Resilience is a crucial component of the success of complex biological systems. The importance of psychobiological resilience in human health is increasingly appreciated in contemporary medicine. Recent neuroscientific methodologic developments and findings are building on classic observations and starting to elucidate elements and mechanisms of resilience (Wu et al. Reference Wu, Feder, Cohen, Kim, Calderon, Charney and Mathe2013). The time is therefore ripe for a synthetic conceptual framework to guide and be refined by empirical work at the brain-mind interface. Kalisch et al. have put forth an impressive integration of ongoing work in the context of a clear model and approach that can advance care across the range of neuropsychiatric disorders, which produce tremendous suffering and constitute an enormous global disease burden.

The homeostatic systems that maintain functioning and success, despite adversity, have been refined over the course of evolution (Bernard Reference Bernard, Hoff, Guillemin and Guillemin L.1878/1974). Kalisch et al. provide a sophisticated overarching account of the functions, processes, and neural circuits involved. They also posit a key role for positive stimulus appraisal processes in shaping adaptive emotional responses to stressors. In so doing, they bring mechanistic focus to a potential fulcrum for optimizing mental health.

Two general aspects of their approach are notable from a psychiatric research agenda perspective. First, the perspective is transdiagnostic. This is timely and important; psychiatry is moving from a categorical, descriptive classification of disorders to a dimensional, biological approach (Cuthbert Reference Cuthbert2014b). Such an approach is more aligned with the rest of medicine, and it will permit the development of biomarkers and the identification of new disease mechanism-based subtypes of illness and subgroups of patients (Silbersweig Reference Silbersweig2013). Biomarkers will, in turn, allow the development of more-targeted therapeutics, as well as the development of predictors of which individual patients will respond to them.

Second, the approach represents a shift from a focus on understanding and reversing negative emotional-behavioral processes toward a (not mutually exclusive) focus on understanding and enhancing positive emotional-behavioral processes (Epstein et al. Reference Epstein, Pan, Kocsis, Yang, Butler, Chusid, Hochberg, Murrough, Strohmayer, Stern and Silbersweig2006). This not only provides new avenues for therapeutic development, but also is consonant with patients' desires to think in terms of maximizing health and well-being.

From a psychological perspective, the highlighting of the protective role of positive appraisal and reappraisal is consistent with current cognitive-behavioral therapy approaches that help patients identify maladaptive, negatively biased appraisal styles and learn skills to shift them toward more-objective, empowering styles (Smits et al. Reference Smits, Julian, Rosenfield and Powers2012).

From a behavioral, neuroscientific perspective, the top-down, prefrontal processes of cognitive appraisal, in the context of goals and experience, meet up with the bottom-up processes in the sensory, subcortical, and limbic processing stream that label the salience of stimuli, events, or experiences (Cutuli Reference Cutuli2014). This connectivity plays an important role in mediating motivation and response selection. Kalisch et al. perform a great service to the field by clarifying terms; by being specific about the mediating neuroanatomy at the sub-region level; and by developing a quantitative, testable resilience equation relating stressor load and mental problem burden, using measures, factors, interactions, and outcomes in a unified, probabilistic model.

From a behavioral, neuroscientific point of view, it is also notable and important that Kalisch et al. seek to identify common underlying and higher-level processes regulating resilience. Doing so makes evolutionary and neurodevelopmental sense, and it is consistent with physiological feed-forward and feedback mechanisms underlying homeostasis and allostasis, for acute and chronic stress (McEwen Reference McEwen2013). It also creates a path toward the development of new interventions, whether biological or cognitive-behavioral. In fact, current models of gene-environment interactions are incorporating epigenetics and synaptic plasticity (Desplats Reference Desplats and Antonelli2015), and they also provide temporally dynamic mechanisms by which emotional experience-dependent learning occurs, and by which either somatic or psychological interventions can modulate the relevant final common neural pathways to reduce maladaptive fear and stress responses or enhance safety responses, or both (Johansen et al. Reference Johansen, Cain, Ostroff and LeDoux2011).

Neurophysiologically, these processes may involve altering the balance between activation and inhibition; modifying response thresholds, magnitude, and duration; switching sets for approach and avoidance behaviors; and altering overall processing capacity and flexibility. Such processes may be automatic and unconscious or volitional. All of this is consistent with the brain's role in real-time integration of its two overarching functions – being the highest-order orchestrator of the changing internal milieu and needs of the organism, and mediating interactions with the changing contingencies of the external (including social) world (Mesulam Reference Mesulam2000; Rolls & Grabenhorst Reference Rolls and Grabenhorst2008).

Kalisch et al.'s metalevel, yet still granular, approach also can provide a foundation for screening capabilities that may be able to distinguish who will develop difficulties in the setting of adversity, trauma, abuse, or neglect. Such biological risk–resilience profiling is a prerequisite for trajectory-altering early intervention and for the ultimate goal – prevention of profound and potentially transgenerational mental and physical disease sequelae.