The biological classification of mental disorders (BeCOME) study: a protocol for an observational deep-phenotyping study for the identification of biological subtypes.

BACKGROUND: A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of the identified (neuro) biological dysfunctions are "transdiagnostic", meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications. METHODS: BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques. DISCUSSION: The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses. TRIAL REGISTRATION: Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).

Disentangling reward anticipation with simultaneous pupillometry / fMRI.

The reward system may provide an interesting intermediate phenotype for anhedonia in affective disorders. Reward anticipation is characterized by an increase in arousal, and previous studies have linked the anterior cingulate cortex (ACC) to arousal responses such as dilation of the pupil. Here, we examined pupil dynamics during a reward anticipation task in forty-six healthy human subjects and evaluated its neural correlates using functional magnetic resonance imaging (fMRI). Pupil size showed a strong increase during monetary reward anticipation, a moderate increase during verbal reward anticipation and a decrease during control trials. For fMRI analyses, average pupil size and pupil change were computed in 1-s time bins during the anticipation phase. Activity in the ventral striatum was inversely related to the pupil size time course, indicating an early onset of activation and a role in reward prediction processing. Pupil dilations were linked to increased activity in the salience network (dorsal ACC and bilateral insula), which likely triggers an increase in arousal to enhance task performance. Finally, increased pupil size preceding the required motor response was associated with activity in the ventral attention network. In sum, pupillometry provides an effective tool for disentangling different phases of reward anticipation, with relevance for affective symptomatology.

Neural correlates of pupil dilation during human fear learning.

BACKGROUND: Fear conditioning and extinction are prevailing experimental and etiological models for normal and pathological anxiety. Pupil dilations in response to conditioned stimuli are increasingly used as a robust psychophysiological readout of fear learning, but their neural correlates remain unknown. We aimed at identifying the neural correlates of pupil responses to threat and safety cues during a fear learning task. METHODS: Thirty-four healthy subjects underwent a fear conditioning and extinction paradigm with simultaneous functional magnetic resonance imaging (fMRI) and pupillometry. After a stringent preprocessing and artifact rejection procedure, trial-wise pupil responses to threat and safety cues were entered as parametric modulations to the fMRI general linear models. RESULTS: Trial-wise magnitude of pupil responses to both conditioned and safety stimuli correlated positively with activity in dorsal anterior cingulate cortex (dACC), thalamus, supramarginal gyrus and insula for the entire fear learning task, and with activity in the dACC during the fear conditioning phase in particular. Phasic pupil responses did not show habituation, but were negatively correlated with tonic baseline pupil diameter, which decreased during the task. Correcting phasic pupil responses for the tonic baseline pupil diameter revealed thalamic activity, which was also observed in an analysis employing a linear (declining) time modulation. CONCLUSION: Pupil dilations during fear conditioning and extinction provide useful readouts to track fear learning on a trial-by-trial level, particularly with simultaneous fMRI. Whereas phasic pupil responses reflect activity in brain regions involved in fear learning and threat appraisal, most prominently in dACC, tonic changes in pupil diameter may reflect changes in general arousal.

Multi-echo EPI of human fear conditioning reveals improved BOLD detection in ventromedial prefrontal cortex.

Standard T2* weighted functional magnetic resonance imaging (fMRI) performed with echo-planar imaging (EPI) suffers from signal loss in the ventromedial prefrontal cortex (vmPFC) due to macroscopic field inhomogeneity. However, this region is of special interest to affective neuroscience and psychiatry. The Multi-echo EPI (MEPI) approach has several advantages over EPI but its performance against EPI in the vmPFC has not yet been examined in a study with sufficient statistical power using a task specifically eliciting activity in this region. We used a fear conditioning task with MEPI to compare the performance of MEPI and EPI in vmPFC and control regions in 32 healthy young subjects. We analyzed activity associated with short (12ms), standard (29ms) and long (46ms) echo times, and a voxel-wise combination of these three echo times. Behavioral data revealed successful differentiation of the conditioned versus safety stimulus; activity in the vmPFC was shown by the contrast "safety stimulus > conditioned stimulus" as in previous research and proved significantly stronger with the combined MEPI than standard single-echo EPI. Then, we aimed to demonstrate that the additional cluster extent (ventral extension) detected in the vmPFC with MEPI reflects activation in a relevant cluster (i.e., not just non-neuronal noise). To do this, we used resting state data from the same subjects to show that the time-course of this region was both connected to bilateral amygdala and the default mode network. Overall, we demonstrate that MEPI (by means of the weighted sum combination approach) outperforms standard EPI in vmPFC; MEPI performs always at least as good as the best echo time for a given brain region but provides all necessary echo times for an optimal BOLD sensitivity for the whole brain. This is relevant for affective neuroscience and psychiatry given the critical role of the vmPFC in emotion regulation.

Spontaneous pupil dilations during the resting state are associated with activation of the salience network.

Resting state functional magnetic resonance imaging (rs-fMRI) is increasingly applied for the development of functional biomarkers in brain disorders. Recent studies have revealed spontaneous vigilance drifts during the resting state, involving changes in brain activity and connectivity that challenge the validity of uncontrolled rs-fMRI findings. In a combined rs-fMRI/eye tracking study, the pupil size of 32 healthy subjects after 2h of sleep restriction was recorded as an indirect index for activity of the locus coeruleus, the brainstem's noradrenergic arousal center. The spontaneous occurrence of pupil dilations, but not pupil size per se, was associated with increased activity of the salience network, thalamus and frontoparietal regions. In turn, spontaneous constrictions of the pupil were associated with increased activity in visual and sensorimotor regions. These results were largely replicated in a sample of 36 healthy subjects who did not undergo sleep restriction, although in this sample the correlation between thalamus and pupil dilation fell below whole-brain significance. Our data show that spontaneous pupil fluctuations during rest are indeed associated with brain circuitry involved in tonic alertness and vigilance. Pupillometry is an effective method to control for changes in tonic alertness during rs-fMRI.

No robust differences in fear conditioning between patients with fear-related disorders and healthy controls.

Fear conditioning and extinction serve as a dominant model for the development and maintenance of pathological anxiety, particularly for phasic fear to specific stimuli or situations. The validity of this model would be supported by differences in the physiological or subjective fear response between patients with fear-related disorders and healthy controls, whereas the model's validity would be questioned by a lack of such differences. We derived pupillometry, skin conductance response and startle electromyography as well as unconditioned stimulus expectancy in a two-day fear acquisition, immediate extinction and recall task and compared an unmedicated group of patients (n = 73) with phobias or panic disorder and a group of patients with posttraumatic stress disorder (PTSD, n = 21) to a group of carefully screened healthy controls (n = 35). Bayesian statistics showed no convincing evidence for a difference in physiological and subjective responses between the groups during fear acquisition, extinction learning or recall. Only the PTSD subgroup had altered startle reactions during extinction learning. Our data do not provide evidence for general differences in associative fear or extinction learning in fear-related pathologies and thereby question the diagnostic validity of the associative fear learning model of these disorders.

Measuring the conditioned response: A comparison of pupillometry, skin conductance, and startle electromyography.

In human fear conditioning studies, different physiological readouts can be used to track conditioned responding during fear learning. Commonly employed readouts such as skin conductance responses (SCR) or startle responses have in recent years been complemented by pupillary readouts, but to date it is unknown how pupillary readouts relate to other measures of the conditioned response. To examine differences and communalities among pupil responses, SCR, and startle responses, we simultaneously recorded pupil diameter, skin conductance, and startle electromyography in 47 healthy subjects during fear acquisition, extinction, and a recall test on 2 consecutive days. The different measures correlated only weakly, displaying most prominent differences in their response patterns during fear acquisition. Whereas SCR and startle responses habituated, pupillary measures did not. Instead, they increased in response to fear conditioned stimuli and most closely followed ratings of unconditioned stimulus (US) expectancy. Moreover, we observed that startle-induced pupil responses showed stimulus discrimination during fear acquisition, suggesting a fear potentiation of the auditory pupil reflex. We conclude that different physiological outcome measures of the conditioned response inform about different cognitive-affective processes during fear learning, with pupil responses being least affected by physiological habituation and most closely following US expectancy.