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Identifying a coupled dynamical system out of many plausible candidates, each of which could serve as the underlying generator of some observed measurements, is a profoundly ill-posed problem that commonly arises when modelling real-world phenomena. In this review, we detail a set of statistical procedures for inferring the structure of nonlinear coupled dynamical systems (structure learning), which has proved useful in neuroscience research. A key focus here is the comparison of competing models of network architectures—and implicit coupling functions—in terms of their Bayesian model evidence. These methods are collectively referred to as dynamic causal modelling. We focus on a relatively new approach that is proving remarkably useful, namely Bayesian model reduction, which enables rapid evaluation and comparison of models that differ in their network architecture. We illustrate the usefulness of these techniques through modelling neurovascular coupling (cellular pathways linking neuronal and vascular systems), whose function is an active focus of research in neurobiology and the imaging of coupled neuronal systems. This article is part of the theme issue ‘Coupling functions: dynamical interaction mechanisms in the physical, biological and social sciences'.

By equipping a previously reported dynamic causal modelling of COVID-19 with an isolation state, we were able to model the effects of self-isolation consequent on testing and tracking. Specifically, we included a quarantine or isolation state occupied by people who believe they might be infected but are asymptomatic—and could only leave if they test negative. We recovered maximum posteriori estimates of the model parameters using time series of new cases, daily deaths, and tests for the UK. These parameters were used to simulate the trajectory of the outbreak in the UK over an 18-month period. Several clear-cut conclusions emerged from these simulations. For example, under plausible (graded) relaxations of social distancing, a rebound of infections is highly unlikely. The emergence of a second wave depends almost exclusively on the rate at which we lose immunity, inherited from the first wave. There exists no testing strategy that can attenuate mortality rates, other than by deferring or delaying a second wave. A testing and tracking policy—implemented at the present time—will defer any second wave beyond a time horizon of 18 months. Crucially, this deferment is within current testing capabilities (requiring an efficacy of tracing and tracking of about 20% of asymptomatic infected cases, with 50,000 tests per day). These conclusions are based upon a dynamic causal model for which we provide some construct and face validation—using a comparative analysis of the United Kingdom and Germany, supplemented with recent serological studies.

Within the human immune system, the expression of GPR56, an adhesion G-protein couple receptor, is restricted to cytotoxic Natural Killer (NK) and T lymphocytes, including T effector memory re-expressing CD45RA (TEMRA) cells. In primary NK cells, GPR56 acts as an inhibitory receptor, as it diminishes their ability to eliminate target cells. Overexpression of GPR56 in immortal NK-92 cells also leads to robust inhibition of cell chemotaxis. GPR56 is speculated to promote retention of cytotoxic lymphocytes in inflamed peripheral tissues. Thus, GPR56 has the potential to regulate immune responses that may lead to excessive inflammation and autoimmunity. The aim of the present study was, therefore, to examine whether GPR56 mediates cytotoxic immune cell functions and whether GPR56 expression is altered in autoimmune diseases. To tackle these questions, we first compared expression of GPR56 in healthy and autoimmune disease patient tissues using scRNA-seq datasets. Next, we tested whether stimulation of GPR56 with a monoclonal antibody modulated the migratory capacity of NK and CD8+ TEMRA cells. We found that chemotaxis toward CXCL12, IL-8, and CX3CL1 was strikingly inhibited by GPR56. Using bulk RNA-seq, we found GPR56-stimulation impacted a multitude of signaling cascades that regulate cell chemotaxis. Taken together, our results confirm that GPR56 is a marker for NK and TEMRA cells in healthy and autoimmune patient tissues and establish GPR56 as a key regulator of lymphocyte chemotaxis.

Contains fulltext : 202961.pdf (Publisher’s version ) (Open Access) We present a significant extension of the Brain Imaging Data Structure (BIDS) to support the specific aspects of magnetoencephalography (MEG) data. MEG measures brain activity with millisecond temporal resolution and unique source imaging capabilities. So far, BIDS was a solution to organise magnetic resonance imaging (MRI) data. The nature and acquisition parameters of MRI and MEG data are strongly dissimilar. Although there is no standard data format for MEG, we propose MEG-BIDS as a principled solution to store, organise, process and share the multidimensional data volumes produced by the modality. The standard also includes well-defined metadata, to facilitate future data harmonisation and sharing efforts. This responds to unmet needs from the multimodal neuroimaging community and paves the way to further integration of other techniques in electrophysiology. MEG-BIDS builds on MRI-BIDS, extending BIDS to a multimodal data structure. We feature several data-analytics software that have adopted MEG-BIDS, and a diverse sample of open MEG-BIDS data resources available to everyone. 12 p.

Primary dystonia has been associated with an underlying dysfunction of a wide network of brain regions including the motor cortex, basal ganglia, cerebellum, brainstem and spinal cord. Dystonia can be effectively treated by pallidal deep brain stimulation although the mechanism of this effect is not well understood. Here, we sought to characterize cortico-basal ganglia functional connectivity using a frequency-specific measure of connectivity-coherence. We recorded direct local field potentials from the human pallidum simultaneously with whole head magnetoencephalography to characterize functional connectivity in the cortico-pallidal oscillatory network in nine patients with idiopathic dystonia. Three-dimensional cortico-pallidal coherence images were compared to surrogate images of phase shuffled data across patients to reveal clusters of significant coherence (family-wise error P < 0.01, voxel extent 1000). Three frequency-specific, spatially-distinct cortico-pallidal networks have been identified: a pallido-temporal source of theta band (4-8 Hz) coherence, a pallido-cerebellar source of alpha band (7-13 Hz) coherence and a cortico-pallidal source of beta band (13-30 Hz) coherence over sensorimotor areas. Granger-based directionality analysis revealed directional coupling with the pallidal local field potentials leading in the theta and alpha band and the magnetoencephalographic cortical source leading in the beta band. The degree of pallido-cerebellar coupling showed an inverse correlation with dystonic symptom severity. Our data extend previous findings in patients with Parkinson's disease describing motor cortex-basal ganglia oscillatory connectivity in the beta band to patients with dystonia. Source coherence analysis revealed two additional frequency-specific networks involving the temporal cortex and the cerebellum. Pallido-cerebellar oscillatory connectivity and its association with dystonic symptoms provides further confirmation of cerebellar involvement in dystonia that has been recently reported using functional magnetic resonance imaging and fibre tracking.

SummaryMutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1creER increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.

Some motor impairments associated with Parkinson’s disease are thought to arise from pathological activity in the neuronal networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in Parkinsonism, we investigated changes to the directed connectivity in these networks following dopamine depletion. We recorded local field potentials in the cortex and basal ganglia of anesthetized rats rendered Parkinsonian by injection of 6-hydroxydopamine (6-OHDA), with dopamine-intact rats as controls. We performed systematic analyses of the networks using a novel tool for estimation of directed neural interactions, as well as a conditioned variant which permits the analysis of the dependence of a connection upon a third reference signal. We find evidence of the dopamine dependency of both low beta (14-20 Hz) and high beta/low gamma (20-40 Hz) directed interactions within the BG and cortico-BG networks. Notably, 6-OHDA lesions were associated with enhancement of the cortical “hyperdirect” connection to the subthalamic nucleus (STN), as well the STN’s feedback to the cortex and striatum. We find beta synchronization to be robust to conditioning using signals from any one structure. Conversely, we find that high beta/gamma drive from the cortex to subcortical regions is weakened by 6-OHDA lesions and is susceptible to conditioning. Furthermore, we provide evidence that gamma is routed from striatum in a pathway that is independent of STN. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in Parkinsonism.New & NoteworthyWe present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aims of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinson’s disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a “short-circuiting” of the network that gives rise to the conditions from which pathological synchronization may arise.

Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that Setdb2 was the only protein lysine methyltransferase induced during infection with influenza virus. Setdb2 expression depended on signaling via type I interferons, and Setdb2 repressed expression of the gene encoding the neutrophil attractant CXCL1 and other genes that are targets of the transcription factor NF-κB. This coincided with occupancy by Setdb2 at the Cxcl1 promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone H3 Lys9 (H3K9me3). Mice with a hypomorphic gene-trap construct of Setdb2 exhibited increased infiltration of neutrophils during sterile lung inflammation and were less sensitive to bacterial superinfection after infection with influenza virus. This suggested that a Setdb2-mediated regulatory crosstalk between the type I interferons and NF-κB pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

Movement is accompanied by changes in the degree to which neurons in corticobasal ganglia loops synchronize their activity within discrete frequency ranges. Although two principal frequency bands—beta (15–30 Hz) and gamma (60–90 Hz)—have been implicated in motor control, the precise functional correlates of their activities remain unclear. Local field potential (LFP) recordings in humans with Parkinson's disease undergoing surgery for deep brain stimulation to the subthalamic nucleus (STN) indicate that spectral changes both anticipate movement and occur perimovement. The extent to which such changes are modulated by cognitive factors involved in making a correct response seems critical in characterizing the functional associations of these oscillations. Accordingly, by recording LFP activity from the STN in parkinsonian patients, we demonstrate that perimovement beta and gamma reactivity is modulated by task complexity in a dopamine-dependent manner, despite the dynamics of the movement remaining unchanged. In contrast, spectral changes occurring in anticipation of future movement were limited to the beta band and, although modulated by dopaminergic therapy, were not modulated by task complexity. Our findings suggest two dopamine-dependent processes indexed by spectral changes in the STN: (1) an anticipatory activity reflected in the beta band that signals the likelihood of future action but does not proactively change with the cognitive demands of the potential response, and (2) perimovement activity that involves reciprocal beta and gamma band changes and is not exclusively related to explicit motor processing. Rather perimovement activity can also vary with, and may reflect, the cognitive complexity of the task.

Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.

Functional neurosurgery has afforded the opportunity to assess interactions between populations of neurons in the human cerebral cortex and basal ganglia in patients with Parkinson’s disease (PD). Interactions occur over a wide range of frequencies, and the functional significance of those above 30 Hz is particularly unclear. Do they improve movement and, if so, in what way? We acquired simultaneously magnetoencephalography (MEG) and direct recordings from the subthalamic nucleus (STN) in 17 PD patients. We examined the effect of synchronous and sequential finger movements and of the dopamine prodrug levodopa on induced power in the contralateral primary motor cortex (M1) and STN and on the coherence between the two structures. We observed discrete peaks in M1 and STN power over 60-90 Hz and 300-400 Hz. All these power peaks increased with movement and levodopa treatment. Only STN activity over 60-90 Hz was coherent with activity in M1. Directionality analysis showed that STN gamma activity at 60-90 Hz tended to drive gamma activity in M1. The effects of levodopa on both local and distant synchronisation over 60-90 Hz correlated with the degree of improvement in bradykinesia-rigidity, as did local STN activity at 300-400 Hz. Despite this, there were no effects of movement type, nor interactions between movement type and levodopa in the STN, nor in the coherence between STN and M1. We conclude that synchronisation over 60-90 Hz in the basal ganglia cortical network is prokinetic, but likely through a modulatory effect rather than any involvement in explicit motor processing.

This article describes the first application of a generic (empirical) Bayesian analysis of between‐subject effects in the dynamic causal modeling (DCM) of electrophysiological (MEG) data. It shows that (i) non‐invasive (MEG) data can be used to characterize subject‐specific differences in cortical microcircuitry and (ii) presents a validation of DCM with neural fields that exploits intersubject variability in gamma oscillations. We find that intersubject variability in visually induced gamma responses reflects changes in the excitation‐inhibition balance in a canonical cortical circuit. Crucially, this variability can be explained by subject‐specific differences in intrinsic connections to and from inhibitory interneurons that form a pyramidal‐interneuron gamma network. Our approach uses Bayesian model reduction to evaluate the evidence for (large sets of) nested models—and optimize the corresponding connectivity estimates at the within and between‐subject level. We also consider Bayesian cross‐validation to obtain predictive estimates for gamma‐response phenotypes, using a leave‐one‐out procedure. Hum Brain Mapp 37:4597–4614, 2016. © The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Antiviral responses must be tightly regulated to rapidly defend against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses1 and their transcription is regulated by a variety of transcription factors2; principal amongst these is the family of interferon regulatory factors (IRFs)3. The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex interactions that give rise to precise coordination of the interferon response. Here we have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription and we have further demonstrated that FOXO3, IRF7 and IFN-I form a coherent feed-forward regulatory circuit. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.

Frontoparietal cortex is involved in the explicit processing (awareness) of stimuli. Frontoparietal activation has also been found in studies of subliminal stimulus processing. We hypothesized that an impairment of top-down processes, involved in recurrent neuronal message-passing and the generation of long-latency electrophysiological responses, might provide a more reliable correlate of consciousness in severely brain-damaged patients, than frontoparietal responses. We measured effective connectivity during a mismatch negativity paradigm and found that the only significant difference between patients in a vegetative state and controls was an impairment of backward connectivity from frontal to temporal cortices. This result emphasizes the importance of top-down projections in recurrent processing that involve high-order associative cortices for conscious perception.

Motivation: Histone acetylation (HAc) is associated with open chromatin, and HAc has been shown to facilitate transcription factor (TF) binding in mammalian cells. In the innate immune system context, epigenetic studies strongly implicate HAc in the transcriptional response of activated macrophages. We hypothesized that using data from large-scale sequencing of a HAc chromatin immunoprecipitation assay (ChIP-Seq) would improve the performance of computational prediction of binding locations of TFs mediating the response to a signaling event, namely, macrophage activation. Results: We tested this hypothesis using a multi-evidence approach for predicting binding sites. As a training/test dataset, we used ChIP-Seq-derived TF binding site locations for five TFs in activated murine macrophages. Our model combined TF binding site motif scanning with evidence from sequence-based sources and from HAc ChIP-Seq data, using a weighted sum of thresholded scores. We find that using HAc data significantly improves the performance of motif-based TF binding site prediction. Furthermore, we find that within regions of high HAc, local minima of the HAc ChIP-Seq signal are particularly strongly correlated with TF binding locations. Our model, using motif scanning and HAc local minima, improves the sensitivity for TF binding site prediction by ∼50% over a model based on motif scanning alone, at a false positive rate cutoff of 0.01. Availability: The data and software source code for model training and validation are freely available online at http://magnet.systemsbiology.net/hac. Contact: aderem@systemsbiology.org; ishmulevich@systemsbiology.org Supplementary information: Supplementary data are available at Bioinformatics online.

Objective The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been hampered by the large artifact that the TMS generates in the EEG. Using TMS with EEG necessitates a sophisticated artifact-resistant EEG system that can acquire reliable signals in the crucial several tens of milliseconds immediately following the TMS pulse. Here, we demonstrate the use of a novel artifact removal algorithm together with a 24-bit EEG system to achieve similar recordings as those obtained with the dedicated TMS-compatible EEG system. Methods This setup was used to compare TMS-evoked responses between a group of healthy controls and a group of patients with schizophrenia, a condition in which effective neural connectivity is thought to be compromised. Results We observe differences in TMS-evoked responses between the two groups, similar to those recently reported in a study that used a dedicated TMS-compatible EEG system. Conclusions The standard 24-bit EEG system combined with an artifact removal algorithm produces results similar to the dedicated TMS-compatible system. Significance This paves the way for more researchers and clinicians to use TMS-evoked responses for research and diagnosis of a wide spectrum of disorders.

The innate immune system is like a double-edged sword: it is absolutely required for host defense against infection, but when uncontrolled, it can trigger a plethora of inflammatory diseases. Here we use systems-biology approaches to predict and confirm the existence of a gene-regulatory network involving dynamic interaction among the transcription factors NF-kappaB, C/EBPdelta and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encoding interleukin 6 and C/EBPdelta and experimentally confirmed the prediction that the combination of an initiator (NF-kappaB), an amplifier (C/EBPdelta) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately.

It is unclear how subthalamic nucleus activity is modulated by the cerebral cortex. Here we investigate the effect of transcranial magnetic stimulation (TMS) of the cortex on oscillatory subthalamic local field potential activity in the 8-35 Hz (alpha/beta) band, as exaggerated synchronization in this band is implicated in the pathophysiology of parkinsonism. We studied nine patients with Parkinson's disease (PD) to test whether cortical stimulation can modulate synchronized oscillations in the human subthalamic nucleus. With patients at rest, single-pulse TMS was delivered every 5 s over each primary motor area and supplementary motor area at intensities of 85-115% resting motor threshold. Subthalamic local field potentials were recorded from deep brain stimulation electrodes implanted into this nucleus for the treatment of PD. Motor cortical stimulation suppressed beta activity in the subthalamic nucleus from approximately 0.2 to 0.6 s after TMS (repeated measures anova; main effect of time, P < 0.01; main effect of side, P = 0.03), regardless of intensity. TMS over the supplementary motor area also reduced subthalamic beta activity at 95% (P = 0.05) and 115% resting motor threshold (P = 0.01). The oscillatory activity decreased to 80 +/- 26% of baseline (averaged across sites and stimulation intensities). Suppression with subthreshold stimuli confirmed that these changes were centrally driven and not due to peripheral afference. The results may have implications for mechanisms underlying the reported therapeutic benefits of cortical stimulation.

Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long-term potentiation-like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN-SSEP) recordings and two-point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near-synchronously to an afferent signal containing mechanoreceptive information, MN-SSEP changes (significant at 21-31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS-induced MN-SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near-synchronous afferent signal contained predominantly proprioceptive information, PAS-induced MN-SSEP changes (20-29 ms) were shifted medially, and tactile performance remained stable. With near-synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN-SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS-evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing-dependent and qualitatively congruent behavioural changes.

This technical note addresses some key reproducibility issues in the dynamic causal modelling of group studies of event related potentials. Specifically, we address the reproducibility of Bayesian model comparison (and inferences about model parameters) from three important perspectives namely: (i) reproducibility with independent data (obtained by averaging over odd and even trials); (ii) reproducibility over formally distinct models (namely, classic ERP and canonical microcircuit or CMC models); and (iii) reproducibility over inversion schemes (inversion of the grand average and estimation of group effects using empirical Bayes). Our hope was to illustrate the degree of reproducibility one can expect from DCM when analysing different data, under different models with different analyses.

Chondroitin sulphate proteoglycan (CSPG) inhibits axonal regeneration in the central nervous system (CNS) and its local degradation promotes repair. We postulated that the enzymatic degradation of CSPG generates reparative products. Here we show that an enzymatic degradation product of CSPG, a specific disaccharide (CSPG-DS), promoted CNS recovery by modulating both neuronal and microglial behaviour. In neurons, acting via a mechanism that involves the PKCalpha and PYK2 intracellular signalling pathways, CSPG-DS induced neurite outgrowth and protected against neuronal toxicity and axonal collapse in vitro. In microglia, via a mechanism that involves ERK1/2 and PYK2, CSPG-DS evoked a response that allowed these cells to manifest a neuroprotective phenotype ex vivo. In vivo, systemically or locally injected CSPG-DS protected neurons in mice subjected to glutamate or aggregated beta-amyloid intoxication. Our results suggest that treatment with CSPG-DS might provide a way to promote post-traumatic recovery, via multiple cellular targets.

The rearrangement of the Golgi apparatus during mitosis is regulated by several protein kinases, including Cdk1 and Plk1. Several peripheral Golgi proteins that dissociate from the Golgi during mitosis are implicated in regulation of cytokinesis or chromosome segregation, thereby coordinating mitotic and cytokinetic events to Golgi rearrangement. Here we show that, at the onset of mitosis, Cdk1 phosphorylates the peripheral Golgi protein Nir2 at multiple sites; of these, S382 is the most prominent. Phosphorylation of Nir2 by Cdk1 facilitates its dissociation from the Golgi apparatus, and phospho-Nir2(pS382) is localized in the cleavage furrow and midbody during cytokinesis. Mitotic phosphorylation of Nir2 is required for docking of the phospho-Ser/Thr binding module, the Polo box domain of Plk1, and overexpression of a Nir2 mutant, which fails to interact with Plk1, affects the completion of cytokinesis. These results demonstrate a mechanism for coordinating mitotic and cytokinetic events with Golgi rearrangement during cell division.

Objective To explore the differences and similarities of oscillatory activity between subregions of the subthalamic nucleus (STN). Background In Parkinson’s disease (PD), treatment driven changes in bradykinesia and rigidity are associated with changes in exaggerated local field potential (LFP) beta (13–30 Hz) power. The power of these oscillations has recently successfully been applied as a biomarker for adaptive deep brain stimulation. However, it is not yet known where in the STN beta can be best recorded, and it remains unclear whether this activity correlates with OFF-state impairment, as opposed to changes in impairment with treatment. Methods In 39 patients with advanced PD who underwent MRI-guided and MRI-verified STN DBS surgery, 229 bipolar LFP’s were recorded in the postoperative week in the OFF dopaminergic state during rest. The location of the electrode in the visualized STN was divided into 5 subregions: superior, dorsolateral, central, anteromedial and inferior. LFP power spectra were obtained by using fast Fourier transformations and were sequentially normalised, log-transformed and divided into alpha (8–13 Hz) and beta band power. Results 95 (41%) of the LFP’s contacts had one or more contacts in the inferior part of the STN. For the anteromedial, central, dorsolateral and superior part of the STN these numbers were 15 (7%), 112 (49%), 66 (29%) and 92 (40%), respectively (Fig. 1). Maximum LFP beta power showed a significant correlation (r = 0.40, p

Rett syndrome is a devastating neurodevelopmental disorder, primarily caused by mutations of methyl CpG-binding protein 2 (MeCP2). Although the genetic cause of disease was identified over a decade ago, a significant gap still remains in both our clinical and scientific understanding of its pathogenesis. Neurons are known to be primary players in pathology, with their dysfunction being the key in Rett syndrome. While studies in mice have demonstrated a clear causative – and potential therapeutic – role for neurons in Rett syndrome, recent work has suggested that other tissues also contribute significantly to progression of the disease. Indeed, Rett syndrome is known to present with several common peripheral pathologies, such as osteopenia, scoliosis, gastrointestinal problems including nutritional defects, and general growth deficit. Mouse models assessing the potential role of non-neuronal cell types have confirmed both roles in disease and potential therapeutic targets. A new picture is emerging in which neurons both initiate and drive pathology, while dysfunction of other cell types and peripheral tissues exacerbate disease, possibly amplifying further neurologic problems, and ultimately result in a positive feedback loop of progressively worsening symptoms. Here, we review what is known about neuronal and non-neuronal cell types, and discuss how this new, integrative understanding of the disease may allow for additional clinical and scientific pathways for treating and understanding Rett syndrome.

Stopping is a critical aspect of brain function. Like other voluntary actions, it is defined by its context as much as by its execution. Its neural substrate must therefore reflect both. Here, we distinguish those elements of the underlying brain circuit that preferentially reflect contextual aspects of stopping from those related to its execution. Contextual complexity of stopping was modulated using a novel “Stop/Change-signal” task, which also allowed us to parameterize the duration of the stopping process. Human magnetoencephalographic activity and behavioral responses were simultaneously recorded. Whereas theta/alpha frequency activity in the right inferior frontal gyrus was most closely associated with the duration of the stopping process, earlier gamma frequency activity in the pre-supplementary motor area was unique in showing contextual modulation. These results differentiate the roles of 2 key frontal regions involved in stopping, a crucial aspect of behavioral control.

The nucleus accumbens is thought to contribute to action selection by integrating behaviorally relevant information from multiple regions, including prefrontal cortex. Studies in rodents suggest that information flow to the nucleus accumbens may be regulated via task-dependent oscillatory coupling between regions. During instrumental behavior, local field potentials (LFP) in the rat nucleus accumbens and prefrontal cortex are coupled at delta frequencies (Gruber AJ, Hussain RJ, O'Donnell P. PLoS One 4: e5062, 2009), possibly mediating suppression of afferent input from other areas and thereby supporting cortical control (Calhoon GG, O'Donnell P. Neuron 78: 181–190, 2013). In this report, we demonstrate low-frequency cortico-accumbens coupling in humans, both at rest and during a decision-making task. We recorded LFP from the nucleus accumbens in six epilepsy patients who underwent implantation of deep brain stimulation electrodes. All patients showed significant coherence and phase-synchronization between LFP and surface EEG at delta and low theta frequencies. Although the direction of this coupling as indexed by Granger causality varied between subjects in the resting-state data, all patients showed a cortical drive of the nucleus accumbens during action selection in a decision-making task. In three patients this was accompanied by a significant coherence increase over baseline. Our results suggest that low-frequency cortico-accumbens coupling represents a highly conserved regulatory mechanism for action selection.

Highlights • A brief treatment of dynamic coordination in terms of predictive coding. • Understanding synchronous message passing in terms of hierarchical predictive coding. • Characterising cortical gain control with the dynamic causal modelling of neural fields. • Characterising pathophysiological oscillations with dynamic causal modelling of neural masses., This review surveys recent trends in the use of local field potentials—and their non-invasive counterparts—to address the principles of functional brain architectures. In particular, we treat oscillations as the (observable) signature of context-sensitive changes in synaptic efficacy that underlie coordinated dynamics and message-passing in the brain. This rich source of information is now being exploited by various procedures—like dynamic causal modelling—to test hypotheses about neuronal circuits in health and disease. Furthermore, the roles played by neuromodulatory mechanisms can be addressed directly through their effects on oscillatory phenomena. These neuromodulatory or gain control processes are central to many theories of normal brain function (e.g. attention) and the pathophysiology of several neuropsychiatric conditions (e.g. Parkinson's disease).

The nonreceptor tyrosine kinase PYK2 represents a stress-sensitive mediator of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) signaling pathways in many cell types. In the present study, we assessed the tyrosine phosphorylation of PYK2 under normal and pathological conditions in the CNS. We generated a polyclonal antibody that selectively recognizes tyrosine-phosphorylated PYK2 at its major autophosphorylation site. By using this antibody, we demonstrate that the phosphorylation profile of PYK2 after focal cerebral ischemia is biphasic. The first phase occurs within 1 hr, when most of the phospho-PYK2 immunoreactivity was observed in cortical neurons, whereas 24–72 hr after ischemia, a striking induction of phospho-PYK2 immunoreactivity was evident in microglia around the necrotic infarcted area. Double-immunostaining analysis using both anti-phospho-PYK2 antibody and antibody against the double-phosphorylated active form of p38MAPK revealed that the two phosphorylated protein kinases exhibit strikingly similar distribution patterns after ischemia. A short time after ischemia, phosphorylation of p38MAPK was evident in the cortical neurons as demonstrated by both immunohistochemistry and immunoblotting analysis, whereas 24–72 hr after ischemia, phospho-p38MAPK was found in activated microglia and colocalized with phospho-PYK2. In contrast to cortical neurons, basal phospho-PYK2 immunoreactivity was observed in hippocampal pyramidal neurons, which was markedly decreased after kainate acid-induced status epilepticus. However, 24 hr after the epileptic onset, a pronounced upregulation of PYK2 and phospho-PYK2 immunoreactivities was evident in microglial cells, as demonstrated by double-immunostaining with the microglial marker OX42. These results provide, for the first time, in situ localization of tyrosine-phosphorylated PYK2 in neuronal stress pathways in the adult rat brain and are consistent with the role of PYK2 as an upstream regulator of p38MAPK signaling cascades in response to stress signals.

Question The ventral intermediate nucleus region (VIMr) of the ventrolateral thalamus and the caudal Zona Incerta (cZi) are established targets for deep brain stimulation (DBS) therapy of medication refractory tremor. While the mechanism of action of DBS remains elusive, evidence points to a modulation of a coordinated network of oscillations. Distinct oscillatory activity patterns may allow large scale interactions between different neural structures. Aberrant activity patterns in these oscillatory networks can lead to the manifestation of specific symptoms, such as tremor, that can be treated with DBS. To characterize the oscillatory cortico-thalamic network we performed simultaneous magnetoencephalographic (MEG) and local field potential (LFP) recordings from the VIMr and cZi DBS electrodes in 10 patients (age: 59 ± 2.7 years) with tremor (6 Parkinson’s disease, 3 essential tremor, 1 orthostatic tremor). Methods Simultaneous MEG-LFP recordings were conducted with the patients at rest with eyes open. LFPs were recorded bipolarly from adjacent contact pairs of the DBS electrodes. The lowermost contact pair was targeted at the cZi (01), while the two upper (12, 23) contact pairs targeted at the VIMr. Dynamic imaging of coherent sources (DICS) beamforming was utilized to visualize peaks of frequency specific cortico-thalamic coherence in Montreal Neurological Institute (MNI) space. Significant clusters were identified using Statistical Parametric Mapping (SPM, FWE corrected threshold p Results Two spatially distinct beta band (13–30 Hz) clusters of cortico-subcortical oscillatory network activity were found for the cZi and VIMr contact pairs, respectively. Coupling of oscillatory beta band activity from the cZi was focally localized in the central cerebellum. In contrast, cortico-thalamic beta band coupling was localized in the motor cortex. No significant clusters were found for the alpha band (7–13 Hz). Conclusions Our results suggest a motor network characterized by beta band coherence between the VIMr and motor cortex and between the cZi and the Cerebellum. These findings extend previous reports on cortico-thalamic LFP-EEG coherence from patients with tremor to a cerebellar connection with the cZi. The reported results are in line with findings from cortico-muscular coherence, FDG-PET and resting state fMRI studies that propose the motor cortex, cerebellum and VIMr as key structures in the tremor network.

The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.

This paper tests the hypothesis that patients with schizophrenia have a deficit in selectively attending to predictable events. We used dynamic causal modeling (DCM) of electrophysiological responses – to predictable and unpredictable visual targets – to quantify the effective connectivity within and between cortical sources in the visual hierarchy in 25 schizophrenia patients and 25 age-matched controls. We found evidence for marked differences between normal subjects and schizophrenia patients in the strength of extrinsic backward connections from higher hierarchical levels to lower levels within the visual system. In addition, we show that not only do schizophrenia subjects have abnormal connectivity but also that they fail to adjust or optimize this connectivity when events can be predicted. Thus, the differential intrinsic recurrent connectivity observed during processing of predictable versus unpredictable targets was markedly attenuated in schizophrenia patients compared with controls, suggesting a failure to modulate the sensitivity of neurons responsible for passing sensory information of prediction errors up the visual cortical hierarchy. The findings support the proposed role of abnormal connectivity in the neuropathology and pathophysiology of schizophrenia.

PURPOSE OF THE REVIEW: Developments in functional neurosurgery for movement disorders and recent advances in electrophysiological techniques have allowed important insights into the role of oscillations in corticobasal ganglia circuits, both in health and in neurological disease states. Here we review recent developments in our understanding of how abnormally synchronized oscillatory activity within the corticobasal ganglia loop may play a key role in the pathophysiology of cognitive and motor phenotypes in Parkinson's disease. RECENT FINDINGS: Recent developments highlight the motor and non-motor roles of α, β and γ oscillations in the context of Parkinson's disease. They also emphasize the importance of oscillatory coupling between basal ganglia and cortex and draw attention to the importance of interactions between different frequency bands. SUMMARY: Oscillatory activities across multiple frequency bands and their cross-frequency interactions within spatially segregated loops of the basal ganglia-thalamo-cortical system may relate to distinct components of clinical impairment, both motor and non-motor. It is hoped that this characterization will lead to improved interventions like deep brain stimulation, tailored to specific components of clinical impairment and their associated spatial and spectral signatures.

The integration of auditory feedback with vocal motor output is important for the control of voice fundamental frequency (F0). We used a pitch-shift paradigm where subjects respond to an alteration, or shift, of voice pitch auditory feedback with a reflexive change in F0. We presented varying magnitudes of pitch shifted auditory feedback to subjects during vocalization and passive listening and measured event related potentials (ERPs) to the feedback shifts. Shifts were delivered at +100 and +400 cents (200 ms duration). The ERP data were modeled with dynamic causal modeling (DCM) techniques where the effective connectivity between the superior temporal gyrus (STG), inferior frontal gyrus and premotor areas were tested. We compared three main factors: the effect of intrinsic STG connectivity, STG modulation across hemispheres and the specific effect of hemisphere. A Bayesian model selection procedure was used to make inference about model families. Results suggest that both intrinsic STG and left to right STG connections are important in the identification of self-voice error and sensory motor integration. We identified differences in left-to-right STG connections between 100 cent and 400 cent shift conditions suggesting that self- and non-self-voice error are processed differently in the left and right hemisphere. These results also highlight the potential of DCM modeling of ERP responses to characterize specific network properties of forward models of voice control.

We review recent methodological developments within a parametric empirical Bayesian (PEB) framework for reconstructing intracranial sources of extracranial electroencephalographic (EEG) and magnetoencephalographic (MEG) data under linear Gaussian assumptions. The PEB framework offers a natural way to integrate multiple constraints (spatial priors) on this inverse problem, such as those derived from different modalities (e.g., from functional magnetic resonance imaging, fMRI) or from multiple replications (e.g., subjects). Using variations of the same basic generative model, we illustrate the application of PEB to three cases: (1) symmetric integration (fusion) of MEG and EEG; (2) asymmetric integration of MEG or EEG with fMRI, and (3) group-optimization of spatial priors across subjects. We evaluate these applications on multi-modal data acquired from 18 subjects, focusing on energy induced by face perception within a time–frequency window of 100–220 ms, 8–18 Hz. We show the benefits of multi-modal, multi-subject integration in terms of the model evidence and the reproducibility (over subjects) of cortical responses to faces.

Both phenotype and treatment response vary in patients with Parkinson’s disease. Anatomical and functional imaging studies suggest that individual symptoms may represent malfunction of different segregated networks running in parallel through the basal ganglia. In this study, we use a newly described, electrophysiological method to describe cortico-subthalamic networks in humans. We performed combined magnetoencephalographic and subthalamic local field potential recordings in thirteen patients with Parkinson’s disease at rest. Two spatially and spectrally separated networks were identified. A temporoparietal-brainstem network was coherent with the subthalamic nucleus in the alpha (7–13 Hz) band, whilst a predominantly frontal network was coherent in the beta (15–35 Hz) band. Dopaminergic medication modulated the resting beta network, by increasing beta coherence between the subthalamic region and prefrontal cortex. Subthalamic activity was predominantly led by activity in the cortex in both frequency bands. The cortical topography and frequencies involved in the alpha and beta networks suggest that these networks may be involved in attentional and executive, particularly motor planning, processes, respectively. * Abbreviations : DICS : dynamic imaging of coherent sources LFP : local field potential SPM : statistical parametric mapping STN-LFP : subthalamic nucleus local field potential UPDRS : Unified Parkinson’s Disease Rating Scale

SPM is a free and open source software written in MATLAB (The MathWorks, Inc.). In addition to standard M/EEG preprocessing, we presently offer three main analysis tools: (i) statistical analysis of scalp-maps, time-frequency images, and volumetric 3D source reconstruction images based on the general linear model, with correction for multiple comparisons using random field theory; (ii) Bayesian M/EEG source reconstruction, including support for group studies, simultaneous EEG and MEG, and fMRI priors; (iii) dynamic causal modelling (DCM), an approach combining neural modelling with data analysis for which there are several variants dealing with evoked responses, steady state responses (power spectra and cross-spectra), induced responses, and phase coupling. SPM8 is integrated with the FieldTrip toolbox , making it possible for users to combine a variety of standard analysis methods with new schemes implemented in SPM and build custom analysis tools using powerful graphical user interface (GUI) and batching tools.

Insight into how brain structures interact is critical for understanding the principles of functional brain architectures and may lead to better diagnosis and therapy for neuropsychiatric disorders. We recorded, simultaneously, magnetoencephalographic (MEG) signals and subcortical local field potentials (LFP) in a Parkinson's disease (PD) patient with bilateral deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN). These recordings offer a unique opportunity to characterize interactions between the subcortical structures and the neocortex. However, high-amplitude artefacts appeared in the MEG. These artefacts originated from the percutaneous extension wire, rather than from the actual DBS electrode and were locked to the heart beat. In this work, we show that MEG beamforming is capable of suppressing these artefacts and quantify the optimal regularization required. We demonstrate how beamforming makes it possible to localize cortical regions whose activity is coherent with the STN-LFP, extract artefact-free virtual electrode time-series from regions of interest and localize cortical areas exhibiting specific task-related power changes. This furnishes results that are consistent with previously reported results using artefact-free MEG data. Our findings demonstrate that physiologically meaningful information can be extracted from heavily contaminated MEG signals and pave the way for further analysis of combined MEG-LFP recordings in DBS patients.

The pedunculopontine nucleus (PPN) has recently been introduced as a new therapeutic target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). In a recent case report it was demonstrated that alpha frequency oscillations appear in PPN after the administration of levodopa in PD, indicating a possible physiological role of these oscillations. Here we confirm this result and investigate the functional connectivity and reactivity of subcortical alpha activity by recording LFP activity from the PPN area and EEG in six patients with PD while at rest and in four of them while they performed ipsi- and contralateral self-paced joystick movements. Levodopa strongly promoted 7-11 Hz oscillatory synchronization in the region of PPN and coupling of this activity with similar activity in the cortical EEG. Such coupling was bidirectional. Moreover, the 7-11 Hz oscillatory synchronization in the PPN area increased about 3 s prior to self-paced movements, but only following levodopa treatment. These findings suggest that alpha oscillations in the PPN area may represent a physiological pattern of activity. The subcortical oscillations are coupled to cortical alpha activity and possibly allied to motor related attentional processes.

The pedunculopontine nucleus has recently been introduced as a new therapeutic target for deep brain stimulation in patients suffering from Parkinson's disease, particularly those with severe gait and postural impairment. Stimulation at this site is typically delivered at low frequencies in contrast to the high frequency stimulation required for therapeutic benefit in the subthalamic nucleus. Therefore, we looked for and demonstrated evidence of low frequency synchronization of activity in the pedunculopontine nucleus of a patient with Parkinson's disease that increased after treatment with dopamine and which might be mimicked by local deep brain stimulation at low frequency.

Synchronized oscillatory activity in the beta frequency band (13-30 Hz) can be detected in the cerebral motor cortex of healthy humans in the form of corticomuscular coherence. Elevated beta activity is associated with impaired processing of new movements and with more efficient postural or tonic contraction. Accordingly, beta activity is suppressed prior to voluntary movements, rebounding thereafter in the face of peripheral afferance. However, it remains to be established whether synchronized activity in the beta band can be up-regulated in a task-appropriate way independently of confounding changes in sensory afferance. Here we show that there is a systematic and prospective increase in beta synchrony prior to an expected postural challenge. This up-regulation of beta synchrony is associated with improved behavioural performance. We instructed nine healthy subjects to perform a reaction-time movement of the index finger in response to an imperative visual cue or to resist a stretch to the finger in the same direction. These events were preceded by congruent and less common incongruent warning cues. Beta synchrony was temporally increased when subjects were warned of an impending stretch and decreased following a warning cue signalling a forthcoming reaction-time task. Finger positions were less successfully maintained in the face of stretches and reaction times were longer when warning cues were incongruent. The results suggest that the beta state is modulated in a task-relevant way with accompanying behavioural consequences.

Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long-term potentiation-like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN-SSEP) recordings and two-point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near-synchronously to an afferent signal containing mechanoreceptive information, MN-SSEP changes (significant at 21-31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS-induced MN-SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near-synchronous afferent signal contained predominantly proprioceptive information, PAS-induced MN-SSEP changes (20-29 ms) were shifted medially, and tactile performance remained stable. With near-synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN-SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS-evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing-dependent and qualitatively congruent behavioural changes.

Excessive synchronization of neuronal activity at around 20 Hz is a common finding in the basal ganglia of patients with untreated Parkinson's disease (PD). Correlative evidence suggests, but does not prove, that this spontaneous activity may contribute to slowness of movement in this condition. Here we investigate whether externally imposed synchronization through direct stimulation of the region of the subthalamic nucleus at 20 Hz can slow motor performance in a simple unimanual tapping task and whether this effect is frequency selective. Tapping rates were recorded on 42 sides in 22 patients with PD after overnight withdrawal of medication. Tapping was performed without stimulation and during bilateral stimulation at 20 Hz, 50 Hz and 130 Hz. We found that tapping rates were slowed by 8.2+/-3.2% (p=0.014) during 20-Hz stimulation in subjects with relatively preserved baseline function in the task. This effect was frequency selective. The current data provide proof of the principle that excessive beta synchrony within the basal ganglia-cortical loop may contribute to the slowing of movements in Parkinson's disease.

Contains fulltext : 55424.pdf (Publisher’s version ) (Closed access) Repetitive median nerve stimulation combined with transcranial magnetic stimulation (TMS) over the contralateral postcentral region (paired associative stimulation, PAS) may induce changes in the amplitude of the P25 component of median nerve somatosensory evoked potentials (MN-SSEP). Here we used 64-channel electroencephalography (EEG) to reveal the early cortical MN-SSEP source(s) that is modified by PAS. In addition, spatial two-point discrimination was tested one day before (day1), immediately after (day2) and one day after (day3) PAS-intervention to assess possible changes of tactile sensitivity corresponding to somatosensory representations inside or outside of the cortical PAS-target, respectively. Eleven healthy volunteers participated in five experiments. MN-SSEPs (1800 trials, ˜3 Hz, 300% perceptual threshold) were recorded before and after PAS intervention. During the intervention the magnetic pulse (180 repetitions at 0.1 Hz, 150% resting motor threshold) was delivered over S1 at one of the following times relative to the subject’s N20 peak: −20, −2.5, 0 and 100 ms (PASN20 − 20, PASN20 − 2.5, PASN20 + 0, PASN20 + 100 ms, respectively). As a control, the TMS pulse was delivered at half time between two median nerve stimulations (PAS+5 s). Following PASN20 − 2.5 and PASN20 + 100 ms, a nonparametric permutation test across all subjects revealed an EEG amplitude increase between 21 and 31 ms. Source analysis showed that the effect of PASN20 − 2.5 ms could be accounted for by an amplitude increase of a tangential source localized at S1. The effect of PASN20 + 100 ms differed in its scalp topography from that of PASN20 − 2.5 ms and may be attributed to a different source at S1. In addition, PAS induced differential effects on tactile performance. Following PASN20 − 20 ms, performance in D2, but not in D5, improved significantly. In contrast, following PASN20 − 2.5 ms, there was a tendency for deterioration in tactile performance of the index finger which was correlated with MN-SSEP changes between 28 and 32 ms (R2 = 0.8). These results lend support to the notion that PASN20 − 2.5 modifies synapses located in superficial cortical layers in Brodmann area 3b and thereby may induce spatially specific differential behavioral changes in tactile performance.

The level of diacylglycerol (DAG) in the Golgi apparatus is crucial for protein transport to the plasma membrane. Studies in budding yeast indicate that Sec14p, a phosphatidylinositol (PI)-transfer protein, is involved in regulating DAG homeostasis in the Golgi complex. Here, we show that Nir2, a peripheral Golgi protein containing a PI-transfer domain, is essential for maintaining the structural and functional integrity of the Golgi apparatus in mammalian cells. Depletion of Nir2 by RNAi leads to substantial inhibition of protein transport from the trans-Golgi network to the plasma membrane, and causes a reduction in the DAG level in the Golgi apparatus. Remarkably, inactivation of cytidine [corrected] 5'-diphosphate (CDP)-choline pathway for phosphatidylcholine biosynthesis restores both effects. These results indicate that Nir2 is involved in maintaining a critical DAG pool in the Golgi apparatus by regulating its consumption via the CDP-choline pathway, demonstrating the interface between secretion from the Golgi and lipid homeostasis.