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Regulations limiting the sale of flavored e-cigarette products are controversial for their potential to interfere with e-cigarette use as a cessation aid in addition to curbing youth use. Limited research suggests that flavor might enhance the addictive potential of e-cigarettes; however, the acute effects of flavored aerosols on brain function among humans have not been assessed. The present study aimed to isolate and compare the neural substrates of flavored and unflavored e-cigarette aerosols on brain function among nine female daily smokers. Participants inhaled aerosolized e-liquid with 36 mg/mL of nicotine with and without a strawberry-vanilla flavor while undergoing functional magnetic resonance imaging. We used general linear modeling to compare whole-brain mean neural activation and seed-to-voxel task-based functional connectivity between the flavored and unflavored inhalation runs. Contrary to our hypothesis, the flavored aerosol was associated with weaker activation than the unflavored aerosol in the brain stem and bilateral parietal-temporal-occipital region of the cortex. Instead, the flavor engaged taste-related brain regions while suppressing activation of the neural circuits typically engaged during smoking and nicotine administration. Alternatively, functional connectivity between subcortical dopaminergic brain seeds and cortical brain regions involved in motivation and reward salience were stronger during the flavored compared to unflavored aerosol run. The findings suggest that fruity and dessert-flavored e-cigarettes may dampen the reward experience of aerosol inhalation for smokers who initiate e-cigarette use by inhibiting activation of dopaminergic brain circuits. These preliminary findings may have implications for understanding how regulations on flavored e-cigarettes might impact their use as cessation aids. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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.

Local susceptibility variations result in B0 field inhomogeneities, causing distortions and signal losses in MR imaging. Susceptibility variations become stronger with increasing B0 magnetic field strength. Active shimming is used to generate corrective magnetic fields, which can be used to improve B0 field homogeneity. FASTMAP is an effective shimming technique for computing optimal coil currents, which uses data from six projection directions (or columns): this technique is routinely used for shimming cubic volumes of interest (VOIs). In this paper, we propose several improvements to FASTMAP at 4T. For each shim coil, using a modified 3D gradient-echo pulse sequence, we compute B0 inhomogeneity maps and project them onto eight 1st and 2nd order spherical harmonic functions. This process is repeated for shim currents between -15,000 to 15,000 with increments of 5000 Digital to Analog Converter (DAC) units, and is used to compute the gradient between spherical harmonic coefficients and DAC values for all 8 shim coils—along with the R2 values of linear fits. A method is proposed (based on R2 values) to further refine optimal shim currents in respective coils. We present an analysis that is numerically robust and completely flexible in the selection of the VOIs for shimming. Performance analyses, phantom results, and in vivo results of a human brain are presented, comparing our methods with the FASTMAP method.

ObjectiveDetermine the neural basis of olfactory impairment in akinetic-rigid (PDAR) and tremor predominant (PDT) Parkinson’s disease subtypes.MethodsWe combined resting-state fMRI (rs-fMRI) with seed based functional connectivity (FC) in order to delineate the olfactory network’s functional connectivity (ON FC) between PDAR and PDT patients. We then contrasted their ON FC patterns with cognitively normal (CN) subjects. All three groups were closely matched in age, demographic variables, and adjusted for relative cognitive performance. Olfactory function was measured using the University of Pennsylvania Smell Identification Test (UPSIT).ResultsUPSIT scores were lower in akinetic-rigid vs tremor subtypes; ON FC values were lower in PDAR compared to PDT and CN, and followed the trend observed in UPSIT scores. UPSIT scores and ON FC values were significantly correlated, reflecting the effects of PD pathologies.ConclusionsThe results show that olfactory function differs between PDAR and PDT suggesting a correlation between PD-related motor symptoms and olfactory deficits. ON FC differences accounts for the impaired olfactory functions observed between PDAR and PDT. PDAR is known to have worse clinical outcomes and faster cognitive decline compared to PDT; therefore, PD-related olfactory dysfunction may serve as a novel metric for enhancing PD prognosis.

Humans naturally integrate signals from the olfactory and intranasal trigeminal systems. A tight interplay has been demonstrated between these two systems, and yet the underlying neural circuitry that mediates olfactory-trigeminal integration remains poorly understood. Using functional magnetic resonance imaging (fMRI), combined with psychophysics, this study investigated the neural mechanisms underlying olfactory-trigeminal 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, relative to air-puff localization without concomitant PEA 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, except the OFC, 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.HIGHLIGHTSPsychophysical and neuroimaging study of olfactory-mechanosensory (OM) integrationBehavior, cortical activity and network connectivity show OM integrationOM integration obeys principles of inverse effectiveness and spatial coincidenceBehavioral and neural measures of OM integration are correlated

Cerebellar involvement in Alzheimer’s disease (AD) has not been studied to the extent that cortical neuropathological changes have. Historical and recent histopathological literature demonstrate cerebellar AD pathology while functional investigation has demonstrated disrupted intrinsic cortical – cerebellar connectivity in AD. Additionally, olfactory deficits occur early in AD, prior to the onset of clinical symptoms. The neurological basis for the involvement of the cerebellum and olfactory system in the disease course remain unclear. 18F-fludeoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed to characterize metabolism in the cerebellum and olfactory region of AD, mild-cognitive impaired (MCI), and age-matched cognitively normal (CN) controls. In contrast to known parietal and temporal lobe FDG hypo-metabolism within the default mode network in AD, a significant FDG hyper-metabolism was found in the cerebellum and olfactory cortical regions (including the piriform cortex, olfactory tubercle, anterior olfactory nucleus, and nucleus accumbens shell). The increase in cerebellum glucose utilization was shown also in late- verses early-MCI patients. The cerebellar and olfactory regions both contain inhibitory distal and inter-neuronal connections that are vulnerable to disruption in AD. The hyper-metabolism in the cerebellum and olfactory structures may reflect disruption of local and system-wide inhibitory networks due to AD neurodegeneration, suggesting a hypothetical mechanism for susceptibility of the olfactory system to early AD pathology.

Brain networks for intranasal chemosensation have been shown to be intrinsically organized in humans [1]. However, little is known about how changes in the intrinsic functional connectivity (FC) in chemosensory networks are related to aging. We, therefore, investigated the impact of age on resting state functional connectivity in the olfactory and trigeminal networks (ON and TN) by combining two freely available resting state fMRI data sets (obtained from the NITRC.org; Atlanta and New York) with data collected in our lab to generate a large sample size (N=103; 51 females) spanning the age range of 20–61 years. Seed regions were defined using MNI coordinates that anchor olfactory and trigeminal networks in activation studies and meta-analyses. The olfactory network (ON) included the piriform cortex and oribtofrontal cortex. The trigeminal network (TN) included the anterior insula and cingulate cortex. Scanner site, sex, and age were used as covariates in group level analyses. The FC between the ON and parahippocampal gyrus was negatively correlated with age. The FC between the TN and parahippocampal gyrus, however, was positively correlated. Similarly, age was positively correlated with the ON FC to the ventral striatum, and the TN FC to the default mode network (DMN). These results reflect divergent age-related alterations of the intrinsic FC of the human chemosensory system.

BACKGROUND Olfactory deficits are present in early Alzheimer's disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing. OBJECTIVE This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD. METHODS We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD subjects using olfactory fMRI with an odor-visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition). RESULTS The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p

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.

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.

Purpose To evaluate the dynamic characteristics of T2* -weighted signal change in exercising skeletal muscle of healthy subjects and peripheral artery disease (PAD) patients under a low-intensity exercise paradigm. Materials and Methods Nine PAD patients and nine age- and sex-matched healthy volunteers underwent a low-intensity exercise paradigm while magnetic resonance imaging (MRI) (3.0T) was obtained. T2*-weighted signal time-courses in lateral gastrocnemius, medial gastrocnemius, soleus, and tibialis anterior were acquired and analyzed. Correlations were performed between dynamic T2*-weighted signal and changes in heart rate, mean arterial pressure, leg pain, and perceived exertion. Results A significant signal decrease was observed during exercise in soleus and tibialis anterior of healthy participants (P = 0.0007–0.04 and 0.001–0.009, respectively). In PAD, negative signals were observed (P = 0.008–0.02 and 0.003–0.01, respectively) in soleus and lateral gastrocnemius during the early exercise stage. Then the signal gradually increased above the baseline in the lateral gastrocnemius during and after exercise in six of the eight patients who completed the study. This signal increase in patients' lateral gastrocnemius was significantly greater than in healthy subjects' during the later exercise stage (two-sample t-tests, P = 0.001–0.03). Heart rate and mean arterial pressure responses to exercise were significantly higher in PAD than healthy subjects (P = 0.036 and 0.008, respectively) and the patients experienced greater leg pain and exertion (P = 0.006 and P = 0.0014, respectively). Conclusion During low-intensity exercise, there were different dynamic T2*-weighted signal behavior in the healthy and PAD exercising muscles. Level of Evidence 2 J. Magn. Reson. Imaging 2016;00:000–000

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.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.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.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.

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 co-stimulation on the perception of intranasal somatosensory stimulation. In this study, twenty-two healthy human subjects, with normal olfactory function, performed a localization task for weak air-puff stimuli, in the presence or absence of a pure odorant, phenyl ethyl alcohol (PEA; rose odor). 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, when accompanied by 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 nostril. Since ipsilateral but not contralateral co-stimulation 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 the olfactory and somatosensory trigeminal systems.

Background Olfactory deficits are prevalent in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). These symptoms precede clinical onset of cognitive and memory deficits and coincide with AD pathology preferentially in the central olfactory structures, suggesting a potential biomarker for AD early detection and progression. Objective Therefore, we tested the hypothesis that structural degeneration of the primary olfactory cortex (POC) could be detected in AD as well as in MCI patients and would be correlated with olfactory functional magnetic resonance imaging (fMRI) alterations, reflecting loss of olfactory cortex activity. Methods Total structural volumes and fMRI activation volumes of the POC and hippocampus were measured along with olfactory and cognitive behavioral tests in 27 cognitively normal (CN), 21 MCI, and 15 AD subjects. Results Prominent atrophy in the POC and hippocampus was found in both AD and MCI subjects and correlated with behavioral measurements. While behavioral and volumetric measurements showed a gradual decline from CN to MCI to AD, olfactory activation volume in the POC and hippocampus showed a steeper decline in the MCI group compared to corresponding tissue volume, resembling the AD group. Conclusions Decline in olfactory activity was correlated with the AD structural degeneration in the POC. A more prominent olfactory activity deficit than that of behavioral and tissue volume measurements was shown in the MCI stage. Olfactory fMRI may thus provide an earlier and more sensitive measure of functional neurodegeneration in AD and MCI patients.

The study of human olfaction is complicated by the myriad of processing demands in conscious perceptual and emotional experiences of odors. Combining functional magnetic resonance imaging with convergent multivariate network analyses, we examined the spatiotemporal behavior of olfactory-generated blood-oxygenated-level-dependent signal in healthy adults. The experimental functional magnetic resonance imaging (fMRI) paradigm was found to offset the limitations of olfactory habituation effects and permitted the identification of five functional networks. Analysis delineated separable neuronal circuits that were spatially centered in the primary olfactory cortex, striatum, dorsolateral prefrontal cortex, rostral prefrontal cortex/anterior cingulate, and parietal-occipital junction. We hypothesize that these functional networks subserve primary perceptual, affective/motivational, and higher order olfactory-related cognitive processes. Results provided direct evidence for the existence of parallel networks with top-down modulation for olfactory processing and clearly distinguished brain activations that were sniffing-related versus odor-related. A comprehensive neurocognitive model for olfaction is presented that may be applied to broader translational studies of olfactory function, aging, and neurological disease.

Purpose To elucidate differences in the disruption of language network function, as measured by blood oxygenation level-dependent (BOLD) contrast functional MRI (fMRI), attributable to two common sedative agents administered to infants under clinical imaging protocols. Materials and Methods The sedatives pentobarbital (Nembutal) and Propofol, administered clinically to infants at 1 year of age, were compared with respect to BOLD activation profiles in response to passive story-listening stimulation. An intermittent event-related imaging protocol was used with which the temporal evolution of language processing resulting from this stimulation was explored. Results Propofol and Nembutal were found to have distinct and complementary responses to story-listening. Propofol exhibited more activation in higher processing networks with increasing response toward the end of narrative stimulus. Nembutal, in contrast, had much more robust activation of primary and secondary sensory cortices but a decreasing response over time in fronto-parietal default-mode regions. This may suggest a breakdown of top-down feedback for Propofol versus the lack of bottom-up feed-forward processing for Nembutal. Conclusion Two popular sedative agents for use in children for clinical fMRI were found to induce distinct alteration of activation patterns from a language stimulus. This has ramifications for clinical fMRI of sedated infants and encourages further study to build a framework for more confident interpretation. J. Magn. Reson. Imaging 2013;38:1184–1195. © 2013 Wiley Periodicals, Inc.

Blood‐oxygen‐level‐dependent magnetic resonance imaging (BOLD MRI) has the potential to quantify skeletal muscle oxygenation with high temporal and high spatial resolution. The purpose of this study was to characterize skeletal muscle BOLD responses during steady‐state plantar flexion exercise (i.e., during the brief rest periods between muscle contraction). We used three different imaging modalities (ultrasound of the popliteal artery, BOLD MRI, and near‐infrared spectroscopy [NIRS]) and two different exercise intensities (2 and 6 kg). Six healthy men underwent three separate protocols of dynamic plantar flexion exercise on separate days and acute physiological responses were measured. Ultrasound studies showed the percent change in popliteal velocity from baseline to the end of exercise was 151 ± 24% during 2 kg and 589 ± 145% during 6 kg. MRI studies showed an abrupt decrease in BOLD signal intensity at the onset of 2 kg exercise, indicating deoxygenation. The BOLD signal was further reduced during 6 kg exercise (compared to 2 kg) at 1 min (−4.3 ± 0.7 vs. −1.2 ± 0.4%, P

Semantic association, an essential element of human language, enables discourse and inference. Neuroimaging studies have revealed localization and lateralization of semantic circuitry, making substantial contributions to cognitive neuroscience. However, because of methodological limitations, these investigations have only identified individual functional components rather than capturing the behavior of the entire network. To overcome these limitations, we have implemented group independent component analysis (ICA) to investigate the cognitive modules used by healthy adults performing the fMRI semantic decision task. When compared with the results of a standard general linear modeling (GLM) analysis, ICA detected several additional brain regions subserving semantic decision. Eight task-related group ICA maps were identified, including left inferior frontal gyrus (BA44/45), middle posterior temporal gyrus (BA39/22), angular gyrus/inferior parietal lobule (BA39/40), posterior cingulate (BA30), bilateral lingual gyrus (BA18/23), inferior frontal gyrus (L>R, BA47), hippocampus with parahippocampal gyrus (L>R, BA35/36), and anterior cingulate (BA32/24). Although most of the components were represented bilaterally, we found a single, highly left-lateralized component that included the inferior frontal gyrus and the medial and superior temporal gyri, the angular and supramarginal gyri, and the inferior parietal cortex. The presence of these spatially independent ICA components implies functional connectivity and can be equated with their modularity. These results are analyzed and presented in the framework of a biologically plausible theoretical model in preparation for similar analyses in patients with right- or left-hemispheric epilepsies.

The ability to process an aurally-presented story is supported by a network of auditory and language-processing brain regions (2-5) that changes during development (6,7). Multiple aspects of language processing are engaged during this naturalistic speech task, including speech perception, word recognition, syntactic processing and discourse coherence. Consequently, this task has been cited as one method for effectively mapping eloquent cortical areas (3,4). In patients undergoing resective surgery, language lateralization information is particularly important, with the goal of using non-invasive functional MRI to replace the invasive and risky intracarotid amobarbital procedure (Wada test). A number of studies (8-10)have demonstrated the ability of fMRI to detect the expected left-lateralized activation pattern associated with in typically-developing children. In addition, fMRI has revealed changes in lateralization associated with neuropathology (11,12). However, a standard paradigm optimized for clinical use in the pediatric population has not been established. In the present study, we investigate two versions of the story processing task that are potentially effective procedures for determining language lateralization and localization in children. Previous fMRI studies have examined the neural basis of story processing in children, using a block-periodic, passive listening (PL) design contrasting short stories with tone sequences (7,13,14). These studies were based on data from a large group of children (313) ages 5−18. Results revealed areas of activation in superior temporal gyrus and superior frontal gyrus (bilaterally), and left posterior superior temporal gyrus. Independent components analysis of the same data (ICA) revealed additional activation in angular gyrus together with the precuneus, posterior cingulate, left inferior parietal lobule and inferior frontal gyrus in addition to the regions mentioned above (7). ICA reveals additional areas of activation compared to standard fMRI analysis using model driven methods because it is a data-driven approach that does not rely on a model of the hemodynamic response function to detect changes in BOLD response(15). One drawback associated with the PL story comprehension task is that no on-line measure of task performance is collected. The studies described above (7,13,14) made use of a post-scan comprehension test on which 87% of participants performed above chance level, suggesting that a majority of children were actively engaged in story comprehension. However, this does not address the accuracy of participant's comprehension during the fMRI scan, nor their level of attention to the stimuli. Young pediatric participants, some of whom require sedation to undergo an MRI procedure, may not be capable of actively generating responses to language stimuli. A passive listening task has already been demonstrated to activate bilateral auditory processing areas in such patients (16). Therefore, examining whether passive listening and active-response tasks evoke similar activation patterns, especially in children, is relevant for application of fMRI in these patients. Continuous fMRI scanning throughout the passive listening task generates acoustic noise that may interfere with participants’ comprehension of the stories. This may also make the identification of task-related activation patterns more difficult due to the presence of background noise (17-19). Schmidt et al. (19) compared BOLD activation in response to identical auditory sentence stimuli tested during continuous fMRI scanning versus sparse fMRI acquisition, and found increased levels of BOLD response in superior temporal regions with the sparse acquisition technique, suggesting that this technique may be more sensitive for detecting activation associated with auditory language stimuli. The present study examines these issues by comparing the PL story paradigm to an active-response (AR) version that includes on-line performance monitoring and utilizes a clustered fMRI acquisition technique that eliminates scanner noise during auditory presentation (20,21). Our goal in developing the AR task was to potentially improve upon the PL version of the task as much as possible since it is regularly used in the clinical setting.

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.

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.

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.

Complex physiological signals are neither deterministic nor random, showing a mixture of long-range dependencies and irregularities (i.e., information) over multiple time scales. In humans, aging and pathology are associated with diminished CNS neurophysiological complexity and impaired cognition. In this study, we computed multiscale entropy (MSE) to measure the time scale dependent complexity (i.e., information) of the resting state BOLD fMRI signal in humans over a large age span (N=138; ages 8-83; 58 male). Physiological noise (heart rate, respiration, head motion and local white matter [WM] signals) was removed from fMRI time courses using linear regression. Data were then bandpass filtered (.008-.1 Hz) to isolate low frequency fluctuations. MSE was computed with parameters m=2 and r=.2 for temporal scales 1-18. BOLD signal in gray matter (GM) and WM gained information with increasing temporal scale and exceeded the information gain from bandpass filtered white and 1/f noise. GM sustained the informa...

The study of human olfaction is complicated by the myriad of processing demands in conscious perceptual and emotional experiences of odors. Combining functional magnetic resonance imaging with convergent multivariate network analyses, we examined the spatiotemporal behavior of olfactory-generated blood-oxygenated-level-dependent signal in healthy adults. The experimental functional magnetic resonance imaging (fMRI) paradigm was found to offset the limitations of olfactory habituation effects and permitted the identification of five functional networks. Analysis delineated separable neuronal circuits that were spatially centered in the primary olfactory cortex, striatum, dorsolateral prefrontal cortex, rostral prefrontal cortex/anterior cingulate, and parietal-occipital junction. We hypothesize that these functional networks subserve primary perceptual, affective/motivational, and higher order olfactory-related cognitive processes. Results provided direct evidence for the existence of parallel networks with top-down modulation for olfactory processing and clearly distinguished brain activations that were sniffing-related versus odor-related. A comprehensive neurocognitive model for olfaction is presented that may be applied to broader translational studies of olfactory function, aging, and neurological disease.

To elucidate differences in the disruption of language network function, as measured by blood oxygenation level-dependent (BOLD) contrast functional MRI (fMRI), attributable to two common sedative agents administered to infants under clinical imaging protocols.The sedatives pentobarbital (Nembutal) and Propofol, administered clinically to infants at 1 year of age, were compared with respect to BOLD activation profiles in response to passive story-listening stimulation. An intermittent event-related imaging protocol was used with which the temporal evolution of language processing resulting from this stimulation was explored.Propofol and Nembutal were found to have distinct and complementary responses to story-listening. Propofol exhibited more activation in higher processing networks with increasing response toward the end of narrative stimulus. Nembutal, in contrast, had much more robust activation of primary and secondary sensory cortices but a decreasing response over time in fronto-parietal default-mode regions. This may suggest a breakdown of top-down feedback for Propofol versus the lack of bottom-up feed-forward processing for Nembutal.Two popular sedative agents for use in children for clinical fMRI were found to induce distinct alteration of activation patterns from a language stimulus. This has ramifications for clinical fMRI of sedated infants and encourages further study to build a framework for more confident interpretation.

Functional MRI mapping of language areas in children frequently employs a covert verb generation task. Because responses are not monitored, the relationship between fMRI activation and task performance is unknown. We compared fMRI activation during covert and overt verb generation to performance during the overt task. 15 children, ages 11-13 years, listened to concrete nouns and responded with related verbs covertly and overtly. A clustered fMRI acquisition allowed for recording of overt responses without motion artifacts. Region of interest analysis was also performed in areas that exhibited correlation between activation and performance during overt verb generation in left inferior frontal and left superior temporal gyri (along with their right hemisphere homologues). Regression analysis determined that during both covert and overt generation, left hemisphere regions showed positive correlations with average counts of verbs generated during the overt task. These results suggest that increased verb generation performance leads to increased activation. In addition, overt performance may be used as an estimator of covert performance.

Human language is a complex and protean cognitive ability. Young children, following well defined developmental patterns learn language rapidly and effortlessly producing full sentences by the age of 3 years. However, the language circuitry continues to undergo significant neuroplastic changes extending well into teenage years. Evidence suggests that the developing brain adheres to two rudimentary principles of functional organization: functional integration and functional specialization. At a neurobiological level, this distinction can be identified with progressive specialization or focalization reflecting consolidation and synaptic reinforcement of a network (Lenneberg 1967; Muller, Rothermel et al. 1998; Berl, Vaidya et al. 2006). In this paper, we used group Independent Component Analysis (ICA) and linear structural equation modeling (LSEM) (McIntosh and Gonzalez-Lima 1994; Karunanayaka, Holland et al. 2007) to tease out the developmental trajectories of the language circuitry based on fMRI data from 336 children ages 5-18 years performing a blocked, covert-verb generation task. The results are analyzed and presented in the framework of theoretical models for neurocognitive brain development. This study highlights the advantages of combining both modular and connectionist approaches to cognitive functions; from a methodological perspective, it demonstrates the feasibility of combining data driven and hypothesis driven techniques to investigate the developmental shifts in the semantic network.

Chronic and progressive brain injury, as seen in epilepsy, may alter brain networks that underlie cognitive functions. To evaluate the effect of epilepsy on language functions we investigated the neuroanatomical basis of semantic processing in patients with left (LHE) or right (RHE) hemispheric onset epilepsy using semantic decision fMRI paradigm and group independent component analysis (ICA); we then compared the results of our investigations with language networks in healthy subjects examined with the same language task (Kim K, Karunanayaka P, Privitera M, Holland S, Szaflarski J. Semantic association investigated with fMRI and independent component analysis. In press). Group ICA is a data-driven technique capable of revealing the functional organization of the human brain based on fMRI data. In addition to providing functional connectivity information, ICA can also provide information about the temporal dynamics of underlying networks subserving specific cognitive functions. In this study, we implemented two complementary analyses to investigate group differences in underlying network dynamics based on associated independent component (IC) time courses (a priori defined criterion or a posteriori identified maximum likelihood descriptor). We detected several differences between healthy controls and patients with epilepsy not previously observed with standard fMRI analysis methods. Our analyses confirmed the presence of different effects of LHE or RHE on the behavior of the language network. In particular, a major difference was noted in the nodes subserving verbal encoding and retrieval in the bilateral medial temporal regions. These effects were dependent on the side of the epilepsy onset; that is, effects were different with left or right hemispheric epilepsy. These findings may explain the differences in verbal and nonverbal memory abilities between patients with left and those with right hemispheric epilepsy. Further, although the effects on other nodes of the network were more subtle, several deviations from normal network function were observed in patients with LHE (e.g., alterations in the functions of the primarily left frontotemporal network module) or in patients with RHE (e.g., differences in the medial retrosplenial module responsible for mental imagery or in the anterior cingulate module subserving attention control). These findings not only highlight the negative effects of epilepsy on the main left hemispheric language network nodes in patients with LHE, but also document the effects of epilepsy on other language network nodes whether exerted by LHE or RHE. Further, these results document the advantages of using group ICA for investigating the effects of disease state (e.g., epilepsy) on the network subserving cognitive processing and provide an interesting avenue for further exploration.

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.