Stimulation Of Medial Forebrain Bundle Research Articles

Physiological paradigm for assessing reward prediction and extinction using cortical direct current potential responses in rats

Anticipating positive outcomes is a core cognitive function in the process of reward prediction. However, no neurophysiological method objectively assesses reward prediction in basic medical research. In the present study, we established a physiological paradigm using cortical direct current (DC) potential responses in rats to assess reward prediction. This paradigm consisted of five daily 1-h sessions with two tones, wherein the rewarded tone was followed by electrical stimulation of the medial forebrain bundle (MFB) scheduled at 1000 ms later, whereas the unrewarded tone was not. On day 1, both tones induced a negative DC shift immediately after auditory responses, persisting up to MFB stimulation. This negative shift progressively increased and peaked on day 4. Starting from day 3, the negative shift from 600 to 1000 ms was significantly larger following the rewarded tone than that following the unrewarded tone. This negative DC shift was particularly prominent in the frontal cortex, suggesting its crucial role in discriminative reward prediction. During the extinction sessions, the shift diminished significantly on extinction day 1. These findings suggest that cortical DC potential is related to reward prediction and could be a valuable tool for evaluating animal models of depression, providing a testing system for anhedonia.

Deep brain stimulation of the medial forebrain bundle - effects on suicidality in treatment-refractory MDD patients?

AbstractDeep brain stimulation (DBS) of brain circuits involved in mood regulation is a novel tool that is being investigated as a potential treatment for some of the most severe patients with mood disorders. At UTHealth Houston, we have had an ongoing clinical trial with DBS of the medial forebrain bundle (MFB).Our preliminary results suggest effects in alleviating depressive symptoms in this very severe, refractory patient group.In this presentation, we will review our latest findings, and will also discuss the potential effects of the MFB stimulation on measures of suicidality in this patient population.Disclosure of InterestNone Declared

Shaped by Neuronal Stimulation: Anatomical and physiological impact of multimodal medial forebrain bundle stimulation

Shaped by Neuronal Stimulation: Anatomical and physiological impact of multimodal medial forebrain bundle stimulation

Somatosensory ECoG-based brain–machine interface with electrical stimulation on medial forebrain bundle

Brain–machine interface (BMI) provides an alternative route for controlling an external device with one’s intention. For individuals with motor-related disability, the BMI technologies can be used to replace or restore motor functions. Therefore, BMIs for movement restoration generally decode the neural activity from the motor-related brain regions. In this study, however, we designed a BMI system that uses sensory-related neural signals for BMI combined with electrical stimulation for reward. Four-channel electrocorticographic (ECoG) signals were recorded from the whisker-related somatosensory cortex of rats and converted to extract the BMI signals to control the one-dimensional movement of a dot on the screen. At the same time, we used operant conditioning with electrical stimulation on medial forebrain bundle (MFB), which provides a virtual reward to motivate the rat to move the dot towards the desired center region. The BMI task training was performed for 7 days with ECoG recording and MFB stimulation. Animals successfully learned to move the dot location to the desired position using S1BF neural activity. This study successfully demonstrated that it is feasible to utilize the neural signals from the whisker somatosensory cortex for BMI system. In addition, the MFB electrical stimulation is effective for rats to learn the behavioral task for BMI.

Enhanced perceptual task performance without deprivation in mice using medial forebrain bundle stimulation

Perceptual decision-making tasks are essential to many fields of neuroscience. Current protocols generally reward deprived animals with water. However, balancing animals' deprivation level with their well-being is challenging, and trial number is limited by satiation. Here, we present electrical stimulation of the medial forebrain bundle (MFB) as an alternative that avoids deprivation while yielding stable motivation for thousands of trials. Using licking or lever press as a report, MFB animals learnt auditory discrimination tasks at similar speed to water-deprived mice. Moreover, they more reliably reached higher accuracy in harder tasks, performing up to 4,500 trials per session without loss of motivation. MFB stimulation did not impact the underlying sensory behavior since psychometric parameters and response times are preserved. MFB mice lacked signs of metabolic or behavioral stress compared with water-deprived mice. Overall, MFB stimulation is a highly promising tool for task learning because it enhances task performance while avoiding deprivation.

Slow Wave Sleep Deficits in the Flinders Sensitive Line Rodent Model of Depression: Effects of Medial Forebrain Bundle Deep-Brain Stimulation

Major Depressive Disorder (MDD) is an affective disorder typically accompanied by sleep disturbances. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) is an emerging intervention for treatment-resistant depression, but its effect on sleep has not been closely examined. Here we aimed to characterise sleep deficits in the Flinders sensitive line, an established rodent model of depression, and investigate the consequences of MFB stimulation on sleep-related phenotypes. Rats were implanted with bilateral stimulation electrodes in the MFB, surface electrodes to record electrocorticography and electromyography for sleep scoring and electrodes within the prelimbic cortex, nucleus accumbens (NAc) and dorsal hippocampus. Recordings of sleep and oscillatory activity were conducted prior to and following twenty-four hours of MFB stimulation. Behavioural anti-depressant effects were monitored using the forced swim test. Previously unreported abnormalities in the Flinders sensitive line rats were observed during slow wave sleep, including decreased circadian amplitude of its rhythm, a reduction in slow wave activity and elevated gamma band oscillations. Previously established rapid eye movement sleep deficits were replicated. MFB stimulation had anti-depressant effects on behavioural phenotype, but did not significantly impact sleep architecture; it suppressed elevated gamma activity during slow wave sleep in the electrocorticogram and prelimbic cortex signals. Diverse abnormalities in Flinders sensitive line rats emphasise slow wave sleep as a state of dysfunction in affective disorders. MFB stimulation is able to affect behaviour and sleep physiology without influencing sleep architecture. Gamma modulation may represent a component of antidepressant mechanism.

Enhancement of Motor Cortical Gamma Oscillations and Sniffing Activity by Medial Forebrain Bundle Stimulation Precedes Locomotion.

The medial forebrain bundle (MFB) is a white matter pathway that traverses through mesolimbic structures and includes dopaminergic neural fibers ascending from the ventral tegmental area (VTA). Since dopaminergic signals represent hedonic responses, electrical stimulation of the MFB in animals has been used as a neural reward for operant and spatial tasks. MFB stimulation strongly motivates animals to rapidly learn to perform a variety of behavioral tasks to obtain a reward. Although the MFB is known to connect various brain regions and MFB stimulation dynamically modulates animal behavior, how central and peripheral functions are affected by MFB stimulation per se is poorly understood. To address this question, we simultaneously recorded electrocorticograms (ECoGs) in the primary motor cortex (M1), primary somatosensory cortex (S1), and olfactory bulb (OB) of behaving rats while electrically stimulating the MFB. We found that MFB stimulation increased the locomotor activity of rats. Spectral analysis confirmed that immediately after MFB stimulation, sniffing activity was facilitated and the power of gamma oscillations in the M1 was increased. After sniffing activity and motor cortical gamma oscillations were facilitated, animals started to move. These results provide insight into the importance of sniffing activity and cortical gamma oscillations for motor execution and learning facilitated by MFB stimulation.

The Convergence Model of Brain Reward Circuitry: Implications for Relief of Treatment-Resistant Depression by Deep-Brain Stimulation of the Medial Forebrain Bundle

Deep-brain stimulation of the medial forebrain bundle (MFB) can provide effective, enduring relief of treatment-resistant depression. Panksepp provided an explanatory framework: the MFB constitutes the core of the neural circuitry subserving the anticipation and pursuit of rewards: the “SEEKING” system. On that view, the SEEKING system is hypoactive in depressed individuals; background electrical stimulation of the MFB alleviates symptoms by normalizing activity. Panksepp attributed intracranial self-stimulation to excitation of the SEEKING system in which the ascending projections of midbrain dopamine neurons are an essential component. In parallel with Panksepp’s qualitative work, intracranial self-stimulation has long been studied quantitatively by psychophysical means. That work argues that the predominant directly stimulated substrate for MFB self-stimulation are myelinated, non-dopaminergic fibers, more readily excited by brief electrical current pulses than the thin, unmyelinated axons of the midbrain dopamine neurons. The series-circuit hypothesis reconciles this view with the evidence implicating dopamine in MFB self-stimulation as follows: direct activation of myelinated MFB fibers is rewarding due to their trans-synaptic activation of midbrain dopamine neurons. A recent study in which rats worked for optogenetic stimulation of midbrain dopamine neurons challenges the series-circuit hypothesis and provides a new model of intracranial self-stimulation in which the myelinated non-dopaminergic neurons and the midbrain dopamine projections access the behavioral final common path for reward seeking via separate, converging routes. We explore the potential implications of this convergence model for the interpretation of the antidepressant effect of MFB stimulation. We also discuss the consistent finding that psychomotor stimulants, which boost dopaminergic neurotransmission, fail to provide a monotherapy for depression. We propose that non-dopaminergic MFB components may contribute to the therapeutic effect in parallel to, in synergy with, or even instead of, a dopaminergic component.

"The Heart Asks Pleasure First"-Conceptualizing Psychiatric Diseases as MAINTENANCE Network Dysfunctions through Insights from slMFB DBS in Depression and Obsessive-Compulsive Disorder.

More than a decade ago, deep brain stimulation (DBS) of the superolateral medial forebrain bundle (slMFB), as part of the greater MFB system, had been proposed as a putative yet experimental treatment strategy for therapy refractory depression (TRD) and later for obsessive–compulsive disorders (OCD). Antidepressant and anti-OCD efficacy have been shown in open case series and smaller trials and were independently replicated. The MFB is anato-physiologically confluent with the SEEKING system promoting euphoric drive, reward anticipation and reward; functions realized through the mesocorticolimbic dopaminergic system. Growing clinical experience concerning surgical and stimulation aspects from a larger number of patients shows an MFB functionality beyond SEEKING and now re-informs the scientific rationale concerning the MFB’s (patho-) physiology. In this white paper, we combine observations from more than 75 cases of slMFB DBS. We integrate these observations with a selected literature review to provide a new neuroethological view on the MFB. We here formulate a re-interpretation of the MFB as the main structure of an integrated SEEKING/MAINTENANCE circuitry, allowing for individual homeostasis and well-being through emotional arousal, basic and higher affect valence, bodily reactions, motor programing, vigor and flexible behavior, as the basis for the antidepressant and anti-OCD efficacy.

Optogenetic stimulation of ventral tegmental area dopaminergic neurons in a female rodent model of depression: The effect of different stimulation patterns.

Major depressive disorder is one of the most common mental disorders, and more than 300million of people suffer from depression worldwide. Recent clinical trials indicate that deep brain stimulation of the superolateral medial forebrain bundle (mfb) can have rapid and long-term antidepressant effects in patients with treatment-resistant depression. However, the mechanisms of action are elusive. In this study, using female rats, we demonstrate the antidepressant effects of selective optogenetic stimulation of the ventral tegmental area's dopaminergic (DA) neurons passing through the mfb and compare different stimulation patterns. Chronic mild unpredictable stress (CMUS) induced depressive-like, but not anxiety-like phenotype. Short-term and long-term stimulation demonstrated antidepressant effect (OSST) and improved anxiolytic effect (EPM), while long-term stimulation during CMUS induction prevented depressive-like behavior (OSST and USV) and improved anxiolytic effect (EPM). The results highlight that long-term accumulative stimulation on DA pathways is required for antidepressant and anxiolytic effect.

Enhanced Performance in Perceptual Decision Making Task Without Deprivation in Mice Using Medial Forebrain Bundle Stimulation

Enhanced Performance in Perceptual Decision Making Task Without Deprivation in Mice Using Medial Forebrain Bundle Stimulation

Delayed reinforcement hinders subsequent extinction

In operant conditioning, animals associate their own behavior with a reinforcer, and the probability of the behavioral responses is increased. This form of learning is called reinforcement. In contrast, when the previously reinforced responses are no longer paired with a reinforcer, these responses are eventually extinguished. The effectiveness of reinforcement depends primarily on time intervals between reinforcers and responses, but it is not fully understood how the intervals affect subsequent extinction. To address this question, we performed electrical stimulation of the rat medial forebrain bundle (MFB), a part of the brain reward system, and an operant task in which the MFB was electrically stimulated 0.1 s (immediate condition) or 1 s (delayed condition) after the rat's nose was poked. During the first half of the task period (a reinforcement period), nose pokes were associated with MFB stimulation. In contrast, during the second half (an extinction period), we did not stimulate the MFB irrespective of nose pokes. We found that rats exhibited increased nose-poke behaviors during the reinforcement period under both conditions, whereas during the extinction period, nose pokes were more persistent in the delayed condition than in the immediate condition. The persistent responses in the extinction period were independent of responses in the reinforcement period. Therefore, reinforcement and extinction are driven by independent neural mechanisms.

Bilateral responses of rat ventral striatum tonically active neurons to unilateral medial forebrain bundle stimulation.

Unilateral medial forebrain bundle (MFB) stimulation is an extremely effective promoter of reinforcement learning irrespective of the conditioned cue's laterality. The effectiveness of unilateral MFB stimulation, which activates the mesolimbic pathway connecting the ventral tegmental area to the ventral striatum (vStr), is surprising considering that these fibers rarely cross to the contralateral hemisphere. Specifically, this type of biased fiber distribution entails the activation of brain structures that are primarily ipsilateral to the stimulated MFB, along with weak to negligible activation of the contralateral structures, thus impeding the formation of a cue-outcome association. To better understand the spread of activation of MFB stimulation across hemispheres, we studied whether unilateral MFB stimulation primarily activates the ipsilateral vStr or the vStr of both hemispheres. We simultaneously recorded neuronal activity in the vStr of both hemispheres in response to several sets of unilateral MFB stimulation in anesthetized and freely moving rats. Unilateral MFB stimulation evoked strong stimulus-dependent activation of vStr tonically active neurons (TANs), presumably the cholinergic interneurons, in both hemispheres. However, the TANs' activation patterns and responsiveness depended on whether the stimulus was delivered ipsilaterally or contralaterally to the recorded neuron. These findings indicate that unilateral MFB stimulation effectively activates the vStr in both hemispheres in a stimulus-dependent manner which may serve as neuronal substrate for the formation of cue-outcome associations during reinforcement learning.

Rewarding deep brain stimulation at the medial forebrain bundle favours avoidance conditioned response in a remote memory test, hinders extinction and increases neurogenesis

Intracranial Self-Stimulation (ICSS) at the medial forebrain bundle consistently facilitates learning and memory in rats when administered post-training or when administered non-concurrent to training, but its scope regarding remote memory has not yet been studied. The present work aims to test whether the combination of these two forms of ICSS administration can cause a greater persistence of the facilitating effect on remote retention and affect neurogenesis in the dentate gyrus (DG) of the hippocampus.Rats were trained in active avoidance conditioning and tested in two retention sessions (10 and 90 days) and later extinction. Subjects received an ICSS session after each of the five avoidance acquisition sessions (post-training treatment) and half of them also received ten additional ICSS sessions during the rest period between retention tests (non-concurrent treatment). All the stimulated groups showed a higher performance in acquisition and retention sessions, but only the rats receiving both ICSS treatments showed greater resistance to extinction. Remarkably, at seven months, rats receiving the non-concurrent ICSS treatment had a greater number of DCX-positive cells in the DG as well as a higher amount of new-born cells within the granular layer compared to rats that did not receive this additional ICSS treatment.Our present findings significantly extend the temporal window of the facilitating effect of ICSS on active avoidance and demonstrate a neurogenic effect of rewarding medial forebrain bundle stimulation.

Cerebellar Modulation of Mesolimbic Dopamine Transmission Is Functionally Asymmetrical.

Cerebral and cerebellar hemispheres are known to be asymmetrical in structure and function, and previous literature supports that asymmetry extends to the neural dopamine systems. Using in vivo fixed potential amperometry with carbon fiber microelectrodes in anesthetized mice, the current study assessed hemispheric lateralization of stimulation-evoked dopamine in the nucleus accumbens (NAc) and the influence of the cerebellum in regulating this reward-associated pathway. Our results suggest that cerebellar output can modulate mesolimbic dopamine transmission, and this modulation contributes to asymmetrically lateralized dopamine release. Dopamine release did not differ between hemispheres when evoked by medial forebrain bundle (MFB) stimulation; however, dopamine release was significantly greater in the right NAc relative to the left when evoked by electrical stimulation of the cerebellar dentate nucleus (DN). Furthermore, cross-hemispheric talk between the left and right cerebellar DN does not seem to influence mesolimbic release given that lidocaine infused into the DN opposite to the stimulated DN did not alter release. These studies may provide a neurochemical mechanism for studies identifying the cerebellum as a relevant node for reward, motivational behavior, saliency, and inhibitory control. An increased understanding of the lateralization of dopaminergic systems may reveal novel targets for pharmacological interventions in neuropathology of the cerebellum and extending projections.

Machine learning\u2014aided personalized DTI tractographic planning for deep brain stimulation of the superolateral medial forebrain bundle using HAMLET

BackgroundGrowing interest exists for superolateral medial forebrain bundle (slMFB) deep brain stimulation (DBS) in psychiatric disorders. The surgical approach warrants tractographic rendition. Commercial stereotactic planning systems use deterministic tractography which suffers from inherent limitations, is dependent on manual interaction (ROI definition), and has to be regarded as subjective. We aimed to develop an objective but patient-specific tracking of the slMFB which at the same time allows the use of a commercial surgical planning system in the context of deep brain stimulation.MethodsThe HAMLET (Hierarchical Harmonic Filters for Learning Tracts from Diffusion MRI) machine learning approach was introduced into the standardized workflow of slMFB DBS tractographic planning on the basis of patient-specific dMRI. Rendition of the slMFB with HAMLET serves as an objective comparison for the refinement of the deterministic tracking procedure. Our application focuses on the tractographic planning of DBS (N = 8) for major depression and OCD.ResultsPrevious results have shown that only fibers belonging to the ventral tegmental area to prefrontal/orbitofrontal axis should be targeted. With the proposed technique, the deterministic tracking approach, that serves as the surgical planning data, can be refined, over-sprouting fibers are eliminated, bundle thickness is reduced in the target region, and thereby probably a more accurate targeting is facilitated. The HAMLET-driven method is meant to achieve a more objective surgical fiber display of the slMFB with deterministic tractography.ConclusionsThe approach allows overlying the results of patient-specific planning from two different approaches (manual deterministic and machine learning HAMLET). HAMLET shows the slMFB as a volume and thus serves as an objective tracking corridor. It helps to refine results from deterministic tracking in the surgical workspace without interfering with any part of the standard software solution. We have now included this workflow in our daily clinical experimental work on slMFB DBS for psychiatric indications.

Optimization of Medial Forebrain Bundle Stimulation Parameters for Operant Conditioning of Rats

Background: The medial forebrain bundle (MFB) is involved in the integration of pleasure and reward. Previous studies have used various stimulation parameters for operant conditioning, though the effectiveness of these parameters has not been systematically studied. Objectives: The purpose of the present study was to investigate the optimal MFB stimulation parameters for controlling the conditioned behavior of rats. Methods: We evaluated four factors, including intensity, frequency, pulse duration, and train duration, to determine the effect of each on lever pressure applied by animals. We further compared burst and tonic stimulation in terms of learning and performance abilities. Results: The number of lever presses increased with each factor. Animals in the burst stimulation group exhibited more lever presses. Furthermore, the average speed in the 田 maze among burst stimulation group subjects was higher. Conclusion: We determined the optimal parameters for movement control of animals in operant conditioning and locomotor tasks by adjusting various electrical stimulation parameters. Our results reveal that a burst stimulation is more effective than a tonic stimulation for increasing the moving speed and number of lever presses. The use of this stimulation technique also allowed us to minimize the training required to control animal behavior.

Adaptation effects of medial forebrain bundle micro-electrical stimulation

ABSTRACT Brain micro-electrical stimulation and its applications are among the most important issues in the field of brain science and neurophysiology. Deep brain stimulation techniques have been used in different theraputic or alternative medicine applications including chronic pain control, tremor control, Parkinson’s disease control and depression control. Recently, brain electrical stimulation has been used for tele-control and navigation of small animals such as rodents and birds. Electrical stimulation of the medial forebrain bundle (MFB) area has been reported to induce a pleasure sensation in rat which can be used as a virtual reward for rat navigation. In all cases of electrical stimulation, the temporal adaptation may deteriorate the instantaneous effects of the stimulation. Here, we study the adaptation effects of the MFB electrical stimulation in rats. The animals are taught to press a key in an operant conditioning chamber to self-stimulate the MFB region and receive a virtual reward for each key press. Based on the number of key presses, and statistical analyses the effects of adaptation on MFB stimulation is evaluated. The stimulation frequency were changed from 100 to 400 Hz, the amplitude were changed from 50 to 170 µA and the pulse-width were changed from 180 to 2000 µs. In the frequency of 250 Hz the adaptation effect were observed. The amplitude did not show a significant effect on MFB adaptation. For all values of pulse-widths, the adaptation occurred over two consecutive days, meaning that the number of key presses on the second day was less than the first day.

Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines.

Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflammatory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL-17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1β, IL-2, IL-5, IL-6, IL-7, IL-18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations.

Desynchronization of Theta Oscillations in Prefrontal Cortex during Self-stimulation of the Medial Forebrain Bundles in Mice.

Stimulation of the medial forebrain bundle (MFB) can reinforce intracranial self-stimulation (ICSS) in rodents (i.e., reward-seeking behavior). The MFB stimulation produces a highly reliable behavioral output that enabled a clear distinction of the animal behavioral states between the non-ICSS and ICSS periods. However, the cortical states during these reward-seeking behaviors are not fully characterized in comparison to those during volitional behavior. This study was designed to characterize the cortical rhythms of and coherence between prefrontal cortex and hippocampus during the wheel-turning behavior reinforced by the ICSS in comparison to the wheel-turning without ICSS. We used a wheel for freely moving mice, which was programmed to deliver cathode currents through an electrode in the MFB at each one-quarter turn of the wheel to induce ICSS. The wheel-turning epochs were extracted from the pre-ICSS, ICSS and post-ICSS sessions and the prefrontal EEGs and the hippocampal LFPs in the epochs were analyzed with power and synchronization analyses. During the ICSS, the EEG power decreased at 6~10 Hz in the prefrontal cortex, while was not significantly altered in the hippocampus. Furthermore, we found that the phase synchrony between the prefrontal cortex and the hippocampus corresponding to information transmission between the two regions during reward-seeking motion decreased preceding MFB stimulation reinforced by ICSS. Our findings suggest that theta-activity can be reliably dissociated from active behavior if the animal is involved in self-stimulation.