Altered structural connectivity has been reported in antisocial juveniles, but findings have been... more Altered structural connectivity has been reported in antisocial juveniles, but findings have been inconsistent. Given the phenotypical heterogeneity among individuals showing antisocial behavior, specification of the association between structural connectivity and the dimensions of psychopathic traits (i.e., callous-unemotional, grandiose-manipulative, and impulsive-irresponsible traits) may aid in more reliably elucidating the neural mechanisms underlying antisocial behavior during adolescence. In this study, a sample of 145 adolescents (mean age 17.6, SD 1.6) from a childhood arrestee cohort participated in a neuroimaging protocol including diffusion tensor imaging (DTI). Fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD), as obtained by tract-based spatial statistics, were associated with juveniles' scores on the Youth Psychopathic Traits Inventory. Grandiose-manipulative traits were positively associated with FA and negatively with RD in a wide ra...
Stimulant use is associated with increased anxiety and a single administration of dexamphetamine ... more Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal cortex in response to biologically salient stimuli in an emotional face matching task (EFMT). Amygdala activity and amygdala connectivity during the EFMT were assessed in 51 cocaine using males and 32 non-drug-using healthy males using functional magnetic resonance imaging (fMRI). Within the cocaine use group, we explored whether amygdala activation was associated with age of first use of cocaine and duration of cocaine use to distinguish between amygdala activation alterations as a cause or a consequence of cocaine use. We observed hyperactivity of the amygdala, thalamus, and hippocampus and reduced amygdala connectivity with the anterior cingulate gyrus in response to angry and fearful ...
In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the front... more In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume ...
Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission... more Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission after various treatment options and develop treatment resistant depression (TRD). So far, little is known about the pathophysiology of TRD. Studies in MDD patients showed aberrant functional connectivity (FC) of three "core" neurocognitive networks: the salience network (SN), cognitive control network (CCN), and default mode network (DMN). We used a cross-sectional design and performed resting-state FC MRI to assess connectivity of the SN, CCN, and both anterior and posterior DMN in 17 severe TRD, 18 non-TRD, and 18 healthy control (HC) subjects. Relative to both non-TRD and HC subjects, TRD patients showed decreased FC between the dorsolateral prefrontal cortex and angular gyrus, which suggests reduced FC between the CCN and DMN, and reduced FC between the medial prefrontal cortex and precuneus/cuneus, which suggests reduced FC between the anterior and posterior DMN. No significant differences in SN FC were observed. Our results suggest that TRD is characterized by a disturbance in neurocognitive networks relative to non-TRD and HC.
Borderline personality disorder (BPD) is characterized by severe difficulties in interpersonal re... more Borderline personality disorder (BPD) is characterized by severe difficulties in interpersonal relationships and emotional functioning. Theories of BPD suggest that individuals with BPD have heightened emotional sensitivity, increased stress reactivity, and problems in making sense of intentions of others. In this study we investigated stress reactivity in BPD and its interference with social cognition, and tested whether any differences are specific for BPD or are inherent to personality disorders in general. We investigated 22 patients with BPD, 23 patients with Cluster C personality disorder (CPD), and 24 nonpatients on facial emotion recognition and social evaluation before and after stress induction based on the Trier Social Stress Test (TSST). The results show that stress increased subjective negative emotions in the BPD group to a larger extent than in the other groups, whereas physiological responses were attenuated. Importantly stress induction increased negative evaluation...
Hormonal fluctuations across the menstrual cycle are thought to play a central role in premenstru... more 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.
Several studies demonstrated improvement of depressive symptoms in treatment resistant depression... more Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3) receptor (D2/3R) binding has not been investigated in TRD subjects. We used [(123)I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p<0.001) but there were no differences in clinical symptoms between TRD AP and TRD pati...
Gonadal hormones are known to influence the regulation of emotional responses and affective state... more 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.
Despite accumulating evidence for a reconsolidation process in animals, support in humans, especi... more Despite accumulating evidence for a reconsolidation process in animals, support in humans, especially for episodic memory, is limited. Using a within-subjects manipulation, we found that a single application of electroconvulsive therapy following memory reactivation in patients with unipolar depression disrupted reactivated, but not non-reactivated, memories for an emotional episode in a time-dependent manner. Our results provide evidence for reconsolidation of emotional episodic memories in humans.
Premenstrual increases in negative mood are thought to arise from changes in gonadal hormone leve... more Premenstrual increases in negative mood are thought to arise from changes in gonadal hormone levels, presumably by influencing mood regulation and stress sensitivity. The amygdala plays a major role in this context, and animal studies suggest that gonadal hormones influence its morphology. Here, we investigated whether amygdala morphology changes over the menstrual cycle and whether this change explains differences in stress sensitivity. Twenty-eight young healthy women were investigated once during the premenstrual phase and once during the late follicular phase. T1-weighted anatomical images of the brain were acquired using magnetic resonance imaging and analyzed with optimized voxel-based morphometry. To measure mood regulation and stress sensitivity, negative affect was assessed after viewing strongly aversive as well as neutral movie clips. Our results show increased gray matter volume in the dorsal part of the left amygdala during the premenstrual phase when compared with the late follicular phase. This volume increase was positively correlated with the premenstrual increase in stress-induced negative affect. This is the first study showing structural plasticity of the amygdala in humans at the macroscopic level that is associated with both endogenous gonadal hormone fluctuations and stress sensitivity. These results correspond with animal findings of gonadal hormone-mediated neural plasticity in the amygdala and have implications for understanding the pathogenesis of specific mood disorders associated with hormonal fluctuations.
Adult attention deficit/hyperactivity disorder (ADHD) is highly comorbid with other psychiatric d... more Adult attention deficit/hyperactivity disorder (ADHD) is highly comorbid with other psychiatric disorders, including substance use disorders (SUD). Patients with ADHD and SUD comorbidity respond less well to pharmacological treatment (e.g., methylphenidate), have more severe ADHD symptoms, and are generally more impulsive than ADHD patients without SUD. However, little is known about structural brain abnormalities that may differentiate ADHD patients with and without comorbid SUD. We compared regional grey matter volumes of 10 non-medicated male ADHD patients with comorbid cocaine dependence, 14 non-medicated male ADHD patients without cocaine dependence and 15 healthy control participants matched for age and premorbid intellectual functioning, using voxel-based morphometry (VBM) using both a whole-brain analysis and a priori ROI analysis based on the existing ADHD VBM literature. In a whole brain analysis, ADHD patients with and without cocaine dependence showed smaller volumes in the right putamen and cerebellum compared to healthy controls. In addition, ADHD patients without cocaine dependence showed larger volumes in the midbrain and in the precentral gyrus compared to healthy control participants and larger volumes in the occipital cortex compared to ADHD patients with comorbid cocaine dependence. A direct comparison using the a priori defined ROI approach showed that ADHD patients with cocaine dependence had smaller putamen volumes than ADHD patients without cocaine dependence. ADHD patients with cocaine dependence show more profound grey matter volume reductions in the striatum compared to ADHD patients without cocaine dependence. Possible implications for treatment are discussed.
Altered structural connectivity has been reported in antisocial juveniles, but findings have been... more Altered structural connectivity has been reported in antisocial juveniles, but findings have been inconsistent. Given the phenotypical heterogeneity among individuals showing antisocial behavior, specification of the association between structural connectivity and the dimensions of psychopathic traits (i.e., callous-unemotional, grandiose-manipulative, and impulsive-irresponsible traits) may aid in more reliably elucidating the neural mechanisms underlying antisocial behavior during adolescence. In this study, a sample of 145 adolescents (mean age 17.6, SD 1.6) from a childhood arrestee cohort participated in a neuroimaging protocol including diffusion tensor imaging (DTI). Fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD), as obtained by tract-based spatial statistics, were associated with juveniles' scores on the Youth Psychopathic Traits Inventory. Grandiose-manipulative traits were positively associated with FA and negatively with RD in a wide ra...
Stimulant use is associated with increased anxiety and a single administration of dexamphetamine ... more Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal cortex in response to biologically salient stimuli in an emotional face matching task (EFMT). Amygdala activity and amygdala connectivity during the EFMT were assessed in 51 cocaine using males and 32 non-drug-using healthy males using functional magnetic resonance imaging (fMRI). Within the cocaine use group, we explored whether amygdala activation was associated with age of first use of cocaine and duration of cocaine use to distinguish between amygdala activation alterations as a cause or a consequence of cocaine use. We observed hyperactivity of the amygdala, thalamus, and hippocampus and reduced amygdala connectivity with the anterior cingulate gyrus in response to angry and fearful ...
In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the front... more In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume ...
Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission... more Approximately one-third of patients with major depressive disorder (MDD) do not achieve remission after various treatment options and develop treatment resistant depression (TRD). So far, little is known about the pathophysiology of TRD. Studies in MDD patients showed aberrant functional connectivity (FC) of three &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;core&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; neurocognitive networks: the salience network (SN), cognitive control network (CCN), and default mode network (DMN). We used a cross-sectional design and performed resting-state FC MRI to assess connectivity of the SN, CCN, and both anterior and posterior DMN in 17 severe TRD, 18 non-TRD, and 18 healthy control (HC) subjects. Relative to both non-TRD and HC subjects, TRD patients showed decreased FC between the dorsolateral prefrontal cortex and angular gyrus, which suggests reduced FC between the CCN and DMN, and reduced FC between the medial prefrontal cortex and precuneus/cuneus, which suggests reduced FC between the anterior and posterior DMN. No significant differences in SN FC were observed. Our results suggest that TRD is characterized by a disturbance in neurocognitive networks relative to non-TRD and HC.
Borderline personality disorder (BPD) is characterized by severe difficulties in interpersonal re... more Borderline personality disorder (BPD) is characterized by severe difficulties in interpersonal relationships and emotional functioning. Theories of BPD suggest that individuals with BPD have heightened emotional sensitivity, increased stress reactivity, and problems in making sense of intentions of others. In this study we investigated stress reactivity in BPD and its interference with social cognition, and tested whether any differences are specific for BPD or are inherent to personality disorders in general. We investigated 22 patients with BPD, 23 patients with Cluster C personality disorder (CPD), and 24 nonpatients on facial emotion recognition and social evaluation before and after stress induction based on the Trier Social Stress Test (TSST). The results show that stress increased subjective negative emotions in the BPD group to a larger extent than in the other groups, whereas physiological responses were attenuated. Importantly stress induction increased negative evaluation...
Hormonal fluctuations across the menstrual cycle are thought to play a central role in premenstru... more 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.
Several studies demonstrated improvement of depressive symptoms in treatment resistant depression... more Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3) receptor (D2/3R) binding has not been investigated in TRD subjects. We used [(123)I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p<0.001) but there were no differences in clinical symptoms between TRD AP and TRD pati...
Gonadal hormones are known to influence the regulation of emotional responses and affective state... more 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.
Despite accumulating evidence for a reconsolidation process in animals, support in humans, especi... more Despite accumulating evidence for a reconsolidation process in animals, support in humans, especially for episodic memory, is limited. Using a within-subjects manipulation, we found that a single application of electroconvulsive therapy following memory reactivation in patients with unipolar depression disrupted reactivated, but not non-reactivated, memories for an emotional episode in a time-dependent manner. Our results provide evidence for reconsolidation of emotional episodic memories in humans.
Premenstrual increases in negative mood are thought to arise from changes in gonadal hormone leve... more Premenstrual increases in negative mood are thought to arise from changes in gonadal hormone levels, presumably by influencing mood regulation and stress sensitivity. The amygdala plays a major role in this context, and animal studies suggest that gonadal hormones influence its morphology. Here, we investigated whether amygdala morphology changes over the menstrual cycle and whether this change explains differences in stress sensitivity. Twenty-eight young healthy women were investigated once during the premenstrual phase and once during the late follicular phase. T1-weighted anatomical images of the brain were acquired using magnetic resonance imaging and analyzed with optimized voxel-based morphometry. To measure mood regulation and stress sensitivity, negative affect was assessed after viewing strongly aversive as well as neutral movie clips. Our results show increased gray matter volume in the dorsal part of the left amygdala during the premenstrual phase when compared with the late follicular phase. This volume increase was positively correlated with the premenstrual increase in stress-induced negative affect. This is the first study showing structural plasticity of the amygdala in humans at the macroscopic level that is associated with both endogenous gonadal hormone fluctuations and stress sensitivity. These results correspond with animal findings of gonadal hormone-mediated neural plasticity in the amygdala and have implications for understanding the pathogenesis of specific mood disorders associated with hormonal fluctuations.
Adult attention deficit/hyperactivity disorder (ADHD) is highly comorbid with other psychiatric d... more Adult attention deficit/hyperactivity disorder (ADHD) is highly comorbid with other psychiatric disorders, including substance use disorders (SUD). Patients with ADHD and SUD comorbidity respond less well to pharmacological treatment (e.g., methylphenidate), have more severe ADHD symptoms, and are generally more impulsive than ADHD patients without SUD. However, little is known about structural brain abnormalities that may differentiate ADHD patients with and without comorbid SUD. We compared regional grey matter volumes of 10 non-medicated male ADHD patients with comorbid cocaine dependence, 14 non-medicated male ADHD patients without cocaine dependence and 15 healthy control participants matched for age and premorbid intellectual functioning, using voxel-based morphometry (VBM) using both a whole-brain analysis and a priori ROI analysis based on the existing ADHD VBM literature. In a whole brain analysis, ADHD patients with and without cocaine dependence showed smaller volumes in the right putamen and cerebellum compared to healthy controls. In addition, ADHD patients without cocaine dependence showed larger volumes in the midbrain and in the precentral gyrus compared to healthy control participants and larger volumes in the occipital cortex compared to ADHD patients with comorbid cocaine dependence. A direct comparison using the a priori defined ROI approach showed that ADHD patients with cocaine dependence had smaller putamen volumes than ADHD patients without cocaine dependence. ADHD patients with cocaine dependence show more profound grey matter volume reductions in the striatum compared to ADHD patients without cocaine dependence. Possible implications for treatment are discussed.
Uploads