Lindsey Ossewaarde

Stress-related noradrenergic activity prompts large-scale neural network reconfiguration

Acute stress leads to reorganization of large-scale neural network connectivity in the brain that is driven by noradrenaline. Acute stress shifts the brain into a state that fosters rapid defense mechanisms. Stress-related neuromodulators are thought to trigger this change by altering properties of large-scale neural populations throughout the brain. We investigated this brain-state shift in humans. During exposure to a fear-related acute stressor, responsiveness and interconnectivity within a network including cortical (frontoinsular, dorsal anterior cingulate, inferotemporal, and temporoparietal) and subcortical (amygdala, thalamus, hypothalamus, and midbrain) regions increased as a function of stress response magnitudes. β-adrenergic receptor blockade, but not cortisol synthesis inhibition, diminished this increase. Thus, our findings reveal that noradrenergic activation during acute stress results in prolonged coupling within a distributed network that integrates information exchange between regions involved in autonomic-neuroendocrine control and vigilant attentional reorienting.

Effects of exogenous testosterone on the ventral striatal BOLD response during reward anticipation in healthy women.

Correlational evidence in humans shows that levels of the androgen hormone testosterone are positively related to reinforcement sensitivity and competitive drive. Structurally similar anabolic-androgenic steroids (AAS) are moreover widely abused, and animal studies show that rodents self-administer testosterone. These observations suggest that testosterone exerts activational effects on mesolimbic dopaminergic pathways involved in incentive processing and reinforcement regulation. However, there are no data on humans supporting this hypothesis. We used functional magnetic resonance imaging (fMRI) to investigate the effects of testosterone administration on neural activity in terminal regions of the mesolimbic pathway. In a placebo-controlled double-blind crossover design, 12 healthy women received a single sublingual administration of .5 mg of testosterone. During MRI scanning, participants performed a monetary incentive delay task, which is known to elicit robust activation of the ventral striatum during reward anticipation. Results show a positive main effect of testosterone on the differential response in the ventral striatum to cues signaling potential reward versus nonreward. Notably, this effect interacted with levels self-reported intrinsic appetitive motivation: individuals with low intrinsic appetitive motivation exhibited larger testosterone-induced increases but had smaller differential responses after placebo. Thus, the present study lends support to the hypothesis that testosterone affects activity in terminal regions of the mesolimbic dopamine system but suggests that such effects may be specific to individuals with low intrinsic appetitive motivation. By showing a potential mechanism underlying central reinforcement of androgen use, the present findings may moreover have implications for our understanding of the pathophysiology of AAS dependency.

Chronic effects of cannabis use on the human reward system: An fMRI study

Cannabis is one of the most used drugs of abuse. It affects the brain reward system in animals, and has proven rewarding and addictive potential in humans. We used functional MRI to measure brain activity during reward anticipation in a monetary reward task. Long-term cannabis users were compared to healthy controls. An additional control group consisting of nicotine users was included. Cannabis users showed attenuated brain activity during reward anticipation in the nucleus accumbens compared to non-smoking controls, but not compared to smoking controls. Cannabis users showed decreased reward anticipation activity in the caudate nucleus, compared to both non-smoking and smoking controls. These data suggest that nicotine may be responsible for attenuated reward anticipation activity in the accumbens, but that differences in the caudate are associated with the use of cannabis. Our findings imply that chronic cannabis use as well as nicotine, may cause an altered brain response to rewarding stimuli.

Gonadal hormone regulation of the emotion circuitry in humans

Gonadal hormones are known to influence the regulation of emotional responses and affective states. Whereas fluctuations in progesterone and estradiol are associated with increased vulnerability for mood disorders, testosterone is mainly associated with social dominance, aggressive, and antisocial behavior. Here, we review recent functional neuroimaging studies that have started to elucidate how these hormones modulate the neural circuitry that is important for emotion regulation, which includes the amygdala and the medial prefrontal (mPFC) and orbitofrontal cortex (OFC). The amygdala is thought to generate emotional responses, and the prefrontal brain regions to regulate those responses. Overall, studies that have investigated women during different phases of the menstrual cycle suggest that progesterone and estradiol may have opposing actions on the amygdala and prefrontal cortex. In addition, the influence of exogenous progesterone appears to be dose-dependent. Endogenous testosterone concentrations are generally positively correlated to amygdala and OFC responses, and exogenous testosterone increases amygdala reactivity. Whereas the administration of progesterone increases amygdala reactivity and its connectivity with the mPFC, testosterone administration increases amygdala reactivity but decreases its connectivity with the OFC. We propose that this opposing influence on amygdala-prefrontal coupling may contribute to the divergent effects of progesterone and testosterone on emotion regulation and behavioral inhibition, respectively, which may promote the differential vulnerability to various psychiatric disorders between women and men. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Neural mechanisms underlying changes in stress sensitivity across the menstrual cycle

Hormonal fluctuations across the menstrual cycle are thought to play a central role in premenstrual mood symptoms. In agreement, fluctuations in gonadal hormone levels affect brain processes in regions involved in emotion regulation. Recent findings, however, implicate psychological stress as a potential mediating factor and thus, we investigated whether effects of moderate psychological stress on relevant brain regions interact with menstrual cycle phase. Twenty-eight healthy women were tested in a crossover design with menstrual cycle phase (late luteal versus late follicular) and stress (stress induction versus control) as within-subject factors. After stress induction (or control), we probed neural responses to facial expressions using fMRI. During the late luteal phase, negative affect was highest and the stress-induced increase in heart rate was mildly augmented. fMRI data of the control condition replicate previous findings of elevated amygdala and medial prefrontal cortex responses when comparing the late luteal with the late follicular phase. Importantly, stress induction had opposite effects in the two cycle phases, with unexpected lower response magnitudes in the late luteal phase. Moreover, the larger the increase in allopregnanolone concentration across the menstrual cycle was, the smaller the amygdala and medial prefrontal cortex responses were after stress induction in the late luteal phase. Our findings show that moderate psychological stress influences menstrual cycle effects on activity in the emotion regulation circuitry. These results provide potential insights into how fluctuations in allopregnanolone that naturally occur during the menstrual cycle may change stress vulnerability.

Stress-induced reduction in reward-related prefrontal cortex function

Acute psychological stress can trigger normal and abnormal motivated behaviors such as reward seeking, habitual behavior, and drug craving. Animal research suggests that such effects may result from actions of catecholamines and glucocorticoids that converge in brain regions that regulate motivated behaviors and incentive processing. At present, however, little is known about the acute effects of stress on these circuits in humans. During functional magnetic resonance imaging (fMRI), twenty-seven healthy young women performed a modified version of the monetary incentive delay (MID) task, which is known to robustly engage ventral striatal and medial prefrontal regions. To induce psychological stress, strongly aversive movie clips (versus neutral movie clips) were shown with the instruction to imagine being an eyewitness. Physiological (cortisol levels, heart rate frequency, and heart rate variability) and subjective measurements confirmed successful induction of moderate levels of acute psychological stress. Brain imaging data revealed that stress induction resulted in a significant decrease in reward-related responses in the medial prefrontal cortex (PFC) without affecting ventral striatal responses. Our results thus show that acute psychological stress induces regionally specific changes in functioning of incentive processing circuits. This regional specificity is in line with animal data showing inverted U-shaped relations between levels of stress-related neuromodulators and functioning of the PFC, a structure that is believed to be critical for coordinating behavior in accordance with higher order internal goals. Our findings thus suggest that stress-related increases in habitual and reward-seeking behaviors may be triggered primarily by an impairment of such PFC-dependent cognitive control mechanisms.

Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons

Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane Cl(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Allopregnanolone and mood disorders

UNLABELLED Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. CONCLUSION These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor.

Changes in functioning of mesolimbic incentive processing circuits during the premenstrual phase

The premenstrual phase of the menstrual cycle is associated with marked changes in normal and abnormal motivated behaviors. Animal studies suggest that such effects may result from actions of gonadal hormones on the mesolimbic dopamine (DA) system. We therefore investigated premenstrual changes in reward-related neural activity in terminal regions of the DA system in humans. Twenty-eight healthy young women underwent functional magnetic resonance imaging on 2 days during the menstrual cycle, once during the late follicular phase and once during the premenstrual phase, in counterbalanced order. Using a modified version of the monetary incentive delay task, we assessed responsiveness of the ventral striatum to reward anticipation. Our results show enhanced ventral striatal responses during the premenstrual as compared to the follicular phase. Moreover, this effect was most pronounced in women reporting more premenstrual symptoms. These findings provide support for the notion that changes in functioning of mesolimbic incentive processing circuits may underlie premenstrual changes in motivated behaviors. Notably, increases in reward-cue responsiveness have previously been associated with DA withdrawal states. Our findings therefore suggest that the sharp decline of gonadal hormone levels in the premenstrual phase may trigger a similar withdrawal-like state.

Two-Week Administration of the Combined Serotonin-Noradrenaline Reuptake Inhibitor Duloxetine Augments Functioning of Mesolimbic Incentive Processing Circuits

BACKGROUND Anhedonia and lack of motivation are core symptoms of major depressive disorder (MDD). Neuroimaging studies in MDD patients have shown reductions in reward-related activity in terminal regions of the mesolimbic dopamine (DA) system, such as the ventral striatum. Monoamines have been implicated in both mesolimbic incentive processing and the mechanism of action of antidepressant drugs. However, not much is known about antidepressant effects on mesolimbic incentive processing in humans, which might be related to the effects on anhedonia. METHODS To investigate the short-term effects of antidepressants on reward-related activity in the ventral striatum, we investigated the effect of the combined serotonin-norepinephrine reuptake inhibitor duloxetine. Healthy volunteers underwent functional magnetic resonance imaging in a randomized, double-blind, placebo-controlled, crossover study. After taking duloxetine (60 mg once a day) or placebo for 14 days, participants completed a monetary incentive delay task that activates the ventral striatum during reward anticipation. RESULTS Our results (n = 19) show enhanced ventral striatal responses after duloxetine administration compared with placebo. Moreover, this increase in ventral striatal activity was positively correlated with duloxetine plasma levels. CONCLUSIONS This is the first study to demonstrate that antidepressants augment neural activity in mesolimbic DA incentive processing circuits in healthy volunteers. These effects are likely caused by the increase in monoamine neurotransmission in the ventral striatum. Our findings suggest that antidepressants may alleviate anhedonia by stimulating incentive processing.