Task-induced Deactivation Research Articles

Task-induced deactivation dysfunction during reward processing is associated with low self-esteem in a possible subtype of major depression.

Low self-esteem is a frequent symptom in major depressive disorder (MDD). This functional magnetic resonance imaging study investigated whether MDD patients with low self-esteem show a distinct neural pathophysiology. Previous studies linked low self-esteem to reduced task-induced deactivation of the pregenual anterior cingulate cortex (pgACC) as a part of the default mode network, and to reduced connectivity between pgACC and reward system. Goya-Maldonado etal. identified an MDD subtype with pgACC and ventral striatal overactivations during reward processing. We hypothesized that this subtype might be characterized by low self-esteem. Eighty-three MDD patients performed the desire-reason dilemma task and completed the Rosenberg Self-Esteem Scale (RSES). Brain activity during bottom-up reward processing was regressed upon the RSES scores, controlling for depression severity measured by the Montgomery-Åsberg Depression Rating Scale. To corroborate the findings, we compared self-esteem scores between patient subgroups with impaired task-induced deactivation (n=31) and with preserved task-induced deactivation (n=31) of the pgACC. Consistent with our a priori hypothesis, activity in a bilateral fronto-striatal network including pgACC and ventral striatum correlated negatively with RSES scores, also when controlling for depression severity. In the additional analysis, patients with impaired task-induced pgACC deactivation showed lower self-esteem (t (52.82)=-2.27; p=.027, d=0.58) compared to those with preserved task-induced pgACC deactivation. We conclude that low self-esteem in MDD patients is linked to a task-induced deactivation dysfunction of the pgACC. Our findings suggest that a previously described possible subtype of MDD with pgACC and ventral striatal overactivations during reward processing is clinically characterized by low self-esteem.

Coexistence of the social semantic effect and non-semantic effect in the default mode network.

Neuroimaging studies have found both semantic and non-semantic effects in the default mode network (DMN), leading to an intense debate on the role of the DMN in semantic processes. Four different views have been proposed: (1) the general semantic view holds that the DMN contains several hub regions supporting general semantic processes; (2) the non-semantic view holds that the semantic effects observed in the DMN (especially the ventral angular gyrus) are confounded by difficulty and do not reflect semantic processing per se; (3) the multifunction view holds that the same areas in the DMN can support both semantic and non-semantic functions; and (4) the multisystem view holds that the DMN contains multiple subnetworks supporting different aspects of semantic processes separately. Using an fMRI experiment, we found that in one of the subnetworks of the DMN, called the social semantic network, all areas showed social semantic activation and difficulty-induced deactivation. The distributions of two non-semantic effects, that is, difficulty-induced and task-induced deactivations, showed dissociation in the DMN. In the bilateral angular gyri, the ventral subdivisions showed social semantic activation independent of difficulty, while the dorsal subdivisions showed no semantic effect but difficulty-induced activation. Our findings provide two insights into the semantic and non-semantic functions of the DMN, which are consistent with both the multisystem and multifunction views: first, the same areas of the DMN can support both social semantic and non-semantic functions; second, similar to the multiple semantic effects of the DMN, the non-semantic effects also vary across its subsystems.

Tasks activating the default mode network map multiple functional systems

Recent developments in network neuroscience suggest reconsidering what we thought we knew about the default mode network (DMN). Although this network has always been seen as unitary and associated with the resting state, a new deconstructive line of research is pointing out that the DMN could be divided into multiple subsystems supporting different functions. By now, it is well known that the DMN is not only deactivated by tasks, but also involved in affective, mnestic, and social paradigms, among others. Nonetheless, it is starting to become clear that the array of activities in which it is involved, might also be extended to more extrinsic functions. The present meta-analytic study is meant to push this boundary a bit further. The BrainMap database was searched for all experimental paradigms activating the DMN, and their activation likelihood estimation maps were then computed. An additional map of task-induced deactivations was also created. A multidimensional scaling indicated that such maps could be arranged along an anatomo-psychological gradient, which goes from midline core activations, associated with the most internal functions, to that of lateral cortices, involved in more external tasks. Further multivariate investigations suggested that such extrinsic mode is especially related to reward, semantic, and emotional functions. However, an important finding was that the various activation maps were often different from the canonical representation of the resting-state DMN, sometimes overlapping with it only in some peripheral nodes, and including external regions such as the insula. Altogether, our findings suggest that the intrinsic–extrinsic opposition may be better understood in the form of a continuous scale, rather than a dichotomy.

Brain structures and activity during a working memory task associated with internet addiction tendency in young adults: A large sample study.

The structural and functional brain characteristics associated with the excessive use of the internet have attracted substantial research attention in the past decade. In current study, we used voxel-based morphometry (VBM) and multiple regression analysis to assess the relationship between internet addiction tendency (IAT) score and regional gray and white matter volumes (rGMVs and rWMVs) and brain activity during a WM task in a large sample of healthy young adults (n = 1,154, mean age, 20.71 ± 1.78 years). We found a significant positive correlation between IAT score and gray matter volume (GMV) of right supramarginal gyrus (rSMG) and significant negative correlations with white matter volume (WMV) of right temporal lobe (sub-gyral and superior temporal gyrus), right sublobar area (extra-nuclear and lentiform nucleus), right cerebellar anterior lobe, cerebellar tonsil, right frontal lobe (inferior frontal gyrus and sub-gyral areas), and the pons. Also, IAT was significantly and positively correlated with brain activity in the default-mode network (DMN), medial frontal gyrus, medial part of the superior frontal gyrus, and anterior cingulate cortex during a 2-back working memory (WM) task. Moreover, whole-brain analyses of rGMV showed significant effects of interaction between sex and the IAT scores in the area spreading around the left anterior insula and left lentiform. This interaction was moderated by positive correlation in women. These results indicate that IAT is associated with (a) increased GMV in rSMG, which is involved in phonological processing, (b) decreased WMV in areas of frontal, sublobar, and temporal lobes, which are involved in response inhibition, and (c) reduced task-induced deactivation of the DMN, indicative of altered attentional allocation.

Causal Interactions Between the Default Mode Network and Central Executive Network in Patients with Major Depression

Two different but interacting neural systems exist in the human brain: the task positive networks and task negative networks. One of the most important task positive networks is the central executive network (CEN), while the task negative network generally refers to the default mode network (DMN), which usually demonstrates task-induced deactivation. Although previous studies have clearly shown the association of both the CEN and DMN with major depressive disorder (MDD), how the causal interactions between these two networks change in depressed patients remains unclear. In the current study, 99 subjects (43 patients with MDD and 56 healthy controls) were recruited with their resting-state fMRI data collected. After data preprocessing, spectral dynamic causal modeling (spDCM) was used to investigate the causal interactions within and between the DMN and CEN. Group commonalities and differences in causal interaction patterns within and between the CEN and DMN in patients and controls were assessed by a parametric empirical Bayes (PEB) model. Both subject groups demonstrated significant effective connectivity between regions of the CEN and DMN. In particular, we detected inhibitory influences from the CEN to the DMN with node-level PEB analyses, which may help to explain the anticorrelations between these two networks consistently reported in previous studies. Compared with healthy controls, patients with MDD showed increased effective connectivity within the CEN and decreased connectivity from regions of the CEN to DMN, suggesting impaired control of the DMN by the CEN in these patients. These findings might provide new insights into the neural substrates of MDD.

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.

Effects of aging on brain networks during swallowing: general linear model and independent component analyses

Swallowing disorders occur more frequently in older adults. However, the effects of the aging process on neural activation when swallowing are unclear. We aimed to identify neural regions activated during swallowing and evaluate changes in neural activation and neural networks with aging. Using a general linear model (GLM) and independent component (IC) analyses, blood oxygen level-dependent (BOLD) signals were observed in the lateral precentral gyrus, postcentral gyrus, anterior insular cortices, supramarginal gyri, and medial frontal gyrus during swallowing. The right thalamus and anterior cingulate gyri were found to be active areas by GLM and IC analyses, respectively. In the correlational analyses, age was negatively correlated with BOLD signals of the lateral precentral gyri, postcentral gyri, and insular cortices in swallowing tasks. Additionally, correlation analyses between ICs of all participants and age revealed negative correlations in the right supramarginal gyrus, both anterior cingulate cortices, putamen, and cerebellum. In the network analysis, the BOLD signal positively correlated with age in the default mode network (DMN), and was negatively correlated in the lateral precentral gyri, postcentral gyri, and insular cortices. The amplitude of low-frequency fluctuations was significantly decreased in the DMN and increased in swallowing-related areas during swallowing tasks. These results suggest that aging has negative effects on the activation of swallowing-related regions and task-induced deactivation of the DMN. These changes may be used to detect early functional decline during swallowing.

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.

Prospective evaluation of functional brain activity and oxidative damage in breast cancer: changes in task-induced deactivation during a working memory task.

Cancer-related cognitive dysfunction is an important issue for breast cancer survivors. Previous research has identified both cross-sectional and longitudinal alterations in brain function related to cancer status and treatment. In this study, we prospectively collected functional magnetic resonance imaging data in breast cancer cases treated with adjuvant chemotherapy and in controls with no cancer history during a working memory task. Data and blood specimens were collected immediately prior to the start of treatment (baseline) and following completion of treatment (follow-up), and at yoked intervals for controls. In secondary analysis we assessed the levels of oxidative DNA damage in peripheral blood lymphocytes of cases and controls using the Comet assay. A significant group*time interaction revealed reduced deactivation in the superior frontal gyrus in the controls at follow-up, in contrast to cases, who exhibited similar magnitude of deactivation at baseline and follow-up. Working memory performance indicated a significant improvement in the controls at follow-up, and no change in performance in cases. In secondary analyses, oxidative DNA damage levels were elevated in the cases at follow-up compared to controls, but no associations were found between the Comet assay variables and functional imaging at either time-point or group. In light of previous reports on task induced deactivations, our findings reflect continuing effortful processing at follow-up in the breast cancer group, with relatively less effortful processing in the control group given the reduced novelty and practice effects from the baseline to follow-up.

Succeeding in deactivating: associations of hair zinc levels with functional and structural neural mechanisms

Zinc is a biologically essential element and involved in a wide range of cellular processes. Here, we investigated the associations of zinc levels in hair with brain activity during the n-back working memory task using functional magnetic resonance imaging, fractional anisotropy (FA) of diffusion tensor imaging, and cognitive differences in a study cohort of 924 healthy young adults. Our findings showed that greater hair zinc levels were associated with lower brain activity during working memory in extensive areas in the default mode network (i.e., greater task-induced deactivation) as well as greater FA in white matter areas near the hippocampus and posterior limbs of the internal capsule. These findings advance previous non-neuroimaging findings of zinc’s associations with excitability, excitability-associated disorders, and myelination.

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.

Originality of divergent thinking is associated with working memory–related brain activity: Evidence from a large sample study

The originality of creativity measured by divergent thinking (CMDT) is a unique variable that is positively correlated with psychometric intelligence and other psychological measures. Here, we aimed to determine the associations of CMDT originality/fluency scores and brain activity associated with working memory (WM) and simple cognitive processes during the N-back paradigm in a cohort of 1221 young adults. We observed that originality/fluency scores were associated with greater brain activity during the 0-back simple cognitive task and 2-back WM task in key nodes of the ventral attention system in the right hemisphere. Further, subjects with higher originality/fluency scores showed lower task-induced deactivations in areas of the default mode network, especially during the 2-back task. Psychological analyses revealed the associations of originality/fluency scores with both psychometric intelligence and systemizing. We also observed the effects of interaction between sex and originality/fluency scores on functional activity during the 0-back task in posterior parts of the default mode network together with other areas as well as simple processing speed. These results indicate that the originality of CMDT is associated with (a) greater activation of the ventral attention system, which is involved in reorienting attention and (b) reduced task-induced deactivation of the default mode network, which is indicative of alterations in attentional reallocation, and (c) cognitive correlates of originality of CMDT and revealed sex differences in these associations.

The effect of response frequency on cognitive brain activity during an alertness task.

A required response forces the brain to react overtly on a stimulus. This may be a factor that influences cognitive activity during a task, as it could facilitate for instance alertness, especially in tasks that are relatively easy. In the current article, we therefore tested the hypothesis that response frequency affects cognitive brain activity in an alertness task. In this 3T functional MRI study, healthy volunteers performed a continuous performance task with three conditions with increasing response frequency. Only scans during presentation of non-targets were analyzed, to exclude activity related to the change in frequency in response selection and motor responses between conditions. To evaluate changes in cognitive brain activity, a network analysis was performed based on two main networks including regions with task-induced activation and task-induced deactivation. We tested for differences in brain activity as an effect of target frequency. Performance results indicated no effect of target frequency on accuracy or reaction time. During non-targets, we found significant signal changes in TID for all three conditions, whereas TIA showed no significant signal changes in any condition. Target frequency did not have a significant effect on the level of signal change at network level, as well as at individual region level. Our study showed predominantly deactivation during non-responses in all three task conditions. Furthermore, our results indicate that response frequency does not influence brain activity during an alertness task. Our results provide additional information relevant for the understanding of the neurophysiological implementation of cognitive control or alertness.

Neuroimaging signatures of brain plasticity in adults with prenatal exposure to polychlorinated biphenyls: Altered functional connectivity on functional MRI

Prenatal exposure to polychlorinated biphenyls (PCBs), persistent organic pollutants in food chains and environment, exerts negative effects on children's cognitive function. To study the long-term effects, we examined cognitive functions in the male children of women with substantial PCB exposure in Taiwan during 1978–1979 and investigated neural basis of cognitive function changes through structural magnetic resonance imaging (MRI) and functional MRI (fMRI), which included resting-state and task-activated fMRI with two paradigms: a 2-back task and a picture rotation task. Ten men aged 30.0 ± 3.7 years with prenatal exposure to PCBs and 11 unexposed controls aged 28.1 ± 3.1 years participated. Both groups had similar cognitive phenotypes and behavioral results. Structural MRI analysis results showed that the PCB group had increased cortical thickness over the right inferior parietal lobule. In the resting-state study, the PCB group showed alterations in the default mode network. During the tasks, the PCB group showed decreased task-induced deactivation signals in cognition–associated brain areas during the 2-back task but enhanced deactivations during the picture rotation task. This study demonstrated altered structural MRI as well as resting and task-related fMRI in men with prenatal PCB exposure, suggesting altered brain plasticity and compensatory neuropsychological performance.

Regional excitation-inhibition balance predicts default-mode network deactivation via functional connectivity

Deactivation of the default mode network (DMN) is one of the most reliable observations from neuroimaging and has significant implications in development, aging, and various neuropsychiatric disorders. However, the neural mechanism underlying DMN deactivation remains elusive. As the coordination of regional neurochemical substrates and interregional neural interactions are both essential in support of brain functions, a quantitative description of how they impact DMN deactivation may provide new insights into the mechanism. Using an n-back working memory task fMRI and magnetic resonance spectroscopy, we probed the pairwise relationship between task-induced deactivation, interregional functional connectivity and regional excitation-inhibition balance (evaluated by glutamate/GABA ratio) in the posterior cingulate cortex/precuneus (PCC/PCu). Task-induced PCC/PCu deactivation correlated with its excitation-inhibition balance and interregional functional connectivity, where participants with lower glutamate/GABA ratio, stronger intra-DMN connections and stronger antagonistic DMN-SN (salience network)/ECN (executive control network) inter-network connections had greater PCC/PCu deactivation. Mediation analyses revealed that the DMN-SN functional interactions partially mediated the relationship between task-induced deactivation and the excitation-inhibition balance at the PCC/PCu. The triple-relationship discovered in the present study has the potential to bridge DMN-deactivation related findings from various neuroimaging modalities and may provide new insights into the neural mechanism of DMN deactivation. Moreover, this finding may have significant implications for neuropsychiatric disorders related to the DMN dysfunction and suggests an integrated application of pharmacological and neuromodulation-based strategies for rescuing DMN deactivation deficits.

General intelligence is associated with working memory-related brain activity: new evidence from a large sample study.

Psychometric intelligence is closely related to working memory capacity. Here we aim to determine the associations of neural activation patterns during the N-back working memory paradigm with psychometric intelligence and working memory performance. We solved the statistical problems of previous studies using (1) a large cohort of 1235 young adults and (2) robust voxel-by-voxel permutation-based statistics at the whole-brain level. Many of the significant correlations were weak, and our findings were not consistent with those of previous studies. We observed that many of the significant correlations involved brain areas in the periphery or boundaries between the task-positive network (TPN) and task-negative network (TNN), suggesting that the expansion of the TPN or TNN is associated with greater cognitive ability. Lower activity in TPN and less task-induced deactivation (TID) in TNN were associated with greater cognitive ability. These findings indicate that subjects with greater cognitive ability have a lower brain response to task demand, consistent with the notion that TID in TNN reflects cognitive demand but partly inconsistent with the prevailing neural efficiency theory. One exception was the pre-supplementary motor area, which plays a key role in cognitive control and sequential processing. In this area, intelligent subjects demonstrated greater activity related to working memory, suggesting that the pre-supplementary motor area plays a unique role in the execution of working memory tasks in intelligent subjects.

Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities

The default mode network (DMN) comprises defined brain regions contributing to internally-directed thought processes. Reductions in task-induced deactivation in the DMN have been associated with increasing age and poorer executive task performance, but factors underlying these functional changes remain unclear. We investigated contributions of white matter (WM) microstructure, WM hyperintensities (WMH) and Alzheimer's pathology to age-related alterations in DMN function. Thirty-five cognitively normal older adults and 29 younger adults underwent working memory task fMRI and diffusion tensor imaging. In the older adults, we measured cerebrospinal fluid tau and Aβ42 (markers of AD pathology), and WMH on FLAIR imaging (marker of cerebrovascular disease). We identified a set of regions showing DMN deactivation and a set of inter-connecting WM tracts (DMN-WM) common to both age groups. There were negative associations between DMN deactivation and task performance in older adults, consistent with previous studies. Decreased DMN deactivation was associated with AD pathology and WM microstructure but not with WMH volume. Mediation analyses showed that WM microstructure mediated declines in DMN deactivation associated with both aging and AD pathology. Together these results suggest that AD pathology may exert a “second-hit” on WM microstructure, over-and-above the effects of age, both contributing to diminished DMN deactivation in older adults.

Task-induced deactivation in diverse brain systems correlates with interindividual differences in distinct autonomic indices

Neuroimaging research has shown that different cognitive tasks induce relatively specific activation patterns, as well as less task-specific deactivation patterns. Here we examined whether individual differences in Autonomic Nervous System (ANS) activity during task performance correlate with the magnitude of task-induced deactivation. In an fMRI study, participants performed a continuous mental arithmetic task in a task/rest block design, while undergoing combined fMRI and heart/respiration rate acquisitions using photoplethysmograph and respiration belt. As expected, task performance increased heart-rate and reduced the RMSSD, a cardiac index related to vagal tone. Across participants, higher heart rate during task was linked to increased activation in fronto-parietal regions, as well as to stronger deactivation in ventromedial prefrontal regions. Respiration frequency during task was associated with similar patterns, but in different regions than those identified for heart-rate. Finally, in a large set of regions, almost exclusively limited to the Default Mode Network, lower RMSSD was associated with greater deactivation, and furthermore, the vast majority of these regions were task-deactivated at the group level. Together, our findings show that inter-individual differences in ANS activity are strongly linked to task-induced deactivation. Importantly, our findings suggest that deactivation is a multifaceted construct potentially linked to ANS control, because distinct ANS measures correlate with deactivation in different regions. We discuss the implications for current theories of cortical control of the ANS and for accounts of deactivation, with particular reference to studies documenting a ”failure to deactivate” in multiple clinical states.

Functional connectivity maps based on hippocampal and thalamic dynamics may account for the default-mode network.

The default-mode network (DMN) has been reported to comprise a set of inter-connected transmodal cortical areas, including the posterior cingulate cortex (PCC), medial prefrontal cortex, posterior inferior parietal lobule, lateral temporal region and others. However, the subcortical constituents of the DMN are still not clear. This study aimed to examine whether the correlation maps derived from subcortical structures may also account for neural pattern of the DMN. Structural magnetic resonance imaging (MRI) and resting-state functional MRI scans of 36 subjects were selected from the Rockland sample (Nathan Kline Institute). The hippocampus and thalamus were chosen as subcortical regions of interest (ROIs). Each ROI was partitioned into composite modules which in turn provided simplified and representative dynamics of blood-oxygen-level-dependent (BOLD) signals. PCC-seeded and ROI-based correlation maps were compared by conjunction analyses and paired t-tests (corrected P<0.05). Our results unveiled that the hippocampus-, thalamus- and PCC-centred correlation patterns actually overlapped to a substantial degree. Integrating the signals in the thalamus and hippocampus altogether fully explained the PCC-seeded DMN. Supplementary analyses based on the BOLD dynamics in several subcortical nuclei (caudate, putamen and globus pallidus) were dissimilar to the DMN. The DMN derived from the ROI/seed-based approach may represent combined limbic and region-specific informatics (and their closely interacting neural substrates). The possible causes for previous methods of task-induced deactivation and seed-based correlation that failed to depict the holistic limbic picture are discussed. The neocortical manifestation of DMN may reflect the limbic information in the transmodal brain regions.

Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial.

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiologic and clinical effects of L-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received L-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (PANSS, SANS, CDSS), cognition (MATRICS composite) and three complementary MRI measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared to placebo, L-methylfolate increased plasma methylfolate levels (d=1.00, p=.0009) and improved PANSS Total (d=.61, p=.03) as well as PANSS Negative and General Psychopathology subscales. While PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving L-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity, and increased cortical thickness. In conclusion, L-methylfolate supplementation was associated with salutary physiologic changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials.