Until the twentieth century, the study of cognition and emotion was largely a philosophical matter. But recent years have witnessed the emergence of powerful new tools for interrogating the brain and new areas of multidisciplinary research focused on identifying the neurobiological mechanisms underlying cognition, emotion, and their role in mental health and disease. In The Cognitive-Emotional Brain, Luiz Pessoa (Reference Pessoa2013) provides an authoritative perspective on this recent work and its implications for our understanding of the basic building blocks of the mind. Here, we highlight four of the book's most important implications for understanding neuropsychiatric disorders, including anxiety, schizophrenia, substance abuse, chronic pain, and autism. These disorders cause enormous suffering for millions of patients and their families, outstripping the global burden of cancer or cardiovascular disease (Collins et al. Reference Collins, Patel, Joestl, March, Insel, Daar, Anderson, Dhansay, Phillips, Shurin, Walport, Ewart, Savill, Bordin, Costello, Durkin, Fairburn, Glass, Hall, Huang, Hyman, Jamison, Kaaya, Kapur, Kleinman, Ogunniyi, Otero-Ojeda, Poo, Ravindranath, Sahakian, Saxena, Singer and Stein2011; Goldberg & McGee Reference Goldberg and McGee2011; Kessler et al. Reference Kessler, Petukhova, Sampson, Zaslavsky and Wittchen2012; Whiteford et al. Reference Whiteford, Degenhardt, Rehm, Baxter, Ferrari, Erskine, Charlson, Norman, Flaxman, Johns, Burstein, Murray and Vos2013). Notably, these disorders involve prominent alterations in both cognition and emotion (Millan et al. Reference Millan, Agid, Brune, Bullmore, Carter, Clayton, Connor, Davis, Deakin, DeRubeis, Dubois, Geyer, Goodwin, Gorwood, Jay, Joëls, Mansuy, Meyer-Lindenberg, Murphy, Rolls, Saletu, Spedding, Sweeney, Whittington and Young2012), pointing to the need for a deeper understanding of the cognitive-emotional brain.

First, The Cognitive-Emotional Brain reminds us that mental faculties emerge from the coordinated interactions of large-scale brain networks. Put simply, fear, reward, attention, and other psychological processes cannot be mapped to isolated brain regions because no one region is both necessary and sufficient. Conversely, similar symptoms can emerge from damage to different regions in the same functional network (Karnath & Smith Reference Karnath and Smith2014). Pain, which is among the most prevalent clinical disorders (Institute of Medicine 2011), nicely illustrates this point. Pain is a multidimensional experience, involving systematic changes in both cognition and emotion: painful stimuli elicit anxiety, capture attention, and motivate action. Neurobiologically, pain is associated with a complex pattern of regional activation, often termed the “pain matrix” (Iannetti et al. Reference Iannetti, Salomons, Moayedi, Mouraux and Davis2013). Stimulation of individual components of the pain matrix does not consistently elicit pain, suggesting that pain and its disorders are emergent properties of regional interactions. This is not a new or contentious idea; pioneers like Mesulam, Goldman-Rakic, and LeDoux highlighted the importance of distributed neural circuits more than two decades ago, and there is widespread agreement among basic and translational researchers (Bullmore & Sporns Reference Bullmore and Sporns2012; Fornito et al. Reference Fornito, Zalesky and Breakspear2015; Goldman-Rakic Reference Goldman-Rakic1988; LeDoux Reference LeDoux1995; Reference LeDoux2012; Mesulam Reference Mesulam1998; Turk-Browne, Reference Turk-Browne2013; Uhlhaas & Singer Reference Uhlhaas and Singer2012). The Cognitive-Emotional Brain is a bracing call for accelerating the transition from localization strategies (i.e., mapping brain structures to function; sometimes termed “neophrenology”) to a network-centered approach. From a clinical neuroscience perspective, this suggests that understanding neuropsychiatric disorders will require embracing the kinds of analytic tools (e.g., functional connectivity fingerprinting, graph theoretic and machine learning approaches) that are necessary for elucidating how psychological constructs and mental disorders are realized in brain circuits (Turk-Browne Reference Turk-Browne2013; Woo et al. Reference Woo, Koban, Kross, Lindquist, Banich, Ruzic, Andrews-Hanna and Wager2014).

Pessoa's second key conclusion is that the identity of brain functional networks, including the circuitry that underlies clinically relevant phenotypes, cannot be inferred from neuroanatomy alone. Pessoa makes it clear that the networks identified by functional magnetic resonance imaging (fMRI) and other neurophysiological techniques do not necessarily recapitulate the pattern of direct connections revealed by invasive anatomical tracing techniques. Indeed, there is ample evidence of robust functional connectivity between brain regions that lack direct structural connections (Adachi et al. Reference Adachi, Osada, Sporns, Watanabe, Matsui, Miyamoto and Miyashita2012; Birn et al. Reference Birn, Shackman, Oler, Williams, McFarlin, Rogers, Shelton, Alexander, Pine, Slattery, Davidson, Fox and Kalin2014; Honey et al. Reference Honey, Sporns, Cammoun, Gigandet, Thiran, Meuli and Hagmann2009; Vincent et al. Reference Vincent, Patel, Fox, Snyder, Baker, Van Essen, Zempel, Snyder, Corbetta and Raichle2007) and increasing evidence that regulatory signals can propagate across complex, indirect pathways (Ekstrom et al. Reference Ekstrom, Roelfsema, Arsenault, Bonmassar and Vanduffel2008). From a clinical perspective, this indicates that fMRI-derived measures of functional connectivity are particularly useful because they can be used to assay dysfunctional networks that encompass polysynaptically connected nodes (Birn et al. Reference Birn, Shackman, Oler, Williams, McFarlin, Rogers, Shelton, Alexander, Pine, Slattery, Davidson, Fox and Kalin2014), just as viral tracers can be used to delineate polysynaptic anatomical pathways in the nervous system (Dum et al. Reference Dum, Levinthal and Strick2009). More broadly, The Cognitive-Emotional Brain implies that many of the signs and symptoms of mental disorders – anhedonia, hypervigilance for threat, working memory impairments, drug seeking, and so on – will reflect complex brain circuits (Okon-Singer et al. Reference Okon-Singer, Hendler, Pessoa and Shackman2015; Seminowicz et al. Reference Seminowicz, Mayberg, McIntosh, Goldapple, Kennedy, Segal and Rafi-Tari2004; Shackman et al. Reference Shackman, Fox, Oler, Shelton, Davidson and Kalin2013; Stout et al. Reference Stout, Shackman and Larson2013).

The third key conclusion is that emotion and cognition are not different in kind but are instead deeply interwoven in the fabric of the brain. Subjectively, we often experience cognition and emotion as fundamentally different. Emotion is saturated with feelings of pleasure or pain and manifests in readily discerned changes in the body, whereas cognition often appears devoid of substantial hedonic, motivational, or somatic features. These apparent differences in phenomenological experience and peripheral physiology have led many scholars to treat emotion and cognition as categorically distinct, even oppositional, mental forces that presumably reflect the operation of segregated brain circuits (de Sousa Reference de Sousa and Zalta2014; Schmitter Reference Schmitter and Zalta2014). A similar dichotomy pervades psychiatric nosology. But careful scrutiny reveals contrary evidence; cognition can arouse the face and body; conversely, emotion can profoundly alter attention, working memory, and cognitive control (Grupe & Nitschke Reference Grupe and Nitschke2013; Okon-Singer et al. Reference Okon-Singer, Hendler, Pessoa and Shackman2015; Shackman et al. Reference Shackman, Salomons, Slagter, Fox, Winter and Davidson2011). The Cognitive-Emotional Brain provides a useful survey of recent brain imaging research demonstrating the integration of emotional and cognitive processes in the brain (Shackman et al. Reference Shackman, Salomons, Slagter, Fox, Winter and Davidson2011). Largely on the basis of brain imaging data, Pessoa joins with other theorists in rejecting claims that emotion and cognition are categorically different (Barrett & Satpute Reference Barrett and Satpute2013; Damasio 2005; Duncan & Barrett Reference Duncan and Barrett2007; Lindquist & Barrett Reference Lindquist and Barrett2012). Elucidating the contribution of the cognitive-emotional brain to psychopathology mandates the joint efforts of cognitive, affective, computational, and clinical neuroscientists. This kind of multidisciplinary research would refine our understanding of the mechanisms that give rise to “mixed” cognitive-emotional symptoms, such as hypervigilance or aberrant reinforcement learning (Cavanagh & Shackman Reference Cavanagh and Shackman2014), and provide novel targets for intervention.

Pessoa's fourth and most original conclusion is a powerful synthesis of the first three. Pessoa argues that widely held beliefs about the constituents of “the emotional brain” and “the cognitive brain” are fundamentally flawed. Regions such as the amygdala are not “emotional,” and regions such as the dorsolateral prefrontal cortex (dlPFC) are not “cognitive” (Birn et al. Reference Birn, Shackman, Oler, Williams, McFarlin, Rogers, Shelton, Alexander, Pine, Slattery, Davidson, Fox and Kalin2014; Buhle et al. Reference Buhle, Silvers, Wager, Lopez, Onyemekwu, Kober, Weber and Ochsner2014; Fox et al. Reference Fox, Oakes, Shelton, Converse, Davidson and Kalin2005; Shackman et al. Reference Shackman, McMenamin, Maxwell, Greischar and Davidson2009). Both regions play a central role in the regulation of adaptive behavior. This should not be surprising – the human brain did not evolve to optimize performance on artificial laboratory probes of “pure” cognition or emotion. Pessoa also makes it clear that brain regions can dynamically assume different roles. Just as an individual can perform psychologically distinct roles in different social networks (e.g., executive, mother, sister, daughter), brain regions are poised to perform a range of functions (a property termed functional “superimposition”) in different neural “contexts” corresponding to their level of participation in particular functional networks. To paraphrase Pearson and colleagues (Pearson et al. Reference Pearson, Watson and Platt2014), key brain regions, such as the orbitofrontal cortex, are functionally heterogeneous, with individual neurons dynamically multiplexed into different functional roles. As such, they will “evade a single, modular, functional role assignment” (p. 954). Our brain reflects evolutionary pressures that demanded distributed neural systems capable of using information about pleasure and pain, derived from stimuli saturated with hedonic and motivational significance, to adaptively regulate attention, learning, somatic mobilization, and action in the service of maximizing reproductive fitness. From this perspective, it is easy to imagine how dysfunction of circumscribed territories of the brain can have a deep impact on distal regions and circuits, as recent work by our group and others demonstrates (Fox & Kalin Reference Fox and Kalin2014; Fox et al. Reference Fox, Shelton, Oakes, Converse, Davidson and Kalin2010; Gratton et al. Reference Gratton, Nomura, Perez and D'Esposito2012). This may help to explain the co-occurrence of cognitive and emotional symptoms, as well as frequent comorbidities, among psychiatric and neurological disorders. Clarifying the nature of the cognitive-emotional brain is likely to have substantial benefits for our understanding of disorders marked by symptoms that blend elements of cognition and emotion (e.g., hypervigilance to potential threat or overgeneralization of threat, in the case of the anxiety disorders [Grupe & Nitschke Reference Grupe and Nitschke2013]).

Although many challenges remain, The Cognitive-Emotional Brain provides a road map to the most fruitful avenues for future research. One of the most important unresolved questions concerns the functional significance of regions activated by both cognitive and emotional challenges. For example, Pessoa highlights a recent meta-analysis from our group demonstrating that the elicitation of negative affect, pain, and cognitive control are all associated with activation in an overlapping region of the MCC (Shackman et al. Reference Shackman, Salomons, Slagter, Fox, Winter and Davidson2011). A key unresolved question is whether the MCC and other regions implicated in both cognitive and emotional processes, such as the anterior insula, perform a single general function (e.g., adaptive control [Cavanagh & Shackman, in press; Shackman et al. Reference Shackman, Salomons, Slagter, Fox, Winter and Davidson2011]) or salience detection (Iannetti et al. Reference Iannetti, Salomons, Moayedi, Mouraux and Davis2013) or multiple specific functions.

On a broader note, much of the evidence surveyed by Pessoa comes from the human brain imaging literature. Accordingly, his conclusions are ultimately tempered by questions about the origins and significance of the fMRI signal and the measures of functional connectivity that underlie network-centered approaches to understanding the cognitive-emotional brain (Akam & Kullmann Reference Akam and Kullmann2014; Cabral et al. Reference Cabral, Kringelbach and Deco2014; Logothetis Reference Logothetis2008). An important challenge for future studies will be to combine mechanistic techniques in animal models (e.g., optogenetics) with the same whole-brain imaging strategies routinely applied in humans (Birn et al. Reference Birn, Shackman, Oler, Williams, McFarlin, Rogers, Shelton, Alexander, Pine, Slattery, Davidson, Fox and Kalin2014; Borsook et al. Reference Borsook, Becerra and Hargreaves2006; Casey et al. Reference Casey, Craddock, Cuthbert, Hyman, Lee and Ressler2013; Narayanan et al. Reference Narayanan, Cavanagh, Frank and Laubach2013; Oler et al. Reference Oler, Birn, Patriat, Fox, Shelton, Burghy, Stodola, Essex, Davidson and Kalin2012; Roseboom et al. Reference Roseboom, Nanda, Fox, Oler, Shackman, Shelton, Davidson and Kalin2014). Combining noninvasive mechanistic techniques (e.g., transcranial magnetic stimulation or transcranial direct current stimulation) or pharmacological manipulations with fMRI provides another opportunity for understanding how circumscribed perturbations can produce distributed dysfunction (Chen et al. Reference Chen, Oathes, Chang, Bradley, Zhou, Williams, Glover, Deisseroth and Etkin2013; Guller et al. Reference Guller, Ferrarelli, Shackman, Sarasso, Peterson, Langheim, Meyerand, Tononi and Postle2012; Paulus et al. Reference Paulus, Feinstein, Castillo, Simmons and Stein2005; Reinhart & Woodman Reference Reinhart and Woodman2014).

For many disorders marked by cognitive and emotional disturbances, extant treatments are inconsistently effective or associated with significant adverse effects (e.g., Bystritsky Reference Bystritsky2006). The Cognitive-Emotional Brain provides an insightful survey of state of the science and a useful stimulus for the next generation of basic and clinical research, reminding us that we have a remarkable opportunity to use new tools for understanding brain function to discover the origins of neuropsychiatric disease.