Extended Figure 1. Mesocircuit theory for recovery of anterior forebrain function with CL/DTTm DBS in msTBI.
Schematic diagram illustrating mesocircuit model for alteration of function following coma and moderate to severe brain injury and restoration of function with CL/DTTm DBS27,54.
Left figure element: Healthy normative function of corticothalamic system. Projections of central lateral thalamic neurons to anterior forebrain mesocircuit and posterior medial complex27,54. CL co-activates frontal-parietal cortico-cortical connections and modulates their feed-forward and feedback connectivity via layer-specific effects within cortical columns20,54–56. CL specifically targets supragranular and infragranular cortical layers avoiding projections into the input layers23; these anatomical specializations support a proposed selective role in modulation of long-range corticocortical functional connectivity56. CL projections to the striatum strongly activate this structure via projections to medium spiny neurons, MSNs and act via AMPA receptors, whereas Cm-Pf afferents act via NMDA receptors22.
Middle figure element: msTBI produces widespread deafferentation of the corticothalamic system leading to loss of CL modulation of cortex and striatum27,54. Two major consequences of this down-regulation of CL output in combination with overall reduction of cerebral background activity are: 1) marked reduction in corticothalamic and corticostriatal outflow, 2) shut down of the medium spiny neuron output from striatum to globus pallidum interna (GPi) producing increased thalamic inhibition and further reduction of thalamocortical and thalamostriatal outflow. Collectively, these changes are proposed to exert a disproportionate impact on the anterior forebrain27,54.
Right figure element: CL/DTTm DBS is proposed to reverse the mesocircuit level effects of reduced corticothalamic, corticostriatal, and striato-pallidal output by direct overdrive pacing of CL output via the DTTm. This model for the effects of direct electrical stimulation of CL/DTTm in msTBI is supported by animal studies that demonstrate broad activation of the frontal cortex and striatum with CL electrical stimulation19,24,25. These and related studies further show that CL electrical stimulation modulates executive attention and arousal in intact24,25,57 and brain-injured rodents58, intact non-human primates19,29,52,59–61, and a human subject in the minimally conscious state28. Cortical evoked responses overlapping those observed here have been obtained in a human subject with CL DBS supporting the further generalizability of the findings28.