Tractographic analysis of historical lesion surgery for depression.

Various surgical brain ablation procedures for the treatment of refractory depression were developed in the twentieth century. Most notably, key target sites were (i) the anterior cingulum, (ii) the anterior limb of the internal capsule, and (iii) the subcaudate white matter, which were regarded as effective targets. Long-term symptom remissions were better following lesions of the anterior internal capsule and subcaudate white matter than of the cingulum. It is possible that the observed clinical improvements of these various surgical procedures may reflect shared influences on presently unspecified brain affect-regulating networks. Such possibilities can now be analyzed using modern brain connectivity procedures such as diffusion tensor imaging (DTI) tractography. We determined whether the shared connectivities of the above lesion sites in healthy volunteers might explain the therapeutic effects of the various surgical approaches. Accordingly, modestly sized historical lesions, especially of the anatomical overlap areas, were 'implanted' in brain-MRI scans of 53 healthy subjects. These were entered as seed regions for probabilistic DTI connectivity reconstructions. We analyzed for the shared connectivities of bilateral anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, and stereotactic limbic leucotomy (a combination of the last two lesion sites). Shared connectivities between the four surgical approaches mapped onto the most mediobasal aspects of bilateral frontal lobe fibers, including the forceps minor and the anterior thalamic radiations that contacted subgenual cingulate regions. Anatomically, convergence of these shared connectivities may derive from the superolateral branch of the medial forebrain bundle (MFB), a structure that connects these frontal areas to the origin of the mesolimbic dopaminergic 'reward' system in the midbrain ventral tegmental area. Thus, all four surgical anti-depressant approaches may be promoting positive affect by converging influences onto the MFB.