Electrical Stimulation of the Lateral Entorhinal Cortex Causes a Frequency-Specific BOLD Response Pattern in the Rat Brain

Abstract

Although deep brain stimulation of the entorhinal cortex has recently shown promise in the treatment of early forms of cognitive decline, the underlying neurophysiological processes remain elusive. Therefore, the lateral entorhinal cortex (LEC) was stimulated with trains of continuous 5 Hz and 20 Hz pulses or with bursts of 100 Hz pulses to visualize activated neuronal networks, i.e., neuronal responses in the dentate gyrus and BOLD responses in the entire brain were simultaneously recorded. Electrical stimulation of the LEC caused a wide spread pattern of BOLD responses. Dependent on the stimulation frequency, BOLD responses were only triggered in the amygdala, infralimbic, prelimbic, and dorsal peduncular cortex (5 Hz), or in the nucleus accumbens, piriform cortex, dorsal medial prefrontal cortex, hippocampus (20 Hz), and contralateral entorhinal cortex (100 Hz). In general, LEC stimulation caused stronger BOLD responses in frontal cortex regions than in the hippocampus. Identical stimulation of the perforant pathway, a fiber bundle projecting from the entorhinal cortex to the dentate gyrus, hippocampus proper, and subiculum, mainly elicited significant BOLD responses in the hippocampus but rarely in frontal cortex regions. Consequently, BOLD responses in frontal cortex regions are mediated by direct projections from the LEC rather than via signal propagation through the hippocampus. Thus, the beneficial effects of deep brain stimulation of the entorhinal cortex on cognitive skills might depend more on an altered prefrontal cortex than hippocampal function.

Modulation of the rat hippocampal‐cortex network and episodic‐like memory performance following entorhinal cortex stimulation

“…In previous studies, EC-DBS facilitated an electrophysiological interaction in the hippocampal-EC network in humans as well as a widespread pattern of BOLD responses in rats, including the PFC, hippocampus and striatum. 7,24 Similarly, in the present study, we further observed increased functional connectivity among the EC, prefrontal-and hippocampal-related networks in the resting state in a short period after acute EC stimulation, suggesting multinetwork modulation induced by EC-DBS.…”

“…23 Krautwald et al revealed that EC stimulation in rats caused stronger BOLD responses in the PFC compared with the hippocampus, suggesting that the beneficial effects of EC-DBS might depend on PFC function. 24 Interestingly, our results also demonstrated an acute EC-DBS effect on increased resting-state functional connectivity between the EC and the PFC, the PFC and CA1, and the CA1 and CA3 (Figure 4).…”

“… 23 Krautwald et al revealed that EC stimulation in rats caused stronger BOLD responses in the PFC compared with the hippocampus, suggesting that the beneficial effects of EC‐DBS might depend on PFC function. 24 Interestingly, our results also demonstrated an acute EC‐DBS effect on increased resting‐state functional connectivity between the EC and the PFC, the PFC and CA1, and the CA1 and CA3 (Figure 4 ). Moreover, this network change effect was reversible, which was only observed 3 days after stimulation and recovered to the control level 4 weeks later, indicating that the short‐term and long‐term effects of EC‐DBS might rely on different brain network modulation mechanisms.…”

“… 22 , 23 Recently, Krautwald et al further reported a stronger response in the prefrontal cortex (PFC) compared with the hippocampus during EC stimulation, indicating that the acute beneficial effects of EC‐DBS may depend on both prefrontal and hippocampal functions. 24 However, to our knowledge, EC‐DBS‐induced functional connectivity changes in the hippocampal‐cortex network, including the prefrontal cortex, hippocampus, and EC, remain unclear.…”

The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties

“…Electrical stimulation of the EC has been found to reduce PFC pyramidal cellular activity (Valenti and Grace, 2009), and to enhance neurogenesis in the dentate gyrus of the hippocampus (Stone et al, 2011). Brain activities, measured by fMRI, were increased in the rat mPFC and hippocampus by 5-20 Hz electrical stimulation of the LEC (Krautwald et al, 2019). Imaging studies have also indicated that the LEC-CA1 pathway is recruited for the processing of exploration of familiar objects and of objectrecency, while the pathway of LEC-dentate gyrus-CA3 is activated for the processing of recognition of novel objects and for object-recency (Aggleton et al, 2012;Kinnavane et al, 2014;Olarte-Sanchez et al, 2014).…”