Septohippocampal Neuromodulation Improves Cognition after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) often results in persistent attention and memory deficits that are associated with hippocampal dysfunction. Although deep brain stimulation (DBS) is used to treat neurological disorders related to motor dysfunction, the effectiveness of stimulation to treat cognition remains largely unknown. In this study, adult male Harlan Sprague-Dawley rats underwent a lateral fluid percussion or sham injury followed by implantation of bipolar electrodes in the medial septal nucleus (MSN) and ipsilateral hippocampus. In the first week after injury, there was a significant decrease in hippocampal theta oscillations that correlated with decreased object exploration and impaired performance in the Barnes maze spatial learning task. Continuous 7.7 Hz theta stimulation of the medial septum significantly increased hippocampal theta oscillations, restored normal object exploration, and improved spatial learning in injured animals. There were no benefits with 100 Hz gamma stimulation, and stimulation of sham animals at either frequency did not enhance performance. We conclude, therefore, that there was a theta frequency-specific benefit of DBS that restored cognitive function in brain-injured rats. These data suggest that septal theta stimulation may be an effective and novel neuromodulatory therapy for treatment of persistent cognitive deficits following TBI.

Keywords: cognition; deep brain stimulation; hippocampal theta oscillation; medial septal nucleus; traumatic brain injury.

Figures

FIG. 1.

(A) Atlas schematic of medial septal nucleus and hippocampal depth electrodes and typical sections showing representative electrode tracts (each “x” represents an estimated location of an electrode tip seen on cresyl violet staining). (B) Representative cresyl violet stain demonstrating the placement of medial septal stimulating/recording electrode. (C) Representative cresyl violet stain demonstrating placement of a hippocampal recording electrode. Color image is available online at www.liebertpub.com/neu

FIG. 2.

(A) During the first 7 days after injury, there was a significant decrease in the hippocampal theta oscillations in TBI rats as determined by calculating the percentage of time theta oscillations are observed in the hippocampus. (B) There was no change in the percentage of time theta was observed in the MSN. (C) Septohippocampal phase coherence was not significantly changed over the first week following TBI. *p < 0.05. MSN, medial septal nucleus; TBI, traumatic brain injury.

FIG. 3.

There was a significant decrease in the peak oscillatory frequency of theta in the hippocampus on post-injury day 3 with a trend toward a decrease on post-injury day 7. *p < 0.05.

FIG. 4.

(A) During stimulation, there was a significant increase in theta oscillations observed in the hippocampus as compared with baseline. There was no stimulation-duration effect on the percentage of time theta was observed among 15, 30, and 60 sec. (B) There was no lasting effect of stimulation on percentage of time or (C) septohippocampal coherence post-stimulation as both values returned to levels seen in animals that had not received stimulation. *p < 0.001.

FIG. 5.

(A) A range of stimulations were evaluated to determine an optimal frequency and intensity to improve performance in the absence of seizures. TBI rats had a significant decrease in object exploration as compared with sham rats. Similarly, TBI rats receiving 20 μA of 7.7 Hz or 80 μA of 100 Hz stimulation also explored objects significantly less than shams. TBI rats receiving 80 μA of 7.7 Hz stimulation explored significantly more than TBI rats receiving no stimulation. (B) Stimulation, regardless of frequency or intensity, did not influence an animal's total activity as measured by distance traveled. *p < 0.05 as compared with sham. ***p < 0.05 as compared with TBI without stimulation. TBI, traumatic brain injury.

FIG. 6.

(A) TBI rats had a significant increase in latency to finding the hidden escape box on the Barnes maze. (B) However, both TBI rats and TBI rats receiving 100 Hz stimulation demonstrated a significantly greater reliance on random search strategies to find the escape box relative to sham rats. *p < 0.05. TBI, traumatic brain injury.

FIG. 7.

(A) 100 Hz stimulation significantly impaired Barnes maze performance in sham rats compared with both sham and sham 7.7 Hz stimulated rats. (B) Whereas latency was similar between sham and sham 7.7 Hz animals, theta stimulated sham rats used significantly fewer random strategies to find the hidden escape box compared with sham rats. *p < 0.05.

FIG. 8.

To control for potential effects of lethargy, theta was analyzed during and compared between epochs of movement and rest. Clearly, there was an increase in theta when animals, regardless of injury, were moving as compared with resting. No differences were observed between sham or TBI on either day 3 or day 7 when comparing 5 sec of continuous activity versus rest. MSN, medial septal nucleus; TBI, traumatic brain injury.