Brain Structure and Function

, Volume 224, Issue 2, pp 779–793 | Cite as

Asymmetric effective connectivity between primate anterior cingulate and lateral prefrontal cortex revealed by electrical microstimulation

  • Verónica NácherEmail author
  • Seyed Alireza Hassani
  • Thilo WomelsdorfEmail author
Original Article


The dorsal anterior cingulate cortex (dACC) and lateral prefrontal cortex (lPFC) of the non-human primate show neural firing correlations and synchronize at theta and beta frequencies during the monitoring and shifting of attention. These functional interactions might be based on synaptic connectivity that is equally efficacious in both directions, but it might be that there are systematic asymmetries in connectivity consistent with reports of more effective inhibition within the dACC than lPFC, or with a preponderance of dACC projections synapsing onto inhibitory neurons in the lPFC. Here, we tested effective dACC-lPFC connectivity in awake monkeys and report systematic asymmetries in the temporal patterning and latencies of effective connectivity as measured using electrical microstimulation. We found that dACC stimulation-triggered evoked fields (EFPs) were more likely to be multiphasic in the lPFC than in the reverse direction, with a large proportion of connections showing 2–4 inflection points resembling resonance in the 20–30 Hz beta frequency range. Stimulation of dACC → lPFC resulted, on average, in shorter-latency EFPs than lPFC → dACC. Overall, latencies and connectivity strength varied more than twofold depending on the precise anterior-to-posterior location of the connections. These findings reveal systematic asymmetries in effective connectivity between dACC and lPFC in the awake non-human primate and document the spatial and temporal patchiness of effective synaptic connections. We discuss that our results suggest that measuring effective connectivity profiles will be essential for understanding how asymmetries in local synaptic efficacy and connectivity translate into functional neuronal interactions during adaptive, goal-directed behavior.


Anterior cingulate cortex Lateral prefrontal cortex Effective connectivity Electrical stimulation Cortical mapping Monkey 



This work was supported by a grant from the Canadian Institutes of Health Research (T.W.). CIHR Grant MOP_102482. The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of this manuscript. The authors would like to thank Hongying Wang for technical support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal care and experimental procedures performed in this study have been approved by the local ethics committee, the York University Council on Animal Care, were in accordance with the Canadian Council on Animal Care guidelines, and are in agreement with the 1964 Helsinki Declaration and its later amendments.


  1. Alexander WH, Brown JW (2011) Medial prefrontal cortex as an action-outcome predictor. Nat Neurosci 14:1338–1344CrossRefPubMedPubMedCentralGoogle Scholar
  2. Arikuni T, Sako H, Murata A (1994) Ipsilateral connections of the anterior cingulate cortex with the frontal and medial temporal cortices in the macaque monkey. Neurosci Res 21:19–39CrossRefPubMedGoogle Scholar
  3. Barbas H (2015) General cortical and special prefrontal connections: principles from structure to function. Annu Rev Neurosci 38:269–289CrossRefPubMedGoogle Scholar
  4. Barbas H, Pandya DN (1989) Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. J Comp Neurol 286:353–375CrossRefPubMedGoogle Scholar
  5. Barbas H, Rempel-Clower N (1997) Cortical structure predicts the pattern of corticocortical connections. Cereb Cortex 7:635–646CrossRefPubMedGoogle Scholar
  6. Barbas H, Hilgetag CC, Saha S, Dermon CR, Suski JL (2005) Parallel organization of contralateral and ipsilateral prefrontal cortical projections in the rhesus monkey. BMC Neurosci 6:32CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bastos AM, Loonis R, Kornblith S, Lundqvist M, Miller EK (2018) Laminar recordings in frontal cortex suggest distinct layers for maintenance and control of working memory. Proc Natl Acad Sci USA 115:1117–1122CrossRefPubMedGoogle Scholar
  8. Buzsaki G, Anastassiou CA, Koch C (2012) The origin of extracellular fields and currents—EEG, ECoG, LFP and spikes. Nat Rev Neurosci 13:407–420CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cavada C, Company T, Tejedor J, Cruz-Rizzolo RJ, Reinoso-Suarez F (2000) The anatomical connections of the macaque monkey orbitofrontal cortex. A review. Cereb Cortex 10:220–242CrossRefPubMedGoogle Scholar
  10. DiCarlo JJ, Lane JW, Hsiao SS, Johnson KO (1996) Marking microelectrode penetrations with fluorescent dyes. J Neurosci Methods 64:75–81CrossRefPubMedGoogle Scholar
  11. Dombrowski SM, Hilgetag CC, Barbas H (2001) Quantitative architecture distinguishes prefrontal cortical systems in the rhesus monkey. Cereb Cortex 11:975–988CrossRefPubMedGoogle Scholar
  12. Ekstrom LB, Roelfsema PR, Arsenault JT, Bonmassar G, Vanduffel W (2008) Bottom-up dependent gating of frontal signals in early visual cortex. Science 321:414–417CrossRefPubMedPubMedCentralGoogle Scholar
  13. Elston GN, Benavides-Piccione R, Defelipe J (2005) A study of pyramidal cell structure in the cingulate cortex of the macaque monkey with comparative notes on inferotemporal and primary visual cortex. Cereb Cortex 15:64–73CrossRefPubMedGoogle Scholar
  14. Elston GN, Benavides-Piccione R, Elston A, Manger PR, Defelipe J (2011) Pyramidal cells in prefrontal cortex of primates: marked differences in neuronal structure among species. Front Neuroanat 5:2CrossRefPubMedPubMedCentralGoogle Scholar
  15. Field CB, Johnston K, Gati JS, Menon RS, Everling S (2008) Connectivity of the primate superior colliculus mapped by concurrent microstimulation and event-related fMRI. PLoS One 3:e3928CrossRefPubMedPubMedCentralGoogle Scholar
  16. Gabbott PL, Bacon SJ (1996) Local circuit neurons in the medial prefrontal cortex (areas 24a,b,c, 25 and 32) in the monkey: II. Quantitative areal and laminar distributions. J Compar Neurol 364:609–636CrossRefGoogle Scholar
  17. Garcia-Cabezas MA, Joyce MKP, John YJ, Zikopoulos B, Barbas H (2017) Mirror trends of plasticity and stability indicators in primate prefrontal cortex. Eur J Neurosci 46:2392–2405CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gloveli T, Dugladze T, Saha S, Monyer H, Heinemann U, Traub RD, Whittington MA, Buhl EH (2005) Differential involvement of oriens/pyramidale interneurones in hippocampal network oscillations in vitro. J Physiol 562:131–147CrossRefPubMedGoogle Scholar
  19. Goldman PS, Nauta WJ (1977) An intricately patterned prefronto-caudate projection in the rhesus monkey. J Compar Neurol 72:369–386CrossRefGoogle Scholar
  20. Hahn G, Bujan AF, Fregnac Y, Aertsen A, Kumar A (2014) Communication through resonance in spiking neuronal networks. PLoS Comput Biol 10:e1003811CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hayden BY, Heilbronner SR, Pearson JM, Platt ML (2011) Surprise signals in anterior cingulate cortex: neuronal encoding of unsigned reward prediction errors driving adjustment in behavior. J Neurosci 31:4178–4187CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hutcheon B, Yarom Y (2000) Resonance, oscillation and the intrinsic frequency preferences for neurons. Trends Neurosci 23:216–222CrossRefPubMedGoogle Scholar
  23. Hutchison RM, Womelsdorf T, Gati JS, Leung LS, Menon RS, Everling S (2012) Resting-state connectivity identifies distinct functional networks in macaque cingulate cortex. Cereb Cortex 22:1294–1308CrossRefPubMedGoogle Scholar
  24. Kennerley SW, Walton ME, Behrens TE, Buckley MJ, Rushworth MF (2006) Optimal decision making and the anterior cingulate cortex. Nat Neurosci 9:940–947CrossRefPubMedGoogle Scholar
  25. Klausberger T, Roberts JD, Somogyi P (2002) Cell type- and input-specific differences in the number and subtypes of synaptic GABA(A) receptors in the hippocampus. J Neurosci 22:2513–2521CrossRefPubMedGoogle Scholar
  26. Klausberger T, Marton LF, O’Neill J, Huck JH, Dalezios Y, Fuentealba P, Suen WY, Papp E, Kaneko T, Watanabe M et al (2005) Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations. J Neurosci 25:9782–9793CrossRefPubMedGoogle Scholar
  27. Kopell N, Börgers C, Pervouchine D, Malerba P, Tort AB (2010) Gamma and theta rhythms in biophysical models of hippocampal circuits. In: Cutsuridis V, Graham BF, Cobb S, Vida I (eds) Hippocampal microcircuits: a computational modeller’s resource book. Springer, New York, pp 423–457CrossRefGoogle Scholar
  28. Logothetis NK, Eschenko O, Murayama Y, Augath M, Steudel T, Evrard HC, Besserve M, Oeltermann A (2012) Hippocampal-cortical interaction during periods of subcortical silence. Nature 491:547–553CrossRefPubMedGoogle Scholar
  29. Lu MT, Preston JB, Strick PL (1994) Interconnections between the prefrontal cortex and the premotor areas in the frontal lobe. J Comp Neurol 341:375–392CrossRefPubMedGoogle Scholar
  30. Matsui T, Tamura K, Koyano KW, Takeuchi D, Adachi Y, Osada T, Miyashita Y (2011) Direct comparison of spontaneous functional connectivity and effective connectivity measured by intracortical microstimulation: An fMRI study in macaque monkeys. Cereb Cortex 21:2348–2356CrossRefPubMedGoogle Scholar
  31. McIntyre CC, Grill WM (2000) Selective microstimulation of central nervous system neurons. Ann Biomed Eng 28:219–233CrossRefPubMedGoogle Scholar
  32. Medalla M, Barbas H (2009) Synapses with inhibitory neurons differentiate anterior cingulate from dorsolateral prefrontal pathways associated with cognitive control. Neuron 61:609–620CrossRefPubMedPubMedCentralGoogle Scholar
  33. Medalla M, Barbas H (2010) Anterior cingulate synapses in prefrontal areas 10 and 46 suggest differential influence in cognitive control. J Neurosci 30:16068–16081CrossRefPubMedPubMedCentralGoogle Scholar
  34. Medalla M, Gilman JP, Wang JY, Luebke JI (2017) Strength and diversity of inhibitory signaling differentiates primate anterior cingulate from lateral prefrontal cortex. J Neurosci 37:4717–4734CrossRefPubMedPubMedCentralGoogle Scholar
  35. Moeller S, Freiwald WA, Tsao DY (2008) Patches with links: a unified system for processing faces in the macaque temporal lobe. Science 320:1355–1359CrossRefPubMedGoogle Scholar
  36. Montgomery EB (2010) Deep brain stimulation programming: principles and practice. Oxford University Press, OxfordGoogle Scholar
  37. Morecraft RJ, Stilwell-Morecraft KS, Cipolloni PB, Ge J, McNeal DW, Pandya DN (2012) Cytoarchitecture and cortical connections of the anterior cingulate and adjacent somatomotor fields in the rhesus monkey. Brain Res Bull 87:457–4997CrossRefPubMedPubMedCentralGoogle Scholar
  38. Ness TV, Remme MWH, Einevoll GT (2016) Active subthreshold denditric conductances shape the local field potential. J Physiol 594:3809–3825CrossRefPubMedPubMedCentralGoogle Scholar
  39. Ninomiya T, Dougherty K, Godlove DC, Schall JD, Maier A (2015) Microcircuitry of agranular frontal cortex: contrasting laminar connectivity between occipital and frontal areas. J Neurophysiol 113:3242–3255CrossRefPubMedPubMedCentralGoogle Scholar
  40. Nyiri G, Freund TF, Somogyi P (2001) Input-dependent synaptic targeting of alpha(2)-subunit-containing GABA(A) receptors in synapses of hippocampal pyramidal cells of the rat. Eur J Neurosci 13:428–442CrossRefPubMedGoogle Scholar
  41. Oemisch M, Westendorff S, Everling S, Womelsdorf T (2015) Interareal spike-train correlations of anterior cingulate and dorsal prefrontal cortex during attention shifts. J Neurosci 35:13076–13089CrossRefPubMedGoogle Scholar
  42. Paxinos G, Huang XF, Petrides M, Toga AW (2008) The rhesus monkey brain in stereotaxic coordinates. Academic Press, LondonGoogle Scholar
  43. Premereur E, Van Dromme IC, Romero MC, Vanduffel W, Janssen P (2015) Effective connectivity of depth-structure-selective patches in the lateral bank of the macaque intraparietal sulcus. PLoS Biol 13:e1002072CrossRefPubMedPubMedCentralGoogle Scholar
  44. Rothe M, Quilodran R, Sallet J, Procyk E (2011) Coordination of high gamma activity in anterior cingulate and lateral prefrontal cortical areas during adaptation. J Neurosci 31:11110–11117CrossRefPubMedGoogle Scholar
  45. Rushworth MF, Noonan MP, Boorman ED, Walton ME, Behrens TE (2011) Frontal cortex and reward-guided learning and decision making. Neuron 70:1054–1069CrossRefPubMedGoogle Scholar
  46. Shenhav A, Cohen JD, Botvinick MM (2016) Dorsal anterior cingulate cortex and the value of control. Nat Neurosci 19:1286–1291CrossRefPubMedGoogle Scholar
  47. Tolias AS, Sultan F, Augath M, Oeltermann A, Tehovnik EJ, Schiller PH, Logothetis NK (2005) Mapping cortical activity elicited with electrical microstimulation using fMRI in the macaque. Neuron 48:901–911CrossRefPubMedGoogle Scholar
  48. Tort AB, Rotstein HG, Dugladze T, Gloveli T, Kopell NJ (2007) On the formation of gamma-coherent cell assemblies by oriens lacunosum-moleculare interneurons in the hippocampus. Proc Natl Acad Sci USA 104:13490–13495CrossRefPubMedGoogle Scholar
  49. Voloh B, Womelsdorf T (2017) Cell-type specific burst firing interacts with theta and beta activity in prefrontal cortex during attention states. Cereb Cortex 1–17Google Scholar
  50. Voloh B, Valiante TA, Everling S, Womelsdorf T (2015) Theta–gamma coordination between anterior cingulate and prefrontal cortex indexes correct attention shifts. Proc Natl Acad Sci USA 112:8457–8462CrossRefPubMedGoogle Scholar
  51. Wallace J, Jackson RK, Shotton TL, Munjal I, McQuade R, Gartside SE (2014) Characterization of electrically evoked field potentials in the medial prefrontal cortex and orbitofrontal cortex of the rat: modulation by monoamines. Eur Neuropsychopharmacol 24:321–332CrossRefPubMedGoogle Scholar
  52. Womelsdorf T, Everling S (2015) Long-range attention networks: circuit motifs underlying endogenously controlled stimulus selection. Trends Neurosci 38:682–700CrossRefPubMedGoogle Scholar
  53. Womelsdorf T, Ardid S, Everling S, Valiante TA (2014a) Burst firing synchronizes prefrontal and anterior cingulate cortex during attentional control. Curr Biol 24:2613–2621CrossRefPubMedGoogle Scholar
  54. Womelsdorf T, Valiante TA, Sahin NT, Miller KJ, Tiesinga P (2014b) Dynamic circuit motifs underlying rhythmic gain control, gating and integration. Nat Neurosci 17:1031–1039CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Vision ResearchYork UniversityTorontoCanada
  2. 2.Department of PsychologyVanderbilt UniversityNashvilleUSA

Personalised recommendations