Unmedicated Female Patients Research Articles

Disorder-specific cingulo-opercular network hyperconnectivity in pediatric OCD relative to pediatric anxiety.

Prior investigation of adult patients with obsessive compulsive disorder (OCD) has found greater functional connectivity within orbitofrontal-striatal-thalamic (OST) circuitry, as well as altered connectivity within and between large-scale brain networks such as the cingulo-opercular network (CON) and default mode network (DMN), relative to controls. However, as adult OCD patients often have high rates of co-morbid anxiety and long durations of illness, little is known about the functional connectivity of these networks in relation to OCD specifically, or in young patients near illness onset. In this study, unmedicated female patients with OCD (ages 8-21 years, n = 23) were compared to age-matched female patients with anxiety disorders (n = 26), and healthy female youth (n = 44). Resting-state functional connectivity was used to determine the strength of functional connectivity within and between OST, CON, and DMN. Functional connectivity within the CON was significantly greater in the OCD group as compared to the anxiety and healthy control groups. Additionally, the OCD group displayed greater functional connectivity between OST and CON compared to the other two groups, which did not differ significantly from each other. Our findings indicate that previously noted network connectivity differences in pediatric patients with OCD were likely not attributable to co-morbid anxiety disorders. Moreover, these results suggest that specific patterns of hyperconnectivity within CON and between CON and OST circuitry may characterize OCD relative to non-OCD anxiety disorders in youth. This study improves understanding of network dysfunction underlying pediatric OCD as compared to pediatric anxiety.

Altered Effective Connectivity within the Fronto-Limbic Circuitry in Response to Negative Emotional Task in Female Patients with Major Depressive Disorder.

Background: Major depressive disorder (MDD) is a mood disorder associated with disruptions in emotional control. Previous studies have investigated abnormal regional activity and connectivity within the fronto-limbic circuit. However, condition-specific connectivity changes and their association with the pathophysiology of MDD remain unexplored. This study investigated effective connectivity in the fronto-limbic circuit induced by negative emotional processing from patients with MDD. Methods: Thirty-four unmedicated female patients with MDD and 28 healthy participants underwent event-related functional magnetic resonance imaging at 7T while viewing emotionally negative and neutral images. Brain regions whose dynamics are driven by experimental conditions were identified by using statistical parametric mapping. Effective connectivity among regions of interest was then estimated by using dynamic causal modeling. Results: Patients with MDD had lower activation of the orbitofrontal cortex (OFC) and higher activation of the parahippocampal gyrus (PHG) than healthy controls (HC). In association with these regional changes, we found that patients with MDD did not have significant modulatory connections from the primary visual cortex (V1) to OFC, whereas those connections of HC were significantly positively modulated during negative emotional processing. Regarding the PHG activity, patients with MDD had greater modulatory connection from the V1, but reduced negative modulatory connection from the OFC, compared with healthy participants. Conclusions: These results imply that disrupted effective connectivity among regions of the OFC, PHG, and V1 may be closely associated with the impaired regulation of negative emotional processing in the female patients with MDD.

Monoamine Oxidase A Hypomethylation in Obsessive-Compulsive Disorder: Reversibility By Successful Psychotherapy?

BackgroundEpigenetic markers such as DNA methylation of the monoamine oxidase A (MAOA) gene have previously been shown to be altered in anxiety- and stress-related disorders and to constitute a potential mechanism of action of psychotherapeutic interventions such as cognitive behavioral therapy in these disorders. The present study for the first time, to our knowledge, investigated MAOA methylation in patients with obsessive-compulsive disorder applying a longitudinal psychotherapy-epigenetic approach.MethodsThe present sample comprised 14 unmedicated female patients with primary obsessive-compulsive disorder and 14 age- and sex-matched healthy controls. MAOA promoter methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from whole blood before and after an 8- to 10-week semi-standardized, obsessive-compulsive disorder–specific cognitive behavioral therapy. Clinical response was assessed by means of the Yale-Brown Obsessive Compulsive Scale.ResultsSignificantly lower MAOA promoter methylation was discerned in obsessive-compulsive disorder patients relative to healthy controls. Data were available for 12 patients with obsessive-compulsive disorder and 14 controls. Furthermore, following cognitive behavioral therapy, clinical improvement, i.e., decreases in obsessive-compulsive disorder symptoms as indicated by lower scores on the Yale-Brown Obsessive Compulsive Scale was found to be significantly correlated with increases in MAOA methylation levels in patients (data available for n = 7).ConclusionsThe present pilot data suggest MAOA hypomethylation as a potential risk marker of obsessive-compulsive disorder and an increase in MAOA methylation levels as a possible mechanistic correlate of response to cognitive behavioral therapy in obsessive-compulsive disorder.

Altered Fractional Amplitude of Low Frequency Fluctuations in Unmedicated Female Patients with Obsessive-Compulsive Disorder.

A number of resting-state functional magnetic resonance imaging (rs-fMRI) studies indicate dysfunction of large-scale brain networks underlying the pathophysiology of obsessive-compulsive disorder (OCD). Recent epidemiology studies show that the prevalence of female OCD patients is higher than that of males. However, the underlying neurobiology mechanism for female OCD patients remains not fully understood. In this study, we are aimed to explore the spontaneous brain neuronal activity in unmedicated female OCD patients using rs-fMRI methodology and fractional amplitude of low frequency fluctuations (fALFF) analysis. Additionally, we examine the relationship between fALFF changes and female OCD symptomatology. Increased fALFF values in right brainstem, right rectus, left middle temporal gyrus and right angular were found in OCD females. And decreased fALFF values in right cerebellum, left middle occipital gyrus, left insula, postcentral gyrus and left precentral gyrus were shown in female OCD patients. Moreover, the fALFF values in left precentral gyrus and left middle temporal gyrus were positively associated with patients YBOCS-Obsessions scores and HAMD scores, respectively. Our findings bring additional insights in understanding the pathophysiology of female OCD patients.

Resting-state functional connectivity of neurotransmitter producing sites in female patients with borderline personality disorder

Impulsive behavior, difficulties in controlling anger and suicidal behavior are typical patterns of affective/behavioral dysregulation in patients with borderline personality disorder (BPD). Previous functional MRI studies in the resting state condition demonstrated altered functional connectivity (FC) between the anterior cingulate cortex (ACC) and the frontoparietal executive control network (ECN), which was significantly associated with impulsivity in BPD. Impulsivity is often defined as a function of inhibitory control, strongly relying on the proper functioning of the fronto-cingulo-striatal network. Noradrenergic, dopaminergic and serotonergic neurotransmitter systems are assumed to be involved in different forms of impulsive behavior and inhibitory control. In our previous study, we investigated the FC of the main monoamine-producing nuclei within the midbrain and brainstem, which were functionally integrated in specific resting-state networks. In the present study we investigated the resting-state FC of midbrain/brainstem nuclei in 33 unmedicated female patients with BPD and 33 matched healthy controls. We further related altered functional connectivity of these nuclei to the patient's degree of impulsivity. The main finding was that BPD patients showed stronger FC from the noradrenergic locus coeruleus (LC) to the ACC. Functional connectivity between the LC and ACC was positively associated with the degree of motor impulsivity in the total group. Controlling for aggression, a stronger FC was also found between serotonergic nucleus centralis superior (NCS) and the frontopolar cortex (FPC) in patients compared to controls. Furthermore, patients showed a weaker “anti-correlation” from the substantia nigra (SNc) to the left dorsolateral prefrontal cortex (DLPFC). The observed enhanced LC-ACC FC in BPD and its association with the motor impulsivity might be indicative of a noradrenergic dysfunction in the neural inhibitory control network, whereas the significant relationship between NCS-FPC FC and aggression points toward serotonergic contribution to prefrontal control of aggressive reactions.

Time course of facial emotion processing in women with borderline personality disorder: an ERP study.

Borderline personality disorder (BPD) is characterized by a negative perception of others. Previous studies have revealed deficits and biases in facial emotion recognition. This study investigates the behavioural and electrophysiological correlates underlying facial emotion processing in individuals with BPD. The present study was conducted between July 2012 and May 2014. In an emotion classification task, unmedicated female patients with BPD as well as healthy women had to classify faces displaying blends of anger and happiness while the electroencephalogram was recorded. We analyzed visual event-related potentials (ERPs) reflecting early (P100), structural (N170) and categorical (P300) facial processing in addition to behavioural responses. We included 36 women with BPD and 29 controls in our analysis. Patients with BPD were more likely than controls to classify predominantly happy faces as angry. Independent of facial emotion, women with BPD showed enhanced early occipital P100 amplitudes. Additionally, temporo-occipital N170 amplitudes were reduced at right hemispherical electrode sites. Centroparietal P300 amplitudes were reduced particularly for predominantly happy faces and increased for highly angry faces in women with BPD, whereas in healthy volunteers this component was modulated by both angry and happy facial affect. Our sample included only women, and no clinical control group was investigated. Our findings suggest reduced thresholds for facial anger and deficits in the discrimination of facial happiness in individuals with BPD. This biased perception is associated with alterations in very early visual as well as deficient structural and categorical processing of faces. The current data could help to explain the negative perception of others that may be related to the patients' impairments in interpersonal functioning.

Dysregulation of Regional Endogenous Opioid Function in Borderline Personality Disorder

Borderline personality disorder is characterized by a lack of effective regulation of emotional responses. The authors investigated the role of the endogenous opioid system and mu-opioid receptors in emotion regulation in borderline personality disorder. Mu-opioid receptor availability in vivo (nondisplaceable binding potential, or BP(ND)) was measured with positron emission tomography and the selective radiotracer [(11)C]carfentanil during neutral and sustained sadness states in 18 unmedicated female patients with borderline personality disorder and 14 healthy female comparison subjects. Patients showed greater regional mu-opioid BP(ND) than did comparison subjects at baseline (neutral state) bilaterally in the orbitofrontal cortex, caudate, and nucleus accumbens and in the left amygdala, but lower BP(ND) in the posterior thalamus. Sadness induction was associated with greater reductions in BP(ND) (endogenous opioid system activation) in the patient group than in the comparison group in the pregenual anterior cingulate, left orbitofrontal cortex, left ventral pallidum, left amygdala, and left inferior temporal cortex. Patients showed evidence of endogenous opioid system deactivation in the left nucleus accumbens, the hypothalamus, and the right hippocampus/parahippocampus relative to comparison subjects. Correlations of baseline measures with the Dissociative Experiences Scale and endogenous opioid system activation with the Barratt Impulsiveness Scale did not remain significant after correction for multiple comparisons. Differences exist between patients with borderline personality disorder and comparison subjects in baseline in vivo mu-opioid receptor concentrations and in the endogenous opioid system response to a negative emotional challenge that can be related to some of the clinical characteristics of patients with borderline personality disorder. The regional network involved is implicated in the representation and regulation of emotion and stress responses.

Metabolic syndrome in female patients with schizophrenia treated with second generation antipsychotics: a 3-month follow-up

The objective of this study was to determine the occurrence of metabolic abnormalities among previously unmedicated female patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia spectrum disorders and their associations with olanzapine and risperidone treatment. We analysed 94 female patients who were treated with olanzapine or risperidone in the period of 3 months. Analysed variables included fasting glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoproteins and triglycerides in blood, blood pressure (BP), waist and hip circumferences and body mass index (BMI). At baseline, 14 patients (15%) fulfilled criteria for metabolic syndrome. After 3 months of treatment, 25 patients (27%) fulfilled criteria for metabolic syndrome, and their baseline BMI was the only predictor for its development. Treatment with both antipsychotics was associated with significant increase in waist circumference. Positive family history of diabetes mellitus contributed to a significant greater increase in abdominal obesity, significant higher baseline levels and a borderline significant increase in fasting glucose among olanzapine-treated patients. Olanzapine admission was associated with a significant increase in LDL and risperidone with a significant increase in triglycerides. Metabolic abnormalities seem to be more prevalent in unmedicated female patients with schizophrenia spectrum disorders than expected based on results in general population (adjusted for age and sex). Olanzapine treatment might induce significant alterations in metabolic profiles, especially among patients with positive family history of diabetes, mostly by inducing abdominal obesity. The association of risperidone application and increase in triglyceride level still needs to be determined.

Enhanced emotion-induced amnesia in borderline personality disorder

Current biological concepts of borderline personality disorder (BPD) emphasize the interference of emotional hyperarousal and cognitive functions. A prototypical example is episodic memory. Pre-clinical investigations of emotion-episodic memory interactions have shown specific retrograde and anterograde episodic memory changes in response to emotional stimuli. These changes are amygdala dependent and vary as a function of emotional arousal and valence. To determine whether there is amygdala hyper-responsiveness to emotional stimuli as the underlying pathological substrate of cognitive dysfunction in BPD, 16 unmedicated female patients with BPD were tested on the behavioural indices of emotion-induced amnesia and hypermnesia established in 16 healthy controls. BPD patients displayed enhanced retrograde and anterograde amnesia in response to presentation of negative stimuli, while positive stimuli elicited no episodic memory-modulating effects. These findings suggest that an amygdala hyper-responsiveness to negative stimuli may serve as a crucial aetiological contributor to emotion-induced cognitive dysfunction in BPD.

Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patients

Multidrug resistant protein (MDR1) gene, which codes for P-glycoprotein and functions as an efflux transporter in different cells, is widely localized in normal tissues including the gastrointestinal tract, blood cells, biliary tract, kidney and brain and plays a major role in absorption, distribution and elimination of various xenobiotics. Therefore, MDR1 gene variants were proposed as potential susceptibility factors for diseases and as determinants of treatment response to various drugs. We investigated the relationships between exon 21 G2677T and exon 26 C3435T genetic variants of MDR1 gene with susceptibility and treatment response in female schizophrenic patients. The study was conducted in two steps. We first compared allele, genotype and haplotype distributions between 117 female schizophrenic patients and 123 control female subjects. Afterwards, we studied treatment response to olanzapine, in 87 out of 117 previously unmedicated female patients. Overall, we found lower representation of G2677/C3435 haplotype in schizophrenic female patients compared to controls. Test result for linkage disequilibrium between loci was found to be significant. Furthermore, we found significant associations between MDR1 exon 21 G2677T genotypes and treatment response measured with positive PANSS percentage changes, with T allele and TT genotype being associated with significantly better treatment response. A borderline, non-significant statistical association was found between MDR1 exon 26 C3435T genotypes and treatment response, with TT genotype being associated with better treatment response. Our data support functional importance of the MDR1 mutations for the susceptibility and treatment response in female schizophrenic patients.

The influence of emotions on inhibitory functioning in borderline personality disorder

Borderline personality disorder (BPD) is characterized by an emotionally unstable and impulsive cognitive and behavioral style. Inhibitory dysfunction has been hypothesized as playing a crucial role in BPD psychopathology. This study aimed to systematically investigate differential inhibitory functions in patients with BPD as compared to healthy controls, and to investigate their expected impairment in the context of aversive emotions by comparing performances in neuropsychological tasks that present both neutral and emotional material. Unmedicated female patients with BPD (n=28) were compared with age-matched healthy female controls (n=30) in the following tasks: the emotional Stroop test (inhibition of interference), directed forgetting (intentional, resource-dependent inhibition), and an emotional variant of the negative priming task (automatic, resource-independent inhibition). In comparison with the controls, the BPD patients showed reduced inhibition of negative material in the directed forgetting task and in the negative priming task. No effect was found in the emotional Stroop test. Significant correlations with current affect as well as trait anxiety and anger (but not impulsiveness) were found in the BPD group specifically for negative stimuli, while no such correlations were found in the control group. In addition to inhibitory deficiencies, BPD patients had difficulties remembering positive words in the directed forgetting task. Our data suggest that individuals with BPD have difficulties in actively suppressing irrelevant information when it is of an aversive nature. Inhibitory dysfunction appears to be closely related to state and trait variables of unstable affect, but not to self-reported impulsiveness.

MR perfusion-weighted imaging and quantitative analysis of cerebral hemodynamics with symptom provocation in unmedicated patients with obsessive–compulsive disorder

We evaluated the potential effectiveness of dynamic contrast-enhanced perfusion-weighted images (PWI) in determining hemodynamic activation in brain structures that may be involved in mediating the symptomatology of patients with obsessive–compulsive disorder (OCD), as manifested by contamination obsessions with washing compulsions. Ten unmedicated female patients with OCD were subjected to PWI, and relative cerebral blood flow (rCBF) in each region of interest (ROI) and self-ratings of OCD symptoms were compared before and after symptom provocation. We found that increases in the Anxiety Analogue Scale (AAS) and OCD Analogue Scale (OCDAS) scores were each significantly associated with provocation. The correlations between OCDAS and AAS scores were also statistically significant during both the control and provoked conditions. Compared with the control state, there was a significant increase in rCBF during the symptomatic state in the right head of caudate nucleus, thalamus, and bilateral orbitofrontal cortices (OFC). No statistical changes in rCBF were found in the bilateral anterior cingulate cortices (ACC). These findings demonstrate that OCD symptomatology is accompanied by anxiety, and that abnormal features are particularly apparent in the orbitofrontal-subcortical circuits.

Affective dysregulation and dissociative experience in female patients with borderline personality disorder: a startle response study

Affective dysregulation and dissociation are currently discussed as core features of borderline personality disorder (BPD). Affective dysregulation is hypothesized to be correlated with increased amygdala functioning and dissociation is linked to inhibited processing on the amygdala and dampened autonomic output, according to the corticolimbic disconnection model of dissociation from Sierra and Berrios [Biological Psychiatry 44 (1998) 898]. We assessed startle response, which is mainly mediated by the amygdala, to investigate the relationship between affective dysregulation and dissociation. We hypothesized that patients with BPD would reveal enhanced responses to startling tones, but that these would be lessened by the presence of state dissociative experiences. 21 unmedicated female patients with BPD and 21 healthy female controls listened to 15 startling tones (95-dB, 500-ms, 1000-Hz) while heart rate, skin conductance and orbicularis oculi electromyogram responses were measured. Covariance analysis showed that the BPD group had a significantly higher startle response in the electromyogram as compared to controls. Furthermore, present-state dissociative experiences significantly influenced the startle response. Patients with low dissociative experiences revealed enhanced startle responses whereas patients with high dissociative experiences showed reduced responses. Our data support affective dysregulation in BPD as well as the corticolimbic disconnection model of dissociation, at least for EMG. Furthermore, it highlights the importance of assessing present-state dissociation in basic research as well as psychotherapy.

Differential nociceptive deficits in patients with borderline personality disorder and self-injurious behavior: laser-evoked potentials, spatial discrimination of noxious stimuli, and pain ratings

Approximately 70–80% of women meeting criteria for borderline personality disorder (BPD) report attenuated pain perception or analgesia during non-suicidal, intentional self-mutilation. The aim of this study was to use laser-evoked potentials (LEPs) and psychophysical methods to differentiate the factors that may underlie this analgesic state. Ten unmedicated female patients with BPD (according to DSM-IV) and 14 healthy female control subjects were investigated using brief radiant heat pulses generated by a thulium laser and five-channel LEP recording. Heat pulses were applied as part of a spatial discrimination task (two levels of difficulty) and during a mental arithmetic task. BPD patients had significantly higher heat pain thresholds (23%) and lower pain ratings (67%) than control subjects. Nevertheless, LEP amplitudes were either normal (N1, P2, P3) or moderately enhanced in BPD patients (N2). LEP latencies and task performance did not differ between patients and control subjects. The P3 amplitudes, the vertex potential (N2–P2), and the N1, which is generated near the secondary somatosensory cortex, were significantly reduced during distraction by mental arithmetic in both groups. In addition, P3 amplitudes reflected task difficulty. This study confirms previous findings of attenuated pain perception in BPD. Normal nociceptive discrimination task performance, normal LEPs, and normal P3 potentials indicate that this attenuation is neither related to a general impairment of the sensory-discriminative component of pain, nor to hyperactive descending inhibition, nor to attention deficits. These findings suggest that hypoalgesia in BPD may primarily be due to altered intracortical processing similar to certain meditative states.

Increased diurnal salivary cortisol in women with borderline personality disorder

Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability in affect regulation, impulse control, interpersonal relationships, and self-image. In previous studies, we have used portable mini-computers to assess the severity of recurrent states of aversive emotional distress and dissociation during ambulatory conditions. Here, we used this approach for the assessment of the hypothalamic–pituitary–adrenal (HPA) axis in patients with BPD. We studied 23 unmedicated female patients with BPD and 24 matched healthy controls. Salivary cortisol was collected from all participants during ambulatory conditions in response to reminders provided by portable mini-computers on 3 consecutive days every 2 h for 14 h after awakening. In addition, cortisol in response to awakening was determined in four 15 min intervals on days 1 and 2. After the last collection of cortisol on the second day, 0.5 mg dexamethasone was administered in order to achieve cortisol suppression on day 3 (low-dose dexamethasone suppression test, DST). Patients with BPD displayed significantly higher salivary cortisol levels than healthy controls as demonstrated by higher total cortisol in response to awakening and higher total daily cortisol levels. There were significantly more non-suppressors of cortisol in the low-dose DST in the patient group when compared to the control group. The ambulatory assessment of saliva cortisol is a suitable approach to study basic parameters of the HPA-axis in patients with BPD. Increased adrenal activity and lowered feedback sensitivity of the HPA-axis may characterise BPD. Further studies have to reveal reasons of heightened adrenal activity in these patients.

Frontolimbic brain abnormalities in patients with borderline personality disorder: a volumetric magnetic resonance imaging study

Background Dual frontolimbic brain pathology has been suggested as a possible correlate of impulsivity and aggressive behavior. One previous study reported volume loss of the hippocampus and the amygdala in patients with borderline personality disorder. We measured limbic and prefrontal brain volumes to test the hypothesis that frontolimbic brain pathology might be associated with borderline personality disorder. Methods Eight unmedicated female patients with borderline personality disorder and eight matched healthy controls were studied. The volumes of the hippocampus, amygdala, and orbitofrontal, dorsolateral prefrontal, and anterior cingulate cortex were measured in the patients using magnetic resonance imaging volumetry and compared to those obtained in the controls. Results We found a significant reduction of hippocampal and amygdala volumes in borderline personality disorder. There was a significant 24% reduction of the left orbitofrontal and a 26% reduction of the right anterior cingulate cortex in borderline personality disorder. Only left orbitofrontal volumes correlated significantly with amygdala volumes. Conclusions While volume loss of a single brain structure like the hippocampus is quite an unspecific finding in neuropsychiatry, the patterns of volume loss of the amygdala, hippocampus, and left orbitofrontal and right anterior cingulate cortex might differentiate borderline personality disorder from other neuropsychiatric conditions.