C. Rob Markus

Methylphenidate improves deficient error evaluation in children with ADHD: an event-related brain potential study

Children with ADHD make more errors than control children in response-conflict tasks. To explore whether this is mediated by enhanced sensitivity to conflict or reduced error-processing, task-related brain activity (N2, Ne/ERN, Pe) was compared between 8- to 12-year-old children with ADHD and healthy controls during performance of a flanker task. Furthermore, effects of methylphenidate were investigated in ADHD children in a second study. ADHD children made more errors, especially in high-response-conflict conditions, without showing post-error slowing. N2 amplitudes were enhanced on trials resulting in an error response, Ne/ERN amplitude was unaffected and Pe amplitude was reduced in the ADHD group. Methylphenidate reduced errors in both low- and high-conflict conditions and normalized Pe amplitudes in children with ADHD. It was concluded that the inaccurate behaviour of ADHD children in conflict tasks might be related to reduced error-awareness and higher sensitivity to response conflict. Methylphenidates ameliorating effects might be established through its influence on brain networks including posterior (parietal) cortex, enabling children with ADHD to allocate more attention to significant events.

Dietary Amino Acids and Brain Serotonin Function; Implications for Stress-Related Affective Changes

Stress-related mood deterioration and affective disorders, such as depression, are among the leading causes of disease burden throughout the world, and are associated with severe medical consequences and mortality. Research has shown the involvement of dysfunctional brain serotonin (5-HT) biochemistry as a vulnerable biological factor in the onset of mood disturbances. Since the production of brain serotonin is limited by the availability of its plasma dietary amino acid precursor tryptophan, different foods and dietary amino acids that influence tryptophan availability are thought to alter affective behavior by changing brain 5-HT synthesis. Most dietary manipulation studies, however, reveal only modest affective changes, and note that these particularly occur in stress-prone or affected (sub-clinical) subjects. The current paper briefly summarizes evidence for the involvement of diminished brain serotonin function in affective disorders, discusses how this can be assessed and influenced by dietary manipulation procedures, and also notes how beneficial effects of dietary brain serotonin manipulation on affective behavior may be mediated by stress-induced brain serotonin vulnerability.

Diet rich in α-lactalbumin improves memory in unmedicated recovered depressed patients and matched controls

Depression is associated with reduced brain serotonin (5-hydroxytryptamine; 5-HT) function and with cognitive dysfunctions. A diet rich in α-lactalbumin protein has been found to increase the ratio tryptophan /large neutral amino acids (Trp/σLNAA), and to improve cognitive functioning in individuals with high neuroticism scores. Since cognitive dysfunctions sometimes persist after remission of depression, the present study investigated the effects of α-lactalbumin-enriched diet on cognition in recovered depressed patients. Twenty-three recovered depressed patients and 20 healthy matched controls without a history of depression consumed meals rich in α-lactalbumin or casein protein in a double-blind crossover design. Mood, cognitive function and plasma amino acids were assessed at both sessions before and after dietary intake. Alpha-lactalbumin protein had no effect on mood, but improved abstract visual memory and impaired simple motor performance. These effects were independent of history of depression. Supplements of lactalbumin may be useful for nutrition research in relation to age- or disease-related memory decline. The present findings should be further examined in different (e.g. medicated) samples. The long-term effects of α-lactalbumin should also be investigated.

Differential effects of 5-HTTLPR genotypes on inhibition of negative emotional information following acute stress exposure and tryptophan challenge

Previous data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may influence stress resilience and stress-related depression symptoms due to interactions between brain 5-HT dysfunction and stress exposure. Although attentional bias for emotional information has been reliably observed in depression, the interaction between 5-HT transporter-linked promoter region (5-HTTLPR), brain 5-HT vulnerability, and acute stress on affective information processing has not yet been investigated. This study examines the effects of tryptophan (TRP) augmentation (indicating 5-HT manipulation) on inhibition of negative emotional information under stress in mainly female S′/S′- vs L′/L′-allele carriers. A total of 15 female homozygotic short-allele 5-HTTLPR (S′/S′=S/S, S/LG, LG/LG) and 13 female homozygotic long-allele 5-HTTLPR (L′/L′=LA/LA) subjects were tested for mood and inhibition of emotional information in a double-blind, placebo-controlled design before and after stress exposure following TRP manipulation. Stress exposure significantly impaired inhibition of negative affective information only in S′/S′ carriers, whereas L′/L′ carriers even showed increased inhibition of negative information. The S′/S′ allele 5-HTTLPR genotype increases cognitive-attentional bias for negative emotional information under acute stress. As this bias is an important component of depression, this may be a mediating mechanism making S′/S′-allele carriers more vulnerability for stress-induced depression symptoms. Moreover, current data suggest that L′/L′-allele genotypes are more resilient, even increasing cognitive emotional (inhibitory) control after stress.

Differential effects of 5-HTTLPR genotypes on mood, memory, and attention bias following acute tryptophan depletion and stress exposure

RationalePolymorphisms of the serotonin transporter gene (5-HTTLPR) may be associated with increased vulnerability to acute tryptophan depletion (ATD) and depression vulnerability especially following stressful life events.ObjectiveThe aim of the present study was to investigate the effects of ATD in subjects with different 5-HTTLPR profiles before and after stress exposure on affective and cognitive–attentional changes.Materials and methodsEighteen subjects with homozygotic short alleles (S′/S′) and 17 subjects with homozygotic long alleles (L′/L′) of the 5-HTTLPR participated in a double-blind, placebo-controlled, crossover design to measure the effects of ATD on mood, memory, and attention before and after acute stress exposure.ResultsATD lowered mood in all subjects independent of genotype. In S′/S′ genotypes, mild acute stress increased depressive mood and in L′/L′ genotypes increased feelings of vigor. Furthermore, S′/S′ genotypes differed from L′/L′ genotypes on measures of attention independent of treatment and memory following ATD.ConclusionsPolymorphisms of the 5-HTTLPR differentially affect responses to mild stress and ATD, suggesting greater vulnerability of S′/S′ carriers to serotonergic manipulations and supporting increased depression vulnerability.

Effect of tryptophan-rich egg protein hydrolysate on brain tryptophan availability, stress and performance

BACKGROUND & AIMS Reduced brain serotonin function is involved in stress-related disturbances and may particularly occur under chronic stress. Although serotonin production directly depends on the availability of its plasma dietary amino acid precursor tryptophan (TRP), previously described effects of tryptophan-rich food sources on stress-related behavior are rather modest. Recently, an egg protein hydrolysate (EPH) was developed that showed a much greater effect on brain TRP availability than pure TRP and other TRP-food sources and therefore may be more effective for performance under stress. The aim of the present study was to investigate the effects of EPH compared to placebo protein on plasma amino acids, stress coping and performance in subjects with high and low chronic stress vulnerabilities. METHODS In a placebo-controlled, double-blind, crossover study, 17 participants with high and 18 participants with low chronic stress vulnerabilities were monitored for mood and performance under acute stress exposure either following intake of EPH or placebo. RESULTS EPH significantly increased plasma TRP availability for uptake into the brain, decreased depressive mood in all subjects and improved perceptual-motor and vigilance performance only in low chronic stress-vulnerable subjects. CONCLUSIONS The acute use of a TRP-rich egg protein hydrolysate (EPH) is an adequate method to increase plasma TRP for uptake into the brain and may be beneficial for perceptual-motor and vigilance performance in healthy volunteers.

Effect of sub chronic tryptophan supplementation on stress-induced cortisol and appetite in subjects differing in 5-HTTLPR genotype and trait neuroticism

Stress or negative effect often increases preference for, and intake of, palatable snack foods and this may be influenced by cognitive and genetic factors related to stress and 5-HT vulnerability. The short (S) compared to the long (L) allele of the 5-HT transporter linked polymorphic region (5-HTTLPR) has been associated (i) with decreased 5-HT transporter function and availability and hence, with 5-HT vulnerability, and (ii) with greater stress-responsiveness. Stress-proneness is furthermore promoted by cognitive stress-vulnerability, a key feature of trait neuroticism. Brain 5-HT function can be manipulated by dietary administration of its amino acid precursor tryptophan (Trp), and the beneficial effects of dietary Trp on stress experience and emotional eating may be greatest following repeated administration in both stress- and 5-HT-vulnerable subjects. The aim was to examine the influence of repeated Trp administration on stress responsiveness and emotional eating in homozygous 5-HTTLPR S-allele (N=60) and L-allele (N=58) carriers with high and low neuroticism. Following seven days of Trp or PLC intake, mood, cortisol and appetite were assessed before and after exposure to acute stress and snack intake and preference were measured post-stress. It was hypothesized that Trp would reduce stress experience and emotional eating particularly in S-allele carriers with high neuroticism. Results revealed Trp treatment caused a clear reduction in stress-induced cortisol levels in S/S-allele carriers exclusively, and prevented a stress-induced increase in appetite only in S/S-allele carriers with high trait neuroticism. The findings reveal an advantageous effect of sub chronic Trp treatment on stress experience and appetite depending on stress and (genetic) serotonergic vulnerability.

Effects of acute tryptophan depletion on affective processing in first-degree relatives of depressive patients and controls after exposure to uncontrollable stress

RationaleIndividuals with a family history of depression may be more likely to develop depression due to an innate vulnerability of their serotonergic system. However, even though serotonergic vulnerability may constitute a risk factor in the development of depression, it does not seem to be sufficient to cause a depressive episode. Based on previous data, it is suggested that stress may be a mediating factor.ObjectivesThis study examined the role of serotonin (5-HT) in stress coping in individuals with or without a family history of depression.Materials and methodsNineteen healthy first-degree relatives of depressive patients (FH+) and 19 healthy controls without a family history of depression (FH−) were tested in a double-blind placebo-controlled design for affective processing under acute stress exposure, following acute tryptophan depletion (ATD) or placebo.ResultsSignificant negative effects were found of stress on affective processing in FH− and FH+. In addition, FH− responded slower to positive words after stress only following ATD, whereas FH+ responded marginally slower under stress already after placebo and before stress following ATD.ConclusionAcute stress exposure reduces positive affective bias; supporting the role of stress as an important predecessor in the development of depression. Furthermore, FH+ may be more susceptible than FH− to the negative effects of stress as well as to the negative effects of ATD. The results support the assumption that the 5-HT system is involved in stress resilience and may be more vulnerable in first-degree relatives of depression.

Physiological and affective reactivity to a 35% CO2 inhalation challenge in individuals differing in the 5-HTTLPR genotype and trait neuroticism

The inhalation of 35% carbon dioxide (CO₂) results in an acute stress response in healthy individuals and may accordingly provide a good paradigm to examine potential vulnerability factors for stress reactivity and stress-related psychopathology. It has been proposed that CO₂ reactivity is moderated by genetic (5-HTTLPR) and personality (neuroticism) factors, yet no experimental study has investigated their effects on CO₂ reactivity simultaneously. The current study examined the singular and interactive effects of the 5-HTTLPR genotype and neuroticism in predicting the affective and physiological response to a 35% CO₂ challenge in a healthy sample of male and female students. From a large group of 771 students, 48 carriers of the low/low expressing allele (S/S, S/Lg, Lg/Lg) and 48 carriers of the high/high expressing allele (La/La) with the lowest and the highest neuroticism scores (77 females, 19 males; mean age ± SD: 20.6 ± 2 years) were selected and underwent a 35% CO₂ inhalation. Visual analogue scales for anxiety and discomfort and the Panic Symptom List were used to assess affective symptomatology, while salivary samples and heart rate were assessed to establish the physiological response. A typical pattern of responses to CO₂ was observed, characterised by increases in anxiogenic symptoms and physical panic symptomatology and a reduction in heart rate; however, no effect on salivary cortisol concentration was observed. Additionally, the CO₂ reactivity did not differ between groups divided by the 5-HTTLPR genotype or neuroticism. Findings of the current study do not support a role for singular or interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological reactivity to a 35% CO₂ inhalation procedure.

Attention switching after dietary brain 5-HT challenge in high impulsive subjects

High levels of impulsivity have adverse effects on performance in cognitive tasks, particularLy in those tasks that require high attention investment. Furthermore, both animal and human research has indicated that reduced brain serotonin (5-HT) function is associated with increases in impulsive behaviour or decreased inhibition ability, but the effects of 5-HT challenge have not yet been investigated in subjects vulnerable to impulsivity. The present study aimed to investigate whether subjects with high trait impulsivity perform worse than low impulsive subjects in a task switching paradigm in which they have to rapidly shift their attention between two response rules, and to investigate the influence of a 5-HT enhancing diet. Healthy subjects with high ( n = 19) and low (n = 18) trait impulsivity scores participated in a double-blind placebo-controlled study. All subjects performed the attention switch task in the morning following breakfast containing either tryptophan-rich alpha-lactalbumin (4.8 g/100 g TRP) or placebo protein (1.4 g/100 g TRP). Whereas there were no baseline differences between high and low impulsive subjects in task switching abilities, high impulsive subjects made significantly more switch errors and responded slower after dietary 5-HT stimulation, whereas no dietary effects were found on task switching performance in low-impulsive subjects. The deterioration in task switching performance induced by the 5-HT enhancing diet in high impulsive subjects was suggested to be established by general arousal/attention-reducing effects of 5-HT, which might have a larger impact in high impulsive subjects due to either different brain circuitry involved in task switching in this group or lower baseline arousal levels.