Resting-state global brain activity affects early ß-amyloid accumulation in default mode network.

It remains unclear why ß-amyloid (Aß) plaque, a hallmark pathology of Alzheimer's disease (AD), first accumulates cortically in the default mode network (DMN), years before AD diagnosis. Resting-state low-frequency ( < 0.1 Hz) global brain activity recently was linked to AD, presumably due to its role in glymphatic clearance. Here we show that the preferential Aß accumulation in the DMN at the early stage of Aß pathology was associated with the preferential reduction of global brain activity in the same regions. This can be partly explained by its failure to reach these regions as propagating waves. Together, these findings highlight the important role of resting-state global brain activity in early preferential Aß deposition in the DMN.

White matter hyperintensities influence distal cortical ß-amyloid accumulation in default mode network pathways.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid ß (Aß) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. METHODS: Regional standard uptake value ratios (SUVr) from Aß-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aß-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. RESULTS: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p = .011). CONCLUSION: The findings suggest that the relation between Aß in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aß and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-ß42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Gaining insight into the neural basis of resting-state fMRI signal.

The blood oxygenation level-dependent (BOLD)-based resting-state functional magnetic resonance imaging (rsfMRI) has been widely used as a non-invasive tool to map brain-wide connectivity architecture. However, the neural basis underpinning the resting-state BOLD signal remains elusive. In this study, we combined simultaneous calcium-based fiber photometry with rsfMRI in awake animals to examine the relationship of the BOLD signal and spiking activity at the resting state. We observed robust couplings between calcium and BOLD signals in the dorsal hippocampus as well as other distributed areas in the default mode network (DMN), suggesting that the calcium measurement can reliably predict the rsfMRI signal. In addition, using the calcium signal recorded as the ground truth, we assessed the impacts of different rsfMRI data preprocessing pipelines on functional connectivity mapping. Overall, our results provide important evidence suggesting that spiking activity measured by the calcium signal plays a key role in the neural mechanism of resting-state BOLD signal.

Coupling relationship between glucose and oxygen metabolisms to differentiate preclinical Alzheimer's disease and normal individuals.

The discovery of preclinical Alzheimer's disease (preAD) provides a wide time window for the early intervention of AD. The coupling relationships between glucose and oxygen metabolisms from hybrid PET/MRI can provide complementary information on the brain's physiological state for preAD. In this study, we purpose to explore the change of coupling relationship among 27 normal controls (NCs), 20 preADs, and 15 cognitive impairments (CIs). For each subject, we calculated the Spearman partial correlation between the fractional amplitude of low-frequency fluctuations (fALFF) and the regional homogeneity (ReHo) from functional image (fMRI), and the standard uptake value ratio (SUVR) from [18F] fluorodeoxyglucose positron emission tomography (18 F-FDG PET), in the whole-brain and default mode network (DMN) as a novel potential biomarker. The diagnostic performance of this biomarker was evaluated by the receiver operating characteristic analysis. Significant Spearman correlations between the FDG SUVR and the fALFF/ReHo were found in 98% of subjects. For the DMN-based biomarker, there was a significant decreasing trend for the preAD and CI groups compared to the NC group, whereas no significant difference in preAD based on whole-brain. The correlation ρ value for the FDG SUVR/ReHo showed the highest area under curve of the preAD classification (0.787). The results imply the coupling relationship changed during the preAD stage in the DMN area.

Dissociations between glucose metabolism and blood oxygenation in the human default mode network revealed by simultaneous PET-fMRI.

The finding of reduced functional MRI (fMRI) activity in the default mode network (DMN) during externally focused cognitive control has been highly influential to our understanding of human brain function. However, these negative fMRI responses, measured as relative decreases in the blood-oxygenation-level-dependent (BOLD) response between rest and task, have also prompted major questions of interpretation. Using hybrid functional positron emission tomography (PET)-MRI, this study shows that task-positive and -negative BOLD responses do not reflect antagonistic patterns of synaptic metabolism. Task-positive BOLD responses in attention and control networks were accompanied by concomitant increases in glucose metabolism during cognitive control, but metabolism in widespread DMN remained high during rest and task despite negative BOLD responses. Dissociations between glucose metabolism and the BOLD response specific to the DMN reveal functional heterogeneity in this network and demonstrate that negative BOLD responses during cognitive control should not be interpreted to reflect relative increases in metabolic activity during rest. Rather, neurovascular coupling underlying BOLD response patterns during rest and task in DMN appears fundamentally different from BOLD responses in other association networks during cognitive control.

The emergent relationship between temporoparietal junction and anosognosia in Alzheimer's disease.

Anosognosia and impairment of insight are characteristic features of Alzheimer's disease (AD), which can lead to delays in appropriate medical care and significant family discord. The default mode network (DMN), a distributed but highly connected network of brain regions more active during rest than during task, is integrally involved in awareness. DMN dysfunction is common in AD, and disrupted communication between memory-related and self-related DMN networks is associated with anosognosia in AD patients. In addition, the temporoparietal junction (TPJ) is a key region of the "social brain" and also contributes to representations of the self. The exact classification of the TPJ within the DMN is unclear, though connections between the TPJ and DMN have been highlighted in multiple avenues of research. Here we discuss the relationship between the TPJ, DMN, and AD, as well as the potential involvement of the TPJ in anosognosia in AD. We review past and present findings to raise attention to the TPJ, with a specific emphasis on neuroimaging technologies which suggest a pivotal role of the TPJ within large-scale brain networks linked to anosognosia in AD.

Integrated phylogeny of the human brain and pathobiology of Alzheimer's disease: A unifying hypothesis.

The disproportionate evolutionary expansion of the human cerebral cortex with reinforcement of cholinergic innervations warranted a major rise in the functional and metabolic load of the conserved basal forebrain (BF) cholinergic system. Given that acetylcholine (ACh) regulates properties of the microtubule-associated protein (MAP) tau and promotes non-amyloidogenic processing of amyloid precursor protein (APP), growing neocortex predicts higher demands for ACh, while the emerging role of BF cholinergic projections in Aß clearance infers greater exposure of source neurons and their innervation fields to amyloid pathology. The higher exposure of evolutionary most recent cortical areas to the amyloid pathology of Alzheimer's disease (AD) with synaptic impairments and atrophy, therefore, might involve attenuated homeostatic effects of BF cholinergic projections, in addition to fall-outs of inherent processes of expanding association areas. This unifying model, thus, views amyloid pathology and loss of cholinergic cells as a quid pro quo of the allometric evolution of the human brain, which in combination with increase in life expectancy overwhelm the fine homeostatic balance and trigger the disease process.

The default mode network and cognition in Parkinson's disease: A multimodal resting-state network approach.

Involvement of the default mode network (DMN) in cognitive symptoms of Parkinson's disease (PD) has been reported by resting-state functional MRI (rsfMRI) studies. However, the relation to metabolic measures obtained by [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is largely unknown. We applied multimodal resting-state network analysis to clarify the association between intrinsic metabolic and functional connectivity abnormalities within the DMN and their significance for cognitive symptoms in PD. PD patients were classified into normal cognition (n = 36) and mild cognitive impairment (MCI; n = 12). The DMN was identified by applying an independent component analysis to FDG-PET and rsfMRI data of a matched subset (16 controls and 16 PD patients) of the total cohort. Besides metabolic activity, metabolic and functional connectivity within the DMN were compared between the patients' groups and healthy controls (n = 16). Glucose metabolism was significantly reduced in all DMN nodes in both patient groups compared to controls, with the lowest uptake in PD-MCI (p < .05). Increased metabolic and functional connectivity along fronto-parietal connections was identified in PD-MCI patients compared to controls and unimpaired patients. Functional connectivity negatively correlated with cognitive composite z-scores in patients (r = -.43, p = .005). The current study clarifies the commonalities of metabolic and hemodynamic measures of brain network activity and their individual significance for cognitive symptoms in PD, highlighting the added value of multimodal resting-state network approaches for identifying prospective biomarkers.

Inhibiting PI3K leads to glucose metabolism disturbance in default mode network.

BACKGROUND: As the symbolic pathological changes of Alzheimer's disease (AD), hyperphosphorylated tau and amyloid plaque play important roles in the progression of the disease. In AD patients, the neural activity in default mode network is abnormal at different stages of the disease, and showed a hypoconnective status. Inhibition of phosphatidylinositol-3-kinase (PI3K) activates glycogen synthase kinase 3 beta (GSK-3ß) and induces tau phosphorylation. OBJECTIVE: We speculated that inhibiting cerebral PI3K altered the glucose metabolism in DMN. We aimed to explore the impacts of PI3K inhibition on tau phosphorylation, cerebral glucose metabolism, and synaptic plasticity. METHODS: We injected wortmannin, an inhibitor of PI3K, lateral ventricularly in rats to mimic the pathology of AD. Immunohistochemistry was carried out to analyze the expression of phosphorylated tau. Region-specific glucose metabolism in the brain was analyzed using 18F-FDG PET imaging. In vivo long-term potentiation (LTP) in the hippocampus was detected to assess the synaptic plasticity. RESULTS: The results show that the phosphorylated tau at T231 increased and the hippocampal LTP was suppressed 24 h after wortmannin administration. In the DMN, glucose uptake was significantly high, indicating a neural activity disturbance. CONCLUSION: We conclude that targeting PI3K-GSK-3ß pathway to mimic AD tau pathology interrupted the glucose metabolism of DMN brain regions.

Altered default mode network activity and cortical thickness as vulnerability indicators for SCZ: a preliminary resting state MRI study.

OBJECTIVE: Alterations in brain function in patients with schizophrenia (SCZ) and other neuropsychiatric disorders are evident not only during specific cognitive challenges, but also from functional MRI data obtained during a resting state. Patients with chronic SCZ have shown deficits in default mood network (DMN) and gray matter volume in resting-state functional magnetic resonance imaging (rs-fMRI). However, cortical thickness and surface area in first-episode schizophrenic patients have rarely been investigated. PATIENTS AND METHODS: In the present study, we applied independent component analysis (ICA) to a series of rs-fMRIs of 15 SCZ patients and 15 matched healthy controls. The data were analyzed using MELODIC of FMRIB's Software Library (FSL version 5.9; www.fmrib.ox.ac.uk/fsl) to identify large-scale patterns of temporal signal-intensity coherence. RESULTS: Patients with SCZ showed significantly higher functional connectivity in the DMN, auditory network, and cerebellum network (p=0.049, p=0.05, and p=0.007, respectively) than matched healthy controls. The patients also exhibited significantly less cortical thickness, primarily in the bilateral prefrontal and parietal cortex, and higher thickness in the bilateral anterior temporal lobes, left medial orbitofrontal cortex, and left cuneus than the matched healthy controls. CONCLUSIONS: These results indicate that significantly abnormal DMN connectivity and cortical thickness contribute to local functional pathology in patients with SCZ.

The surprising role of the default mode network in naturalistic perception.

The default mode network (DMN) is a group of high-order brain regions recently implicated in processing external naturalistic events, yet it remains unclear what cognitive function it serves. Here we identified the cognitive states predictive of DMN fMRI coactivation. Particularly, we developed a state-fluctuation pattern analysis, matching network coactivations across a short movie with retrospective behavioral sampling of movie events. Network coactivation was selectively correlated with the state of surprise across movie events, compared to all other cognitive states (e.g. emotion, vividness). The effect was exhibited in the DMN, but not dorsal attention or visual networks. Furthermore, surprise was found to mediate DMN coactivations with hippocampus and nucleus accumbens. These unexpected findings point to the DMN as a major hub in high-level prediction-error representations.

Nicotinic receptor modulation of the default mode network.

RATIONALE: Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects OBJECTIVES: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation. METHODS: Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified. RESULTS: Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal. CONCLUSIONS: The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.

Effective connectivity in the default mode network is distinctively disrupted in Alzheimer's disease-A simultaneous resting-state FDG-PET/fMRI study.

A prominent finding of postmortem and molecular imaging studies on Alzheimer's disease (AD) is the accumulation of neuropathological proteins in brain regions of the default mode network (DMN). Molecular models suggest that the progression of disease proteins depends on the directionality of signaling pathways. At network level, effective connectivity (EC) reflects directionality of signaling pathways. We hypothesized a specific pattern of EC in the DMN of patients with AD, related to cognitive impairment. Metabolic connectivity mapping is a novel measure of EC identifying regions of signaling input based on neuroenergetics. We simultaneously acquired resting-state functional MRI and FDG-PET data from patients with early AD (n = 35) and healthy subjects (n = 18) on an integrated PET/MR scanner. We identified two distinct subnetworks of EC in the DMN of healthy subjects: an anterior part with bidirectional EC between hippocampus and medial prefrontal cortex and a posterior part with predominant input into medial parietal cortex. Patients had reduced input into the medial parietal system and absent input from hippocampus into medial prefrontal cortex (p < 0.05, corrected). In a multiple linear regression with unimodal imaging and EC measures (F4,25 = 5.63, p = 0.002, r2 = 0.47), we found that EC (ß = 0.45, p = 0.012) was stronger associated with cognitive deficits in patients than any of the PET and fMRI measures alone. Our approach indicates specific disruptions of EC in the DMN of patients with AD and might be suitable to test molecular theories about downstream and upstream spreading of neuropathology in AD.

Neural Signatures of Memory Encoding in Schizophrenia Are Modulated by Antipsychotic Treatment.

There is no pharmacological treatment to remediate cognitive impairment in schizophrenia (SZ). It is imperative to characterize underlying pathologies of memory processing in order to effectively develop new treatments. In this longitudinal study, we combined functional magnetic resonance imaging during a memory encoding task with proton MR spectroscopy to measure hippocampal glutamate + glutamine (Glx). Seventeen SZ were scanned while unmedicated and after 6 weeks of treatment with risperidone and compared to a group of matched healthy controls (HC) scanned 6 weeks apart. Unmedicated patients showed reduced blood oxygen level dependent (BOLD) response in several regions, including the hippocampus, and greater BOLD response in regions of the default mode network (DMN) during correct memory encoding. Post hoc contrasts from significant group by time interactions indicated reduced hippocampal BOLD response at baseline with subsequent increase following treatment. Hippocampal Glx was not different between groups at baseline, but at week 6, hippocampal Glx was significantly lower in SZ compared to HC. Finally, in unmedicated SZ, higher hippocampal Glx predicted less deactivation of the BOLD response in regions of the DMN. Using 2 brain imaging modalities allowed us to concurrently investigate different mechanisms involved in memory encoding dysfunction in SZ. Hippocampal pathology during memory encoding stems from decreased hippocampal recruitment and faulty deactivation of the DMN, and hippocampal recruitment during encoding can be modulated by antipsychotic treatment. High Glx in unmedicated patients predicted less deactivation of the DMN; these results suggest a mechanism by which faulty DMN deactivation, a hallmark of pathological findings in SZ, is achieved.

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice.

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.

Interrelations between dopamine and serotonin producing sites and regions of the default mode network.

Recent functional magnetic resonance imaging (fMRI) studies showed that blood oxygenation level-dependent (BOLD) signal fluctuations in the default mode network (DMN) are functionally tightly connected to those in monoaminergic nuclei, producing dopamine (DA), and serotonin (5-HT) transmitters, in the midbrain/brainstem. We combined accelerated fMRI acquisition with spectral Granger causality and coherence analysis to investigate causal relationships between these areas. Both methods independently lead to similar results and confirm the existence of a top-down information flow in the resting-state condition, where activity in core DMN areas influences activity in the neuromodulatory centers producing DA/5-HT. We found that latencies range from milliseconds to seconds with high inter-subject variability, likely attributable to the resting condition. Our novel findings provide new insights into the functional organization of the human brain.

Cumulative Risk on Oxytocin-Pathway Genes Impairs Default Mode Network Connectivity in Trauma-Exposed Youth.

Background: Although the default mode network (DMN) is a core network essential for brain functioning, little is known about its developmental trajectory, particularly on factors associated with its coherence into a functional network. In light of adult studies indicating DMN's susceptibility to stress-related conditions, we examined links between variability on oxytocin-pathway genes and DMN connectivity in youth exposed to chronic war-related trauma Methods: Following a cohort of war-exposed children from early childhood, we imaged the brains of 74 preadolescents (age 11-13 years; 39 war-exposed) during rest using magnetoencephalography (MEG). A cumulative risk index on oxytocin-pathway genes was constructed by combining single nucleotide polymorphisms on five genes previously linked with social deficits and psychopathology; OXTR rs1042778, OXTR rs2254298, OXTRrs53576, CD38 rs3796863, and AVPR1A RS3. Avoidant response to trauma reminders in early childhood and anxiety disorders in late childhood were assessed as predictors of disruptions to DMN theta connectivity. Results: Higher vulnerability on oxytocin-pathway genes predicted greater disruptions to DMN theta connectivity. Avoidant symptoms in early childhood and generalized anxiety disorder in later childhood were related to impaired DMN connectivity. In combination, stress exposure, oxytocin-pathway genes, and stress-related symptoms explained 24.6% of the variance in DMN connectivity, highlighting the significant effect of stress on the maturing brain. Conclusions: Findings are the first to link the oxytocin system and maturation of the DMN, a core system sustaining autobiographical memories, alteration of intrinsic and extrinsic attention, mentalization, and sense of self. Results suggest that oxytocin may buffer the effects of chronic early stress on the DMN, particularly theta rhythms that typify the developing brain.