Neuroscientists have described a mechanism that is involved in the development of treatment-resistant depression. In experiments on marmosets, they showed that inhibition of the dorsolateral prefrontal cortex (dlPFC) leads to a decrease in motivation and an increase in anxiety, but the effect depends only on the left hemisphere. They then demonstrated how the dlPFC is connected to two areas of the subcallosal cingulate cortex and canceled the effect by injecting ketamine into one of these areas. The study was published in Science.
Transcranial magnetic stimulation of the dorsolateral prefrontal cortex (dlPFC), which is underactive in the disease, is used to treat treatment-resistant depression. This stimulation reduces symptoms of depression and anxiety and normalizes the hyperactivity of neurons in area 25 in the subcallosal cingulate cortex (scACC), which is characteristic of the disease. Stimulation of the part of the dlPFC that belongs to Brodmann area 46 works best: the activity of this area is negatively correlated with the activity of area 25. However, the mechanisms by which dlPFC and scACC interact remain unclear.
To figure this out, a team of scientists from the University of Cambridge, led by Christian M. Wood, conducted experiments with common marmosets (Callithrix jacchus). First, they assessed the motivation of six monkeys to press a button on a touchscreen to receive a milkshake as a reward. After each reward, the marmosets had to press the button more times than before to get the next milkshake. The scientists then chemogenetically inactivated the neurons in area 46. After this, the marmosets' motivation decreased: they stopped pressing the button earlier and, accordingly, received less of the milkshake. The speed of pressing and appetite did not change - the primates simply gave up faster.
Because similar motivational blunting had been previously observed with hyperactivity in area 25, the researchers injected ketamine, a drug used for anesthesia and sometimes to treat resistant depression, into the area. It blocked the motivational decline caused by inhibition of area 46 neurons. Areas 25 and 46 are connected by another region of the cingulate cortex, area 32: its neurons receive signals from area 46 and themselves project to area 25. Chemogenetic inactivation of area 32 neurons also reduced motivation in marmosets, and ketamine injected into area 25 reversed this effect. If the marmoset neurons were not inhibited, ketamine did not change their behavior.
The scientists then tested how the three fields were related to anxiety, which often accompanies depression, and transcranial stimulation of the dlPFC usually reduces it. Hyperactivity of field 25 is known to increase the sensitivity of marmosets to threats. To make them anxious, a stranger stood next to the cage for two minutes. In response, the animals froze and made anxious vocalizations. Chemogenetic inactivation of field 46 or 32 increased the anxiety response.
The scientists then checked for functional asymmetry and found that motivation and anxiety were affected by dysfunction of the dlPFC and scACC in the left hemisphere only. When the scientists inactivated area 46 on the left side only or on both sides, the marmosets became more anxious, but inactivation of the right area 46 did not affect the monkeys’ behavior. The same was true for motivation, but in this case the scientists affected the left area 32. This is consistent with the fact that left-sided transcranial stimulation of the dlPFC is more often used in the treatment of depression, apparently due to its greater effectiveness.
Thus, a functional network that regulates motivation and anxiety operates in the left hemisphere of marmosets. It includes the dorsolateral prefrontal cortex, related to area 46, and areas 25 and 32 in the subcallosal cingulate cortex. These data help to understand how symptoms of treatment-resistant depression develop and how transcranial stimulation and ketamine can reduce them.
Previously, scientists showed that a drug used to treat Parkinson's disease could help with treatment-resistant depression, but only in combination with antidepressants.
