Computational modeling of light processing in the habenula and dorsal raphe based on laser ablation of functionally-defined cells.

BACKGROUND: The habenula is a major regulator of serotonergic neurons in the dorsal raphe, and thus of brain state. The functional connectivity between these regions is incompletely characterized. Here, we use the ability of changes in irradiance to trigger reproducible changes in activity in the habenula and dorsal raphe of zebrafish larvae, combined with two-photon laser ablation of specific neurons, to establish causal relationships. RESULTS: Neurons in the habenula can show an excitatory response to the onset or offset of light, while neurons in the anterior dorsal raphe display an inhibitory response to light, as assessed by calcium imaging. The raphe response changed in a complex way following ablations in the dorsal habenula (dHb) and ventral habenula (vHb). After ablation of the ON cells in the vHb (V-ON), the raphe displayed no response to light. After ablation of the OFF cells in the vHb (V-OFF), the raphe displayed an excitatory response to darkness. After ablation of the ON cells in the dHb (D-ON), the raphe displayed an excitatory response to light. We sought to develop in silico models that could recapitulate the response of raphe neurons as a function of the ON and OFF cells of the habenula. Early attempts at mechanistic modeling using ordinary differential equation (ODE) failed to capture observed raphe responses accurately. However, a simple two-layer fully connected neural network (NN) model was successful at recapitulating the diversity of observed phenotypes with root-mean-squared error values ranging from 0.012 to 0.043. The NN model also estimated the raphe response to ablation of D-off cells, which can be verified via future experiments. CONCLUSION: Lesioning specific cells in different regions of habenula led to qualitatively different responses to light in the dorsal raphe. A simple neural network is capable of mimicking experimental observations. This work illustrates the ability of computational modeling to integrate complex observations into a simple compact formalism for generating testable hypotheses, and for guiding the design of biological experiments.

Neurosurgical relevance of the dissection of the diencephalic white matter tracts using the Klingler technique.

OBJECTIVE: The Klingler fiber dissection technique is a relevant and reliable method for neurosurgery to identify with accuracy the fine structure of the brain anatomy highlighting white matter tracts. In order to demonstrate the significance of the application of this technique, we aimed to observe the course and relations of the mammillothalamic and habenulo-interpeduncular tracts as there are very few papers showing these important diencephalic tracts. MATERIAL AND METHODS: Twelve formalin-fixed brains were dissected using the Klingler technique in order to expose the medial diencephalic surface. Diencephalic white matter tracts, particularly the mammillothalamic and habenulo-interpeduncular tracts, were dissected using wooden spatulas and metallic dissectors with different sizes and tips. Several measurements were performed in both dissected hemispheres relative to the mammillothalamic and habenulo-interpeduncular tracts. RESULTS: The course and length of these two tracts were visualized and the relations with other fiber systems and with the neighboring gray matter structures quantified and registered. The mammillothalamic tract approximately marks the anteroposterior coordinate of the anterior pole of the subthalamic nucleus in the anterior commissure - posterior commissure plane. CONCLUSION: The present study helps to understand the three-dimensional architecture of the white matter systems of tracts when the Klingler technique is used. The numerical data obtained may be helpful to neurosurgeons while approaching brain paraventricular and ventricular lesions and deep brain stimulation. Finally, the anatomical knowledge can lower surgical complications and improve patient care particularly in the field of neurosurgery.

Endoscopic fenestration at the splenial-habenular junctional area for symptomatic cavum and tumor at the foramen of Monro: case reports and anatomical review.

The splenial-habenular junctional area is an alternative site for neuroendoscopic fenestration to divert CSF flow into the quadrigeminal cistern in cases in which endoscopic third ventriculostomy is not amenable. In some patients with obstructive hydrocephalus, the splenium of the corpus callosum can be elevated from the habenular complex. This exposes the membranous connection between the splenium and habenula, which can be fenestrated to divert the CSF flow into the quadrigeminal cistern. This technique can be performed in patients in whom the foramen of Monro or the third ventricle is blocked by a lesion. Here, the authors present 3 complex cases that were managed by neuronavigation-guided transventricular transcavum endoscopic fenestration of the splenial-habenular junctional area. These cases may increase the knowledge and understanding of the anatomy of this region.

A potential target for the treatment of Parkinson's disease: effect of lateral habenula lesions.

OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that is caused predominantly by the degeneration of the nigrostriatal dopaminergic pathway. Lateral habenula (LHb) has efferent projections that terminate in the substantia nigra pars compacta (SNpc) and electrical stimulation of the LHb effectively suppresses the activity of dopamine-containing neurons in the SNpc. This study was aimed to investigate whether LHb lesions can ameliorate the syndromes of PD via affecting the activities of SNpc neurons in 6-hydroxydopamine (6-OHDA)-induced PD model rats. METHODS: Concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, which is the area projected by the SNpc dopaminergic neurons were assayed by high-performance liquid chromatography (HPLC) coupled with fluorescence detection. The immunohistochemical method was applied to detect the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra. RESULTS: The results showed that LHb lesions induced a significant reduction in apomorphine-induced rotational behavior. The DA, DOPAC and HVA levels in the striatum of PD model rats were increased by the LHb lesions. CONCLUSION: Therefore, we speculate that the LHb lesions induced a significant amelioration in motor disorders via increasing the DA levels in the striatum, which may lead to a potential therapeutic strategy for the treatment of PD.

Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression.

In the present study, we aim to determine the antidepressant effects of chronic deep brain stimulation (DBS) of the lateral habenula nucleus (LHb) in a rat model of depression and to explore the potential mechanism of DBS induced improvement of depressive symptoms. To establish the rat depression model, animals were repeatedly exposed to a set of chronic mild stressors for four consecutive weeks. The open-field and sucrose consumption tests were used as measures of depression. For DBS treatment, rats were stereotaxically implanted with electrodes into the LHb and stimulated over a course of 28 d. A separate positive control group was given pharmacotherapy with clomipramine hydrochloride. Open-field testing was used to determine behavioral changes following DBS treatment. Monoamine concentrations in blood and brain tissues were determined by fluorescence spectrophotometry. This study demonstrates that DBS of the LHb region significantly improved depressive-like symptoms in the rat model. These improvements manifested as elevated numbers of crossings and rearings during the open-field test in DBS-treated depressed rats compared to controls. In addition, concentrations of monoamines including norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in blood serum and brain tissues were also increased by DBS of the LHb. Therefore, significant improvements in all outcomes were detected following chronic DBS treatment. These results indicate that long-term DBS treatment of the LHb region effectively improved depressive symptoms in rats, likely as a result of elevated monoamine levels. LHb DBS may therefore provide a valuable therapeutic strategy for the clinical treatment of depression.

Psychosurgery and deep brain stimulation as ultima ratio treatment for refractory depression.

For decades, the most severe, protracted and therapy-resistant forms of major depression have compelled clinicians and researchers to look for last resort treatment. Early psychosurgical procedures were hazardous and often associated with severe and persistent side effects including avolition, apathy and change of personality. With the introduction of psychopharmacological treatments in the 1950s, the frequency of ablative procedures declined rapidly. The past decade, however, has witnessed the resurgence of surgical strategies as a result of refined techniques and advances such as high frequency stimulation of deep brain nuclei. Recent data suggest that the overall effect of high frequency stimulation lies in the functional inhibition of neural activity in the region stimulated. Contrary to other psychosurgical procedures, high frequency stimulation reversibly modulates targeted brain areas and allows a postsurgical adaption of the stimulation parameters according to clinical outcome. With increased understanding of the brain regions and functional circuits involved in the pathogenesis of psychiatric disorders, major depression has emerged as a target for new psychosurgical approaches to selectively and precisely modulate neural areas involved in the disease process. Recent studies of minimally intervening procedures report good clinical outcome in the treatment of therapy-resistant forms of major depression. High frequency stimulation was successfully applied in several small samples of patients with treatment-resistant depression when the stimulation focused on different areas, e.g., nucleus accumbens, the lateral habenula or cortical areas. Nevertheless, the reticence toward psychosurgery, even for those patients suffering from the most debilitating forms of depression, still prevails, even though recent studies have shown significant improvement in terms of quality of life with the limitation that the number of treated cases has been small. In any event, valid and unambiguous criteria for patient eligibility have yet to be refined and standardized. In this review, we suggest possible standard criteria for the application of deep brain stimulation on patients suffering from otherwise treatment-resistant depression.

Targeting the caudal intralaminar nuclei for functional neurosurgery of movement disorders.

The caudal intralaminar nuclei, in particular the Centrum-Medianum Parafascicularis (CM-Pf) nucleus complex, are involved in various functions, particularly in pain processing and in motor control, through their projections to the subthalamic nucleus and their afferents from the pallidum internus (GPi) (or entopeduncular nucleus in the rat). The nociceptive inputs received by the CM-Pf are modulated by the somato-sensory thalamus. The lateral habenula (HbL) receives noxious inputs and has an inhibitory influence on the nigral dopaminergic neurons. CM-Pf and the HbL share comparable response characteristics to noxious inputs and might play comparable, and perhaps complementary, roles in conveying the nociceptive information to the basal ganglia system, thereby modulating motor responses, such as freezing and dyskinesias. The interaction between CM-Pf, HbL, GPi, STN and SNC might provide a new template for high frequency stimulation strategies in the treatment of movement disorders.

Potential surgical targets for deep brain stimulation in treatment-resistant depression.

OBJECT: The goal of this study was to evaluate the definition of treatment-resistant depression (TRD), review the literature regarding deep brain stimulation (DBS) for TRD, and identify potential anatomical and functional targets for future widespread clinical application. METHODS: A comprehensive literature review was performed to determine the current status of DBS for TRD, with an emphasis on the scientific support for various implantation sites. RESULTS: The definition of TRD is presented, as is its management scheme. The rationale behind using DBS for depression is reviewed. Five potential targets have been identified in the literature: ventral striatum/nucleus accumbens, subgenual cingulate cortex (area 25), inferior thalamic peduncle, rostral cingulate cortex (area 24a), and lateral habenula. Deep brain stimulation electrodes thus far have been implanted and activated in only the first 3 of these structures in humans. These targets have proven to be safe and effective, albeit in a small number of cases. CONCLUSIONS: Surgical intervention for TRD in the form of DBS is emerging as a viable treatment alternative to existing modalities. Although the studies reported thus far have small sample sizes, the results appear to be promising. Various surgical targets, such as the subgenual cingulate cortex, inferior thalamic peduncle, and nucleus accumbens, have been shown to be safe and to lead to beneficial effects with various stimulation parameters. Further studies with larger patient groups are required to adequately assess the safety and efficacy of these targets, as well as the optimal stimulation parameters and long-term effects.