Abstracts

Rationale: Anhedonia, defined as the loss of pleasurable responses to previously rewarding stimuli, characterizes severe depression and predicts suicidality in both psychiatric and neurological disorders. Stimulating the bed nucleus of the stria terminalis (BNST) in severely depressed patients can reverse anhedonia, although treatment variability and side effects have been reported. Although stimulation parameters are important, arguably a significant reason for response variability, the most difficult variable to manipulate post-surgically, likely involves the precise stimulation location within this complex and heterogeneous structure. Here, we hypothesized that limiting stimulation to the dorsal-anterior portion of the BNST (daBNST) will reverse anhedonic behavior in a rat model of temporal lobe epilepsy (TLE), in a manner that correlates with decreased seizure frequency and severity. We chose to study anhedonia in a TLE model, mainly due to the high rates of anhedonia, depression, and suicide in TLE patients, and the difficulty in treating such affective dysfunction, as well as comorbid seizures, in this population.


Methods: In naïve rats, we measured anhedonic behavior using the two-bottle-choice sucrose preference test, in which rats were given one-hour limited-access to one bottle containing a 1% sucrose solution and one bottle containing water. Rats demonstrating greater than 85% sucrose preference were included in the study. To induce the TLE model, we infused glutamine synthetase inhibitor (chemoconvulsant) into the central amygdaloid nucleus. We implanted recording screw electrodes subdurally, and stimulating electrodes bilaterally in either the daBNST or in surrounding regions. Following one week recovery from surgery, we resumed daily sucrose preference testing and recorded continuous video/encephalography to determine frequency and severity of seizures. Following one week of baseline recordings, rats received either electrical stimulation (30-70µA at 130 Hz, 2 second duration, square pulse, 30 minutes prior to sucrose preference testing) or sham stimulation (no current). Stimulation occurred daily over a one-week period.


Results: Prior to stimulation and following surgery, all rats seized and demonstrated a decrease in preference to chance levels (~ 50%). There was no correlation between sucrose preference and either seizure frequency or severity. Following baseline recordings, daBNST stimulation (n=8) revived sucrose preference to baseline levels, while neither sham stimulation (n=8), nor stimulation of adjacent regions (n=7) revived preference. In fact, sucrose preference continued to decrease in these control rats. Again, sucrose preference did not correlate with either seizure frequency or severity.

Conclusions: These results clarify the consistent effectiveness of selectively targeting the dorsal-anterior portion of the BNST to reverse anhedonic behavior, and suggest that, although interconnected, independent mechanisms may underlie seizures and anhedonia, and thus both may need to be treated separately to most effectively improve patient quality of life.

Funding: This work was supported by grants from the American Epilepsy Society and Yale University Swebilius Foundation.