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Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making

Nature Neuroscience volume 15, pages 776–785 (2012)Cite this article

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Abstract

The pregenual anterior cingulate cortex (pACC) has been implicated in human anxiety disorders and depression, but the circuit-level mechanisms underlying these disorders are unclear. In healthy individuals, the pACC is involved in cost-benefit evaluation. We developed a macaque version of an approach-avoidance decision task used to evaluate anxiety and depression in humans and, with multi-electrode recording and cortical microstimulation, we probed pACC function as monkeys performed this task. We found that the macaque pACC has an opponent process-like organization of neurons representing motivationally positive and negative subjective value. Spatial distribution of these two neuronal populations overlapped in the pACC, except in one subzone, where neurons with negative coding were more numerous. Notably, microstimulation in this subzone, but not elsewhere in the pACC, increased negative decision-making, and this negative biasing was blocked by anti-anxiety drug treatment. This cortical zone could be critical for regulating negative emotional valence and anxiety in decision-making.

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Figure 1: Task procedures and recording regions.
Figure 2: Behavioral patterns.
Figure 3: Classification of units recorded in the pACC region.
Figure 4: Activity profiles of pACC units.
Figure 5: Distributions of pACC units classified by the correlation analyses.
Figure 6: Effects of pACC microstimulation on decision-making.
Figure 7: Distribution and dynamics of stimulations affecting decision-making.
Figure 8: Evidence suggesting potential negative affective state changes induced by microstimulation.

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References

  1. Lewin, K.Z. A Dynamic Theory of Personality (McGraw-Hill, New York, 1935).

  2. Miller, N.E. Selected Papers on Conflict, Displacement, Learned Drives and Theory (Aldine Atherton, Chicago, 1971).

  3. Elliot, A.J. Handbook of Approach and Avoidance Motivation (Psychology Press, New York, 2008).

  4. Elliot, A.J. & Thrash, T.M. Approach-avoidance motivation in personality: approach and avoidance temperaments and goals. J. Pers. Soc. Psychol. 82, 804–818 (2002).

    Article  Google Scholar 

  5. Millan, M.J. The neurobiology and control of anxious states. Prog. Neurobiol. 70, 83–244 (2003).

    Article  CAS  Google Scholar 

  6. Dickson, J.M. Perceived consequences underlying approach goals and avoidance goals in relation to anxiety. Pers. Individ. Dif. 41, 1527–1538 (2006).

    Article  Google Scholar 

  7. Dickson, J.M. & MacLeod, A.K. Approach and avoidance goals and plans: their relationship to anxiety and depression. Cognit. Ther. Res. 28, 415–432 (2004).

    Article  Google Scholar 

  8. Ottenbreit, N.D. & Dobson, K.S. Avoidance and depression: the construction of the cognitive-behavioral avoidance scale. Behav. Res. Ther. 42, 293–313 (2004).

    Article  Google Scholar 

  9. Vogel, J.R., Beer, B. & Clody, D.E. A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21, 1–7 (1971).

    Article  CAS  Google Scholar 

  10. Rowlett, J.K., Lelas, S., Tornatzky, W. & Licata, S.C. Anti-conflict effects of benzodiazepines in rhesus monkeys: relationship with therapeutic doses in humans and role of GABAA receptors. Psychopharmacology (Berl.) 184, 201–211 (2006).

    Article  CAS  Google Scholar 

  11. Treit, D. Animal models for the study of anti-anxiety agents: a review. Neurosci. Biobehav. Rev. 9, 203–222 (1985).

    Article  CAS  Google Scholar 

  12. Kennerley, S.W., Dahmubed, A.F., Lara, A.H. & Wallis, J.D. Neurons in the frontal lobe encode the value of multiple decision variables. J. Cogn. Neurosci. 21, 1162–1178 (2009).

    Article  Google Scholar 

  13. Kennerley, S.W. & Wallis, J.D. Evaluating choices by single neurons in the frontal lobe: outcome value encoded across multiple decision variables. Eur. J. Neurosci. 29, 2061–2073 (2009).

    Article  Google Scholar 

  14. Hayden, B.Y. & Platt, M.L. Neurons in anterior cingulate cortex multiplex information about reward and action. J. Neurosci. 30, 3339–3346 (2010).

    Article  CAS  Google Scholar 

  15. Seo, H. & Lee, D. Temporal filtering of reward signals in the dorsal anterior cingulate cortex during a mixed-strategy game. J. Neurosci. 27, 8366–8377 (2007).

    Article  CAS  Google Scholar 

  16. Ito, S., Stuphorn, V., Brown, J.W. & Schall, J.D. Performance monitoring by the anterior cingulate cortex during saccade countermanding. Science 302, 120–122 (2003).

    Article  CAS  Google Scholar 

  17. Matsumoto, M., Matsumoto, K., Abe, H. & Tanaka, K. Medial prefrontal cell activity signaling prediction errors of action values. Nat. Neurosci. 10, 647–656 (2007).

    Article  CAS  Google Scholar 

  18. Hayden, B.Y., Pearson, J.M. & Platt, M.L. Fictive reward signals in the anterior cingulate cortex. Science 324, 948–950 (2009).

    Article  CAS  Google Scholar 

  19. Vogt, B.A. & Pandya, D.N. Cingulate cortex of the rhesus monkey. II. Cortical afferents. J. Comp. Neurol. 262, 271–289 (1987).

    Article  CAS  Google Scholar 

  20. Eblen, F. & Graybiel, A.M. Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. J. Neurosci. 15, 5999–6013 (1995).

    Article  CAS  Google Scholar 

  21. Ghashghaei, H.T., Hilgetag, C.C. & Barbas, H. Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. Neuroimage 34, 905–923 (2007).

    Article  CAS  Google Scholar 

  22. Tom, S.M., Fox, C.R., Trepel, C. & Poldrack, R.A. The neural basis of loss aversion in decision-making under risk. Science 315, 515–518 (2007).

    Article  CAS  Google Scholar 

  23. Croxson, P.L., Walton, M.E., O'Reilly, J.X., Behrens, T.E. & Rushworth, M.F. Effort-based cost-benefit valuation and the human brain. J. Neurosci. 29, 4531–4541 (2009).

    Article  CAS  Google Scholar 

  24. Talmi, D., Dayan, P., Kiebel, S.J., Frith, C.D. & Dolan, R.J. How humans integrate the prospects of pain and reward during choice. J. Neurosci. 29, 14617–14626 (2009).

    Article  CAS  Google Scholar 

  25. Bush, G., Luu, P. & Posner, M.I. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn. Sci. 4, 215–222 (2000).

    Article  CAS  Google Scholar 

  26. Etkin, A., Egner, T., Peraza, D.M., Kandel, E.R. & Hirsch, J. Resolving emotional conflict: a role for the rostral anterior cingulate cortex in modulating activity in the amygdala. Neuron 51, 871–882 (2006).

    Article  CAS  Google Scholar 

  27. Pizzagalli, D.A. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 36, 183–206 (2011).

    Article  Google Scholar 

  28. Fitzgerald, K.D. et al. Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder. Biol. Psychiatry 57, 287–294 (2005).

    Article  Google Scholar 

  29. Kasai, K. et al. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol. Psychiatry 63, 550–556 (2008).

    Article  Google Scholar 

  30. Goldstein, R.Z. et al. Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction. Proc. Natl. Acad. Sci. USA 106, 9453–9458 (2009).

    Article  CAS  Google Scholar 

  31. Mayberg, H.S. et al. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 8, 1057–1061 (1997).

    Article  CAS  Google Scholar 

  32. Pizzagalli, D. et al. Anterior cingulate activity as a predictor of degree of treatment response in major depression: evidence from brain electrical tomography analysis. Am. J. Psychiatry 158, 405–415 (2001).

    Article  CAS  Google Scholar 

  33. Mayberg, H.S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

    Article  CAS  Google Scholar 

  34. Padoa-Schioppa, C. & Assad, J.A. Neurons in the orbitofrontal cortex encode economic value. Nature 441, 223–226 (2006).

    Article  CAS  Google Scholar 

  35. Padoa-Schioppa, C. Neurobiology of economic choice: a good-based model. Annu. Rev. Neurosci. 34, 333–359 (2011).

    Article  CAS  Google Scholar 

  36. McFadden, D. Conditional logit analysis of qualitative choice behavior. in Frontiers in Econometrics (ed. Zarembka, P.) 105–142 (Academic Press, New York, 1974).

  37. Levy, I., Snell, J., Nelson, A.J., Rustichini, A. & Glimcher, P.W. Neural representation of subjective value under risk and ambiguity. J. Neurophysiol. 103, 1036–1047 (2010).

    Article  Google Scholar 

  38. Von Neumann, J & Morgenstern, O. Theory of Games and Economic Behavior (Princeton University Press, Princeton, 1947).

  39. Botvinick, M.M., Cohen, J.D. & Carter, C.S. Conflict monitoring and anterior cingulate cortex: an update. Trends Cogn. Sci. 8, 539–546 (2004).

    Article  Google Scholar 

  40. Machens, C.K., Romo, R. & Brody, C.D. Flexible control of mutual inhibition: a neural model of two-interval discrimination. Science 307, 1121–1124 (2005).

    Article  CAS  Google Scholar 

  41. Smith, W.K. The functional significance of the rostral cingular cortex as revealed by its responses to electrical excitation. J. Neurophysiol. 8, 241–255 (1945).

    Article  Google Scholar 

  42. Rudebeck, P.H., Buckley, M.J., Walton, M.E. & Rushworth, M.F. A role for the macaque anterior cingulate gyrus in social valuation. Science 313, 1310–1312 (2006).

    Article  CAS  Google Scholar 

  43. Vogt, B.A., Vogt, L., Farber, N.B. & Bush, G. Architecture and neurocytology of monkey cingulate gyrus. J. Comp. Neurol. 485, 218–239 (2005).

    Article  Google Scholar 

  44. Lee, D., Rushworth, M.F., Walton, M.E., Watanabe, M. & Sakagami, M. Functional specialization of the primate frontal cortex during decision making. J. Neurosci. 27, 8170–8173 (2007).

    Article  CAS  Google Scholar 

  45. Fujiyama, F. et al. Exclusive and common targets of neostriatofugal projections of rat striosome neurons: a single neuron-tracing study using a viral vector. Eur. J. Neurosci. 33, 668–677 (2011).

    Article  Google Scholar 

  46. Graybiel, A.M. Habits, rituals, and the evaluative brain. Annu. Rev. Neurosci. 31, 359–387 (2008).

    Article  CAS  Google Scholar 

  47. Rajakumar, N., Elisevich, K. & Flumerfelt, B.A. Compartmental origin of the striato-entopeduncular projection in the rat. J. Comp. Neurol. 331, 286–296 (1993).

    Article  CAS  Google Scholar 

  48. Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111–1115 (2007).

    Article  CAS  Google Scholar 

  49. Tye, K.M. et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471, 358 (2011).

    Article  CAS  Google Scholar 

  50. Paton, J.J., Belova, M.A., Morrison, S.E. & Salzman, C.D. The primate amygdala represents the positive and negative value of visual stimuli during learning. Nature 439, 865–870 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Amemori and M. Cantor for their help with animal training and surgical procedures, P. Tierney, H. Shimazu, T. Desrochers, J. Feingold and Y. Ninokura and H. Hall for their technical advice, and D. Pizzagalli, R. Desimone, K. Goosens, J. Goldberg, D. Pfaff and Y. Kubota for reading the manuscript in draft form. This work was supported by a US National Institutes of Health Javits Merit grant (R01 NS025529), the Office of Naval Research (N000140710903), the Lynn Diamond Fellowship of the National Parkinson Foundation and Mr. Ira J. Jaffe.

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  1. and Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Ken-ichi Amemori & Ann M Graybiel

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  1. Ken-ichi Amemori
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K.A. and A.M.G. designed the experiments and performed the surgeries. K.A. collected the data. K.A. and A.M.G. analyzed the data and wrote the manuscript.

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Correspondence to Ann M Graybiel.

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Amemori, Ki., Graybiel, A. Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making. Nat Neurosci 15, 776–785 (2012). https://doi.org/10.1038/nn.3088

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