Anterior Insula Drives Progressive Structural Brain Network Atrophy in the Behavioural Variant of Frontotemporal Dementia

Patients with schizophrenia exhibit impairments in working memory that often appear in attenuated form in persons at high risk for the illness. The authors hypothesized that deviations in task-related brain activation and deactivation would occur in persons with an at-risk mental state performing a working memory task that entailed the maintenance and manipulation of letters. Participants at ultra high risk for developing psychosis (N=60), identified using the Comprehensive Assessment of At-Risk Mental States, and healthy comparison subjects (N=38) 14 to 29 years of age underwent functional MRI while performing a verbal working memory task. Group differences in brain activation were identified using analysis of covariance. The two groups did not show significant differences in speed or accuracy of performance, even after accounting for differences in education. Irrespective of task condition, at-risk participants exhibited significantly less activation than healthy comparison subjects in the left anterior insula. During letter manipulation, at-risk persons exhibited greater task-related deactivation within the default-mode network than comparison subjects. Region-of-interest analysis in the at-risk group revealed significantly greater right dorsolateral prefrontal cortex activation during manipulation of letters. Despite comparable behavioral performance, at-risk participants performing a verbal working memory task exhibited altered brain activation compared with healthy subjects. These findings demonstrate an altered pattern of brain activation in at-risk persons that contains elements of reduced function as well as compensation.

To investigate the effect of acupuncture on the brain functional activities of the patients with primary dysmenorrhea based on the resting-state functional magnetic resonance imaging (rs-fMRI), and to provide visual evidence for the central mechanism of acupuncture in treatment of primary dysmenorrhea. Forty-two patients of primary dysmenorrhea were enrolled and randomly divided into an observation group (21 cases, 1 case dropped off) and a control group (21 cases, 2 cases dropped off, 3 cases withdrawal). In the observation group, acupuncture was exerted at Sanyinjiao (SP 6) and Guanyuan (CV 4), started 5-7 days before menstrual flow, once a day till menstrual onset, for a total of 3 menstrual cycles. No intervention was applied in the control group. The scores of visual analogue scale (VAS) and Cox menstrual symptom scale (CMSS) were observed in both groups before and after treatment. Based on rs-fMRI, the data of resting-state functional magnetic resonance were collected from two groups before and after treatment. Combined with functional connectivity strength (FCS) and functional connectivity (FC) analysis, the differences of brain regions before and after treatment were compared between the two groups and the correlation was analyzed between their functional connectivity changes and the improvements in VAS and CMSS scores of the patients in the observation group. In the observation group, the scores of VAS and CMSS were all decreased after treatment (P<0.05), while the scores related to the symptom time in CMSS was reduced in comparison with that before treatment in the control group (P<0.05). The score reducing ranges of VAS and CMSS in the observation group were larger than the control group (P<0.05). Compared before treatment, FCS of the right middle cingulate cortex and the left cuneus was increased, while FCS of the left inferior parietal lobule was decreased after treatment in the observation group. In the control group, FCS of the left orbital frontal cortex was increased after treatment. Compared with the control group, FCS of the left anterior insula was increased in the observation group after treatment. FC analysis was performed using the left anterior insula as the seed point. In comparison with the control group, FC of the left anterior insula was increased either with the inferior temporal gyrus or with the right hippocampus; and was decreased either with the middle occipital lobe or with the right dorsolateral prefrontal cortex in the observation group after treatment. In the observation group, FC between the left anterior insula and the right hippocampus was positively correlated with the improvements in symptom severity (r =0.385, P<0.05) and symptom time (r =0.510, P<0.05) of CMSS, and FC between the right dorsolateral prefrontal cortex and the left anterior insula was negatively correlated with the improvement in symptom severity of CMSS after treatment (r =-0.373, P<0.05). The anterior insula may be the key brain region in treatment of primary dysmenorrhea with acupuncture. Acupuncture may relieve dysmenorrhea and the related symptoms through strengthening the functional connectivity of anterior insula-limbic system and anterior insula-control network.

The salience network is a distributed neural system that maintains homeostasis by regulating autonomic nervous system activity and social-emotional function. Here we examined how within-network connectivity relates to individual differences in human (including males and females) baseline parasympathetic and sympathetic nervous activity. We measured resting autonomic nervous system physiology in 24 healthy controls and 23 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease characterized by baseline autonomic deficits. Participants also underwent structural and task-free fMRI. First, we used voxel-based morphometry to determine whether salience network atrophy was associated with lower baseline respiratory sinus arrhythmia (a parasympathetic measure) and skin conductance level (a sympathetic measure) in bvFTD. Next, we examined whether functional connectivity deficits in 21 autonomic-relevant, salience network node-pairs related to baseline autonomic dysfunction. Lower baseline respiratory sinus arrhythmia was associated with smaller volume in left ventral anterior insula (vAI), weaker connectivity between bilateral vAI and bilateral anterior cingulate cortex (ACC), and stronger connectivity between bilateral ACC and bilateral hypothalamus/amygdala. Lower baseline skin conductance level, in contrast, was associated with smaller volume in inferior temporal gyrus, dorsal mid-insula, and hypothalamus; weaker connectivity between bilateral ACC and right hypothalamus/amygdala; and stronger connectivity between bilateral dorsal anterior insula and periaqueductal gray. Our results suggest that baseline parasympathetic and sympathetic tone depends on the integrity of lateralized salience network hubs (left vAI for parasympathetic and right hypothalamus/amygdala for sympathetic) and highly calibrated ipsilateral and contralateral network connections. In bvFTD, deficits in this system may underlie resting parasympathetic and sympathetic disruption.SIGNIFICANCE STATEMENT The salience network maintains homeostasis and regulates autonomic nervous system activity. Whether within-network connectivity patterns underlie individual differences in resting parasympathetic and sympathetic nervous system activity, however, is not well understood. We measured baseline autonomic nervous system activity in healthy controls and patients with behavioral variant frontotemporal dementia, a neurodegenerative disease characterized by resting autonomic deficits, and probed how salience network dysfunction relates to diminished parasympathetic and sympathetic outflow. Our results indicate that baseline parasympathetic and sympathetic tone are the product of complex, opposing intranetwork nodal interactions and depend on the integrity of highly tuned, lateralized salience network hubs (i.e., left ventral anterior insula for parasympathetic activity and right hypothalamus/amygdala for sympathetic activity).

Objective To provide a basic profile of resting-state functional connectivity (FC) in unmedicated patients with major depressive disorder (MDD). Methods Fifty unmedicated patients with MDD and 51 healthy controls underwent the resting-state functional magnetic resonance imaging (rs-fMRI). After preprocessing of rs-fMRI, the seed-based resting-state FC of the insular subdivisions, including the anterior insula, middle insula, and posterior insula, was evaluated. Two-sample t-test and multiple comparison correction of Threshold-Free Cluster Enhancement (TFCE) were used to compare the FC values of each group to locate the regions with significant change, where its correlation to the Hamilton Depression Scale (HAMD24) scores was also explored. Results In comparison to the healthy controls, the MDD patients decreased FC between the left anterior insula and bilateral anterior cingulate cortices (t=-4.83, P<0.05, TFCE correction), and increased FC between the left anterior insula and the left middle frontal gyrus, as well as the bilateral posterior cingulate cortices/precuneus (t=4.08, 4.42; both P<0.05, TFCE correction). There were no significant correlations between the HAMD24 scores and the FC values from the left anterior insula to the bilateral anterior cingulate cortices (r=-0.125, P=0.387), the left middle frontal gyrus (r=0.149, P=0.302), and the bilateral posterior cingulate cortices/precuneus (r=-0.207, P=0.148). Conclusion Patients with depression have abnormal functional connectivity between the left anterior insula and the other two regions, such as the limbic system and the frontal cortex, which may present with an aweakened insula-anterior cingulate gyrus connectivity, and the enhanced insular-frontal, and insula-posterior cingulate/precuneus connectivity. Key words: Depressive disorder; Magnetic resonance imaging; Cerebral cortex

Two insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA

On Altered Patterns of Brain Activation in At-Risk Adolescents and Young Adults

Background: There is growing evidence supporting behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS) as extreme points of a disease spectrum. The aim of this study was to delineate the common and different patterns of gray matter atrophy associated with bvFTD and with ALS by pooling together the results of previous voxel-based morphometry (VBM) studies.Methods: We retrieved VBM studies that investigated gray matter atrophy in bvFTD patients vs. controls and in ALS patients vs. controls. Stereotactic data were extracted from those studies and subsequently tested for convergence and differences using activation likelihood estimation (ALE). A behavioral analysis using the BrainMap database was performed to assess the functional roles of the regions affected by bvFTD and/or ALS.Results: Our study demonstrated a convergence of gray matter atrophy in the frontolimbic structures that involve the bilateral anterior insula and anterior cingulate cortex. Comparing the pattern of GM atrophy in bvFTD and ALS patients revealed greater atrophy in the frontomedial cortex, bilateral caudate, left anterior insula, and right thalamus in those with bvFTD and a higher degree of atrophy in the right motor cortex of those with ALS. Behavioral analysis revealed that the pattern of the affected regions contributed to the dysfunction of emotional and cognitive processing in bvFTD patients and the dysfunction of motor execution in ALS patients.Conclusion: Our results revealed a shared neural basis between bvFTD and ALS subjects, as well as a specific and distinct neural signature that underpinned the clinical manifestations of those two diseases. Those findings outlined the role of the frontomedial-caudate circuit in the development of bvFTD-like deficits in ALS patients.

Orbitofrontal metabolic impairment is characteristic of the frontal variant of frontotemporal dementia (fv-FTD), as are early changes in emotional and social conduct. Two main types of behavioral disturbances have been distinguished in fv-FTD patients: apathetic and disinhibited manifestations. In this study, we searched for relationships between brain metabolism and presence of apathetic or disinhibited behavior. Metabolic activity and behavioral data were collected in 41 fv-FTD patients from European PET centers. A conjunction analysis of the PET data showed an expected impairment of metabolic activity in the anterior cingulate, ventromedial and orbital prefrontal cortex, the dorsolateral prefrontal cortex and the left anterior insula in fv-FTD subjects compared to matched controls. A correlation was observed between disinhibition scores on the Neuropsychiatric Inventory scale and a cluster of voxels located in the posterior orbitofrontal cortex (6, 28, –24). Comparison of brain activity between apathetic and nonapathetic fv-FTD patients from two centers also revealed a specific involvement of the posterior orbitofrontal cortex in apathetic subjects (4, 22, –22). The results confirm that the main cerebral metabolic impairment in fv-FTD patients affects areas specializing in emotional evaluation and demonstrate that decreased orbitofrontal activity is related to both disinhibited and apathetic syndromes in fv-FTD.

(156) Differences in regional gray-matter density between fibromyalgia patients and controls: A voxel-based morphometry study

Chronic pain of different aetiologies and localization has been associated with less grey matter volume (GMV) in several cortical and subcortical brain areas. Recent meta-analyses reported low reproducibility of GMV alterations between studies and pain syndromes. To investigate GMV in common chronic pain conditions defined by body location (chronic back pain, n = 174; migraine, n = 92; craniomandibular disorder, n = 39) compared to controls (n = 296), we conducted voxel-based morphometry and determined GMV from high-resolution cranial MRIs obtained in an epidemiologic survey. Mediation analyses were performed between the presence of chronic pain and GMV testing the mediators stress and mild depression. The predictability of chronic pain was investigated with binomial logistic regression. Whole-brain analyses yielded reduced GMV within the left anterior insula and the anterior cingulate cortex, for a ROI approach additionally the left posterior insula and left hippocampus showing less GMV across all patients with chronic pain. The relationship of pain with GMV in the left hippocampus was mediated by self-reported stressors in the last 12 months. Binomial logistic regression revealed a predictive effect for GMV in the left hippocampus and left anterior insula/temporal pole for the presence of chronic pain. Chronic pain across three different pain conditions was characterized by less GMV in brain regions consistently described for different chronic pain conditions before. Less GMV in the left hippocampus mediated by experienced stress during the last year might be related to altered pain learning mechanisms in chronic pain patients. Grey matter reorganization could serve as a diagnostic biomarker for chronic pain. In a large cohort, we here replicated findings of less grey matter volume across three pain conditions in the left anterior and posterior insula, anterior cingulate and left hippocampus. Less hippocampal grey matter was mediated by experienced stress.

Regions affected late in neurodegenerative disease are thought to be anatomically connected to regions affected earlier. The subcallosal medial prefrontal cortex (SMPC) has connections with the dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), and hippocampus (HC), which are regions that may become atrophic in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). We hypothesized that the SMPC is a common site of frontal atrophy in the FTLD subtypes and in AD. The volume of the SMPC, DLPFC, OFC, HC, and entorhinal cortex (EC) were manually delineated for 12 subjects with frontotemporal dementia (FTD), 13 with semantic dementia (SD), 9 with progressive nonfluent aphasia (PNFA), 10 AD cases, and 13 controls. Results revealed significant volume loss in the left SMPC in FTD, SD, and PNFA, while the right SMPC was also atrophied in SD and FTD. In AD a non significant tendency of volume loss in the left SMPC was found (p = 0.08), with no volume loss on the right side. Results indicated that volume loss reflected the degree of brain connectivity. In SD and AD temporal regions displayed most atrophy. Among the frontal regions, the SMPC (which receives the strongest temporal projections) demonstrated most volume loss, the OFC (which receives less temporal projections) less volume loss, while the DLPFC (which is at multisynaptic distance from the temporal regions) demonstrated no volume loss. In PNFA, the left SMPC was atrophic, possibly reflecting progression from the left anterior insula, while FTD patients may have had SMPC atrophy at the initial stages of the disease. Atrophy of the SMPC may thus be affected by either initial temporal or initial frontal atrophy, making it a common site of frontal atrophy in the dementia subtypes investigated.

BackgroundStudies exploring topological properties of the metabolic network during the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce. However, such knowledge is important for understanding brain function and disease pathogenesis. Therefore, we aimed to explore FTD-specific patterns of metabolism topology reconfiguration in microtubule-associated protein tau (MAPT) mutation carriers before the onset of symptoms.MethodsSix asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who all belonged to the same family of FTD. For comparison, we included 32 behavioral variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and a hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) scan. Voxel-wise gray matter volumes and standardized uptake value ratios were calculated and compared for structural MRI and fluorodeoxyglucose (FDG)-PET, separately. The sparse inverse covariance estimation method (SICE) was applied to topological properties and metabolic connectomes of brain functional networks derived from 18F-FDG PET/MRI data. Independent component analysis was used to explore the metabolic connectivity of the salience (SN) and default mode networks (DMN).ResultsThe asymptomatic MAPT carriers performed normal global parameters of the metabolism network, whereas bvFTD patients did not. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers compared with non-carriers, which overlapped with the comparisons between bvFTD patients and controls. Similarly, significant differences in local parameters of these nodes were present between asymptomatic carriers and non-carriers. The reduction in the connectivity of lost hub regions and the enhancement of connectivity between reconfigured hubs and components of the frontal cortex were marked during the asymptomatic stage. Metabolic connectivity within the SN and DMN was enhanced in asymptomatic carriers compared with non-mutation carriers but reduced in bvFTD patients relative to controls.ConclusionsOur findings showed that metabolism topology reconfiguration, characterized by the earliest involvement of medial prefrontal areas and active compensation in task-related regions, was present in the presymptomatic phase of genetic FTD with MAPT mutation, which may be used as an imaging biomarker of increased risk of FTD.

Damage to left frontal regulatory circuits produces greater positive emotional reactivity in frontotemporal dementia

ObjectivesFunctional magnetic resonance imaging (fMRI) has unveiled how many foods and basic rewards are processed, but imaging has not been widely used to investigate stimulation of solid foods, like steak, due to safety and quality issues that can arise. Resting state fMRI scans allow for administration of a stimulus before scanning, and literature has shown resting state networks reflect functional connectivity between brain regions. Resting state scans show connected regions by evaluating downstream effects of neural connectivity that are correlated to other regions of interest. We believe that hedonic circuits will be activated while eating steak, similar to other rewards. The objective of this experiment was to evaluate functional connectivity after consuming different qualities of steak.Materials and MethodsResting state scans of trained participants (n = 8) were taken prior to, directly after, and an extended time (25 to 30 minutes) after receiving high or low quality steak samples. Participants were re-scanned on a separate day, when they were fed the other quality steak. Blood oxygen level dependant imaging displayed hemodynamic fluctuation through the brain during fMRI procedures. Initial images were taken in the scanner before consumption. Participants left the scanning room to eat their sample, and marked a 152.4 mm anchored visual analog scale (VAS) at any point along the line as a subjective evaluation of tenderness, juiciness, flavor, and overall liking. The VAS was anchored as terrible, very poor, poor, fair, good, very good, and excellent at 0, 25.4, 50.8, 76.2, 101.6, 127.0, and 152.4 mm, respectively. After re-entry scans were taken as soon as possible, then participants cleansed their palates in a separate room before a final resting state scan was taken. Analysis of fMRI data was conducted using fMRI Expert Analysis Tool. A priori analysis investigated connectivity to the right and left amygdala, as well as the right and left anterior insula. Analysis of VAS data was conducted using SAS (SAS Inst. Inc., Cary, NC).ResultsImaging data showed that high quality steak resulted in greater functional connectivity between the left and right anterior insula as well as the left and right amygdala to the striatum, medial orbitofrontal cortex, and insular cortex directly after consumption (P ≥ 0.05). There was also greater functional connectivity between the left and right anterior insula as well as the left and right amygdala to the striatum, orbitofrontal cortex, and hippocampus an extended time after consumption (P ≤ 0.05). High quality steak was perceived superior for each palatability trait, having mean VAS measurements of 140.46, 134.37, 142.75, and 139.19, for tenderness, juiciness, flavor, and overall liking, respectively. Low quality steak had mean VAS measurements of 49.28, 49.53, 49.02, and 52.58, for tenderness, juiciness, flavor, and overall liking, respectively (P ° 0.01).ConclusionThese results suggest that resting state fMRI may be useful for evaluating neural processes following sensory experience, paprticularly steak consumption. We observed variation in functional connectivity of steak, due to quality. This novel technique has potential to bring about new methods of sensory evaluation for meat products that incorporate use of neuroimaging. This research adds knowledge and understanding to many areas of study about neural responses to hedonic stimuli.

Studies of visual-spatial attention typically use instructional cues to direct attention to a relevant location, but in everyday vision, attention is often focused volitionally, in the absence of external signals. Although investigations of cued attention comprise hundreds of behavioral and physiological studies, remarkably few studies of voluntary attention have addressed the challenging question of how spatial attention is initiated and controlled in the absence of external instructions, which we refer to as willed attention. To explore this question, we employed a trial-by-trial spatial attention task using electroencephalography and functional magnetic resonance imaging (fMRI). The fMRI results reveal a unique network of brain regions for willed attention that includes the anterior cingulate cortex, left middle frontal gyrus (MFG), and the left and right anterior insula (AI). We also observed two event-related potentials (ERPs) associated with willed attention; one with a frontal distribution occurring 250-350 ms postdecision cue onset (EWAC: Early Willed Attention Component), and another occurring between 400 and 800 ms postdecision-cue onset (WAC: Willed Attention Component). In addition, each ERP component uniquely correlated across subjects with different willed attention-specific sites of BOLD activation. The EWAC was correlated with the willed attention-specific left AI and left MFG activations and the later WAC was correlated only with left AI. These results offer a comprehensive and novel view of the electrophysiological and anatomical profile of willed attention and further illustrate the relationship between scalp-recorded ERPs and the BOLD response.