Cue reactivity towards bodies in anorexia nervosa - common and differential effects in adolescents and adults.

BACKGROUND: Aberrant reward mechanisms with regard to slim body shapes are discussed in patients with anorexia nervosa (AN). The aim of the present study was to examine of cue reactivity toward body shapes in AN via the late positive potential (LPP), an event-related electroencephalography (EEG) component. By including adolescents and adults, aspects of development and chronification could be studied (2 × 2 design). METHODS: Thirty-two female AN patients (19 adolescents and 13 adults) and 37 control participants (16 adolescents and 21 adults) were included. Standardized photographic stimuli showing women's bodies in underwear from five body mass index (BMI) categories (extremely underweight to extremely overweight) were presented. During picture evaluation, EEG activity was recorded (10-20 system). The LPP was measured in two time windows characterized by different topographies (450-700 ms: posterior; 1000-1300 ms: central). RESULTS: Regarding the posterior component, LPP amplitudes were clearly reduced in adult but not in adolescent patients; for both time windows the LPP showed differential patterns over BMI categories for patients and controls. Regarding the central component, a highly significant linear decrease from extremely underweight to extremely overweight body shapes was revealed in patients and no significant modulation in control participants. CONCLUSIONS: Adolescent and adult patients show increased sustained attention toward extremely underweight bodies. In chronically ill patients, this bias appears to be accompanied by generally reduced automatic attention. The LPP findings provide a differentiated picture of aberrant cue reactivity which could be interpreted as motivated attention toward body shapes in AN.

Prenatal and adult androgen activities in alcohol dependence.

OBJECTIVE: Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. METHOD: We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). RESULTS: The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P < 0.001) and alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P < 0.005). Moreover, stress levels (P = 0.002), alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). CONCLUSION: Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence.

Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression.

Because chronic stress is an important risk factor for anxiety states and depressive disorders, we studied hypothalamus-pituitary-adrenal (HPA) axis and sympathetic system activity via changes in cortisol and alpha amylase activity levels in pediatric generalized anxiety disorder (GAD) patients (n = 26) with comorbid depression and a healthy comparison group (n = 26). Morning plasma cortisol and diurnal profiles of salivary cortisol and salivary alpha amylase (sAA) activity were assessed, also reactivity of HPA-axis, sAA activity, and heart rate following a psychosocial stressor (Trier Social Stress Test for children). GAD patients with comorbid depression showed increased morning plasma and salivary cortisol levels, ameliorating throughout in-patient treatment, and higher sAA activity in their diurnal profile. Both HPA and sympathetic activity positively correlated with the severity of anxiety and depression. We also demonstrated a blunted HPA and sympathetic response to acute stress in patients. This pattern of neuroendocrine and sympathetic changes seems to be distinct from the one previously reported in pediatric patients with only social anxiety or depressive disorders. We propose morning plasma and saliva cortisol levels as potential physiological indicators for supporting the evaluation of symptoms' severity and treatment progress in children with GAD and comorbid depressive disorder.

Effects of In utero environment and maternal behavior on neuroendocrine and behavioral alterations in a mouse model of prenatal trauma.

Maternal posttraumatic stress disorder (PTSD) following trauma exposure during pregnancy is associated with an increased risk of affective disorders in children. To investigate the mechanisms by which prenatal trauma and/or maternal PTSD affect brain development and behavior we established a mouse model of prenatal traumatic (PT) experience based on the application of an electric foot shock to C57Bl/6N female mice on the gestational day 12 during their pregnancy. The model is based on a previously validated animal model of PTSD. We found high anxiety levels and poor maternal care along with reduced serum prolactin and increased corticosterone levels in dams following maternal trauma (MT). PT-pups were born smaller and stayed smaller throughout their life. We show increased time and frequency of ultrasonic calls in PT-pups when separated from the mothers on the postnatal day (PND) 9. Cross-fostering experiments reveal lower anxiety levels in PT pups raised by healthy mothers as compared to trauma-naive pups raised by MT-dams. Importantly, the combination of prenatal trauma and being raised by a traumatized mother leads to: (1) the highest corticosterone levels in pups, (2) longest USV-call time and (3) highest anxiety levels in comparison to other experimental groups. Our data indicates a distinct change in maternal care following MT which is possibly associated with trauma-induced decrease in prolactin levels. Furthermore, we show that maternal behavior is crucial for the development of the offspring anxiety and specific aspects in maternal care overwrite to a significant extend the effects of in utero and postnatal environment. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1254-1265, 2016.

αCaMKII controls the establishment of cocaine's reinforcing effects in mice and humans.

Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca(2+)/calmodulin-dependent protein kinase-II (αCaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. The autophosphorylation of αCaMKII was shown to accelerate learning. Thus, we investigated the role of αCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg(-1), intraperitoneal). In vivo microdialysis revealed that αCaMKII(T286A) mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg(-1), intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in αCaMKII(T286A) mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n=688) and Switzerland (n=141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that αCaMKII controls the speed for the establishment of cocaine's reinforcing effects.

Association between body weight of newborn rats and density of serotonin transporters in the frontal cortex at adulthood.

Persisting alterations in monoaminergic innervation patterns have been observed following various environmental manipulations and neuro-psychopharmacological treatments during fetal or early postnatal life. The present study investigates the question how differences in initial growth conditions at birth might interfere with subsequent development of both serotonergic and noradrenergic innervation in the rat frontal cortex (FC) and brain stem. For this purpose, newborn rat littermates were divided into two groups, a low and a high birth weight group, and the densities of both serotonin (5-HT) and norepinephrine (NE) transporters in the FC and brain stem were analyzed at adulthood. 5-HT transporter density in the FC was significantly higher in the high birth weight group as compared with the low birth weight group. No significant differences were observed between both groups in the density of 5-HT transporters in the brain stem and in the densities of NE transporters in FC and brain stem. It is discussed that differences in birth weight may affect the postnatal development of 5-HT projections to the frontal cortex.

Epigenetic factors differentially influence postnatal maturation of serotonin (5-HT) innervation in cerebral cortex of gerbils: interaction of rearing conditions and early methamphetamine challenge.

The effects of disjunctive environmental deprivation combined with a single methamphetamine (MA) challenge on postnatal maturation of the serotonin (5-HT) innervation pattern in cerebral cortex of gerbils were studied. Gerbils were assigned to either enriched (ER) or impoverished (IR) environmental rearing conditions. On postnatal day 110, 5-HT was immunostained. The 5-HT innervation pattern of the brain was qualitatively evaluated and provided in graphic form. The densities of 5-HT fibres were quantified in areas of prefrontal, insular, frontal, parietal, and entorhinal cortices of the right hemisphere using digital image analysis. The early MA challenge led to an overshoot of the fibre density in medial and orbital prefrontal cortex and entorhinal cortex of ER animals. IR animals mostly resisted MA effects except of a restraint of the innervation of the insular cortex. In comparison to enriched rearing, restricted rearing caused overshoot maturation of 5-HT innervation in insular and entorhinal cortices. The present data provide evidence for a region-specific postnatal vulnerability of the maturing 5-HT innervation, namely in association cortices. In contrast, both sensory and motor cortices showed no significant changes at all. The results are discussed in context with previously presented findings of alterations of the cortical dopamine innervation depending on both epigenetic factors. In conclusion, both experimental variables together give new insight into raphe-cortical plasticity that may contribute to a better understanding of the role of 5-HT fibre systems in structural maturation of the cortex. Postnatal environment may be involved in individual vulnerability of a variety of mental disorders during adolescence and aging.

Methylphenidate enhances both intracortical inhibition and facilitation in healthy adults.

Transcranial magnetic stimulation was used to investigate the effect of the psychostimulant drug methylphenidate (MPH) on motor cortex excitability in healthy adults (n = 12) in a placebo-controlled, crossover design study. MPH caused an enhancement of intracortical inhibition as well as intracortical facilitation. Enhancement of both of these TMS parameters was unexpected and suggests that MPH exerts its action on the motor cortex not only through the dopaminergic neurotransmitter system.

Methylphenidate and intracortical excitability: opposite effects in healthy subjects and attention-deficit hyperactivity disorder.

OBJECTIVE: To test the effects of a standard dosage of the psychostimulant methylphenidate (MPH) - which significantly enhances intracortical inhibition but had no effects on intracortical facilitation in children with attention-deficit hyperactivity disorder (ADHD) - on intracortical excitability in healthy subjects. METHOD: In 12 healthy subjects, aged 20-40 years, intracortical inhibition and facilitation were investigated before and 70 min after the intake of 10 mg MPH using the technique of transcranial magnetic stimulation (TMS) with the paired-stimulus paradigm. RESULTS: In comparison of the two TMS measurements, a significant enhancement in intracortical facilitation but no effects on intracortical inhibition could be stated under MPH administration. CONCLUSION: This study provides first evidence for opposite effects of MPH on intracortical excitability in healthy adult subjects showing enhanced intracortical facilitation in contrast to ADHD children in whom enhanced intracortical inhibition has recently been shown.

Time-on-task analysis using wavelet networks in an event-related potential study on attention-deficit hyperactivity disorder.

OBJECTIVE: The aim of this event-related potential (ERP) study was to test time-on-task analysis at the level of single sweeps in a clinical trial. Since inattentiveness is one of the main symptoms of attention-deficit hyperactivity disorder (ADHD), this child psychiatric disorder was chosen as an exemplary application. METHODS: Twenty-four healthy and 24 ADHD boys, aged 9--15 years, performed an auditory selective attention task for about 5 min. ERP single trials were analyzed using wavelet networks. Time-on-task analysis was applied to omission errors, reaction time and slow ERP components (frontal negativity, parietal positivity), represented by a low-frequency wavelet component. RESULTS: Both performance and ERP measures showed distinct temporal dynamics. Time-on-task effects were not only linear, but also of higher order and started after less than 1 min. For ADHD children, earlier time-on-task effects, i.e. an earlier increase of omission errors and frontal negativity, resulted. Healthy children could allocate more attentional resources during the course of the experiment. CONCLUSION: Time-on-task analysis at the level of single trials revealed phenomena probably reflecting ADHD children's attentional deficits. Thus, a more differentiated ERP analysis may provide a better understanding of the pathophysiological background in neuropsychiatric disorders.

Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters.

Methylphenidate is widely and effectively used for the treatment of attention deficit hyperactivity disorder during early childhood and adolescence, but until now possible effects of this treatment on brain development and the maturation of monoaminergic systems have not been investigated systematically. This experimental animal study describes the effects of methylphenidate administration (2 mg/kg/day) for 2 weeks to very young (prepubertal) and somewhat older (postpubertal) rats on the densities of dopamine, serotonin, and norepinephrine transporters in the striatum and in the midbrain. As shown by ligand-binding-assays, the K(D) values of all three transporters were unaffected by this treatment. No alterations were found for the Bmax values of [3H]-paroxetine and [3H]-nisoxetine binding, but the density of dopamine transporters (Bmax values of [3H]-GBR binding) in the striatum (but not in the midbrain) was significantly reduced after early methylphenidate administration (by 25% at day 45), and this decline reached almost 50% at adulthood (day 70), that is, long after termination of the treatment. This is the first empirical demonstration of long-lasting changes in the development of the central dopaminergic system caused by the administration of methylphenidate during early juvenile life.

Children with comorbid attention-deficit-hyperactivity disorder and tic disorder: evidence for additive inhibitory deficits within the motor system.

For children with attention-deficit-hyperactivity disorder (ADHD) or tic disorder (TD), we recently reported deficient inhibitory mechanisms within the motor system by using transcranial magnetic stimulation. These deficits--stated as reduced intracortical inhibition in ADHD and shortened cortical silent period in TD--could be seen as neurophysiological correlates of motor hyperactivity and tics, respectively. To investigate neurophysiological aspects of comorbidity, we measured motor system excitability for the first time also in children with combined ADHD and TD. The findings of a reduced intracortical inhibition as well as a shortened cortical silent period in these comorbid children provide evidence for additive effects at the level of motor system excitability.

[Transcranial magnetic stimulation in child and adolescent psychiatry: excitability of the motor system in tic disorders and/or attention deficit hyperactivity disorders]. / Transkranielle Magnetstimulation in der Kinder- und Jugendpsychiatrie: Exzitabilität des motorischen Systems bei Tic-Störungen und/oder Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen.

Motor system excitability can be investigated in vivo by means of single and paired pulse transcranial magnetic stimulation (TMS). Whereas the cortical silent period reflects the general degree of inhibitory mechanisms mainly within the sensorimotor loop, intracortical excitability measures the focused degree of inhibitory and facilitatory mechanisms within the motor cortex. In child and adolescent psychiatric disorders with uncontrollable motor behavior such as tics in tic disorder or motoric hyperactivity in attention deficit hyperactivity disorder (ADHD), different dysfunctional patterns of motor system excitability could be demonstrated compared to age-matched healthy controls: (1) In tic disorder, a shortened cortical silent period was observed, providing evidence of deficient inhibitory mechanisms within the sensorimotor loop, probably primarily at the level of the basal ganglia. (2) In ADHD, a decreased intracortical inhibition was found, probably reflecting deficient inhibitory mechanisms within the motor cortex (but enhancement of intracortical inhibition after oral intake of 10 mg methylphenidate). In order to investigate neurophysiological aspects of comorbidity, (3) motor system excitability was also measured in children with combined ADHD and tic disorder. The findings of a reduced intracortical inhibition as well as a shortened cortical silent period in these comorbid children provide evidence of additive effects at the level of motor system excitability. These decreased inhibitory mechanisms within the entire sensorimotor loop and especially the motor cortex could be essential neurobiological substrates of the deficient inhibitory motor control and regulation, respectively, in tic disorder and ADHD.

Comorbidity in ADHD-children: effects of coexisting conduct disorder or tic disorder on event-related brain potentials in an auditory selective-attention task.

In children with attention-deficit hyperactivity disorder (ADHD) some deficits in auditory information processing seem to exist. Further, comorbidity of ADHD with conduct disorder (CD) and tic disorder (Tic) is quite common but not yet fully understood. Thus, we investigated the effects of these two disturbances, when combined with ADHD, on electrophysiological correlates of auditory information processing. An auditory selective-attention task was used, and temporal as well as frontal lobe sensitive event-related electrical brain activity indicators like mismatch negativity (MMN) and negative difference wave (Nd), as well as P300 were registered in four groups of children (healthy controls, ADHD-only, and combined ADHD + CD as well as ADHD + Tic; total number 42). Performance measures showed that ADHD + CD had a higher impact on errors and reaction times than ADHD + Tic. The MMN effect indicated that all ADHD groups showed lower MMN amplitudes compared to normals, but only the group with ADHD + CD suffered from a significant deficiency in automatic auditory information processing. Nd and P300 amplitudes showed no significant group differences. It may be assumed that neurodynamic sufficiency in ADHD-only and ADHD + Tic children seems to be similarly impaired while there might be a greater deficit in ADHD + CD.

Quantitative and qualitative aspects of obsessive-compulsive behaviour in children with attention-deficit hyperactivity disorder compared with tic disorder.

OBJECTIVE: Within the framework of associated psychopathology in child psychiatric disorders, this study focused on quantitative and qualitative aspects of obsessive-compulsive behaviour (OCB) in both attention-deficit hyperactivity disorder (ADHD) and chronic tic disorder/Tourette's disorder (TD). METHOD: Forty-two healthy controls, 41 children with ADHD and 38 children with TD, aged 9-13 years, were investigated using the Leyton Obsessional Inventory--Child Version (LOI-CV), the Child Behaviour Checklist (CBCL) and an expert-rated structured parent interview to reflect a cross-informant view of OCB. RESULTS: Unexpectedly, self-reports of children with ADHD rather than children with TD showed the highest OCB scores in the LOI-CV. Qualitatively, ADHD-related OCB focused on the item subsets concerning 'dirt and contamination', 'repetition', 'overconscientiousness', and 'hoarding'. In the parent-rated CBCL, similar levels of OCB were reported for ADHD and TD patients. In contrast, only children with TD showed clinically relevant OCB according to expert ratings. CONCLUSION: Not only young TD patients but also children with ADHD should be investigated and monitored carefully for quantitative and qualitative aspects of OCB comorbidity.

Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate.

In children with attention-deficit hyperactivity disorder (ADHD), motoric hyperactivity is one of the striking abnormalities. Because this symptom might be due to an insufficient motor control, motor system excitability in 18 drug-naive ADHD-children aged 8-12 years was compared to 18 age-matched healthy children using the technique of transcranial magnetic stimulation (TMS). Whereas motor thresholds, cortical silent period, and intracortical facilitation did not differ between the two groups, ADHD-children had significantly reduced intracortical inhibition compared to healthy controls. In all ADHD-children, a second TMS could be started after their first intake of 10 mg methylphenidate. Under this medication, a significant enhancement in intracortical inhibition could be stated. This study provides the first evidence for inhibitory deficits within the motor cortex in ADHD-children and for an enhancement of inhibitory mechanisms in this brain region by methylphenidate.

Age-associated changes in the densities of presynaptic monoamine transporters in different regions of the rat brain from early juvenile life to late adulthood.

The binding parameters of highly selective ligands of serotonin (5-HT) transporters ([3H]paroxetine), noradrenaline (NE) transporters ([3H]nisoxetine), and of dopamine (DA) transporters ([3H]GBR-12935) were determined on membrane preparations from frontal cortex, striatum, midbrain and brain stem of Wistar rats on postnatal days 25, 50, 90 and 240, i.e., from the time of weaning till late adulthood. No age-dependent alterations in the affinity-parameters (K(D)-values) of all three monoamine transporters were observed. Age-associated changes in B(max)-values of the binding of all three specific ligands were most pronounced in the phylogenetically younger, late maturing brain regions (frontal cortex, striatum). Most likely, these changes reflect age-related changes in 5-HT, NE and DA-innervation densities. In the frontal cortex, 5-HT-transporter density increased steadily from weaning (day 25) till late adulthood, whereas the density of NE-transporters was highest at weaning, declined till puberty (day 50) and remained at this level until old age. DA-transporter density in the frontal cortex was not reliably measurable by [3H]GBR-binding assays. In the striatum, DA-transporter density increased till puberty and declined thereafter considerably and steadily to about one-fourth of the pubertal values at old age. No such age-associated changes in DA-transporter density were seen in the midbrain. Densities of 5-HT and NE remained at the level reached already at weaning until old age in the striatum, midbrain and brain stem. These findings provide the first comprehensive description of the normally occurring changes in the densities of all three presynaptically located monoamine transporters in the rat brain throughout the life span from weaning to late adulthood.

Deficient motor control in children with tic disorder: evidence from transcranial magnetic stimulation.

Decreased motor inhibition was reported in adult patients with tic disorder (TD) using the technique of transcranial magnetic stimulation. Since tics usually begin during childhood, motor threshold, cortical silent period (CSP) and intracortical inhibition/facilitation were measured in 21 TD children and 25 healthy children aged 10-16 years. In TD children motor threshold was normal. The CSP was significantly shortened compared to healthy controls but did not depend on tic localization. Intracortical inhibition and facilitation did not differ between the two groups. This study confirms that the finding of decreased motor control in adult patients also holds true for children wherever the tics in the latter group were located.

Single-sweep analysis of event-related potentials by wavelet networks--methodological basis and clinical application.

OBJECTIVE: Trial-to-trial variabilities in event-related potentials (ERP's), which are neglected by investigating averaged ERP's, can be important to establish group-specific effects in clinical studies. Single ERP responses have to be analyzed to quantify these variations. In order to overcome the disadvantages of existing single-sweep estimators, we have developed a new procedure based on wavelet networks (WN's) and applied this novel approach in a study concerning attention deficit hyperactivity disorder (ADHD) in children. METHOD: WN's represent signals as a linear combination of wavelet nodes, i.e., components characterized by time-frequency features related to the wavelet transformation. In single-sweep analysis, each wavelet node is restricted to a specific region of the time-frequency plane during the recursive WN training process. This is achieved by means of tapering and bandpass filtering with Gaussian functions which are automatically adapted and closely related to the Morlet basis wavelet. The time course of a single event-related response can be reliably estimated. Furthermore, the WN method automatically provides well-defined parameters for single event-related responses, respectively ERP trial-to-trial variabilities. RESULTS: In a psychophysiological study on ADHD using auditory evoked potentials (AEP's), latency and amplitude parameters extracted from averaged ERP's did not reveal any significant differences between 25 control and 25 ADHD boys. In contrast, interesting group-specific differences could be established by WN single-sweep analysis. CONCLUSION: WN single-sweep analysis can be recommended as a sensitive tool for clinical ERP studies which should be applied in addition to the investigation of averaged responses. INDEX TERMS: Attention deficit hyperactivity disorder (ADHD), event-related potentials, single-sweep estimation, single-sweep parameterization, time-frequency method, wavelet networks.