Lateral Temporal Cortex Research Articles

Fiber connectivity density mapping in end-stage renal disease patients: a preliminary study.

Abnormal brain structural connectivity of end-stage renal disease(ESRD) is associated with cognitive impairment. However, the characteristics of cortical structural connectivity have not been investigated in ESRD patients. Here, we study structural connectivity of the entire cerebral cortex using a fiber connectivity density(FiCD) mapping method derived from diffusion tensor imaging(DTI) data of 25 ESRD patients and 20 healthy controls, and between-group differences were compared in a vertexwise manner. We also investigated the associations between these abnormal cortical connectivities and the clinical variables using Pearson correlation analysis and multifactor linear regression analysis. Our results demonstrated that the mean global FiCD value was significantly decreased in ESRD patients. Notably, FiCD values were significantly changed(decreased or increased) in certain cortical regions, which mainly involved the bilateral dorsolateral prefrontal cortex(DLPFC), inferior parietal cortex, lateral temporal cortex and middle occipital cortex. In ESRD patients, we found a trend of negative correlation between the increased FiCD values of bilateral middle frontal gyrus and serum creatinine, urea, parathyroid hormone(PTH) levels and dialysis duration. Only the white matter hyperintensity(WMH) scores were significantly negatively correlated with the global FiCD value in multifactor regression analysis. Our results suggested that ESRD patients exhibited extensive impaired cortical structural connectivity, which was related to the severity of WMHs. A compensation mechanism of cortical structural recombination may play a role in how the brain adapts to maintain optimal network function. Additionally, the serum creatinine, urea and PTH levels may be risk factors for brain structural network decompensation in ESRD patients.

Towards clinical application of tau PET: Prognostics

AbstractBackgroundTau PET is now considered to be a disease stage biomarker for reflecting of Alzheimer’s disease (AD) severity. Recent longitudinal studies showed a progression of cortical tau burden and a predictability of baseline tau PET for further tau accumulation, cortical atrophy, and even clinical progression in the short term. In this study, we sought to investigate long‐term changes in tau burden and predictability of tau PET for long‐term disease progression.MethodIn a cohort with 273 participants who had completed visit 1 (V1) assessments including two PET scans (18F‐florbetaben and 18F‐flortaucipir), MR imaging studies and neuropsychological function tests, 77 Aβ+ participants [9 cognitively unimpaired (CU) and 38 mild cognitive impairment (MCI), and 30 AD dementia (DEM)] completed visit 2 (V2) assessments at two years, and subsequently 39 Aβ+ participants (6 CU, 24 MCI, and 9 DEM) completed visit 3 (V3) assessments at about four years (mean 4.6 years) after the V1 study. After correcting for partial volume effect, we measured regional standardized uptake value ratio (SUVR) values with cerebellar crus median as a reference and regional volumes, as well.ResultDuring the short‐ (V1 to V2) and long‐term (V1 to V3) periods, tau burden significantly increased in the widespread cortex, particularly in the medial and lateral temporal cortices. In 33 cognitively impaired patients who completed both V2 and V3 scans, DEM patients exhibited higher global cortical tau accumulation rates (V1 to V2 = 0.066 and V2 to V3 = 0.058 SUVR/year) than MCI patients (V1 to V2 = 0.044 and V2 to V3 = 0.051 SUVR/year). Tau burden at V1 correlated strongly with the tau accumulation and volume reduction rates, particularly in the lateral temporal cortex and also correlated with the global cognitive decline rate, particularly in the prefrontal and parietal cortices. Likewise, in both short‐ and long‐term data, tau accumulation rate correlated with the volume reduction and global cognitive decline rates.ConclusionTau accumulated progressively throughout a four year long‐term follow‐up period. Progression of tau pathology, cortical atrophy and cognitive decline can be predicted by baseline tau burden. Tau PET is a useful imaging biomarker in predicting long‐term disease progression.

Lesion‐network mapping of tau accumulation is predictive of domain‐specific cognitive deficits in Alzheimer’s disease

AbstractBackgroundClinical heterogeneity is present in a substantial portion of patients with Alzheimer’s disease (AD). Understanding the underlying pathological differences is an unmet goal towards patient‐tailored medicine in AD. We hypothesized that the brain localization of tau deposition, a key driver of neurodegeneration, is predictive of which cognitive domain predominantly affected. We adopted a symptom‐network mapping approach applied to tau PET, reasoning that the functional connectivity of local tau PET to a cognitive‐domain specific network is predictive of which cognitive ability is impaired.MethodWe included 448 participants consisting of 234 amyloid‐PET‐negative cognitively normal subjects (CN‐Aβ‐), 95 amyloid‐PET‐positive mild cognitive impairment (MCI‐Aβ+) and 119 amyloid‐PET‐positive cognitively normal (CN‐Aβ+) patients. AV1451 tau‐PET was parcellated using the 400 ROI Schaefer atlas. Adopting a lesion‐network mapping approach (Darby et al. Brain 2018), we computed in the Aβ+ participants, subject‐level W‐scores, i.e. the standardized deviation of tau‐PET ROI values from those in CN‐Aβ‐. We computed for each subject and tau‐PET lesion (ROI W‐score > 2) the seed‐based connectivity based on resting‐state fMRI data from Human Connectome Project (n = 1000), rendering patient‐level lesion network maps. In order to identify symptom‐specific lesion‐networks, we regressed composite scores of episodic memory (ADNI‐MEM), executive function (ADNI‐EF), and language (ADNI‐LAN) onto the subject‐level lesion‐network maps, using partial least squares.ResultSubstantial variability in the tau‐PET lesions locations between subjects were observed (Figure 1A), with highest overlaps observed in the lateral and medial temporal cortex and posterior cingulate (Figure 1B). We found for each cognitive domain, a specific tau‐lesion network map: stronger connectivity of tau‐PET lesions to lateral temporal, posterior parietal and lateral prefrontal cortex were associated with lower episodic memory (ADNI‐MEM). In contrast, stronger connectivity to pre‐ and post‐central gyri and superior parietal cortex was associated with lower executive function (ADNI‐EF), and stronger connectivity to inferior frontal and auditory cortex was associated with language function, suggesting the presence of cognitive‐domain specific networks of tau lesions.ConclusionWe identified functional network patterns of local tau PET accumulation that map onto impairment in specific cognitive domains. This approach thus contributes to precision medicine guided prediction of specific cognitive impairments in AD.

Cerebrospinal fluid and brain PET measures of synaptic density glycoprotein 2A: Biomarkers of synaptic density in Alzheimer’s disease

AbstractBackgroundSynaptic loss is linked with Alzheimer’s disease (AD) progression and provides a novel target for exploration with fluid and imaging biomarkers. Studies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early AD. The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. This study examined the association between a SV2A measured with brain [11C]UCB‐J–PET and cerebrospinal fluid (CSF) levels of SV2A.MethodUsing [11C]UCB‐J binding to SV2A, synaptic density was measured in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT after a bolus injection of [11C]UCB‐J. Synaptic density was calculated as the distribution volume ratio (DVR) using SRTM2 with a cerebellum reference region. CSF SV2A was measured by an in‐house ELISA method.ResultAs previously demonstrated, synaptic density measured with SV2A PET was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. CSF SV2A was also reduced in participants with AD (762 ± 148) pg/mL) compared to CN participants (935 ± 134 pg/mL, P = 0.01, Figure 1). Within the AD group (n = 21), CSF SV2A was significantly correlated with synaptic density measured with [11C]UCB‐J–PET in a composite of AD‐affected regions (r = 0.65, P = 0.001, Figure 2). A regional analysis showed that CSF and PET measures of SV2A were significantly correlated broadly in the neocortex, but not in medial temporal regions such as the hippocampus, entorhinal cortex, and amygdala.ConclusionThis study supports a previous report of decreased CSF SV2A in AD. In the primary analysis, SV2A measured in CSF and SV2A measured with brain PET were strongly correlated within a group of individuals with AD, indicating that decreases in both measures may reflect synaptic loss during disease progression. Further studies will focus on longitudinal changes in CSF and PET measures of SV2A, as well as other CSF measures of synaptic and neuronal damage to investigate the neurobiology of AD.

Tau and synaptic biomarkers but not amyloid‐β are associated with cerebral perfusion in the Alzheimer’s disease spectrum

AbstractBackgroundA large body of evidence has shown decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD). However, the link between CBF and the primary AD pathologies as well as synaptic integrity remains unclear.MethodBaseline CBF was measured using arterial spin labeling (ASL) in a 3T MRI scanner in 137 cognitively unimpaired individuals with and without amyloid‐beta (Aβ) pathology, in addition to 119 cognitively impaired participants with mild cognitive impairment or AD dementia who all had Aβ pathology from the Swedish BioFINDER‐2 study. Aβ and tau pathology were measured using cerebrospinal fluid (CSF) levels of Aβ42/40 and amyloid‐PET, as well as CSF P‐tau217 levels and tau‐PET, respectively. Synaptic integrity was estimated using CSF neuronal pentraxin 2 (NPTX2)/total‐tau (T‐tau) ratio. Voxel‐wise and linear regression analyses in a set of a priori defined regions of interest (ROIs) were used to assess between‐group differences in CBF, and the relationship between CBF and the PET and CSF measures.ResultCBF was decreased in the lateral temporal, lateral and medial parietal and superior lateral occipital cortex in the cognitively impaired compared to cognitively unimpaired individuals, independent of Aβ pathology. In contrast, no differences were found in CBF between the cognitively unimpaired groups with and without Aβ pathology. Further, in cognitively unimpaired individuals, CBF was not associated with any of the biomarkers of Aβ, tau or synaptic integrity. However, in individuals on the AD spectrum i.e., those with Aβ pathology regardless of their cognitive status, an inverse association was observed between CBF and tau pathology (tau‐PET and CSF P‐tau217), but not Aβ pathology (CSF Aβ42/40 and amyloid‐PET), predominantly in the occipito‐temporo‐parietal regions. Moreover, lower NPTX2/T‐tau was associated with hypoperfusion in similar regions.ConclusionThese findings suggest that tau‐tangle pathology and synaptic degeneration are more closely associated with overt changes in CBF than Aβ pathology. This supports the notion that blood flow changes, at least those measured by ASL, are not an early event associated with the build‐up of Aβ pathology during the preclinical phases of AD.

Amyloid‐β and tau pathologies relate to distinctive brain dysconnectomics in autosomal‐dominant Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD)‐related pathology (i.e., amyloid‐β and neurofibrillary tangles) disrupts functional networks that support higher‐order cognitive functions. Yet, it is not well known how the brain’s functional architecture is differentially associated with in vivo pathology in preclinical AD, which is critical for predicting disease risk and progression. We intersected functional connectivity and PET images to examine how in vivo amyloid‐β and tau pathologies are associated with weighted‐degree centrality patterns, known to be important for understanding network organization and information transmission hubs, in cognitively‐unimpaired individuals with autosomal‐dominant AD due to the Presenilin‐1 (PSEN‐1) E280A mutation.Method21 cognitively‐unimpaired PSEN1 E280A carriers and 31 non‐carriers underwent resting‐state fMRI, 11C Pittsburgh compound B‐PET and 18F Flortaucipir‐PET. We used graph‐based network analyses to examine weighted‐degree centrality, the sum of weights from edges connecting to a node. A general linear model was used to compare connectivity maps between groups, and partial correlations were used to examine the relationship between individual‐subject maps with whole‐brain amyloid‐β and tau PET. A significance threshold of p<0.05 was used. Analyses were covaried for age and corrected for multiple comparisons.ResultCompared to non‐carriers, mutation carriers exhibited reduced weighted‐degree in the medial occipitoparietal and posterior cingulate cortices. Greater amyloid‐β was associated with reduced weighted‐degree in the lateral temporal lobe and fusiform gyrus, and greater weighted‐degree in the lateral and medial prefrontal cortices. In turn, greater tau burden was associated with greater weighted‐degree in the lateral and medial temporal regions, anterior and posterior cingulate cortices, lateral parietal cortex and precuneus, and decreased weighted‐degree in dorsomedial prefrontal cortex.ConclusionOur findings show that cognitively‐unimpaired individuals who are genetically‐determined to develop AD dementia in their forties have abnormal patterns of functional connectivity that resemble spatial patterns of amyloid‐β and tau propagation. Regions that had weaker connections with nearby and distant regions showed greater amyloid‐β burden, while regions that were highly functionally connected exhibited greater tau burden, which has been suggested to increase the probability of tau seeding and propagation. These findings contribute to our understanding of how functional connectivity patterns can help predict risk and monitor AD progression from preclinical to clinical stages.

The relationship between beta‐amyloid accumulation and P3 event‐related potential in older adults: A pilot study

AbstractBackgroundEmerging evidence from animal and human studies shows that beta‐amyloid (Aβ) may induce neuronal hyperexcitability in the early stage of Alzheimer’s disease (AD). Electroencephalography (EEG) offers unparalleled temporal resolution in tracing distinct neurophysiological processes even in preclinical AD. The aim of this pilot study was to determine the relationship of Aβ accumulation and event‐related potential (ERP) in cognitively normal older adults.MethodAβ accumulation was characterized with [18F] Florbetapir positron emission tomography (PET) scans. Global Aβ burden was assessed by taking the mean standard uptake value ratios (SUVR) of 6 predefined regions: anterior cingulate, posterior cingulate, precuneus, inferior medial frontal, lateral temporal, and superior parietal cortex. All participants completed a working memory task with three levels of difficulty (0‐,1‐,2‐back). ERP P3 peak amplitude and latency were extracted from the task effect (non‐target minus target). We used Pearson r to calculate associations between mean SUVR and P3 ERP at the midline channels Fz and Cz. Since the working memory task induced frontal cortical activity, we also explored the relationship between SUVR in the inferior medial frontal cortex and the frontal channels Fz, F3, and F4.ResultTwenty‐seven (age: 73.9 ± 5.5; MOCA: 27.37 ± 2.0) completed both PET and EEG scans. Mean SUVR ranged from 0.95 to 1.60 and correlated negatively with P3 latency of the 2‐back at Cz (r = ‐0.40; p = 0.04) and Fz (r = ‐0.58; p = 0.002). SUVR in the inferior medial frontal cortex correlated negatively with P3 peak latency of 1‐back at Fz (r = ‐0.42; p = 0.03) and F3 (r = ‐0.49; p = 0.009), and of 2‐back at Fz (‐0.54; p = 0.004) and F3 (r = ‐0.40; p = 0.045). No correlations were found between global Aβ burden and P3 peak amplitude.ConclusionThe negative relationship between Aβ accumulation and P3 latency provides preliminary support for the neuronal hyperexcitability hypothesis in preclinical AD. However, these findings need to be confirmed in a longitudinal cohort study with larger sample size.

The relationship between cortical grey to white matter signal contrast (GWC) and tau pathology in atypical AD

AbstractBackgroundGrey to white matter signal intensity ratio (GWC) has been studied as a novel metric of integrity and as a marker of neurodegeneration in Alzheimer’s disease (AD). Regions with reduced GWC co‐localize with regions of cortical atrophy in AD (Salat et al. 2011; Salat et al. 2009). Cortical atrophy in AD robustly colocalizes with tau pathology measured using tau PET ligands (Putcha et al. 2019). For this study, we hypothesized that GWC co‐localizes with tau pathology and shows greater sensitivity to tau pathology than cortical atrophy across the atypical phenotypic spectrum of AD.MethodWe studied 29 amyloid‐positive atypical AD patients, including 16 patients with posterior cortical atrophy (PCA), 10 with logopenic variant primary progressive aphasia (lvPPA), and 3 with an amnestic dysexecutive presentation. Whole‐cortex maps of GWC and cortical atrophy were generated for each individual using FreeSurfer. Tau PET (18F‐Flortaucipir) signal was projected for each individual to the cortical surface using PETsurfer. Eta squared (η2) was computed to determine the spatial overlap of each measure of neurodegeneration (GWC, cortical atrophy) with tau PET signal for each subject and then averaged across the whole group.ResultBoth GWC and cortical atrophy revealed a pattern of neurodegeneration consistent with AD, including in medial parietal, lateral parietal, and posterior lateral temporal cortices. Lower GWC was also observed in several regions beyond the areas of cortical atrophy in patients including in bilateral dorsolateral and dorsomedial prefrontal cortices. Supporting our hypothesis, there was greater spatial overlap between the GWC and tau PET maps (η2 = 0.30) compared to cortical atrophy and tau PET maps (η2 = 0.24; t=4.49, p=0.0001).ConclusionWhile both measures of neurodegeneration (GWC, cortical atrophy) showed a high degree of spatial overlap with tau PET signal across our sample of atypical AD participants, we conclude that GWC, a novel MRI‐derived biomarker of neurodegeneration in AD, correlates more strongly with AD‐related tau neuropathology than traditional cortical atrophy measures. This suggests that GWC could be a sensitive biomarker of AD‐related tissue changes that may represent neuronal injury or neurodegeneration. Further work is needed to establish how GWC tracks with tau pathology over time.

Narrative imagery: Emotional modulation in the default mode network

The default mode network (DMN) is activated when constructing and imagining narrative events, with functional brain activity in the medial-prefrontal cortex hypothesized to be modulated during emotional processing by adding value (or pleasure) to the episodic representation. However, since enhanced reactivity during emotional, compared to neutral, content is a more frequent finding in both the brain and body in physiological, neural, and behavioral measures, the current study directly assesses the effects of pleasure and emotion during narrative imagery in the DMN by using a within-subject design to first identify the DMN during resting state and then assess activation during pleasant, neutral, or unpleasant imagery. Replicating previous findings, enhanced functional activity in the medial prefrontal cortex was found when imagining pleasant, compared to unpleasant, events. On the other hand, emotion-related activation was found when imagining either pleasant or unpleasant, compared to neutral, events in other nodes of the DMN including the posterior cingulate cortex (PCC), angular gyrus, anterior hippocampus, lateral temporal cortex, temporal pole, dorsomedial prefrontal cortex (dmPFC), and ventrolateral prefrontal cortex (vlPFC). Pervasive emotional modulation in the DMN is consistent with the view that a primary function of event retrieval and construction is to remember, recreate, and imagine motivationally relevant events important for planning adaptive behavior.

An engram of intentionally forgotten information

Successful forgetting of unwanted memories is crucial for goal-directed behavior and mental wellbeing. While memory retention strengthens memory traces, it is unclear what happens to memory traces of events that are actively forgotten. Using intracranial EEG recordings from lateral temporal cortex, we find that memory traces for actively forgotten information are partially preserved and exhibit unique neural signatures. Memory traces of successfully remembered items show stronger encoding-retrieval similarity in gamma frequency patterns. By contrast, encoding-retrieval similarity of item-specific memory traces of actively forgotten items depend on activity at alpha/beta frequencies commonly associated with functional inhibition. Additional analyses revealed selective modification of item-specific patterns of connectivity and top-down information flow from dorsolateral prefrontal cortex to lateral temporal cortex in memory traces of intentionally forgotten items. These results suggest that intentional forgetting relies more on inhibitory top-down connections than intentional remembering, resulting in inhibitory memory traces with unique neural signatures and representational formats.

Common and Distinct Disruptions of Cortical Surface Morphology Between Autism Spectrum Disorder Children With and Without SHANK3 Deficiency.

SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3)-caused autism spectrum disorder (ASD) may present a unique opportunity to clarify the heterogeneous neuropathological mechanisms of ASD. However, the specificity and commonality of disrupted large-scale brain organization in SHANK3-deficient children remain largely unknown. The present study combined genetic tests, neurobehavioral evaluations, and magnetic resonance imaging, aiming to explore the disruptions of both local and networked cortical structural organization in ASD children with and without SHANK3 deficiency. Multiple surface morphological parameters such as cortical thickness (CT) and sulcus depth were estimated, and the graph theory was adopted to characterize the topological properties of structural covariance networks (SCNs). Finally, a correlation analysis between the alterations in brain morphological features and the neurobehavioral evaluations was performed. Compared with typically developed children, increased CT and reduced nodal degree were found in both ASD children with and without SHANK3 defects mainly in the lateral temporal cortex, prefrontal cortex (PFC), temporo-parietal junction (TPJ), superior temporal gyrus (STG), and limbic/paralimbic regions. Besides commonality, our findings showed some distinct abnormalities in ASD children with SHANK3 defects compared to those without. Locally, more changes in the STG and orbitofrontal cortex were exhibited in ASD children with SHANK3 defects, while more changes in the TPJ and inferior parietal lobe (IPL) in those without SHANK3 defects were observed. For the SCNs, a trend toward regular network topology was observed in ASD children with SHANK3 defects, but not in those without. In addition, ASD children with SHANK3 defects showed more alterations of nodal degrees in the anterior and posterior cingulate cortices and right insular, while there were more disruptions in the sensorimotor areas and the left insular and dorsomedial PFC in ASD without SHANK3 defects. Our findings indicate dissociable disruptions of local and networked brain morphological features in ASD children with and without SHANK3 deficiency. Moreover, this monogenic study may provide a valuable path for parsing the heterogeneity of brain disturbances in ASD.

Effect of acupuncture on default mode network in patients with migraine based on functional Magnetic Resonance Imaging: a preliminary study

To investigate the effect of acupuncture on default mode network (DMN) in migraine patients without aura based on functional Magnetic Resonance Imaging (fMRI). Fifteen patients with migraine were included and treated with acupuncture based on "root-knot" theory (Zuqiaoyin [GB 44] for shaoyang headache, Lidui [ST 45] for yangming headache, Zhiyin [BL 67] for taiyang headache, and ashi point), once every other day, three times a week for 4 weeks. The patients received fMRI scanning before and after acupuncture treatment, the effect of acupuncture on DMN in patients with migraine was observed; the frequency of migraine attack, visual analogue scale (VAS) score and the using of analgesic medication before and after treatment were recorded to evaluate the curative effect of acupuncture; the migraine-specific quality of life questionnaire (MSQ), self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were used to evaluate the improvements of quality of life and emotional state. Compared before acupuncture, the functional connections of left parahippocampal cortex (PHC) and anterior medial prefrontal cortex (aMPFC), dorsal medial prefrontal cortex (dMPFC) and lateral temporal cortex (LTC) in DMN after acupuncture were weakened (P<0.05), and the functional connections of bilateral posterior cingulate cortex (PCC) and dMPFC were weakened (P<0.05). Compared before treatment, the frequency of migraine attack, VAS, SAS and SDS scores after treatment were decreased (P<0.05), and MSQ score was increased (P<0.05). Acupuncture shows good clinical efficacy for migraine without aura, and could adjust the functional connection of DMN.

Disruption in Surface-Based Functional Connectivity in the Right Posterior Hippocampal CA3 Subfield: A Probable Neural Basis of Visuospatial Working Memory Impairment in Patients With Right Temporal Lobe Epilepsy.

Visuospatial working memory (VSWM) impairment is common in patients with right temporal lobe epilepsy (rTLE). The posterior hippocampus is critical for spatial memory, but the contributions of the different subfields to VSWM deficits remain unclear. Forty-six rTLE patients and 42 healthy controls (HCs) were recruited. Resting-state fMRI (rsfMRI) and structural MRI scans were administered, followed by a VSWM_Nback test. The right posterior hippocampus was automatically segmented, and the surface-based functional connectivity (SBFC) of the subiculum (Sub), CA1, CA3, dentate gyrus (DG), hippocampal tail, and right entorhinal cortex (EC) were compared between groups. Correlation analysis was performed between the altered SBFC and VSWM_Nback scores for rTLE patients. The results showed that rTLE patients underperformed in the VSWM_Nback test, with longer mean reaction time of accurate response (ACCmeanRT) in 0back and 2back condition, lower hit rate (HR) and higher false alarm rate (FAR) in 2back condition. Compared with HCs, the rCA3 in the rTLE group exhibited decreased SBFC with inferior parietal cortex (IPC), temporal lateral cortex (TLC), and posterior visual cortex (PVC) in the right hemisphere as well as the bilateral dorsolateral prefrontal cortex (DLPFC). The SBFC of the rEC and right anterior cingulate cortex (rACC) increased in the rTLE group. Within the rTLE group, the decreased SBFC of the rCA3-rIPC and rCA3-rLTC were correlated with worse VSWM performance. Therefore, the decreased SBFC of the rCA3-rIPC and rCA3-rLTC might be the critical aberrant FC pattern reflecting VSWM impairment in rTLE patients. The mechanism might involve functional disruption between the core subsystem and the medial temporal subsystem of the default mode network (DMN).

Connectivity alterations in autism reflect functional idiosyncrasy

Autism spectrum disorder (ASD) is commonly understood as an alteration of brain networks, yet case-control analyses against typically-developing controls (TD) have yielded inconsistent results. Here, we devised a novel approach to profile the inter-individual variability in functional network organization and tested whether such idiosyncrasy contributes to connectivity alterations in ASD. Studying a multi-centric dataset with 157 ASD and 172 TD, we obtained robust evidence for increased idiosyncrasy in ASD relative to TD in default mode, somatomotor and attention networks, but also reduced idiosyncrasy in lateral temporal cortices. Idiosyncrasy increased with age and significantly correlated with symptom severity in ASD. Furthermore, while patterns of functional idiosyncrasy were not correlated with ASD-related cortical thickness alterations, they co-localized with the expression patterns of ASD risk genes. Notably, we could demonstrate that patterns of atypical idiosyncrasy in ASD closely overlapped with connectivity alterations that are measurable with conventional case-control designs and may, thus, be a principal driver of inconsistency in the autism connectomics literature. These findings support important interactions between inter-individual heterogeneity in autism and functional signatures. Our findings provide novel biomarkers to study atypical brain development and may consolidate prior research findings on the variable nature of connectome level anomalies in autism.

Longitudinal assessment of amyloid-beta deposition in initially amyloid-negative non-demented individuals with [11C]-PIB PET imaging.

This study aimed to assess the longitudinal changes in amyloid beta (Aβ) deposition in cortical regions with [11C]-PIB PET in initially amyloid-negative non-demented subjects and evaluate whether amyloid-negative subjects convert to amyloid-positive.Sixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (aged 60–75 years), who were amyloid-negative at baseline, underwent 60-minute dynamic [11C]-PIB PET and cognitive assessment over 5.0 to 9.4 years of a long follow-up, and the apolipoprotein-E (APOE) genotype was assessed. Regions of interest were defined in the bilateral cortex on coregistered MRI. Quantitative analysis of [11C]-PIB was performed using the distribution value ratio (DVR). Longitudinal changes in global and regional PIB DVRs were evaluated in the same regions, and the annual rate of change in the PIB DVR was calculated.Seven (30.4%) of 23 initially amyloid-negative non-demented subjects converted to globally amyloid-positive (global PIB DVR ≥1.40) over a follow-up of 6.5 ± 1.4 years (converter). The global PIB DVR in converters increased from 1.22 ± 0.07 at baseline to 1.63 ± 0.15 (n = 7, P < .01) at last follow-up, and an annual increase of global PIB DVR was 0.057 ± 0.019/year (n = 7, P < .01). In contrast, the global PIB DVR in the remaining 16 subjects was 1.15 ± 0.07 at baseline and did not change over a follow-up period (stable). The APOE ε4 allele was present in 4 (57.1%) of the 7 converters, differing from 2 (12.5%) of 16 stable subjects (Fisher's exact test, P < .05). Three amyloid-negative MCI subjects had an annual increase in global PIB DVR above 0.061/year and became positive at 2.8 ± 0.5 years of follow-up, which was faster than 5.0 ± 2.0 years in 4 CN subjects. The regional PIB DVR that increased early above the regional positivity threshold was most frequently found in the right lateral temporal cortex (71.4%), followed by the left frontal cortex (41.8%).Our results suggest that the initially amyloid-negative CN and MCI subjects, especially with APOE ε4, can become globally amyloid-positive over a longer time, based on early regional Aβ deposition in the lateral temporal cortex and/or frontal cortex.

Effects of hippocampal interictal discharge timing, duration, and spatial extent on list learning

Interictal epileptiform discharges (IEDs) can impair memory. The properties of IEDs most detrimental to memory, however, are undefined. We studied the impact of temporal and spatial characteristics of IEDs on list learning. Subjects completed a memory task during intracranial EEG recordings including hippocampal depth and temporal neocortical subdural electrodes. Subjects viewed a series of objects, and after a distracting task, recalled the objects from the list. The impacts of IED presence, duration, and propagation to neocortex during encoding of individual stimuli were assessed. The effects of IED total number and duration during maintenance and recall periods on delayed recall performance were also determined. The influence of IEDs during recall was further investigated by comparing the likelihood of IEDs preceding correctly recalled items vs. periods of no verbal response. Across 6 subjects, we analyzed 28 hippocampal and 139 lateral temporal contacts. Recall performance was poor, with a median of 17.2% correct responses (range 10.4–21.9%). Interictal epileptiform discharges during encoding, maintenance, and recall did not significantly impact task performance, and there was no significant difference between the likelihood of IEDs during correct recall vs. periods of no response. No significant effects of discharge duration during encoding, maintenance, or recall were observed. Interictal epileptiform discharges with spread to lateral temporal cortex during encoding did not adversely impact recall. A post hoc analysis refining model assumptions indicated a negative impact of IED count during the maintenance period, but otherwise confirmed the above results. Our findings suggest no major effect of hippocampal IEDs on list learning, but study limitations, such as baseline hippocampal dysfunction, should be considered. The impact of IEDs during the maintenance period may be a focus of future research.

Regional glucose metabolic decreases with ageing are associated with microstructural white matter changes: a simultaneous PET/MR study.

Human ageing is associated with a regional reduction in cerebral neuronal activity as assessed by numerous studies on brain glucose metabolism and perfusion, grey matter (GM) density and white matter (WM) integrity. As glucose metabolism may impact energetics to maintain myelin integrity, but changes in functional connectivity may also alter regional metabolism, we conducted a cross-sectional simultaneous FDG PET/MR study in a large cohort of healthy volunteers with a wide age range, to directly assess the underlying associations between reduced glucose metabolism, GM atrophy and decreased WM integrity in a single ageing cohort. In 94 healthy subjects between 19.9 and 82.5years (mean 50.1 ± 17.1; 47M/47F, MMSE ≥ 28), simultaneous FDG-PET, structural MR and diffusion tensor imaging (DTI) were performed. Voxel-wise associations between age and grey matter (GM) density, RBV partial-volume corrected (PVC) glucose metabolism, white matter (WM) fractional anisotropy (FA) and mean diffusivity (MD), and age were assessed. Clusters representing changes in glucose metabolism correlating significantly with ageing were used as seed regions for tractography. Both linear and quadratic ageing models were investigated. An expected age-related reduction in GM density was observed bilaterally in the frontal, lateral and medial temporal cortex, striatum and cerebellum. After PVC, relative FDG uptake was negatively correlated with age in the inferior and midfrontal, cingulate and parietal cortex and subcortical regions, bilaterally. FA decreased with age throughout the entire brain WM. Four white matter tracts were identified connecting brain regions with declining glucose metabolism with age. Within these, relative FDG uptake in both origin and target clusters correlated positively with FA (0.32 ≤ r ≤ 0.71) and negatively with MD (- 0.75 ≤ r ≤ - 0.41). After appropriate PVC, we demonstrated that regional cerebral glucose metabolic declines with age and that these changes are related to microstructural changes in the interconnecting WM tracts. The temporal course and potential causality between ageing effects on glucose metabolism and WM integrity should be further investigated in longitudinal cohort PET/MR studies.

Heterogeneity of Tau Deposition and Microvascular Involvement in MCI and AD.

BackgroundReduced cerebrovascular function and accumulation of tau pathology are key components of cognitive decline in Alzheimer’s disease (AD). Recent multimodal neuroimaging studies show a correlation between cortical tau accumulation and reduced cerebral perfusion. However, animal models predict that tau exerts capillary-level changes that may not be fully captured by standard imaging protocols.ObjectiveUsing newly-developed magnetic resonance imaging (MRI) technology to measure capillary-specific perfusion parameters, we examined a series of mild cognitive impairment (MCI) and AD patients with tau positron emission tomography (PET) to observe whole-brain capillary perfusion alterations and their association with tau deposition.MethodsSeven subjects with MCI or AD received Flortaucipir PET to measure tau deposition and spin-echo dynamic susceptibility contrast (SE-DSC) MRI to measure microvascular perfusion (<10μm radius vessels). Gradient-echo (GE) DSC and pseudocontinuous arterial spin labeling (PCASL) MRI were also acquired to assess macrovascular perfusion. Tau PET, microvascular perfusion, and cortical thickness maps were visually inspected in volumetric slices and on cortical surface projections.ResultsHigh tau PET signal was generally observed in the lateral temporal and parietal cortices, with uptake in the occipital cortex in one subject. Global blood flow measured by PCASL was reduced with increasing tau burden, which was consistent with previous studies. Tau accumulation was spatially associated with variable patterns of microvascular cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in the cortex and with increased capillary transit heterogeneity (CTH) in adjacent periventricular white matter, independent of amyloid-β status.ConclusionAlthough macrovascular perfusion generally correlated with tau deposition at the whole-cortex level, regional changes in microvascular perfusion were not uniformly associated with either tau pathology or cortical atrophy. This work highlights the heterogeneity of AD-related brain changes and the challenges of implementing therapeutic interventions to improve cerebrovascular function.

Overlapping and specific neural correlates for empathizing, affective mentalizing, and cognitive mentalizing: A coordinate-based meta-analytic study.

While the discussion on the foundations of social understanding mainly revolves around the notions of empathy, affective mentalizing, and cognitive mentalizing, their degree of overlap versus specificity is still unclear. We took a meta‐analytic approach to unveil the neural bases of cognitive mentalizing, affective mentalizing, and empathy, both in healthy individuals and pathological conditions characterized by social deficits such as schizophrenia and autism. We observed partially overlapping networks for cognitive and affective mentalizing in the medial prefrontal, posterior cingulate, and lateral temporal cortex, while empathy mainly engaged fronto‐insular, somatosensory, and anterior cingulate cortex. Adjacent process‐specific regions in the posterior lateral temporal, ventrolateral, and dorsomedial prefrontal cortex might underpin a transition from abstract representations of cognitive mental states detached from sensory facets to emotionally‐charged representations of affective mental states. Altered mentalizing‐related activity involved distinct sectors of the posterior lateral temporal cortex in schizophrenia and autism, while only the latter group displayed abnormal empathy related activity in the amygdala. These data might inform the design of rehabilitative treatments for social cognitive deficits.

Integrating Multilevel Functional Characteristics Reveals Aberrant Neural Patterns during Audiovisual Emotional Processing in Depression.

Emotion dysregulation is one of the core features of major depressive disorder (MDD). However, most studies in depression have focused on unimodal emotion processing, whereas emotional perception in daily life is highly dependent on multimodal sensory inputs. Here, we proposed a novel multilevel discriminative framework to identify the altered neural patterns in processing audiovisual emotion in MDD. Seventy-four participants underwent an audiovisual emotional task functional magnetic resonance imaging scanning. Three levels of whole-brain functional features were extracted for each subject, including the task-evoked activation, task-modulated connectivity, combined activation and connectivity. Support vector machine classification and prediction models were built to identify MDD from controls and evaluate clinical relevance. We revealed that complex neural networks including the emotion regulation network (prefrontal areas and limbic-subcortical regions) and the multisensory integration network (lateral temporal cortex and motor areas) had the discriminative power. Moreover, by integrating comprehensive information of local and interactive processes, multilevel models could lead to a substantial increase in classification accuracy and depression severity prediction. Together, we highlight the high representational capacity of machine learning algorithms to characterize the complex network abnormalities associated with emotional regulation and multisensory integration in MDD. These findings provide novel evidence for the neural mechanisms underlying multimodal emotion dysregulation of depression.