Imminent cognitive decline in normal elderly individuals is associated with hippocampal hyperconnectivity in the variant neural correlates of episodic memory.

The secondary prevention trials of Alzheimer's disease (AD) require an enrichment strategy to recruit individuals with imminent cognitive decline at the preclinical stage. Previously, we demonstrated a variant neural correlates of episodic memory (EM) function in apolipoprotein E (APOE) ε4 carriers. Herein, we investigated whether this variation was associated with longitudinal EM performance. This 3-year longitudinal study included 88 normal elderly subjects with EM assessment and resting-state functional MRI data at baseline; 48 subjects (27 ε3 homozygotes and 21 ε4 carriers) underwent follow-up EM assessment. In the identified EM neural correlates, multivariable regression models examined the association between hippocampal functional connectivity (HFC) and longitudinal EM change. Independent validation was performed using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. At baseline, the EM neural correlates were characterized in the Papez circuit regions in the ε3 homozygotes, but in the sensorimotor cortex and cuneus in the ε4 carriers. Longitudinally, the ε4 carriers exhibited a negative association of the baseline HFC strength in the EM neural correlates with annual rate of EM change (R2 = 0.25, p = 0.05). This association also showed a trend in the ADNI dataset (R2 = 0.42, p = 0.06). These results indicate that hippocampal hyperconnectivity in the variant EM neural correlates is associated with imminent EM decline in ε4 carriers, which may serve as a promising enrichment strategy for secondary prevention trials of AD.

Amygdala Functional Connectivity Features in Grief: A Pilot Longitudinal Study.

OBJECTIVE: Acute grief, in an important minority of older adults, can become protracted, intense, and debilitating, leading to the development of complicated grief (CG). However, the neurobiologic mechanisms underlying a maladaptive grief response after an attachment loss are unknown. The current study aimed to examine the amygdala brain network features that cross-sectionally explain the symptom variance and longitudinally relate to grief symptom trajectories after an attachment loss. METHODS: Baseline amygdala functional connectivity (Fc) was assessed using a seed-based resting-state functional magnetic resonance imaging method in 35 adults who were within 1-year after death of a loved one and 21 healthy comparison (HC) participants. Magnetic resonance imaging scans were obtained at baseline, and clinical assessments, including the inventory of complicated grief (ICG) were completed at weeks 0, 8, 16, and 26 (endpoint). RESULTS: Relative to HC participants, grief participants showed increased amygdala Fc in the posterior default mode (bilateral medial temporal lobes and left precuneus) and thalamus. Amygdala Fc in the default mode and ventral affective regions positively correlated with ICG scores at baseline. Furthermore, increased baseline amygdala functional connections with the dorsal frontal executive control and salience network regions correlated with worsening ICG scores over time. These longitudinal findings persisted after controlling for covariates, including baseline depressive and anxiety symptoms. CONCLUSION: These results provide novel preliminary evidence suggesting amygdala-based brain network measures to cross-sectionally explain symptom variance and longitudinally correlate with grief symptom trajectories in grievers. Amygdala brain network function measures may have the potential to serve as biomarkers of CG.

Interplay of spinal and vagal pathways on esophageal acid-related anterior cingulate cortex functional networks in rats.

Esophageal acid sensory signals are transmitted by both vagal and spinal pathways to the cerebral cortex. The influence and interplay of these pathways on esophageal acid-related functional connectivity has been elusive. Our aim was to evaluate the esophageal acid exposure-related effect on the anterior cingulate cortex (ACC) functional connectivity networks using functional MRI-guided functional connectivity MRI (fcMRI) analysis. We studied six Sprague-Dawley rats for fcMRI experiments under dexmedetomidine hydrochloride anesthesia. Each rat was scanned for 6 min before and after esophageal hydrochloric acid infusion (0.1 N, 0.2 ml/min). The protocol was repeated before and after bilateral cervical vagotomy on the same rat. Seed-based fcMRI analysis was used to examine ACC networks and acid-induced network alterations. Three-factor repeated-measures ANOVA analysis among all four subgroups revealed that the interaction of acid infusion and bilateral vagotomy was mainly detected in the hypothalamus, insula, left secondary somatosensory cortex, left parietal cortex, and right thalamus in the left ACC network. In the right ACC network, this interaction effect was detected in the caudate putamen, insula, motor, primary somatosensory cortex, secondary somatosensory cortex, and thalamic regions. These regions in the ACC networks showed decreased intranetwork connectivity due to acid infusion. However, after bilateral vagotomy, intranetwork connectivity strength inversed and became stronger following postvagotomy acid infusion. Signals transmitted through both the vagal nerve and spinal nerves play a role in esophageal acid-related functional connectivity of the ACC. The vagal signals appear to dampen the acid sensation-related functional connectivity of the ACC networks. NEW & NOTEWORTHY These studies show that esophageal acid-induced brain functional connectivity changes are vagally mediated and suggest that signals transmitted through both the vagal nerve and spinal nerves play a role in esophageal acid-related functional connectivity of the anterior cingulate cortex. This paper focuses on the development of a novel rat functional MRI model fostering improved understanding of acid-related esophageal disorders.

Neuroanatomical correlates of personality traits in temporal lobe epilepsy: Findings from the Epilepsy Connectome Project.

Behavioral and personality disorders in temporal lobe epilepsy (TLE) have been a topic of interest and controversy for decades, with less attention paid to alterations in normal personality structure and traits. In this investigation, core personality traits (the Big 5) and their neurobiological correlates in TLE were explored using the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) and structural magnetic resonance imaging (MRI) through the Epilepsy Connectome Project (ECP). NEO-FFI scores from 67 individuals with TLE (34.6 ±â€¯9.5 years; 67% women) were compared to 31 healthy controls (32.8 ±â€¯8.9 years; 41% women) to assess differences in the Big 5 traits (agreeableness, openness, conscientiousness, neuroticism, and extraversion). Individuals with TLE showed significantly higher neuroticism, with no significant differences on the other traits. Neural correlates of neuroticism were then determined in participants with TLE including cortical and subcortical volumes. Distributed reductions in cortical gray matter volumes were associated with increased neuroticism. Subcortically, hippocampal and amygdala volumes were negatively associated with neuroticism. These results offer insight into alterations in the Big 5 personality traits in TLE and their brain-related correlates.

Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease.

The apolipoprotein E (APOE) ϵ4 allele is a confirmed genetic risk factor and the APOE ϵ2 allele is a protective factor related to late-onset Alzheimer's disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations between APOE ϵ2 and ϵ4 alleles, despite their opposite susceptibilities to AD. To address this apparent discrepancy, we recruited 129 cognitively normal elderly subjects, including 36 ϵ2 carriers, 44 ϵ3 homozygotes, and 49 ϵ4 carriers. All subjects underwent resting-state functional MRI scans. We hypothesized that aging could influence the APOE ϵ2 and ϵ4 allele effects that contribute to their appropriate AD risks differently. Using the stepwise regression analysis, we demonstrated that although both ϵ2 and ϵ4 carriers showed decreased functional connectivity (FC) compared with ϵ3 homozygotes, they have opposite aging trajectories in the default mode network-primarily in the bilateral anterior cingulate cortex. As age increased, ϵ2 carriers showed elevated FC, whereas ϵ4 carriers exhibited decreased FC. Behaviorally, the altered DMN FC positively correlated with information processing speed in both ϵ2 and ϵ4 carriers. It is suggested that the opposite aging trajectories between APOE ϵ2 and ϵ4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.

FMRI and fcMRI phenotypes map the genomic effect of chromosome 13 in Brown Norway and Dahl salt-sensitive rats.

Genes have been implicated as major contributors to many biological traits and susceptibility to specific diseases. However, the mechanisms of genotype action on central nervous system function have been elusive. It has been previously observed that inbred Brown Norway (BN) rats exhibit a number of quantitative complex traits markedly different from those of inbred Dahl salt-sensitive (SS) rats. These strains have become so important to cardiovascular research that a novel chromosome substitution approach was used to create SS and BN strains that have a single chromosome replaced by the homologous chromosome of the other strain. The present study was conducted in an effort to evaluate whether fMRI neuroimaging measures could be employed as a phenotype of genetic influence on neural biology in SS, BN, and consomic SSBN13 rat strains. Electrical forepaw stimulation evoked robust differential BOLD-fMRI activation along the thalamocortical pathway among the three strains across different stimulus frequencies. Moreover, using the fMRI-guided seeds in thalamus and somatosensory cortex for the analysis of fcMRI, we were able to characterize the strain-specific difference in secondary somatosensory cortex, temporal association cortex, and the CA3 region. We were also able to define the genetic influences of Chr-13 on the projection and integration of sensory information in consomic SS-13(BN) strain. We provided objective imaging evidence supporting the hypothesis that rat strain-specific fMRI and fcMRI combined with consomic strategy can be a useful tool in identifying the complex genetic divergence that is related to neural circuits. These findings prove the concept of neuroimaging-based phenotypes as a novel approach to visualize and fine-map the genetic effects onto brain biology at a systems level.

Functional connectivity of the cortical swallowing network in humans.

INTRODUCTION: Coherent fluctuations of blood oxygenation level dependent (BOLD) signal have been referred to as "functional connectivity" (FC). Our aim was to systematically characterize FC of underlying neural network involved in swallowing, and to evaluate its reproducibility and modulation during rest or task performance. METHODS: Activated seed regions within known areas of the cortical swallowing network (CSN) were independently identified in 16 healthy volunteers. Subjects swallowed using a paradigm driven protocol, and the data analyzed using an event-related technique. Then, in the same 16 volunteers, resting and active state data were obtained for 540 s in three conditions: 1) swallowing task; 2) control visual task; and 3) resting state; all scans were performed twice. Data was preprocessed according to standard FC pipeline. We determined the correlation coefficient values of member regions of the CSN across the three aforementioned conditions and compared between two sessions using linear regression. Average FC matrices across conditions were then compared. RESULTS: Swallow activated twenty-two positive BOLD and eighteen negative BOLD regions distributed bilaterally within cingulate, insula, sensorimotor cortex, prefrontal and parietal cortices. We found that: 1) Positive BOLD regions were highly connected to each other during all test conditions while negative BOLD regions were tightly connected among themselves; 2) Positive and negative BOLD regions were anti-correlated at rest and during task performance; 3) Across all three test conditions, FC among the regions was reproducible (r>0.96, p<10(-5)); and 4) The FC of sensorimotor region to other regions of the CSN increased during swallowing scan. CONCLUSIONS: 1) Swallow activated cortical substrates maintain a consistent pattern of functional connectivity; 2) FC of sensorimotor region is significantly higher during swallow scan than that observed during a non-swallow visual task or at rest.

Assessing breast cancer angiogenesis in vivo: which susceptibility contrast MRI biomarkers are relevant?

PURPOSE: There is an impending need for noninvasive biomarkers of breast cancer angiogenesis to evaluate the efficacy of new anti-angiogenic therapies in vivo. The purpose of this study was to systematically evaluate the sensitivity of in vivo steady-state susceptibility contrast-MRI biomarkers of angiogenesis in a human breast cancer model. METHODS: Orthotopic MDA-MB-231 human breast cancer xenografts were imaged by steady-state susceptibility contrast-MRI at post-inoculation week 3 and post-inoculation week 5, followed by ex vivo whole tumor 3D micro-CT angiography. "Absolute" (i.e., measures of vascular morphology in appropriate units) and "relative" (i.e., proportional to measures of vascular morphology) MRI biomarkers of tumor blood volume, vessel size, and vessel density were computed and their ability to predict the corresponding micro-CT analogs assessed using cross-validation analysis. RESULTS: All MRI biomarkers significantly correlated with their micro-CT analogs and were sensitive to the micro-CT-measured decreases in tumor blood volume and vessel density from post-inoculation week 3 to post-inoculation week 5. However, cross-validation analysis revealed there was no significant difference between the predictive accuracy of "absolute" and "relative" biomarkers. CONCLUSION: As "relative" biomarkers are more easily computed from steady-state susceptibility contrast-MRI (i.e., without additional MRI measurements) than "absolute" biomarkers, it makes them promising candidates for assessing breast cancer angiogenesis in vivo.

Differential effects of deep sedation with propofol on the specific and nonspecific thalamocortical systems: a functional magnetic resonance imaging study.

BACKGROUND: The current state of knowledge suggests that disruption of neuronal information integration may be a common mechanism of anesthetic-induced unconsciousness. A neural system critical for information integration is the thalamocortical system whose specific and nonspecific divisions may play the roles for representing and integrating information, respectively. How anesthetics affect the function of these systems individually is not completely understood. The authors studied the effect of propofol on thalamocortical functional connectivity in the specific and nonspecific systems, using functional magnetic resonance imaging. METHODS: Eight healthy volunteers were instructed to listen to and encode 40 English words during wakeful baseline, light sedation, deep sedation, and recovery in the scanner. Functional connectivity was determined as the temporal correlation of blood oxygen level-dependent signals with seed regions defined within the specific and nonspecific thalamic nuclei. RESULTS: Thalamocortical connectivity at baseline was dominantly medial and bilateral frontal and temporal for the specific system, and medial frontal and medial parietal for the nonspecific system. During deep sedation, propofol reduced functional connectivity by 43% (specific) and 79% (nonspecific), a significantly greater reduction in the nonspecific than in the specific system and in the left hemisphere than in the right. Upon regaining consciousness, functional connectivity increased by 58% (specific) and 123% (nonspecific) during recovery, exceeding their values at baseline. CONCLUSIONS: Propofol conferred differential changes in functional connectivity of the specific and nonspecific thalamocortical systems, particularly in left hemisphere, consistent with the verbal nature of stimuli and task. The changes in nonspecific thalamocortical connectivity may correlate with the loss and return of consciousness.

Adaptive Kalman filtering for real-time mapping of the visual field.

This paper demonstrates the feasibility of real-time mapping of the visual field for clinical applications. Specifically, three aspects of this problem were considered: (1) experimental design, (2) statistical analysis, and (3) display of results. Proper experimental design is essential to achieving a successful outcome, particularly for real-time applications. A random-block experimental design was shown to have less sensitivity to measurement noise, as well as greater robustness to error in modeling of the hemodynamic impulse response function (IRF) and greater flexibility than common alternatives. In addition, random encoding of the visual field allows for the detection of voxels that are responsive to multiple, not necessarily contiguous, regions of the visual field. Due to its recursive nature, the Kalman filter is ideally suited for real-time statistical analysis of visual field mapping data. An important feature of the Kalman filter is that it can be used for nonstationary time series analysis. The capability of the Kalman filter to adapt, in real time, to abrupt changes in the baseline arising from subject motion inside the scanner and other external system disturbances is important for the success of clinical applications. The clinician needs real-time information to evaluate the success or failure of the imaging run and to decide whether to extend, modify, or terminate the run. Accordingly, the analytical software provides real-time displays of (1) brain activation maps for each stimulus segment, (2) voxel-wise spatial tuning profiles, (3) time plots of the variability of response parameters, and (4) time plots of activated volume.

A clustering-based method to detect functional connectivity differences.

Recently, resting-state functional magnetic resonance imaging (R-fMRI) has emerged as a powerful tool for investigating functional brain organization changes in a variety of neurological and psychiatric disorders. However, the current techniques may need further development to better define the reference brain networks for quantifying the functional connectivity differences between normal and diseased subject groups. In this study, we introduced a new clustering-based method that can clearly define the reference clusters. By employing group difference information to guide the clustering, the voxels within the reference clusters will have homogeneous functional connectivity changes above predefined levels. This method identified functional clusters that were significantly different between the amnestic mild cognitively impaired (aMCI) and age-matched cognitively normal (CN) subjects. The results indicated that the distribution of the clusters and their functionally disconnected regions resembled the altered memory network regions previously identified in task fMRI studies. In conclusion, the new clustering method provides an advanced approach for studying functional brain organization changes associated with brain diseases.

Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment.

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimer's disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.

Reproducibility of swallow-induced cortical BOLD positive and negative fMRI activity.

Functional MRI (fMRI) studies have demonstrated that a number of brain regions (cingulate, insula, prefrontal, and sensory/motor cortices) display blood oxygen level-dependent (BOLD) positive activity during swallow. Negative BOLD activations and reproducibility of these activations have not been systematically studied. The aim of our study was to investigate the reproducibility of swallow-related cortical positive and negative BOLD activity across different fMRI sessions. We studied 16 healthy volunteers utilizing an fMRI event-related analysis. Individual analysis using a general linear model was used to remove undesirable signal changes correlated with motion, white matter, and cerebrospinal fluid. The group analysis used a mixed-effects multilevel model to identify active cortical regions. The volume and magnitude of a BOLD signal within each cluster was compared between the two study sessions. All subjects showed significant clustered BOLD activity within the known areas of cortical swallowing network across both sessions. The cross-correlation coefficient of percent fMRI signal change and the number of activated voxels across both positive and negative BOLD networks were similar between the two studies (r ≥ 0.87, P < 0.0001). Swallow-associated negative BOLD activity was comparable to the well-defined "default-mode" network, and positive BOLD activity had noticeable overlap with the previously described "task-positive" network. Swallow activates two parallel cortical networks. These include a positive and a negative BOLD network, respectively, correlated and anticorrelated with swallow stimulus. Group cortical activity maps, as well as extent and amplitude of activity induced by volitional swallowing in the cortical swallowing network, are reproducible between study sessions.

A method to determine the necessity for global signal regression in resting-state fMRI studies.

In resting-state functional MRI studies, the global signal (operationally defined as the global average of resting-state functional MRI time courses) is often considered a nuisance effect and commonly removed in preprocessing. This global signal regression method can introduce artifacts, such as false anticorrelated resting-state networks in functional connectivity analyses. Therefore, the efficacy of this technique as a correction tool remains questionable. In this article, we establish that the accuracy of the estimated global signal is determined by the level of global noise (i.e., non-neural noise that has a global effect on the resting-state functional MRI signal). When the global noise level is low, the global signal resembles the resting-state functional MRI time courses of the largest cluster, but not those of the global noise. Using real data, we demonstrate that the global signal is strongly correlated with the default mode network components and has biological significance. These results call into question whether or not global signal regression should be applied. We introduce a method to quantify global noise levels. We show that a criteria for global signal regression can be found based on the method. By using the criteria, one can determine whether to include or exclude the global signal regression in minimizing errors in functional connectivity measures.

Ventral striatal subregional dysfunction in late-life grief: Relationships with yearning and depressive symptoms.

Bereaved older adults experiencing high grief in the first year after an attachment loss is at increased risk for prolonged grief disorder (PGD) via unknown mechanisms. Yearning, a core grief symptom, is linked to the ventral striatal (VS) brain function, but the role of this neuronal system in late-life grief is poorly understood. As a first step, we examined the VS subregional abnormalities associated with multidimensional symptoms in bereaved elders during the first year post-loss. Sixty-five bereaved elders completed clinical assessments within 13 months post-loss. Ventral caudate (VCau) and nucleus accumbens (NAcc) functional connectivity (FC) was assessed using seed-based resting-state functional MRI. VCau and NAcc FC differences between high (inventory of complicated grief [ICG] score≥30; n = 35) and low (ICG score<30; n = 30) grief, and the relationships between ventral striatal subregional FC and clinical measures (yearning and depressive symptoms) were assessed after covariate adjustments (α < 0.05; 3dClustSim corrected). Relative to low grief participants, those with high grief showed higher FC between VCau and the medial prefrontal, orbitofrontal, and subgenual cingulate cortices. VCau FC abnormalities positively correlated with yearning (r2 = 0.24, p < 0.001). In contrast, FC between VCau and temporoparietal junction negatively correlated with depressive symptoms, a commonly co-occurring symptom (r2 = 0.37, p < 0.001). The FC between NAcc and insula/striatum positively correlated with yearning (r2 = 0.35, p < 0.001); no other NAcc FC findings were seen in the full sample. In women, higher FC between the NAcc and bilateral posterior cingulate, precuneus, and visual areas were found in those with high, relative to low grief symptoms. Distinct VS subregional abnormalities associate with yearning and depressive symptoms in bereaved elders. Whether ventral striatal dysfunction correlates with PGD development and/or worsening depression remains to be elucidated.

Classification of Alzheimer disease, mild cognitive impairment, and normal cognitive status with large-scale network analysis based on resting-state functional MR imaging.

PURPOSE: To use large-scale network (LSN) analysis to classify subjects with Alzheimer disease (AD), those with amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) subjects. MATERIALS AND METHODS: The study was conducted with institutional review board approval and was in compliance with HIPAA regulations. Written informed consent was obtained from each participant. Resting-state functional magnetic resonance (MR) imaging was used to acquire the voxelwise time series in 55 subjects with clinically diagnosed AD (n = 20), aMCI (n =15), and normal cognitive function (n = 20). The brains were divided into 116 regions of interest (ROIs). The Pearson product moment correlation coefficients of pairwise ROIs were used to classify these subjects. Error estimation of the classifications was performed with the leave-one-out cross-validation method. Linear regression analysis was performed to analyze the relationship between changes in network connectivity strengths and behavioral scores. RESULTS: The area under the receiver operating characteristic curve (AUC) yielded 87% classification power, 85% sensitivity, and 80% specificity between the AD group and the non-AD group (subjects with aMCI and CN subjects) in the first-step classification. For differentiation between subjects with aMCI and CN subjects, AUC was 95%; sensitivity, 93%; and specificity, 90%. The decreased network indexes were significantly correlated with the Mini-Mental State Examination score in all tested subjects. Similarly, changes in network indexes significantly correlated with Rey Auditory Verbal Leaning Test delayed recall scores in subjects with aMCI and CN subjects. CONCLUSION: LSN analysis revealed that interconnectivity patterns of brain regions can be used to classify subjects with AD, those with aMCI, and CN subjects. In addition, the altered connectivity networks were significantly correlated with the results of cognitive tests.

Recovery of hippocampal network connectivity correlates with cognitive improvement in mild Alzheimer's disease patients treated with donepezil assessed by resting-state fMRI.

PURPOSE: To identify the neural correlates of cognitive improvement in mild Alzheimer's disease (AD) subjects following 12 weeks of donepezil treatment. MATERIALS AND METHODS: Resting-state functional connectivity magnetic resonance imaging (R-fMRI) was used to measure the hippocampal functional connectivity (HFC) in 14 mild AD and 18 age-matched normal (CN) subjects. AD subjects were scanned at baseline and after donepezil treatment. CN subjects were scanned only at baseline as a reference to identify regions correlated or anticorrelated to the hippocampus. Before each scan, participants underwent cognitive, behavioral, and functional assessments. RESULTS: After donepezil treatment, neural correlates of cognitive improvement measured by Mini-Mental State Examination scores were identified in the left parahippocampus, dorsolateral prefrontal cortex (DLPFC), and inferior frontal gyrus. Improvement in AD Assessment Scale-cognitive subscale scores correlated with the HFC changes in the left DLPFC and middle frontal gyrus. Stronger recovery in the network connectivity was associated with cognitive improvement. CONCLUSION: R-fMRI may provide novel insights into the brain's responses to AD treatment in clinical pharmacological trials, and also may predict clinical response.

Enhancing effects of flavored nutritive stimuli on cortical swallowing network activity.

A better understanding of the central control of the physiology of deglutition is necessary for devising interventions aimed at correcting pathophysiological conditions of swallowing. Positive modulation of the cortical swallowing network can have clinical ramifications in dysphagia due to central nervous system deficits. Our aim was to determine the effect of nutritive sensory input on the cortical swallowing network. In 14 healthy right-handed volunteers, we utilized a paradigm-driven protocol to quantify the number of activated voxels and their signal intensity within the left hemispheric cortical swallowing network by high-resolution functional MRI (fMRI) during five different swallowing conditions. Swallowing conditions included a dry swallow (saliva) and natural water-, lemon-, popcorn-, and chocolate-flavored liquid swallows. Each flavored liquid was presented simultaneously by its image, scent, and taste in random order and tested over three runs. fMRIs were analyzed in a blinded fashion. Average fMRI blood oxygenation level-dependent signal intensity and number of activated voxels during swallowing concurrent with nutritive gustatory, olfactory, and visual stimulations were significantly increased compared with dry/natural water swallows throughout the cortical swallowing network (P < 0.001 and P < 0.05, respectively). Subregion analysis showed the increased activity for flavored liquids in prefrontal, cingulate gyrus, and sensory/motor cortex, but not in precuneus and insula. Concurrent gustatory, olfactory, and visual nutritive stimulation enhances the activity of the cortical swallowing network. This finding may have clinical implications in management of swallowing disorders due to cortical lesions.

Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly.

The apolipoprotein E (APOE) ε4 and ε2 alleles are acknowledged genetic factors modulating Alzheimer's disease (AD) risk and episodic memory (EM) deterioration in an opposite manner. Mounting neuroimaging studies describe EM-related brain activity differences among APOE alleles but remain limited in elucidating the underlying mechanism. Here, we hypothesized that the APOE ε2, ε3, and ε4 alleles have distinct EM neural substrates, as a manifestation of degeneracy, underlying their modulations on EM-related brain activity and AD susceptibility. To test the hypothesis, we identified neural correlates of EM function by correlating intrinsic hippocampal functional connectivity networks with neuropsychological EM performances in a voxelwise manner, with 129 cognitively normal elderly subjects (36 ε2 carriers, 44 ε3 homozygotes, and 49 ε4 carriers). We demonstrated significantly different EM neural correlates among the three APOE allele groups. Specifically, in the ε3 homozygotes, positive EM neural correlates were characterized in the Papez circuit regions; in the ε4 carriers, positive EM neural correlates involved the lateral temporal cortex, premotor cortex/sensorimotor cortex/superior parietal lobule, and cuneus; and in the ε2 carriers, negative EM neural correlates appeared in the bilateral frontopolar, posteromedial, and sensorimotor cortex. Further, in the ε4 carriers, the interaction between age and EM function occurred in the temporoparietal junction and prefrontal cortex. Our findings suggest that the underlying mechanism of APOE polymorphism modulations on EM function and AD susceptibility is genetically related to the neural degeneracy of EM function across APOE alleles.

Predicting progression from mild cognitive impairment to Alzheimer's disease on an individual subject basis by applying the CARE index across different independent cohorts.

The purposes of this study are to investigate whether the Characterizing Alzheimer's disease Risk Events (CARE) index can accurately predict progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) on an individual subject basis, and to investigate whether this model can be generalized to an independent cohort. Using an event-based probabilistic model approach to integrate widely available biomarkers from behavioral data and brain structural and functional imaging, we calculated the CARE index. We then applied the CARE index to identify which MCI individuals from the ADNI dataset progressed to AD during a three-year follow-up period. Subsequently, the CARE index was generalized to the prediction of MCI individuals from an independent Nanjing Aging and Dementia Study (NADS) dataset during the same time period. The CARE index achieved high prediction performance with 80.4% accuracy, 75% sensitivity, 82% specificity, and 0.809 area under the receiver operating characteristic (ROC) curve (AUC) on MCI subjects from the ADNI dataset over three years, and a highly validated prediction performance with 87.5% accuracy, 81% sensitivity, 90% specificity, and 0.861 AUC on MCI subjects from the NADS dataset. In conclusion, the CARE index is highly accurate, sufficiently robust, and generalized for predicting which MCI individuals will develop AD over a three-year period. This suggests that the CARE index can be usefully applied to select individuals with MCI for clinical trials and to identify which individuals will convert from MCI to AD for administration of early disease-modifying treatment.