Effective connectivity between deep brain stimulation targets in individuals with treatment-resistant depression

The therapeutic effect of deep brain stimulation on patients with treatment-resistant depression is strongly dependent on the connectivity of the stimulation region with other regions associated with depression. The aims of this study are to characterize the effective connectivity between the brain regions playing important roles in depression and further investigate the underlying pathophysiological mechanisms of treatment-resistant depression and the mechanisms involving deep brain stimulation. Thirty-three individuals with treatment-resistant depression and 29 healthy control subjects were examined. All subjects underwent resting-state functional MRI scanning. The coupling parameters reflecting the causal interactions among deep brain stimulation targets and medial prefrontal cortex were estimated using spectral dynamic causal modelling. Our results showed that compared to the healthy control subjects, in the left hemisphere of treatment-resistant depression patients, the nucleus accumbens was inhibited by the inferior thalamic peduncle and excited the ventral caudate and the subcallosal cingulate gyrus, which in turn excited the lateral habenula. In the right hemisphere, the lateral habenula inhibited the ventral caudate and the nucleus accumbens, both of which inhibited the inferior thalamic peduncle, which in turn inhibited the cingulate gyrus. The ventral caudate excited the lateral habenula and the cingulate gyrus, which excited the medial prefrontal cortex. Furthermore, these effective connectivity links varied between males and females, and the left and right hemispheres. Our findings suggest that intrinsic excitatory/inhibitory connections between deep brain stimulation targets are impaired in treatment-resistant depression patients, and that these connections are sex dependent and hemispherically lateralized. This knowledge can help to better understand the underlying mechanisms of treatment-resistant depression, and along with tractography, structural imaging, and other relevant clinical information, may assist to determine the appropriate region for deep brain stimulation therapy in each treatment-resistant depression patient.