AbstractThe identification and understanding of resilience mechanisms holds potential for the development of mechanistically informed prevention and interventions in psychiatry. However, ...investigating resilience mechanisms is conceptually and methodologically challenging because resilience does not merely constitute the absence of disease-specific risk but rather reflects active processes that aid in the maintenance of physiological and psychological homeostasis across a broad range of environmental circumstances. In this conceptual review, we argue that the principle used in gene-by-environment interaction studies may help to unravel resilience mechanisms on different investigation levels. We present how this could be achieved by top-down designs that start with gene-by-environment interaction effects on disease phenotypes as well as by bottom-up approaches that start at the molecular level. We also discuss how recent technological advances may improve both top-down and bottom-up strategies.
Repetitive transcranial magnetic stimulation (rTMS) protocols increasingly use subgenual anterior cingulate cortex (sgACC) functional connectivity to individualize treatment targets. However, the ...efficacy of this approach is unclear, with conflicting findings and varying effect sizes across studies. Here, the authors investigated the effect of the stimulation site's functional connectivity with the sgACC (sgACC-StimFC) on treatment outcome to rTMS in 295 patients with major depression.
The reliability and accuracy of estimating sgACC functional connectivity were validated with data from individuals who underwent extensive functional MRI testing. Electric field modeling was used to analyze associations between sgACC-StimFC and clinical improvement using standardized assessments and to evaluate sources of heterogeneity.
An imputation-based method provided reliable and accurate sgACC functional connectivity estimates. Treatment responses weakly but robustly correlated with sgACC-StimFC (r=-0.16), but only when the stimulated cortex was identified using electric field modeling. Surprisingly, this association was driven by patients with strong global signal fluctuations stemming from a specific periodic respiratory pattern (r=-0.49).
Functional connectivity between the sgACC and the stimulated cortex was correlated with individual differences in treatment outcomes, but the association was weaker than those observed in previous studies and was accentuated in a subgroup of patients with distinct, respiration-related signal patterns in their scans. These findings indicate that in a large representative sample of patients with major depressive disorder, individual differences in sgACC-StimFC explained only ∼3% of the variance in outcomes, which may limit the utility of existing sgACC-based targeting protocols. However, these data also provide strong evidence for a true-albeit small-effect and highlight opportunities for incorporating additional functional connectivity measures to generate models of rTMS response with enhanced predictive power.
Transcranial magnetic stimulation (TMS) is used to treat multiple psychiatric and neurological conditions by manipulating activity in particular brain networks and circuits, but individual responses ...are highly variable. In clinical settings, TMS coil placement is typically based on either group average functional maps or scalp heuristics. Here, we found that this approach can inadvertently target different functional networks in depressed patients due to variability in their functional brain organization. More precise TMS targeting should be feasible by accounting for each patient’s unique functional neuroanatomy. To this end, we developed a targeting approach, termed targeted functional network stimulation (TANS). The TANS approach improved stimulation specificity in silico in 8 highly sampled patients with depression and 6 healthy individuals and in vivo when targeting somatomotor functional networks representing the upper and lower limbs. Code for implementing TANS and an example dataset are provided as a resource.
•Current TMS targeting approaches stimulate different functional networks across patients•A method for selective stimulation of patient-specific functional networks is introduced•Targeted functional network stimulation (TANS) improves stimulation specificity•Code for implementing TANS and an example dataset are provided as a public resource
Transcranial magnetic stimulation (TMS) is used to treat multiple psychiatric and neurological conditions by manipulating activity in particular brain networks and circuits. Lynch et al. demonstrate that more precise TMS targeting is possible by accounting for each patient’s unique functional neuroanatomy and cortical folding patterns using their method called targeted functional network stimulation (TANS).
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.
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 stressmodulates hemodynamic response properties as part of the physiological stress response and suggest that HRF indices could serve as endophenotype of stress-related disorders.
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 (t64 = 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.
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 additive effects. Here, we show that a cortisol response to the placement of an intravenous catheter attenuated reactivity to a subsequent psychosocial stress task on the neural, endocrine, autonomous, and subjective level.
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.
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.
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.
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.
Spatial targeting in transcranial magnetic stimulation protocols does not typically account for the idiosyncratic functional organization of individual human brains. Here, we provide a protocol for ...implementing targeted functional network stimulation (TANS), which accounts for each individual’s unique functional neuroanatomy and cortical folding patterns. Using an example dataset, we describe how to create a head model and estimate the best coil placement and stimulation intensity to minimize off-target effects.
For complete details on the use and execution of this protocol, please refer to Lynch et al. (2022).1
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•Protocol for selective stimulation of individual-specific functional networks•Improved stimulation specificity with atargeted functional network stimulation (TANS)•Code for implementing TANS with an example precision functional mapping dataset•Steps for finding the best coil placement and estimation of the optimal stimulation dose
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Spatial targeting in transcranial magnetic stimulation protocols does not typically account for the idiosyncratic functional organization of individual human brains. Here, we provide a protocol for implementing targeted functional network stimulation, which accounts for each individual’s unique functional neuroanatomy and cortical folding patterns. Using an example dataset, we describe how to create a head model and estimate the best coil placement and stimulation intensity to minimize off-target effects.
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.
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