Tuning Neuromodulation Effects by Orientation Selective Deep Brain Stimulation in the Rat Medial Frontal Cortex
Lauri J Lehto1, Pavel Filip1,2, Hanne Laakso1,3, Alejandra Sierra3, Julia Slopsema4, Matthew D Johnson4, Lynn E Eberly5, Walter C Low6, Olli Gröhn3, Heikki Tanila3, Silvia Mangia1, and Shalom Michaeli1

1Center Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States, 2First Department of Neurology, Faculty of Medicine, Masaryk University and St. Anne’s Teaching Hospital, Brno, Czech Republic, 3A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland, 4Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States, 5Division of Biostatistics, University of Minnesota, Minneapolis, MN, United States, 6Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States


With simultaneous fMRI and Deep Brain Stimulation (DBS), we demonstrate modulation of activity in rat amygdala by using axon Orientation Selective Stimulation (OSS) DBS in rat infralimbic cortex, a homologue brain region for treating depression in humans. Our results demonstrate orientation selectivity based on number of activated pixels especially in the amygdala, though qualitatively also other brain areas showed modulation based on stimulation angle. OSS may add a new level of optimization for treating major depression disorders.


Thus far treating major depressive disorder using deep brain stimulation (DBS) has led to mixed results 1-3. This calls for better understanding of the targeted neural circuitry and inter-individual variability in clinical and cognitive phenotypes 4, which may be directly relevant for optimizing the stimulation parameters and the implantation site 5. Advances in electrode design 6 and stimulation paradigms 7,8 are promising avenues for optimizing stimulation outcomes. One such method is the recently introduced orientation selective stimulation (OSS) 9 that sensitizes stimulation to axons with different orientations. OSS was shown to be effective in the highly organized area of corpus callosum, but its effectiveness in more complex circuitry has not been investigated. The rat infralimbic cortex (IL) is the homologue of human subgenual cingulate cortex, a DBS target for treating major depression.10-14 IL sends strong connections to e.g. the medial frontal cortex, insula, medial thalamus, basal forebrain, amygdala and hypothalamus. Conventional electric stimulation would likely touch all these connections and thus influence all related networks.15 The objective of this study was to compare the network-level responses to IL DBS across multiple electric field orientations employing OSS and across multiple DBS frequencies using simultaneous fMRI.


Three-channel tungsten wire electrodes (127 µm diameter per wire) were implanted in the rat IL (Fig 1A). For OSS, the stimulation angle was adjusted in 30° steps for a total of 12 fMRI acquisitions (Fig 1B; n = 8). The stimulation frequency dependence of the IL was tested with 20, 35, 70, 100, 130, 160 and 200 Hz (n = 6), and OSS was conducted using 20 Hz stimulation frequency. The waveform consisted of square, biphasic charge balanced pulses with no interpulse delay, 180 µs duration with amplitudes of 1.4 – 1.7 mA.

The fMRI stimulation paradigm consisted of 60 s of rest and 18 s of stimulation, repeated three times and ending in rest. Imaging was conducted at 9.4 T using Multi-Band SWeep Imaging with Fourier Transformation (MB-SWIFT; Fig 1C) 16,17 with the following parameters: TR = 0.97 ms, 3094 spokes per volume, resulting in temporal resolution of 3 s, bandwidth = 192 kHz, matrix size = 643, FOV = 3.5 x 3.5 x 6.4 cm3 and flip angle = 6°. Data analysis was performed using MATLAB, SPM5 and Aedes. Number of activated pixels and fMRI amplitude averaged over the animals were quantified using regions of interest (ROI).


The stimulation activated widespread networks or brain regions known to be connected with the IL including e.g. the prefrontal cortex, medial orbitofrontal cortex, anterior cingulate cortex, anterior insula, olfactory tubercle and piriform cortex, basal forebrain structures, lateral septum and amygdala. ROI analyses were performed on IL and amygdala (Fig 2A). fMRI amplitude was seen to reduce with increasing stimulation frequency (Fig 2B), while the number of activated pixels did not show statistically significant differences with increasing frequency. On the other hand, when applying OSS, statistically significant orientation dependence was detected in the amygdala in number of activated pixels (Fig 2C), but not in fMRI amplitude. Overlapping individual animal activation maps 18 clearly show orientation dependence of stimulation in the amygdala (Fig 3). Qualitatively, modulation of activity based on the stimulation angle was also observed in various other brain regions.

Discussion and Conclusion

The complexity of MDD DBS targets necessitates highly discriminatory modulation of desired pathways while ideally evading various high-risk neural circuits. DBS in IL has been shown effective even after destroying neuronal bodies and sparing axons using ibotenic acid in a rat model.12 This major role of axons in the DBS effect in IL indicates great potential for OSS paradigms capable of angle-dependent axonal stimulation.9 Indeed, our current findings show adjustable activation of the rat amygdala when applying OSS to the IL when looking at the number of activated pixels. The lack of effect in fMRI amplitude is likely related to the rather coarse electrode design where the large electrode stimulated a significant amount of the IL regardless of the stimulation angle. This may be alleviated with high-density silicon shanks.6

As the activation cluster near the electrode was insensitive to the changes of the stimulation angle but the terminal zone structures were differentially stimulated, our findings substantiate the ability of OSS to recruit neuronal pathways of distinct orientations relative to the position of the electrode, even in complex circuits such as those involved in MDD. OSS DBS technique may offer a new avenue for stimulus parameter optimization during DBS, so that relevant pathways are stimulated, while simultaneously avoiding crossing pathways associated with side effects.


This work was supported by the National Institutes of Health U01-NS103569-01, the Center for Magnetic Resonance Research NIH core grant P41-EB015894, P30 NS076408, NIH R01-NS094206, NIH R01-NS094206, WM KECK Foundation, the EU H2020 Marie Skłodowska RISE project #691110 (MICROBRADAM), Erkko foundation (OG), Academy of Finland (AS) and The Emil Aaltonen Foundation (LJL).


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Figure 1. (A) Location of the electrode in the infralimbic cortex (IL) (rostrocaudal 3.0 mm, mediolateral 0.6 mm and dorsoventral 5.2 mm), (B) orientation of the dipole under the electrode tip during OSS in IL, and (C) susceptibility artefact in T2-weighted FSE, SE-EPI and MB-SWIFT MRI.

Figure 2. Region of interest (ROI) analysis. (A) ROIs of amygdala and IL; (B) fMRI amplitude averaged over animals and peaks of stimulation periods (60 s of rest, 18 s of stimulation, repeated three times) in response to different stimulation frequencies. (C) Number of activated pixels averaged over animals in response to different stimulation angles using OSS. In (B) *pFDR < 0.05 one tailed paired t-test comparing 20 Hz to other frequencies; in (C) *pFDR < 0.05 Wilcoxon signed-rank test comparing 180° to other stimulation angles. Blue indicates mean and green indicates standard deviation in (B, C).

Figure 3. Pixel by pixel overlap maps of first level SPM analysis results at the level of the amygdala. 0 implies no activation in any of the animals, 1 implies an activation in all animals. Orientation dependence is seen in amygdala.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)