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The value of clinical and translational neuroscience approaches to psychiatric illness

Published online by Cambridge University Press:  06 March 2019

Juyoen Hur
Affiliation:
Department of Psychology, University of Maryland, College Park, MD 20742. jhur1@umd.edurmtillma@umd.edu
Rachael M. Tillman
Affiliation:
Department of Psychology, University of Maryland, College Park, MD 20742. jhur1@umd.edurmtillma@umd.edu
Andrew S. Fox
Affiliation:
Department of Psychology, University of California, Davis, CA 95616. dfox@ucdavis.eduhttp://foxlab.ucdavis.edu California National Primate Research Center, University of California, Davis, CA 95616.
Alexander J. Shackman
Affiliation:
Department of Psychology, University of Maryland, College Park, MD 20742. jhur1@umd.edurmtillma@umd.edu Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD 20742. Maryland Neuroimaging Center, University of Maryland, College Park, MD 20742. shackman@umd.eduhttp://shackmanlab.org1

Abstract

Borsboom et al. confuse biological approaches with extreme biological reductionism and common-cause models of psychopathology. In muddling these concepts, they mistakenly throw the baby out with the bathwater. Here, we highlight recent work underscoring the unique value of clinical and translational neuroscience approaches for understanding the nature and origins of psychopathology and for developing improved intervention strategies.

Type
Open Peer Commentary
Copyright
Copyright © Cambridge University Press 2019 

Borsboom et al. conflate biological approaches to psychopathology with extreme biological reductionism and common-cause models of psychiatric illness. In fusing these three distinct ideas, Borsboom et al. use evidence against extreme reductionism and common causes to dismiss clinical and translational neuroscience – effectively throwing the baby out with the bathwater. But like the paper-and-pencil approaches favored by Borsboom et al., biological approaches do not necessitate either extreme reductionism or singular causes. And while mental illness is undeniably based in brains and genes (Geschwind & Flint Reference Geschwind and Flint2015; Turkheimer Reference Turkheimer1998), we agree with Borsboom et al. that biological interventions are not the only or even the best way of tackling every mental illness (Kendler Reference Kendler2012b; Lilienfeld Reference Lilienfeld2014; Miller Reference Miller2010). We also agree that psychopathology reflects the interaction of multiple contexts and causes – from molecular pathways to culture – with their relative importance varying across individuals, development, sexes, and disorders (Birnbaum & Weinberger Reference Birnbaum and Weinberger2017; Kendler Reference Kendler2012b; Shackman & Fox Reference Shackman and Fox2018).

The network framework championed by Borsboom et al. describes patterns among symptoms, but it fails to provide a deeper explanation – biological, cognitive, or computational – for where those patterns come from. With respect to risk and etiology, it focuses on symptoms, environmental factors (e.g., stress), and the connection strengths (covariance) among them. Although this framework can provide important new insights, it cannot explain why some individuals and their biological relatives are predisposed to experience specific symptoms in maladaptive ways or how environmental factors interact with particular symptoms to produce psychopathology. In contrast, biological approaches are beginning to do just that. For example:

  1. 1. Anxiety patients and individuals at risk for developing anxiety disorders show increased reactivity (Fox & Shackman, Reference Fox and Shackmanin press; Fox et al. Reference Fox, Oler, Shackman, Shelton, Raveendran, McKay, Converse, Alexander, Davidson, Blangero, Rogers and Kalin2015; Shackman et al. Reference Shackman, Tromp, Stockbridge, Kaplan, Tillman and Fox2016b) and aberrant functional connectivity in the extended amygdala (Birn et al. Reference Birn, Shackman, Oler, Williams, McFarlin, Rogers, Shelton, Alexander, Pine, Slattery, Davidson, Fox and Kalin2014).

  2. 2. Like the anxiety disorders, extended amygdala function is heritable (Fox et al. Reference Fox, Oler, Shackman, Shelton, Raveendran, McKay, Converse, Alexander, Davidson, Blangero, Rogers and Kalin2015; Reference Fox, Oler, Birn, Shackman, Alexander and Kalin2018), associated with specific molecular pathways (Fox et al. Reference Fox, Oler, Shelton, Nanda, Davidson, Roseboom and Kalin2012; Roseboom et al. Reference Roseboom, Nanda, Fox, Oler, Shackman, Shelton, Davidson and Kalin2014), and amplified by stress (Shackman et al. Reference Shackman, Tromp, Stockbridge, Kaplan, Tillman and Fox2016b).

  3. 3. Heightened amygdala reactivity confers risk for the development of future internalizing symptoms, particularly among those exposed to stress (Shackman et al. Reference Shackman, Tromp, Stockbridge, Kaplan, Tillman and Fox2016b).

  4. 4. Amygdala reactivity is amplified by exposure to the same kinds of stressors and psychological pathogens that can precipitate acute psychopathology (Shackman et al. Reference Shackman, Kaplan, Stockbridge, Tillman, Tromp, Fox and Gamer2016a; Shackman et al. Reference Shackman, Tromp, Stockbridge, Kaplan, Tillman and Fox2016b).

  5. 5. Anxiolytics transiently dampen amygdala reactivity (e.g., Del-Ben et al. Reference Del-Ben, Ferreira, Sanchez, Alves-Neto, Guapo, de Araujo and Graeff2012) and amygdala damage markedly reduces signs and symptoms of fear and anxiety in humans, monkeys, and rodents (Feinstein et al. Reference Feinstein, Adolphs, Damasio and Tranel2011; Oler et al. Reference Oler, Fox, Shackman, Kalin, Amaral and Adolphs2016).

  6. 6. Stimulation of the extended amygdala elicits subjective feelings of fear and anxiety in humans (Inman et al., Reference Inman, Bijanki, Bass, Gross, Hamann and Williein press) and heightened defensive responses to threat in monkeys (Kalin et al. Reference Kalin, Fox, Kovner, Riedel, Fekete, Roseboom, Tromp, Grabow, Olsen, Brodsky, McFarlin, Alexander, Emborg, Block, Fudge and Oler2016).

These observations motivate the hypothesis that circuits centered on the extended amygdala causally contribute to the development of maladaptive anxiety (Shackman et al. Reference Shackman, Kaplan, Stockbridge, Tillman, Tromp, Fox and Gamer2016a). Such observations are hardly limited to the amygdala and anxiety. Other work highlights the importance of ventral striatal circuits to anhedonia (Bewernick et al. Reference Bewernick, Kayser, Sturm and Schlaepfer2012; Greer et al. Reference Greer, Trujillo, Glover and Knutson2014; Nugent et al. Reference Nugent, Diazgranados, Carlson, Ibrahim, Luckenbaugh, Brutsche, Herscovitch, Drevets and Zarate2014; Pizzagalli Reference Pizzagalli2014; Schlaepfer et al. Reference Schlaepfer, Cohen, Frick, Kosel, Brodesser, Axmacher, Joe, Kreft, Lenartz and Sturm2008; Stringaris et al. Reference Stringaris, Vidal-Ribas Belil, Artiges, Lemaitre, Gollier-Briant, Wolke, Vulser, Miranda, Penttila, Struve, Fadai, Kappel, Grimmer, Goodman, Poustka, Conrod, Cattrell, Banaschewski, Bokde, Bromberg, Buchel, Flor, Frouin, Gallinat, Garavan, Gowland, Heinz, Ittermann, Nees, Papadopoulos, Paus, Smolka, Walter, Whelan, Martinot, Schumann and Paillere-Martinot2015).

In rejecting common-cause models, Borsboom et al. neglect evidence that uncorrelated and dissimilar disease phenotypes can reflect common substrates (Kotov et al. Reference Kotov, Krueger, Watson, Achenbach, Althoff, Bagby, Brown, Carpenter, Caspi, Clark, Eaton, Forbes, Forbush, Goldberg, Hasin, Hyman, Ivanova, Lynam, Markon, Miller, Moffitt, Morey, Mullins-Sweatt, Ormel, Patrick, Regier, Rescorla, Ruggero, Samuel, Sellbom, Simms, Skodol, Slade, South, Tackett, Waldman, Waszczuk, Widiger, Wright and Zimmerman2017; Zhu et al. Reference Zhu, Need, Petrovski and Goldstein2014), a pattern not readily explained by symptom-network models. Individual differences in amygdala metabolism, for example, are associated with both neuroendocrine and behavioral signs of anxiety – two phenotypes that are only weakly correlated with one another (Shackman et al. Reference Shackman, Fox, Oler, Shelton, Davidson and Kalin2013). Likewise, lesions and other perturbations of the amygdala produce coherent changes in a range of disease-relevant phenotypes – neuroendocrine activity, passive avoidance, vigilance, and anxious feelings – suggesting that the amygdala-centered circuits represent a common cause (but likely not the only one) for some (but certainly not all) key features of pathological anxiety (Feinstein et al. Reference Feinstein, Adolphs, Damasio and Tranel2011; Fox & Shackman, Reference Fox and Shackmanin press; Oler et al. Reference Oler, Fox, Shackman, Kalin, Amaral and Adolphs2016).

Mental illness imposes a staggering burden on global public health, and there is an urgent need to develop better treatments (Global Burden of Disease Collaborators 2016; U.S. Burden of Disease Collaborators 2018). Symptom-network treatment approaches represent, at best, incremental improvements over current clinical practice. Many, perhaps even most clinicians already focus more on symptoms and their interconnections than on DSM diagnoses and their myriad specifiers (e.g., Waszczuk et al. Reference Waszczuk, Zimmerman, Ruggero, Li, MacNamara, Weinberg, Hajcak, Watson and Kotov2017). In contrast to symptom-network approaches, recent biological research highlights the possibility of developing completely novel interventions, reducing heterogeneity in clinical trials, more efficiently matching patients to treatments (“stratified medicine”), and more accurately predicting clinical course (Drysdale et al. Reference Drysdale, Grosenick, Downar, Dunlop, Mansouri, Meng, Fetcho, Zebley, Oathes, Etkin, Schatzberg, Sudheimer, Keller, Mayberg, Gunning, Alexopoulos, Fox, Pascual-Leone, Voss, Casey, Dubin and Liston2017; Koutsouleris et al. Reference Koutsouleris, Kambeitz-Ilankovic, Ruhrmann, Rosen, Ruef, Dwyer, Paolini, Chisholm, Kambeitz, Haidl, Schmidt, Gillam, Schultze-Lutter, Falkai, Reiser, Riecher-Rössler, Upthegrove, Hietala, Salokangas, Pantelis, Meisenzahl, Wood, Beque, Brambilla and Borgwardt2018; Woo et al. Reference Woo, Chang, Lindquist and Wager2017). Ongoing genomics research represents one of the few feasible paths to identifying and prioritizing new molecular targets, a prerequisite for developing improved drugs (Evangelou et al. Reference Evangelou, Warren, Mosen-Ansorena, Mifsud, Pazoki, Gao and Caulfield2018; Gandal et al. Reference Gandal, Leppa, Won, Parikshak and Geschwind2016; Pankevich et al. Reference Pankevich, Altevogt, Dunlop, Gage and Hyman2014). In short, biological approaches afford opportunities for improving the lives of patients that go beyond those afforded by symptom-centric frameworks.

So where do we go from here? Borsboom et al. remind us that clinical and translational neuroscience has historically been oversold and under-delivered. (For a related perspective, see Gordon & Redish Reference Gordon, Redish, Redish and Gordon2016.) Billions of dollars have failed to uncover new assays or cures (Shackman & Fox Reference Shackman and Fox2018). Although Borsboom et al. tell us that this reflects the futility of biological reductionism, a growing number of neuroscientists – including the architects of the National Institute of Mental Health Research Domain Criteria (RDoC) – have concluded that past underperformance reflects limitations of DSM diagnoses, rather than any intrinsic limitation of biological approaches (Gordon & Redish Reference Gordon, Redish, Redish and Gordon2016; Kozak & Cuthbert Reference Kozak and Cuthbert2016). Categorical diagnoses pose several critical barriers to discovering the nature and origins of psychopathology, including rampant co-morbidity, low symptom specificity, marked disorder heterogeneity, and poor reliability (Conway et al. Reference Conway, Forbes, Forbush, Fried, Hallquist, Kotov, Mullins-Sweatt, Shackman, Skodol, South, Sunderland, Waszczuk, Zald, Afzali, Bornovalova, Carragher, Docherty, Jonas, Krueger, Patalay, Pincus, Tackett, Reininghaus, Waldman, Wright, Zimmerman, Bach, Bagby, Chmielewski, Cicero, Clark, Dalgleish, DeYoung, Hopwood, Ivanova, Latzman, Patrick, Ruggero, Samuel, Watson and Eaton2018; Fried & Nesse Reference Fried and Nesse2015; Galatzer-Levy & Bryant Reference Galatzer-Levy and Bryant2013; Hasin et al. Reference Hasin, Shmulewitz, Stohl, Greenstein, Aivadyan, Morita, Saha, Aharonovich, Jung, Zhang, Nunes and Grant2015; Kessler et al. Reference Kessler, Chiu, Demler and Walters2005; Olbert et al. Reference Olbert, Gala and Tupler2014; Regier et al. Reference Regier, Narrow, Clarke, Kraemer, Kuramoto, Kuhl and Kupfer2013; Watson & Stasik Reference Watson, Stasik, Richards and O'Hara2014). Addressing these problems requires that we focus on understanding the computational, cognitive, and biological bases of circumscribed symptoms or symptom clusters (e.g., anxiety, anhedonia). This “symptoms-not-syndromes” approach (Fried Reference Fried2015) would also align more naturally with mechanistic work in animals (Fox & Shackman, Reference Fox and Shackmanin press).

In conclusion, there is a real intellectual danger to adopting Borsboom et al.’s framework wholesale. Although symptom-network approaches are valuable, they steer us away from deeper explanations for why some individuals and their biological relatives are prone to particular symptoms. A more holistic approach – one that embraces both biological and non-biological approaches (e.g., assessing relations between symptom networks and neural circuits) – is likely to yield greater dividends for understanding the nature and bases of psychopathology and accelerate the development of improved interventions for patient suffering.

Acknowledgments

The commentary authors acknowledge assistance from K. DeYoung and L. Friedman. This work was supported by the University of California, Davis; University of Maryland, College Park; and National Institutes of Health (Grant numbers DA040717 and MH107444).

Footnotes

1.

This web address, http://shackmanlab.org, applies to 3 authors: Juyoen Hur, Rachael Tillman, and Alexander Shackman. Andrew Fox's different web address is given separately.

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