Deterioration of executive functioning in chronic ecstasy users; evidence for multiple drugs effects.

A quantitative meta-analysis was carried out on the chronic effects of ecstasy use on working memory (WM), assumed to consist of a central executive (CE) and four executive subcomponents: Updating, Attention shifting, Inhibition and Access to long term memory. Publications dating from January 1998 to January 2008 were only included when they fulfilled the criteria for a meta-analysis (number of subjects, means and standard deviations) and when polydrug users were used as controls. In addition, we also determined effect sizes for lifetime consumption differences between the groups of other psycho-active substances than ecstasy. Both Lifetime Total Ecstasy Consumption (LTEC) and the effect sizes for alcohol, nicotine, amphetamine, cocaine and lysergic acid diethylamide (LSD) were regressed on the mean effect sizes (mES) of the WM subcomponents in order to study dose-response relationships. Ecstasy users appeared to score significantly lower on the subcomponents Updating, Attention shifting and Access to long term memory, but not on Inhibition. We did not find significant regressions of LTEC on any of the executive functioning subcomponents mES values. Ecstasy users also consumed significantly more amphetamine, cocaine, alcohol, nicotine and LSD, but less alcohol than polydrug controls. However, also for these drugs no indications were found for a dose-response relationship with executive functioning.

Effects of object complexity and type on the gaze behavior of children with pervasive developmental disorder.

The looking behavior of children with pervasive developmental disorder (PDD) and age- and IQ-matched normal control children was studied using infrared oculography. Stimuli varying in complexity and topic were presented to test whether children with PDD have specific abnormalities in looking behavior to complex stimuli and/or to faces. All children showed more and longer fixations on the complex objects than on the simple objects, especially the complex nonsense figure, but group differences were not found. The results show no evidence for specific abnormalities in looking behavior to either faces or to complex stimuli in high functioning children with PDD.

No effects of l-dopa and bromocriptine on psychophysiological parameters of human selective attention.

Patients with schizophrenia exhibit diverse cognitive deficits, one of which is a loss of the ability to focus attention. According to the revised dopamine hypothesis of schizophrenia both an increased mesolimbic and a decreased prefrontal dopaminergic activity is suggested to be involved in schizophrenia. The current study was designed to explore the relationship between dopamine and two psychophysiological parameters of selective attention, i.e. P300 amplitude and processing negativity (PN) in healthy volunteers. In two separate experiments, with a double-blind, balanced and placebo-controlled crossover design, 18 healthy male volunteers were orally administered either 300 mg l-dopa (precursor of dopamine) or placebo (experiment I), or 1.25mg bromocriptine (D2 agonist) or placebo (experiment II). Following this treatment they were tested in an auditory, dichotic selective attention paradigm. An increase in P300 amplitude was found following deviant stimuli when compared to standard stimuli and following attended stimuli when compared to unattended stimuli, regardless of treatment. Similarly, PN was found regardless of treatment. Neither l-dopa nor bromocriptine affected task performance or the amplitudes of PN or P300. In the present study neither l-dopa nor bromocriptine affected PN, P300 amplitude or task performance in healthy controls, phenomena which are usually found to be disrupted in schizophrenia. This indicates that P300 amplitude and PN are neither affected by a global (l-dopa) increased dopaminergic activity, nor by a more selectively towards striatal areas targeted (bromocriptine) increase in dopaminergic activity.

Stopping and changing in adults with ADHD.

BACKGROUND: A lack of inhibitory control has been suggested to be the core deficit in children with attention deficit hyperactivity disorder (ADHD). This means that a primary deficit in behavioral inhibition mediates a cascade of secondary deficits in other executive functions, such as arousal regulation. Clinical observations have revealed that with increasing age symptoms of hyperactivity and impulsivity decline at a higher rate than those of inattention. This might imply that a deficit in attention rather than a lack of inhibitory control is the major feature in adult ADHD. METHOD: To study whether an attentional or inhibitory deficit predominates, the stop-signal task and the stop-change task were presented to 24 adults with ADHD combined subtype and 24 controls. RESULTS: Relative to controls, the stop-signal reaction time (SSRT) was significantly more prolonged than the go-stimulus reaction time (RT) in patients with ADHD. This disproportionate elongation of the SSRT was comparable across tasks, even though the stop-change task exerted more complex (or at least different) demands on the inhibitory system than the stop-signal task. ADHD patients had a higher proportion of choice errors, possibly reflecting more premature responses. Specifically in the stop-change task, patients had more variable choice responses and made more inappropriate change responses, which may also reflect enhanced impulsivity. CONCLUSIONS: The results support a core deficit in behavioral inhibition in adults with ADHD. We further suggest that there is more evidence for a critical role of deficient inhibitory control in adults than in children with ADHD.

Attention deficit and impulsivity: selecting, shifting, and stopping.

The present selective review addresses attention, inhibition, and their underlying brain mechanisms, especially in relation to attention deficit/hyperactivity disorders (AD/HD), and the effects of methylphenidate. In particular, event-related potential (ERP) studies suggest a deficit in the early-filtering aspect of selective attention in children with AD/HD. Results from stop tasks are consistent with impairments in stopping performance in AD/HD, but in children (as opposed to adults) these effects cannot be easily dissociated from more general impairments in attention to the task, and therefore an interpretation in terms of inhibitory control is not straightforward. On the other hand, the beneficial effects of methylphenidate are more specific to stopping, and there are no clearcut effects of methylphenidate on measures of selective attention. Even when group differences pertain specifically to stopping performance (as with adults with AD/HD), ERP evidence suggests at least a partial contribution of differences in switching attention to the stop signal, as revealed in measures of sensory cortex activation. ERP evidence from cued go/nogo tasks underlines the importance of taking into account the contribution of higher order control processes involved in anticipation of and preparation for task stimuli. It suggests that in certain conditions, expectancy, rather than response bias, contributes to increased behavioral response tendencies, and that a presumed index of response inhibition, the nogo N2, may rather reflect conflict monitoring. In sum, direct reflections of brain activity suggest that mechanisms of expectation and attention, rather than of response bias or inhibitory control, govern behavioral manifestations of impulsivity.

In search of neurophysiological markers of pervasive developmental disorders: smooth pursuit eye movements?

Genetic studies of autism would benefit from the identification of (neurophysiological) markers of the disease. Reports that subjects with autism suffer from abnormalities of visual motor processing, indicate that abnormalities in smooth pursuit eye movements (SPEM) may be a marker of the disorder. Sixteen high-functioning school-aged children with pervasive developmental disorder (PDD) were compared with a matched group of eighteen normally developing controls on performance of a SPEM task and a task which tested the integrity of visually guided saccadic eye movements. Both groups of children had normal eye movements during performance of these tasks. Thus abnormalities in SPEM would appear not to be a marker of PDD. The earlier reported abnormalities in visual motion processing might need to be reinterpreted.

Increasing dopaminergic activity: effects of L-dopa and bromocriptine on human sensory gating.

Schizophrenic patients show a loss of sensory gating, which is reflected in a reduced P50 suppression. Because most of the symptoms in schizophrenia can be reduced by antagonists of the dopaminergic (D2) system, the loss in sensory gating might be related to an increased dopaminergic activity. Therefore, in the present study, the effects of increased dopaminergic neurotransmisson on sensory gating in healthy volunteers were investigated. In a double-blind, balanced, placebo-controlled design, healthy male volunteers were challenged in two separate studies with either 300 mg L-dopa (precursor of dopamine) or placebo (n=16) and 1.25 mg bromocriptine (D2 agonist) or placebo (n=17). Subsequently, they were tested for their sensory gating (P50 suppression). P50 suppression values in the placebo condition were comparable to those found in literature. Although both L-dopa and bromocriptine reduced P50 amplitude, they did so in an equal ratio for both the response to the conditioning (C) and the testing (T) stimuli, therefore not resulting in a reduction of the P50 suppression ratio (T/C). In the present study, neither L-dopa nor bromocriptine reduced sensory gating in healthy volunteers. This suggests that an increased dopaminergic activity in humans is not responsible for the reduction in sensory gating as seen, for example, in schizophrenia.

Electrophysiological correlates of attention, inhibition, sensitivity and bias in a continuous performance task.

OBJECTIVE: The aim was to verify the occurrence of proposed electrophysiological correlates of attention, inhibition, sensitivity and bias in a continuous performance task and to support their functional interpretation by using a manipulation intended to enhance subjects' response bias. METHODS: Electroencephalographic activity was recorded during administration of a transformed version of the AX continuous performance task in which cues signaled response alternatives. RESULTS: The previously reported parietal P3, NoGo-N2, NoGo-P3 and contingent negative variation were replicated. Besides, the frontal selection positivity and the lateralized readiness potential were demonstrated. With increasing Go-probability, the parietal P3 to the cue increased without changes in other cue-related correlates. In addition, reaction times decreased, non-parametric measures of sensitivity and bias decreased, the NoGo-N2 increased, and the parietal Go-P3 decreased. CONCLUSIONS: The proposed electrophysiological correlates were identified. Sub-threshold LRPs suggested a central inhibition mechanism. Cue-related correlates revealed that anticipation of a high-probability Go-stimulus involves attention rather than bias. This implies that the increased NoGo-N2 reflected an increase in conflict rather than an increase in inhibition. SIGNIFICANCE: Electrophysiological measures can greatly enhance our understanding of normal and abnormal information processing during continuous performance and related tasks.

Dipole source localization of event-related brain activity indicative of an early visual selective attention deficit in ADHD children.

OBJECTIVE: This study was aimed at investigating whether attention-deficit hyperactivity disorder (ADHD) children suffer from specific early selective attention deficits in the visual modality with the aid of event-related brain potentials (ERPs). Furthermore, brain source localization was applied to identify brain areas underlying possible deficits in selective visual processing in ADHD children. METHODS: A two-channel visual color selection task was administered to 18 ADHD and 18 control subjects in the age range of 7-13 years and ERP activity was derived from 30 electrodes. RESULTS: ADHD children exhibited lower perceptual sensitivity scores resulting in poorer target selection. The ERP data suggested an early selective-attention deficit as manifested in smaller frontal positive activity (frontal selection positivity; FSP) in ADHD children around 200 ms whereas later occipital and fronto-central negative activity (OSN and N2b; 200-400 ms latency) appeared to be unaffected. Source localization explained the FSP by posterior-medial equivalent dipoles in control subjects, which may reflect the contribution of numerous surrounding areas. CONCLUSIONS: ADHD children have problems with selective visual processing that might be caused by a specific early filtering deficit (absent FSP) occurring around 200 ms. The neural sources underlying these problems have to be further identified. Source localization also suggested abnormalities in the 200-400 ms time range, pertaining to the distribution of attention-modulated activity in lateral frontal areas.

Differences between low and high trait impulsivity are not associated with differences in inhibitory motor control.

OBJECTIVE: The present study investigates whether there is an association between trait impulsivity in the normal population and inhibitory motor control as assessed by the stop task. METHOD: Low- and high-impulsive participants (as assessed by the I7 questionnaire; both groups n = 31) performed the stop task. Differences in performance were analyzed by an independent samples t-test. Furthermore, a short meta-analysis was performed on this study and three previous studies with a similar aim. RESULTS: The low- and high-impulsive groups did not differ on the speed to stop the response (SSRT). However, the meta-analysis revealed that high-impulsives are marginally slower in stopping than low-impulsives (effect size = -0.26, p= 0.06). CONCLUSIONS: There is only minor evidence that impulsivity inthe common population is associated with poor inhibitory motor control.

Effects of methylphenidate, desipramine, and L-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder.

The objective of this study was to investigate the effects of methylphenidate (MPH) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were. In addition to MPH, two other drugs were administered in order to affect both transmitter systems more selectively, L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task that measures the ability to inhibit an ongoing action, in a double-blind randomized within-subjects design. Each child received an acute clinical dose of MPH, DMI, L-dopa, and placebo; measures of performance and plasma were determined. The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa. The response-time to the stop-signal was marginally shortened after intake of DMI. MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone. No effects of L-dopa whatsoever were noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo. It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms. The improved inhibition under DMI could be serotonergically mediated.

Differential effects of amitriptyline, nefazodone and paroxetine on performance and brain indices of visual selective attention and working memory.

RATIONALE: Antidepressants may vary widely in their potential to impair cognitive and psychomotor functions. Little is known about their effects on event-related brain potentials (ERPs).OBJECTIVES. To compare the effects of three pharmacologically different antidepressants on performance and ERPs in tasks of selective attention and working memory. METHODS: Subjects were treated for 8 days with amitriptyline (sedative/anticholinergic TCA), nefazodone (5-HT(2) receptor antagonist), paroxetine (SSRI) and placebo, in a double-blind, crossover design. Measurements were carried out on day 1 and 8 of each treatment period. A task was used in which memory load (two and four items) and attention (focused, divided) were orthogonally varied. RESULTS: On day 1 amitriptyline increased reaction times (focused attention) and the percentage of misses (load 4>load 2) and false alarms. Sensitivity (A') was reduced as a function of memory load. Effects were greatly diminished on day 8. The ERP analysis yielded a reduced early frontal positive difference wave related to memory load (day 1). Attention-related search negativity was slightly prolonged. P3 latency (stimulus evaluation time) was prolonged. P3 amplitude was reduced (mainly on day 8) suggesting diminished attention capacity. Nefazodone increased reaction times and miss rates and reduced sensitivity (A') on day 8 only. Paroxetine speeded responses on day 1 and slightly increased miss rates on day 8. Performance effects of nefazodone and paroxetine did not interact with the task factors. Search negativity and P3 measures were not affected. CONCLUSIONS: The results suggest that the pharmacologically selective serotonergic antidepressants lack the specific memory and attention deficits seen with amitriptyline. Both performance and ERP data suggest that paroxetine and nefazodone may influence response-related processes, while for nefazodone an effect on other processes cannot be excluded.

Gaze behavior of children with pervasive developmental disorder toward human faces: a fixation time study.

BACKGROUND: The abnormal gaze behavior of autistic children toward human faces, as observed in daily-life situations, are investigated in two fixation time studies. It has been argued that faces are a special kind of stimuli for normal individuals and that this might not be the case for autistic children. METHODS: A group of high-functioning autistic children (including a group of sub-threshold PDD-NOS children) was compared with a group of normal children, with respect to their fixation behavior for photographs of human faces. Using an infrared eye-tracking device, fixation times for the whole face and for the facial elements of faces were compared between the two groups. The first study dealt with faces having an emotional expression. The second study dealt with neutral faces presented either upright or upside-down. RESULTS: Results of the two studies showed that autistic children have the same fixation behavior as normal children for upright faces, with or without an emotional expression. Furthermore, results of the second study showed that normal children spent less time looking at upside-down faces, but that the fixation times of autistic children were not influenced by the orientation of the faces. CONCLUSIONS: These results plead against the notion that the abnormal gaze behavior in everyday life is due to the presence of facial stimuli per se. Furthermore, the absence of a face orientation effect in autistic children might be a reflection of a lack of holistic processing of human faces in autism.

Looking at images with human figures: comparison between autistic and normal children.

Based on clinical observations of abnormal gaze behavior of autistic children, it has been suggested that autistic children have a problem in processing social information. Several studies on eye movements have indeed found indications that children with autism show particularly abnormal gaze behavior in relation to social stimuli. However, the methodology used in such investigations did not allow for precise gaze analysis. In the present study, the looking behavior of autistic children toward cartoon-like scenes that included a human figure was measured quantitatively using an infrared eye-tracking device. Fixation behavior of autistic children was similar to that of their age- and IQ-matched normal peers. These results do not support the notion that autistic children have a specific problem in processing socially loaded visual stimuli. Also, there is no indication for an abnormality in gaze behavior in relation to neutral objects. It is suggested that the often-reported abnormal use of gaze in everyday life is not related to the nature of the visual stimuli but that other factors, like social interaction, may play a decisive role.

Threat-induced cortical processing and startle potentiation.

This paper presents cortical responses as reflected in event-related potentials (ERP) in an instructed fear paradigm. Safe cues and threat cues that predict shock were presented at an unprecedented fast rate (mean SOA of 2.1 s). Startle and subjective measures confirmed that threat relative to safe cues elicited fear. Several ERP correlates of fear processing were predicted and confirmed: modulation of exogenous sensory components, frontal selection positivity, and increase of P3. Furthermore, a frontal negative slow wave was observed. These results are discussed in relation to attentional selection models and emotional processing.

Stimulus-preceding negativity induced by fear: a manifestation of affective anticipation.

The Stimulus-Preceding Negativity (SPN), a slow cortical potential, has been studied in relation to anticipatory attention. A review of the literature suggests that most instances of SPN are observed in anticipation of motivational stimuli, such as aversive stimuli and stimuli that provide Knowledge of Results. In the present study, SPN was recorded in 12 subjects in a threat-of-shock experiment. This manipulation induced fear, as shown by subjective ratings and potentiation of the eyeblink startle. The fear-induced SPN showed a frontocentral maximum and coarse source analysis suggested that it was generated in midline frontal areas, possibly by the anterior cingulate cortex. It is concluded that the fear-induced SPN is a manifestation of affective anticipation. Possible thalamocortical and amygdalocortical contributions to its generation are discussed.

Eye movements, visual attention, and autism: a saccadic reaction time study using the gap and overlap paradigm.

BACKGROUND: On the basis of the literature on autism, it was hypothesized that children with autism have deficits in attentional (dis-)engagement mechanisms. METHODS: A saccadic gap-overlap task was used to study visual engagement and disengagement in 16 high-functioning autistic children of about 10 years of age and 15 age- and IQ-matched normal control children. Subjects were asked to make saccadic eye movements from a fixation point to a suddenly appearing target as fast as possible. The saccadic reaction time was compared in two conditions: 1) the overlap condition, in which the fixation point was continuously visible, and 2) the gap condition, in which the fixation point was turned off 200 msec before the target appeared. RESULTS: Although no differences between the groups in either condition was observed, the gap effect (i.e., the difference in saccadic reaction time between the overlap condition and the gap condition) was smaller in the autistic group than in the control group. CONCLUSIONS: We concluded that autistic children show a lower level of attentional engagement.

Affective pictures processing, attention, and pain tolerance.

Two experiments were conducted to determine whether attention mediates the effects of affective distractors on cold pressor pain, or whether the cognitive processes of priming and appraisal best account for the effects. In Experiment I, 65 male respondents were exposed to either pleasant, neutral or unpleasant pictures selected from the International Affective Pictures System (IAPS). The cold-pressor test was administered simultaneously. Consistent with predictions based on priming and appraisal hypotheses, results revealed a linear trend across conditions, such that pain tolerance scores were higher as a function of picture pleasantness. A second study was conducted to examine the role of pain cues in the effects of negative affect on cold pressor pain. Thirty-nine male respondents were exposed to unpleasant pictures that either did or did not include pain-related material. Respondents who viewed pictures without pain cues tolerated the cold water for a longer period of time than respondents who viewed pictures that contained pain-related information. Priming and appraisal processes that might underlie the observed differences, and the type of affective distractors that could be meaningful for enhancing pain tolerance, are discussed.

Attentional capacity, a probe ERP study: differences between children with attention-deficit hyperactivity disorder and normal control children and effects of methylphenidate.

In the present study it was investigated whether the smaller P3s in attention-deficit hyperactivity disorder (ADHD) children are caused by a shortage of capacity underlying P3 processes or whether they are due to a capacity allocation problem. Also, effects of methylphenidate on these processes were investigated. Performance and event-related potentials (ERPs) of 14 ADHD and 14 control children were measured using an irrelevant-probe technique. Three types of task irrelevant visual probes (standards, deviants, and novels) were presented against the background of two visual tasks that varied in task difficulty. The parietal P3 wave was measured in response to task stimuli and probes. ADHD subjects made significantly fewer correct detections than normal controls in both the easy and the hard tasks. Controls showed an enhanced P3 to task-relevant stimuli in the hard task, whereas ADHD children did not. Probe (novel) P3 amplitudes decreased from the easy to the hard task to the same extent in both groups. Methylphenidate enhanced the percentage of correct responses and task P3 amplitudes in both the easy and the hard task but probe P3 amplitudes were not influenced by methylphenidate. It was concluded that ADHD children do not suffer from a shortage in attentional capacity; rather, the evidence is in favor of a problem with capacity allocation. Furthermore, methylphenidate had enhancing effects on performance and ERPs, but did not improve the capacity-allocation deficit.

On the processing of spatial frequencies as revealed by evoked-potential source modeling.

OBJECTIVES AND METHODS: Visually evoked potentials (VEPs) are known to be sensitive to spatial frequency, especially in the time range between 50 and 100 ms post-stimulus. In two experiments we localized the cortical activity elicited by stimuli of varying spatial frequency in scalp-recorded brain potentials, using multi-electrode recordings and dipole-source analysis. RESULTS: Low spatial frequencies (<1 c/d) activated relatively lateral occipital areas, the orientation of the neural ensembles involved being predominantly perpendicular to the scalp surface. In contrast, high spatial frequencies (>4 c/d) induced activation of more medial occipital areas with the predominant orientation of the sources being much more parallel to the scalp surface. Furthermore, at about 100 ms latency the lateral-occipital response to low spatial frequencies was stronger in the right hemisphere; no such asymmetry was found for the responses to the high spatial frequencies. These findings were consistent across varying recording conditions, individual subjects, subject populations, stimulus characteristics (grating orientation, grating vs. checkerboard), and task conditions (active vs. passive). CONCLUSION: The results indicate that there are differences in sensitivity to specific spatial frequencies between primary and secondary visual areas, as well as between the right and the left hemispheres.