An ERP measure of non-conscious memory reveals dissociable implicit processes in human recognition using an open-source automated analytic pipeline.

Non-conscious processing of human memory has traditionally been difficult to objectively measure and thus understand. A prior study on a group of hippocampal amnesia (N = 3) patients and healthy controls (N = 6) used a novel procedure for capturing neural correlates of implicit memory using event-related potentials (ERPs): old and new items were equated for varying levels of memory awareness, with ERP differences observed from 400 to 800 ms in bilateral parietal regions that were hippocampal-dependent. The current investigation sought to address the limitations of that study by increasing the sample of healthy subjects (N = 54), applying new controls for construct validity, and developing an improved, open-source tool for automated analysis of the procedure used for equating levels of memory awareness. Results faithfully reproduced prior ERP findings of parietal effects that a series of systematic control analyses validated were not contributed to nor contaminated by explicit memory. Implicit memory effects extended from 600 to 1000 ms, localized to right parietal sites. These ERP effects were found to be behaviorally relevant and specific in predicting implicit memory response times, and were topographically dissociable from other traditional ERP measures of implicit memory (miss vs. correct rejections) that instead occurred in left parietal regions. Results suggest first that equating for reported awareness of memory strength is a valid, powerful new method for revealing neural correlates of non-conscious human memory, and second, behavioral correlations suggest that these implicit effects reflect a pure form of priming, whereas misses represent fluency leading to the subjective experience of familiarity.

Impaired Fixation-Related Theta Modulation Predicts Reduced Visual Span and Guided Search Deficits in Schizophrenia.

During normal visual behavior, individuals scan the environment through a series of saccades and fixations. At each fixation, the phase of ongoing rhythmic neural oscillations is reset, thereby increasing efficiency of subsequent visual processing. This phase-reset is reflected in the generation of a fixation-related potential (FRP). Here, we evaluate the integrity of theta phase-reset/FRP generation and Guided Visual Search task in schizophrenia. Subjects performed serial and parallel versions of the task. An initial study (15 healthy controls (HC)/15 schizophrenia patients (SCZ)) investigated behavioral performance parametrically across stimulus features and set-sizes. A subsequent study (25-HC/25-SCZ) evaluated integrity of search-related FRP generation relative to search performance and evaluated visual span size as an index of parafoveal processing. Search times were significantly increased for patients versus controls across all conditions. Furthermore, significantly, deficits were observed for fixation-related theta phase-reset across conditions, that fully predicted impaired reduced visual span and search performance and correlated with impaired visual components of neurocognitive processing. By contrast, overall search strategy was similar between groups. Deficits in theta phase-reset mechanisms are increasingly documented across sensory modalities in schizophrenia. Here, we demonstrate that deficits in fixation-related theta phase-reset during naturalistic visual processing underlie impaired efficiency of early visual function in schizophrenia.

Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation approach in which low level currents are administered over the scalp to influence underlying brain function. Prevailing theories of tDCS focus on modulation of excitation-inhibition balance at the local stimulation location. However, network level effects are reported as well, and appear to depend upon differential underlying mechanisms. Here, we evaluated potential network-level effects of tDCS during the Serial Reaction Time Task (SRTT) using convergent EEG- and fMRI-based connectivity approaches. Motor learning manifested as a significant (p<.0001) shift from slow to fast responses and corresponded to a significant increase in beta-coherence (p<.0001) and fMRI connectivity (p<.01) particularly within the visual-motor pathway. Differential patterns of tDCS effect were observed within different parametric task versions, consistent with network models. Overall, these findings demonstrate objective physiological effects of tDCS at the network level that result in effective behavioral modulation when tDCS parameters are matched to network-level requirements of the underlying task.

Electrophysiological Evidence for Hyperfocusing of Spatial Attention in Schizophrenia.

A recently proposed hyperfocusing hypothesis of cognitive dysfunction in schizophrenia proposes that people with schizophrenia (PSZ) tend to concentrate processing resources more narrowly but more intensely than healthy control subjects (HCS). The present study tests a key prediction of this hypothesis, namely, that PSZ will hyperfocus on information presented at the center of gaze. This should lead to greater filtering of peripheral stimuli when the task requires focusing centrally but reduced filtering of central stimuli when the task requires attending broadly in the periphery. These predictions were tested in a double oddball paradigm, in which frequent standard stimuli and rare oddball stimuli were presented at central and peripheral locations while event-related potentials were recorded. Participants were instructed to discriminate between the standard and oddball stimuli at either the central location or at the peripheral locations. PSZ and HCS showed opposite patterns of spatial bias at the level of early sensory processing, as assessed with the P1 component: PSZ exhibited stronger sensory suppression of peripheral stimuli when the task required attending narrowly to the central location, whereas HCS exhibited stronger sensory suppression of central stimuli when the task required attending broadly to the peripheral locations. Moreover, PSZ exhibited a stronger stimulus categorization response than HCS, as assessed with the P3b component, for central stimuli when the task required attending to the peripheral region. These results provide strong evidence of hyperfocusing in PSZ, which may provide a unified mechanistic account of multiple aspects of cognitive dysfunction in schizophrenia.SIGNIFICANCE STATEMENT Schizophrenia clearly involves impaired attention, but attention is complex, and delineating the precise nature of attentional dysfunction in schizophrenia has been difficult. The present study tests a new hyperfocusing hypothesis, which proposes that people with schizophrenia (PSZ) tend to concentrate processing resources more intensely but more narrowly than healthy control subjects (HCS). Using electrophysiological measures of sensory and cognitive processing, we found that PSZ were actually superior to HCS in focusing attention at the point of gaze and filtering out peripheral distractors when the task required a narrow focusing of attention. This finding of superior filtering in PSZ supports the hyperfocusing hypothesis, which may provide the mechanism underlying a broad range of cognitive impairments in schizophrenia.

Rapid feature-driven changes in the attentional window.

Spatial attention must adjust around an object of interest in a manner that reflects the object's size on the retina as well as the proximity of distracting objects, a process often guided by nonspatial features. This study used ERPs to investigate how quickly the size of this type of "attentional window" can adjust around a fixated target object defined by its color and whether this variety of attention influences the feedforward flow of subsequent information through the visual system. The task involved attending either to a circular region at fixation or to a surrounding annulus region, depending on which region contained an attended color. The region containing the attended color varied randomly from trial to trial, so the spatial distribution of attention had to be adjusted on each trial. We measured the initial sensory ERP response elicited by an irrelevant probe stimulus that appeared in one of the two regions at different times after task display onset. This allowed us to measure the amount of time required to adjust spatial attention on the basis of the location of the task-relevant feature. We found that the probe-elicited sensory response was larger when the probe occurred within the region of the attended dots, and this effect required a delay of approximately 175 msec between the onset of the task display and the onset of the probe. Thus, the window of attention is rapidly adjusted around the point of fixation in a manner that reflects the spatial extent of a task-relevant stimulus, leading to changes in the feedforward flow of subsequent information through the visual system.

Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning impairments in schizophrenia.

Motor learning is a fundamental skill to our daily lives. Dysfunction in motor performance in schizophrenia (Sz) is associated with poor social and functional outcomes, but nevertheless remains understudied relative to other neurocognitive domains. Moreover, transcranial direct current stimulation (tDCS) can influence underlying brain function in Sz and may be especially useful in enhancing local cortical plasticity, but underlying neural mechanisms remain incompletely understood. Here, we evaluated performance of Sz individuals on the Serial Reaction Time Task (SRTT), which has been extensively used in prior tDCS research, in combination with concurrent tDCS and EEG source localization first to evaluate the integrity of visuomotor learning in Sz relative to other cognitive domains and second to investigate underlying neural mechanisms. Twenty-seven individuals with Sz and 21 healthy controls (HC) performed the SRTT task as they received sham or active tDCS and simultaneous EEG recording. Measures of motor, neuropsychological and global functioning were also assessed. Impaired SRTT performance correlated significantly with deficits in motor performance, working memory, and global functioning. Time-frequency ("Beamformer") EEG source localization showed beta-band coherence across supplementary-motor, primary-motor and visual cortex regions, with reduced visuomotor coherence in Sz relative to HC. Cathodal tDCS targeting both visual and motor regions resulted in significant modulation in coherence particularly across the motor-visual nodes of the network accompanied by significant improvement in motor learning in both controls and patients. Overall, these findings demonstrate the utility of the SRTT to study mechanisms of visuomotor impairment in Sz and demonstrate significant tDCS effects on both learning and connectivity when applied over either visual or motor regions. The findings support continued study of dysfunctional dorsal-stream visual connectivity and motor plasticity as components of cognitive impairment in Sz, of local tDCS administration for enhancement of plasticity, and of source-space EEG-based biomarkers for evaluation of underlying neural mechanisms.

Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning in schizophrenia.

Motor learning is a fundamental skill to our daily lives. Dysfunction in motor performance in schizophrenia (Sz) has been associated with poor social and functional outcomes. Transcranial direct current stimulation (tDCS), a non-invasive electrical brain stimulation approach, can influence underlying brain function with potential for improving motor learning in Sz. We used a well-established Serial Reaction Time Task (SRTT) to study motor learning, in combination with simultaneous tDCS and EEG recording, to investigate mechanisms of motor and procedural learning deficits in Sz, and to develop refined non-invasive brain stimulation approaches to improve neurocognitive dysfunction. We recruited 27 individuals with Sz and 21 healthy controls (HC). Individuals performed the SRTT task as they received sham and active tDCS with simultaneous EEG recording. Reaction time (RT), neuropsychological, and measures of global functioning were assessed. SRTT performance was significantly impaired in Sz and showed significant correlations with motor-related and working memory measures as well as global function. Source-space time-frequency decomposition of EEG showed beta-band coherence across supplementary-motor, primary-motor and visual cortex forming a network involved in SRTT performance. Motor-cathodal and visual-cathodal stimulations resulted in significant modulation in coherence particularly across the motor-visual nodes of the network accompanied by significant improvement in motor learning in both controls and patients. Here, we confirm earlier reports of SRTT impairment in Sz and demonstrate significant reversal of the deficits with tDCS. The findings support continued development of tDCS for enhancement of plasticity-based interventions in Sz, as well as source-space EEG analytic approaches for evaluating underlying neural mechanisms.

Gamma-band entrainment abnormalities in schizophrenia: Modality-specific or cortex-wide impairment?

A growing body of literature suggests that cognitive impairment in people with schizophrenia (PSZ) results from disrupted cortical excitatory/inhibitory (E-I) balance, which may be linked to gamma entrainment and can be measured noninvasively using electroencephalography (EEG). However, it is not yet known the degree to which these entrainment abnormalities covary within subjects across sensory modalities. Furthermore, the degree to which cross-modal gamma entrainment reflects variation in biological processes associated with cognitive performance remains unclear. We used EEG to measure entrainment to repetitive auditory and visual stimulation at beta (20 Hz) and gamma (30 and 40 Hz) frequencies in PSZ (n = 78) and healthy control subjects (HCS; n = 80). Three indices were measured for each frequency and modality: event-related spectral perturbation (ERSP), intertrial coherence (ITC), and phase-lag angle (PLA). Cognition and symptom severity were also assessed. We found little evidence that gamma entrainment covaried across sensory modalities. PSZ exhibited a modest correlation between modalities at 40 Hz for ERSP and ITC measures (r = 0.23-0.24); however, no other significant correlations between modalities emerged for either HCS or PSZ. Both univariate and multivariate analyses revealed that (a) the pattern of entrainment abnormalities in PSZ differed across modalities, and (b) modality rather than frequency band was the main source of variance. Finally, we observed a significant association between cognition and gamma entrainment in the auditory domain only in HCS. Gamma-band EEG entrainment does not reflect a unitary transcortical mechanism but is instead modality specific. To the extent that entrainment reflects the integrity of cortical E-I balance, the deficits observed in PSZ appear to be modality specific and not consistently associated with cognitive impairment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Deficits in Pre-attentive Processing of Spatial Location and Negative Symptoms in Subjects at Clinical High Risk for Schizophrenia.

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types.

Meta-analysis of mismatch negativity to simple versus complex deviants in schizophrenia.

Mismatch negativity (MMN) deficits in schizophrenia (SCZ) have been studied extensively since the early 1990s, with the vast majority of studies using simple auditory oddball task deviants that vary in a single acoustic dimension such as pitch or duration. There has been a growing interest in using more complex deviants that violate more abstract rules to probe higher order cognitive deficits. It is still unclear how sensory processing deficits compare to and contribute to higher order cognitive dysfunction, which can be investigated with later attention-dependent auditory event-related potential (ERP) components such as a subcomponent of P300, P3b. In this meta-analysis, we compared MMN deficits in SCZ using simple deviants to more complex deviants. We also pooled studies that measured MMN and P3b in the same study sample and examined the relationship between MMN and P3b deficits within study samples. Our analysis reveals that, to date, studies using simple deviants demonstrate larger deficits than those using complex deviants, with effect sizes in the range of moderate to large. The difference in effect sizes between deviant types was reduced significantly when accounting for magnitude of MMN measured in healthy controls. P3b deficits, while large, were only modestly greater than MMN deficits (d=0.21). Taken together, our findings suggest that MMN to simple deviants may still be optimal as a biomarker for SCZ and that sensory processing dysfunction contributes significantly to MMN deficit and disease pathophysiology.

Impaired Motion Processing in Schizophrenia and the Attenuated Psychosis Syndrome: Etiological and Clinical Implications.

OBJECTIVE: The ability to perceive the motion of biological objects, such as faces, is a critical component of daily function and correlates with the ability to successfully navigate social situations (social cognition). Deficits in motion perception in schizophrenia were first demonstrated about 20 years ago but remain understudied, especially in the early, potentially prodromal, stages of the illness. The authors examined the neural bases of visual sensory processing impairments, including motion, in patients with schizophrenia (N=63) and attenuated psychosis (clinical high risk) (N=32) compared with age-matched healthy control subjects (N=67). METHOD: Electrophysiological recordings during stimulus and motion processing were analyzed using oscillatory (time frequency) approaches that differentiated motion-onset-evoked activity from stimulus-onset sensory-evoked responses. These were compared with functional MRI (fMRI) measures of motion processing. RESULTS: Significant deficits in motion processing were observed across the two patient groups, and these deficits predicted impairments in both face-emotion recognition and cognitive function. In contrast to motion processing, sensory-evoked stimulus-onset responses were intact in patients with attenuated psychosis, and, further, the relative deficit in motion-onset responses compared with stimulus-onset responses predicted transition to schizophrenia. In patients with schizophrenia, motion detection deficits mapped to impaired activation in motion-sensitive visual cortex during fMRI. Additional visual impairments in patients with schizophrenia, not present in patients with attenuated psychosis, implicated other visual regions, including the middle occipital gyrus and pulvinar thalamic nucleus. CONCLUSIONS: The study findings emphasize the importance of sensory-level visual dysfunction in the etiology of schizophrenia and in the personal experience of individuals with the disorder and demonstrate that motion-processing deficits may predate illness onset and contribute to impaired function even in patients with attenuated psychosis.

ERPLAB: an open-source toolbox for the analysis of event-related potentials.

ERPLAB toolbox is a freely available, open-source toolbox for processing and analyzing event-related potential (ERP) data in the MATLAB environment. ERPLAB is closely integrated with EEGLAB, a popular open-source toolbox that provides many EEG preprocessing steps and an excellent user interface design. ERPLAB adds to EEGLAB's EEG processing functions, providing additional tools for filtering, artifact detection, re-referencing, and sorting of events, among others. ERPLAB also provides robust tools for averaging EEG segments together to create averaged ERPs, for creating difference waves and other recombinations of ERP waveforms through algebraic expressions, for filtering and re-referencing the averaged ERPs, for plotting ERP waveforms and scalp maps, and for quantifying several types of amplitudes and latencies. ERPLAB's tools can be accessed either from an easy-to-learn graphical user interface or from MATLAB scripts, and a command history function makes it easy for users with no programming experience to write scripts. Consequently, ERPLAB provides both ease of use and virtually unlimited power and flexibility, making it appropriate for the analysis of both simple and complex ERP experiments. Several forms of documentation are available, including a detailed user's guide, a step-by-step tutorial, a scripting guide, and a set of video-based demonstrations.

The spotlight of attention illuminates failed feature-based expectancies.

A well-replicated finding is that visual stimuli presented at an attended location are afforded a processing benefit in the form of speeded reaction times and increased accuracy (Mangun, ; Posner,). This effect has been described using a spotlight metaphor, in which all stimuli within the focus of spatial attention receive facilitated processing, irrespective of other stimulus parameters. However, the spotlight metaphor has been brought into question by a series of combined expectancy studies that demonstrated that the behavioral benefits of spatial attention are contingent on secondary feature-based expectancies (Kingstone,). The present work used an event-related potential (ERP) approach to reveal that the early neural signature of the spotlight of spatial attention is not sensitive to the validity of secondary feature-based expectancies.

Shifting visual attention away from fixation is specifically associated with alpha band activity over ipsilateral parietal regions.

We studied brain activity during the displacement of attention in a modified visuo-spatial orienting paradigm. Using a behaviorally relevant no-shift condition as a control, we asked whether ipsi- or contralateral parietal alpha band activity is specifically related to covert shifts of attention. Cue-related event-related potentials revealed an attention directing anterior negativity (ADAN) contralateral to the shift of attention and P3 and contingent negative variation waveforms that were enhanced in both shift conditions as compared to the no-shift task. When attention was shifted away from fixation, alpha band activity over parietal regions ipsilateral to the attended hemifield was enhanced relative to the control condition, albeit with different dynamics in the upper and lower alpha subbands. Contralateral-to-attended parietal alpha band activity was indistinguishable from the no-shift task.