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Medial Forebrain Bundle Deep Brain Stimulation (MFB‐DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute‐repetitive DBS are lacking. Long‐Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb‐DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non‐behaving animals. DBS‐induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long‐term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)‐mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration‐dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS. [ABSTRACT FROM AUTHOR]

Abstract 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.

The ability to learn by observing the behavior of others is energy efficient and brings high survival value, making it an important learning tool that has been documented in a myriad of species in the animal kingdom. In the laboratory, rodents have proven useful models for studying different forms of observational learning, however, the most robust learning paradigms typically rely on aversive stimuli, like foot shocks, to drive the social acquisition of fear. Non-fear-based tasks have also been used but they rarely succeed in having observer animals perform a new behavior de novo. Consequently, little known regarding the cellular mechanisms supporting non-aversive types of learning, such as visuomotor skill acquisition. To address this we developed a reward-based observational learning paradigm in adult rats, in which observer animals learn to tap lit spheres in a specific sequence by watching skilled demonstrators, with successful trials leading to rewarding intracranial stimulation in both observers and performers. Following three days of observation and a 24-hour delay, observer animals outperformed control animals on several metrics of task performance and efficiency, with a subset of observers demonstrating correct performance immediately when tested. This paradigm thus introduces a novel tool to investigate the neural circuits supporting observational learning and memory for visuomotor behavior, a phenomenon about which little is understood, particularly in rodents. [ABSTRACT FROM AUTHOR]

Abstract Major Depressive Disorder continues to remain one of the most prevalent psychiatric diseases globally. Despite multiple trials of conventional therapies, a subset of patients fail to have adequate benefit to treatment. Deep brain stimulation (DBS) is a promising treatment in this difficult to treat population and has shown strong antidepressant effects across multiple cohorts. Nearly two decades of work have provided insights into the potential for chronic focal stimulation in precise brain targets to modulate pathological brain circuits that are implicated in the pathogenesis of depression. In this paper we review the rationale that prompted the selection of various brain targets for DBS, their subsequent clinical outcomes and common adverse events reported. We additionally discuss some of the pitfalls and challenges that have prevented more widespread adoption of this technology as well as future directions that have shown promise in improving therapeutic efficacy of DBS in the treatment of depression.

Abstract Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, with a progressive loss of dopaminergic cells and fibers. The purpose of this study was to use different doses of 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB) of mice to mimic the different stages of the disease and to characterize in detail their motor and non-motor behavior, as well as neuropathological features in the nigrostriatal pathway. MFB were injected with 0.5 μg, 1 μg, 2 μg of 6-OHDA using a brain stereotaxic technique. 6-OHDA induced mitochondrial damage dose-dependently, as well as substantia nigra pars compacta (SNpc) tyrosine hydroxylase-positive (TH+) cell loss and striatal TH fiber loss. Activation of astrocytes and microglia in the SNpc and striatum were consistently observed at 7 weeks, suggesting a long-term glial response in the nigrostriatal system. Even with a partial or complete denervation of the nigrostriatal pathway, 6-OHDA did not cause anxiety, although depression-like behavior appeared. Certain gait disturbances were observed in 0.5 μg 6-OHDA lesioned mice, and more extensive in 1 μg group. Despite the loss of more neurons from 2 μg 6-OHDA, there was no further impairment in behaviors compared to 1 μg 6-OHDA. Our data have implications that 1 μg 6-OHDA was necessary and sufficient to induce motor and non-motor symptoms in mice, thus a valuable mouse tool to explore disease progression and new treatment in PD.

There have been several attempts to navigate the locomotion of animals by neuromodulation. The most common method is animal training with electrical brain stimulation for directional cues and rewards; the basic principle is to activate dopamine-mediated neural reward pathways such as the medial forebrain bundle (MFB) when the animal correctly follows the external commands. In this study, the amygdala, which is the brain region responsible for fear modulation, was targeted for punishment training. The brain regions of MFB, amygdala, and barrel cortex were electrically stimulated for reward, punishment, and directional cues, respectively. Electrical stimulation was applied to the amygdala of rats when they failed to follow directional commands. First, two different amygdala regions, i.e., basolateral amygdala (BLA) and central amygdala (CeA), were stimulated and compared in terms of behavior responses, success and correction rates for training, and gene expression for learning and memory. Then, the training was performed in three groups: group R (MFB stimulation for reward), group P (BLA stimulation for punishment), and group RP (both MFB and BLA stimulation for reward and punishment). In group P, after the training, RNA sequencing was conducted to detect gene expression and demonstrate the effect of punishment learning. Group P showed higher success rates than group R, and group RP exhibited the most effective locomotion control among the three groups. Gene expression results imply that BLA stimulation can be more effective as a punishment in the learning process than CeA stimulation. We developed a new method to navigate rat locomotion behaviors by applying amygdala stimulation. [ABSTRACT FROM AUTHOR]

Effective neural stimulation for the treatment of severe psychiatric disorders needs accurate characterisation of surgical targets. This is especially true for the medial subthalamic region (MSR) which contains three targets: the anteromedial STN for obsessive compulsive disorder (OCD), the medial forebrain bundle (MFB) for depression and OCD, and the "Sano triangle" for pathological aggressiveness. Blocks containing the subthalamic area were obtained from two human brains. After obtaining 11.7-Tesla MRI, blocks were cut in regular sections for immunohistochemistry. Fluorescent in situ hybridisation was performed on the macaque MSR. Electron microscopic observation for synaptic specialisation was performed on human and macaque subthalamic fresh samples. Images of human brain sections were reconstructed in a cryoblock which was registered on the MRI and histological slices were then registered. The STN contains glutamatergic and fewer GABAergic neurons and has no strict boundary with the adjacent MSR. The anteromedial STN has abundant dopaminergic and serotoninergic innervation with very sparse dopaminergic neurons. The MFB is composed of dense anterior dopaminergic and posterior serotoninergic fibres, and fewer cholinergic and glutamatergic fibres. Medially, the Sano triangle presumably contains orexinergic terminals from the hypothalamus, and neurons with strong nuclear oestrogen receptor-alpha staining with a decreased anteroposterior and mediolateral gradient of staining. These findings provide new insight regarding MSR cells and their fibre specialisation, forming a transition zone between the basal ganglia and the limbic systems. Our 3D reconstruction enabled us to visualize the main histological features of the three targets which should enable better targeting and understanding of neuromodulatory stimulation results in severe psychiatric conditions. [ABSTRACT FROM AUTHOR]

Receipt of an intense reward boosts motivation to work for more of that reward. This phenomenon is called the priming effect of rewards. Using a novel measurement method, we show that the priming effect of rewarding electrical brain stimulation depends on the cost, as well as on the strength, of the anticipated reward. Previous research on the priming effect of electrical brain stimulation utilized a runway paradigm in which running speed serves as the measure of motivation. In the present study, the measure of motivation was the vigour with which rats executed a two‐lever response chain, in a standard operant‐conditioning chamber, to earn rewarding electrical stimulation of the lateral hypothalamus. In a second experiment, we introduced a modification that entails self‐administered priming stimulation and alternating blocks of primed and unprimed trials. Reliable, consistent priming effects of substantial magnitude were obtained in the modified paradigm, which is closely analogous to the runway paradigm. In a third experiment, the modified paradigm served to assess the dependence of the priming effect on dopamine D2‐like receptors. The priming effect proved resilient to the effect of eticlopride, a selective D2‐like receptor antagonist. These results are discussed within the framework of a new model of brain reward circuitry in which non‐dopaminergic medial forebrain bundle fibers and dopamine axons provide parallel inputs to the final common paths for reward and incentive motivation. [ABSTRACT FROM AUTHOR]

RationaleMethamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/-) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/- on innate and MA-modulated reward sensitivity are not known.ObjectivesWe examined innate reward sensitivity and facilitation by MA in H1+/- mice via intracranial self-stimulation (ICSS).MethodsWe used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5-4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions.ResultsH1+/- mice displayed reduced normalized maximum response rates in response to MA. H1+/- females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior.ConclusionsH1+/- mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/- females (lower normalized M50 values).

• The use of MFB DBS for depression can be efficacious even in those patients who fail DBS at a separate target. • Having both MFB and SCC DBS seems to augment the treatment response in terms of patient-reported HAM-D score. • The increased efficacy of both systems together is likely due to combinatorial targeting of underlying disease networks. [ABSTRACT FROM AUTHOR]

BackgroundAlcohol (ethanol) produces both rewarding and aversive effects, and sensitivity to these effects is associated with risk for an alcohol use disorder (AUD). Measurement of these motivational effects in animal models is an important but challenging aspect of preclinical research into the neurobiology of AUD. Here, we evaluated whether a discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure can be used to assess both reward-enhancing and aversive responses to ethanol in mice.MethodsMale and female C57BL/6J mice were surgically implanted with bipolar stimulating electrodes targeting the medial forebrain bundle and trained on a discrete-trial current-intensity ICSS procedure. Mice were tested for changes in response thresholds after various doses of ethanol (0.5 g/kg-1.75 g/kg; n = 5-7 per dose), using a Latin square design.ResultsA 1 g/kg dose of ethanol produced a significant reward-enhancement (i.e., lowered response thresholds), whereas a 1.75 g/kg dose produced an aversive effect (elevated response thresholds). Ethanol doses from 1 to 1.75 g/kg increased response latencies as compared to saline treatment.ConclusionsThe discrete-trial current-intensity ICSS procedure is an effective assay for measuring both reward-enhancing responses to ethanol as well as aversive responses in the same animal. This should prove to be a useful tool for assessing the effects of experimental manipulations on the motivational effects of ethanol in mice.

[Display omitted] • MFB-ICSS reverses spatial memory deficits in Aβ-injected rats. • MFB-ICSS reserves ptau levels in CA1 and enthorhinal cortex in Aβ rats. • DBN levels in temporal regions are restored in MFB-ICSS treated Aβ rats. • DBN levels and behavioral afectation correlations change after MFB-ICSS. No curative or fully effective treatments are currently available for Alzheimer's disease (AD), the most common form of dementia. Electrical stimulation of deep brain areas has been proposed as a novel neuromodulatory therapeutic approach. Previous research from our lab demonstrates that intracranial self-stimulation (ICSS) targeting medial forebrain bundle (MFB) facilitates explicit and implicit learning and memory in rats with age or lesion-related memory impairment. At a molecular level, MFB-ICSS modulates the expression of plasticity and neuroprotection-related genes in memory-related brain areas. On this basis, we suggest that MFB could be a promising stimulation target for AD treatment. In this study, we aimed to assess the effects of MFB-ICSS on both explicit memory as well as the levels of neuropathological markers ptau and drebrin (DBN) in memory-related areas, in an AD rat model obtained by Aβ icv-injection. A total of 36 male rats were trained in the Morris water maze on days 26–30 after Aβ injection and tested on day 33. Results demonstrate that this Aβ model displayed spatial memory impairment in the retention test, accompanied by changes in the levels of DBN and ptau in lateral entorhinal cortex and hippocampus, resembling pathological alterations in early AD. Administration of MFB-ICSS treatment consisting of 5 post-training sessions to AD rats managed to reverse the memory deficits as well as the alteration in ptau and DBN levels. Thus, this paper reports both cognitive and molecular effects of a post-training reinforcing deep brain stimulation procedure in a sporadic AD model for the first time. [ABSTRACT FROM AUTHOR]

Abstract Objective The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%–5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson’s disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. Methods Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. Results The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. Conclusions The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action. [ABSTRACT FROM AUTHOR]

Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been achieved through the use of deep brain stimulation of the medial forebrain bundle (MFB). The beneficial effect of such stimulation appears strong, safe, and enduring. The proposed neural substrate for this promising clinical finding includes midbrain dopamine neurons and a subset of their cortical afferents. Here, we aim to broaden the discussion of the candidate circuitry by exploring potential implications of a new "convergence" model of brain reward circuitry in rodents. We chart the evolution of the new model from its predecessors, which held that midbrain dopamine neurons constituted an obligatory stage of the final common path for reward seeking. In contrast, the new model includes a directly activated, non-dopaminergic pathway whose output ultimately converges with that of the dopaminergic neurons. On the basis of the new model and the relative ineffectiveness of dopamine agonists in the treatment of depression, we ask whether non-dopaminergic circuitry may contribute to the clinical efficacy of deep brain stimulation of the MFB. [ABSTRACT FROM AUTHOR]

Background: Intracranial self-stimulation (ICSS) is a technique by which rats press a lever to stimulate their brains through an electrode chronically implanted in brain reward areas. Currently only two laboratories in the world, one in India and one in Spain, are intensively studying the effect of this kind of deep brain stimulation on learning and memory. This paper will present the main findings. Methods: Different groups of young and old healthy and braindamaged rats with electrodes implanted in the medial forebrain bundle received a treatment of ICSS after being trained in several paradigms of implicit and explicit learning. Memory was tested over short and long-term periods. Structural and molecular post-mortem analyses of their brains were examined in relation to memory results. Results: ICSS enhances implicit and explicit memory, especially in animals showing poor performance in the learning tasks, such as brain-damaged subjects. At the structural and molecular level, ICSS enhances size and dendritic arborization and promotes neurogenesis in specific hippocampal areas. ICSS also regulates the expression of genes related to learning and memory. Conclusions: Through activating reward and neural plasticity mechanisms, ICSS in the medial forebrain bundle is a promising technique for memory-enhancing treatments. [ABSTRACT FROM AUTHOR]

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferiorthalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD. [ABSTRACT FROM AUTHOR]

Medial Forebrain Bundle Deep Brain Stimulation (MFB-DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute-repetitive DBS are lacking. Long-Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb-DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non-behaving animals. DBS-induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long-term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)-mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration-dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS., (© 2024 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

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. • We performed nose-poke tests using rats. • We delivered electrical stimulation of the rat medial forebrain bundles as a reward. • The nose-poke behavior persisted even after the rewarding stimulation was terminated. • Rats continued to stay around the active nose-poke hole. [ABSTRACT FROM AUTHOR]

The ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) are essential for experiencing pleasure and initiating motivated behaviour. The VTA, NAcc, and PFC are connected through the medial forebrain bundle (MFB). In humans, two branches have been described: an infero-medial branch (imMFB) and a supero-lateral branch (slMFB). This study aimed to explore the associations between structural connectivity of the MFB, functional connectivity (FC) of the VTA, anhedonia, and depression severity in patients with depression. Fifty-six patients with unipolar depression and 22 healthy controls matched for age, sex, and handedness were recruited at the University Hospital of Psychiatry and Psychotherapy in Bern, Switzerland. Diffusion-weighted imaging and resting-state functional magnetic resonance imaging scans were acquired. Using manual tractography, the imMFB and slMFB were reconstructed bilaterally for each participant. Seed-based resting-state FC was computed from the VTA to the PFC. Hedonic tone was assessed using the Fawcett-Clark Pleasure Scale. We identified reduced tract volume and reduced number of tracts in the left slMFB. There was an increase in FC between the VTA and right medial PFC in patients with depression. Depression severity was associated with reduced tract volume and fewer tracts in the left slMFB. Reduced hedonic tone was associated with reduced tract volume. Conversely, reduced hedonic tone was associated with increased FC between the VTA and the PFC. In conclusion, our results suggest reduced structural connectivity of the slMFB in patients with depression. Increases in FC between the VTA and PFC may be associated with anhedonia or compensatory hyperactivity.

The aim of the study is to understand the rationale behind the application of deep brain stimulation (DBS) in the treatment of depression. Male Wistar rats, rendered depressive with chronic unpredictable mild stress (CUMS) were implanted with electrode in the lateral hypothalamus-medial forebrain bundle (LH-MFB) and subjected to deep brain stimulation (DBS) for 4 h each day for 14 days. DBS rats, as well as controls, were screened for a range of parameters indicative of depressive state. Symptomatic features noticed in CUMS rats like the memory deficit, anhedonia, reduction in body weight and 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in mPFC and elevated plasma corticosterone were reversed in rats subjected to DBS. DBS arrested CUMS induced degeneration of 5-HT cells in interfascicular region of dorsal raphe nucleus (DRif) and fibers in LH-MFB and induced dendritic proliferation in mPFC neurons. MFB is known to serve as a major conduit for the DRif-mPFC serotoninergic pathway. While the density of serotonin fibers in the LH-MFB circuit was reduced in CUMS, it was upregulated in DBS-treated rats. Furthermore, microinjection of 5-HT1A receptor antagonist, WAY100635 into mPFC countered the positive effects of DBS like the antidepressant and memory-enhancing action. In this background, we suggest that DBS at LH-MFB may exercise positive effect in depressive rats via upregulation of the serotoninergic system. While these data drawn from the experiments on rat provide meaningful clues, we suggest that further studies aimed at understanding the usefulness of DBS at LH-MFB in humans may be rewarding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation is a promising therapeutic approach for patients with treatment-resistant obsessive-compulsive disorder, a condition linked to abnormalities in corticobasal ganglia networks. Effective targets are placed in one of four subcortical areas with the goal of capturing prefrontal, anterior cingulate, and basal ganglia connections linked to the limbic system. These include the anterior limb of the internal capsule, the ventral striatum, the subthalamic nucleus, and a midbrain target. The goal of this review is to examine these 4 targets with respect to the similarities and differences of their connections. Following a review of the connections for each target based on anatomic studies in nonhuman primates, we examine the accuracy of diffusion magnetic resonance imaging tractography to replicate those connections in nonhuman primates, before evaluating the connections in the human brain based on diffusion magnetic resonance imaging tractography. Results demonstrate that the four targets generally involve similar connections, all of which are part of the internal capsule. Nonetheless, some connections are unique to each site. Delineating the similarities and differences across targets is a critical step for evaluating and comparing the effectiveness of each and how circuits contribute to the therapeutic outcome. It also underscores the importance that the terminology used for each target accurately reflects its position and its anatomic connections, so as to enable comparisons across clinical studies and for basic scientists to probe mechanisms underlying deep brain stimulation. [ABSTRACT FROM AUTHOR]

Objective: The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%–5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. Methods: Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. Results: The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. Conclusions: The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD. [ABSTRACT FROM AUTHOR]

Degeneration of dopamine (DA) neurons in Parkinson's disease (PD) causes hypokinesia, but DA replacement therapy can elicit exaggerated voluntary and involuntary behaviors that have been attributed to enhanced DA receptor sensitivity in striatal projection neurons. Here we reveal that in hemiparkinsonian mice, striatal D1 receptor-expressing medium spiny neurons (MSNs) directly projecting to the substantia nigra reticulata (SNr) lose tonic presynaptic inhibition by GABAB receptors. The absence of presynaptic GABAB response potentiates evoked GABA release from MSN efferents to the SNr and drives motor sensitization. This alternative mechanism of sensitization suggests a synaptic target for PD pharmacotherapy.

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Purpose: Deep brain stimulation (DBS) is a relatively new and still experimental treatment modality for treatment-resistant depression (TRD). There is preliminary evidence that stimulation of brain reward circuit structures or their connecting white matter bundles may exert an antidepressant effect. The main nucleus of the reward circuit is the nucleus accumbens (NAc), which plays a critical role in reward-seeking behavior, motivation, and addiction. Also, white matter bundles connecting different structures of the reward circuit have been studied clinically as targets for DBS, including the medial forebrain bundle (MFB) -- a central com- ponent of the mesolimbic dopaminergic reward circuit. This review aims to present the clinical outcomes of MFB DBS for TRD. Views: The scientific literature was reviewed using the following keywords: 'DBS', 'major depressive disorders', 'TRD', and 'MFB'. The identified studies were assessed on the basis of patient characteristics, clinical outcomes, and adverse events related to DBS. The search revealed five open-label clinical case studies and four case reports reporting the cumulative number of 35 patients treated by MFB DBS for TRD. Conclusions: The current clinical data of MFB DBS are limited by small sample size and the small number of clinical open-label trials. There is an urgent need for more clinical trials targeting the MFB for TRD. The results obtained in these studies showed a very rapid antidepressant effect observed within one week after the start of stimulation. MFB DBS for TRD should be considered as a last resort treatment due to its invasive character. However, this treatment may be a promising alternative for TRD patients. [ABSTRACT FROM AUTHOR]

Navigation requires coordination of egocentric and allocentric spatial reference frames and may involve vectorial computations relative to landmarks. Creation of a representation of target heading relative to landmarks could be accomplished from neurons that encode the conjunction of egocentric landmark bearings with allocentric head direction. Landmark vector representations could then be created by combining these cells with distance encoding cells. Landmark vector cells have been identified in rodent hippocampus. Given remembered vectors at goal locations, it would be possible to use such cells to compute trajectories to hidden goals. To look for the first stage in this process, we assessed parietal cortical neural activity as a function of egocentric cue light location and allocentric head direction in rats running a random sequence to light locations around a circular platform. We identified cells that exhibit the predicted egocentric-by-allocentric conjunctive characteristics and anticipate orienting toward the goal.

Abstract Background Prepulse inhibition (PPI) of the acoustic startle response, a measurement of sensorimotor gaiting, is modulated by monoaminergic, presumably dopaminergic neurotransmission. Disturbances of the dopaminergic system can cause deficient PPI as found in neuropsychiatric diseases. A target specific influence of deep brain stimulation (DBS) on PPI has been shown in animal models of neuropsychiatric disorders. In the present study, three patients with early dementia of Alzheimer type underwent DBS of the median forebrain bundle (MFB) in a compassionate use program to maintain cognitive abilities. This provided us the unique possibility to investigate the effects of different stimulation conditions of DBS of the MFB on PPI in humans. Results Separate analysis of each patient consistently showed a frequency dependent pattern with a DBS-induced increase of PPI at 60 Hz and unchanged PPI at 20 or 130 Hz, as compared to sham stimulation. Conclusions Our data demonstrate that electrical stimulation of the MFB modulates PPI in a frequency-dependent manner. PPI measurement could serve as a potential marker for optimization of DBS settings independent of the patient or the examiner.

Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been achieved through the use of deep brain stimulation of the medial forebrain bundle (MFB). The beneficial effect of such stimulation appears strong, safe, and enduring. The proposed neural substrate for this promising clinical finding includes midbrain dopamine neurons and a subset of their cortical afferents. Here, we aim to broaden the discussion of the candidate circuitry by exploring potential implications of a new “convergence” model of brain reward circuitry in rodents. We chart the evolution of the new model from its predecessors, which held that midbrain dopamine neurons constituted an obligatory stage of the final common path for reward seeking. In contrast, the new model includes a directly activated, non-dopaminergic pathway whose output ultimately converges with that of the dopaminergic neurons. On the basis of the new model and the relative ineffectiveness of dopamine agonists in the treatment of depression, we ask whether non-dopaminergic circuitry may contribute to the clinical efficacy of deep brain stimulation of the MFB.

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action.

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress‐related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post‐traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Lower reward responsiveness has been associated with fatigue in multiple sclerosis (MS). However, association of MS‐related fatigue with damage to the mesocorticolimbic reward pathway (superolateral medial forebrain bundle [slMFB]) has not been assessed. We investigated the association of fatigue and depression with slMFB damage in MS patients stratified based on longitudinal fatigue patterns. METHODS: Patient stratification: 1. Sustained Fatigue (SF): latest two Modified Fatigue Impact Scale (MFIS) ≥ 38 (n = 26); 2. Reversible Fatigue (RF): latest MFIS < 38, and at least one previous MFIS ≥ 38 (n = 25); 3. Never Fatigued (NF): ≥ 5 consecutive MFIS < 38 (n = 42); 4. Healthy Controls (n = 6). Diffusion MRI‐derived measures of fractional anisotropy (FA), axial (AD), mean (MD), and radial diffusivity (RD) of the slMFB were compared between the groups. Depression was assessed using the Center for Epidemiologic Studies‐Depression Scale (CES‐D). RESULTS: Depressed (CES‐D ≥ 16) SF patients showed significantly higher MD and RD than nondepressed SF and RF, and depressed RF patients, and significantly lower FA than nondepressed SF and depressed RF patients in their left slMFB. Depressed SF patients showed significantly higher left slMFB MD and AD than healthy controls. CONCLUSION: Microstructural changes to the left slMFB may play a role in the comorbid development of fatigue and depression in MS. [ABSTRACT FROM AUTHOR]

Objective: Major depression affects millions of people worldwide and has important social and economic consequences. Since up to 30% of patients do not respond to several lines of antidepressive drugs, deep brain stimulation (DBS) has been evaluated for the management of treatment-resistant depression (TRD). The superolateral branch of the medial forebrain bundle (slMFB) appears as a "hypothesis-driven target" because of its role in the reward-seeking system, which is dysfunctional in depression. Although initial results of slMFB-DBS from open-label studies were promising and characterized by a rapid clinical response, long-term outcomes of neurostimulation for TRD deserve particular attention. Therefore, we performed a systematic review focused on the long-term outcome of slMFB-DBS., Materials and Methods: A literature search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria was conducted to identify all studies reporting changes in depression scores after one-year follow-up and beyond. Patient, disease, surgical, and outcome data were extracted for statistical analysis. The Montgomery-Åsberg Depression Rating Scale (ΔMADRS) was used as the clinical outcome, defined as percentage reduction from baseline to follow-up evaluation. Responders' and remitters' rates were also calculated., Results: From 56 studies screened for review, six studies comprising 34 patients met the inclusion criteria and were analyzed. After one year of active stimulation, ΔMADRS was 60.7% ± 4%; responders' and remitters' rates were 83.8% and 61.5%, respectively. At the last follow-up, four to five years after the implantation, ΔMADRS reached 74.7% ± 4.6%. The most common side effects were stimulation related and reversible with parameter adjustments., Conclusions: slMFB-DBS appears to have a strong antidepressive effect that increases over the years. Nevertheless, to date, the overall number of patients receiving implantations is limited, and the slMFB-DBS surgical technique seems to have an important impact on the clinical outcome. Further multicentric studies in a larger population are needed to confirm slMFB-DBS clinical outcomes., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Abstract Background Intracranial Self-Stimulation (ICSS) of the medial forebrain bundle (MFB) is a deep brain stimulation procedure, which has a powerful enhancement effect on explicit and implicit memory. However, the downstream synaptic plasticity events of MFB-ICSS in memory related areas have not been described thoroughly. This study complements previous work studying the effect of MFB-ICSS on the expression of the activity-regulated cytoskeleton-associated (Arc) protein, which has been widely established as a synaptic plasticity marker. We provide new integrated measurements from memory related regions and take possible regional hemispheric differences into consideration. Results Arc protein expression levels were analyzed 4.5 h after MFB-ICSS by immunohistochemistry in the hippocampus, habenula, and memory related amygdalar and thalamic nuclei, in both the ipsilateral and contralateral hemispheres to the stimulating electrode location. MFB-ICSS was performed using the same paradigm which has previously been shown to facilitate memory. Our findings illustrate that MFB-ICSS upregulates the expression of Arc protein in the oriens and radiatum layers of ipsilateral CA1 and contralateral CA3 hippocampal regions; the hilus bilaterally, the lateral amygdala and dorsolateral thalamic areas as well as the central medial thalamic nucleus. In contrast, the central amygdala, mediodorsal and paraventricular thalamic nuclei, and the habenular complex did not show changes in Arc expression after MFB-ICSS. Conclusions Our results expand our knowledge of which specific memory related areas MFB-ICSS activates and, motivates the definition of three functionally separate groups according to their Arc-related synaptic plasticity response: (1) the hippocampus and dorsolateral thalamic area, (2) the central medial thalamic area and (3) the lateral amygdala.

It is important to monitor serotonin neurochemistry in the context of brain disorders. Specifically, a better understanding of biophysical alterations and associated biochemical functionality within subregions of the brain will enable better of understanding of diseases such as depression. Fast voltammetric tools at carbon fiber microelectrodes provide an opportunity to make direct evoked and ambient serotonin measurements in vivo in mice. In this study, we characterize novel stimulation and measurement circuitries for serotonin analyses in brain regions relevant to psychiatric disease. Evoked and ambient serotonin in these brain areas, the CA2 region of the hippocampus and the medial prefrontal cortex, are compared to ambient and evoked serotonin in the substantia nigra pars reticulata, an area well established previously for serotonin measurements with fast voltammetry. Stimulation of a common axonal location evoked serotonin in all three brain regions. Differences are observed in the serotonin release and reuptake profiles between these three brain areas which we hypothesize to arise from tissue physiology heterogeneity around the carbon fiber microelectrodes. We validate this hypothesis mathematically and via confocal imaging. We thereby show that fast voltammetric methods can provide accurate information about local physiology and highlight implications for chemical mapping. Cover Image for this issue: doi: 10.1111/jnc.14739. [ABSTRACT FROM AUTHOR]

The clinicoanatomic cases of acquired pedophilia that have been published in the medical and forensic literature up to 2019 are reviewed. Twenty-two cases fit our inclusion criteria. All but one were men, and in only one case the injury was localized to the left hemisphere. Hypersexuality was present in 18 cases. The damaged areas fell within the frontotemporoinsular cortices and related subcortical nuclei; however, the anterior hypothalamus was spared. Damage to parts of the right frontotemporoinsular lobes with sparing of the anterior hypothalamus seems to be critical for the emergence of acquired pedophilia. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) can reverse depressive-like symptoms clinically and in experimental models of depression, but the mechanisms of action are unknown. Objectives: This study investigated the role of dopaminergic mechanisms in MFB stimulation-mediated behavior changes, in conjunction with raclopride administration and micropositron emission tomography (micro-PET). Methods: Flinders Sensitive Line (FSL) rats were allocated into 4 groups: FSL (no treatment), FSL+ (DBS), FSL.R (FSL with raclopride), and FSL.R+ (FSL with raclopride and DBS). Animals were implanted with bilateral electrodes targeting the MFB and given 11 days access to raclopride in the drinking water with or without concurrent continuous bilateral DBS over the last 10 days. Behavioral testing was conducted after stimulation. A PET scan using [18F]desmethoxyfallypride was performed to determine D2 receptor availability before and after raclopride treatment. Changes in gene expression in the nucleus accumbens and the hippocampus were assessed using quantitative polymerase chain reaction. Results: Micro-PET imaging showed that raclopride administration blocked 36% of the D2 receptor in the striatum, but the relative level of blockade was reduced/modulated by stimulation. Raclopride treatment enhanced depressive-like symptoms in several tasks, and the MFB DBS partially reversed the depressive-like phenotype. The raclopride-treated MFB DBS animals had increased levels of mRNA coding for dopamine receptor D1 and D2 suggestive of a stimulation-mediated increase in dopamine receptors. Conclusion: Data suggest that chronic and continuous MFB DBS could act via the modulation of the midbrain dopaminergic transmission, including impacting on the postsynaptic dopamine receptor profile. [ABSTRACT FROM AUTHOR]