Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study).

BACKGROUND: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD. METHODS: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses. RESULTS: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance. CONCLUSIONS: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions.

Excessive psychological stress preceding the onset of idiopathic cervical dystonia.

Idiopathic cervical dystonia (ICD) is the largest subgroup of dystonia. Psychological stress as a triggering factor has long been discussed, but detailed descriptions are lacking. We report on a group of 13 patients with ICD and preceding excessive psychological stress (age at ICD onset 39.0 ± 13.9 years, 7 females, 6 males). The observation period was 7.8 ± 5.0 years. Excessive psychological stress included partner conflicts (divorce and separation, domestic violence), special familial burdens, legal disputes and migration. It started 8.3 ± 3.9 months before ICD onset. In 85% of our patients (typical cases), ICD developed within 5.8 ± 4.4 weeks, then lasted 18.5 ± 8.3 months, before it started to remit 2.7 ± 0.8 years after its onset to 54.5 ± 35.3% of its maximal severity. Idiopathic dystonia is thought to be based upon a genetic predisposition triggered by epigenetic factors. Our study suggests that excessive psychological stress could be one of them. Pathophysiologic elements are only vaguely identified, but could include the endoplasmic reticulum stress response, cerebellar 5HT-2A receptors and the metabolism of heat shock proteins. Whilst the clinical presentation of ICD preceded by excessive psychological stress is typical, its course is atypical with rapid onset and fast and substantial remission.

The natural course of idiopathic cervical dystonia.

Idiopathic cervical dystonia (ICD) is by far the largest subgroup of dystonia. Still, its natural course is largely unknown. We studied the natural course of 100 ICD patients from our botulinum toxin clinics (age at ICD onset 45.8 ± 13.5 years, female/male ratio 2.0) over a period of 17.5 ± 11.5 years with follow-ups during botulinum toxin therapy and with semi-structured interviews. Two courses of ICD could be distinguished by symptom development of more or less than 6 months. ICD-type 2 was less frequent (19% vs 81%, p < 0.001), had a more rapid onset (8.7 ± 8.0 weeks vs 3.8 ± 3.5 years), a higher remission rate (92% vs 5%, p < 0.001) and a higher prevalence of excessive psychological stress preceding ICD (63% vs 1%, p < 0.001). In both ICD-types, the plateau phase was non-progressive. Significant differences in patient age at ICD onset, latency and extent of remission, female/male ratio and prevalence of family history of dystonia could not be detected. ICD is a non-progressive disorder. ICD-type 1 represents the standard course. ICD-type 2 features rapid onset, preceding excessive psychological stress and a high remission rate. These findings will improve prognosis, treatment strategies and understanding of underlying disease mechanisms. They contradict the widespread fear of patients of a constant and continued decline of their condition. Excessive psychological stress may be an epigenetic factor triggering the manifestation of genetically predetermined dystonia.

Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).

BACKGROUND: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To assess cognitive performance and changes over time in NMOSD. METHODS: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. RESULTS: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. CONCLUSIONS: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Electroencephalographic correlates of temporal Bayesian belief updating and surprise.

The brain predicts the timing of forthcoming events to optimize responses to them. Temporal predictions have been formalized in terms of the hazard function, which integrates prior beliefs on the likely timing of stimulus occurrence with information conveyed by the passage of time. However, how the human brain updates prior temporal beliefs is still elusive. Here we investigated electroencephalographic (EEG) signatures associated with Bayes-optimal updating of temporal beliefs. Given that updating usually occurs in response to surprising events, we sought to disentangle EEG correlates of updating from those associated with surprise. Twenty-six participants performed a temporal foreperiod task, which comprised a subset of surprising events not eliciting updating. EEG data were analyzed through a regression-based massive approach in the electrode and source space. Distinct late positive, centro-parietally distributed, event-related potentials (ERPs) were associated with surprise and belief updating in the electrode space. While surprise modulated the commonly observed P3b, updating was associated with a later and more sustained P3b-like waveform deflection. Results from source analyses revealed that neural encoding of surprise comprises neural activity in the cingulo-opercular network (CON) and parietal regions. These data provide evidence that temporal predictions are computed in a Bayesian manner, and that this is reflected in P3 modulations, akin to other cognitive domains. Overall, our study revealed that analyzing P3 modulations provides an important window into the Bayesian brain. Data and scripts are shared on OSF: https://osf.io/ckqa5/.

Botulinum toxin dosing in arm muscles: contextual factors.

Botulinum toxin (BT) has been successfully used for many years to treat various muscle hyperactivity disorders including dystonia and spasticity. Its dosing is guided by dosing tables describing target muscles and dose ranges. To refine the BT dosing, we wanted to analyse how contextual factors may influence the injector's final dosing decision.In a retrospective review of real-life data of 1170 BT treatments, we studied the influence of various contextual factors on the BT doses in 21 arm muscles of 252 patients receiving BT therapy for different muscle hyperactivity disorders.We found that BT arm doses are significantly higher in treatment of spasticity than in treatment of dystonia. We also found that spontaneous arm dystonia requires higher BT doses in a proximal application pattern, whereas task specific writer's cramp requires considerably reduced BT doses with a distal application pattern. Injections of non-arm muscles influence the BT dosing in arm muscles only marginally.Our study demonstrates that BT dosing does not only depend on the particularities of the individual target muscle injected, such as its volume and its static or phasic function. BT dosing and its application pattern rather depend on additional contextual factors such as the aetiology and pathophysiology of the muscle hyperactivity treated. These contextual factors need to be included in dosing tables and may improve the outcome of BT therapy.

Identification of a rare SEPT9 variant in a family with autosomal dominant Charcot-Marie-Tooth disease.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neurological disorders. A growing number of genes, involved in glial and neuronal functions, have been associated with different subtypes of CMT leading to improved diagnostics and understanding of pathophysiological mechanisms. However, some patients and families remain genetically unsolved. METHODS: We report on a German family including four affected members over three generations with a CMT phenotype accompanied by cognitive deficits, predominantly with regard to visual abilities and episodic memory. RESULTS: A comprehensive clinical characterization followed by a sequential diagnostic approach disclosed a heterozygous rare SEPT9 missense variant c.1406 T > C, p.(Val469Ala), that segregates with disease. SEPT9 has been linked to various intracellular functions, such as cytokinesis and membrane trafficking. Interestingly, SEPT9-mutations are known to cause hereditary neuralgic amyotrophy (HNA), a recurrent focal peripheral neuropathy. CONCLUSION: We, for the first time, present a SEPT9 variant associated to a CMT phenotype and suggest SEPT9 as new sufficient candidate gene in CMT.

Stimulus- and response-based interference contributes to the costs of switching between cognitive tasks.

Little is known about how stimulus- and response-based interference might interact to contribute to the costs of switching between cognitive tasks. We analyzed switch costs in a novel cued task-switching/card-matching paradigm in a large study (N = 95). We reasoned that interference from previously active task sets may be contingent upon the retrieval of these task sets via stimulus processing, or alternatively, via response processing. We examined the efficacy of these two factors through eligibility manipulations. That is, stimulus/response features that were capable of retrieving task sets from the previous trial remained eligible (or not) on the current trial. We report three main findings: first, no switch costs were found when neither stimulus features, nor response features, were adequate for the retrieval of the previously executed task sets. Second, we found substantial switch costs when, on switch trials, stimulus features kept the previously executed task eligible, and we found roughly equivalent switch costs when the previously executed response remained eligible. Third, evidence for stimulus-induced switch costs was exclusively observed when previously executed responses remained ineligible. These data indicate that stimulus-based interference, and of importance, response-based interference, contribute comparably to switch costs. Possible interpretations of non-additive switch costs are discussed.

Comparing lanbotulinumtoxinA (Hengli®) with onabotulinumtoxinA (Botox®) and incobotulinumtoxinA (Xeomin®) in the mouse hemidiaphragm assay.

LanbotulinumtoxinA (LAN) is manufactured and registered in China since 1994. Despite its widespread use in China and its increasing use in other Asian countries and in South America, it is not yet well known elsewhere. We wanted to compare its potency labelling using the mouse diaphragm assay (MDA), an isolated muscle model for botulinum toxin (BT) potency measurements, which is superior to clinical tests and which was recently refined as an alternative batch release assay for BT manufacturing. We also wanted to estimate LAN manufacturing quality by testing its inter-batch potency consistency. Potencies of 20, 60 and 100 MU of LAN, onabotulinumtoxinA (ONA) and incobotulinumtoxinA (INCO) were measured by the inversely related paresis time (PT) in the MDA. The PT (M ± SD) of all doses of LAN, ONA and INCO was 90.4 ± 27.0 min, 114.9 ± 46.5 min and 94.3 ± 29.9 min, respectively. Statistical analysis demonstrated indistinguishable potency labelling of LAN and INCO, but revealed a slightly lower potency of ONA compared to LAN and INCO. PT of LAN batch 1 and LAN batch 2 was 86.9 ± 21.2 min and 94.0 ± 32.8 min, respectively (no statistically significant difference), suggesting an adequate LAN manufacturing consistency. The MDA is an appropriate instrument for potency testing of BT drugs, including new ones currently under development. Our results allow comparing therapeutic effects, adverse effects and economics of LAN, ONA and INCO. They also suggest adequate manufacturing consistency of LAN.

Data quality over data quantity in computational cognitive neuroscience.

We analyzed factors that may hamper the advancement of computational cognitive neuroscience (CCN). These factors include a particular statistical mindset, which paves the way for the dominance of statistical power theory and a preoccupation with statistical replicability in the behavioral and neural sciences. Exclusive statistical concerns about sampling error occur at the cost of an inadequate representation of the problem of measurement error. We contrasted the manipulation of data quantity (sampling error, by varying the number of subjects) against the manipulation of data quality (measurement error, by varying the number of data per subject) in a simulated Bayesian model identifiability study. The results were clear-cut in showing that - across all levels of signal-to-noise ratios - varying the number of subjects was completely inconsequential, whereas the number of data per subject exerted massive effects on model identifiability. These results emphasize data quality over data quantity, and they call for the integration of statistics and measurement theory.

P300 amplitude variations, prior probabilities, and likelihoods: A Bayesian ERP study.

The capability of the human brain for Bayesian inference was assessed by manipulating probabilistic contingencies in an urn-ball task. Event-related potentials (ERPs) were recorded in response to stimuli that differed in their relative frequency of occurrence (.18 to .82). A veraged ERPs with sufficient signal-to-noise ratio (relative frequency of occurrence > .5) were used for further analysis. Research hypotheses about relationships between probabilistic contingencies and ERP amplitude variations were formalized as (in-)equality constrained hypotheses. Conducting Bayesian model comparisons, we found that manipulations of prior probabilities and likelihoods were associated with separately modifiable and distinct ERP responses. P3a amplitudes were sensitive to the degree of prior certainty such that higher prior probabilities were related to larger frontally distributed P3a waves. P3b amplitudes were sensitive to the degree of likelihood certainty such that lower likelihoods were associated with larger parietally distributed P3b waves. These ERP data suggest that these antecedents of Bayesian inference (prior probabilities and likelihoods) are coded by the human brain.

Cognitive Flexibility in Primary Dystonia.

Objectives Although primary dystonia is typically characterized as a movement disorder, it is also associated with cognitive alterations in the domain of executive functioning which may arise from changes in cortico-basal ganglia circuits. Specifically, in comparison to healthy controls, patients with dystonia show deficits in neuropsychological tests of cognitive flexibility. However, it is unclear whether cognitive inflexibility is caused by the pathomechanisms underlying primary dystonia or by confounding factors such as depression or symptom-related distraction.Methods The present study aimed to eliminate these confounds by examining cognitive flexibility in dystonia patients and in patients with similar motor symptoms but without a comparable central pathophysiology. Eighteen patients with primary blepharospasm, a common form of dystonia affecting the muscles around the eyes, and 19 patients with hemifacial spasm, a facial nerve disorder causing similar eyelid spasms, completed a computerized version of the Wisconsin Card Sorting Test (cWCST). The two groups were further compared on tests of global cognitive functioning, psychiatric symptoms, health status, and impulsiveness. Results Blepharospasm patients committed significantly more errors on the cWCST than patients with hemifacial spasm. Group differences were most pronounced with regard to integration errors, a measure of rule-inference processes on the cWCST. Integration errors were also associated with impulsiveness in patients with blepharospasm. Conclusions Primary blepharospasm is related to deficits in cognitive flexibility, even when blepharospasm patients are compared with patients who suffer from motor symptoms of non-dystonic origin. Our results support the possibility that cognitive inflexibility results from the specific pathophysiological processes underlying primary dystonia. (JINS, 2016, 22, 662-670).

Prior probabilities modulate cortical surprise responses: A study of event-related potentials.

The human brain predicts events in its environment based on expectations, and unexpected events are surprising. When probabilistic contingencies in the environment are precisely instructed, the individual can form expectations based on quantitative probabilistic information ('inference-based learning'). In contrast, when probabilistic contingencies are imprecisely instructed, expectations are formed based on the individual's cumulative experience ('experience-based learning'). Here, we used the urn-ball paradigm to investigate how variations in prior probabilities and in the precision of information about these priors modulate choice behavior and event-related potential (ERP) correlates of surprise. In the urn-ball paradigm, participants are repeatedly forced to infer hidden states responsible for generating observable events, given small samples of factual observations. We manipulated prior probabilities of the states, and we rendered the priors calculable or incalculable, respectively. The analysis of choice behavior revealed that the tendency to consider prior probabilities when making decisions about hidden states was stronger when prior probabilities were calculable, at least in some of our participants. Surprise-related P3b amplitudes were observed in both the calculable and the incalculable prior probability condition. In contrast, calculability of prior probabilities modulated anteriorly distributed ERP amplitudes: when prior probabilities were calculable, surprising events elicited enhanced P3a amplitudes. However, when prior probabilities were incalculable, surprise was associated with enhanced N2 amplitudes. Furthermore, interindividual variability in reliance on prior probabilities was associated with attenuated P3b surprise responses under calculable in comparison to incalculable prior probabilities. Our results suggest two distinct neural systems for probabilistic learning that are recruited depending on contextual cues such as the precision of probabilistic information. Individuals with stronger tendencies to rely on calculable prior probabilities seem to have better adapted expectations at their disposal, as indicated by an attenuation of their P3b surprise responses when prior probabilities are calculable.

A computational analysis of the neural bases of Bayesian inference.

Empirical support for the Bayesian brain hypothesis, although of major theoretical importance for cognitive neuroscience, is surprisingly scarce. This hypothesis posits simply that neural activities code and compute Bayesian probabilities. Here, we introduce an urn-ball paradigm to relate event-related potentials (ERPs) such as the P300 wave to Bayesian inference. Bayesian model comparison is conducted to compare various models in terms of their ability to explain trial-by-trial variation in ERP responses at different points in time and over different regions of the scalp. Specifically, we are interested in dissociating specific ERP responses in terms of Bayesian updating and predictive surprise. Bayesian updating refers to changes in probability distributions given new observations, while predictive surprise equals the surprise about observations under current probability distributions. Components of the late positive complex (P3a, P3b, Slow Wave) provide dissociable measures of Bayesian updating and predictive surprise. Specifically, the updating of beliefs about hidden states yields the best fit for the anteriorly distributed P3a, whereas the updating of predictions of observations accounts best for the posteriorly distributed Slow Wave. In addition, parietally distributed P3b responses are best fit by predictive surprise. These results indicate that the three components of the late positive complex reflect distinct neural computations. As such they are consistent with the Bayesian brain hypothesis, but these neural computations seem to be subject to nonlinear probability weighting. We integrate these findings with the free-energy principle that instantiates the Bayesian brain hypothesis.

Age-related changes in neural recruitment for cognitive control.

The dual mechanisms of control (DMC; Braver, Gray, & Burgess, 2007) framework postulates a distinction between proactive and reactive modes of cognitive control. Event-related brain potentials (ERPs) were used to examine age differences in the neural correlates of proactive and reactive control for task-switching. Whereas proactive control is associated with brain activity for anticipatory task preparation, reactive control is accompanied by reduced preparatory activity, but increased activation during task execution. Switching between tasks was based on feedback-based transition cueing which places particularly high demands on mechanisms for cognitive control. Older adults maintained good performance accuracy at the expense of slower response times. No age-related increase in behavioral switching costs was observed. The cue-locked ERP (P3a) data revealed an age-related decrease in neural activity related to the processing of switch cues. In the target-locked ERPs, there was an increased frontal focus of the P3b in older adults. These ERP data indicate an age-related neural under-recruitment for proactive cognitive control and an age-related neural over-recruitment for reactive cognitive control. They are consistent with the idea that older adults may not fully implement task settings before target onset, after which they need to catch up on the omitted preparatory task settings.

The future of neuropsychology is digital, theory-driven, and Bayesian: a paradigmatic study of cognitive flexibility.

Introduction: This study explores the transformative potential of digital, theory-driven, and Bayesian paradigms in neuropsychology by combining digital technologies, a commitment to evaluating theoretical frameworks, and Bayesian statistics. The study also examines theories of executive function and cognitive flexibility in a large sample of neurotypical individuals (N = 489). Methods: We developed an internet-based Wisconsin Card-Sorting Task (iWCST) optimized for online assessment of perseveration errors (PE). Predictions of the percentage of PE, PE (%), in non-repetitive versus repetitive situations were derived from the established supervisory attention system (SAS) theory, non-repetitive PE (%) < repetitive PE (%), and the novel goal-directed instrumental control (GIC) theory, non-repetitive PE (%) > repetitive PE (%). Results: Bayesian t-tests revealed the presence of a robust error suppression effect (ESE) indicating that PE are less likely in repetitive situations than in non-repetitive situations, contradicting SAS theory with posterior model probability p < 0.001 and confirming GIC theory with posterior model probability p > 0.999. We conclude that repetitive situations support cognitive set switching in the iWCST by facilitating the retrieval of goal-directed, instrumental memory that associates stimulus features, actions, and outcomes, thereby generating the ESE in neurotypical individuals. We also report exploratory data analyses, including a Bayesian network analysis of relationships between iWCST measures. Discussion: Overall, this study serves as a paradigmatic model for combining digital technologies, theory-driven research, and Bayesian statistics in neuropsychology. It also provides insight into how this integrative, innovative approach can advance the understanding of executive function and cognitive flexibility and inform future research and clinical applications.

Performance on the Frontal Assessment Battery is sensitive to frontal lobe damage in stroke patients.

BACKGROUND: The Frontal Assessment Battery (FAB) is a brief battery of six neuropsychological tasks designed to assess frontal lobe function at bedside [Neurology 55:1621-1626, 2000]. The six FAB tasks explore cognitive and behavioral domains that are thought to be under the control of the frontal lobes, most notably conceptualization and abstract reasoning, lexical verbal fluency and mental flexibility, motor programming and executive control of action, self-regulation and resistance to interference, inhibitory control, and environmental autonomy. METHODS: We examined the sensitivity of performance on the FAB to frontal lobe damage in right-hemisphere-damaged first-ever stroke patients based on voxel-based lesion-behavior mapping. RESULTS: Voxel-based lesion-behavior mapping of FAB performance revealed that the integrity of the right anterior insula (BA13) is crucial for the FAB global composite score, for the FAB conceptualization score, as well as for the FAB inhibitory control score. Furthermore, the FAB conceptualization and mental flexibility scores were sensitive to damage of the right middle frontal gyrus (MFG; BA9). Finally, the FAB inhibitory control score was sensitive to damage of the right inferior frontal gyrus (IFG; BA44/45). CONCLUSIONS: These findings indicate that several FAB scores (including composite and item scores) provide valid measures of right hemispheric lateral frontal lobe dysfunction, specifically of focal lesions near the anterior insula, in the MFG and in the IFG.

Musical Expertise and Executive Functions in Experienced Musicians.

Extensive music practice has been suggested to enhance the development of cognitive abilities over and above musical expertise. Executive functions (EFs) have been particularly investigated, given their generalizability across different domains and their crucial role in almost all aspects of cognition. However, the relationship between musical expertise and EFs is still not completely understood, as several studies have reported conflicting results. The present study aims to investigate the relationship between musical expertise and EFs, determining which facets-if any-of EFs might be particularly relevant to extensive music practice. Thirty-five student pianists completed a set of neuropsychological tasks which assessed EFs (the Trail Making Task, Design Fluency, Numerical Stroop, and the Tower of London). They also performed a short musical excerpt inspired by the piano literature. Musical expertise was assessed by considering three parameters, namely the highest academic degree in music, the lifetime amount of music practice, and the quality of the sample-based musical performance. The results indicate that postgraduate piano students did not show advantages in EFs compared to undergraduate piano students. More extensive lifetime practice in music was solely associated with faster visual reaction times on the Numerical Stroop task. The Trail Making and Design Fluency scores were significant predictors of the quality of the sample-based musical performance. In conclusion, the present data suggests that EFs and the amount of music practice do not seem to be correlated in student pianists. Nevertheless, some facets of EFs and the quality of musical performance may share substantial amounts of variance.

Habits, Goals, and Behavioral Signs of Cognitive Perseveration on Wisconsin Card-Sorting Tasks.

Wisconsin card-sorting tasks provide unique opportunities to study cognitive flexibility and its limitations, which express themselves behaviorally as perseverative errors (PE). PE refer to those behavioral errors on Wisconsin card-sorting tasks that are committed when cognitive rules are maintained even though recently received outcomes demand to switch to other rules (i.e., cognitive perseveration). We explored error-suppression effects (ESE) across three Wisconsin card-sorting studies. ESE refer to the phenomenon that PE are reduced on repetitive trials compared to non-repetitive trials. We replicated ESE in all three Wisconsin card-sorting studies. Study 1 revealed that non-associative accounts of ESE, in particular the idea that cognitive inhibition may account for them, are not tenable. Study 2 suggested that models of instrumental learning are among the most promising associative accounts of ESE. Instrumental learning comprises goal-directed control and the formation of corresponding associative memories over and above the formation of habitual memories according to dual-process models of instrumental learning. Study 3 showed that cognitive, rather than motor, representations of responses should be conceptualized as elements entering goal-directed instrumental memories. Collectively, the results imply that ESE on Wisconsin card-sorting tasks are not only a highly replicable phenomenon, but they also indicate that ESE provide an opportunity to study cognitive mechanisms of goal-directed instrumental control. Based on the reported data, we present a novel theory of cognitive perseveration (i.e., the 'goal-directed instrumental control' GIC model), which is outlined in the Concluding Discussion.

The relation between implicit statistical learning and proactivity as revealed by EEG.

Environmental events often occur on a probabilistic basis but can sometimes be predicted based on specific cues and thus approached proactively. Incidental statistical learning enables the acquisition of knowledge about probabilistic cue-target contingencies. However, the neural mechanisms of statistical learning about contingencies (SLC), the required conditions for successful learning, and the role of implicit processes in the resultant proactive behavior are still debated. We examined changes in behavior and cortical activity during an SLC task in which subjects responded to visual targets. Unbeknown to them, there were three types of target cues associated with high-, low-, and zero target probabilities. About half of the subjects spontaneously gained explicit knowledge about the contingencies (contingency-aware group), and only they showed evidence of proactivity: shortened response times to predictable targets and enhanced event-related brain responses (cue-evoked P300 and contingent negative variation, CNV) to high probability cues. The behavioral and brain responses were strictly associated on a single-trial basis. Source reconstruction of the brain responses revealed activation of fronto-parietal brain regions associated with cognitive control, particularly the anterior cingulate cortex and precuneus. We also found neural correlates of SLC in the contingency-unaware group, but these were restricted to post-target latencies and visual association areas. Our results document a qualitative difference between explicit and implicit learning processes and suggest that in certain conditions, proactivity may require explicit knowledge about contingencies.