mPFC Stimulation Research Articles

Optogenetic Stimulation of mPFC Alleviates White Matter Injury-Related Cognitive Decline after Chronic Ischemia through Adaptive Myelination.

White matter injury (WMI), which reflects myelin loss, contributes to cognitive decline or dementia caused by cerebral vascular diseases. However, because pharmacological agents specifically for WMI are lacking, novel therapeutic strategies need to be explored. It is recently found that adaptive myelination is required for homeostatic control of brain functions. In this study, adaptive myelination-related strategies are appliedto explore the treatment for ischemicWMI-related cognitive dysfunction. Here, bilateral carotid artery stenosis (BCAS) is used to model ischemic WMI-related cognitive impairment and uncover that optogenetic and chemogenetic activation of glutamatergic neurons in the medial prefrontal cortex (mPFC) promote the differentiation of oligodendrocyte precursor cells (OPCs) in the corpus callosum, leading to improvements in myelin repair and working memory. Mechanistically, these neuromodulatory techniques exert a therapeutic effect by inducing the secretion of Wnt2 from activated neuronal axons, which acts on oligodendrocyte precursor cells and drives oligodendrogenesis and myelination. Thus, this study suggests that neuromodulation is a promising strategy for directing myelin repair and cognitive recovery through adaptive myelination in the context of ischemic WMI.

Neuromodulation Using Transcranial Focused Ultrasound on the Bilateral Medial Prefrontal Cortex.

Transcranial focused ultrasound (tFUS) is a promising technique of non-invasive brain stimulation for modulating neuronal activity with high spatial specificity. The medial prefrontal cortex (mPFC) has been proposed as a potential target for neuromodulation to prove emotional and sleep qualities. We aim to set up an appropriate clinical protocol for investigating the effects of tFUS stimulation of the bilateral mPFC for modulating the function of the brain-wide network using different sonication parameters. Seven participants received 20 min of 250 kHz tFUS to the bilateral mPFC with excitatory (70% duty cycle with sonication interval at 5 s) or suppressive (5% duty cycle with no interval) sonication protocols, which were compared to a sham condition. By placing the cigar-shaped sonication focus on the falx between both mPFCs, it was possible to simultaneously stimulate the bilateral mPFCs. Brain activity was analyzed using continuous electroencephalographic (EEG) recording during, before, and after tFUS. We investigated whether tFUS stimulation under the different conditions could lead to distinctive changes in brain activity in local brain regions where tFUS was directly delivered, and also in adjacent or remote brain areas that were not directly stimulated. This kind of study setting suggests that dynamic changes in brain cortical responses can occur within short periods of time, and that the distribution of these responses may differ depending on local brain states and functional brain architecture at the time of tFUS administration, or perhaps, at least temporarily, beyond the stimulation time. If so, tFUS could be useful for temporarily modifying regional brain activity, modulating functional connectivity, or reorganizing brain functions associated with various neuropsychiatric diseases, such as insomnia and depression.

Tonic excitation of nucleus reuniens decreases prefrontal-hippocampal coordination during slow-wave states.

The nucleus reuniens of the thalamus (RE) is an important node between the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Previously, we have shown that its mode of activity and its influence in mPFC-HPC communication is dependent upon brain state. During slow-wave states, RE units are closely and rhythmically coupled to the ongoing mPFC-slow oscillation (SO), while during activated (theta) states, RE neurons fire in an arrhythmic and tonically active manner. Inactivating the RE selectively impoverishes coordination of the SO between mPFC and HPC and interestingly, both mPFC and RE stimulation during the SO cause larger responses in the HPC than during theta. It is unclear if the activity patterns within the RE across states may play a role in both phenomena. Here, we optogenetically excited RE neurons in a tonic fashion to assess the impact on mPFC-HPC coupling. This stimulation decreased the influence of mPFC stimulation in the HPC during SO states, in a manner similar to what is observed across state changes into theta. Importantly, this type of stimulation had no effect on evoked responses during theta. Perhaps more interestingly, tonic optogenetic excitation of the RE also decreased mPFC-HPC SO coherence. Thus, it may not be the integrity of the RE per se that is responsible for efficient communication between mPFC and HPC, but rather the particular state in which RE neurons find themselves. Our results have direct implications for how distant brain regions can communicate most effectively, an issue that is ultimately important for activity-dependent processes occurring during slow-wave sleep-dependent memory consolidation.

Medial prefrontal cortex stimulation disrupts observational learning in Barnes maze in rats.

Observational learning, which improves one's own behavior by observing the adaptive behavior of others, has been experimentally demonstrated in primates and rodents in several behavioral studies, including our previous study. However, its neural mechanisms remain unclear. We electrically stimulated the brain regions of rats and disturbed their neural activities during observation periods in the observational learning task using Barnes maze. According to comparison of escaping latencies of the observer and model rats, the observer rats with stimulation of the medial prefrontal cortex (mPFC) showed no observational learning, whereas both of the observer rats with stimulation of the dorsal hippocampus and with no stimulation (control) showed observational learning. These results suggest that mPFC stimulation disrupts observational learning and confirms that the mPFC is an important brain region for it in rats.

Electroacupuncture Attenuates Anxiety-Like Behaviors in a Rat Model of Post-traumatic Stress Disorder: The Role of the Ventromedial Prefrontal Cortex.

Electroacupuncture (EA) is a promising clinical approach to treating posttraumatic stress disorder (PTSD), yet the mechanisms whereby EA can alleviate anxiety and other PTSD symptoms have yet to be clarified. In the present report, rats underwent EA for 14 consecutive days following modified single prolonged stress (MSPS) exposure. These animals were then evaluated in open field and elevated plus maze tests (OFT and EPM), while Fos immunohistochemical staining was performed to assess ventromedial prefrontal cortex (vmPFC) functional activation. In addition, an extracellular recording and stimulation system was used to analyze vmPFC inputs into the ventral tegmental area (VTA) in these rats. Temporary vmPFC inactivation was further performed to assess whether this was sufficient to reverse the anxiolytic effects of EA. Overall, rats that underwent EA treatment spent more time in the central region (OFT) and the open arm (EPM) relative to MSPS model animals (P < 0.05). These MSPS model animals also exhibited significantly fewer activated Fos-positive nuclei in the vmPFC following behavioral testing, while EA was associated with a significant relative increase in c-Fos expression in this region. The transient inactivation of the vmPFC was sufficient to reverse the effects of EA treatment on anxiety-like behaviors in MSPS model rats. MSPS and SEA rats exhibiting no differences in bursting activity between baseline and vmPFC stimulation, whereas bursting activity rose relative to baseline upon ventral mPFC stimulation in EA treated and control rats. Together, these findings indicate that the vmPFC and its inputs into the VTA are functionally linked to the anxiolytic activity of EA, implicating this pathway in the EA-mediated treatment of PTSD.

Medial Prefrontal Cortex Has a Causal Role in Selectively Enhanced Consolidation of Emotional Memories after a 24-Hour Delay: A TBS Study.

Previous research points to an association between retrieval-related activity in the medial prefrontal cortex (mPFC) and preservation of emotional information compared with co-occurring neutral information following sleep. Although the role of the mPFC in emotional memory likely begins at encoding, little research has examined how mPFC activity during encoding interacts with consolidation processes to enhance emotional memory. This issue was addressed in the present study using transcranial magnetic stimulation in conjunction with an emotional memory paradigm. Healthy young adults encoded negative and neutral scenes while undergoing concurrent TMS with a modified short intermittent theta burst stimulation (sTBS) protocol. Participants received stimulation to either the mPFC or an active control site (motor cortex) during the encoding phase. Recognition memory for scene components (objects and backgrounds) was assessed after a short delay (30 min) and a long delay [24 h (including a night of sleep)] to obtain measures of specific and gist-based memory processes. The results demonstrated that, relative to control stimulation, sTBS to the mPFC enhanced memory for negative objects on the long delay test (collapsed across specific and gist-based memory measures). mPFC stimulation had no discernable effect on memory for objects on the short delay test nor on the background images at either test. These results suggest that mPFC activity occurring during encoding interacts with consolidation processes to preferentially preserve negatively salient information.SIGNIFICANCE STATEMENT Understanding how emotional information is remembered over time is critical to understanding memory in the real world. The present study used noninvasive brain stimulation [repetitive transcranial magnetic stimulation (rTMS)] to investigate the interplay between mPFC activity that occurs during memory encoding and its subsequent interactions with consolidation processes. rTMS delivered to the mPFC during encoding enhanced memory for negatively valenced pictures on a test following a 24 h delay, with no such effect on a test occurring shortly after the encoding phase. These results are consistent with the hypothesis that emotional aspects of memories are differentially subjected to consolidation processes, and that the mPFC might contribute to this "tag-and-capture" mechanism during the initial formation of such memories.

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial

BackgroundPosttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD. MethodsImmediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers. ResultsClinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024). ConclusionsBoth groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory–mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

6 Hz transcranial alternating current stimulation of mPFC improves sustained attention and modulates alpha phase synchronization and power in dorsal attention network

ABSTRACT Transcranial alternating current stimulation (tACS) is a noninvasive brain stimulation tool appropriate to modulate cortical oscillations and activity via the application of weak currents. The major goal of this study was to investigate the effects of medial Prefrontal Cortex (mPFC) stimulation on sustained attention task performance measured by Rapid Visual Information Processing (RVIP) task and the brain networks assumed to be critical to sustained attention. mPFC has been shown to be involved in sustained attention performance and as a main hub in default mode network (DMN). mPFC activity modulation via theta tACS was implemented in this study. This was a single blind study with 21 participants receiving active and sham stimulation with the electrodes on FPz and the Inion. tACS was able to impact different RVIP measures (total hits, A’ (sensitivity to target), total correct rejection, etc.). Relative power spectrum density (PSD) analysis yielded significant increases in theta frequency mostly in the fronto-central regions after active tACS and current source density (CSD) analysis yielded significant power modulations in theta frequency band in post-central gyrus. Furthermore, phase locking value (PLV) analysis showed that there were significant changes in cortical connections in the Dorsal Attention Network (DAN) in alpha frequency band. This study showed that theta frequency tACS over mPFC, was able to produce significant modulations in an RVIP task and its associated brain networks in healthy participants.

A prefrontal-paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice.

Juvenile social isolation reduces sociability in adulthood, but the neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex (mPFC) neurons projecting to the posterior paraventricular thalamus (pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC->pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC->pPVT neurons and increased inhibitory input drive from low-threshold spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC->pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific mPFC excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.

Abstract WP496: Optogenetic Neuronal Stimulation Promotes Myelination After Subcortical Ischemic Vascular Dementia

Introduction: Subcortical ischemic small vessel disease (SIVD) causing hypoxic-ischemic white matter lesions is one of the major subtypes of Vascular dementia. White matter damage is associated with short-term working memory deficits in which medial prefrontal cortex (mPFC) plays a central role. Recent studies have reported that active neurons may produce white matter changes and enhance connectivity. However, little is known about how white matter damage impairs short-term working memory and whether neuronal activity promotes white matter restore in SIVD. In the present study, we used optogenetics in bilateral common carotid artery stenosis (BCAS) model mice to find the damaged circuit and explore whether neuronal activity could ameliorate white matter damage. Methods: Fiber photometry system monitoring in vivo calcium (Ca 2+ ) transients was performed to explore the damaged circuit of BCAS model mice. The damaged circuit were labelled using AAV expressing channel-rhodopsin 2 (CHR2). Optogenetics were used to selectively activate neurons expressing CHR2. The thymidine analog 5-ethynyl-2 ’ -deoxyuridine (EDU) was administered at the time of optogenetic stimulation to mark dividing cells and immunofluorescence was performed to identify the proliferating cell types. Transmission electron microscope (TEM) was used to evaluate myelin thickness. Y-mazes were performed to evaluated short-term working memory. Results and Conclusions: The structure and function of glutamatergic neurons in the circuit from mPFC to corpus callosum (CC) were damaged in BCAS model mice. And optogenetics stimulation of mPFC projecting glutamatergic neurons resulted in proliferation of oligodendrocyte in CC. Besides, an increase of myelin thickness and improved short-term working memory were found after three weeks of optogenetics stimulation. These results suggest that SIVD affected short-term working memory through damaging neuron projections from mPFC to CC, and optogenetic neuronal activity could regulate myelination and restore white matter damage.

Anodal transcranial direct current stimulation of MPFC enhances humor processing

ABSTRACTThe purpose of this study was to investigate whether the comprehension of a specific type of humorous situation requires the involvement of brain regions associated to mentalization or Theory of Mind processing and if the electrical stimulation of these areas would facilitate the comprehension of humor. To this aim, we analyzed the effects of tDCS stimulation on the MPFC and rTPJ during the presentation of humorous and non-humorous comic strips. In particular, the stimulus set included strips containing humorous scenes that required ToM abilities in order to be comprehended (Humorous ToM), non-ToM humorous strips (Humorous non-ToM), non-humorous strips which were semantically coherent but not funny (Congruent), and non-humorous strips which were semantically incoherent (Incongruent). Results suggest that the MPFC appears to be involved in both humor processing and in the incongruity resolution process: MPFC stimulation improved the ability to identify a non-humorous incongruent element and to recognize the humorous element of the scene. On the other hand, RTPJ activity doesn’t seem to be specifically involved in humorous processing network and appears to be more related to the ability to understand the cognitive element of a social context.

Corticostriatal Oscillations Predict High vs. Low Drinkers in a Rat Model of Limited Access Alcohol Consumption.

Individuals differ in their vulnerability to develop alcohol dependence, which is determined by innate and environmental factors. The corticostriatal circuit is heavily involved in the development of alcohol dependence and may contain neural information regarding vulnerability to drink excessively. In the current experiment, we hypothesized that we could characterize high and low alcohol-drinking rats (HD and LD, respectively) based on corticostriatal oscillations and that these subgroups would differentially respond to corticostriatal brain stimulation. Male Sprague–Dawley rats (n = 13) were trained to drink 10% alcohol in a limited access paradigm. In separate sessions, local field potentials (LFPs) were recorded from the nucleus accumbens shell (NAcSh) and medial prefrontal cortex (mPFC). Based on training alcohol consumption levels, we classified rats using a median split as HD or LD. Then, using machine-learning, we built predictive models to classify rats as HD or LD by corticostriatal LFPs and compared the model performance from real data to the performance of models built on data permutations. Additionally, we explored the impact of NAcSh or mPFC stimulation on alcohol consumption in HD vs. LD. Corticostriatal LFPs were able to predict HD vs. LD group classification with greater accuracy than expected by chance (>80% accuracy). Moreover, NAcSh stimulation significantly reduced alcohol consumption in HD, but not LD (p < 0.05), while mPFC stimulation did not alter drinking behavior in either HD or LD (p > 0.05). These data collectively show that the corticostriatal circuit is differentially involved in regulating alcohol intake in HD vs. LD rats, and suggests that corticostriatal activity may have the potential to predict a vulnerability to develop alcohol dependence in a clinical population.

Electrical stimulation mPFC affects morphine addiction by changing glutamate concentration in the ventral tegmental area.

Morphine addiction is known as a serious social problem. Medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) are two important sites of the brain that contribute to this type of addiction, and a complicated relation exists in between. In addition, neurotransmitters like glutamate and γ--Amino Butyric Acid (GABA) play an important role in the formation of these relations. Thus, the present study was undertaken to investigate these relations by evaluating the level of associated changes in the indicated neurotransmitters in the VTA, using HPLC method. This was performed after electrical stimulation and inducing lesion of mPFC and through microinjections of N-Methyl-D-Aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, respectively AP5 and CNQX, into the VTA of addicted rats. Our results showed that intra-peritoneal (i.p.) administration of morphine in 9days in the morphine group, and also electrical stimulation (100μA) of mPFC, receiving (i.p.) morphine, caused an increase in the glutamate release in the VTA, compared to the control group, but the increase of glutamate levels in the VTA in the morphine-stimulation group was not significant, compared to the morphine group. Moreover, GABA release into this area was decreasing in morphine and morphine- stimulation groups, compared to the control group. Our findings also showed that electrical lesion (0.4mA) of mPFC, and also microinjection of glutamate antagonists into the VTA, receiving (i.p.) morphine in rats, caused a decrease of glutamate in the VTA. Therefore, it could be concluded that the relation between mPFC and VTA is highly effective in the formation of reward system.

Medial Prefrontal Cortical Modulation of Whisker Thalamic Responses in Anesthetized Rats

The medial prefrontal cortex (mPFC) has been implicated in novelty detection and attention. We studied the effect of mPFC electrical stimulation on whisker responses recorded in the ventroposterior medial thalamic nucleus (VPM), the posterior thalamic nucleus (POm) and the primary somatosensory (S1) cortex in urethane anesthetized rats. Field potentials and unit recordings were performed in the VPM or POm thalamic nuclei, in S1 cortex, and in the Zona Incerta (ZI). Somatosensory evoked potentials were elicited by whisker deflections. Current pulses were delivered by bipolar stimulating electrodes aimed at the prelimbic (PL) or infralimbic (IL) areas of mPFC. PL train stimulation (50 Hz, 500 ms) induced a facilitation of whisker responses in the VPM nucleus that lasted minutes and a short inhibition in the POm nucleus. IL stimulation induced a facilitation of whisker responses in both VPM and POm nuclei. Facilitation was due to corticofugal projections because it was reduced after S1 cortical inactivation with lidocaine, and by activation of NMDA glutamatergic receptors because it was blocked by APV. Paired stimulation of mPFC and whiskers revealed an inhibitory effect at short intervals (<100 ms), which was mediated by ZI inhibitory neurons since PL stimulation induced response facilitation in the majority of ZI neurons (42%) and muscimol injection into ZI nucleus reduced inhibitory effects, suggesting that the mPFC may inhibit the POm neurons by activation of GABAergic ZI neurons. In conclusion, the mPFC may control the flow of somatosensory information through the thalamus by activation of S1 and ZI neurons.

High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: involvement of the prefrontal cortex and dorsal raphe?

Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.

Differential release of dopamine in the nucleus accumbens evoked by low-versus high-frequency medial prefrontal cortex stimulation

The medial prefrontal cortex (mPFC) coordinates goal-directed behaviors, which may be mediated through mPFC regulation of dopamine release in the nucleus accumbens (NAc). Furthermore, frequency-specific oscillatory activity between the frontal cortex and downstream structures may facilitate inter-region communication. Although high-frequency (e.g., 60 Hz) mPFC stimulation is known to increase basal dopamine levels in the NAc, little is known about how phasic dopamine release is affected by mPFC stimulation. Understanding the frequency-specific control of phasic dopamine release by mPFC stimulation could elucidate mechanisms by which the mPFC modulates other regions. It could also inform optimization of deep brain stimulation for treatment of neurological disorders. ObjectiveThe goal of this work was to characterize the frequency response of NAc dopamine release resultant from mPFC stimulation. We hypothesized that the magnitude of dopamine release in the NAc would increase with increasing stimulation frequency. MethodsElectrical stimulation of the mPFC of anesthetized rats was delivered at 4–60 Hz and at varying durations while measuring NAc dopamine release with fast-scan cyclic voltammetry. ResultsmPFC stimulation resulted in phasic dopamine release in the NAc. Furthermore, 20 Hz stimulation evoked the largest peak response for stimulation intervals >5 s when compared to higher or lower frequencies. ConclusionsActivation of the mPFC drives dopamine release in the NAc in a complex frequency- and duration-dependent manner. This has implications for the use of deep brain stimulation treatment of disorders marked by dopaminergic dysregulation, and suggest that mPFC may exert more specialized control over neuromodulator release than previously understood.

Effect of Transcranial Direct Current Stimulation of the Medial Prefrontal Cortex on the Gratitude of Individuals with Heterogeneous Ability in an Experimental Labor Market.

Gratitude is an important aspect of human sociality, which benefits mental health and interpersonal relationships. Thus, elucidating the neural mechanism of gratitude, which is only now beginning to be investigated, is important. To this end, this study specifies the medial prefrontal cortex (mPFC) involved in the gratitude of heterogeneous individuals using the transcranial direct current stimulation (tDCS) technique. Previous neural studies have shown the involvement of mPFC in social cognition and value evaluation, which are closely related to gratitude. However, the causal relationship between this neural area and gratitude has not been fully examined and the effect of individual social heterogeneity has been ignored. Meanwhile, behavioral economics studies have proposed that the abilities of employees in the labor market would affect their gratitude and emotional response. Thus, we designed an experiment based on gift exchange game to investigate the relationship between mPFC and gratitude of heterogeneous employees. Before the experiment, participants were asked to perform self-cognition of their abilities through an appropriately difficult task. We then used the effort of participants to imply their gratitude and analyzed the effort levels of employees with different abilities under anodal, cathodal, and sham stimulations. The results showed that employees under anodal stimulation were significantly likely to increase their effort than those under sham stimulation, and employees under cathodal stimulation ranked at the bottom of the list. Moreover, the effort levels of low-ability employees were obviously higher than those of high-ability employees. The cathodal stimulation of mPFC significantly reduced the effort levels of low-ability employees, whereas its anodal tDCS stimulation increased the effort levels of high-ability employees. These outcomes verify the relationship between mPFC and gratitude using tDCS and provided one of the first instances of neural evidence for the incentive mechanism design in the labor market to a certain extent.

Inhibitory modulation of medial prefrontal cortical activation on lateral orbitofrontal cortex-amygdala information flow.

The basolateral complex of the amygdala (BLA) receives input from the lateral orbitofrontal cortex (lOFC) for cue-outcome contingencies and the medial prefrontal cortex (mPFC) for emotion control. Here we examined how the mPFC modulates lOFC-BLA information flow. We found that the majority of BLA neurons responsive to lOFC stimulation were also responsive to mPFC stimulation. Activation of the mPFC exerted an inhibitory modulation of the lOFC-BLA pathway, which was reversed with intra-amygdala blockade of GABAergic receptors. mPFC tetanus potentiated the lOFC-BLA pathway, but did not alter its inhibitory modulatory gating. These results show that the mPFC potently inhibits lOFC drive of the BLA in a GABA-dependent manner, which is informative in understanding the normal and potential pathophysiological state of emotion and contingency associations in regulating behaviour. Several neocortical projections converge onto the basolateral complex of the amygdala (BLA), including the lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC). Lateral orbitofrontal input to the BLA is important for cue-outcome contingencies, while medial prefrontal input is essential for emotion control. In this study, we examined how the mPFC, specifically the infralimbic division of the mPFC, modulates lOFC-BLA information flow, using combined in vivo extracellular single-unit recordings and pharmacological manipulations in anaesthetized rats. We found that the majority (over 95%) of BLA neurons that responded to lOFC stimulation also responded to mPFC stimulation. Compared to basal condition, pharmacological (N-methyl-d-aspartate) or electrical activation of the mPFC exerted an inhibitory modulation of the lOFC-BLA pathway, which was reversed with intra-amygdala blockade of GABAergic receptors with combined GABAA and GABAB antagonists (bicuculline and saclofen). Moreover, mPFC tetanus potentiated the lOFC-BLA pathway, but mPFC tetanus or low-frequency stimulation did not alter its inhibitory modulatory gating on the lOFC-BLA pathway. These results show that the mPFC potently inhibits lOFC drive of BLA neurons in a GABA-dependent manner. Our result is informative in understanding the normal and potential pathophysiological state of emotion and contingency associations regulating behaviour.

Response to Deep Brain Stimulation in Three Brain Targets with Implications in Mental Disorders: A PET Study in Rats.

ObjectiveTo investigate metabolic changes in brain networks by deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) and dorsomedial thalamus (DM) using positron emission tomography (PET) in naïve rats.Methods43 male Wistar rats underwent stereotactic surgery and concentric bipolar platinum-iridium electrodes were bilaterally implanted into one of the three brain sites. [18F]-fluoro-2-deoxy-glucose-PET (18FDG-PET) and computed tomography (CT) scans were performed at the 7th (without DBS) and 9th day (with DBS) after surgery. Stimulation period matched tracer uptake period. Images were acquired with a small-animal PET-CT scanner. Differences in glucose uptake between groups were assessed with Statistical Parametric Mapping.ResultsDBS induced site-specific metabolic changes, although a common increased metabolic activity in the piriform cortex was found for the three brain targets. mPFC-DBS increased metabolic activity in the striatum, temporal and amygdala, and reduced it in the cerebellum, brainstem (BS) and periaqueductal gray matter (PAG). NAcc-DBS increased metabolic activity in the subiculum and olfactory bulb, and decreased it in the BS, PAG, septum and hypothalamus. DM-DBS increased metabolic activity in the striatum, NAcc and thalamus and decreased it in the temporal and cingulate cortex.ConclusionsDBS induced significant changes in 18FDG uptake in brain regions associated with the basal ganglia-thalamo-cortical circuitry. Stimulation of mPFC, NAcc and DM induced different patterns of 18FDG uptake despite interacting with the same circuitries. This may have important implications to DBS research suggesting individualized target selection according to specific neural modulatory requirements.

EP 18. Deep Brain Stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia

Background A growing body of evidence suggests that schizophrenia (scz) is a neurodevelopmental disorder in which some brain alterations already occur during early brain development and others progress along the developmental course. This progressive nature of scz raises interest in the development of preventive avenues, i.e. therapeutic interventions prior to the full symptoms manifestation. For that however, a profounder understanding of the exact nature of altered brain development in scz is needed. Given methodological and ethical limitations of human studies, the use of appropriate animal models of schizophrenia is an invaluable tool. Methods This study used a maternal immune stimulation (MIS) rodent model of schizophrenia together with a neuromodulation approach, namely deep brain stimulation (DBS), to investigate the neurobiological and behavioral alterations during the course of disease. In this model, the exposure of pregnant rodents on their gestational day 15 to the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) results in schizophrenia-relevant behavioral abnormalities which first emerge in adulthood, complying with the postnatal delay of this disorder. We applied DBS-interventions to the medial prefrontal cortex (mPFC) or nucleus accumbens (Nacc) to either poly I:C progeny or controls, at two different time points of scz development: a continuous DBS during a pre-symptomatic adolescence period and an acute DBS at the full symptomatic period of adulthood. In adulthood, we tested the effects of both interventions on two behavioral processes known to be disrupted in scz and in this model: sensorimotor gating and attentional selectivity. In addition, we studied the effects of DBS on several neurobiological parameters at post mortem . Results When applied at adulthood, DBS to both regions was found to be successful in alleviating sensorimotor gating and attentional selectivity deficits in the MIS model. However, when applied in adolescence only mPFC stimulation prevented both behavioral deficits, whereas Nacc stimulation only normalized sensorimotor deficits. Moreover, stimulation in those two brain sites induced different brain metabolic effects and neurochemical alterations, even if the effect on behavior was identical. Conclusions This study adds to the growing literature suggesting that electrical stimulation of specific brain regions improves behavioral deficits in neuro-psychiatric disorders and also scz. Moreover, this study indicates that early neuro-modulation might halt the progression of scz in reliance on stimulation site.