp 38:2067–2079, 2017. © 2017 Wiley Periodicals, Inc.     

Disturbed spatial cognitive processing of body-related stimuli in a case of a lesion to the right fusiform gyrus

The fusiform gyrus (FG) is well known as one of the main neural sites of human face and body processing. We report the case of a young male patient with epilepsy and a circumscribed lesion in the right FG who presented with isolated impairments in spatial cognitive processing of body-related stimuli. However, he did not show any clinical signs of prosopagnosia. In particular, handling/processing of body and face stimuli was impaired, when stimuli were presented in unconventional views and orientations, thus requiring additional spatial cognitive operations. In this case study, we discuss the patient’s selective impairment from the view of current empirical and theoretical work on the segregation of functions in the FG.     

Functional dissociation of the left and right fusiform gyrus in self-face recognition

It is well known that the fusiform gyrus is engaged in face perception, such as the processes of face familiarity and identity. However, the functional role of the fusiform gyrus in face processing related to high-level social cognition remains unclear. The current study assessed the functional role of individually defined fusiform face area (FFA) in the processing of self-face physical properties and self-face identity. We used functional magnetic resonance imaging to monitor neural responses to rapidly presented face stimuli drawn from morph continua between self-face (Morph 100%) and a gender-matched friend's face (Morph 0%) in a face recognition task. Contrasting Morph 100% versus Morph 60% that differed in self-face physical properties but were both recognized as the self uncovered neural activity sensitive to self-face physical properties in the left FFA. Contrasting Morphs 50% that were recognized as the self versus a friend on different trials revealed neural modulations associated with self-face identity in the right FFA. Moreover, the right FFA activity correlated with the frequency of recognizing Morphs 50% as the self. Our results provide evidence for functional dissociations of the left and right FFAs in the representations of self-face physical properties and self-face identity.     

Determination of the posterior boundary of Wernicke's area based on multimodal connectivity profiles

Wernicke's area is one of the most important language regions and has been widely studied in both basic research and clinical neurology. However, its exact anatomy has been controversial. In this study, we proposed to address the anatomy of Wernicke's area by investigating different connectivity profiles. First, the posterior superior temporal gyrus (STG), traditionally called “Wernicke's area”, was parcellated into three component subregions with diffusion MRI. Then, whole‐brain anatomical connectivity, resting‐state functional connectivity (RSFC) and meta‐analytic connectivity modeling (MACM) analyses were used to establish the anatomical, resting‐state and task‐related coactivation network of each subregion to identify which subregions participated in the language network. In addition, behavioral domain analysis, meta‐analyses of semantics, execution speech, and phonology and intraoperative electrical stimulation were used to determine which subregions were involved in language processing. Anatomical connectivity, RSFC and MACM analyses consistently identified that the two anterior subregions in the posterior STG primarily participated in the language network, whereas the most posterior subregion in the temporoparietal junction area primarily participated in the default mode network. Moreover, the behavioral domain analyses, meta‐analyses of semantics, execution speech and phonology and intraoperative electrical stimulation mapping also confirmed that only the two anterior subregions were involved in language processing, whereas the most posterior subregion primarily participated in social cognition. Our findings revealed a convergent posterior anatomical border for Wernicke's area and indicated that the brain's functional subregions can be identified on the basis of its specific structural and functional connectivity patterns. Hum Brain Mapp 36:1908–1924, 2015. © 2015 Wiley Periodicals, Inc .     

Functional topography of the right inferior parietal lobule structured by anatomical connectivity profiles

The nature of the relationship between structure and function is a fundamental question in neuroscience, especially at the macroscopic neuroimaging level. Although mounting studies have revealed that functional connectivity reflects structural connectivity, whether similar structural and functional connectivity patterns can reveal corresponding similarities in the structural and functional topography remains an open problem. In our current study, we used the right inferior parietal lobule (RIPL), which has been demonstrated to have similar anatomical and functional connectivity patterns at the subregional level, to directly test the hypothesis that similar structural and functional connectivity patterns can inform the corresponding topography of this area. In addition, since the association between the RIPL regions and particular functions and networks is still largely unknown, post‐hoc functional characterizations and connectivity analyses were performed to identify the main functions and cortical networks in which each subregion participated. Anatomical and functional connectivity‐based parcellations of the RIPL have consistently identified five subregions. Our functional characterization using meta‐analysis‐based behavioral and connectivity analyses revealed that the two anterior subregions (Cl1 and Cl2) primarily participate in interoception and execution, respectively; whereas the posterior subregion (Cl3) in the SMG primarily participates in attention and action inhibition. The two posterior subregions (Cl4, Cl5) in the AG were primarily involved in social cognition and spatial cognition, respectively. These results indicated that similar anatomical and functional connectivity patterns of the RIPL are reflected in corresponding structural and functional topographies. The identified cortical connectivity and functional characterization of each subregion may facilitate RIPL‐related clinical research. Hum Brain Mapp 37:4316–4332, 2016. © 2016 Wiley Periodicals, Inc.     

A Golgi-electron microscopic study of fusiform neurons in the hilar region of the dentate gyrus

The fusiform cells of the dentate gyrus are located in a portion of the hilus within 100 micron of the granule cell layer. They have ovoid somata and bipolar dendrites that generally run parallel to the granule cell layer. The dendrites of these cells are either spiny or sparsely spiny. The spiny fusiform cell has numerous spines along its dendrites, which are contacted by terminals with the features of granule cell axon collaterals. This cell type also displays somal spines that are contacted by similar terminals. In contrast, the sparsely spiny fusiform cell displays only a few spines, which are contacted by multiple small axon terminals that synapse with both the stalk and end bulb of the spine. Most synaptic input for this cell type is made with the smooth surfaces of the soma and dendrites. A variety of terminals form synapses with the sparsely spiny fusiform cell, including terminals that resemble the fine axon collaterals of mossy fibers. The somata of these two cell types also display differences in the amount of Nissl bodies and the degree of nuclear infolding. The results indicate that spiny fusiform cells are similar to mossy cells, another hilar cell type that receives its major synaptic input from axon collaterals of mossy fibers from granule cells. The distribution of the dendrites of spiny fusiform cells and the pattern of granule cell axon collaterals suggest a high degree of convergence from granule cells. In contrast, the variety of axodendritic synapses for sparsely spiny fusiform cells suggests that more diverse inputs affect this cell's activity. Therefore, the structure and circuitry of these two hilar cell types are probably different. This study adds further evidence to indicate that the hilus contains a large variety of cell types with different neuronal connections.     

Functional connectivity as revealed by spatial independent component analysis of fMRI measurements during rest

Cortical functional connectivity, as indicated by the concurrent spontaneous activity of spatially segregated regions, is being studied increasingly because it may determine the reaction of the brain to external stimuli and task requirements and it is reportedly altered in many neurological and psychiatric disorders. In functional magnetic resonance imaging (fMRI), such functional connectivity is investigated commonly by correlating the time course of a chosen "seed voxel" with the remaining voxel time courses in a voxel-by-voxel manner. This approach is biased by the actual choice of the seed voxel, however, because it only shows functional connectivity for the chosen brain region while ignoring other potentially interesting patterns of coactivation. We used spatial independent component analysis (sICA) to assess cortical functional connectivity maps from resting state data. SICA does not depend on any chosen temporal profile of local brain activity. We hypothesized that sICA would be able to find functionally connected brain regions within sensory and motor regions in the absence of task-related brain activity. We also investigated functional connectivity patterns of several parietal regions including the superior parietal cortex and the posterior cingulate gyrus. The components of interest were selected in an automated fashion using predefined anatomical volumes of interest. SICA yielded connectivity maps of bilateral auditory, motor and visual cortices. Moreover, it showed that prefrontal and parietal areas are also functionally connected within and between hemispheres during the resting state. These connectivity maps showed an extremely high degree of consistency in spatial, temporal, and frequency parameters within and between subjects. These results are discussed in the context of the recent debate on the functional relevance of fluctuations of neural activity in the resting state.     

Isoflurane induces dose‐dependent alterations in the cortical connectivity profiles and dynamic properties of the brain's functional architecture

Despite their widespread use, the effect of anesthetic agents on the brain's functional architecture remains poorly understood. This is particularly true of alterations that occur beyond the point of induced unconsciousness. Here, we examined the distributed intrinsic connectivity of macaques across six isoflurane levels using resting‐state functional MRI (fMRI) following the loss of consciousness. The results from multiple analysis strategies showed stable functional connectivity (FC) patterns between 1.00% and 1.50% suggesting this as a suitable range for anesthetized nonhuman primate resting‐state investigations. Dose‐dependent effects were evident at moderate to high dosages showing substantial alteration of the functional topology and a decrease or complete loss of interhemispheric cortical FC strength including that of contralateral homologues. The assessment of dynamic FC patterns revealed that the functional repertoire of brain states is related to anesthesia depth and most strikingly, that the number of state transitions linearly decreases with increased isoflurane dosage. Taken together, the results indicate dose‐specific spatial and temporal alterations of FC that occur beyond the typically defined endpoint of consciousness. Future work will be necessary to determine how these findings generalize across anesthetic types and extend to the transition between consciousness and unconsciousness. Hum Brain Mapp 35:5754–5775, 2014. © 2014 Wiley Periodicals, Inc.     

Altered fusiform connectivity during processing of fearful faces in social anxiety disorder

Social anxiety disorder (SAD) has been associated with hyper-reactivity in limbic brain regions like the amygdala, both during symptom provocation and emotional face processing tasks. In this functional magnetic resonance imaging study we sought to examine brain regions implicated in emotional face processing, and the connectivity between them, in patients with SAD (n=14) compared with healthy controls (n=12). We furthermore aimed to relate brain reactivity and connectivity to self-reported social anxiety symptom severity. SAD patients exhibited hyper-reactivity in the bilateral fusiform gyrus in response to fearful faces, as well as greater connectivity between the fusiform gyrus and amygdala, and decreased connectivity between the fusiform gyrus and ventromedial prefrontal cortex. Within the SAD group, social anxiety severity correlated positively with amygdala reactivity to emotional faces, amygdala-fusiform connectivity and connectivity between the amygdala and superior temporal sulcus (STS). These findings point to a pivotal role for the fusiform gyrus in SAD neuropathology, and further suggest that altered amygdala-fusiform and amygdala-STS connectivity could underlie previous findings of aberrant socio-emotional information processing in this anxiety disorder.     

Functional connectivity constrains the category‐related organization of human ventral occipitotemporal cortex

One of the most robust and oft‐replicated findings in cognitive neuroscience is that several spatially distinct, functionally dissociable ventral occipitotemporal cortex (VOTC) regions respond preferentially to different categories of concrete entities. However, the determinants of this category‐related organization remain to be fully determined. One recent proposal is that privileged connectivity of these VOTC regions with other regions that store and/or process category‐relevant properties may be a major contributing factor. To test this hypothesis, we used a multicategory functional magnetic resonance imaging (MRI) localizer to individually define category‐related brain regions of interest (ROIs) in a large group of subjects (n = 33). We then used these ROIs in resting‐state functional connectivity MRI analyses to explore spontaneous functional connectivity among these regions. We demonstrate that during rest, distinct category‐preferential VOTC regions show differentially stronger functional connectivity with other regions that have congruent category‐preference, as defined by the functional localizer. Importantly, a “tool”‐preferential region in the left medial fusiform gyrus showed differentially stronger functional connectivity with other left lateralized cortical regions associated with perceiving and knowing about common tools—posterior middle temporal gyrus (involved in perception of nonbiological motion), lateral parietal cortex (critical for reaching, grasping, manipulating), and ventral premotor cortex (involved in storing/executing motor programs)—relative to other category‐related regions in VOTC of both the right and left hemisphere. Our findings support the claim that privileged connectivity with other cortical regions that store and/or process category‐relevant properties constrains the category‐related organization of VOTC. Hum Brain Mapp 36:2187–2206, 2015. © Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

The impact of aging on the subregions of the fusiform gyrus in healthy older adults

The fusiform gyrus is known to decrease in size with increasing age. However, reported findings are inconsistent and existing studies differ in terms of the cohorts examined and/or the methods applied. Here, we analyzed age‐related links in four distinct subregions of the fusiform gyrus through integrating imaging‐based intensity information with microscopically defined cytoarchitectonic probabilities. In addition to age effects we investigated sex effects as well as age‐by‐sex interactions in a relatively large sample of 468 healthy subjects (272 females/196 males) covering a broad age range (42–97 years). We observed significant negative correlations between age and all four subregions of the fusiform gyrus indicating volume decreases over time, albeit with subregion‐specific trajectories. Additionally, we observed significant negative quadratic associations with age for some subregions, suggesting an accelerating volume loss over time. These findings may serve as a frame of reference for future cross‐sectional as well as longitudinal studies, not only for normative samples but also potentially for clinical conditions that present with abnormal atrophy of the fusiform gyrus. We did not detect any significant sex differences or sex‐by‐age interactions, suggesting that the size of the fusiform gyrus is similar in male and female brains and that age‐related atrophy follows a similar trajectory in both men and women.     

Functional network connectivity impairments and core cognitive deficits in schizophrenia

Cognitive deficits contribute to functional disability in patients with schizophrenia and may be related to altered functional networks that serve cognition. We evaluated the integrity of major functional networks and assessed their role in supporting two cognitive functions affected in schizophrenia: processing speed (PS) and working memory (WM). Resting‐state functional magnetic resonance imaging (rsfMRI) data, N = 261 patients and 327 controls, were aggregated from three independent cohorts and evaluated using Enhancing NeuroImaging Genetics through Meta Analysis rsfMRI analysis pipeline. Meta‐ and mega‐analyses were used to evaluate patient‐control differences in functional connectivity (FC) measures. Canonical correlation analysis was used to study the association between cognitive deficits and FC measures. Patients showed consistent patterns of cognitive and resting‐state FC (rsFC) deficits across three cohorts. Patient‐control differences in rsFC calculated using seed‐based and dual‐regression approaches were consistent (Cohen's d: 0.31 ± 0.09 and 0.29 ± 0.08, p < 10^?4). RsFC measures explained 12–17% of the individual variations in PS and WM in the full sample and in patients and controls separately, with the strongest correlations found in salience, auditory, somatosensory, and default‐mode networks. The pattern of association between rsFC (within‐network) and PS (r = .45, p = .07) and WM (r = .36, p = .16), and rsFC (between‐network) and PS (r = .52, p = 8.4 × 10^?3) and WM (r = .47, p = .02), derived from multiple networks was related to effect size of patient‐control differences in the functional networks. No association was detected between rsFC and current medication dose or psychosis ratings. Patients demonstrated significant reduction in several FC networks that may partially underlie some of the core neurocognitive deficits in schizophrenia. The strength of connectivity‐cognition relationships in different networks was strongly associated with network's vulnerability to schizophrenia.