Emotion-Induced Frontal Alpha Asymmetry as a Candidate Predictor of Relapse After Discontinuation of Antidepressant Medication.

BACKGROUND: One in 3 patients relapse after antidepressant discontinuation. Thus, the prevention of relapse after achieving remission is an important component in the long-term management of major depressive disorder. However, no clinical or other predictors are established. Frontal reactivity to sad mood as measured by functional magnetic resonance imaging has been reported to relate to relapse independently of antidepressant discontinuation and is an interesting candidate predictor. METHODS: Patients (n = 56) who had remitted from a depressive episode while taking antidepressants underwent electroencephalography (EEG) recording during a sad mood induction procedure prior to gradually discontinuing their medication. Relapse was assessed over a 6-month follow-up period. Thirty five healthy control participants were also tested. Current source density of the EEG power in the alpha band (8-13 Hz) was extracted and alpha asymmetry was computed by comparing the power across 2 hemispheres at frontal electrodes (F5 and F6). RESULTS: Sad mood induction was robust across all groups. Reactivity of alpha asymmetry to sad mood did not distinguish healthy control participants from patients with remitted major depressive disorder on medication. However, the 14 (25%) patients who relapsed during the follow-up period after discontinuing medication showed significantly reduced reactivity in alpha asymmetry compared with patients who remained well. This EEG signal provided predictive power (69% out-of-sample balanced accuracy and a positive predictive value of 0.75). CONCLUSIONS: A simple EEG-based measure of emotional reactivity may have potential to contribute to clinical prediction models of antidepressant discontinuation. Given the very small sample size, this finding must be interpreted with caution and requires replication in a larger study.

A comparison of visual and acoustic mismatch negativity as potential biomarkers in schizophrenia.

Mismatch negativity (MMN) is an event-related potential (ERP) component generated when an unexpected deviant stimulus occurs in a pattern of standard stimuli. Several studies showed that the MMN response to both auditory and visual stimuli is attenuated in schizophrenia. While previous studies investigated auditory and visual MMN in different cohorts, here we examined the potential clinical utility of MMN responses to auditory and visual stimuli within the same group of patients. Altogether 39 patients with schizophrenia and 39 healthy controls matched in age, gender, and education were enrolled. We recorded EEG using 64 channels in eight experimental blocks where we presented auditory and visual stimulus sequences. Mismatch responses were obtained by subtracting responses to standard from the physically identical deviant stimuli. We found a significant MMN response to the acoustic stimuli in the control group, whereas no significant mismatch response was observed in the patient group. The group difference was significant for the acoustic stimuli. The 12 vane windmill pattern evoked a significant MMN response in the early time window in the control group but not in the patient group. The 6 vane windmill pattern evoked MMN only in the patient group. However, we found no significant difference between the groups. Furthermore, we found no correlation between the clinical variables and the MMN amplitudes. Our results suggest that predictive processes underlying mismatch generation in patients with schizophrenia may be more affected in the acoustic compared to the visual domain. Acoustic MMN tends to be a more promising biomarker in schizophrenia.

Endogenous modulation of delta phase by expectation-A replication of Stefanics et al., 2010.

The human brain efficiently extracts the temporal statistics of sensory environments and automatically generates expectations about future events. An influential Hypothesis holds that these expectations can find their implementation in neural oscillations, notably in the delta band (.5-3 Hz). Rhythmic fluctuations of cortical excitement are thought to align and match up in phase to the temporal structure of the sensory environment. This alignment is thought to result in the more excitable phase range of neural oscillations to overlap with the predicted onset of sensory events which in turn results in more efficient processing of sensory input, especially so in audition. An unresolved issue concerns whether such phase-aligned rhythmic brain activity is driven exclusively by the exogenous temporal structure of the input, or whether it also reflects phase re-alignment due to endogenous expectations based on stimulus probability and task relevance. In a seminal study, Stefanics et al. (2010) presented stimuli in a rhythmic stream and observed that delta phase consistency across trials was modulated by endogenous target onset expectations: delta phase consistency was higher prior to more probable (strongly expected) compared to less probable (weakly expected) target onsets. The present study replicates Experiment II of the original study, most importantly the modulation of delta phase consistency by endogenous expectations, and underlines a direct relationship between phase locking and behaviour. Our additional analyses locate the sources of the delta phase-alignment to motor, pre-motor, parietal, and temporal areas, and provide evidence for an ongoing delta oscillation, in line with the interpretation of oscillatory phase alignment rather than a transient evoked response. Importantly, this work shows that the phase of delta oscillations can be modulated by top-down control, and hence qualifies as a potential mechanism for the neural implementation of (rhythmic) temporal predictions.

Fronto-thalamic structural and effective connectivity and delusions in schizophrenia: a combined DTI/DCM study.

BACKGROUND: Schizophrenia (SZ) is a complex disorder characterized by a range of behavioral and cognitive symptoms as well as structural and functional alterations in multiple cortical and subcortical structures. SZ is associated with reduced functional network connectivity involving core regions such as the anterior cingulate cortex (ACC) and the thalamus. However, little is known whether effective coupling, the directed influence of one structure over the other, is altered during rest in the ACC-thalamus network. METHODS: We collected resting-state fMRI and diffusion-weighted MRI data from 18 patients and 20 healthy controls. We analyzed fronto-thalamic effective connectivity using dynamic causal modeling for cross-spectral densities in a network consisting of the ACC and the left and right medio-dorsal thalamic regions. We studied structural connectivity using fractional anisotropy (FA). RESULTS: We found decreased coupling strength from the right thalamus to the ACC and from the right thalamus to the left thalamus, as well as increased inhibitory intrinsic connectivity in the right thalamus in patients relative to controls. ACC-to-left thalamus coupling strength correlated with the Positive and Negative Syndrome Scale (PANSS) total positive syndrome score and with delusion score. Whole-brain structural analysis revealed several tracts with reduced FA in patients, with a maximum decrease in white matter tracts containing fronto-thalamic and cingulo-thalamic fibers. CONCLUSIONS: We found altered effective and structural connectivity within the ACC-thalamus network in SZ. Our results indicate that ACC-thalamus network activity at rest is characterized by reduced thalamus-to-ACC coupling. We suggest that positive symptoms may arise as a consequence of compensatory measures to imbalanced fronto-thalamic coupling.

Timing of repetition suppression of event-related potentials to unattended objects.

Current theories of object perception emphasize the automatic nature of perceptual inference. Repetition suppression (RS), the successive decrease of brain responses to repeated stimuli, is thought to reflect the optimization of perceptual inference through neural plasticity. While functional imaging studies revealed brain regions that show suppressed responses to the repeated presentation of an object, little is known about the intra-trial time course of repetition effects to everyday objects. Here, we used event-related potentials (ERPs) to task-irrelevant line-drawn objects, while participants engaged in a distractor task. We quantified changes in ERPs over repetitions using three general linear models that modeled RS by an exponential, linear, or categorical "change detection" function in each subject. Our aim was to select the model with highest evidence and determine the within-trial time-course and scalp distribution of repetition effects using that model. Model comparison revealed the superiority of the exponential model indicating that repetition effects are observable for trials beyond the first repetition. Model parameter estimates revealed a sequence of RS effects in three time windows (86-140, 322-360, and 400-446 ms) and with occipital, temporoparietal, and frontotemporal distribution, respectively. An interval of repetition enhancement (RE) was also observed (320-340 ms) over occipitotemporal sensors. Our results show that automatic processing of task-irrelevant objects involves multiple intervals of RS with distinct scalp topographies. These sequential intervals of RS and RE might reflect the short-term plasticity required for optimization of perceptual inference and the associated changes in prediction errors and predictions, respectively, over stimulus repetitions during automatic object processing.

Feature-specific prediction errors for visual mismatch.

Predictive coding (PC) theory posits that our brain employs a predictive model of the environment to infer the causes of its sensory inputs. A fundamental but untested prediction of this theory is that the same stimulus should elicit distinct precision weighted prediction errors (pwPEs) when different (feature-specific) predictions are violated, even in the absence of attention. Here, we tested this hypothesis using functional magnetic resonance imaging (fMRI) and a multi-feature roving visual mismatch paradigm where rare changes in either color (red, green), or emotional expression (happy, fearful) of faces elicited pwPE responses in human participants. Using a computational model of learning and inference, we simulated pwPE and prediction trajectories of a Bayes-optimal observer and used these to analyze changes in blood oxygen level dependent (BOLD) responses to changes in color and emotional expression of faces while participants engaged in a distractor task. Controlling for visual attention by eye-tracking, we found pwPE responses to unexpected color changes in the fusiform gyrus. Conversely, unexpected changes of facial emotions elicited pwPE responses in cortico-thalamo-cerebellar structures associated with emotion and theory of mind processing. Predictions pertaining to emotions activated fusiform, occipital and temporal areas. Our results are consistent with a general role of PC across perception, from low-level to complex and socially relevant object features, and suggest that monitoring of the social environment occurs continuously and automatically, even in the absence of attention.

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis.

Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients' quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.

Automatic Processing of Changes in Facial Emotions in Dysphoria: A Magnetoencephalography Study.

It is not known to what extent the automatic encoding and change detection of peripherally presented facial emotion is altered in dysphoria. The negative bias in automatic face processing in particular has rarely been studied. We used magnetoencephalography (MEG) to record automatic brain responses to happy and sad faces in dysphoric (Beck's Depression Inventory ≥ 13) and control participants. Stimuli were presented in a passive oddball condition, which allowed potential negative bias in dysphoria at different stages of face processing (M100, M170, and M300) and alterations of change detection (visual mismatch negativity, vMMN) to be investigated. The magnetic counterpart of the vMMN was elicited at all stages of face processing, indexing automatic deviance detection in facial emotions. The M170 amplitude was modulated by emotion, response amplitudes being larger for sad faces than happy faces. Group differences were found for the M300, and they were indexed by two different interaction effects. At the left occipital region of interest, the dysphoric group had larger amplitudes for sad than happy deviant faces, reflecting negative bias in deviance detection, which was not found in the control group. On the other hand, the dysphoric group showed no vMMN to changes in facial emotions, while the vMMN was observed in the control group at the right occipital region of interest. Our results indicate that there is a negative bias in automatic visual deviance detection, but also a general change detection deficit in dysphoria.

Visual Mismatch and Predictive Coding: A Computational Single-Trial ERP Study.

Predictive coding (PC) posits that the brain uses a generative model to infer the environmental causes of its sensory data and uses precision-weighted prediction errors (pwPEs) to continuously update this model. While supported by much circumstantial evidence, experimental tests grounded in formal trial-by-trial predictions are rare. One partial exception is event-related potential (ERP) studies of the auditory mismatch negativity (MMN), where computational models have found signatures of pwPEs and related model-updating processes. Here, we tested this hypothesis in the visual domain, examining possible links between visual mismatch responses and pwPEs. We used a novel visual "roving standard" paradigm to elicit mismatch responses in humans (of both sexes) by unexpected changes in either color or emotional expression of faces. Using a hierarchical Bayesian model, we simulated pwPE trajectories of a Bayes-optimal observer and used these to conduct a comprehensive trial-by-trial analysis across the time × sensor space. We found significant modulation of brain activity by both color and emotion pwPEs. The scalp distribution and timing of these single-trial pwPE responses were in agreement with visual mismatch responses obtained by traditional averaging and subtraction (deviant-minus-standard) approaches. Finally, we compared the Bayesian model to a more classical change model of MMN. Model comparison revealed that trial-wise pwPEs explained the observed mismatch responses better than categorical change detection. Our results suggest that visual mismatch responses reflect trial-wise pwPEs, as postulated by PC. These findings go beyond classical ERP analyses of visual mismatch and illustrate the utility of computational analyses for studying automatic perceptual processes.SIGNIFICANCE STATEMENT Human perception is thought to rely on a predictive model of the environment that is updated via precision-weighted prediction errors (pwPEs) when events violate expectations. This "predictive coding" view is supported by studies of the auditory mismatch negativity brain potential. However, it is less well known whether visual perception of mismatch relies on similar processes. Here we combined computational modeling and electroencephalography to test whether visual mismatch responses reflected trial-by-trial pwPEs. Applying a Bayesian model to series of face stimuli that violated expectations about color or emotional expression, we found significant modulation of brain activity by both color and emotion pwPEs. A categorical change detection model performed less convincingly. Our findings support the predictive coding interpretation of visual mismatch responses.

EEG and ERP biomarkers of Alzheimer's disease: a critical review.

Here we critically review studies that used electroencephalography (EEG) or event-related potential (ERP) indices as a biomarker of Alzheimer's disease. In the first part we overview studies that relied on visual inspection of EEG traces and spectral characteristics of EEG. Second, we survey analysis methods motivated by dynamical systems theory (DST) as well as more recent network connectivity approaches. In the third part we review studies of sleep.  Next, we compare the utility of early and late ERP components in dementia research. In the section on mismatch negativity (MMN) studies we summarize their results and limitations and outline the emerging field of computational neurology. In the following we overview the use of EEG in the differential diagnosis of the most common neurocognitive disorders. Finally, we provide a summary of the state of the field and conclude that several promising EEG/ERP indices of synaptic neurotransmission are worth considering as potential biomarkers. Furthermore, we highlight some practical issues and discuss future challenges as well.

Visual mismatch negativity (vMMN): A review and meta-analysis of studies in psychiatric and neurological disorders.

The visual mismatch negativity (vMMN) response is an event-related potential (ERP) component, which is automatically elicited by events that violate predictions based on prior events. VMMN experiments use visual stimulus repetition to induce predictions, and vMMN is obtained by subtracting the response to rare unpredicted stimuli from those to frequent stimuli. One increasingly popular interpretation of the mismatch response postulates that vMMN, similar to its auditory counterpart (aMMN), represents a prediction error response generated by cortical mechanisms forming probabilistic representations of sensory signals. Here we discuss the physiological and theoretical basis of vMMN and review thirty-three studies from the emerging field of its clinical applications, presenting a meta-analysis of findings in schizophrenia, mood disorders, substance abuse, neurodegenerative disorders, developmental disorders, deafness, panic disorder and hypertension. Furthermore, we include reports on aging and maturation as they bear upon many clinically relevant conditions. Surveying the literature we found that vMMN is altered in several clinical populations which is in line with aMMN findings. An important potential advantage of vMMN however is that it allows the investigation of deficits in predictive processing in cognitive domains which rely primarily on visual information; a principal sensory modality and thus of vital importance in environmental information processing and response, and a modality which arguably may be more sensitive to some pathological changes. However, due to the relative infancy of research in vMMN compared to aMMN in clinical populations its potential for clinical application is not yet fully appreciated. The aim of this review and meta-analysis therefore is to present, in a detailed systematic manner, the findings from clinically-based vMMN studies, to discuss their potential impact and application, to raise awareness of this measure and to improve our understanding of disease upon fundamental aspects of visual information processing.

Effects of concurrent caffeine and mobile phone exposure on local target probability processing in the human brain.

Millions of people use mobile phones (MP) while drinking coffee or other caffeine containing beverages. Little is known about the potential combined effects of MP irradiation and caffeine on cognitive functions. Here we investigated whether caffeine intake and concurrent exposure to Universal Mobile Telecommunications System (UMTS) MP-like irradiation may interactively influence neuro-cognitive function in an active visual oddball paradigm. In a full factorial experimental design, 25 participants performed a simple visual target detection task while reaction time (RT) and electroencephalogram (EEG) was recorded. Target trials were divided into Low and High probability sets based on target-to-target distance. We analyzed single trial RT and alpha-band power (amplitude) in the pre-target interval. We found that RT was shorter in High vs. Low local probability trials, and caffeine further shortened RT in High probability trials relative to the baseline condition suggesting that caffeine improves the efficiency of implicit short-term memory. Caffeine also decreased pre-target alpha amplitude resulting in higher arousal level. Furthermore, pre-target gamma power positively correlated with RT, which may have facilitated target detection. However, in the present pharmacologically validated study UMTS exposure either alone or in combination with caffeine did not alter RT or pre-stimulus oscillatory brain activity.

Elementary sensory deficits in schizophrenia indexed by impaired visual mismatch negativity.

INTRODUCTION: Mismatch negativity (MMN) is an automatic brain response to unexpected events. It represents a prediction error (PE) response, reflecting the difference between the sensory input and predictions. While deficits in auditory MMN are well known in schizophrenia, only few studies investigated impairments in predictive visual processing in schizophrenia. These studies used complex stimuli such as motion direction and emotional facial expressions. Here we studied whether automatic predictive processing of elementary features such as orientation is also impaired in schizophrenia. METHODS: Altogether 28 patients with schizophrenia and 27 healthy controls matched in age, gender, and education participated in the study. EEG was recorded using 128 channels in the two experimental blocks. Using an oddball paradigm, horizontal stripes of Gabor patches were presented as frequent standards and vertical stripes as rare deviants in one block. Stimulus probabilities were swapped in the other block. Mismatch responses were obtained by subtracting responses to standard from those to deviant stimuli. RESULTS: We found significant mismatch responses in healthy controls but not in patients in the prefrontal and occipital-parietal regions in the 90-200ms interval. Furthermore patients showed significantly decreased deviant minus standard difference waveforms relative to controls in the same regions with moderate to large effect sizes. CONCLUSIONS: Our findings demonstrate that predictive processing of unattended low-level visual features such as orientation is impaired in schizophrenia. Our results complement reports of sensory deficits found in tasks requiring attentive processing and suggest that deficits are present in automatic visual sensory processes putatively mediated by glutamatergic functioning.

Altered cortical activation from the hand after facial botulinum toxin treatment.

Plastic interactions between face and hand cortical tactile circuits occur after severe injuries that affect the hand such as in amputation or spinal cord injury. However, whether loss of facial movements alters the cortical circuits involved in processing tactile inputs from the hand remains unknown. In this prospective observational study we used electroencephalography (EEG) to measure cortical activity evoked by tactile stimulation of the hands before and after botulinum toxin-A-induced facial paralysis. We found a reduction in the tactile event-related potentials (ERPs) 6 weeks after the treatment. This suggests that the limited paralysis of facial muscles induced during cosmetic interventions designed to smooth lines and wrinkles on the face is sufficient to alter the cortical processing of tactile inputs from the hand.

Visual mismatch negativity: a predictive coding view.

An increasing number of studies investigate the visual mismatch negativity (vMMN) or use the vMMN as a tool to probe various aspects of human cognition. This paper reviews the theoretical underpinnings of vMMN in the light of methodological considerations and provides recommendations for measuring and interpreting the vMMN. The following key issues are discussed from the experimentalist's point of view in a predictive coding framework: (1) experimental protocols and procedures to control "refractoriness" effects; (2) methods to control attention; (3) vMMN and veridical perception.

Lack of interaction between concurrent caffeine and mobile phone exposure on visual target detection: an ERP study.

BACKGROUND: Caffeine affects information processing by acting predominantly on cortical activation, arousal and attention. Millions consume caffeine and simultaneously use their mobile phone (MP) during everyday activities. However, it is not known whether and how MP-emitted electromagnetic fields (EMFs) can modulate known psychoactive effects of caffeine. Here we investigated behavioral and neural correlates of caffeine and simultaneous MP exposure in a third generation (3G) Universal Mobile Telecommunication System (UMTS) signal modulation scheme. METHODS: We recorded electroencephalography (EEG) and event related potentials (ERP) in an oddball paradigm to frequent standard (p=0.8) and rare target (p=0.2) stimuli in a placebo controlled, double blind, within-subject protocol in four experimental sessions: 1) no caffeine and no MP, 2) caffeine only, 3) MP only, and 4) caffeine and MP. The subjects' task was to discriminate between standard and target stimuli and respond to the latter by pressing a button while reaction time (RT) and EEG were recorded. To provide a complete analysis of any possible caffeine and/or MP treatment effects that may have occurred, we analyzed the P300 ERP wave using four different ERP measures: 1) peak latency, 2) peak amplitude, 3) 50% fractional area latency (FAL) and 4) area under the curve (AUC). RESULTS: Caffeine significantly shortened RT and decreased AUC of the P300 component compared to the control or the UMTS MP alone conditions. However, no effects were observed on RT or P300 in the UMTS MP exposure sessions, neither alone nor in combination with caffeine. CONCLUSION: Overall, the present results did not demonstrate any interactive or synergistic effects of caffeine and UMTS MP like EMF exposure on basic neural or cognitive measures. However, we found that caffeine consistently enhanced behavioral and ERP measures of visual target detection, showing that present results were obtained using a pharmacologically validated, consistent and replicable methodology.

Event-related theta synchronization predicts deficit in facial affect recognition in schizophrenia.

Growing evidence suggests that abnormalities in the synchronized oscillatory activity of neurons in schizophrenia may lead to impaired neural activation and temporal coding and thus lead to neurocognitive dysfunctions, such as deficits in facial affect recognition. To gain an insight into the neurobiological processes linked to facial affect recognition, we investigated both induced and evoked oscillatory activity by calculating the Event Related Spectral Perturbation (ERSP) and the Inter Trial Coherence (ITC) during facial affect recognition. Fearful and neutral faces as well as nonface patches were presented to 24 patients with schizophrenia and 24 matched healthy controls while EEG was recorded. The participants' task was to recognize facial expressions. Because previous findings with healthy controls showed that facial feature decoding was associated primarily with oscillatory activity in the theta band, we analyzed ERSP and ITC in this frequency band in the time interval of 140-200 ms, which corresponds to the N170 component. Event-related theta activity and phase-locking to facial expressions, but not to nonface patches, predicted emotion recognition performance in both controls and patients. Event-related changes in theta amplitude and phase-locking were found to be significantly weaker in patients compared with healthy controls, which is in line with previous investigations showing decreased neural synchronization in the low frequency bands in patients with schizophrenia. Neural synchrony is thought to underlie distributed information processing. Our results indicate a less effective functioning in the recognition process of facial features, which may contribute to a less effective social cognition in schizophrenia.