The topography of 4 subtraction ERP-waveforms derived from a 3-tone auditory oddball task in healthy young adults

Introduction: Five components were studied in 4 subtraction waveforms derived from ERPs obtained in passive and active conditions of a 3-tone oddball task (common=70%, C, 0.8 KHz; deviant=15%, D, 2 KHz; 1.4 KHz=15%, t, also used as a target (T)). These waveforms reflect different stimulus-mismatch processes and thus their topography could be revealing of different brain regions mediating them. Methods: The following mismatches were studied: stimulus-mismatch (deviant - common, D/C, rarity and pitch confounded, known as the mismatch negativity, MMN), pitch-mismatch (T - deviant, T/D, rarity not target features controlled, known as processing negativity PN), attention - mismatch (T - t), T/t, controlled for pitch and rarity to show the influence of target features, known as the Negative difference Nd). These are compared with Goodin's procedure (G-wv, (T-common (active) - (t-common (passive)- the "Goodin-waveform"). Results: There were main site effects in normalized data in all cases (not P2 and N2 latency). There were separate frontal and posterior contributions to P1, with the former emphasized where target comparisons were involved. Frontal N1 peaks, largest in D/C (MMN), spread posterior and to the right where target matching was involved. P2 posterior maxima were also less localized where target features were involved in the comparison. N2 topography was similar between waveforms but spread slightly more to each side in the T/t comparison (i.e. Nd). Onset was earlier in the D/C comparison (i.e MMN). Parietal P3 peaks in waves based on target-ERPs showed a left temporal shift (vs D/C), though in T/D P3 was in fact maximal on the right (i.e. PN waveform). Conclusions: Thus an attentional effect(controlled processing) is evident as early as 60 ms. Target features modify the anteroposterior distribution of positivity and negativity for the early components and in the lateralization of P3-like positivity. A comparison of waveforms by latency of potential shift (running t-test) vs. peak identification (MANOVA) is illustrated and discussed. D/C (MMN) and T/t (Nd) waveforms, rather than T/D or G-wv (PN & Goodin waveforms) waveforms are recommended for distinguishing comparator mechanisms for stimulus- and task-relevant features

Differential measures of 'sustained attention' in children with attention-deficit/hyperactivity or tic disorders: relations to monoamine metabolism

Introduction: Controversy exists on whether the constructs related to sustained attention and tested by paper/pencil tasks and computerized continuous-performance-tests (CPT) are similar, and whether the deficits recorded in children with attention-deficit/hyperactivity symptoms (ADHD) using these different forms of testing information processing are comparable. Methods: Signal-detection measures (d-prime and beta-criterion) and type of error were recorded on four such tests of 'sustained attention', with increasing working-memory requirements (respond to 'x', respond to 'x' only after 'a') in healthy children (n = 14, mean 10 years of age), and those with ADHD (n = 14, mean 10 years of age) or a tic syndrome (TS, n = 11, mean 11 years of age). Clinical associations were sought from 24h-urinary measures of monoamine activity (parent amines and metabolites), - dopamine (DA), HVA, noradrenaline (NA), MHPG, serotonin (5-HT), 5-HIAA. Results: The cancellation paper/pencil test revealed no group differences for errors or signal detection measures. In contrast, on the CPTx ADHD children made more omission and commission errors than controls, but TS children made mostly omissions. This reflected the poor perceptual sensitivity (d-prime, d') for ADHD and conservative response criteria (beta) for TS children. This group difference extended to the CPT ax which was shown on a regression analysis to test for putative working-memory-related abilities as well as concentration. In all children immediate response-feedback (vs. feedback at the end of the test) reduced omissions, and modestly improved d'. CPT ax performance related negatively to dopamine metabolism in controls and to serotonin metabolism in the ADHD group. But comparisons between the metabolites in the ADHD group suggest that increased serotonin- and decreased noradrenaline- with respect to dopamine-metabolism may detract from CPT performance in terms of d-prime. Conclusions: CPT tasks demonstrated a perceptual-based impairment in ADHD and response conservatism in TS patients independent of difficulty. Catecholamine activity was implicated in the promotion of perceptual processing in normal and ADHD children, but serotonin activity may contribute to poor CPTax performance (emphasis on working-memory function) in ADHD patients

Connections between studies of the neurobiology of attention, psychotic processes and event-related potentials

Attention: the selective aspect of perception, requires wakefulness (organism), activation (behavior) and inhibition (neuronal systems). It may be observed momentarily (concentration), over time (vigilance) and in the selection between channels (e.g. the rejection of irrelevance in focussed and divided conditions). Anatomical Organisation: Information ascending through the thalamus not only alerts the sensory cortices, but thalamic projections to association areas receive direct feedback allowing gating and preparation of sensory areas for further analysis. A frontal organizational role is subserved by descending pathways allowing for valuation (orbitofrontal cortex, amygdala), association (hippocampal complex) and response possibilities (basal forebrain). Interactions between the latter allow for automatic processes, but with the former limbic connections bring the possibility of conscious control. Neurotransmitters: Additional involvement of brainstem mechanisms allows for volume-control (serotonin, 5HT), tuning (noradrenaline, NA) and switching (dopamine, DA) mechanisms in determining priority in selective mechanisms. Failures of brainstem mechanisms can impair the modulation of several systems ranging from affect (e.g. 5HT, hostility) to the assessment of information relevance (DA, perseveration, switching). Such non-specific features of psychotic processes can be incurred by unusual amino-acid transmission (e.g. Glu, Asp, GABA) from the neo- and archicortices. Psychopathology: The locus of supra- or sub-liminal damage may provide specificity to the symptom and speculatively the schizophrenic syndromes of poverty, disorganization and reality distortion. Useful "attentional" paradigms for the study of the nature and distribution of these processes include sustained attention, the influence of irrelevant stimuli (learned inattention -"blocking"), the covert orienting of attention (cost/benefits of cueing), dichotic and multidiscrimination (allocation), prepulse inhibition and masking (sensory gating) and concept formation. Psychophysiology: Our own work shows, for example, that mismatch negativity is severely reduced in young patients with schizophrenia with or without reality distortion (by 50% and again by 50%, respectively). But only the non-paranoid patients show an abnormal loosening of selection processes, reflected in reduced conditioned blocking (that in turn reflects switching between relevant and irrelevant stimuli and learning about both). This latter result proved to be related to changes of daily DA utilization (measured in 24h-urine samples) consistent with a DA role in switching

Stimulus dimension shifts in patients with schizophrenia, with and without paranoid hallucinatory symptoms, or obsessive compulsive disorder: strategies, blocking and monoamine status

Introduction: Reversal and intra-dimensional (ID) and extra-dimensional (ED) non-reversal shifts in task discrimination learning were compared. The aim was to see if "learned inattention" to the irrelevant dimension differentially influenced the efficacy of learning and of the stimulus choice strategy. (An overall indicator of monoamine metabolism was measured for potential congruence between switches of attention and dopamine activity: see Oades, Neurosci. Biobehav. Rev., , 9, 261-283, 1985). Methods: Performance on pattern-discrimination discrimination shifts was compared with conditioned blocking (CB: another test of "learned inattention") and related to the status of monoamine neurotransmitter metabolism reflected in 24h-urine samples between tests. Results are reported for 29 healthy subjects (mean age 18.0y), 13 patients with obsessive compulsive disorder (OCD: mean age16.3y), and 28 with schizophrenia, including 14 paranoid hallucinatory (PH: 19.6y) and 14 nonparanoid patients (NP: 17.5y). Results: 1. PH and NP patients improved learning with practice but showed an impaired shift on each task. 2. Unlike PH and control subjects, the NP shift impairment was non-specific and related to their problems on simple reversal of the discrimination. 3. The length of the stimulus-response sequences showed that all subjects were able to acquire a set for colour. 4. An analysis of choice on sequential pairs of stimuli showed that while all patients showed fewer win-stay sequences, only PH patients perseverated with lose-stay sequences. This type of error in PH patients contrast with the increase of win-shift errors in NP patients (figure 1). 5. Learning about the added stimulus on the CB task related to the efficiency of intra-dimensional shift in NP patients. 6. An impairment with OCD patients was restricted to the ED-shift (not reversal or ID-shift). 7. Increases of dopamine activity related to slower initial learning, but to more switches (and rapid learning) on all shift tasks: (positive correlations with win/lose-shift, negative with win-stay). NA activity in PH and NP patients related to increased win-stay and decreased lose-shift decisions (figure 1). 8. Increased serotonin activity correlated with faster learning in controls, OCD and PH patients. But the opposite relationships for dopamine and serotonin activity held for NP patients (figure 2). Conclusions: The different tasks of the "learned inattention" paradigm have different if related requirements and correlates. The monoamine data are consistent with the postulated function of noradrenaline in tuning and dopamine in switching operations. The behavioural data are consistent with the automatization of endogenous information processing, while NP patients use exogenous attentional strategies fir selecting information and PH patients show inefficient endogenous control of attention

Development and topography of auditory event-related potentials (ERPs): Mismatch and processing negativity in individuals 8-22 years of age

Introduction: How do ERPs reflecting auditory information processing develop across adolescence? This development is described for the amplitude and latency of five ERP components and four difference-waves in four groups of 11 healthy subjects with mean ages of 10, 14, 17 & 21 years. Methods: Vector normalised data were recorded from 19 sites during diffuse and focused attention in a three-tone oddball. (i.e. in passive, diffuse-attention and active, focussed-attention, discrimination conditions) to see how ERP loci varied with age for tone-type, attention-condition and for four types of difference-wave reflecting nontarget and target comparisons: (mismatch negativity, MMN, an auditory working memory trace; Negative difference, Nd, an attentional trace, but also Processing Negativity, PN and the Goodin-waveform). Results: Age interacted with site for most components. P1 loci sensitive to rare tones moved posteriorly and N1 loci lost their right bias at early puberty. But P2 loci did not move anterior to Cz until adulthood. N2 amplitude, sensitive to attention condition, developed a mature frontal focus by 17 years. Right-biased P3 loci move to the midline with focused attention in young and old alike. Difference-waves reflected three developmental stages (figure 2): In 10 year-olds early deflections (<150 ms) were diffusely distributed; in mid-adolescence the main frontal negative component (150-300 ms) became well-formed and lost an earlier right bias; over 17 years the late positive complex developed a right bias in target-derived waves. Latency decreases for early frontal components were marked in 10-14y olds and for later posterior components in 14-17y olds. MMN topography matured (from a right lateral to bilateral distribution) between 10 and 14 y, while Nd topography matured and became bilateral between 14 and 17y. Conclusions: Major developments of brain function appear at the onset of adolescence (<14y) in early stimulus-selection processes and during adolescence in the differential use of this information (N2- and P3-like latencies

Impaired attention-dependent augmentation of MMN in nonparanoid vs paranoid schizophrenic patients: a comparison with obsessive-compulsive disorder and healthy subjects

Introduction: Mismatch negativity (MMN), in the deviant-minus-standard event-related potential (ERP) difference-waveform, may represent a working memory trace for tone differences (a deviant among a sequence of standards). Most, but not all studies find MMN reduced in patients with schizophrenia. Aims: This report investigates if differences may be attributable to experimental condition (diffuse vs focused attention), component identification (N1-like vs N2-like), topographic distribution and clinical condition (with / without paranoid -hallucinatory symptoms, PH/NP). Comparisons were made for 12 PH and 12 NP schizophrenic patients with 13 obsessive compulsive and 25 normal control subjects. Results: Frontal MMN reduction in schizophrenics largely resulted from an absence of an increase in focused attention conditions as in comparison groups. But there was marked activity recorded from sites over the temporal lobe in NP patients. These features were not reflected in other components except for a visible but nonsignifiant N1-like temporal locus in NP patients. Further, schizophrenic patients did not show an increase in late positivity with focused attention like the comparison groups. Conclusions: The results show that so-called automatic processing deficits in schizophrenia (amount and locus of MMN) are best seen in situations requiring the activation of controlled attentional processes. It is suggested that impaired processing of irrelevant stimuli and reduced frontal MMN in NP patients may reflect reduced dopaminergic responsivity

Neuropsychological measures of attention and memory function in schizophrenia: relationships with symptom dimensions and serum monoamine activity

BACKGROUND: Some clinical symptoms or cognitive functions have been related to the overall state of monoamine activity in patients with schizophrenia, (e.g. inverse correlation of the dopamine metabolite HVA with delusions or visual-masking performance). However, profiles (as presented here) of the relations of the activity of dopamine, noradrenaline and serotonin to neuropsychologic (dys)functions in major patient sub-groups with their very different symptomatic and cognitive characteristics have not been reported. METHODS: Serum measures of dopamine, noradrenaline and serotonin turnover were examined by regression analyses for the prediction of performance on 10 neuropsychological measures reflecting left- and right-hemispheric and frontal-, parietal- and temporal-lobe function in 108 patients with schizophrenia and 63 matched controls. The neuropsychological battery included tests of verbal fluency, Stroop interference, trail-making, block-design, Mooney faces recognition, picture-completion, immediate and delayed visual and verbal recall. Paranoid and nonparanoid subgroups were based on ratings from the Positive and Negative Syndrome Scale (PANSS). Groups with high and low ratings of ideas-of-reference and thought-disorder were formed from a median split on the Scale for Assessment of Positive Symptoms (SAPS). RESULTS: Verbal-fluency and Stroop-interference (left frontal and fronto-cingulate function) were negatively associated with noradrenergic turnover in nonparanoid and thought-disordered patients. High dopamine turnover related to speeded trail-making (frontal modulation of set switching) in those with many ideas-of-reference. In contrast, low dopamine turnover predicted poor recall in nonparanoid patients and those with little thought disorder. Serotonin metabolism did not independently contribute to the prediction any measure of cognitive performance. But, with regard to the relative activity between monoaminergic systems, increased HVA/5-HIAA ratios predicted visual-reproduction and Mooney's face-recognition performance (right-hemisphere functions) in highly symptomatic patients. Decreased HVA/MHPG predicted non-verbal recall. CONCLUSION: Clinical state and function are differentially sensitive to overall levels of monoamine activity. In particular, right-lateralised cerebral function was sensitive to the relative activities of the monoamines. Increased noradrenergic activity was associated with enhanced frontal but impaired temporal lobe function in nonparanoid syndromes. Low dopaminergic activity predicted poor attentional set control in those with ideas-of-reference, but poor recall in nonparanoid patients. These data, especially the HVA/5-HIAA ratios, provide a basis for planning the nature of antipsychotic treatment aimed at patient specific symptom dimensions and cognitive abilities

Childhood autism: an appeal for an integrative and psychobiological approach

Introduction: Childhood autism, overtly expressed as social indifference and repetitive motor patterns, in fact involves a range of problems covering sensory, attentional, cognitive, emotional, language as well as motor areas of function - 25 symptoms can be listed. Although a reduced verbal IQ and language difficulties are frequent, a major intervening variable may be problems with the development of a "theory-of-mind" ....the ability to comprehend the mental states of others. Prevalence rates per 10,000 of the population range from 2 to 16 in different countries, rising to 50 if one includes spectrum autistic disorder. A number of sometimes related organic associations and potentially separate aetiologies are described. Biology: Evidence for delayed neurotransmission (evoked potentials) and a lack of flexibility in physiological responses (signal detection, cross-modal integration) may underlie the attenuation of monitoring processes that lead to withdrawal and stereotypies. Neuropsychological task performance provides limited and qualified evidence for impaired frontal function, although this could explain event-related potential (ERP) evidence for more of a deficit with controlled attention (Nd) than in automatic processing (MMN). [ERPs also underline the difficulties in generating differential responses to relevant and irrelevant stimuli.] Imaging studies show some structural abnormalities in half the patients (e.g. ventricle volume increases), but indices of activation, though in the normal range do not appear situation-appropriate. Pharmacology: a) A significant proportion of autistic subjects show increased peripheral measures of serotonin and quite often raised dopamine metabolism - that in some high-functioning cases has been claimed to be beneficial. It is plausible that changes in monoaminergic transmission are inadequately compensated by changes in the other transmitter systems. b) With serotonin and dopamine responsible for inhibition/volume-control and for switching/flexibility we propose an imbalance of these systems that results in a stop-go form of neuronal communication that inevitably leads to anomalous responses at the whole organism level. c) At least 20 forms of pharmocotherapy have been attempted, the best with improvement limited to a few patients improving particular symptoms only. The best have proved to be dopamine or opioid antagonists, but at best - these have a limited and modest role to play in clinical care Conclusions: The impairment of children with autism manifests itself at many levels - treatment concepts must attempt to integrate these, with emphasis on the particular abilities and difficulties of the individual. The need is to synthesize the different levels of analysis for a psychobiological approach to be integrated into the wide-ranging remedial programmes currently practised.