Olfactory-trigeminal integration in the primary olfactory cortex.

Humans naturally integrate signals from the olfactory and intranasal trigeminal systems. A tight interplay has been demonstrated between these two systems, and yet the neural circuitry mediating olfactory-trigeminal (OT) integration remains poorly understood. Using functional magnetic resonance imaging (fMRI), combined with psychophysics, this study investigated the neural mechanisms underlying OT integration. Fifteen participants with normal olfactory function performed a localization task with air-puff stimuli, phenylethyl alcohol (PEA; rose odor), or a combination thereof while being scanned. The ability to localize PEA to either nostril was at chance. Yet, its presence significantly improved the localization accuracy of weak, but not strong, air-puffs, when both stimuli were delivered concurrently to the same nostril, but not when different nostrils received the two stimuli. This enhancement in localization accuracy, exemplifying the principles of spatial coincidence and inverse effectiveness in multisensory integration, was associated with multisensory integrative activity in the primary olfactory (POC), orbitofrontal (OFC), superior temporal (STC), inferior parietal (IPC) and cingulate cortices, and in the cerebellum. Multisensory enhancement in most of these regions correlated with behavioral multisensory enhancement, as did increases in connectivity between some of these regions. We interpret these findings as indicating that the POC is part of a distributed brain network mediating integration between the olfactory and trigeminal systems. PRACTITIONER POINTS: Psychophysical and neuroimaging study of olfactory-trigeminal (OT) integration. Behavior, cortical activity, and network connectivity show OT integration. OT integration obeys principles of inverse effectiveness and spatial coincidence. Behavioral and neural measures of OT integration are correlated.

Olfactory Costimulation Influences Intranasal Somatosensory Perception.

Olfactory sensitivity is influenced by intranasal trigeminal sensation. For instance, sniffing is central to how humans and animals perceive odorants. Here, we investigated the influence of olfactory costimulation on the perception of intranasal somatosensory stimulation. In this study, 22 healthy human subjects, with normal olfactory function, performed a localization task for stimulation using weak air puffs, a pure odorant, phenyl ethyl alcohol (PEA; rose odor), or their combination. Visual cues were used to inform participants to briefly hold their breath while weak, poorly localizable, air puffs and/or PEA were delivered to either nostril. Although PEA alone could not be localized to the correct nostril, when it accompanied a weak air puff in the ipsilateral nostril, localization accuracy significantly improved, relative to presentation of the air puff without the odorant. The enhancement of localization was absent when the air puff and PEA were presented to opposite nostrils. Since ipsilateral but not contralateral costimulation with PEA increased the accuracy of weak air puff localization, the results argue against a non-specific alerting effect of PEA. These findings suggest an interaction between olfactory and intranasal somatosensory stimuli leading to their integration.

Functional Connectivity between the Resting-State Olfactory Network and the Hippocampus in Alzheimer's Disease.

Olfactory impairment is associated with prodromal Alzheimer's disease (AD) and is a risk factor for the development of dementia. AD pathology is known to disrupt brain regions instrumental in olfactory information processing, such as the primary olfactory cortex (POC), the hippocampus, and other temporal lobe structures. This selective vulnerability suggests that the functional connectivity (FC) between the olfactory network (ON), consisting of the POC, insula and orbital frontal cortex (OFC) (Tobia et al., 2016), and the hippocampus may be impaired in early stage AD. Yet, the development trajectory of this potential FC impairment remains unclear. Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to investigate FC changes between the ON and hippocampus in four groups: aged-matched cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. FC was calculated using low frequency fMRI signal fluctuations in the ON and hippocampus (Tobia et al., 2016). We found that the FC between the ON and the right hippocampus became progressively disrupted across disease states, with significant differences between EMCI and LMCI groups. Additionally, there were no significant differences in gray matter hippocampal volumes between EMCI and LMCI groups. Lastly, the FC between the ON and hippocampus was significantly correlated with neuropsychological test scores, suggesting that it is related to cognition in a meaningful way. These findings provide the first in vivo evidence for the involvement of FC between the ON and hippocampus in AD pathology. Results suggest that functional connectivity (FC) between the olfactory network (ON) and hippocampus may be a sensitive marker for Alzheimer's disease (AD) progression, preceding gray matter volume loss.

Disruptions of the olfactory and default mode networks in Alzheimer's disease.

INTRODUCTION: Olfactory deficits are prevalent in early Alzheimer's disease (AD) and are predictive of progressive memory loss and dementia. However, direct neural evidence to relate AD neurodegeneration to deficits in olfaction and memory is limited. METHODS: We combined the University of Pennsylvania Smell Identification Test (UPSIT) with olfactory functional magnetic resonance imaging (fMRI) to investigate links between neurodegeneration, the olfactory network (ON) and the default mode network (DMN) in AD. RESULTS: Behaviorally, olfactory and memory scores showed a strong positive correlation in the study cohorts. During olfactory fMRI, the ON showed reduced task-related activation and the DMN showed reduced task-related suppression in mild cognitive impairment (MCI) and AD subjects compared to age-matched cognitively normal subjects. CONCLUSIONS: The results provide in vivo evidence for selective vulnerability of ON and DMN in AD and significantly improves the viable clinical applications of olfactory testing. A network-based approach, focusing on network integrity rather than focal pathology, seems beneficial to olfactory prediction of dementia in AD.

Default mode network deactivation during odor-visual association.

Default mode network (DMN) deactivation has been shown to be functionally relevant for goal-directed cognition. In this study, the DMN's role during olfactory processing was investigated using two complementary functional magnetic resonance imaging (fMRI) paradigms with identical timing, visual-cue stimulation, and response monitoring protocols. Twenty-nine healthy, non-smoking, right-handed adults (mean age = 26 ± 4 years, 16 females) completed an odor-visual association fMRI paradigm that had two alternating odor + visual and visual-only trial conditions. During odor + visual trials, a visual cue was presented simultaneously with an odor, while during visual-only trial conditions the same visual cue was presented alone. Eighteen of the twenty-nine participants (mean age = 27.0 ± 6.0 years, 11 females) also took part in a control no-odor fMRI paradigm that consisted of a visual-only trial condition which was identical to the visual-only trials in the odor-visual association paradigm. Independent Component Analysis (ICA), extended unified structural equation modeling (euSEM), and psychophysiological interaction (PPI) were used to investigate the interplay between the DMN and olfactory network. In the odor-visual association paradigm, DMN deactivation was evoked by both the odor + visual and visual-only trial conditions. In contrast, the visual-only trials in the no-odor paradigm did not evoke consistent DMN deactivation. In the odor-visual association paradigm, the euSEM and PPI analyses identified a directed connectivity between the DMN and olfactory network which was significantly different between odor + visual and visual-only trial conditions. The results support a strong interaction between the DMN and olfactory network and highlights the DMN's role in task-evoked brain activity and behavioral responses during olfactory processing. Hum Brain Mapp 38:1125-1139, 2017. © 2016 Wiley Periodicals, Inc.

Default mode network differences between rigidity- and tremor-predominant Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) traditionally is characterized by tremor, rigidity, and bradykinesia, although cognitive impairment also is a common symptom. The clinical presentation of PD is heterogeneous and associated with different risk factors for developing cognitive impairment. PD patients with primary akinetic/rigidity (PDAR) are more likely to develop cognitive deficits compared to those with tremor-predominant symptoms (PDT). Because cognitive impairment in PD appears to be related to changes in the default mode network (DMN), this study tested the hypothesis that DMN integrity is different between PDAR and PDT subtypes. METHOD: Resting state fMRI (rs-fMRI) and whole brain volumetric data were obtained from 17 PDAR, 15 PDT and 24 healthy controls (HCs) using a 3T scanner. PD patients were matched closely to HCs for demographic and cognitive variables, and showed no symptoms of dementia. Voxel-based morphometry (VBM) was used to examine brain gray matter (GM) volume changes between groups. Independent component analysis (ICA) interrogated differences in the DMN among PDAR, PDT, and HC. RESULTS: There was decreased activity in the left inferior parietal cortex (IPC) and the left posterior cingulate cortex (PCC) within the DMN between PDAR and both HC and PDT subjects, even after controlling for multiple comparisons, but not between PDT and HC. GM volume differences between groups were detected at a lower threshold (p < 0.001, uncorrected). Resting state activity in IPC and PCC were correlated with some measures of cognitive performance in PD but not in HC. CONCLUSION: This is the first study to demonstrate DMN differences between cognitively comparable PDAR and PDT subtypes. The DMN differences between PD and HC appear to be driven by the PDAR subtype. Further studies are warranted to understand the underlying neural mechanisms and their relevance to clinical and cognitive outcomes in PDAR and PDT subtypes.

Rapidly acquired multisensory association in the olfactory cortex.

BACKGROUND: The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain. METHOD: The dynamics of odor and visual association in olfaction was investigated using three functional magnetic resonance imaging (fMRI) paradigms. In two paradigms, a visual cue was paired with an odor. In the third, the same visual cue was never paired with an odor. In this experimental design, if the visual cue was not influenced by odor-visual pairing, then the blood-oxygen-level-dependent (BOLD) signal elicited by subsequent visual cues should be similar across all three paradigms. Additionally, intensity, a major dimension of odor perception, was used as a modulator of associative learning which was characterized in terms of the spatiotemporal behavior of the BOLD signal in olfactory structures. RESULTS: A single odor-visual pairing cue could subsequently induce primary olfactory cortex activity when only the visual cue was presented. This activity was intensity dependent and was also detected in secondary olfactory structures and hippocampus. CONCLUSION: This study provides evidence for a rapid learning response in the olfactory system by a visual cue following odor and visual cue pairing. The novel data and paradigms suggest new avenues to explore the dynamics of odor learning and multisensory representations that contribute to the construction of a unified odor percept in the human brain.

Language networks in children: evidence from functional MRI studies.

OBJECTIVE: The purpose of our study was to review functional MRI and other neuroimaging studies of language skills in children from infancy to adulthood. CONCLUSION: Functional MRI (fMRI) and other neuroimaging studies show developmental changes in the networks of brain regions supporting language, which can be affected by brain injuries or neurologic disorders. Particular aspects of language rely on networks that lateralize to the dominant hemisphere; others rely on bilateral or nondominant mechanisms. Multiple fMRI tasks for pediatric patients characterize functional brain reorganization that may accompany language deficits.

Comparison of fMRI data from passive listening and active-response story processing tasks in children.

PURPOSE: To use functional MRI (fMRI) methods to visualize a network of auditory and language-processing brain regions associated with processing an aurally-presented story. We compare a passive listening (PL) story paradigm to an active-response (AR) version including online performance monitoring and a sparse acquisition technique. MATERIALS AND METHODS: Twenty children (ages 11-13 years) completed PL and AR story processing tasks. The PL version presented alternating 30-second blocks of stories and tones; the AR version presented story segments, comprehension questions, and 5-second tone sequences, with fMRI acquisitions between stimuli. fMRI data was analyzed using a general linear model approach and paired t-test identifying significant group activation. RESULTS: Both tasks showed activation in the primary auditory cortex, superior temporal gyrus bilaterally, and left inferior frontal gyrus (IFG). The AR task demonstrated more extensive activation, including the dorsolateral prefrontal cortex and anterior/posterior cingulate cortex. Comparison of effect size in each paradigm showed a larger effect for the AR paradigm in a left inferior frontal region-of-interest (ROI). CONCLUSION: Activation patterns for story processing in children are similar in PL and AR tasks. Increases in extent and magnitude of activation in the AR task are likely associated with memory and attention resources engaged across acquisition intervals.

Neural substrate differences in language networks and associated language-related behavioral impairments in children with TBI: a preliminary fMRI investigation.

The present study examined whether functional MRI (fMRI) can identify changes in the neural substrates of language in young children following traumatic brain injury (TBI). Eight children with TBI (F/M=3/5, age (Mean +/- SD)=7.98 +/- 1 years, range = 6-9 years) and a comparison group of nine children with orthopedic injuries (OI) (F/M=4/5, age (Mean +/- SD)=7.4 +/- 1 years, range=6-9 years) participated in an fMRI study of covert verb generation (VG). Results revealed significantly different BOLD signal activation in perisylvian language areas between the groups, after accounting for potential confounders such as verbal fluency and executive function. We also found significant associations between the BOLD signal activation and performance on language-specific neuropsychological tests (NEPSY verbal fluency score, Verbal IQ) and Glasgow Coma Scale (GCS) score. This study suggests that children with TBI have significantly different brain activation patterns in language circuitry compared to children with orthopedic injuries. Although we found clear differences in brain activation between the two groups, conventional MR images showed no evidence of structural abnormalities in five of eight children with TBI. Our study demonstrates the feasibility and potential utility of fMRI as a means of quantifying changes associated with language deficits in future pediatric TBI studies.

Functional MRI of language lateralization during development in children.

Changes in the distribution of language function in the brain have been documented from infancy through adulthood. Even macroscopic measures of language lateralization reflect a dynamic process of language development. In this review, we summarize a series of functional MRI studies of language skills in children ages of five to 18 years, both typically-developing children and children with brain injuries or neurological disorders that occur at different developmental stages with different degrees of severity. These studies used a battery of fMRI-compatible language tasks designed to tap sentential and lexical language skills that develop early and later in childhood. In typically-developing children, lateralization changes with age are associated with language skills that have a protracted period of development, reflecting the developmental process of skill acquisition rather than general maturation of the brain. Normative data, across the developmental period, acts as a reference for disentangling developmental patterns in brain activation from changes due to developmental or acquired abnormalities. This review emphasizes the importance of considering age and child development in neuroimaging studies of language.

Age-related connectivity changes in fMRI data from children listening to stories.

The way humans comprehend narrative speech plays an important part in human development and experience. A group of 313 children with ages 5-18 were subjected to a large-scale functional magnetic resonance imaging (fMRI) study in order to investigate the neural correlates of auditory narrative comprehension. The results were analyzed to investigate the age-related brain activity changes involved in the narrative language comprehension circuitry. We found age-related differences in brain activity which may either reflect changes in local neuroplasticity (of the regions involved) in the developing brain or a more global transformation of brain activity related to neuroplasticity. To investigate this issue, Structural Equation Modeling (SEM) was applied to the results obtained from a group independent component analysis (Schmithorst, V.J., Holland, S.K., et al., 2005. Cognitive modules utilized for narrative comprehension in children: a functional magnetic resonance imaging study. NeuroImage) and the age-related differences were examined in terms of changes in path coefficients between brain regions. The group Independent Component Analysis (ICA) had identified five bilateral task-related components comprising the primary auditory cortex, the mid-superior temporal gyrus, the most posterior aspect of the superior temporal gyrus, the hippocampus, the angular gyrus and the medial aspect of the parietal lobule (precuneus/posterior cingulate). Furthermore, a left-lateralized network (sixth component) was also identified comprising the inferior frontal gyrus (including Broca's area), the inferior parietal lobule, and the medial temporal gyrus. The components (brain regions) for the SEM were identified based on the ICA maps and the results are discussed in light of recent neuroimaging studies corroborating the functional segregation of Broca's and Wernicke's areas and the important role played by the right hemisphere in narrative comprehension. The classical Wernicke-Geschwind (WG) model for speech processing is expanded to a two-route model involving a direct route between Broca's and Wernicke's area and an indirect route involving the parietal lobe.