E.J. Giltay

Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations.

Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations. SIGNIFICANCE STATEMENT Norepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding.

Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain.

The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior–posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity. SIGNIFICANCE STATEMENT The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system.

A Network Approach to Bipolar Symptomatology in Patients with Different Course Types.

Objective The longitudinal mood course is highly variable among patients with bipolar disorder(BD). One of the strongest predictors of the future disease course is the past disease course, implying that the vulnerability for developing a specific pattern of symptoms is rather consistent over time. We therefore investigated whether BD patients with different longitudinal course types have symptom correlation networks with typical characteristics. To this end we used network analysis, a rather novel approach in the field of psychiatry. Method Based on two-year monthly life charts, 125 patients with complete 2 year data were categorized into three groups: i.e., a minimally impaired (n = 47), a predominantly depressed (n = 42) and a cycling course (n = 36). Associations between symptoms were defined as the groupwise Spearman’s rank correlation coefficient between each pair of items of the Young Mania Rating Scale (YMRS) and the Quick Inventory of Depressive Symptomatology (QIDS). Weighted symptom networks and centrality measures were compared among the three groups. Results The weighted networks significantly differed among the three groups, with manic and depressed symptoms being most strongly interconnected in the cycling group. The symptoms with top centrality that were most interconnected also differed among the course group; central symptoms in the stable group were elevated mood and increased speech, in the depressed group loss of self-esteem and psychomotor slowness, and in the cycling group concentration loss and suicidality. Conclusion Symptom networks based on the timepoints with most severe symptoms of bipolar patients with different longitudinal course types are significantly different. The clinical interpretation of this finding and its implications are discussed.

The effect of atomoxetine on random and directed exploration in humans

The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity.

A cluster analysis of early onset in common anxiety disorders

Early onset is regarded as an important characteristic of anxiety disorders, associated with higher severity. However, previous findings diverge, as definitions of early onset vary and are often unsubstantiated. We objectively defined early onset in social phobia, panic disorder, agoraphobia, and generalised anxiety disorder, using cluster analysis with data gathered in the general population. Resulting cut-off ages for early onset were ≤22 (social phobia), ≤31 (panic disorder), ≤21 (agoraphobia), and ≤27 (generalised anxiety disorder). Comparison of psychiatric comorbidity and general wellbeing between subjects with early and late onset in the general population and an outpatient cohort, demonstrated that among outpatients anxiety comorbidity was more common in early onset agoraphobia, but also that anxiety- as well as mood comorbidity were more common in late onset social phobia. A major limitation was the retrospective assessment of onset. Our results encourage future studies into correlates of early onset of psychiatric disorders.

Elevated salivary alpha-amylase levels at awakening in patients with depression

BACKGROUND Specific Major Depressive Disorder (MDD) biomarkers could help improve our understanding of MDD pathophysiology and aid in the refinement of current MDD criteria. While salivary cortisol (SC) can differentiate between healthy controls and patients with psychiatric disorders, salivary alpha amylase (sAA), may be a putative candidate biomarker for MDD specifically. METHODS In a naturalistic cohort of consecutive out-patients and healthy controls, sAA and SC were determined in 833 participants (97 MDD patients, 142 patients with other mood, anxiety, and/or somatoform (MAS-) disorders, and 594 healthy controls). Samples were collected at 7 different time points (at awakening, after 30, 45, and 60 min, at 10:00 p.m., at 11:00 p.m., and at awakening on day 2). RESULTS The mean age of the sample was 43.8 years (SD = 12.9; 63.9% female). Concerning sAA, MDD patients had higher sAA levels upon awakening on two consecutive days (p = 0.04, p = 0.01 respectively), as well as a higher area under the curve with respect to the increase (AUCi; p = 0.04) in comparison to both controls and the other MAS-disorders group. Regarding SC, mean levels of evening SC were elevated in MDD patients (p = 0.049) in comparison to both controls and the other MAS-disorders group. SC values on day 2 after ingestion of dexamethasone were elevated in both MDD patients and the other MAS-disorders group (p = 0.04, p = 0.047 respectively). CONCLUSIONS sAA at awakening and not cortisol differentiates MDD from other psychiatric disorders in outpatients. This suggests that sAA may be a valuable candidate biomarker specifically for MDD.

Diurnal salivary alpha-amylase and not cortisol differentiates major depressive disorder in out-patients

Introduction To date, there are few putative biomarkers specifically for MDD. Such biomarkers could help improve our understanding of MDD pathophysiology, and aid in the refinement of current MDD criteria. Research has shown that the stress hormone cortisol in saliva, a non-invasive marker of hypothalamus pituitary adrenal (HPA) axis activity, can differentiate between healthy controls and patients with psychiatric disorders on a group level. Another interesting system for putative biomarkers is the autonomic nervous system (ANS). Animal studies have indicated the involvement of the ANS, and specifically the sympathetic nervous system (SNS) in the release of the enzyme alpha amylase in saliva (sAA), whereby sAA has been proposed to be an index of sympathoadrenal medullary (SAM) activity. This theory is based on the premise that the (para-)sympathetic branches of the autonomic nervous system innervate salivary glands, whereby sympathetic stimulation increases salivary protein secretion [1]. In line with these findings, sAA has been positively correlated with the acute SNS stress response in adults [2]. Many studies have since demonstrated that MDD patients generally have higher sAA in comparison to healthy controls within experimental settings [i.e.3]. However, what remains unknown is the natural diurnal sAA profile of MDD patients in comparison to patients with other psychiatric disorders and healthy controls. Aims To determine the diurnal profiles of sAA and salivary cortisol in out-patients with MDD, patients with other affective disorders, and healthy controls. Methods sAA and salivary cortisol levels were determined from 7 saliva samples collected over the course of the day from 833 participants that partook in our Routine Outcome Monitoring [4] measurement (i.e., 97 MDD patients, 142 patients with other psychiatric problems, and 594 controls). ANOCVAs were conducted to examine the differences in both diurnal sAA and salivary cortisol between the MDD patient group, the other psychiatric disorder group, and healthy controls. In this, covariates were entered into the model in accordance with factors that have been found to be influential on these markers in previous research. Results On average, MDD patients had higher sAA levels upon awakening and (Area under the Curve) AUCi in comparison to both controls and patients with other psychiatric problems. Elevated evening cortisol levels were found in MDD patients in comparison to both controls and patients with other psychiatric problems. Cortisol values in MDD patients and patients with other psychiatric problems were higher after ingestion of dexamethasone upon awakening on day 2. Conclusion sAA levels were found to be higher in MDD patients at awakening and with respect to the AUCi, whereas no time-point measured indicated elevated sAA levels in the other affective disorders group or the healthy controls. Salivary cortisol was unable to differentiate between MDD and other affective disorders as successfully as sAA, suggesting that sAA levels at awakening may have stronger differentiating qualities for MDD specifically.

EPA-1204 – Stressful life events in bipolar i and ii disorder: cause or consequence of mood symptoms?

Objective To examine whether positive and negative life events precede bipolar mood symptoms or whether bipolar mood symptoms precede life events in bipolar I and bipolar II outpatients. Method 173 bipolar outpatients with a diagnosis of bipolar disorder type 1 (BD I) or 2 (BD II) were assessed every three months for a total of two years. Life events were assessed by Paykels self-report questionnaire. The NIMH monthly retrospective life chart method (LCM-r) was used to assess monthly functional impairment due to manic or depressive symptomatology. Mood symptoms were assessed every six months with the Quick Inventory of Depressive Symptomatology- Self Report (QIDS) and the Young Mania Rating Scale (YMRS). Results Multilevel regression analyses (linear mixed-models) showed that negative life events are significantly associated with both subsequent severity of mania and depressive symptoms and functional impairment, whereas positive life events only preceded functional impairment due to manic symptoms and mania severity. These associations were significantly stronger in BD I patients compared to BD II patients. For the opposite temporal direction, we found that mania symptoms preceded the occurrence of positive life events and depressive symptoms preceded negative life events. Conclusions Life events appear to precede the occurrence of mood symptoms and functional impairment, and this association is stronger in BD I patients. Mood symptoms also precede the occurrence of life event, but no differences were found between BD I and II patients.

O-59 - Baseline individual depressive symptoms predict naturalistic outcome in depressive disorders: the leiden routine outcome monitoring study

Introduction Being able to predict a chronic course in depressive disorders is highly relevant for clinicians. Naturalistic studies on clinical predictors at symptom level are scarce. Objectives and aims To investigate the predictive value of individual depressive symptoms measured with the widely used Beck Depression Inventory self-report scale (BDI-II) on naturalistic outcome (remission/response; measured on the observer-rated Montgomery Asberg Depression Rating Scale [MADRS]) in a large cohort of depressive outpatients in a psychiatry outpatient setting. Methods We used a cohort of 1489 adult patients aged 18–65 years with MDD or dysthymic disorder established with the MINI-Plus diagnostic interview. All patients had a Routine Outcome Monitoring (ROM) baseline measurement in 2004–2009, with a maximum of two years of follow-up. We used multivariable Cox regression models to predict remission and response measured on the MADRS, and adjusted for clinical and demographic characteristics that had been identified as correlates of outcome in earlier studies. Results Of the 21 BDI-II items, the symptoms pessimism and loss of energy independently predicted non-remission and non-response. For pessimism, the HRs for remission and response were 0.81 (95% CI: 0.73–0.89, P Conclusions These findings in a naturalistic treatment setting may help clinicians to identify depressive patients at risk for an unfavourable outcome.

FC15-04 - The leiden routine outcome monitoring study

Introduction It is likely that’real-life patients’ differ from randomized controlled trial (RCT) patients and from non-treatment seeking populations. However, much of what is known about characteristics of patients with depression and anxiety is based on RCTs and studies in the general population. Data on’naturalistic’ or’real-life patients’ are scarce. Objectives & aims In several studies so far, we investigated specific characteristics of patients with depression and anxiety in routine psychiatric specialty care. We studied gender differences in depression, and differences in age of onset of depression. Another study aimed to establish predictors for deliberate self-harm and suicidal ideation (DSHI) in patients with depression and anxiety. Methods We used baseline data of the Routine Outcome Monitoring (ROM) study. From 2004–2007, 3798 patients had been routinely assessed with ROM, by specially trained nurses. ROM consists of both self report and observational instruments. Results Female patients with depression reported more severe complaints on self-report instruments, as well as worse general health. Observational instruments showed no differences. In addition, patients with depression onset before the age of 18 reported more current suicidality and previous suicide attempts. Finally, low education, being unmarried, comorbidity, more severe symptoms of anxiety and depression, and emotional instability were independent predictors of DSHI. Conclusions Our findings in naturalistic outpatients differed from previous findings based on RCTs and studies in the general population. Since our findings are based on routinely obtained measurements in treatment seeking patients, these data may reflect the phenomenology of real life patients more closely.