H.C.M. Niermann

Anti-epileptogenesis: Electrophysiology, diffusion tensor imaging and behavior in a genetic absence model

The beneficial effects of chronic and early pharmacological treatment with ethosuximide on epileptogenesis were studied in a genetic absence epilepsy model comorbid for depression. It was also investigated whether there is a critical treatment period and treatment length. Cortical excitability in the form of electrical evoked potentials, but also to cortico-thalamo-cortical network activity (spike-wave discharges, SWD and afterdischarges), white matter changes representing extra cortico-thalamic functions and depressive-like behavior were investigated. WAG/Rij rats received either ethosuximide for 2 months (post natal months 2-3 or 4-5), or ethosuximide for 4 months (2-5) in their drinking water, while control rats drank plain water. EEG measurements were made during treatment, and 6 days and 2 months post treatment. Behavioral test were also done 6 days post treatment. DTI was performed ex vivo post treatment. SWD were suppressed during treatment, and 6 days and 2 months post treatment in the 4 month treated group, as well as the duration of AD elicited by cortical electrical stimulation 6 days post treatment. Increased fractional anisotropy in corpus callosum and internal capsula on DTI was found, an increased P8 evoked potential amplitude and a decreased immobility in the forced swim test. Shorter treatments with ETX had no large effects on any parameter. Chronic ETX has widespread effects not only within but also outside the circuitry in which SWD are initiated and generated, including preventing epileptogenesis and reducing depressive-like symptoms. The treatment of patients before symptom onset might prevent many of the adverse consequences of chronic epilepsy.

Infant attachment predicts bodily freezing in adolescence: evidence from a prospective longitudinal study.

Early life-stress, particularly maternal deprivation, is associated with long-lasting deviations in animals’ freezing responses. Given the relevance of freezing for stress-coping, translational research is needed to examine the relation between insecure infant-parent attachment and bodily freezing-like behavior in humans. Therefore, we investigated threat-related reductions in body sway (indicative of freezing-like behavior) in 14-year-old adolescents (N = 79), for whom attachment security was earlier assessed in infancy. As expected, insecure (vs. secure) attachment was associated with less body sway for angry vs. neutral faces. This effect remained when controlling for intermediate life events. These results suggest that the long-lasting effects of early negative caregiving experiences on the human stress and threat systems extend to the primary defensive reaction of freezing. Additionally, we replicated earlier work in adults, by observing a significant correlation (in adolescents assessed as securely attached) between subjective state anxiety and reduced body sway in response to angry vs. neutral faces. Together, this research opens venues to start exploring the role of freezing in the development of human psychopathology.

Individual differences in defensive stress-responses: The potential relevance for psychopathology

Alterations in primary freeze and fight-or-flight reactions in animals have been associated with increased vulnerability to develop anxious or aggressive symptomatology. Despite the potential relevance of these primary defensive responses for human stress-coping, they are still largely unexplored in humans. The present paper reviews recent evidence suggesting that individual differences in primary defensive stress responses in humans are associated with individual differences in anxiety and aggression. In addition, we discuss (neuro)endocrine systems that may underlie increased freezing and flight behavior in anxiety and increased fight tendencies in aggression-related disorders. We conclude with a research agenda for the study of human defensive stress-responses as potential behavioral markers for stress-related disorders, including anxiety and aggression.

The relation between procrastination and symptoms of attention-deficit hyperactivity disorder (ADHD) in undergraduate students.

Procrastination is defined as the tendency to delay activities that have to be completed before a deadline. It is often part of psychotherapies for adults with attention‐deficit hyperactivity disorder (ADHD). However, procrastination is officially not acknowledged as an ADHD‐related symptom. Therefore, little is known about the role of procrastination in ADHD. We investigated the relation between procrastination and ADHD‐related symptoms of inattention, hyperactivity, and impulsivity in 54 students with varying levels of self‐reported ADHD‐related behaviours. Various measures of procrastination were used, including questionnaires of academic, general procrastination and susceptibility to temptation as well as direct observation of academic procrastination while solving math problems. We expected a positive relation between severity of ADHD‐related behaviours and procrastination, specifically for impulsivity. However, partial correlations (corrected for the other symptom domain of ADHD) indicated that only inattention was correlated with general procrastination. This specific and preliminary finding can stimulate future research in individuals diagnosed with ADHD. Copyright

Early-life and pubertal stress differentially modulate grey matter development in human adolescents

Animal and human studies have shown that both early-life traumatic events and ongoing stress episodes affect neurodevelopment, however, it remains unclear whether and how they modulate normative adolescent neuro-maturational trajectories. We characterized effects of early-life (age 0–5) and ongoing stressors (age 14–17) on longitudinal changes (age 14 to17) in grey matter volume (GMV) of healthy adolescents (n = 37). Timing and stressor type were related to differential GMV changes. More personal early-life stressful events were associated with larger developmental reductions in GMV over anterior prefrontal cortex, amygdala and other subcortical regions; whereas ongoing stress from the adolescents’ social environment was related to smaller reductions over the orbitofrontal and anterior cingulate cortex. These findings suggest that early-life stress accelerates pubertal development, whereas an adverse adolescent social environment disturbs brain maturation with potential mental health implications: delayed anterior cingulate maturation was associated with more antisocial traits – a juvenile precursor of psychopathy.

Effects of stress on bodily freezing in adolescents

Freezing is a major defensive stress-response, characterized by reduced body-sway and heart rate. Exacerbated freezing in threatening situations has been associated with increased basal and stress-induced glucocorticoid levels and with long-lasting stress-related symptoms in animals. However, the effects of stress-induced changes on human freezing are unknown. A new measure has been developed to quantify freezing-like behavior in humans using a stabilometric force-platform such that shifts in body-sway can be assessed with high temporal and spatial accuracy. Previous research has shown that exposure to angry (vs. neutral) faces can induce reductions in body-sway and heart rate in humans. In our study, we used this method to assess the effects of stress and stress-induced cortisol on human freezing responses to angry versus happy and neutral faces. Participants were 90 adolescents (age 17) who were tested at three time points: prior to, immediately after, and 55 min after the Maastricht Acute Stress Test. To ascertain stress-induction, self-reported, physiological, and hormonal measures were collected prior to, immediately after, and 20, 30, 40, and 55 min after stress-onset. Preliminary analyses of the self-report and blood pressure measures indicated a successful stress-induction. Additionally, we predicted that stress-induced cortisol levels are associated with increased freezing. Finally, we will explore the association between stress-induced freezing and affective symptoms (e.g., anxiety) to gain a better understanding why adolescence is a phase of increased vulnerability for stress-related symptoms. We will discuss our results in terms of the translation between animal and human models of stress and defensive responses to threat.

Investigation of the stability of human freezing-like responses to social threat from mid to late adolescence

Freezing behavior, a commonly observed defensive stress response, shows relatively high stability over time in animals. Given the relevance of freezing for stress-coping and human psychopathology, it is relevant to know whether freezing behavior is also stable in humans, particularly during adolescence, when most affective symptoms develop. In a prospective longitudinal study, we investigated freezing-like behavior in response to social threat in 75 adolescents at age 14, repeated 3 years later at age 17. We used a well-established method combining electrocardiography (ECG; heart rate) and posturography (body sway) in response to emotional picture-viewing of angry, happy, and neutral faces. We hypothesized that individual differences in freezing-like behavior in response to social threat—operationalized by contrasting angry vs. neutral faces—would be relatively stable over time. Our results indeed showed relative stability between ages 14 and 17 in individual differences in freezing-like behavior in heart rate (r = 0.82), as well as in combined heart rate and body sway measures (r = 0.65). These effects were not specific for the angry vs. neutral contrast; they were also visible in other emotion contrasts. Exploratory analysis in males and females separately showed stability in body sway specifically for angry vs. neutral faces only in females. Together, these results suggest moderate to strong stability in human freezing-like behavior in response to social threat from mid to late adolescence (with exception for the body sway measure in males). This relative stability was not specific for threat-induction and may reflect a general stability that is particularly strong for heart rate. The fact that this relative stability was found over a relatively long time range of 3 years is promising for studies aiming to use freezing-like behavior as a marker for internalizing symptoms in adolescent development.

Defensive freezing links Hypothalamic-Pituitary-Adrenal-axis activity and internalizing symptoms in humans

The Hypothalamic-Pituitary-Adrenal (HPA)-axis plays an important role in the expression of defensive freezing. Adaptive freezing reactivity, characterized by an immediate increase in acute stress and timely termination upon threat offset or need to act, is essential for adequate stress coping. Blunted HPA-axis activity in animals is associated with blunted freezing reactivity and internalizing symptoms. Despite their potential relevance, it remains unknown whether these mechanisms apply to humans and human psychopathology. Using a well-established method combining electrocardiography and posturography, we assessed freezing before, immediately after, and one hour after a stress induction in 92 human adolescents. In line with animal models, human adolescents showed stress-induced freezing, as quantified by relative reductions in heart rate and body sway after, as compared to before, stress. Moreover, relatively lower basal cortisol was associated with reduced stress-induced freezing reactivity (i.e., less immediate freezing and less recovery). Path analyses showed that decreased freezing recovery in individuals with reduced cortisol levels was associated with increased levels of internalizing symptoms. These findings suggest that reduced freezing recovery may be a promising marker for the etiology of internalizing symptoms.