Default Mode Network Deactivation Research Articles

Distinctive and Complementary Roles of Default Mode Network Subsystems in Semantic Cognition.

The default mode network (DMN) typically deactivates to external tasks, yet supports semantic cognition. It comprises medial temporal (MT), core, and frontotemporal (FT) subsystems, but its functional organization is unclear: the requirement for perceptual coupling versus decoupling, input modality (visual/verbal), type of information (social/spatial), and control demands all potentially affect its recruitment. We examined the effect of these factors on activation and deactivation of DMN subsystems during semantic cognition, across four task-based human functional magnetic resonance imaging (fMRI) datasets, and localized these responses in whole-brain state space defined by gradients of intrinsic connectivity. FT showed activation consistent with a central role across domains, tasks, and modalities, although it was most responsive to abstract, verbal tasks; this subsystem uniquely showed more "tuned" states characterized by increases in both activation and deactivation when semantic retrieval demands were higher. MT also activated to both perceptually coupled (scenes) and decoupled (autobiographical memory) tasks and showed stronger responses to picture associations, consistent with a role in scene construction. Core DMN consistently showed deactivation, especially to externally oriented tasks. These diverse contributions of DMN subsystems to semantic cognition were related to their location on intrinsic connectivity gradients: activation was closer to the sensory-motor cortex than deactivation, particularly for FT and MT, while activation for core DMN was distant from both visual cortex and cognitive control. These results reveal distinctive yet complementary DMN responses: MT and FT support different memory-based representations that are accessed externally and internally, while deactivation in core DMN is associated with demanding, external semantic tasks.

Default mode network scaffolds immature frontoparietal network in cognitive development.

The default mode network (DMN) is a workspace for convergence of internal and external information. The frontal parietal network (FPN) is indispensable to executive functioning. Yet, how they interplay to support cognitive development remains elusive. Using longitudinal developmental fMRI with an n-back paradigm, we show a heterogeneity of maturational changes in multivoxel activity and network connectivity among DMN and FPN nodes in 528 children and 103 young adults. Compared with adults, children exhibited prominent longitudinal improvement but still inferior behavioral performance, which paired with less pronounced DMN deactivation and weaker FPN activation in children, but stronger DMN coupling with FPN regions. Children's DMN reached an adult-like level earlier than FPN at both multivoxel activity pattern and intranetwork connectivity levels. Intrinsic DMN-FPN internetwork coupling in children mediated the relationship between age and working memory-related functional coupling of these networks, with posterior cingulate cortex (PCC)-dorsolateral prefrontal cortex (DLPFC) coupling emerging as most prominent pathway. Coupling of PCC-DLPFC may further work together with task-invoked activity in PCC to account for longitudinal improvement in behavioral performance in children. Our findings suggest that the DMN provides a scaffolding effect in support of an immature FPN that is critical for the development of executive functions in children.

P01.05.A Working memory performance is associated with functional connectivity between the right dlPFC and DMN in glioma patients

Abstract Background Patients with primary brain tumors frequently suffer from cognitive impairments in multiple domains, leading to serious consequences for socio-professional functioning and quality of life. The functional-anatomical basis of these impairments is still poorly understood. The study of correlated BOLD activity in the brain (i.e. functional connectivity) has greatly contributed to our understanding of how brain activity supports cognitive function. In particular, activity observed during the execution of specific tasks can be related to various distributed functional networks, stressing the importance of interactions between remote brain regions. Among these networks, the Default Mode Network (DMN) and the Fronto-Parietal Network (FPN) have consistently been associated with working memory performance. Recently, using task-fMRI in glioma patients, poor performance in a working memory task was associated with less deactivation of the DMN during this task and to a lack of task-evoked changes in the DMN-FPN structure. In this study, we investigated whether these effects are reflected in the resting-state (RS) functional connectivity of the same patient group, i.e. when no task was performed during fMRI. We additionally zoomed in on the part of the FPN located in the dorsolateral Prefrontal Cortex (dlPFC), since this region is believed to be mainly responsible for DMN deactivation. Material and Methods Resting-state functional MRI data were acquired pre-operatively from 45 brain tumor patients (20 low- and 25 high-grade glioma patients). Results of a pre-operative in-scanner N-back working memory fMRI task were used to assess working memory performance. Patient brains were parcellated into ROIs using both the Gordon and Yeo atlas, which have the FPN and DMN network identities readily available. The dlPFC was defined based on masks retrieved from NeuroSynth. To measure DMN-FPN functional connectivity the average Pearson correlation between the activation time series in the regions belonging to the FPN and the DMN was calculated. Functional connectivity between the DMN and the dlPFC was calculated in a similar way. Results The average correlation between the resting-state fMRI activity in the right dlPFC and in the DMN was negatively associated with working memory performance for both the Gordon atlas (p < 0.003) and Yeo atlas (p < 0.007). No association was found for the correlation between activity in the left dlPFC and the DMN, nor for the correlation between the activity in the whole FPN and the DMN. Conclusion Our findings show that working memory performance of glioma patients is related to interactions between networks that can be measured with resting-state fMRI. Furthermore, the results provide further evidence that not only specific brain regions are important for cognitive performance, but that also the interactions between large-scale networks should be considered.

Altered functional connectivity within default mode network after rupture of anterior communicating artery aneurysm

BackgroundRupture of anterior communicating artery (ACoA) aneurysm often leads to cognitive impairment, especially memory complaints. The medial superior frontal gyrus (SFGmed), a node of the default mode network (DMN), has been extensively revealed to participate in various cognitive processes. However, the functional connectivity (FC) characteristics of SFGmed and its relationship with cognitive performance remain unknown after the rupture of the ACoA aneurysm.MethodsResting-state functional MRI (fMRI) and cognitive assessment were acquired in 27 eligible patients and 20 controls. Seed-based FC between unilateral SFGmed and the rest of the brain was calculated separately, and then compared their intensity differences between the two groups. Furthermore, we analyzed the correlation between abnormal FC and cognitive function in patients with ruptured ACoA aneurysm.ResultsCognitive impairment was confirmed in 51.9% of the patients. Compared with the controls, patients suffering from ruptured ACoA aneurysm exhibited a similar FC decline between each side of SFGmed and predominant nodes within DMN, including the precuneus, angular gyrus, cingulate cortex, left hippocampus, left amygdala, left temporal pole (TPO), and left medial orbitofrontal cortex (mOFC). Besides, significantly decreased FC of left SFGmed and left insula, right middle temporal gyrus (MTG), as well as right mOFC, were also found. In addition, only enhanced insular connectivity with right SFGmed was determined, whereas increased FC of the left SFGmed was not observed. Correlation analyses showed that lower total cognitive performance or stronger subjective memory complaints were related to reduced connectivity in the SFGmed and several cortical regions such as the angular gyrus and middle cingulate cortex (MCC).ConclusionOur results suggest that patients with ruptured ACoA aneurysm exist long-term cognitive impairment and intrinsic hypoconnectivity of cognition-related brain regions within DMN. Deactivation of DMN may be a potential neural mechanism leading to cognitive deficits in these patients.

Fitness and arterial stiffness in healthy aging: Modifiable cardiovascular risk factors contribute to altered default mode network patterns during executive function

Increases in cardiovascular risks such as high blood pressure and low physical fitness have been independently associated with altered default mode network (DMN) activation patterns in healthy aging. However, cardiovascular risk is a multidimensional health problem. Therefore, we need to investigate multiple cardiovascular risk factors and their contributions to cognition and DMN activations in older adults, which has not yet been done. The current fMRI study examined contributions of two common modifiable cardiovascular risk factors (arterial stiffness and physical fitness) on DMN activations involved during random n-back, a task of executive functioning and working memory, in older adults. The results show that high cardiovascular risk of either increased arterial stiffness or decreased fitness independently contributed to worse task performance and reduced deactivations in two DMN regions: the anterior and posterior cingulate cortices. We then examined not only the potential interaction between the two risk factors, but also their additive (i.e., combined) effect on performance and DMN deactivations. A significant interaction between the two cardiovascular risk factors was observed on performance, with arterial stiffness moderating the relationship between physical fitness and random n-back accuracy. The additive effect of the two factors on task performance was driven by arterial stiffness. Arterial stiffness was also found to be the driving factor when the additive effect of the two risk factors was examined on DMN deactivations. However, in posterior cingulate cortex, a hub region of the DMN, the additive effect on its deactivation was significantly higher than the effect of each risk factor alone. These results suggest that the effects of cardiovascular risks on the aging brain are complicated and multi-dimensional, with arterial stiffness moderating or driving the combined effects on performance and anterior DMN deactivations, but physical fitness contributing additional effect to posterior DMN deactivation during executive functioning.

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging.

BackgroundIn epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined.MethodsHere, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). “Drug load” was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication.ResultsIn people taking “moderate” ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking “severe” ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with “moderate” ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex.ConclusionOur study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.

Medial prefrontal cortex pyramidal neurons exhibit functional defects during early stage of Alzheimer’s disease in 3xTg‐AD mice

The brain regions that show early increase of beta-amyloid (Aβ) in Alzheimer's disease (AD) overlap with the default mode network (DMN) (Palmqvist, S. et. al., 2017), which comprises, but is not limited to, the medial prefrontal cortex (mPFC), a key regulator of neurocognition (Zott, B. et al., 2018). DMN is active during mental processes that don't require attention, but it is deactivated when undertaking neurocognitive tasks (Zott, B. et al., 2018). However, such DMN deactivation is impaired in AD, often preceding formation of the Aβ plaque and onset of clinical symptoms (Chhatwal, J. P. et al., 2013; Sheline, Y. I. et al., 2010). Previous studies suggest that neuronal hyperexcitability is responsible for increased DMN vulnerability to Aβ deposition (Bero, A. W. et al., 2011; Li, X. et al., 2013). But whether and how mPFC neuronal function are altered in the early stages of AD is unknown and has not been studied.In this study, we used young 3xTg-AD mice (3-5 months of age) to mimic the early stages of AD before the formation of cortical Aβ plaques. Patch-clamp electrophysiology was applied to assess functional activity of mPFC pyramidal neurons in brain slices. Action potentials were evoked by depolarizing currents and spontaneous excitatory postsynaptic currents (sEPSCs) were assessed in Mg2+ -free bath with holding potential of -70mV. Ca2+ spikes (indicating Ca2+ influx through voltage-gated Ca2+ channels) were evoked by membrane depolarization with blockade of voltage-gated Na+ /K+ channels.We found that mPFC pyramidal neurons in young 3xTg-AD mice showed significantly increased firing, associated with depolarized resting membrane potential, decreased rheobase, increased input resistance, and reduced firing threshold. We also found that the frequency of sEPSCs was significantly increased. Meanwhile, Ca2+ spikes showed a trend of increase in their duration/area (a larger sample size is needed to confirm this finding) in mPFC neurons.Collectively, these novel findings demonstrate that the neuronal excitability and excitatory neurotransmission are aberrantly increased in the young mPFC during the early stages of AD preceding Aβ plaque formation. Whether such mPFC neuronal dysfunction could contribute to Aβ plaque accumulation is currently unknown and requires further investigation.

FMRI Evidence for Default Mode Network Deactivation Associated with Rapid Eye Movements in Sleep.

System-specific brain responses—time-locked to rapid eye movements (REMs) in sleep—are characteristically widespread, with robust and clear activation in the primary visual cortex and other structures involved in multisensory integration. This pattern suggests that REMs underwrite hierarchical processing of visual information in a time-locked manner, where REMs index the generation and scanning of virtual-world models, through multisensory integration in dreaming—as in awake states. Default mode network (DMN) activity increases during rest and reduces during various tasks including visual perception. The implicit anticorrelation between the DMN and task-positive network (TPN)—that persists in REM sleep—prompted us to focus on DMN responses to temporally-precise REM events. We timed REMs during sleep from the video recordings and quantified the neural correlates of REMs—using functional MRI (fMRI)—in 24 independent studies of 11 healthy participants. A reanalysis of these data revealed that the cortical areas exempt from widespread REM-locked brain activation were restricted to the DMN. Furthermore, our analysis revealed a modest temporally-precise REM-locked decrease—phasic deactivation—in key DMN nodes, in a subset of independent studies. These results are consistent with hierarchical predictive coding; namely, permissive deactivation of DMN at the top of the hierarchy (leading to the widespread cortical activation at lower levels; especially the primary visual cortex). Additional findings indicate REM-locked cerebral vasodilation and suggest putative mechanisms for dream forgetting.

Acute Brain Activation Patterns of High- Versus Low-Frequency Stimulation of the Anterior Nucleus of the Thalamus During Deep Brain Stimulation for Epilepsy.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an increasingly utilized treatment of drug-resistant epilepsy. To date, the effect of high-frequency stimulation (HFS) vs low-frequency stimulation (LFS) in ANT DBS is poorly understood. To assess differences in the acute effect of LFS vs HFS in ANT DBS utilizing blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI). In this prospective study of 5 patients with ANT DBS for epilepsy, BOLD activation and deactivation were modeled for 145-Hz and 30-Hz ANT stimulation using an fMRI block design. Data were analyzed with a general linear model and combined via 2-stage mixed-effects analysis. Z-score difference maps were nonparametrically thresholded using cluster threshold of z >3.1 and a (corrected) cluster significance threshold of P=.05. HFS produced significantly greater activation within multiple regions, in particular the limbic and default mode network (DMN). LFS produced minimal activation and failed to produce significant activation within these same networks. HFS produced widespread cortical and subcortical deactivation sparing most of the limbic and DMN regions. Meanwhile, LFS produced deactivation in most DMN and limbic structures. Our results show that HFS and LFS produce substantial variability in both local and downstream network effects. In particular, largely opposing effects were identified within the limbic network and DMN. These findings may serve as a mechanistic basis for understanding the potential of HFS vs LFS in various epilepsy syndromes.

Functional MRI Shows Altered Deactivation and a Corresponding Decrease in Functional Connectivity of the Default Mode Network in Patients with Gliomas

The default mode network normally decreases in activity during externally directed tasks. Although default mode network connectivity is disrupted in numerous brain pathologies, default mode network deactivation has not been studied in patients with brain tumors. We investigated default mode network deactivation with language task-based fMRI by measuring the anticorrelation of a critical default mode network node, the posterior cingulate cortex, in patients with gliomas and controls; furthermore, we examined default mode network functional connectivity in these patients with task-based and resting-state fMRI. In 10 healthy controls and 30 patients with gliomas, the posterior cingulate cortex was identified on task-based fMRI and was used as an ROI to create connectivity maps from task-based and resting-state fMRI data. We compared the average correlation in each default mode network region between patients and controls for each correlation map and stratified patients by tumor location, hemisphere, and grade. Patients with gliomas (P = .001) and, in particular, patients with tumors near the posterior default mode network (P < .001) showed less posterior cingulate cortex anticorrelation in task-based fMRI than controls. Patients with both left- and right-hemisphere tumors, as well as those with grade IV tumors, showed significantly lower posterior cingulate cortex anticorrelation than controls (P = .02, .03, and <.001, respectively). Functional connectivity in each default mode network region was not significantly different between task-based and resting-state maps. Task-based fMRI showed impaired deactivation of the default mode network in patients with gliomas. The functional connectivity of the default mode network in both task-based and resting-state fMRI in patients with gliomas using the posterior cingulate cortex identified in task-based fMRI as an ROI for seed-based correlation analysis has strong overlap.

Object-Location Memory Training in Older Adults Leads to Greater Deactivation of the Dorsal Default Mode Network

Substantial evidence indicates that cognitive training can be efficacious for older adults, but findings regarding training-related brain plasticity have been mixed and vary depending on the imaging modality. Recent years have seen a growth in recognition of the importance of large-scale brain networks on cognition. In particular, task-induced deactivation within the default mode network (DMN) is thought to facilitate externally directed cognition, while aging-related decrements in this neural process are related to reduced cognitive performance. It is not yet clear whether task-induced deactivation within the DMN can be enhanced by cognitive training in the elderly. We previously reported durable cognitive improvements in a sample of healthy older adults (age range = 60–75) who completed 6 weeks of process-based object-location memory training (N = 36) compared to an active control training group (N = 31). The primary aim of the current study is to evaluate whether these cognitive gains are accompanied by training-related changes in task-related DMN deactivation. Given the evidence for heterogeneity of the DMN, we examine task-related activation/deactivation within two separate DMN branches, a ventral branch related to episodic memory and a dorsal branch more closely resembling the canonical DMN. Participants underwent functional magnetic resonance imaging (fMRI) while performing an untrained object-location memory task at four time points before, during, and after the training period. Task-induced (de)activation values were extracted for the ventral and dorsal DMN branches at each time point. Relative to visual fixation baseline: (i) the dorsal DMN was deactivated during the scanner task, while the ventral DMN was activated; (ii) the object-location memory training group exhibited an increase in dorsal DMN deactivation relative to the active control group over the course of training and follow-up; (iii) changes in dorsal DMN deactivation did not correlate with task improvement. These results indicate a training-related enhancement of task-induced deactivation of the dorsal DMN, although the specificity of this improvement to the cognitive task performed in the scanner is not clear.

Ketamine specifically reduces cognitive symptoms in depressed patients: An investigation of associated neural activation patterns

Major depressive disorder (MDD) is characterized by heterogeneous cognitive, affective and somatic symptoms. Hence, the investigation of differential treatment effects on these symptoms as well as the identification of symptom specific biomarkers might crucially contribute to the development of individualized treatment strategies.We here aimed to examine symptom specific responses to treatment with ketamine, which repeatedly demonstrated rapid antidepressant effects in severe MDD. Additionally, we investigated working memory (WM) related brain activity associated with changes in distinct symptoms in order to identify specific response predictors. In a sample of 47 MDD patients receiving a single sub-anesthetic dose of ketamine, we applied a three-factor solution of the Beck Depression Inventory (BDI) to detect symptom specific changes 24 h post-infusion. A subsample of 16 patients underwent additional fMRI scanning during an emotional working memory task prior to ketamine treatment. Since functional aberrations in the default mode network (DMN) as well as in the dorsolateral prefrontal cortex (DLPFC) have been associated with impaired cognitive and emotional processing in MDD, we investigated neural activity in these regions.Our results showed that ketamine differentially affects MDD symptoms, with the largest symptom reduction in the cognitive domain. WM related neuroimaging results indicated that a more pronounced effect of ketamine on cognitive symptoms is predicted by lower DMN deactivation and higher DLPFC activation. Findings thereby not only indicate that ketamine's antidepressant efficacy is driven by a pro-cognitive mechanism, but also suggest that this might be mediated by increased potential for adaptive adjustment in the circumscribed brain regions.

Nicotinic receptor modulation of the default mode network.

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. 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. 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. 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.

Experimentally induced low back pain influences brain networks activity

Purpose of this study was to answer the question whether the recognized patterns of brain activity are likely to change under the influence of experimentally induced low back pain (LBP), and also to determine the functional networks of the brain engaged in this process. Twenty healthy subjects (8 women) participated. An experimental design was applied with repeated measurements of the blood oxygen level-dependent (BOLD) signal from the brain during two different voluntary contractions of the abdominal muscles without and with experimentally induced LBP. Brain areas showing significant differences in activity were identified and ascribed to the three functional neuronal brain networks: default mode network (DMN), pain matrix (PM), and sensorimotor (SM) areas. After implementation of the experimental painful stimulus the overall level of brain activity appears to be higher. No higher brain deactivations are seen in painful conditions and no higher activations in pain-free conditions. During isolated-type of muscular contraction a slight tendency to DMN deactivation may be observed.

A functional MRI study of presurgical cognitive deficits in glioma patients.

BackgroundThe main goal of this functional MRI (fMRI) study was to examine whether cognitive deficits in glioma patients prior to treatment are associated with abnormal brain activity in either the central executive network (CEN) or default mode network (DMN).MethodsForty-six glioma patients, and 23 group-matched healthy controls (HCs) participated in this fMRI experiment, performing an N-back task. Additionally, cognitive profiles of patients were evaluated outside the scanner. A region of interest–based analysis was used to compare brain activity in CEN and DMN between groups. Post hoc analyses were performed to evaluate differences between low-grade glioma (LGG) and high-grade glioma (HGG) patients.ResultsIn-scanner performance was lower in glioma patients compared to HCs. Neuropsychological testing indicated cognitive impairment in LGG as well as HGG patients. fMRI results revealed normal CEN activation in glioma patients, whereas patients showed reduced DMN deactivation compared to HCs. Brain activity levels did not differ between LGG and HGG patients.ConclusionsOur study suggests that cognitive deficits in glioma patients prior to treatment are associated with reduced responsiveness of the DMN, but not with abnormal CEN activation. These results suggest that cognitive deficits in glioma patients reflect a reduced capacity to achieve a brain state necessary for normal cognitive performance, rather than abnormal functioning of executive brain regions. Solely focusing on increases in brain activity may well be insufficient if we want to understand the underlying brain mechanism of cognitive impairments in patients, as our results indicate the importance of assessing deactivation.

Elucidating the function of brain resting‐state networks and their relation to the pathophysiology of neuropsychiatric diseases

AbstractAt the end of the 1990s, PET studies revealed synchronized deactivation during cognitive tasks in a network of dissociated brain regions named the default mode network. In addition to default mode network deactivation during cognitive tasks, hyperactivation of the default mode network during non‐cognitive activities such as mind‐wandering state has been revealed by resting‐state functional magnetic resonance imaging studies. Progress in magnetic resonance imaging devices and analysis methods have allowed the physiological dynamics of functional brain networks to be elucidated as either task‐negative resting‐state networks such as the default mode network or task‐positive networks. Moreover, the anatomical overlap between brain areas with reduced mental load‐dependent default mode network deactivation and those with amyloid beta protein deposition in patients with Alzheimer's disease suggests a close interaction between abnormalities in functional connectivity and aggregation of the pathological protein. Apart from Alzheimer's disease, recent resting‐state functional magnetic resonance imaging studies have additionally revealed associations not only of dysfunctional resting‐state networks with neurodegenerative diseases, but also with various psychiatric disorders. Below we outline the physiological characteristics of brain resting‐state networks and their relation to the progression of neuropsychiatric diseases. The aim of this paper was to provide evidence that resting‐state networks are crucial for understanding the mechanisms of human cognitive function.

Functional imaging evidence for task-induced deactivation and disconnection of a major default mode network hub in the mouse brain

The default mode network (DMN) has been defined in functional brain imaging studies as a set of highly connected brain areas, which are active during wakeful rest and inactivated during task-based stimulation. DMN function is characteristically impaired in major neuropsychiatric diseases, emphasizing its interest for translational research. However, in the mouse, a major preclinical rodent model, there is still no functional imaging evidence supporting DMN deactivation and deconnection during high-demanding cognitive/sensory tasks. Here we have developed functional ultrasound (fUS) imaging to properly visualize both activation levels and functional connectivity patterns, in head-restrained awake and behaving mice, and investigated their modulation during a sensory-task, whisker stimulation. We identified reproducible and highly symmetric resting-state networks, with overall connectivity strength directly proportional to the wakefulness level of the animal. We show that unilateral whisker stimulation leads to the expected activation of the contralateral barrel cortex in lightly sedated mice, while interhemispheric inhibition reduces activity in the ipsilateral barrel cortex. Whisker stimulation also leads to elevated bilateral connectivity in the hippocampus. Importantly, in addition to functional changes in these major hubs of tactile information processing, whisker stimulation during genuine awake resting-state periods leads to highly specific reductions both in activation and interhemispheric correlation within the restrosplenial cortex, a major hub of the DMN. These results validate an imaging technique for the study of activation and connectivity in the lightly sedated awake mouse brain and provide evidence supporting an evolutionary preserved function of the DMN, putatively improving translational relevance of preclinical models of neuropsychiatric diseases.

Toward a "treadmill test" for cognition: Improved prediction of general cognitive ability from the task activated brain.

General cognitive ability (GCA) refers to a trait‐like ability that contributes to performance across diverse cognitive tasks. Identifying brain‐based markers of GCA has been a longstanding goal of cognitive and clinical neuroscience. Recently, predictive modeling methods have emerged that build whole‐brain, distributed neural signatures for phenotypes of interest. In this study, we employ a predictive modeling approach to predict GCA based on fMRI task activation patterns during the N‐back working memory task as well as six other tasks in the Human Connectome Project dataset (n = 967), encompassing 15 task contrasts in total. We found tasks are a highly effective basis for prediction of GCA: The 2‐back versus 0‐back contrast achieved a 0.50 correlation with GCA scores in 10‐fold cross‐validation, and 13 out of 15 task contrasts afforded statistically significant prediction of GCA. Additionally, we found that task contrasts that produce greater frontoparietal activation and default mode network deactivation—a brain activation pattern associated with executive processing and higher cognitive demand—are more effective in the prediction of GCA. These results suggest a picture analogous to treadmill testing for cardiac function: Placing the brain in a more cognitively demanding task state significantly improves brain‐based prediction of GCA.

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.

Differential tDCS and tACS Effects on Working Memory-Related Neural Activity and Resting-State Connectivity.

Transcranial direct and alternating current stimulation (tDCS and tACS, respectively) entail capability to modulate human brain dynamics and cognition. However, the comparability of these approaches at the level of large-scale functional networks has not been thoroughly investigated. In this study, 44 subjects were randomly assigned to receive sham (N = 15), tDCS (N = 15), or tACS (N = 14). The first electrode (anode in tDCS) was positioned over the left dorsolateral prefrontal cortex, the target area, and the second electrode (cathode in tDCS) was placed over the right supraorbital region. tDCS was delivered with a constant current of 2 mA. tACS was fixed to 2 mA peak-to-peak with 6 Hz frequency. Stimulation was applied concurrently with functional magnetic resonance imaging (fMRI) acquisitions, both at rest and during the performance of a verbal working memory (WM) task. After stimulation, subjects repeated the fMRI WM task. Our results indicated that at rest, tDCS increased functional connectivity particularly within the default-mode network (DMN), while tACS decreased it. When comparing both fMRI WM tasks, it was observed that tDCS displayed decreased brain activity post-stimulation as compared to online. Conversely, tACS effects were driven by neural increases online as compared to post-stimulation. Interestingly, both effects primarily occurred within DMN-related areas. Regarding the differences in each fMRI WM task, during the online fMRI WM task, tACS engaged distributed neural resources which did not overlap with the WM-dependent activity pattern, but with some posterior DMN regions. In contrast, during the post-stimulation fMRI WM task, tDCS strengthened prefrontal DMN deactivations, being these activity reductions associated with faster responses. Furthermore, it was observed that tDCS neural responses presented certain consistency across distinct fMRI modalities, while tACS did not. In sum, tDCS and tACS modulate fMRI-derived network dynamics differently. However, both effects seem to focus on DMN regions and the WM network-DMN shift, which are highly affected in aging and disease. Thus, albeit exploratory and needing further replication with larger samples, our results might provide a refined understanding of how the DMN functioning can be externally modulated through commonly used non-invasive brain stimulation techniques, which may be of eventual clinical relevance.