Transcranial direct current stimulation: a roadmap for research, from mechanism of action to clinical implementation.

Transcranial direct current stimulation (tDCS) is a promising method for altering the function of neural systems, cognition, and behavior. Evidence is emerging that it can also influence psychiatric symptomatology, including major depression and schizophrenia. However, there are many open questions regarding how the method might have such an effect, and uncertainties surrounding its influence on neural activity, and human cognition and functioning. In the present critical review, we identify key priorities for future research into major depression and schizophrenia, including studies of the mechanism(s) of action of tDCS at the neuronal and systems levels, the establishment of the cognitive impact of tDCS, as well as investigations of the potential clinical efficacy of tDCS. We highlight areas of progress in each of these domains, including data that appear to favor an effect of tDCS on neural oscillations rather than spiking, and findings that tDCS administration to the prefrontal cortex during task training may be an effective way to enhance behavioral performance. Finally, we provide suggestions for further empirical study that will elucidate the impact of tDCS on brain and behavior, and may pave the way for efficacious clinical treatments for psychiatric disorders.

Adaptation to Animacy Violations during Listening Comprehension.

The goal of this study was to examine adaptation to various types of animacy violations in cartoon-like stories. We measured the event-related potentials (ERPs) elicited by words at the beginning, middle, and end of four-sentence stories in order to examine adaptation over time to conflicts between stored word knowledge and context-derived meaning (specifically, to inanimate objects serving as main characters, as they might in a cartoon). The fourth and final sentence of each story contained a predicate that required either an animate or an inanimate subject. The results showed that listeners quickly adapted to stories in the Inanimate Noun conditions, consistent with previous research (Filik & Leuthold, 2008; Nieuwland & Van Berkum, 2006). They showed evidence of processing difficulty for animacy-requiring predicates in the Inanimate Noun conditions in Sentence 1, but the effect dissipated in Sentences 2 and 3. In Sentences 2 and 4, we measured ERPs at three critical points where it was possible to observe the influence of both context-based expectations and expectations from prior knowledge on processing. Overall, the pattern of results demonstrates how listeners flexibly adapt to unusual, conflict-ridden input, using previous context to generate expectations about upcoming input, but that current context is weighted appropriately in combination with expectations from background knowledge and prior language experience.

Sensitivity to Referential Ambiguity in Discourse: The Role of Attention, Working Memory, and Verbal Ability.

The establishment of reference is essential to language comprehension. The goal of this study was to examine listeners' sensitivity to referential ambiguity as a function of individual variation in attention, working memory capacity, and verbal ability. Participants listened to stories in which two entities were introduced that were either very similar (e.g., two oaks) or less similar (e.g., one oak and one elm). The manipulation rendered an anaphor in a subsequent sentence (e.g., oak) ambiguous or unambiguous. EEG was recorded as listeners comprehended the story, after which participants completed tasks to assess working memory, verbal ability, and the ability to use context in task performance. Power in the alpha and theta frequency bands when listeners received critical information about the discourse entities (e.g., oaks) was used to index attention and the involvement of the working memory system in processing the entities. These measures were then used to predict an ERP component that is sensitive to referential ambiguity, the Nref, which was recorded when listeners received the anaphor. Nref amplitude at the anaphor was predicted by alpha power during the earlier critical sentence: Individuals with increased alpha power in ambiguous compared with unambiguous stories were less sensitive to the anaphor's ambiguity. Verbal ability was also predictive of greater sensitivity to referential ambiguity. Finally, increased theta power in the ambiguous compared with unambiguous condition was associated with higher working-memory span. These results highlight the role of attention and working memory in referential processing during listening comprehension.

Graded expectations: Predictive processing and the adjustment of expectations during spoken language comprehension.

The goal of this study was to investigate the use of the local and global contexts for incoming words during listening comprehension. Local context was manipulated by presenting a target noun (e.g., "cake," "veggies") that was preceded by a word that described a prototypical or atypical feature of the noun (e.g., "sweet," "healthy"). Global context was manipulated by presenting the noun in a scenario that was consistent or inconsistent with the critical noun (e.g., a birthday party). Event-related potentials (ERPs) were examined at the feature word and at the critical noun. An N400 effect was found at the feature word, reflecting the effect of compatibility with the global context. Global predictability and the local feature word consistency interacted at the critical noun: A larger N200 was found to nouns that mismatched predictions when the context was maximally constraining, relative to nouns in the other conditions. A graded N400 response was observed at the critical noun, modulated by global predictability and feature consistency. Finally, post-N400 positivity effects of context updating were observed to nouns that were supported by one contextual cue (global/local) but were unsupported by the other. These results indicate that (1) incoming words that are compatible with context-based expectations receive a processing benefit; (2) when the context is sufficiently constraining, specific lexical items may be activated; and (3) listeners dynamically adjust their expectations when input is inconsistent with their predictions, provided that the inconsistency has some level of support from either the global or the local context.

Spared and impaired spoken discourse processing in schizophrenia: effects of local and global language context.

Individuals with schizophrenia are impaired in a broad range of cognitive functions, including impairments in the controlled maintenance of context-relevant information. In this study, we used ERPs in human subjects to examine whether impairments in the controlled maintenance of spoken discourse context in schizophrenia lead to overreliance on local associations among the meanings of individual words. Healthy controls (n = 22) and patients (n = 22) listened to short stories in which we manipulated global discourse congruence and local priming. The target word in the last sentence of each story was globally congruent or incongruent and locally associated or unassociated. ERP local association effects did not significantly differ between control participants and schizophrenia patients. However, in contrast to controls, patients only showed effects of discourse congruence when targets were primed by a word in the local context. When patients had to use discourse context in the absence of local priming, they showed impaired brain responses to the target. Our findings indicate that schizophrenia patients are impaired during discourse comprehension when demands on controlled maintenance of context are high. We further found that ERP measures of increased reliance on local priming predicted reduced social functioning, suggesting that alterations in the neural mechanisms underlying discourse comprehension have functional consequences in the illness.

A Transdiagnostic Study of Effort-Cost Decision-Making in Psychotic and Mood Disorders.

BACKGROUND: Research suggests that effort-cost decision-making (ECDM), the estimation of work required to obtain reward, may be a relevant framework for understanding motivational impairment in psychotic and mood pathology. Specifically, research has suggested that people with psychotic and mood pathology experience effort as more costly than controls, and thus pursue effortful goals less frequently. This study examined ECDM across psychotic and mood pathology. HYPOTHESIS: We hypothesized that patient groups would show reduced willingness to expend effort compared to controls. STUDY DESIGN: People with schizophrenia (N = 33), schizoaffective disorder (N = 28), bipolar disorder (N = 39), major depressive disorder (N = 40), and controls (N = 70) completed a physical ECDM task. Participants decided between completing a low-effort or high-effort option for small or larger rewards, respectively. Reward magnitude, reward probability, and effort magnitude varied trial-by-trial. Data were analyzed using standard and hierarchical logistic regression analyses to assess the subject-specific contribution of various factors to choice. Negative symptoms were measured with a clinician-rated interview. STUDY RESULTS: There was a significant effect of group, driven by reduced choice of high-effort options in schizophrenia. Hierarchical logistic regression revealed that reduced choice of high-effort options in schizophrenia was driven by weaker contributions of probability information. Use of reward information was inversely associated with motivational impairment in schizophrenia. Surprisingly, individuals with major depressive disorder and bipolar disorder did not differ from controls. CONCLUSIONS: Our results provide support for ECDM deficits in schizophrenia. Additionally, differences between groups in ECDM suggest a seemingly similar behavioral phenotype, reduced motivation, could arise from disparate mechanisms.

Assessing Trial-by-Trial Electrophysiological and Behavioral Markers of Attentional Control and Sensory Precision in Psychotic and Mood Disorders.

BACKGROUND AND HYPOTHESIS: The current study investigated the extent to which changes in attentional control contribute to performance on a visual perceptual discrimination task, on a trial-by-trial basis in a transdiagnostic clinical sample. STUDY DESIGN: Participants with schizophrenia (SZ; N = 58), bipolar disorder (N = 42), major depression disorder (N = 51), and psychiatrically healthy controls (N = 92) completed a visual perception task in which stimuli appeared briefly. The design allowed us to estimate the lapse rate and the precision of perceptual representations of the stimuli. Electroencephalograms (EEG) were recorded to examine pre-stimulus activity in the alpha band (8-13 Hz), overall and in relation to behavior performance on the task. STUDY RESULTS: We found that the attention lapse rate was elevated in the SZ group compared with all other groups. We also observed group differences in pre-stimulus alpha activity, with control participants showing the highest levels of pre-stimulus alpha when averaging across trials. However, trial-by-trial analyses showed within-participant fluctuations in pre-stimulus alpha activity significantly predicted the likelihood of making an error, in all groups. Interestingly, our analysis demonstrated that aperiodic contributions to the EEG signal (which affect power estimates across frequency bands) serve as a significant predictor of behavior as well. CONCLUSIONS: These results confirm the elevated attention lapse rate that has been observed in SZ, validate pre-stimulus EEG markers of attentional control and their use as a predictor of behavior on a trial-by-trial basis, and suggest that aperiodic contributions to the EEG signal are an important target for further research in this area, in addition to alpha-band activity.

Half-listening or zoned out? It's about the same: the impact of attentional state on word processing in context.

Language comprehension must require some degree of attentional focus, but how do periods of inattention and/or split attention impact how language is processed? Here EEG was recorded while participants listened to full-length stories, and were periodically asked about whether they were fully attentive, were completely inattentive, or felt that they were in a split attention state. The ERP response to the words immediately preceding these attention questions was examined as a function of participant response, which allowed for the comparison of word processing in each of these attentional states. When participants were on-task, typical N400 effects of lexical frequency (smaller N400 for common compared to less common words), word position (smaller N400 for words appearing late in a sentence compared to words appearing with less preceding context), and surprisal (smaller N400 for relatively expected words compared to relatively unexpected words) were observed. When participants were in a fully inattentive state, the word-level effect of frequency was intact, but the context-dependent effects of word position and surprisal were significantly reduced. Interestingly, the pattern of results when participants were in a split attention state closely matched that of the fully inattentive state. Overall, the results demonstrate how attentional state influences sensitivity to language context during comprehension, and show that the consequences of inattention and split attention on word processing in context are quite similar, at least on the indices measured here.

Managing EEG studies: How to prepare and what to do once data collection has begun.

In this paper, we provide guidance for the organization and implementation of EEG studies. This work was inspired by our experience conducting a large-scale, multi-site study, but many elements could be applied to any EEG project. Section 1 focuses on study activities that take place before data collection begins. Topics covered include: establishing and training study teams, considerations for task design and piloting, setting up equipment and software, development of formal protocol documents, and planning communication strategy with all study team members. Section 2 focuses on what to do once data collection has already begun. Topics covered include: (1) how to effectively monitor and maintain EEG data quality, (2) how to ensure consistent implementation of experimental protocols, and (3) how to develop rigorous preprocessing procedures that are feasible for use in a large-scale study. Links to resources are also provided, including sample protocols, sample equipment and software tracking forms, sample code, and tutorial videos (to access resources, please visit: https://osf.io/wdrj3/).

Neural correlates of word representation vectors in natural language processing models: Evidence from representational similarity analysis of event-related brain potentials.

Natural language processing models based on machine learning (ML-NLP models) have been developed to solve practical problems, such as interpreting an Internet search query. These models are not intended to reflect human language comprehension mechanisms, and the word representations used by ML-NLP models and human brains might therefore be quite different. However, because ML-NLP models are trained with the same kinds of inputs that humans must process, and they must solve many of the same computational problems as the human brain, ML-NLP models and human brains may end up with similar word representations. To distinguish between these hypotheses, we used representational similarity analysis to compare the representational geometry of word representations in two ML-NLP models with the representational geometry of the human brain, as indexed with event-related potentials (ERPs). Participants listened to stories while the electroencephalogram was recorded. We extracted averaged ERPs for each of the 100 words that occurred most frequently in the stories, and we calculated the similarity of the neural response for each pair of words. We compared this 100 × 100 similarity matrix to the 100 × 100 similarity matrix for the word pairs according to two ML-NLP models. We found significant representational similarity between the neural data and each ML-NLP model, beginning within 250 ms of word onset. These results indicate that ML-NLP systems that are designed to solve practical technology problems have a representational geometry that is correlated with that of the human brain, presumably because both are influenced by the structural properties and statistics of language.

Using prefrontal transcranial direct current stimulation (tDCS) to enhance proactive cognitive control in schizophrenia.

The goal of this study was to use transcranial direct current stimulation (tDCS) to examine the role of the prefrontal cortex (PFC) in neural oscillatory activity associated with proactive cognitive control in schizophrenia. To do so, we tested the impact of PFC-targeted tDCS on behavioral and electrophysiological markers of proactive cognitive control engagement in individuals with schizophrenia. Using a within-participants, double-blinded, sham-controlled crossover design, we recorded EEG while participants with schizophrenia completed a proactive cognitive control task (the Dot Pattern Expectancy (DPX) Task), after receiving 20 min of active prefrontal stimulation at 2 mA or sham stimulation. We hypothesized that active stimulation would enhance proactive cognitive control, leading to changes in behavioral performance on the DPX task and in activity in the gamma frequency band during key periods of the task designed to tax proactive cognitive control. The results showed significant changes in the pattern of error rates and increases in EEG gamma power as a function of tDCS condition (active or sham), that were indicative of enhanced proactive cognitive control. These findings, considered alongside our previous work in healthy adults, provides novel support for the role gamma oscillations in proactive cognitive control and they suggest that frontal tDCS may be a promising approach to enhance proactive cognitive control in schizophrenia.

Cross-diagnostic analysis of cognitive control in mental illness: Insights from the CNTRACS consortium.

BACKGROUND: In recent years, psychiatry research has increasingly focused on understanding mental illnesses from a cross-diagnostic, dimensional perspective in order to better align their neurocognitive features with underlying neurobiological mechanisms. In this multi-site study, we examined two measures of cognitive control (d-prime context and lapsing rate) during the Dot Probe Expectancy (DPX) version of the AX-Continuous Performance Task in patients with either schizophrenia (SZ), schizoaffective disorder (SZ-A), or Type I bipolar disorder (BD) as well as healthy control (HC) subjects. We hypothesized significantly lower d-prime context and higher lapsing rate in SZ and SZ-A patients and intermediate levels in BD patients relative to HC. METHODS: 72 HC, 84 SZ, 77 SZ-A, and 58 BD patients (ages 18-56) were included in the final study sample. RESULTS: Significant main effects of diagnosis were observed on d-prime context (F(3,279) = 9.59, p < 0.001) and lapsing (F(3,279) = 8.08, p < 0.001). A priori linear contrasts suggesting intermediate dysfunction in BD patients were significant (p < 0.001), although post-hoc tests showed the BD group was only significantly different from HC on d-prime context. Group results for d-prime context remained significant after covarying for lapsing rate. Primary behavioral measures were associated with mania and disorganization symptoms as well as everyday functioning. CONCLUSIONS: These findings suggest a continuum of dysfunction in cognitive control (particularly d-prime context) across diagnostic categories in psychiatric illness. These results further suggest that lapsing and d-prime context, while related, make unique contributions towards explaining deficits in cognitive control in these disorders.

Electrophysiological correlates of adaptive control and attentional engagement in patients with first episode schizophrenia and healthy young adults.

The goal of this study was to investigate the neural dynamics of error processing and post-error adjustments in cognitive control and attention to a cognitive task in schizophrenia. We adopted a time-frequency approach in order to examine activity in the theta and alpha frequency bands as indices of cognitive control and attentional engagement. The results showed that error processing was characterized by increases in theta-band activity, accompanied by decreases in alpha-band activity, in both healthy control participants and participants with schizophrenia. However, both the theta and alpha effects were significantly reduced in participants with schizophrenia. Post-error increases in theta activity were associated with improved accuracy on subsequent trials in control participants but not in participants with schizophrenia. In addition, increases in alpha-band activity were found in the prestimulus period before partial attention lapses, but only for control participants and participants with schizophrenia with relatively low positive symptom severity. These results provide evidence for a deficit in cognitive control mechanisms mediated by midfrontal theta activity in schizophrenia, and suggest a particularly pronounced deficit in patients' ability to engage adaptive control mechanisms following errors. Our results also indicate that partial attention lapses can be indexed in both control participants and participants with schizophrenia by increases in alpha activity, but that in schizophrenia this varies as a function of positive symptom severity. We suggest that disrupted theta-band function represents a key deficit of schizophrenia, whereas disruptions in the alpha band may be the byproduct of atypically regulated attention.

How many trials does it take to get a significant ERP effect? It depends.

In designing an ERP study, researchers must choose how many trials to include, balancing the desire to maximize statistical power and the need to minimize the length of the recording session. Recent studies have attempted to quantify the minimum number of trials needed to obtain reliable measures for a variety of ERP components. However, these studies have largely ignored other variables that affect statistical power in ERP studies, including sample size and effect magnitude. The goal of the present study was to determine whether and how the number of trials, number of participants, and effect magnitude interact to influence statistical power, thus providing a better guide for selecting an appropriate number of trials. We used a Monte Carlo approach to measure the probability of obtaining a statistically significant result when testing for (a) the presence of an ERP effect, (b) within-participant condition differences in an ERP effect, and (c) between-participants group differences in an ERP effect. Each of these issues was examined in the context of the error-related negativity and the lateralized readiness potential. We found that doubling the number of trials recommended by previous studies led to more than a doubling of statistical power under many conditions. Thus, when determining the number of trials that should be included in a given study, researchers must consider the sample size, the anticipated effect magnitude, and the noise level, rather than relying solely on general recommendations about the number of trials needed to obtain a "stable" ERP waveform.

Language context processing deficits in schizophrenia: The role of attentional engagement.

Individuals with schizophrenia exhibit problems in language comprehension that are most evident during discourse processing. We hypothesized that deficits in cognitive control contribute to these comprehension deficits during discourse processing, and investigated the underlying cognitive-neural mechanisms using EEG (alpha power) and ERPs (N400). N400 amplitudes to globally supported or unsupported target words near the end of stories were used to index sensitivity to previous context. ERPs showed reduced sensitivity to context in patients versus controls. EEG alpha-band activity was used to index attentional engagement while participants listened to the stories. We found that context effects varied with attentional engagement in both groups, as well as with negative symptom severity in patients. Both groups demonstrated trial-to-trial fluctuations in alpha. Relatively high alpha power was associated with compromised discourse processing in participants with schizophrenia when it occurred during any early portion of the story. In contrast, discourse processing was only compromised in controls when alpha was relatively high for longer segments of the stories. Our results indicate that shifts in attention from the story context may be more detrimental to discourse processing for participants with schizophrenia than for controls, most likely due to an impaired ability to benefit from global context.

Cognitive Control of Episodic Memory in Schizophrenia: Differential Role of Dorsolateral and Ventrolateral Prefrontal Cortex.

BACKGROUND: Dorsal (DLPFC) and ventral (VLPFC) subregions in lateral prefrontal cortex play distinct roles in episodic memory, and both are implicated in schizophrenia. We test the hypothesis that schizophrenia differentially impairs DLPFC versus VLPFC control of episodic encoding. METHODS: Cognitive control was manipulated by requiring participants to encode targets and avoid encoding non-targets based upon stimulus properties of test stimuli. The more automatic encoding response (target versus non-target) was predicted to engage VLPFC in both groups. Conversely, having to overcome the prepotent encoding response (non-targets versus targets) was predicted to produce greater DLPFC activation in controls than in patients. Encoding occurred during event-related fMRI in a sample of 21 individuals with schizophrenia and 30 healthy participants. Scanning was followed by recognition testing outside the scanner. RESULTS: Patients were less successful differentially remembering target versus non-target stimuli, and retrieval difficulties correlated with more severe disorganized symptoms. As predicted, the target versus non-target contrast activated the VLPFC and correlated with retrieval success in both groups. Conversely, the non-target versus target contrast produced greater DLPFC activation in controls than in patients, and DLPFC activation correlated with performance only in controls. CONCLUSION: Individuals with schizophrenia can successfully engage the VLPFC to provide control over semantic encoding of individual items, but are specifically impaired at engaging the DLPFC to main context for task-appropriate encoding and thereby generate improved memory for target versus non-target items. This extends previous cognitive control models based on response selection tasks to the memory domain.

Priming prepositional phrase attachment: evidence from eye-tracking and event-related potentials.

Three syntactic-priming experiments investigated the effect of structurally similar or dissimilar prime sentences on the processing of target sentences, using eye tracking (Experiment 1) and event-related potentials (ERPs) (Experiments 2 and 3) All three experiments tested readers' response to sentences containing a temporary syntactic ambiguity. The ambiguity occurred because a prepositional phrase modifier (PP-modifier) could attach either to a preceding verb or to a preceding noun. Previous experiments have established that (a) noun-modifying expressions are harder to process than verb-modifying expressions (when test sentences are presented in isolation); and (b) for other kinds of sentences, processing a structurally similar prime sentence can facilitate processing a target sentence. The experiments reported here were designed to determine whether a structurally similar prime could facilitate processing of noun-attached modifiers and whether such facilitation reflected syntactic-structure-building or semantic processes. These findings have implications for accounts of structural priming during online comprehension and for accounts of syntactic representation and processing in comprehension.

Evidence for Priming Across Intervening Sentences During On-Line Sentence Comprehension.

Three experiments investigated factors contributing to syntactic priming during on-line comprehension. In all of the experiments, a prime sentence containing a reduced relative clause was presented prior to a target sentence that contained the same structure. Previous studies have shown that people respond more quickly when a syntactically related prime sentence immediately precedes a target. In the current study, ERP and eyetracking measures were used to assess whether priming in sentence comprehension persists when one or more unrelated filler sentences appear between the prime and the target. In experiment 1, a reduced P600 was found to target sentences both when there were no intervening unrelated fillers, and when there was one unrelated filler between the prime and the target. Thus, processing the prime sentence facilitated processing of the syntactic form of the target sentence. Experiments 2 and 3, eye-tracking experiments, showed that target sentence processing was facilitated when three filler sentences intervened between the prime and the target. These experiments show that priming effects in comprehension can be observed when unrelated material appears after a prime sentence and before the target. We interpret the results with respect to residual activation and implicit learning accounts of priming.