The reinforcing value of delay escape in attention deficit/hyperactivity disorder: An electrophysiological study.

The delay aversion hypothesis argues that the tendency for impulsive choice (preference for smaller sooner over larger later rewards) is motivated by the escape of negative affective states associated with delay. This model predicts that individuals with ADHD find the imposition of delay before an outcome or event especially aversive and its escape reinforcing. Consistent with this, fMRI studies show that ADHD is associated with amygdala hyper-sensitivity to cues of delay. However, evidence that delay escape is reinforcing is lacking. Here we extend fMRI research by using electrophysiological methods to study the reinforcing properties of delay-escape in ADHD. Thirty controls and 25 adolescents with ADHD aged 10-15 years performed the Escape Delay Incentive (EDI) task- in which pre-target cues indicated three conditions: i) CERTAIN DELAY: delay would follow a response irrespective of response speed ii) CONDITIONAL DELAY: delay would only follow if the response was too slow and iii) NO DELAY: delay would follow the response whatever the speed. We focused on the Contingent Negative Variation (CNV), a cue-evoked marker of motivated response preparation, across two time windows (CNV1 and CNV2). We took measures of parent, teacher and self-rated ADHD symptoms, task performance (RT) and self-rated delay aversion. We isolated CNV components and compared these between ADHD and controls. Adolescents with ADHD displayed a larger CNV2 to the CONDITIONAL DELAY than the CERTAIN DELAY cues compared to controls. However, this effect was not mirrored at the performance level and was unrelated to self-reported delay aversion. Our study provides the first ERP evidence that delay escape differentially reinforcers neural activation of attention preparation in ADHD cases. Future studies should examine the impact of varying cognitive load on task EDI performance.

An electrophysiological investigation of reinforcement effects in attention deficit/hyperactivity disorder: Dissociating cue sensitivity from down-stream effects on target engagement and performance.

OBJECTIVE: Neural hypo-sensitivity to cues predicting positive reinforcement has been observed in ADHD using the Monetary Incentive Delay (MID) task. Here we report the first study using an electrophysiological analogue of this task to distinguish between (i) cue related anticipation of reinforcement and downstream effects on (ii) target engagement and (iii) performance in a clinical sample of adolescents with ADHD and controls. METHODS: Thirty-one controls and 32 adolescents with ADHD aged 10-16 years performed the electrophysiological (e)-MID task - in which preparatory cues signal whether a response to an upcoming target will be reinforced or not - under three conditions; positive reinforcement, negative reinforcement (response cost) and no consequence (neutral). We extracted values for both cue-related potentials known to be, both, associated with response preparation and modulated by reinforcement (Cue P3 and Cue CNV) and target-related potentials (target P3) and compared these between ADHD and controls. RESULTS: ADHD and controls did not differ on cue-related components on neutral trials. Against expectation, adolescents with ADHD displayed Cue P3 and Cue CNV reinforcement-related enhancement (versus neutral trials) compared to controls. ADHD individuals displayed smaller target P3 amplitudes and slower and more variable performance - but effects were not modulated by reinforcement contingencies. When age, IQ and conduct problems were controlled effects were marginally significant but the pattern of results did not change. DISCUSSION: ADHD was associated with hypersensitivity to positive (and marginally negative) reinforcement reflected on components often thought to be associated with response preparation - however these did not translate into improved attention to targets. In the case of ADHD, upregulated CNV may be a specific marker of hyper-arousal rather than an enhancement of anticipatory attention to upcoming targets. Future studies should examine the effects of age, IQ and conduct problems on reinforcement sensitivity in ADHD.

Separating stages of arithmetic verification: An ERP study with a novel paradigm.

In studies of arithmetic verification, participants typically encounter two operands and they carry out an operation on these (e.g. adding them). Operands are followed by a proposed answer and participants decide whether this answer is correct or incorrect. However, interpretation of results is difficult because multiple parallel, temporally overlapping numerical and non-numerical processes of the human brain may contribute to task execution. In order to overcome this problem here we used a novel paradigm specifically designed to tease apart the overlapping cognitive processes active during arithmetic verification. Specifically, we aimed to separate effects related to detection of arithmetic correctness, detection of the violation of strategic expectations, detection of physical stimulus properties mismatch and numerical magnitude comparison (numerical distance effects). Arithmetic correctness, physical stimulus properties and magnitude information were not task-relevant properties of the stimuli. We distinguished between a series of temporally highly overlapping cognitive processes which in turn elicited overlapping ERP effects with distinct scalp topographies. We suggest that arithmetic verification relies on two major temporal phases which include parallel running processes. Our paradigm offers a new method for investigating specific arithmetic verification processes in detail.

Neural adaptation to non-symbolic number and visual shape: an electrophysiological study.

Several studies assumed that the analysis of numerical information happens in a fast and automatic manner in the human brain. Utilizing the high temporal resolution of electroencephalography (EEG) in a passive oddball adaptation paradigm, we compared event-related brain potentials (ERPs) evoked by unattended shape changes and unattended numerosity changes. We controlled visual stimulus properties in a stringent manner. Unattended changes in shape elicited significant, gradual adaptation effects in the range of early visual components, indicating the fast and automatic processing of shapes. Changes in numerosity did not elicit significant changes in these early ERP components. The lack of early number-specific effects was qualified by a significant interaction between Shape and Number conditions. Number change elicited gradual ERP effects only on late ERP components. We conclude that numerosity is a higher-level property assembled from naturally correlating perceptual cues and hence, it is identified later in the cognitive processing stream.

Cognitive components of a mathematical processing network in 9-year-old children.

We determined how various cognitive abilities, including several measures of a proposed domain-specific number sense, relate to mathematical competence in nearly 100 9-year-old children with normal reading skill. Results are consistent with an extended number processing network and suggest that important processing nodes of this network are phonological processing, verbal knowledge, visuo-spatial short-term and working memory, spatial ability and general executive functioning. The model was highly specific to predicting arithmetic performance. There were no strong relations between mathematical achievement and verbal short-term and working memory, sustained attention, response inhibition, finger knowledge and symbolic number comparison performance. Non-verbal intelligence measures were also non-significant predictors when added to our model. Number sense variables were non-significant predictors in the model and they were also non-significant predictors when entered into regression analysis with only a single visuo-spatial WM measure. Number sense variables were predicted by sustained attention. Results support a network theory of mathematical competence in primary school children and falsify the importance of a proposed modular 'number sense'. We suggest an 'executive memory function centric' model of mathematical processing. Mapping a complex processing network requires that studies consider the complex predictor space of mathematics rather than just focusing on a single or a few explanatory factors.

Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism.

Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.

Late cortical plasticity in motor and auditory cortex: role of met-allele in BDNF Val66Met polymorphism.

The brain-derived neurotropic factor (BDNF) Val66Met polymorphism has been associated with abnormalities of synaptic plasticity in animal models, and abnormalities in motor cortical plasticity have also been described in humans using transcranial direct current stimulation. No study has yet been done on plasticity in non-motor regions, and the effect of two Met alleles (i.e. 'Met dose') is not well understood. We studied the effect of the BDNF Val66Met polymorphism on the after-effects of transcranial direct current stimulation and tetanic auditory stimulation in 65 subjects (23; Val66Val, 22; Val66Met and 20; Met66Met genotypes). In the first session, motor evoked potentials (MEP) were recorded under stereotaxic guidance for 90 min after 9 min of anodal transcranial direct current stimulation (TDCS). In the second session, auditory-evoked potentials (AEP) were recorded before and after 2 min of auditory 13 Hz tetanic stimulation. There was a difference in MEP facilitation post-TDCS comparing Met carriers with non-Met carriers, with Met carriers having a modest late facilitation at 30-90 min. There was no difference in responses between Val66Met genotype and Met66Met genotype subjects. Tetanic auditory stimulation also produced late facilitation of N1-P2 AEP at 25 min, but there was no apparent effect of genetic status. This study indicates that Met66Met carriers behave like Val66Met carriers for TDCS-induced plasticity, and produce a late facilitation of MEPs. Auditory cortical plasticity was not affected by the BDNF Val66Met polymorphism. This study sheds light on the differences between auditory and motor cortical plasticity and the role of the BDNF Val66Met polymorphism.

Oscillatory underpinnings of mismatch negativity and their relationship with cognitive function in patients with schizophrenia.

BACKGROUND: Impairments in mismatch negativity (MMN) generation have been consistently reported in patients with schizophrenia. However, underlying oscillatory activity of MMN deficits in schizophrenia and the relationship with cognitive impairments have not been investigated in detail. Time-frequency power and phase analyses can provide more detailed measures of brain dynamics of MMN deficits in schizophrenia. METHOD: 21 patients with schizophrenia and 21 healthy controls were tested with a roving frequency paradigm to generate MMN. Time-frequency domain power and phase-locking (PL) analysis was performed on all trials using short-time Fourier transforms with Hanning window tapering. A comprehensive battery (CANTAB) was used to assess neurocognitive functioning. RESULTS: Mean MMN amplitude was significantly lower in patients with schizophrenia (95% CI 0.18 - 0.77). Patients showed significantly lower EEG power (95% CI -1.02 - -0.014) in the ~4-7 Hz frequency range (theta band) between 170 and 210 ms. Patients with schizophrenia showed cognitive impairment in multiple domains of CANTAB. However, MMN impairments in amplitude and power were not correlated with clinical measures, medication dose, social functioning or neurocognitive performance. CONCLUSION: The findings from this study suggested that while MMN may be a useful marker to probe NMDA receptor mediated mechanisms and associated impairments in gain control and perceptual changes, it may not be a useful marker in association with clinical or cognitive changes. Trial-by-trial EEG power analysis can be used as a measure of brain dynamics underlying MMN deficits which also can have implications for the use of MMN as a biomarker for drug discovery.

Effects of the BDNF Val66Met polymorphism and met allele load on declarative memory related neural networks.

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.

Differential entrainment of neuroelectric delta oscillations in developmental dyslexia.

Oscillatory entrainment to the speech signal is important for language processing, but has not yet been studied in developmental disorders of language. Developmental dyslexia, a difficulty in acquiring efficient reading skills linked to difficulties with phonology (the sound structure of language), has been associated with behavioural entrainment deficits. It has been proposed that the phonological 'deficit' that characterises dyslexia across languages is related to impaired auditory entrainment to speech at lower frequencies via neuroelectric oscillations (<10 Hz, 'temporal sampling theory'). Impaired entrainment to temporal modulations at lower frequencies would affect the recovery of the prosodic and syllabic structure of speech. Here we investigated event-related oscillatory EEG activity and contingent negative variation (CNV) to auditory rhythmic tone streams delivered at frequencies within the delta band (2 Hz, 1.5 Hz), relevant to sampling stressed syllables in speech. Given prior behavioural entrainment findings at these rates, we predicted functionally atypical entrainment of delta oscillations in dyslexia. Participants performed a rhythmic expectancy task, detecting occasional white noise targets interspersed with tones occurring regularly at rates of 2 Hz or 1.5 Hz. Both groups showed significant entrainment of delta oscillations to the rhythmic stimulus stream, however the strength of inter-trial delta phase coherence (ITC, 'phase locking') and the CNV were both significantly weaker in dyslexics, suggestive of weaker entrainment and less preparatory brain activity. Both ITC strength and CNV amplitude were significantly related to individual differences in language processing and reading. Additionally, the instantaneous phase of prestimulus delta oscillation predicted behavioural responding (response time) for control participants only.

Developmental dyscalculia is related to visuo-spatial memory and inhibition impairment.

Developmental dyscalculia is thought to be a specific impairment of mathematics ability. Currently dominant cognitive neuroscience theories of developmental dyscalculia suggest that it originates from the impairment of the magnitude representation of the human brain, residing in the intraparietal sulcus, or from impaired connections between number symbols and the magnitude representation. However, behavioral research offers several alternative theories for developmental dyscalculia and neuro-imaging also suggests that impairments in developmental dyscalculia may be linked to disruptions of other functions of the intraparietal sulcus than the magnitude representation. Strikingly, the magnitude representation theory has never been explicitly contrasted with a range of alternatives in a systematic fashion. Here we have filled this gap by directly contrasting five alternative theories (magnitude representation, working memory, inhibition, attention and spatial processing) of developmental dyscalculia in 9-10-year-old primary school children. Participants were selected from a pool of 1004 children and took part in 16 tests and nine experiments. The dominant features of developmental dyscalculia are visuo-spatial working memory, visuo-spatial short-term memory and inhibitory function (interference suppression) impairment. We hypothesize that inhibition impairment is related to the disruption of central executive memory function. Potential problems of visuo-spatial processing and attentional function in developmental dyscalculia probably depend on short-term memory/working memory and inhibition impairments. The magnitude representation theory of developmental dyscalculia was not supported.

Gender differences in developmental dyscalculia depend on diagnostic criteria.

Developmental dyscalculia (DD) is a learning difficulty specific to mathematics learning. The prevalence of DD may be equivalent to that of dyslexia, posing an important challenge for effective educational provision. Nevertheless, there is no agreed definition of DD and there are controversies surrounding cutoff decisions, specificity and gender differences. In the current study, 1004 British primary school children completed mathematics and reading assessments. The prevalence of DD and gender ratio were estimated in this sample using different criteria. When using absolute thresholds, the prevalence of DD was the same for both genders regardless of the cutoff criteria applied, however gender differences emerged when using a mathematics-reading discrepancy definition. Correlations between mathematics performance and the control measures selected to identify a specific learning difficulty affect both prevalence estimates and whether a gender difference is in fact identified. Educational implications are discussed.

Functional definition of the N450 event-related brain potential marker of conflict processing: a numerical stroop study.

BACKGROUND: Several conflict processing studies aimed to dissociate neuroimaging phenomena related to stimulus and response conflict processing. However, previous studies typically did not include a paradigm-independent measure of either stimulus or response conflict. Here we have combined electro-myography (EMG) with event-related brain potentials (ERPs) in order to determine whether a particularly robust marker of conflict processing, the N450 ERP effect usually related to the activity of the Anterior Cingulate Cortex (ACC), is related to stimulus- or to response-conflict processing. EMG provided paradigm-independent measure of response conflict. In a numerical Stroop paradigm participants compared pairs of digits and pressed a button on the side where they saw the larger digit. 50% of digit-pairs were preceded by an effective cue which provided accurate information about the required response. 50% of trials were preceded by a neutral cue which did not communicate the side of response. RESULTS: EMG showed that response conflict was significantly larger in neutrally than in effectively cued trials. The N450 was similar when response conflict was high and when it was low. CONCLUSIONS: We conclude that the N450 is related to stimulus or abstract, rather than to response conflict detection/resolution. Findings may enable timing ACC conflict effects.

Reduced phase locking to slow amplitude modulation in adults with dyslexia: an MEG study.

Perception of speech at multiple temporal scales is important for the efficient extraction of meaningful phonological elements. Individuals with developmental dyslexia have difficulty in the accurate neural representation of phonological aspects of speech, across languages. Recently, it was proposed that these difficulties might arise in part because of impaired phase locking to the slower modulations in the speech signal (<10 Hz), which would affect syllabic parsing and segmentation of the speech stream (the "temporal sampling" hypothesis, Goswami, 2011). Here we measured MEG responses to different rates of amplitude modulated white noise in adults with and without dyslexia. In line with the temporal sampling hypothesis, different patterns of phase locking to amplitude modulation at the delta rate of 2 Hz were found when comparing participants with dyslexia to typically-reading participants. Typical readers exhibited better phase locking to slow modulations in right auditory cortex, whereas adults with dyslexia showed more bilateral phase locking. The results suggest that oscillatory phase locking mechanisms for slower temporal modulations are atypical in developmental dyslexia.

Event-related brain potentials dissociate the developmental time-course of automatic numerical magnitude analysis and cognitive control functions during the first three years of primary school.

In this study we set out to dissociate the developmental time course of automatic symbolic number processing and cognitive control functions in grade 1-3 British primary school children. Event-related potential (ERP) and behavioral data were collected in a physical size discrimination numerical Stroop task. Task-irrelevant numerical information was processed automatically already in grade 1. Weakening interference and strengthening facilitation indicated the parallel development of general cognitive control and automatic number processing. Relationships among ERP and behavioral effects suggest that control functions play a larger role in younger children and that automaticity of number processing increases from grade 1 to 3.

The development of inhibitory control: an averaged and single-trial Lateralized Readiness Potential study.

Inhibitory control (IC) is an important contributor to educational performance, and undergoes rapid development in childhood. Age-related changes in IC were assessed using an in-depth analysis of reaction time, the Lateralized Readiness Potential (LRP), and other event-related potential (ERP) measures to control for speed of processing. Five-year-olds, 8-year-olds and adults completed an adapted Stroop task. Both reaction time and ERP results suggest that IC does develop in this age range, over and above changes in speed of processing. The LRP identified two processes that contribute to IC. These processes develop at different rates--an early process, involving how the conflict is initially responded to is mature by age 5, while a later process, involving how the conflict is overcome is still developing after 8 years of age. We propose that these early and late processes reflect interference suppression and response inhibition, respectively. Further, a single-trial analysis of the LRP in the incongruent condition provides evidence that the LRP is consistent across trials and functionally similar in each age group. These results corroborate previous findings regarding the development of IC, and present a new and useful tool for assessing IC across development.

Symbolic number: the integration of magnitude and spatial representations in children aged 6 to 8 years.

The process of learning symbolic Arabic digits in early childhood requires that magnitude and spatial information integrates with the concept of symbolic digits. Previous research has separately investigated the development of automatic access to magnitude and spatial information from symbolic digits. However, developmental trajectories of symbolic number knowledge cannot be fully understood when considering components in isolation. In view of this, we have synthesized the existing lines of research and tested the use of both magnitude and spatial information with the same sample of British children in Years 1, 2, and 3 (6-8 years of age). The physical judgment task of the numerical Stroop paradigm demonstrated that automatic access to magnitude was present from Year 1 and the distance effect signaled that a refined processing of numerical information had developed. Additionally, a parity judgment task showed that the onset of the spatial-numerical association of response codes effect occurs in Year 2. These findings uncover the developmental timeline of how magnitude and spatial representations integrate with symbolic number knowledge during early learning of Arabic digits and resolve inconsistencies between previous developmental and experimental research lines.

Event-related brain potentials to violations of arithmetic syntax represented by place value structure.

We dissociated ERP markers of semantic (numerical distance) vs. syntactic (place value) incongruence in the domain of arithmetic. Participants verified additions with four-digit numbers. Semantic incongruencies elicited the N400 ERP effect. A centro-parietal (putative P600) effect to place value violations was not related to arithmetic syntax. Rather, this effect was an enlarged P3b reflecting different surprise values of place value vs. non-place value violations. This potential confound should be considered in numerical cognition experiments. The latency of the N400 and P3a effects were differentially affected by place value analysis. The amplitude of the P3a and that of a fronto-central positive effect (FP600) was sensitive to place value analysis and digit content. Results suggest that ERPs can index the syntactical analysis of multi-digit numbers. Both ERP and behavioral data confirmed that multi-digit numbers were decomposed into their constituent digits, rather than evaluated holistically.

Stimulus and response conflict in the color-word Stroop task: a combined electro-myography and event-related potential study.

We aimed to separate stimulus and response conflict in a manual color-word Stroop task by combining electro-myography (EMG) and event-related brain potentials (ERPs). EMG served as a measure of response conflict by detecting incorrect response hand activation in correctly responded trials. Response conflict was enhanced in both the incongruent and congruent conditions relative to neutral conditions. This suggests that the Stroop conflict (incongruent vs. congruent condition) could be explained by stimulus conflict in our study and that response conflict was not restricted to the incongruent condition of the Stroop task. Incorrect response activity was detected in a neutral condition using words but not in a neutral condition with non-words. This suggests that the mere presence of task-irrelevant stimuli semantically related to task-relevant stimuli can prime incorrect response activity. The above factors are important to consider in studies which do not have any explicit measure of response conflict. We have detected a robust marker of Stroop conflict, the N450 ERP effect, which has been related to ACC activity. The N450 was probably affected by stimulus conflict in our study and it may be a marker of general conflict processing.

Relationships between magnitude representation, counting and memory in 4- to 7-year-old children: a developmental study.

BACKGROUND: The development of an evolutionarily grounded analogue magnitude representation linked to the parietal lobes is frequently thought to be a major factor in the arithmetic development of humans. We investigated the relationship between counting and the development of magnitude representation in children, assessing also children's knowledge of number symbols, their arithmetic fact retrieval, their verbal skills, and their numerical and verbal short-term memory. METHODS: The magnitude representation was tested by a non-symbolic magnitude comparison task. We have perfected previous experimental designs measuring magnitude discrimination skills in 65 children kindergarten (4-7-year-olds) by controlling for several variables which were not controlled for in previous similar research. We also used a large number of trials which allowed for running a full factorial ANOVA including all relevant factors. Tests of verbal counting, of short term memory, of number knowledge, of problem solving abilities and of verbal fluency were administered and correlated with performance in the magnitude comparison task. RESULTS AND DISCUSSION: Verbal counting knowledge and performance on simple arithmetic tests did not correlate with non-symbolic magnitude comparison at any age. Older children performed successfully on the number comparison task, showing behavioural patterns consistent with an analogue magnitude representation. In contrast, 4-year-olds were unable to discriminate number independently of task-irrelevant perceptual variables. Sensitivity to irrelevant perceptual features of the magnitude discrimination task was also affected by age, and correlated with memory, suggesting that more general cognitive abilities may play a role in performance in magnitude comparison tasks. CONCLUSION: We conclude that young children are not able to discriminate numerical magnitudes when co-varying physical magnitudes are methodically pitted against number. We propose, along with others, that a rather domain general magnitude representation provides the later basis for a specialized representation of numerical magnitudes. For this representational specialization, the acquisition of the concept of abstract numbers, together with the development of other cognitive abilities, is indispensable.