Assessing hypo-arousal during reward anticipation with pupillometry in patients with major depressive disorder: replication and correlations with anhedonia.

Major depressive disorder (MDD) is a devastating and heterogenous disorder for which there are no approved biomarkers in clinical practice. We recently identified anticipatory hypo-arousal indexed by pupil responses as a candidate mechanism subserving depression symptomatology. Here, we conducted a replication and extension study of these findings. We analyzed a replication sample of 40 unmedicated patients with a diagnosis of depression and 30 healthy control participants, who performed a reward anticipation task while pupil responses were measured. Using a Bayesian modelling approach taking measurement uncertainty into account, we could show that the negative correlation between pupil dilation and symptom load during reward anticipation is replicable within MDD patients, albeit with a lower effect size. Furthermore, with the combined sample of 136 participants (81 unmedicated depressed and 55 healthy control participants), we further showed that reduced pupil dilation in anticipation of reward is inversely associated with anhedonia items of the Beck Depression Inventory in particular. Moreover, using simultaneous fMRI, particularly the right anterior insula as part of the salience network was negatively correlated with depressive symptom load in general and anhedonia items specifically. The present study supports the utility of pupillometry in assessing noradrenergically mediated hypo-arousal during reward anticipation in MDD, a physiological process that appears to subserve anhedonia.

Free-viewing gaze patterns reveal a mood-congruency bias in MDD during an affective fMRI/eye-tracking task.

Major depressive disorder (MDD) has been related to abnormal amygdala activity during emotional face processing. However, a recent large-scale study (n = 28,638) found no such correlation, which is probably due to the low precision of fMRI measurements. To address this issue, we used simultaneous fMRI and eye-tracking measurements during a commonly employed emotional face recognition task. Eye-tracking provide high-precision data, which can be used to enrich and potentially stabilize fMRI readouts. With the behavioral response, we additionally divided the active task period into a task-related and a free-viewing phase to explore the gaze patterns of MDD patients and healthy controls (HC) and compare their respective neural correlates. Our analysis showed that a mood-congruency attentional bias could be detected in MDD compared to healthy controls during the free-viewing phase but without parallel amygdala disruption. Moreover, the neural correlates of gaze patterns reflected more prefrontal fMRI activity in the free-viewing than the task-related phase. Taken together, spontaneous emotional processing in free viewing might lead to a more pronounced mood-congruency bias in MDD, which indicates that combined fMRI with eye-tracking measurement could be beneficial for our understanding of the underlying psychopathology of MDD in different emotional processing phases.Trial Registration: The BeCOME study is registered on ClinicalTrials (gov: NCT03984084) by the Max Planck Institute of Psychiatry in Munich, Germany.

Stress-induced brain responses are associated with BMI in women.

Overweight and obesity are associated with altered stress reactivity and increased inflammation. However, it is not known whether stress-induced changes in brain function scale with BMI and if such associations are driven by peripheral cytokines. Here, we investigate multimodal stress responses in a large transdiagnostic sample using predictive modeling based on spatio-temporal profiles of stress-induced changes in activation and functional connectivity. BMI is associated with increased brain responses as well as greater negative affect after stress and individual response profiles are associated with BMI in females (pperm < 0.001), but not males. Although stress-induced changes reflecting BMI are associated with baseline cortisol, there is no robust association with peripheral cytokines. To conclude, alterations in body weight and energy metabolism might scale acute brain responses to stress more strongly in females compared to males, echoing observational studies. Our findings highlight sex-dependent associations of stress with differences in endocrine markers, largely independent of peripheral inflammation.

Data-Driven Pupil Response Profiles as Transdiagnostic Readouts for the Detection of Neurocognitive Functioning in Affective and Anxiety Disorders.

BACKGROUND: Neurocognitive functioning is a relevant transdiagnostic dimension in psychiatry. As pupil size dynamics track cognitive load during a working memory task, we aimed to explore if this parameter allows identification of psychophysiological subtypes in healthy participants and patients with affective and anxiety disorders. METHODS: Our sample consisted of 226 participants who completed the n-back task during simultaneous functional magnetic resonance imaging and pupillometry measurements. We used latent class growth modeling to identify clusters based on pupil size in response to cognitive load. In a second step, these clusters were compared on affective and anxiety symptom levels, performance in neurocognitive tests, and functional magnetic resonance imaging activity. RESULTS: The clustering analysis resulted in two distinct pupil response profiles: one with a stepwise increasing pupil size with increasing cognitive load (reactive group) and one with a constant pupil size across conditions (nonreactive group). A larger increase in pupil size was significantly associated with better performance in neurocognitive tests in executive functioning and sustained attention. Statistical maps of parametric modulation of pupil size during the n-back task showed the frontoparietal network in the positive contrast and the default mode network in the negative contrast. The pupil response profile of the reactive group was associated with more thalamic activity, likely reflecting better arousal upregulation and less deactivation of the limbic system. CONCLUSIONS: Pupil measurements have the potential to serve as a highly sensitive psychophysiological readout for detection of neurocognitive deficits in the core domain of executive functioning, adding to the development of valid transdiagnostic constructs in psychiatry.

Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience.

Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic (Fkbp5Nex) and GABAergic (Fkbp5Dlx) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.

Startle Latency as a Potential Marker for Amygdala-Mediated Hyperarousal.

BACKGROUND: Fear-related disorders are characterized by hyperexcitability in reflexive circuits and maladaptive associative learning mechanisms. The startle reflex is suited to investigate both processes, either by probing it under baseline conditions or by deriving it in fear conditioning studies. In anxiety research, the amplitude of the fear-potentiated startle has been shown to be influenced by amygdalar circuits and has typically been the readout of interest. In schizophrenia research, prolonged startle peak latency under neutral conditions is an established readout, thought to reflect impaired processing speed. We therefore explored whether startle latency is an informative readout for human anxiety research. METHODS: We investigated potential similarities and differences of startle peak latency and amplitude derived from a classical fear conditioning task in a sample of 206 participants with varying severity levels of anxiety disorders and healthy control subjects. We first reduced startle response to stable components and regressed individual amygdala gray matter volumes onto the resulting startle measures. We then probed time, stimulus, and group effects of startle latency. RESULTS: We showed that startle latency and startle amplitude were 2 largely uncorrelated measures; startle latency, but not amplitude, showed a sex-specific association with gray matter volume of the amygdala; startle latencies showed a fear-dependent task modulation; and patients with fear-related disorders displayed shorter startle latencies throughout the fear learning task. CONCLUSIONS: These data provide support for the notion that probing startle latencies under threat may engage amygdala-modulated threat processing, making them a complementary marker for human anxiety research.

Non-REM sleep in major depressive disorder.

Disturbed sleep is a key symptom in major depressive disorder (MDD). REM sleep alterations are well described in the current literature, but little is known about non-REM sleep alterations. Additionally, sleep disturbances relate to a variety of cognitive symptoms in MDD, but which features of non-REM sleep EEG contribute to this, remains unknown. We comprehensively analyzed non-REM sleep EEG features in two central channels in three independently collected datasets (N = 284 recordings of 216 participants). This exploratory and descriptive study included MDD patients with a broad age range, varying duration and severity of depression, unmedicated or medicated, age- and gender-matched to healthy controls. We explored changes in sleep architecture including sleep stages and cycles, spectral power, sleep spindles, slow waves (SW), and SW-spindle coupling. Next, we analyzed the association of these sleep features with acute measures of depression severity and overnight consolidation of procedural memory. Overall, no major systematic alterations in non-REM sleep architecture were found in patients compared to controls. For the microstructure of non-REM sleep, we observed a higher spindle amplitude in unmedicated patients compared to controls, and after the start of antidepressant medication longer SWs with lower amplitude and a more dispersed SW-spindle coupling. In addition, long-term, but not short-term medication seemed to lower spindle density. Overnight procedural memory consolidation was impaired in medicated patients and associated with lower sleep spindle density. Our results suggest that alterations of non-REM sleep EEG in MDD might be more subtle than previously reported. We discuss these findings in the context of antidepressant medication intake and age.

Why do mice squeak? Toward a better understanding of defensive vocalization.

Although mice mostly communicate in the ultrasonic range, they also emit audible calls. We demonstrate that mice selectively bred for high anxiety-related behavior (HAB) have a high disposition for emitting sonic calls when caught by the tail. The vocalization was unrelated to pain but sensitive to anxiolytics. As revealed by manganese-enhanced MRI, HAB mice displayed an increased tonic activity of the periaqueductal gray (PAG). Selective inhibition of the dorsolateral PAG not only reduced anxiety-like behavior but also completely abolished sonic vocalization. Calls were emitted at a fundamental frequency of 3.8 kHz, which falls into the hearing range of numerous predators. Indeed, playback of sonic vocalization attracted rats if associated with a stimulus mouse. If played back to HAB mice, sonic calls were repellent in the absence of a conspecific but attractive in their presence. Our data demonstrate that sonic vocalization attracts both predators and conspecifics depending on the context.

Spatiotemporal Dynamics of Stress-Induced Network Reconfigurations Reflect Negative Affectivity.

BACKGROUND: Maladaptive stress responses are important risk factors in the etiology of mood and anxiety disorders, but exact pathomechanisms remain to be understood. Mapping individual differences of acute stress-induced neurophysiological changes, especially on the level of neural activation and functional connectivity (FC), could provide important insights in how variation in the individual stress response is linked to disease risk. METHODS: Using an established psychosocial stress task flanked by two resting states, we measured subjective, physiological, and brain responses to acute stress and recovery in 217 participants with and without mood and anxiety disorders. To estimate blockwise changes in stress-induced activation and FC, we used hierarchical mixed-effects models based on denoised time series within predefined stress-related regions. We predicted inter- and intraindividual differences in stress phases (anticipation vs. stress vs. recovery) and transdiagnostic dimensions of stress reactivity using elastic net and support vector machines. RESULTS: We identified four subnetworks showing distinct changes in FC over time. FC but not activation trajectories predicted the stress phase (accuracy = 70%, pperm < .001) and increases in heart rate (R2 = 0.075, pperm < .001). Critically, individual spatiotemporal trajectories of changes across networks also predicted negative affectivity (ΔR2 = 0.075, pperm = .030) but not the presence or absence of a mood and anxiety disorder. CONCLUSIONS: Spatiotemporal dynamics of brain network reconfiguration induced by stress reflect individual differences in the psychopathology dimension of negative affectivity. These results support the idea that vulnerability for mood and anxiety disorders can be conceptualized best at the level of network dynamics, which may pave the way for improved prediction of individual risk.

Pupillometry tracks cognitive load and salience network activity in a working memory functional magnetic resonance imaging task.

The diameter of the human pupil tracks working memory processing and is associated with activity in the frontoparietal network. At the same time, recent neuroimaging research has linked human pupil fluctuations to activity in the salience network. In this combined functional magnetic resonance imaging (fMRI)/pupillometry study, we recorded the pupil size of healthy human participants while they performed a blockwise organized working memory task (N-back) inside an MRI scanner in order to monitor the pupil fluctuations associated neural activity during working memory processing. We first confirmed that mean pupil size closely followed working memory load. Combining this with fMRI data, we focused on blood oxygen level dependent (BOLD) correlates of mean pupil size modeled onto the task blocks as a parametric modulation. Interrogating this modulated task regressor, we were able to retrieve the frontoparietal network. Next, to fully exploit the within-block dynamics, we divided the blocks into 1 s time bins and filled these with corresponding pupil change values (first-order derivative of pupil size). We found that pupil change within N-back blocks was positively correlated with BOLD amplitudes in the areas of the salience network (namely bilateral insula, and anterior cingulate cortex). Taken together, fMRI with simultaneous measurement of pupil parameters constitutes a valuable tool to dissect working memory subprocesses related to both working memory load and salience of the presented stimuli.

Myo-Inositol Levels in the Dorsal Hippocampus Serve as Glial Prognostic Marker of Mild Cognitive Impairment in Mice.

Dementia is a devastating age-related disorder. Its therapy would largely benefit from the identification of susceptible subjects at early, prodromal stages of the disease. To search for such prognostic markers of cognitive impairment, we studied spatial navigation in male BALBc vs. B6N mice in combination with in vivo magnetic resonance spectroscopy (1H-MRS). BALBc mice consistently showed higher escape latencies than B6N mice, both in the Water Cross Maze (WCM) and the Morris water maze (MWM). These performance deficits coincided with higher levels of myo-inositol (mIns) in the dorsal hippocampus before and after training. Subsequent biochemical analyses of hippocampal specimens by capillary immunodetection and liquid chromatography mass spectrometry-based (LC/MS) metabolomics revealed a higher abundance of glial markers (IBA-1, S100B, and GFAP) as well as distinct alterations in metabolites including a decrease in vitamins (pantothenic acid and nicotinamide), neurotransmitters (acetylcholine), their metabolites (glutamine), and acetyl-L-carnitine. Supplementation of low abundant acetyl-L-carnitine via the drinking water, however, failed to revert the behavioral deficits shown by BALBc mice. Based on our data we suggest (i) BALBc mice as an animal model and (ii) hippocampal mIns levels as a prognostic marker of mild cognitive impairment (MCI), due to (iii) local changes in microglia and astrocyte activity, which may (iv) result in decreased concentrations of promnesic molecules.

Structural correlates of trauma-induced hyperarousal in mice.

Post-traumatic stress disorder (PTSD) is a chronic disease caused by traumatic incidents. Numerous studies have revealed grey matter volume differences in affected individuals. The nature of the disease renders it difficult to distinguish between a priori versus a posteriori changes. To overcome this difficulty, we studied the consequences of a traumatic event on brain morphology in mice before and 4 weeks after exposure to brief foot shocks (or sham treatment), and correlated morphology with symptoms of hyperarousal. In the latter context, we assessed hyperarousal upon confrontation with acoustic, visual, or composite (acoustic/visual/tactile) threats and integrated the individual readouts into a single Hyperarousal Score using logistic regression analysis. MRI scans with subsequent whole-brain deformation-based morphometry (DBM) analysis revealed a volume decrease of the dorsal hippocampus and an increase of the reticular nucleus in shocked mice when compared to non-shocked controls. Using the Hyperarousal Score as regressor for the post-exposure MRI measurement, we observed negative correlations with several brain structures including the dorsal hippocampus. If the development of changes with respect to the basal MRI was considered, reduction in globus pallidus volume reflected hyperarousal severity. Our findings demonstrate that a brief traumatic incident can cause volume changes in defined brain structures and suggest the globus pallidus as an important hub for the control of fear responses to threatening stimuli of different sensory modalities.

Lack of FKBP51 Shapes Brain Structure and Connectivity in Male Mice.

BACKGROUND: Stress exposure as well as psychiatric disorders are often associated with abnormalities in brain structure or connectivity. The co-chaperone FK506-binding protein 51 (FKBP51) is a regulator of the stress system and is associated with a risk to develop stress-related mental illnesses. PURPOSE: To assess the effect of a general FKBP51 knockout on brain structure and connectivity in male mice. STUDY TYPE: Animal study. ANIMAL MODEL: Two cohorts of FKBP51 knockout (51KO) and wildtype (WT) mice. The first cohort was comprised of n = 18 WT and n = 17 51KOs; second cohort n = 10 WT and n = 9 51KOs. FIELD STRENGTH/SEQUENCE: 9.4T/3D gradient echo (VBM), DTI-EPI (DTI). ASSESSMENT: Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). For VBM, all procedures were executed in SPM12. DTI: FMRIB Software Library (FSL) Tract Based Statistics (TBSS) were integrated within DTI-TK, allowing the creation of a mean FA skeleton. A voxelwise statistical analysis was applied between WT and 51KO mice. STATISTICAL TEST: Volumetric differences were collected at a threshold of P < 0.005, and only clusters surviving a familywise error correction on the cluster level (pFWE, cluster <0.05) were further considered. VBM data were analyzed using a two-sample t-test. The Threshold Free Cluster Enhancement (TFCE) method was used to derive uncorrected-P statistical results at a P-level of 0.01. RESULTS: The structural analysis revealed two clusters of significantly larger volumes in the hypothalamus, periaqueductal gray, and dorsal raphe region of WT animals. DTI measurements, however, demonstrated statistically higher fractional anisotropy (FA) values for 51KO animals in locations including the anterior commissure, fornix, and posterior commissure/superior colliculus commissure region. DATA CONCLUSION: This study used in vivo structural MRI and DTI to demonstrate that a lack of FKBP51 leads to alterations in brain architecture and connectivity in male mice. These findings are of particular translational relevance for our understanding of the neuroanatomy underlying the interaction of FKBP5 genetic status, stress susceptibility, and psychiatric disorders. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Pupil Dilation during Reward Anticipation Is Correlated to Depressive Symptom Load in Patients with Major Depressive Disorder.

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the brain-physiological processes that are altered during depressive states are not well understood. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. We translated these findings to human subjects with concomitant pupillometry/fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls. We could show that the upregulation and maintenance of arousal in anticipation of reward was disrupted in patients in a symptom-load dependent manner. We could further show that the failure to maintain reward anticipatory arousal showed state-marker properties, as it tracked the load and impact of depressive symptoms independent of prior diagnosis status. Further, group differences of anticipatory arousal and continuous correlations with symptom load were not traceable only at the level of pupillometric responses, but were mirrored also at the neural level within salience network hubs. The upregulation and maintenance of arousal during reward anticipation is a novel translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification and targeted interventions.

Psychosocial stress reactivity habituates following acute physiological stress.

Acute and chronic stress are important factors in the development of mental disorders. Reliable measurement of stress reactivity is therefore pivotal. Critically, experimental induction of stress often involves multiple "hits" and it is an open question whether individual differences in responses to an earlier stressor lead to habituation, sensitization, or simple additive effects on following events. Here, we investigated the effect of the individual cortisol response to intravenous catheter placement (IVP) on subsequent neural, psychological, endocrine, and autonomous stress reactivity. We used an established psychosocial stress paradigm to measure the acute stress response (Stress) and recovery (PostStress) in 65 participants. Higher IVP-induced cortisol responses were associated with lower pulse rate increases during stress recovery (b = -4.8 bpm, p = .0008) and lower increases in negative affect after the task (b = -4.2, p = .040). While the cortisol response to IVP was not associated with subsequent specific stress-induced neural activation patterns, the similarity of brain responses Pre- and PostStress was higher IVP-cortisol responders (t[64] = 2.35, p = .022) indicating faster recovery. In conclusion, preparatory stress induced by IVP reduced reactivity in a subsequent stress task by modulating the latency of stress recovery. Thus, an individually stronger preceding release of cortisol may attenuate a second physiological response and perceived stress suggesting that relative changes, not absolute levels are crucial for stress attribution. Our study highlights that considering the entire trajectory of stress induction during an experiment is important to develop reliable individual biomarkers.

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).

Looping Star fMRI in Cognitive Tasks and Resting State.

BACKGROUND: Conventional T2 *-weighted functional magnetic resonance imaging (fMRI) is performed with echo-planar imaging (EPI) sequences that create substantial acoustic noise. The loud acoustic noise not only affects the activation of the auditory cortex, but may also interfere with resting state and task fMRI experiments. PURPOSE: To demonstrate the feasibility of a novel, quiet, T2 *, whole-brain blood oxygenation level-dependent (BOLD)-fMRI method, termed Looping Star, compared to conventional multislice gradient-echo EPI. STUDY TYPE: Prospective. PHANTOM/SUBJECTS: Glover stability QA phantom; 10 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3.0T: gradient echo (GE)-EPI and T2 * Looping Star fMRI. ASSESSMENT: Looping Star fMRI was presented and compared to GE-EPI with a working memory (WM) task and resting state (RS) experiments. Temporal stability and acoustic measurements were obtained for both methods. Functional maps and activation accuracy were compared to evaluate the performance of the novel sequence. STATISTICAL TESTS: Mean and standard deviation values were analyzed for temporal stability and acoustic noise tests. Activation maps were assessed with one-sample t-tests and contrast estimates (CE). Paired t-tests and receiver operator characteristic (ROC) were used to compare fMRI sensitivity and performance. RESULTS: Looping Star presented a 98% reduction in sound pressure compared with GE-EPI, with stable temporal stability (0.09% percent fluctuation), but reduced temporal signal-to-noise ratio (tSNR) (mean difference = 15.9%). The novel method yielded consistent activations for RS and WM (83.4% and 69.5% relative BOLD sensitivity), which increased with task difficulty (mean CE 2-back = 0.56 vs. 0-back = 0.08, P < 0.05). A few differences in spatial activations were found between sequences, leading to a 4-8% lower activation accuracy with Looping Star. DATA CONCLUSION: Looping Star provides a suitable approach for whole-brain coverage with sufficient spatiotemporal resolution and BOLD sensitivity, with only 0.5 dB above ambient noise. From the comparison with GE-EPI, further developments of Looping Star fMRI should target increased sensitivity and spatial specificity for both RS and task experiments. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:739-751.

The brain's hemodynamic response function rapidly changes under acute psychosocial stress in association with genetic and endocrine stress response markers.

Ample evidence links dysregulation of the stress response to the risk for psychiatric disorders. However, we lack an integrated understanding of mechanisms that are adaptive during the acute stress response but potentially pathogenic when dysregulated. One mechanistic link emerging from rodent studies is the interaction between stress effectors and neurovascular coupling, a process that adjusts cerebral blood flow according to local metabolic demands. Here, using task-related fMRI, we show that acute psychosocial stress rapidly impacts the peak latency of the hemodynamic response function (HRF-PL) in temporal, insular, and prefrontal regions in two independent cohorts of healthy humans. These latency effects occurred in the absence of amplitude effects and were moderated by regulatory genetic variants of KCNJ2, a known mediator of the effect of stress on vascular responsivity. Further, hippocampal HRF-PL correlated with both cortisol response and genetic variants that influence the transcriptional response to stress hormones and are associated with risk for major depression. We conclude that acute stress modulates hemodynamic response properties as part of the physiological stress response and suggest that HRF indices could serve as endophenotype of stress-related disorders.

In Vivo Visualization of Active Polysynaptic Circuits With Longitudinal Manganese-Enhanced MRI (MEMRI).

Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful tool for in vivo non-invasive whole-brain mapping of neuronal activity. Mn2+ enters active neurons via voltage-gated calcium channels and increases local contrast in T1-weighted images. Given the property of Mn2+ of axonal transport, this technique can also be used for tract tracing after local administration of the contrast agent. However, MEMRI is still not widely employed in basic research due to the lack of a complete description of the Mn2+ dynamics in the brain. Here, we sought to investigate how the activity state of neurons modulates interneuronal Mn2+ transport. To this end, we injected mice with low dose MnCl2 2. (i.p., 20 mg/kg; repeatedly for 8 days) followed by two MEMRI scans at an interval of 1 week without further MnCl2 injections. We assessed changes in T1 contrast intensity before (scan 1) and after (scan 2) partial sensory deprivation (unilateral whisker trimming), while keeping the animals in a sensory enriched environment. After correcting for the general decay in Mn2+ content, whole brain analysis revealed a single cluster with higher signal in scan 1 compared to scan 2: the left barrel cortex corresponding to the right untrimmed whiskers. In the inverse contrast (scan 2 > scan 1), a number of brain structures, including many efferents of the left barrel cortex were observed. These results suggest that continuous neuronal activity elicited by ongoing sensory stimulation accelerates Mn2+ transport from the uptake site to its projection terminals, while the blockage of sensory-input and the resulting decrease in neuronal activity attenuates Mn2+ transport. The description of this critical property of Mn2+ dynamics in the brain allows a better understanding of MEMRI functional mechanisms, which will lead to more carefully designed experiments and clearer interpretation of the results.

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.