Frequency-dependent electrical stimulation of fimbria-fornix preferentially affects the mesolimbic dopamine system or prefrontal cortex

Abstract

Background: The fimbria/fornix fiber system is an essential part of the hippocampal-VTA loop, and therefore activities that are propagated through this fiber system control the activity of the mesolimbic dopamine system. Objectives/hypothesis: We hypothesized that stimulation of the fimbria/fornix with an increasing number of electrical pulses would cause increasing activity of the mesolimbic dopamine system, which coincides with concurrent changes in neuronal activities in target regions of the mesolimbic dopaminergic system. Methods: Right fimbria/fornix fibers were electrically stimulated with different pulse protocols. Stimulus-induced changes in neuronal activities were visualized with BOLD-fMRI, whereas stimulusinduced release of dopamine, as measured for the activity of the mesolimbic dopamine system, was determined in the nucleus accumbens with in vivo fast-scan cyclic voltammetry. Results: Dependent on the protocol, electrical fimbria/fornix stimulation caused BOLD responses in various targets of the mesolimbic dopamine system. Stimulation in the low theta frequency range (5 Hz) triggered significant BOLD responses mainly in the hippocampal formation, infralimbic cortex, and septum. Stimulation in the beta frequency range (20 Hz) caused additional activation in the medial prefrontal cortex (mPFC), nucleus accumbens, striatum, and VTA. Stimulation in the high-gamma frequency range (100 Hz) caused further activation in the hippocampus proper and mPFC. The strong activation in the mPFC during 100 Hz stimulations depended not only on the number of pulses but also on the frequency. Thus, short bursts of 5 or 20 high-frequency pulses caused stronger activation in the mPFC than continuous 5 or 20 Hz pulses. In contrast, high-frequency burst fimbria/fornix stimulation did not further activate the mesolimbic dopamine system when compared to continuous 5 or 20 Hz pulse stimulation. Conclusions: There exists a frequency-dependent dissociation between BOLD responses and activation of the dopaminergic system. Low frequencies were more efficient to activate the mesolimbic dopamine system, whereas high frequencies were more efficient to trigger BOLD responses in target regions of the mesolimbic dopamine system, particularly the mPFC.

Non-invasive temporal interference electrical stimulation of the human hippocampus

“…Taken together, our results demonstrate a non-invasive focal modulation of evoked neural activity in the targeted hippocampus. The hippocampal decrease in BOLD signal observed during the TI 1:3 condition is in alignment with previous animal studies, showing theta frequency stimulation decreases the magnitude of the BOLD signal in the hippocampus 31-33 . This would suggest that larger field magnitudes should result in larger decreases in BOLD signal.…”

“…The hippocampal decrease in BOLD signal observed during the TI 1:3 condition is in alignment with previous animal studies, showing theta frequency stimulation decreases the magnitude of the BOLD signal in the hippocampus (Angenstein, 2019; Helbing and Angenstein, 2020; Riemann et al, 2017). This would suggest that larger field magnitudes should result in larger decreases in BOLD signal.…”

“…Since TI stimulation modulates neural activity at the difference frequency of the kHz-frequency electric fields (Grossman et al, 2017), we anticipate that its application with a theta-band difference frequency will modulate endogenous theta oscillations in the local hippocampal network, resulting in a change in BOLD signal. Whilst the direction of neuronal activity cannot be unambiguously inferred from BOLD responses, and discrepancies in the relationship between BOLD signal and neural activity across cortical and hippocampal regions are well documented (Ekstrom, 2021), our observed reduction of hippocampal BOLD signal due to the TI stimulation is consistent with previous reports in animal models delivering theta frequency electrical stimulation to the hippocampal circuit (Angenstein, 2019; Helbing and Angenstein, 2020; Riemann et al, 2017). Multimodal data, demonstrated that a reduction in hippocampal BOLD signal can be observed alongside increased blood volume and increased spiking activity as a consequence of local increases in deoxyhaemoglobin (Angenstein, 2019; Schridde et al, 2008; Shaw et al, 2021).…”

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

“…Another potential source of input may arise from the hippocampus, which has likewise been implicated in fear-related changes in behavior in ELS-experienced animals (Reincke and Hanganu-Opatz, 2017). Consistent with this interpretation, high-gamma electrical stimulations in the fibria-fornix preferentially enhanced coordination between PFC and hippocampus, suggesting a likely route of communication on this frequency (Helbing and Angenstein, 2020). Future investigations will need to investigate these pathways, and in particular, why this frequency is uniquely disrupted while others are relatively unaffected.…”

Olfactory Information Storage Engages Subcortical and Cortical Brain Regions That Support Valence Determination

“…Using established methods ( Bovet-Carmona et al. 2019 ; Helbing and Angenstein 2020 ), the following VOIs were marked individually in a 3D standard rat brain that was generated from a rat of the same age and strain: right/left hippocampus (HC), right/left entorhinal cortex (EC), right/left nucleus accumbens, right/left striatum, right/left basolateral amygdala (BLA), right/left piriform cortex, right/left AON, dorsal medial prefrontal cortex (mPFC), PrL-IL, nucleus of the vertical limb of the diagonal band (VDB), septum, and ventral tegmental area–substantia nigra (VTA-SN). With regard to the VOIs located more medially in the brain, the spatial resolution of fMRI recordings did not permit an unambiguous distinction of left and right hemispheres.…”