The 40-Hz auditory steady-state response in bipolar disorder: A meta-analysis.

OBJECTIVE: Bipolar disorder is characterized by aberrant neurophysiological responses as measured with electroencephalography (EEG) and magnetoencephalography (MEG), including the 40-Hz auditory steady-state response (ASSR). 40-Hz ASSR deficits are also found in patients with schizophrenia and may represent a transdiagnostic biomarker of neuronal circuit dysfunction. In this systematic review and meta-analysis, we summarize and evaluate the evidence for 40-Hz ASSR deficits in patients with bipolar disorder. METHODS: We identified studies from PubMed, EMBASE, and SCOPUS. We assessed the risk of bias, calculated Hedges' g meta-level effect sizes, and investigated small-study effects using funnel plots and Egger regression. RESULTS: Seven studies, comprising 396 patients with bipolar disorder and 404 healthy controls, were included in the meta-analysis. Studies displayed methodological heterogeneity and an overall high risk of bias. Patients with bipolar disorder showed consistent reductions in 40-Hz ASSR evoked power (Hedges' g = -0.49; 95% confidence intervals [-0.67, -0.31]) and inter-trial phase coherence (ITPC) (Hedges' g = -0.43; 95 %CI [-0.58, -0.29]) compared with healthy controls. CONCLUSIONS: Our meta-analysis provides evidence that 40-Hz ASSRs are reduced in patients with bipolar disorder compared with healthy controls. SIGNIFICANCE: Future large-scale studies are warranted to link 40-Hz ASSR deficits to clinical features and developmental trajectories.

Activated N-methyl-D-aspartate receptor ion channels detected in focal epilepsy with [18 F]GE-179 positron emission tomography.

OBJECTIVE: Imaging activated glutamate N-methyl-D-aspartate receptor ion channels (NMDAR-ICs) using positron emission tomography (PET) has proved challenging due to low brain uptake, poor affinity and selectivity, and high metabolism and dissociation rates of candidate radioligands. The radioligand [18 F]GE-179 is a known use-dependent marker of NMDAR-ICs. We studied whether interictal [18 F]GE-179 PET would detect foci of abnormal NMDAR-IC activation in patients with refractory focal epilepsy. METHODS: Ten patients with refractory focal epilepsy and 18 healthy controls had structural magnetic resonance imaging (MRI) followed by a 90-min dynamic [18 F]GE-179 PET scan with simultaneous electroencephalography (EEG). PET and EEG findings were compared with MRI and previous EEGs. Standard uptake value (SUV) images of [18 F]GE-179 were generated and global gray matter uptake was measured for each individual. To localize focal increases in uptake of [18 F]GE-179, the individual SUV images were interrogated with statistical parametric mapping in comparison to a normal database. Additionally, individual healthy control SUV images were compared with the rest of the control database to determine their prevalence of increased focal [18 F]GE-179 uptake. RESULTS: Interictal [18 F]GE-179 PET detected clusters of significantly increased binding in eight of 10 patients with focal epilepsy but none of the controls. The number of clusters of raised [18 F]GE-179 uptake in the patients with epilepsy exceeded the focal abnormalities revealed by the simultaneously recorded EEG. Patients with extensive clusters of raised [18 F]GE-179 uptake showed the most abnormal EEGs. SIGNIFICANCE: Detection of multiple foci of abnormal NMDAR-IC activation in 80% of our patients with refractory focal epilepsy using interictal [18 F]GE-179 PET could reflect enhanced neuronal excitability due to chronic seizure activity. This indicates that chronic epileptic activity is associated with abnormal NMDAR ion channel activation beyond the initial irritative zones. [18 F]GE-179 PET could be a candidate marker for identifying pathological brain areas in patients with treatment-resistant focal epilepsy.

Perceptual learning of tone patterns changes the effective connectivity between Heschl's gyrus and planum temporale.

Learning of complex auditory sequences such as music can be thought of as optimizing an internal model of regularities through unpredicted events (or "prediction errors"). We used dynamic causal modeling (DCM) and parametric empirical Bayes on functional magnetic resonance imaging (fMRI) data to identify modulation of effective brain connectivity that takes place during perceptual learning of complex tone patterns. Our approach differs from previous studies in two aspects. First, we used a complex oddball paradigm based on tone patterns as opposed to simple deviant tones. Second, the use of fMRI allowed us to identify cortical regions with high spatial accuracy. These regions served as empirical regions-of-interest for the analysis of effective connectivity. Deviant patterns induced an increased blood oxygenation level-dependent response, compared to standards, in early auditory (Heschl's gyrus [HG]) and association auditory areas (planum temporale [PT]) bilaterally. Within this network, we found a left-lateralized increase in feedforward connectivity from HG to PT during deviant responses and an increase in excitation within left HG. In contrast to previous findings, we did not find frontal activity, nor did we find modulations of backward connections in response to oddball sounds. Our results suggest that complex auditory prediction errors are encoded by changes in feedforward and intrinsic connections, confined to superior temporal gyrus.

Reduced effective connectivity between right parietal and inferior frontal cortex during audiospatial perception in neglect patients with a right-hemisphere lesion.

A lesion to the right hemisphere of the brain in humans commonly leads to perceptual neglect of the left side of the sensorium. The clinical observation that lesions to disparate cortical and subcortical areas converge upon similar behavioural symptoms points to neglect as a dysconnection syndrome that may result from the disruption of a distributed network, rather than aberrant computations in any particular brain region. To test this hypothesis, we used Bayesian analysis of effective connectivity based on electroencephalographic recordings in ten patients (6 male, 4 female; age range 41-68) with left-sided neglect following a right-hemisphere lesion. In line with previous research, age-matched healthy controls showed a contralateral increase in connection strength between parietal and frontal cortex with respect to the laterality of audiospatial oddball stimuli. Neglect patients, however, showed a dysconnection between parietal and frontal cortex in the right hemisphere when oddballs appeared on their left side, but preserved connectivity in the left hemisphere when stimuli appeared on their right. This preserved fronto-parietal connectivity was associated with lower neglect severity. Moreover, we saw ipsilateral fronto-temporal connectivity increases for oddballs appearing on the neglected side, which might be a compensatory mechanism for residual left side awareness. No group differences were found in intrinsic (within-region) connectivity. While further validation is required in a bigger sample, our findings are in keeping with the idea that neglect results from the disruption of a distributed network, rather than a lesion to any single brain region. SIGNIFICANCE STATEMENT: Lesions to the right hemisphere of the brain commonly lead to neglect syndrome, characterized by perceptual deficits where patients are unaware of the left side of their body and environment. Using analysis of non-invasive electrophysiological recordings, we provide evidence that patients with left-sided neglect have reduced connectivity between the right parietal and frontal cortex during audiospatial stimuli, but preserved connectivity between regions in the non-lesioned left hemisphere. Moreover, for these intact connections we observed an ipsilateral fronto-temporal increase in connectivity during oddballs appearing on the neglected side, which might be a compensatory mechanism for residual perception. Crucially, we found that patients with more severe neglect symptoms had reduced connectivity between parietal and frontal cortex in the left hemisphere. This suggests that neglect may be caused by the disruption of a distributed network in the brain, rather than a lesion to any particular brain region.

Aberrant effective connectivity is associated with positive symptoms in first-episode schizophrenia.

Schizophrenia is a neurodevelopmental psychiatric disorder thought to result from synaptic dysfunction that affects distributed brain connectivity, rather than any particular brain region. While symptomatology is traditionally divided into positive and negative symptoms, abnormal social cognition is now recognized a key component of schizophrenia. Nonetheless, we are still lacking a mechanistic understanding of effective brain connectivity in schizophrenia during social cognition and how it relates to clinical symptomatology. To address this question, we used fMRI and dynamic causal modelling (DCM) to test for abnormal brain connectivity in twenty-four patients with first-episode schizophrenia (FES) compared to twenty-five matched controls performing the Human Connectome Project (HCP) social cognition paradigm. Patients had not received regular therapeutic antipsychotics, but were not completely drug naïve. Whilst patients were less accurate than controls in judging social stimuli from non-social stimuli, our results revealed an increase in feedforward connectivity from motion-sensitive V5 to posterior superior temporal sulcus (pSTS) in patients compared to matched controls. At the same time, patients with a higher degree of positive symptoms had more disinhibition within pSTS, a region computationally involved in social cognition. We interpret these findings the framework of active inference, where increased feedforward connectivity may encode aberrant prediction errors from V5 to pSTS and local disinhibition within pSTS may reflect aberrant encoding of the precision of cortical representations about social stimuli.

The CI MuMuFe - A New MMN Paradigm for Measuring Music Discrimination in Electric Hearing.

Cochlear implants (CIs) allow good perception of speech while music listening is unsatisfactory, leading to reduced music enjoyment. Hence, a number of ongoing efforts aim to improve music perception with a CI. Regardless of the nature of these efforts, effect measurements must be valid and reliable. While auditory skills are typically examined by behavioral methods, recording of the mismatch negativity (MMN) response, using electroencephalography (EEG), has recently been applied successfully as a supplementary objective measure. Eleven adult CI users and 14 normally hearing (NH) controls took part in the present study. To measure their detailed discrimination of fundamental features of music we applied a new multifeature MMN-paradigm which presented four music deviants at four levels of magnitude, incorporating a novel "no-standard" approach to be tested with CI users for the first time. A supplementary test measured behavioral discrimination of the same deviants and levels. The MMN-paradigm elicited significant MMN responses to all levels of deviants in both groups. Furthermore, the CI-users' MMN amplitudes and latencies were not significantly different from those of NH controls. Both groups showed MMN strength that was in overall alignment with the deviation magnitude. In CI users, however, discrimination of pitch levels remained undifferentiated. On average, CI users' behavioral performance was significantly below that of the NH group, mainly due to poor pitch discrimination. Although no significant effects were found, CI users' behavioral results tended to be in accordance with deviation magnitude, most prominently manifested in discrimination of the rhythm deviant. In summary, the study indicates that CI users may be able to discriminate subtle changes in basic musical features both in terms of automatic neural responses and of attended behavioral detection. Despite high complexity, the new CI MuMuFe paradigm and the "no-standard" approach provided reliable results, suggesting that it may serve as a relevant tool in future CI research. For clinical use, future studies should investigate the possibility of applying the paradigm with the purpose of assessing discrimination skills not only at the group level but also at the individual level.

Now you hear it: a predictive coding model for understanding rhythmic incongruity.

Rhythmic incongruity in the form of syncopation is a prominent feature of many contemporary musical styles. Syncopations afford incongruity between rhythmic patterns and the meter, giving rise to mental models of differently accented isochronous beats. Syncopations occur either in isolation or as part of rhythmic patterns, so-called grooves. On the basis of the predictive coding framework, we discuss how brain processing of rhythm can be seen as a special case of predictive coding. We present a simple, yet powerful model for how the brain processes rhythmic incongruity: the model for predictive coding of rhythmic incongruity. Our model proposes that a given rhythm's syncopation and its metrical uncertainty (precision) is at the heart of how the brain models rhythm and meter based on priors, predictions, and prediction error. Our minimal model can explain prominent features of brain processing of syncopation: why isolated syncopations lead to stronger prediction error in the brains of musicians, as evidenced by larger event-related potentials to rhythmic incongruity, and why we all experience a stronger urge to move to grooves with a medium level of syncopation compared with low and high levels of syncopation.

Expectation violation and attention to pain jointly modulate neural gain in somatosensory cortex.

The neural processing and experience of pain are influenced by both expectations and attention. For example, the amplitude of event-related pain responses is enhanced by both novel and unexpected pain, and by moving the focus of attention towards a painful stimulus. Under predictive coding, this congruence can be explained by appeal to a precision-weighting mechanism, which mediates bottom-up and top-down attentional processes by modulating the influence of feedforward and feedback signals throughout the cortical hierarchy. The influence of expectation and attention on pain processing can be mapped onto changes in effective connectivity between or within specific neuronal populations, using a canonical microcircuit (CMC) model of hierarchical processing. We thus implemented a CMC within dynamic causal modelling for magnetoencephalography in human subjects, to investigate how expectation violation and attention to pain modulate intrinsic (within-source) and extrinsic (between-source) connectivity in the somatosensory hierarchy. This enabled us to establish whether both expectancy and attentional processes are mediated by a similar precision-encoding mechanism within a network of somatosensory, frontal and parietal sources. We found that both unexpected and attended pain modulated the gain of superficial pyramidal cells in primary and secondary somatosensory cortex. This modulation occurred in the context of increased lateralized recurrent connectivity between somatosensory and fronto-parietal sources, driven by unexpected painful occurrences. Finally, the strength of effective connectivity parameters in S1, S2 and IFG predicted individual differences in subjective pain modulation ratings. Our findings suggest that neuromodulatory gain control in the somatosensory hierarchy underlies the influence of both expectation violation and attention on cortical processing and pain perception.

Anterior insula coordinates hierarchical processing of tactile mismatch responses.

The body underlies our sense of self, emotion, and agency. Signals arising from the skin convey warmth, social touch, and the physical characteristics of external stimuli. Surprising or unexpected tactile sensations can herald events of motivational salience, including imminent threats (e.g., an insect bite) and hedonic rewards (e.g., a caressing touch). Awareness of such events is thought to depend upon the hierarchical integration of body-related mismatch responses by the anterior insula. To investigate this possibility, we measured brain activity using functional magnetic resonance imaging, while healthy participants performed a roving tactile oddball task. Mass-univariate analysis demonstrated robust activations in limbic, somatosensory, and prefrontal cortical areas previously implicated in tactile deviancy, body awareness, and cognitive control. Dynamic Causal Modelling revealed that unexpected stimuli increased the strength of forward connections along a caudal to rostral hierarchy-projecting from thalamic and somatosensory regions towards insula, cingulate and prefrontal cortices. Within this ascending flow of sensory information, the AIC was the only region to show increased backwards connectivity to the somatosensory cortex, augmenting a reciprocal exchange of neuronal signals. Further, participants who rated stimulus changes as easier to detect showed stronger modulation of descending PFC to AIC connections by deviance. These results suggest that the AIC coordinates hierarchical processing of tactile prediction error. They are interpreted in support of an embodied predictive coding model where AIC mediated body awareness is involved in anchoring a global neuronal workspace.

Being asked to tell an unpleasant truth about another person activates anterior insula and medial prefrontal cortex.

"Truth" has been used as a baseline condition in several functional magnetic resonance imaging (fMRI) studies of deception. However, like deception, telling the truth is an inherently social construct, which requires consideration of another person's mental state, a phenomenon known as Theory of Mind. Using a novel ecological paradigm, we examined blood oxygenation level dependent (BOLD) responses during social and simple truth telling. Participants (n = 27) were randomly divided into two competing teams. Post-competition, each participant was scanned while evaluating performances from in-group and out-group members. Participants were asked to be honest and were told that their evaluations would be made public. We found increased BOLD responses in the medial prefrontal cortex, bilateral anterior insula and precuneus when participants were asked to tell social truths compared to simple truths about another person. At the behavioral level, participants were slower at responding to social compared to simple questions about another person. These findings suggest that telling the truth is a nuanced cognitive operation that is dependent on the degree of mentalizing. Importantly, we show that the cortical regions engaged by truth telling show a distinct pattern when the task requires social reasoning.

Ambivalence, equivocation and the politics of experimental knowledge: a transdisciplinary neuroscience encounter.

This article is about a transdisciplinary project between the social, human and life sciences, and the felt experiences of the researchers involved. 'Transdisciplinary' and 'interdisciplinary' research-modes have been the subject of much attention lately--especially as they cross boundaries between the social/humanistic and natural sciences. However, there has been less attention, from within science and technology studies, to what it is actually like to participate in such a research-space. This article contributes to that literature through an empirical reflection on the progress of one collaborative and transdisciplinary project: a novel experiment in neuroscientific lie detection, entangling science and technology studies, literary studies, sociology, anthropology, clinical psychology and cognitive neuroscience. Its central argument is twofold: (1) that, in addition to ideal-type tropes of transdisciplinary conciliation or integration, such projects may also be organized around some more subterranean logics of ambivalence, reserve and critique; (2) that an account of the mundane ressentiment of collaboration allows for a more careful attention to the awkward forms of 'experimental politics' that may flow through, and indeed propel, collaborative work more broadly. Building on these claims, the article concludes with a suggestion that such subterranean logics may be indissociable from some forms of collaboration, and it proposes an ethic of 'equivocal speech' as a way to live with and through these kinds of transdisciplinary experiences.

Contextualizing neuro-collaborations: reflections on a transdisciplinary fMRI lie detection experiment.

Recent neuroscience initiatives (including the E.U.'s Human Brain Project and the U.S.'s BRAIN Initiative) have reinvigorated discussions about the possibilities for transdisciplinary collaboration between the neurosciences, the social sciences, and the humanities. As STS scholars have argued for decades, however, such inter- and transdisciplinary collaborations are potentially fraught with tensions between researchers. This essay build on such claims by arguing that the tensions of transdisciplinary research also exist within researchers' own experiences of working between disciplines - a phenomenon that we call "disciplinary double consciousness" (DDC). Building on previous work that has characterized similar spaces (and especially on the Critical Neuroscience literature), we argue that "neuro-collaborations" inevitably engage researchers in DDC - a phenomenon that allows us to explore the useful dissonance that researchers can experience when working between a "home" discipline and a secondary discipline. Our case study is a five-year research project in functional magnetic resonance imaging (fMRI) lie detection involving a transdisciplinary research team made up of social scientists, a neuroscientist, and a humanist. In addition to theorizing neuro-collaborations from the inside-out, this essay presents practical suggestions for developing transdisciplinary infrastructures that could support future neuro-collaborations.

Effective connectivity reveals right-hemisphere dominance in audiospatial perception: implications for models of spatial neglect.

Detecting the location of salient sounds in the environment rests on the brain's ability to use differences in sounds arriving at both ears. Functional neuroimaging studies in humans indicate that the left and right auditory hemispaces are coded asymmetrically, with a rightward attentional bias that reflects spatial attention in vision. Neuropsychological observations in patients with spatial neglect have led to the formulation of two competing models: the orientation bias and right-hemisphere dominance models. The orientation bias model posits a symmetrical mapping between one side of the sensorium and the contralateral hemisphere, with mutual inhibition of the ipsilateral hemisphere. The right-hemisphere dominance model introduces a functional asymmetry in the brain's coding of space: the left hemisphere represents the right side, whereas the right hemisphere represents both sides of the sensorium. We used Dynamic Causal Modeling of effective connectivity and Bayesian model comparison to adjudicate between these alternative network architectures, based on human electroencephalographic data acquired during an auditory location oddball paradigm. Our results support a hemispheric asymmetry in a frontoparietal network that conforms to the right-hemisphere dominance model. We show that, within this frontoparietal network, forward connectivity increases selectively in the hemisphere contralateral to the side of sensory stimulation. We interpret this finding in light of hierarchical predictive coding as a selective increase in attentional gain, which is mediated by feedforward connections that carry precision-weighted prediction errors during perceptual inference. This finding supports the disconnection hypothesis of unilateral neglect and has implications for theories of its etiology.