Multimodal Neuroimaging Measures Research Articles

Early life adversity in primates: Behavioral, endocrine, and neural effects

BackgroundEvidence suggests that early life adversity is associated with maladaptive behaviors and is commonly an antecedent of stress-related psychopathology. This is particularly relevant to rearing in primate species as infant primates depend on prolonged, nurturant rearing by caregivers for normal development. To further understand the consequences of early life rearing adversity, and the relation among alterations in behavior, physiology and brain function, we assessed young monkeys that had experienced maternal separation followed by peer rearing with behavioral, endocrine and multimodal neuroimaging measures. Methods50 young rhesus monkeys were studied, half of which were rejected by their mothers and peer reared, and the other half were reared by their mothers. Assessments were performed at approximately 1.8 years of age and included: threat related behavioral and cortisol responses, cerebrospinal fluid (CSF) measurements of oxytocin and corticotropin releasing hormone (CRH), and multimodal neuroimaging measures (anatomical scans, resting functional connectivity, diffusion tensor imaging, and threat-related regional glucose metabolism). ResultsThe results demonstrated alterations across behavioral, endocrine, and neuroimaging measures in young monkeys that were reared without their mothers. At a behavioral level in response to a potential threat, peer reared animals engaged in significantly less freezing behavior (p = 0.022) along with increased self-directed behaviors (p < 0.012). Levels of oxytocin in the CSF, but not plasma, were significantly reduced in the peer reared animals (p = 0.019). No differences in plasma cortisol or CSF CRH were observed. Diffusion tensor imaging revealed significantly decreased white matter density across the brain. Exploratory correlational and permutation analyses suggest that the impact of peer rearing on behavior, endocrine and brain structural alterations are mediated by separate parallel mechanisms. ConclusionsTaken together, these results demonstrate in NHPs the importance of maternal rearing on the development of brain, behavior and hormonal systems that are linked to social functioning and adaptive responses. The findings suggest that the effects of maternal deprivation are mediated via multiple independent pathways which may account for the heterogeneity in behavioral and biological alterations observed in individuals that have experienced this early life adversity.

The curse and opportunity of heterogeneity in the pursuit of psychiatric biomarkers.

The curse and opportunity of heterogeneity in the pursuit of psychiatric biomarkers.

A critical role of brain network architecture in a continuum model of autism spectrum disorders spanning from healthy individuals with genetic liability to individuals with ASD

Studies have shown cortical alterations in individuals with autism spectrum disorders (ASD) as well as in individuals with high polygenic risk for ASD. An important addition to the study of altered cortical anatomy is the investigation of the underlying brain network architecture that may reveal brain-wide mechanisms in ASD and in polygenic risk for ASD. Such an approach has been proven useful in other psychiatric disorders by revealing that brain network architecture shapes (to an extent) the disorder-related cortical alterations. This study uses data from a clinical dataset—560 male subjects (266 individuals with ASD and 294 healthy individuals, CTL, mean age at 17.2 years) from the Autism Brain Imaging Data Exchange database, and data of 391 healthy individuals (207 males, mean age at 12.1 years) from the Pediatric Imaging, Neurocognition and Genetics database. ASD-related cortical alterations (group difference, ASD-CTL, in cortical thickness) and cortical correlates of polygenic risk for ASD were assessed, and then statistically compared with structural connectome-based network measures (such as hubs) using spin permutation tests. Next, we investigated whether polygenic risk for ASD could be predicted by network architecture by building machine-learning based prediction models, and whether the top predictors of the model were identified as disease epicenters of ASD. We observed that ASD-related cortical alterations as well as cortical correlates of polygenic risk for ASD implicated cortical hubs more strongly than non-hub regions. We also observed that age progression of ASD-related cortical alterations and cortical correlates of polygenic risk for ASD implicated cortical hubs more strongly than non-hub regions. Further investigation revealed that structural connectomes predicted polygenic risk for ASD (r = 0.30, p < 0.0001), and two brain regions (the left inferior parietal and left suparmarginal) with top predictive connections were identified as disease epicenters of ASD. Our study highlights a critical role of network architecture in a continuum model of ASD spanning from healthy individuals with genetic risk to individuals with ASD. Our study also highlights the strength of investigating polygenic risk scores in addition to multi-modal neuroimaging measures to better understand the interplay between genetic risk and brain alterations associated with ASD.

Anterior default mode network and posterior insular connectivity is predictive of depressive symptom reduction following serial ketamine infusion.

Ketamine is a rapidly-acting antidepressant treatment with robust response rates. Previous studies have reported that serial ketamine therapy modulates resting state functional connectivity in several large-scale networks, though it remains unknown whether variations in brain structure, function, and connectivity impact subsequent treatment success. We used a data-driven approach to determine whether pretreatment multimodal neuroimaging measures predict changes along symptom dimensions of depression following serial ketamine infusion. Patients with depression (n = 60) received structural, resting state functional, and diffusion MRI scans before treatment. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17), the Inventory of Depressive Symptomatology (IDS-C), and the Rumination Response Scale (RRS) before and 24 h after patients received four (0.5 mg/kg) infusions of racemic ketamine over 2 weeks. Nineteen unaffected controls were assessed at similar timepoints. Random forest regression models predicted symptom changes using pretreatment multimodal neuroimaging and demographic measures. Two HDRS-17 subscales, the HDRS-6 and core mood and anhedonia (CMA) symptoms, and the RRS: reflection (RRSR) scale were predicted significantly with 19, 27, and 1% variance explained, respectively. Increased right medial prefrontal cortex/anterior cingulate and posterior insula (PoI) and lower kurtosis of the superior longitudinal fasciculus predicted reduced HDRS-6 and CMA symptoms following treatment. RRSR change was predicted by global connectivity of the left posterior cingulate, left insula, and right superior parietal lobule. Our findings support that connectivity of the anterior default mode network and PoI may serve as potential biomarkers of antidepressant outcomes for core depressive symptoms.

Neural mechanisms of modulations of empathy and altruism by beliefs of others' pain.

Perceived cues signaling others' pain induce empathy which in turn motivates altruistic behavior toward those who appear suffering. This perception-emotion-behavior reactivity is the core of human altruism but does not always occur in real-life situations. Here, by integrating behavioral and multimodal neuroimaging measures, we investigate neural mechanisms underlying modulations of empathy and altruistic behavior by beliefs of others' pain (BOP). We show evidence that lack of BOP reduces subjective estimation of others' painful feelings and decreases monetary donations to those who show pain expressions. Moreover, lack of BOP attenuates neural responses to their pain expressions within 200 ms after face onset and modulates neural responses to others' pain in the insular, post-central, and frontal cortices. Our findings suggest that BOP provide a cognitive basis of human empathy and altruism and unravel the intermediate neural mechanisms.

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study

IntroductionWe aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia. MethodsThe study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. ResultsCompared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02). ConclusionsEarly cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.

The diagnostic potential of multimodal neuroimaging measures in Parkinson's disease and atypical parkinsonism.

IntroductionFor the diagnosis of Parkinson's disease (PD) and atypical parkinsonism (AP) using neuroimaging, structural measures have been largely employed since structural abnormalities are most noticeable in the diseases. Functional abnormalities have been known as well, though less clearly seen, and thus, the addition of functional measures to structural measures is expected to be more informative for the diagnosis. Here, we aimed to assess whether multimodal neuroimaging measures of structural and functional alterations could have potential for enhancing performance in diverse diagnostic classification problems.MethodsFor 77 patients with PD, 86 patients with AP comprising multiple system atrophy and progressive supranuclear palsy, and 53 healthy controls (HC), structural and functional MRI data were collected. Gray matter (GM) volume was acquired as a structural measure, and GM regional homogeneity and degree centrality were acquired as functional measures. The measures were used as predictors individually or in combination in support vector machine classifiers for different problems of distinguishing between HC and each diagnostic type and between different diagnostic types.ResultsIn statistical comparisons of the measures, structural alterations were extensively seen in all diagnostic types, whereas functional alterations were limited to specific diagnostic types. The addition of functional measures to the structural measure generally yielded statistically significant improvements to classification accuracy, compared to the use of the structural measure alone.ConclusionWe suggest the fusion of multimodal neuroimaging measures as an effective strategy that could generally cope with diverse prediction problems of clinical concerns.

Multimodal neuroimaging measures and intelligence influence pedophile child sexual offense behavior

Pedophilia is a heterogeneous disorder for which the neurobiological correlates are not well established. In particular, there are no biological markers identifying individuals with high risk to commit child sexual offense (CSO). Pedophiles with CSO (P+CSO; N = 73), pedophiles without CSO (P-CSO; N = 77), and non-pedophilic controls (NPC; N = 133) were assessed using multimodal structural neuroimaging measures including: cortical thickness (CT), surface area (SA), and white matter fractional anisotropy (FA), as well as full scale IQ (FSIQ) performance. Cortex-wise mediation analyses were used to assess the relationships among brain structure, FSIQ and CSO behavior. Lower FSIQ performance was strongly predict with P+CSO (Wald Chi2 = 13.0, p = 3.1 × 10-5). P+CSO had lower CT in the right motor cortex and pronounced reductions in SA spanning the bilateral frontal, temporal, cingulate, and insular regions (PFWE-corrected < 0.05). P+CSO also had lower FA particularly in the corpus callosum (PFWE-corrected < 0.05). The relationship between SA and P+CSO was significantly mediated by FSIQ, particularly in the prefrontal and anterior insular cortices (PFWE-corrected < 0.05). Within P+CSO, left prefrontal and right anterior cingulate SA negatively correlated with number of CSOs (PFWE-corrected < 0.05). This study demonstrates converging neurobiological findings in which P+CSO had lower FSIQ performance, reduced CT, reduced SA, and reduced FA, compared to P-CSO as well as NPC. Further, FSIQ potentially mediates abuse by pedophiles via aberrant SA, whereas the CT and FA associations were independent of FSIQ differences. These findings suggest aberrant neuroanatomy and lower intelligence as a potential core feature underlying child sexual abuse behavior by pedophiles.

CHANGES IN WHITE MATTER INTEGRITY AND CEREBRAL BLOOD FLOW IN THE EPISODIC MEMORY NETWORK IN COGNITIVELY NORMAL OLDER ADULTS WITH β-AMYLOID PATHOLOGY

A large proportion of asymptomatic older adults present beta-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer's disease. Using multimodal neuroimaging measures, we assessed how Aβ deposition relates to resting-state cerebral blood flow (CBF) and white matter integrity (WMI) in brain regions critical for episodic memory among cognitively normal older adults. We assessed cerebral blood flow and white matter integrity that were measured by arterial spin labeling and diffusion tensor imaging (DTI), respectively, in cognitively normal older adults who participated in the Alzheimer's Disease Neuroimaging Initiative (ADNI). A level of Aβ deposition was quantified by 18F-Florbetapir positron emission tomography (PET). Forty and 47 cognitively normal older adults (mean age = 72.8, 25 females) were included for CBF and DTI results, respectively, and classified into either Aβ+ or Aβ− according to the criteria set by the ADNI processing pipeline. Effects of dichotomized and continuous Aβ measures on CBF and WMI in a priori regions of interest were assessed using analyses of covariance and multiple regression models. For behavioral measures, baseline scores and slopes representing longitudinal changes in the 11-item ADAS-cog and RAVLT immediate recall and percent forgetting were assessed and related to biomarker measures. Higher Aβ deposition was associated with lower CBF in entorhinal cortex but increased CBF in posterior cingulate cortex, the latter of which further predicted steeper longitudinal decline in RAVLT among Aβ+ older adults. Higher Aβ deposition was associated with significant reduction in white matter integrity in most association fibers including superior longitudinal fasciculus, inferior fronto-occipital fasciculus, cingulum, and body of corpus callosum. Despite cognitively normal status, clinically intact older adults undergo Aβ-related differences in both functional and structural brain measures. Cerebral blood flow and white matter tract integrity measures may serve as an early biomarker for amyloid pathology at the initial stage of Alzheimer's disease. Longitudinal studies are warranted to address the directionality between these measures and amyloid pathology.

VISUAL LEARNING ON THE COGSTATE BATTERY IS ASSOCIATED WITH AMYLOID, TAU, AND NEURODEGENERATION IN COGNITIVELY NORMAL OLDER ADULTS

The CogState Preclinical Alzheimer's Battery has been developed to detect subtle cognitive changes in those at risk for development of Alzheimer's Disease (AD). One of the subtests, visual learning, is particularly impaired in AD. Since neuropathological features in AD begin to appear decades before disease onset, we sought to assess the association of visual learning from the CogState Preclinical Alzheimer's battery in cognitively normal older adults (CN) with multimodal neuroimaging measures of amyloid deposition, tau deposition, and neurodegeneration in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The CogState Preclinical Alzheimer's Battery and [18F]Flortaucipir, [18F]Florbetapir, and structural MRI scans were acquired in 20 cognitively normal controls (CN) from ADNI. The percentage of errors per items given (% errors) for the one card learning test was calculated. Voxel-wise regression models in SPM8 were used to evaluate the relationship of % errors on the one card learning test with tau and amyloid deposition and gray matter density (GMD) from VBM, processed using standard techniques. Age, sex, and education were used as covariates for all analyses, as well as APOE ε4 status and total intracranial volume for the [18F]Florbetapir and MRI analyses, respectively. Significant findings for [18F]Flortaucipir and [18F]Florbetapir were shown at p<0.01 (uncorrected) and at a minimum cluster threshold (k) of 50 voxels, while MRI results were displayed at p<0.001 (uncorrected) and k=50 voxels. Higher % errors during the one card learning test was associated with higher levels of both amyloid and tau deposition and reduced GMD. Notably, higher % errors was associated amyloid in the temporal and parietal cortices (Figure 1A). High tau load was also associated with a higher % errors, predominantly in the parietal cortex (Figure 1B). Atrophy showed association with % errors in only focal regions (Figure 1C).

Functional selectivity for face processing in the temporal voice area of early deaf individuals

Brain systems supporting face and voice processing both contribute to the extraction of important information for social interaction (e.g., person identity). How does the brain reorganize when one of these channels is absent? Here, we explore this question by combining behavioral and multimodal neuroimaging measures (magneto-encephalography and functional imaging) in a group of early deaf humans. We show enhanced selective neural response for faces and for individual face coding in a specific region of the auditory cortex that is typically specialized for voice perception in hearing individuals. In this region, selectivity to face signals emerges early in the visual processing hierarchy, shortly after typical face-selective responses in the ventral visual pathway. Functional and effective connectivity analyses suggest reorganization in long-range connections from early visual areas to the face-selective temporal area in individuals with early and profound deafness. Altogether, these observations demonstrate that regions that typically specialize for voice processing in the hearing brain preferentially reorganize for face processing in born-deaf people. Our results support the idea that cross-modal plasticity in the case of early sensory deprivation relates to the original functional specialization of the reorganized brain regions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0(sd=2.0) from 3 clinical sites. Linear regression using the LASSO method for variable selection was used to predict severity of future behavioral and emotional dysregulation [measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)] at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors, and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained approximately one-third of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit

Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT's neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region. Using real-time intraoperative magnetic resonance imaging-guided convection-enhanced delivery, five monkeys received bilateral dorsal amygdala Ce-region infusions of adeno-associated virus serotype 2 containing the CRF construct. Their cagemates served as unoperated control subjects. AT, regional brain metabolism, resting functional magnetic resonance imaging, and diffusion tensor imaging were assessed before and 2 months after viral infusions. Dorsal amygdala CRF overexpression significantly increased AT and metabolism within the dorsal amygdala. Additionally, we observed changes in metabolism in other AT-related regions, as well as in measures of functional and structural connectivity. This study provides a translational roadmap that is important for understanding human psychopathology by combining molecular manipulations used in rodents with behavioral phenotyping and multimodal neuroimaging measures used in humans. The results indicate that chronic CRF overexpression in primates not only increases AT but also affects metabolism and connectivity within components of AT's neural circuitry.

Can multi-modal neuroimaging evidence from hippocampus provide biomarkers for the progression of amnestic mild cognitive impairment?

Impaired structure and function of the hippocampus is a valuable predictor of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD). As a part of the medial temporal lobe memory system, the hippocampus is one of the brain regions affected earliest by AD neuropathology, and shows progressive degeneration as aMCI progresses to AD. Currently, no validated biomarkers can precisely predict the conversion from aMCI to AD. Therefore, there is a great need of sensitive tools for the early detection of AD progression. In this review, we summarize the specific structural and functional changes in the hippocampus from recent aMCI studies using neurophysiological and neuroimaging data. We suggest that a combination of advanced multi-modal neuroimaging measures in discovering biomarkers will provide more precise and sensitive measures of hippocampal changes than using only one of them. These will potentially affect early diagnosis and disease-modifying treatments. We propose a new sequential and progressive framework in which the impairment spreads from the integrity of fibers to volume and then to function in hippocampal subregions. Meanwhile, this is likely to be accompanied by progressive impairment of behavioral and neuropsychological performance in the progression of aMCI to AD.