Table 3.

A list of preclinical studies on deep brain stimulation of the medial prefrontal cortex in rodents.

Authors	Target	Animal	Animal Models & DBS Design	Stimulation Parameters	Behavioral Tests	Outcomes
Jia et al. (2019) [116]	vmPFC	Sprague-Dawley rats, male.	CUS animal model. Open field test and forced swim test before DBS.	Unipolar High Frequency Frequency: 130 Hz Amplitude: 100 μA Pulse Width: 90 μs Low Frequency Frequency: 20 Hz Amplitude: 400 μA Pulse Width: 0.2 μs	Sucrose preference test	CUS rats had a lowered sucrose preference compared to control rats.
					Open field test	No significant difference in locomotion was recorded between CUS and control groups.
					Forced swim test	Both High- and Low-Frequency Stimulation reduced immobility compared to sham rats.
Papp et al. (2019) [117]	vmPFC	Wistar-Kyoto rats, male (DBS) Wistar rats, male [Venlafaxine(VFX)-treated]	CMS animal model. Two, 2-h DBS sessions were conducted, one on the preceding evening and the other on the following morning before each sucrose intake test and the NORT T1 session.	Frequency: 130 Hz Amplitude: 250 μA Pulse width: 90 μs	Sucrose intake test	During the first 2 wks of CMS, sucrose intake decreased >50% across groups. VFX treatment restored sucrose intake levels.
					Novel object recognition test	Wistar Kyoto rats: DBS rescued novel object recognition test across all groups. Wistar rats: VFX rescued novel object recognition test in CMS animals administered with D2 antagonist, but not in D2-administered CMS animals. VFX also did not rescue groups administered with D3 antagonist.
Bhaskar et al. (2018) [105]	vmPFC	Wistar rats, male.	Naïve animal model. DBS for 15 min prior to and throughout behavioral testing.	Bipolar Frequency: 100 Hz Amplitude: 200 µA Pulse Width: 100 µs	Home-cage emergence test	Enriched environment potentiated the efficacy of HFS on reduced escape latency time in the Naïve animal model.
					Elevated plus maze	HFS with an enriched environment reduced the anxiety index and increased head dips.
					Novel object recognition test	No significant difference.
Bregman et al. (2018) [97]	vmPFC	SERT homozygous knockout and wildtype mice, male.	Serotonin transporter (SERT) knockout model. DBS for 4 h before forced swim test and open field test.	Bilateral Monopolar Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Forced swim test	Both wild-type and knockout-DBS mice had reduced immobility time compared to sham.
					Open field test	Knockout-DBS mice had lower locomotion counts than sham and wild-type mice.
Lehto et al. (2018) [114]	IL	Sprague-Dawley rats, male.	Naïve animal model. All stimulation paradigms consisted of three blocks of 60 s of rest and 18 s of stimulation, ending with an additional rest period, giving a total paradigm of 4 min 54 s.	Monopolar Frequency: 20/35/70/100/130/160/200 Hz tested in randomized order. Amplitude: 1.4–1.7 mA distributed equally among the three electrode channels Pulse Width: 180-μs	N.A.	fMRI conducted to characterize changes in the brain following DBS. IL-DBS at varying stimulation parameters significantly triggered the amygdala. Orientation selective stimulation was able to recruit neuronal pathways of distinct orientations relative to the position of the electrode.
Papp et al. (2018) [118]	vmPFC	Wistar rats, male.	CMS animal model. Two, 2-h DBS sessions were conducted, one on the previous evening and one the next morning 15 min before each behavioral test.	Bipolar Frequency: 130 Hz, Amplitude: 250 μA, Pulse Width: 90 μs	Sucrose intake test	DBS increased sucrose intake across all treatment groups, except for imipramine-treated animals.
					Elevated plus maze	DBS increased the anxiolytic open arm entries in all treatment groups.
					Novel object recognition test	DBS rescued the abolished novel object recognition in CMS sham-treated animals, across all treatment groups.
Perez-Caballero et al. (2018) [115]	IL	Wistar rats, male.	Six independent sets of animals using naïve (unoperated controls) and DBS-off animals.	N.A.	Paw-pressure test	Ibuprofen, tramadol, and morphine significantly increased the paw withdrawal threshold in naïve animals relative to respective vehicle alone, demonstrating a clear analgesic effect.
					Open field test	No analgesics altered the motor activity of rats.
					Modified forced swim test	Electrode implantation induced a significant reduction in the immobility scores of vehicle-treated animals. Ibuprofen abolished the antidepressant-like effect of electrode implantation in the modified forced swim test, increasing the DBS-off animal’s immobility. Neither morphine nor tramadol counteracted the antidepressant-like effect of DBS-off animals.
					Novelty suppressed feeding test	Electrode implantation reduced latency to feed compared to naïve animals. Ibuprofen increased latency to feed relative to VEH-treated animals. Neither morphine nor tramadol reduced the latency to feed in electrode-implanted animals.
Torres-Sanchez et al. (2018) [110]	vmPFC	Wistar rats, male.	Naive animal model. DBS for (i) 4 h at 24 h after surgery, then (ii) 2 h at 48 h after surgery	Bipolar Monophasic Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Forced swim test	Reduced immobility time and increased climbing compared to control.
Volle et al. (2018) [119]	vmPFC	Sprague-Dawley rats, male.	Stimulation was delivered 1 week after surgery for either (i) a single day (acute stimulation; 8 h/day) or (ii) 12 days (chronic stimulation daily for 8 h/day) using a portable stimulator (ANS model 3510) to different groups of rats	Frequency: 130 Hz Amplitude: 200 μA Pulse Width: 90 μs	N.A.	Both treatments increase serotonin (5-HT) release, although fluoxetine resulted in a higher sustained concentration, even upon chronic treatment. Chronic DBS resulted in lowered 5HT release by Day 12. DBS reduced raphe SERT expression. DBS induced changes in 5-HT1B receptor expression, whereas fluoxetine induced changes in 5-HT1A receptors expression in the prefrontal cortex. Research highlighted different effects of both treatments on the serotonergic system.
Reznikov et al. (2017) [109]	IL	Sprague-Dawley rats, male.	Posttraumatic stress disorder animal model. 3-day fear conditioning DBS from 1 week after extinction recall to the end of experiment, 8 h/day, or 2 h before and 4 h after behavioral tests.	Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Extinction recall test	Higher freezing scores in DBS-weak extinction than DBS-strong extinction.
					Open field test	No significant difference between groups.
					Novelty suppressed feeding test	Reduced latency to feeding in DBS-weak extinction, but not strong extinction.
					Elevated plus maze	No significant difference observed between groups.
Bruchim-Samuel et al. (2016) [96]	vmPFC VTA	Flinders Sensitive Line rats, male. Sprague-Dawley rats, male. (Control)	Flinders Sensitive Line model. DBS for 15 min/day, for 10 days.	Bilateral, Monopolar vmPFC Stimulation Frequency: 20 Hz Amplitude: 400 µA Pulse Width: 200 µs VTA Stimulation (control) Frequency: 10 Hz Amplitude: 300 µA Pulse Width: 200 µs	Sweetened condensed milk intake test	No significant difference between vmPFC groups. Significant difference between VTA groups for Flinders Sensitive Line rats.
					Novelty Exploration Test	No significant difference between vmPFC groups. Significant difference between VTA groups for Flinders sensitive line rats.
					Forced swim test	Decreased immobility for vmPFC-stimulated rats after DBS for 10 days, half relapsed at day 28. VTA-stimulated Sprague-Dawley rats had persistently reduced immobility until the end of the experiment.
Jiménez-Sánchez et al. (2016) [33]	IL	Wistar rats, male.	Olfactory bulbectomized model animal model. DBS 1 h daily stimulation, beginning 2 days after electrode implantation before behavioral testing.	Bipolar Biphasic Frequency: 130 Hz Amplitude: 200 µA Pulse Width: 90 µs	Social interaction test	Increased duration of active contact.
					Sucrose preference test	Increased percentage of sucrose consumption in total liquid consumption.
					Forced swim test	Reduced immobility and increased climbing but not swimming.
					Hyperemotionality test	Reduced total behavioral scores when compared to olfactory bulbectomized sham rats.
Jiménez-Sánchez et al. (2016) [81]	IL PrL	Wistar rats, male.	Naïve animal model. DBS for 1 h daily before behavioral testing.	Bipolar Biphasic Frequency: 130 Hz Amplitude: 200 µA Pulse Width: 90 µs	Forced swim test	Reduced immobility and increased climbing in IL-DBS No significant behavioral changes in PrL-DBS.
					Open field test	Insignificant locomotor changes in IL-DBS.
					Novelty suppressed feeding test	Decreased latency to feed in IL-DBS.
Rummel et al. (2016) [113]	vmPFC	Flinders Sensitive Line rats, male. Congenitally learned helplessness rats, Male.	Experiment 1 Chronic intermittent DBS 1 week after surgery in Flinders sensitive line rats, 30 min each morning and extra 30-min stimulation on afternoons before the day of behavioral test. Experiment 2 Chronic continuous DBS 1 week after surgery for 16 days. Experiment 3 Chronic intermittent DBS in congenitally learned helpless rats, procedures followed that in experiment 1.	Chronic intermittent DBS Frequency: 130 Hz Amplitude: 300 µA Pulse Width: 100 µs Chronic continuous DBS Frequency: 130 Hz Amplitude: 150 µA Pulse Width: 100 µs	Sucrose consumption test	Chronic intermittent DBS increased sucrose intake in Flinders sensitive line rats but not in congenitally learned helplessness rats. Chronic continuous DBS did not affect sucrose intake in Flinders sensitive line rats and congenitally learned helplessness rats.
					Forced swim test	Chronic intermittent DBS and chronic continuous DBS increased latency to immobility in Flinders sensitive line rats but not congenitally learned helplessness rats.
					Learned helplessness paradigm	Chronic intermittent DBS and chronic continuous DBS decreased helplessness in Flinders sensitive line rats but not cLH rats.
					Sucrose intake test	No significant difference observed.
					Novelty exploration test	No significant difference observed.
Bambico et al. (2015) [98]	vmPFC	Fisher rats, Male.	CUS animal model CUS for ~4 weeks until anhedonia inferred by SPI scores, then performed implantation DBS for 3 weeks after implantation, 8 h per day, 7 days per week	Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Novelty-suppressed feeding test	Reduced latency to feeding in CUS-DBS animals compared to CUS-sham animals.
					Open field test	No significant difference observed.
					Elevated plus maze test	More time in open arms in CUS-DBS animals compared to CUS-sham animals.
					Forced swim test	Reduced immobility time in CUS-DBS animals compared to CUS-sham animals.
Edemann-Callesen et al. (2015) [94]	vmPFC; Medial forebrain bundle.	Flinders sensitive line rats, male. Sprague-Dawley rats, male.	Naïve animal model DBS was applied in an Intra-cranial self- stimulation protocol.	Bilateral, Monopolar Frequency: 20–200 Hz Amplitude: 170–560 µA Pulse Width: 100 µs	Intra-cranial self-stimulation	For Flinders Sensitive Line rats, vmPFC-DBS did not affect the reward-seeking behavior compared to medial forebrain bundle DBS.
Etiévant et al. (2015) [103]	IL	Sprague-Dawley rats, male.	Naïve animal model. DBS for 4 h after forced swim pre-test and 2 h before forced swim test.	Bipolar Unilateral Frequency: 130 Hz Amplitude: 150 µA Pulse Width: 60 µs	Forced swim test	Reduced immobility duration in IL-DBS compared to control.
Insel et al. (2015) [111]	IL	Sprague-Dawley rats, male.	Naïve animal model. DBS for 8 h per day, for 10 days.	Monopolar Bilateral Frequency: 130 Hz Amplitude: 100 μA Pulse Width: 90 μs	Spontaneous behavior recording	Coherence between ventral hippocampus and IL was reduced after 10-day DBS compared to sham in 2–4 Hz brain activity range, but was not reduced after only 1 day of treatment. Coherence was not affected by fluoxetine, indicating that IL-DBS observations were independent of the serotonergic pathways.
Lim et al. (2015) [102]	vmPFC	Sprague-Dawley rats, male.	Experiment 1 Naïve animal model. Experiment 2 CUS animal model. CUS for 3 weeks, each stressor lasted for 10–14 h DBS for 15 min before home-cage emergence test, before and during open field test.	Bipolar Biphasic Experiment 1 Frequency:10/100 Hz Amplitude: 100 µA Pulse Width: 100 µs Experiment 2 Frequency: 100 Hz Amplitude: 100µA Pulse Width: 100µs	Home-cage emergence test	HFS reduced escape latency time in Naïve and CUS animal model.
					Open-field test	Insignificant effect in Naïve animals for both HFS and LFS. Increased time spent in the central zone for HFS-CUS.
					Food-intake test	HFS increased food intake in naïve animals. No significance difference observed in CUS animals.
					Sucrose-intake test	Insignificant in Naïve animals for both HFS and LFS. Increased sucrose intake in HFS-CUS.
					Forced swim test	Insignificant in Naïve for both HFS and LFS. Reduced immobility duration in HFS-CUS.
Lim et al. (2015) [108]	PrL	Sprague-Dawley rats, male.	Naïve animal model. DBS for 15 min before and during sucrose intake test (same for forced swim test) and before sacrifice for 1 h.	Bipolar Biphasic Frequency: 100 Hz Amplitude: 100 µA Pulse Width: 100 µs	Sucrose intake test	Increased sucrose consumption.
					Forced swim test	Reduced immobility.
Liu et al. (2015) [99]	vmPFC	Sprague-Dawley rats, male. 4 months old and 12 months old.	Acute DBS Naïve animal model. DBS for 30 min before the behavioral tests. Chronic DBS Naïve animal model. DBS for 1 h daily including days of behavioral tests.	Bipolar Biphasic Acute DBS Frequency: 10/100 Hz Amplitude: 50/100/200/400 µA Pulse Width: 100 µs Chronic DBS Frequency: 100 Hz Amplitude: 100 µA Pulse Width: 100 µs	Novel object recognition test	Acute HFS at 200 µA produced higher novel object exploration than familiar object in short-term memory test. Chronic HFS increased novel object exploration in short- and long-term memory than familiar object, as well as the durations.
					Morris water maze	Shorter latency to reach platform on day 1 and 2 in chronic HFS compared to sham. More time spent in the target quadrant and less in the opposite quadrant in chronic HFS compared to sham.
Hamani et al. (2014) [100]	vmPFC	Sprague-Dawley rats, male.	Naïve animal model. DBS for 4 h after FST on day 1, 2 h before swimming on day 2 DBS 1 week after forced swim test, 4 h on day 1, 2 h on day 2, then assessed in open field test	Monopolar Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Forced swim test	Reduced immobility and increased climbing frequency between groups.
					Open field test	No significant difference in locomotion observed.
Laver et al. (2014) [112]	vmPFC	Sprague-Dawley rats, male.	Naïve animal model. Serotonin reuptake inhibitors/vehicle were injected i.p. 1 h and 5 h after forced swim test on day 1 and 1 h before forced swim test on day 2. DBS for 4 h on day 1 of forced swim pre-test and 2 h before forced swim test on day 2.	Monopolar Bilateral Frequency: 130 Hz Amplitude: 100 μA Pulse Width: 90 μs	Forced swim test	DBS-saline, DBS-buspirone, DBS-Risperidone, DBS-pindolol-treated animals had higher swimming and lower observed immobility frequencies.
					Open field test	No significant difference observed
Perez-Caballero et al. (2013) [45]	IL	Wistar rats, male.	CUS animal model. Electrode implantation after week 4 of CUS, then CUS resumed. DBS for 4 h after forced swim pre-test and 2 h before forced swim test. Some animals received pre-treatment with indomethacin or ibuprofen.	Bipolar Monophasic Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Forced swim test	Reduced immobility and increased swimming in DBS-off-IL and DBS-on-IL compared to sham- and naïve-animals. Increased immobility and reduced swimming in DBS-off-IL animals treated with NSAIDs.
					Open field test	No significant difference.
Rea et al. (2014) [95]	vmPFC	Flinders sensitive line rats, male. Flinders resistant line rats, male. (Control)	DBS for 30 min each morning for 2 weeks. Extra DBS for 30 min in the afternoon before the day of behavioral tests and during behavioral tests.	Monopolar Frequency: 130 Hz Amplitude: 300 µA Pulse Width: 100 µs	Forced swim test	DBS reduced immobility in both groups of rats.
					Sucrose consumption test	DBS increased sucrose consumption in both groups of rats.
Veerakumar et al. (2014) [104]	vmPFC	C57BL/6 mice, male.	Chronic social defeat stress animal model. DBS for 5 h/day, for 7 days.	Bipolar Unilateral Frequency: 160 Hz Amplitude: 150 µA Pulse Width: 60 µs	Social interaction test	Before DBS, defeat-susceptible mice showed lower interaction times. Defeated animals with DBS spent longer in the interaction zone than sham and similar to non-stressed animals. DBS increased the total distance traveled.
Hamani et al. (2012) [92]	vmPFC	Wistar rats, male.	CUS animal model. DBS for 8 h/day, for 2 weeks	Monopolar Frequency: 130 Hz Amplitude: 200 µA Pulse Width: 90 µs	Sucrose preference test	Higher preference observed in CUS-treated DBS animals when compared to CUS-sham animals. Higher sucrose consumption in CUS-treated DBS than CUS-sham alone.
Hamani et al. (2010) [93]	vmPFC, IL, PrL	Sprague-Dawley rats, male	Naïve animal model DBS for 4 h after FST on day 1, 2 h before swimming on day 2	Frequency: 20 Hz/130 Hz Amplitude: 100/200/300/400 µA Pulse Width: 90 µs	Forced swim test	Parameters of 130 Hz, 90 µs, 200 µA reduced immobility the most in vmPFC-DBS, also at 100 µA and 300 µA. PrL stimulation at 130 Hz, 90 µs, 200 µA reduced immobility, but IL stimulation was insignificant.
Hamani et al. (2010) [91]	vmPFC	Sprague-Dawley rats, male	Naïve animal model, with serotonergic depletion, or norepinephrine lesion. DBS for Forced Swim Test Day 1: 4 h after forced swim test Day 2: 2 h before forced swim test DBS for open field test, novelty suppressed feeding test, and learned helplessness. Pre-test Day 1: 4 h Pre-test Day 2: 2 h	Monopolar Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Forced swim test	DBS reduced immobility and increased swimming counts in naïve animals. DBS in animals with ibotenic acid injection had lower immobility and higher swimming counts than control. Rats with DBS without serotonergic depletion exhibited lower immobility than DBS animals with serotonergic depletion. Rats with DBS without norepinephrine lesion had lower immobility than control, similar reduction in immobility was shown in animals with DBS and norepinephrine lesion.
					Open field test	No significant difference.
					Novelty suppressed feeding test	DBS reduced latency to feed compared to control.
					Learned helplessness paradigm	Insignificant difference in escape latency between DBS and control.
			Animals predisposed to helplessness. DBS for 2 h before baseline assessment, 2 h before footshock at 2 days after baseline test, and DBS for 2 h before sucrose consumption test on the next day	Monopolar Frequency: 130 Hz Amplitude: 100 µA Pulse Width: 90 µs	Sucrose consumption test	DBS reduced the sucrose drinking time in animals after footshock, but this was insignificant.

Abbreviations: Cg, cingulate cortex; CUS, chronic unpredictable stress; EPM, elevated plus maze; FST, forced swim test; HFS, high-frequency stimulation; IL, infralimbic cortex; LFS, low-frequency stimulation; MWM, Morris water maze test; NORT, novel object recognition test; NSFT, novelty-suppressed feeding test; OBX, olfactory bulbectomy; OFT, open field test; PrL, prelimbic cortex; SD, Sprague-Dawley; SPI, sucrose preference index; vmPFC, ventromedial prefrontal cortex.