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The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging
Accepted Manuscript Review The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging Georgios P. Skandalakis, Christos Koutsarnakis, Aristotelis V. Kalyvas, Panagiotis Skandalakis, Elizabeth O. Johnson, George Stranjalis PII: DOI: Reference:
S0006-8993(18)30243-9 https://doi.org/10.1016/j.brainres.2018.04.041 BRES 45781
To appear in:
Brain Research
Received Date: Revised Date: Accepted Date:
8 November 2017 28 April 2018 30 April 2018
Please cite this article as: G.P. Skandalakis, C. Koutsarnakis, A.V. Kalyvas, P. Skandalakis, E.O. Johnson, G. Stranjalis, The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging, Brain Research (2018), doi: https://doi.org/10.1016/j.brainres.2018.04.041
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The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging. Georgios P. Skandalakis, BBA, MSc1-4*, Christos Koutsarnakis, MD1-3, Aristotelis V. Kalyvas, MD, MSc1-3, Panagiotis Skandalakis, MD, PhD 3,4, Elizabeth O. Johnson, PhD3,4, George Stranjalis, MD, PhD1,2
1
Athens Microneurosurgery Laboratory, National and Kapodistrian University of Athens Medical School, Greece 2
Department of Neurosurgery, Evangelismos General Hospital, National and Kapodistrian University of Athens Medical School, Greece 3
Department of Anatomy and Surgical Anatomy, National and Kapodistrian University of Athens Medical School, Greece 4
Laboratory for Education and Research in Neurosciences (LERNs), National and Kapodistrian University of Athens Medical School, Greece
Corresponding author: Georgios P. Skandalakis, National & Kapdistrian University of Athens, Mikras Asias 75, Goudi 11527, Athens, Greece. Email: [email protected]
Abstract Background: The habenula is a small, mostly underrated structure in the pineal region. Multidisciplinary findings demonstrate an underlying complex connectivity of the habenula with the rest of the brain, subserving its major role in normal behavior and the pathophysiology of depression. These findings suggest the potential application of “habenular psychosurgery” in the treatment of mental disorders.
Objective/Hypothesis: The remission of two patients with treatment-resistant major depression treated with deep brain stimulation of the habenula supported the hypothesis that the habenula is an effective target for deep brain stimulation and initiated a surge of basic science research. This review aims to assess the viability of the deep brain stimulation of the habenula as a treatment option for treatment resistant depression.
Methods: PubMed and the Cochrane Library databases were searched with no chronological restrictions for the identification of relevant articles.
Results: The results of this review are presented in a narrative form describing the functional neuroanatomy of the human habenula, its implications in major depression, findings of electrode implantation of this region and findings of deep brain stimulation of the habenula for the treatment of depression.
Conclusion: Data assessing the hypothesis are scarce. Nonetheless, findings highlight the major role of the habenula in normal, as well as in pathological brain function, particularly in depression disorders. Moreover, findings of studies utilizing electrode implantation in the region of the habenula underscore our growing realization that research in neuroscience and deep brain stimulation complement each other in a reciprocal relationship; they are as self-reliant, as much as they depend on each other.
Keywords: Depression, TRD, habenula, psychosurgery, deep brain stimulation, DBS
Abbreviations/Acronyms: HB = habenula, LHb = lateral habenula, MHb = medial habenula, VTA = ventral tegmental area, SN= Substantia nigra DBS= deep brain stimulation, TRD =Treatment Resistant Depression, ElectroConvulsive Therapy = ECT
Introduction
Advances in functional neuroanatomy, biological psychiatry, neurobiology, functional imaging and stereotaxy are now converging to support a more behaviorally relevant, functional neurosurgical approach to treat psychiatric disorders.1 Moreover, the idea of using neurosurgery as a treatment option for Major Depression Disorder (MDD) has gained support over the last years.2 Major Depression Disorder is a disabling psychiatric disorder with a high incidence.3 Among the characteristics that constitute the diagnostic features established by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) which include depressed mood, anhedonia or loss of interest, appetite changes, sleep disturbances, suicidal ideation and increased guilt, depressed patients also have maladaptive responses to the prediction of and responses to negative events and feedback.4,5 The underlying neuroanatomical and neurocircuitry correlates of depression and stress-like disorders have long been the focus of neuroscientists.6,7 In addition, the habenula has been proposed to be intimately involved in the reward pathways. Consequently, it is believed to contribute to the prediction and response to negative outcomes.5
Although the anatomy of the habenula has been studied throughout the past century, with a noteworthy detailed anatomical study by Marburg in 1944,8 this small conserved part of the epithalamus has been largely ignored until recently. New founded interest in the habenula is attributed to novel findings indicating that the habenula is activated in the stress response, and is connected with other regions that exert direct effects on emotion and behavior.9,10 The habenula is implicated in several emotional and cognitive processes, because of its abundant connections with structures of the prefrontal cortex, basal forebrain, limbic system, basal ganglia and the brainstem monoaminergic neurotransmitter systems.10,11
Treatment-refractory depression (TRD) is defined as “the lack of clinical response after adequate pharmacotherapy has been attempted”12 or the lack of achieving remission after two or more antidepressant schemes.13 Today, DBS of defined anatomical regions, such as the subcallosal cingulate cortex, ventral striatum, ventral capsule and medial forebrain bundle, that have been implicated in the circuitry of depression has been effectively used for the treatment of TRD patients.14 Among the potential targets of DBS for the management of TRD the habenula has been proposed as a viable option, and has resulted in the successful treatment of two patients with severe TRD.15
The aim of this paper is to address the data assessing the viability of the habenula as a target for DBS in the treatment of TRD. To do this, we review the most important features regarding the functional anatomy of the human habenula and discuss the recent patient findings supporting its involvement in the pathophysiology of MDD. A brief history of the neurophysiological findings from animal studies involving surgically implanted electrodes to stimulate the habenula is also presented. These findings have served as the impetus of a recent surge of studies, including the application of DBS in TRD patients and several animal studies aiming to assess the effects of the DBS of the habenula in the treatment of MDD.
Historical Background Examples of efforts to influence human behavior by altering the brain structure have been recorded long before the advent of modern psychosurgery in the 19th century.
Trephinations, which were performed by Shamans to relieve spiritual or psychiatric disturbances, have been documented from the Neolithic Period.16 In 1891, Burckhardt performed the first topectomies in “pathologic” brain areas with the aim to treat behavioral disturbances.17
The beginning of modern psychosurgery was marked by the work of Egas Moniz, a Portuguese neurologist, who conducted a neurosurgical clinical trial for the treatment of psychiatric disorders, including depression, schizophrenia, panic disorder and bipolar disorder, by using the technique of prefrontal leucotomy.18 Based on Moniz’s findings, Walter Freeman and James Watts performed prefrontal lobectomies through bilateral transorbital burr holes (the so-called, transorbital “ice pick lobotomy”). Despite the lack of long-term objective data, Moniz’s study generated considerable interest and enthusiasm, resulting in Moniz receiving the Nobel Prize in Medicine and Physiology in 1949.19 The prefrontal leucotomy was subsequently widely used in the USA, with more than 50,000 procedures being performed in the 1940s and 1950s.19,20 While there was some symptomatic improvement in the broad spectrum of psychiatric patients studied, the crude lesions produced by the procedure resulted in adverse effects and consequently, raised questions regarding the outcomes and ethical concerns.18 With the advent of psychopharmacology, psychosurgery slowly began to decline and despite its controversial evolution, psychosurgery was finally defined in 1976 by the World Health Organization as “the selective surgical removal or destruction of nerve pathways for the purposes of influencing behavior” 21
Studies in neurosurgery continued, focusing on more clearly defined psychiatric conditions, and on more carefully defined and significantly smaller brain lesions such as the anterior cingulotomy, obtained by using more precise instrumentation, such as radiofrequency lesioning or gamma knife irradiations. The main disadvantage of these ablative treatment modalities is that they are irreversible. Because of the reversibility of its effects and the ability to vary both the sites and parameters of stimulation, deep brain stimulation (DBS) has gained support as a possible treatment option for psychiatric disorders. Today, neurosurgeons have gained the ability to safely target regions of the brain smaller than half centimeter through DBS resulting in the remission of specific psychiatric diseases such as major depression disorder.14
Functional neuroanatomy The brain region defined as the habenula (Hb) consists of nuclei located bilaterally on the dorsomedial surfaces of the thalami, lateral to the third ventricle and anterior to the pineal recess. The Hb nuclei are divided into two groups, the lateral Hb (LHb) and the medial Hb (MHb) nuclei, which are interconnected via the habenular commissure. The habenular commissure runs superior to the pineal recess, whereas the posterior commissure runs inferiorly (Fig.1).22
Strategically located in one of the central-most regions of the brain, the habenular nuclei are connected, mainly through the stria medullaris and the fasciculus retroflexus, with the majority of central core of the brain namely the thalamus, the bed nucleus of the stria terminalis, the head of the caudate, the putamen, globus pallidus internus, posterior insular cortex, the amygdalar nuclei, posterior hippocampus, septal nuclei, basal nucleus of Meynert, medial prefrontal cortex, the periaqueductal gray matter, ventral tegmental area (VTA), substantial nigra (SN), dorsal raphe nuclei and interpenducular nucleus, in addition to numerous cortical structures such as the inferior frontal gyrus, the cingulate, retrosplenial and calcarine cortices and Heschl’s gyrus, as revealed by white matter dissections and radiological studies. 23-28 Although animal studies have described the connectivity of the habenula in great detail,9 studies in humans have yet to distinguish which connections are afferent and which are efferent as well as which connections concern the LHb and which the MHb.29 While data on the connectivity of the habenula have derived from both animal and human studies, for the sake of specificity this section is limited in findings coming from human studies.
While the LHb and MHb have been distinguished both in radiological and histological studies, differences in their connectivity with other regions have not been rigorously established in human studies.29 In general, it appears that the LHb seems to be mostly connected with the forebrain and limbic system, while the MHb is mainly connected to the brainstem and habenular commisure30,31
The habenular nuclei are connected to the serotonergic system through the dorsal raphe nucleus, to the dopaminergic system through the VTA and SN, and to the noradrenergic system through the locus ceruleus. The habenular function in the cholinergic system is mediated through its anatomical connectivity to the basal nucleus of Meynert 29 which is regarded as the primary cholinergic projection system to the cortex32.
Besides revealing connectivity, fMRI studies of healthy subjects have also provided most of the findings regarding the functional significance of the habenula by assessing its activation in response to specific tasks or induced stimuli.
Such studies have identified activation of the habenula during multiple learning tasks; therefore, revealing its key role in learning and motivation.33 In addition, evidence supports its participation in the process of error detection and the ability to adjust accordingly through a circuit involving the VTA, SN and the amygdala.24 A similar study in healthy volunteers has disclosed a tight functional correlation of habenular nuclei to the negative reward prediction errors.34 Recent research has also linked the habenula to the processing of aversive stimuli through its connection to the VTA, in a circuit that also involves the dopaminergic projections of the VTA to the putamen and medial prefrontal cortex.25 Finally, a study mapping the activation of the habenula following administration of painful thermal stimuli, suggests that it has a role in the perception of pain.35
Pathophysiological implications Regardless of its small size, the habenula appears to play a central role in the pathophysiology of depression. This has been supported by several animal studies over the last decades.31 There is some, albeit limited evidence in humans, deriving mainly from histological and radiological studies (MRI- fMRI) in patients suffering from MDD, which shows differences in the volume of the habenula in addition to alterations in its activation pattern.
Structural findings Studies assessing the structural changes of the habenula associated with MDD have revealed interesting but also inconsistent findings. A post-mortem brain study investigating the
morphology of the habenula in MDD and schizophrenic patients reported that MDD patients had a smaller habenula volume compared to control subjects; a finding not observed in schizophrenic patients.36 Significantly increased habenula volumes were also found in drug-naive MDD patients in an MRI study that compared habenula volumes among drug-naive, medicated MDD patients and healthy controls.37 In contrast, other studies have reported smaller habenular sizes in MDD patients, as compared to healthy subjects, a finding, however, that was not statistically significant. Nonetheless, their post-hoc analysis showed significantly smaller habenular volumes in female patients suffering from MDD.38,39 Additionally, smaller habenular volumes were found in TRD patients when compared to healthy subjects, as reported in a recent MRI study.40 A radiologic study that sought to compare the habenular volume of MDD patients in different phases of their disease, documented smaller sizes only in female patients undergoing their first depressive episode.36 Interesting findings also derive from a study that assessed the habenular volume of MDD patients before and after ElectroConvulsive Therapy (ECT), which showed a significant increase in the habenular grey matter two weeks following ECT.41
Functional findings The habenula is involved in the serotonergic system by modulating the activity of the median and dorsal raphe nuclei directly through its efferent projection fibers and indirectly via the forebrain, which projects to the habenula and likewise controls the raphe nuclei. These findings implicate this small structure in the pathophysiology of MDD. This suggestion is also supported by radiological studies that document its over-activation in MDD. 42 More specifically, fMRI studies showed increased activity of the habenula and raphe nuclei in induced tryptophan depleted states.42,43 Furthermore, Furman & Gotlib who studied the activation patterns of the LHb in response to negative and to positive feedback, demonstrated a more profound activation of the LHb in negative rather than positive feedback responses in both MDD patients and healthy controls. Surprisingly though, this study also reported a left lateralized hypo-activation in response to negative feedback among the depressed patients when compared to healthy controls.5 A recent report investigating phasic habenula function in MDD patients during anticipation of an aversive stimulus, showed abnormal responses compared to those of healthy volunteers. More specifically, the habenula activation pattern was assessed in a group of MDD patients and a
healthy control group performing classical (Pavlovian) conditioning tasks in which an electric shock was the unconditioned stimulus. Interestingly, habenular responses decreased within the patient group, as the unconditioned stimulus became progressively more shock predicting. In contrast, healthy volunteers showed increased habenular responses as the conditioned stimulus became more shock predicting.44
Surgical applications
Initial data regarding the effects of electrode implantation in the habenula of mice were published in 1989 and 1992. These studies monitored the levels of specific neurotransmitter levels through implanted probes in various brain areas during stimulation of the LHb. In addition, they also explored the means by which habenular stimulation would increase the levels of those neurotransmitters through induced lesions in specific bundles or nuclei. The authors reported that LHb stimulation induced increased serotonin levels in the striatum mediated through the dorsal raphe nucleus, 45 along with increased noradrenaline levels in the hippocampus, 46 medial frontal cortex and nucleus accumbens 47 via fibers of the dorsal noradrenergic bundle and fasciculus retroflexus. 45-47 More recently, a study in primates investigated the effect of habenular electrode implantation in reward circuits, in which stimulation of the habenula inhibited dopaminergic neurons of the subtantia nigra (SN).48
In 2007, Sartorius and colleagues proposed the habenula as a potential target for DBS in the treatment of depression.49 The authors reviewed the pathophysiology of depression in relation to altered serotonin and norepinephrine levels, noting the correlation of habenular function to these neurotransmitters and the general role of the habenula in depression. Furthermore, the authors proposed a set of clinical characteristics of MDD patients which could benefit from treatment with habenular DBS. They have also postulated that the effects of habenular DBS could be demonstrated by a case of a treatment resistant MDD patient who underwent successful DBS of the inferior thalamic peduncle area.50 This hypothesis was based on the fact that this DBS target also resulted in the functional inhibition of the stria medullaris, which is the main afferent tract of the habenula. Finally, the authors claimed that the antidepressive effect of habenular DBS
could be achieved by high frequency stimulation of its afferent projections, since data show that in this way habenular serotonergic projections to the dorsal raphe nucleus are inhibited while GABAergic projections are spared.49 The first case of habenular DBS for the treatment of resistant MDD was reported in 2010.51 A 64 year-old woman who had been suffering from MDD since the age of 18 and for the last nine years was unresponsive both to medical and electroconvulsive therapy underwent bilateral DBS of the habenular region and reportedly had complete remission after 4 months of high frequency stimulation.51 A second case of resistant MDD was also treated with habenular DBS resulting again in its gradual complete remission.52 Notably, the authors state that the electrode trajectory should target the lateral habenular complex, which includes the stria medullaris apart from the LHb, to ensure that this fiber tract is also sufficiently stimulated.52 Thus, it is important to clarify that the treatment effect could be possibly attributed to the stimulation of the stria medullaris and not to the LHb itself. Moreover, the authors state that both patients experienced a rapid relapse when the pacemaker stopped working followed by a slow remission after the stimulation was restored. These findings contradict the immediate effect seen in DBS for neurological disorders and could be attributed to brain plasticity procedures.15 Long term outcome data of these cases or additional reports have not been published since.
Paradoxically, animal studies investigating the role of habenular DBS for the treatment of depression succeeded that of human patients. Aiming to elucidate the underlying mechanism of DBS of the habenula for the treatment of depression, these studies have also aided in understanding the more global effects of DBS on brain function and neuroplasticity.
In 2011 an animal study on models of depression in mice showed that DBS of the LHb ameliorated depressive symptoms, resulting in the reduction of the learned helplessness behaviors. The mechanism underlying this behavioral change induced by the DBS was attributed to the suppression of the habenula’s efferent projections to the VTA.53 In the same direction, another mice study which demonstrated relief of depressive symptoms following DBS of the LHb suggested that this could be attributed to increased monoamine neurotransmitter levels (serotonin, dopamine and noradrenaline) measured in the depressive rats undergoing DBS in
contrast to the lower neurotransmitters levels measured in the non-treated depressed rats.54 Finally, the rationale of habenular DBS for MDD is also supported by a recent study in mice that explored additional molecular mechanisms involving the calcium/calmodulin dependent Kinase Type II, glycogen synthase kinase 3 and AMP-activated protein kinase. Phosphorylation of these proteins was positively correlated with the therapeutic effects of DBS.55
Conclusion While the initial findings support the hypothesis that the habenula may serve as an effective target for DBS in the management of complex neuropsychiatric disorders, such as MMD, data are very scarce (only two patients underwent habenular DBS) and have not been replicated. In addition, long-term outcome data of these two patients have not been published. Moreover, due to the concurrent targeting of the stria medullaris thalami in the aforementioned cases, the treatment effect could also be attributed to stimulation of this specific tract and not to the habenula itself. As such, whether the habenula is an effective target for DBS of patients with TRD remains subject to question. Nevertheless, data in the literature highlight the role of the habenula in normal, as well as pathological brain function and particularly in depression disorders. Thus, more studies are needed in order to enhance our anatomical and functional knowledge of the human habenula and document its potential implication in modern psychosurgery. References
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25. Hennigan K, D'Ardenne K, McClure SM. Distinct midbrain and habenula pathways are involved in processing aversive events in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience. Jan 07 2015;35(1):198-208. 26. Kim JW, Naidich TP, Ely BA, et al. Human habenula segmentation using myelin content. NeuroImage. Apr 15 2016;130:145-156. 27. Munte TF, Marco-Pallares J, Bolat S, et al. The human globus pallidus internus is sensitive to rewards - Evidence from intracerebral recordings. Brain stimulation. Feb 14 2017. 28. Silva SM, Cunha-Cabral D, Andrade JP. Neurosurgical relevance of the dissection of the diencephalic white matter tracts using the Klingler technique. Clinical neurology and neurosurgery. Mar 02 2017;156:35-40. 29. Torrisi S, Nord CL, Balderston NL, Roiser JP, Grillon C, Ernst M. Resting state connectivity of the human habenula at ultra-high field. NeuroImage. Feb 15 2017;147:872-879. 30. Strotmann B, Heidemann RM, Anwander A, et al. High-resolution MRI and diffusionweighted imaging of the human habenula at 7 tesla. Journal of magnetic resonance imaging : JMRI. Apr 2014;39(4):1018-1026. 31. Fakhoury M. The habenula in psychiatric disorders: More than three decades of translational investigation. Neuroscience and biobehavioral reviews. Feb 13 2017. 32. Li CS, Ide JS, Zhang S, Hu S, Chao HH, Zaborszky L. Resting state functional connectivity of the basal nucleus of Meynert in humans: in comparison to the ventral striatum and the effects of age. NeuroImage. Aug 15 2014;97:321-332. 33. Lawson RP, Seymour B, Loh E, et al. The habenula encodes negative motivational value associated with primary punishment in humans. Proceedings of the National Academy of Sciences of the United States of America. Aug 12 2014;111(32):11858-11863. 34. Salas R, Baldwin P, de Biasi M, Montague PR. BOLD Responses to Negative Reward Prediction Errors in Human Habenula. Frontiers in human neuroscience. 2010;4:36. 35. Shelton L, Pendse G, Maleki N, et al. Mapping pain activation and connectivity of the human habenula. Journal of neurophysiology. May 2012;107(10):2633-2648. 36. Ranft K, Dobrowolny H, Krell D, Bielau H, Bogerts B, Bernstein HG. Evidence for structural abnormalities of the human habenular complex in affective disorders but not in schizophrenia. Psychological medicine. 2010;40(04):557-567. 37. Schmidt FM, Schindler S, Adamidis M, et al. Habenula volume increases with disease severity in unmedicated major depressive disorder as revealed by 7T MRI. European archives of psychiatry and clinical neuroscience. Mar 2017;267(2):107-115. 38. Savitz JB, Nugent AC, Bogers W, et al. Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging study. Biological psychiatry. 2011;69(4):336-343. 39. Savitz JB, Rauch SL, Drevets WC. Reproduced from Habenula volume in bipolar disorder and major depressive disorder: a high-resolution magnetic resonance imaging study. Molecular psychiatry. May 2013;18(5):523. 40. Johnston BA, Steele JD, Tolomeo S, Christmas D, Matthews K. Structural MRI-Based Predictions in Patients with Treatment-Refractory Depression (TRD). PloS one. 2015;10(7):e0132958. 41. Sartorius A, Demirakca T, Bohringer A, et al. Electroconvulsive therapy increases temporal gray matter volume and cortical thickness. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. Mar 2016;26(3):506-517.
42. Morris JS, Smith KA, Cowen PJ, Friston KJ, Dolan RJ. Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. NeuroImage. Aug 1999;10(2):163-172. 43. Roiser JP, Levy J, Fromm SJ, et al. The effects of tryptophan depletion on neural responses to emotional words in remitted depression. Biological psychiatry. Sep 01 2009;66(5):441-450. 44. Lawson RP, Nord CL, Seymour B. Disrupted habenula function in major depression. Feb 2017;22(2):202-208. 45. Kalen P, Strecker RE, Rosengren E, Bjorklund A. Regulation of striatal serotonin release by the lateral habenula-dorsal raphe pathway in the rat as demonstrated by in vivo microdialysis: role of excitatory amino acids and GABA. Brain research. Jul 17 1989;492(1-2):187-202. 46. Kalen P, Lindvall O, Bjorklund A. Electrical stimulation of the lateral habenula increases hippocampal noradrenaline release as monitored by in vivo microdialysis. Experimental brain research. 1989;76(1):239-245. 47. Cenci MA, Kalen P, Mandel RJ, Bjorklund A. Regional differences in the regulation of dopamine and noradrenaline release in medial frontal cortex, nucleus accumbens and caudateputamen: a microdialysis study in the rat. Brain research. May 29 1992;581(2):217-228. 48. Matsumoto M, Hikosaka O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature. Jun 28 2007;447(7148):1111-1115. 49. Sartorius A, Henn FA. Deep brain stimulation of the lateral habenula in treatment resistant major depression. Medical hypotheses. 2007;69(6):1305-1308. 50. Jimenez F, Velasco F, Salin-Pascual R, et al. A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery. Sep 2005;57(3):585-593; discussion 585-593. 51. Sartorius A, Kiening KL, Kirsch P, et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biological psychiatry. Jan 15 2010;67(2):e9-e11. 52. Schneider TM, Beynon C, Sartorius A, Unterberg AW, Kiening KL. Deep brain stimulation of the lateral habenular complex in treatment-resistant depression: traps and pitfalls of trajectory choice. Neurosurgery. Jun 2013;72(2 Suppl Operative):ons184-193; discussion ons193. 53. Li B, Piriz J, Mirrione M, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470(7335):535-539. 54. Meng H, Wang Y, Huang M, Lin W, Wang S, Zhang B. Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression. Brain research. Nov 08 2011;1422:32-38. 55. Kim Y, Morath B, Hu C, et al. Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex. Behavioural brain research. Jun 01 2016;306:170-177. Figure 1. (a) A Diffusion Tensor Imaging (DTI) figure demonstrating the trajectory of the stria medullaris i.e. the main afferent and efferent tract of the habenula. (b) Photo of a medial side of a left cerebral hemisphere illustrating the microcircuitry of the habenula. The medial part of the thalamus has been dissected to reveal the stria medullaris. Ant C = anterior commissure, Diagonal Band = diagonal band of Brocca, Gn = genu of the corpus calosum, Hb = habenula Hb C = habenula commissure, MB mamilary bodies, Nucleus Basalis = nucleus basalis of Meyernt,
OC = optic chiasm, P = pineal gland, Post C = posterior commissure, Septal Nuclei = medial septal nuclei Spl = Splenium of the corpus calosum, Stria Medullaris = stria medulllaris thalami.
HIGHLIGHTS
•
The habenula is a small volume region strategically located in one of the central-most regions of the human brain.
•
It is vastly connected with structures of the prefrontal cortex, basal forebrain, limbic system, basal ganglia and the brainstem monoaminergic neurotransmitter systems.
•
Its functional implications span from emotional and cognitive processes in normal behavior to the underlying mechanism of the pathophysiology of mental disorders.
•
Deep brain stimulation of the habenula in two patients suffering from treatment resistant depression resulted in their remission.
S0006-8993(18)30243-9 https://doi.org/10.1016/j.brainres.2018.04.041 BRES 45781
To appear in:
Brain Research
Received Date: Revised Date: Accepted Date:
8 November 2017 28 April 2018 30 April 2018
Please cite this article as: G.P. Skandalakis, C. Koutsarnakis, A.V. Kalyvas, P. Skandalakis, E.O. Johnson, G. Stranjalis, The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging, Brain Research (2018), doi: https://doi.org/10.1016/j.brainres.2018.04.041
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The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging. Georgios P. Skandalakis, BBA, MSc1-4*, Christos Koutsarnakis, MD1-3, Aristotelis V. Kalyvas, MD, MSc1-3, Panagiotis Skandalakis, MD, PhD 3,4, Elizabeth O. Johnson, PhD3,4, George Stranjalis, MD, PhD1,2
1
Athens Microneurosurgery Laboratory, National and Kapodistrian University of Athens Medical School, Greece 2
Department of Neurosurgery, Evangelismos General Hospital, National and Kapodistrian University of Athens Medical School, Greece 3
Department of Anatomy and Surgical Anatomy, National and Kapodistrian University of Athens Medical School, Greece 4
Laboratory for Education and Research in Neurosciences (LERNs), National and Kapodistrian University of Athens Medical School, Greece
Corresponding author: Georgios P. Skandalakis, National & Kapdistrian University of Athens, Mikras Asias 75, Goudi 11527, Athens, Greece. Email: [email protected]
Abstract Background: The habenula is a small, mostly underrated structure in the pineal region. Multidisciplinary findings demonstrate an underlying complex connectivity of the habenula with the rest of the brain, subserving its major role in normal behavior and the pathophysiology of depression. These findings suggest the potential application of “habenular psychosurgery” in the treatment of mental disorders.
Objective/Hypothesis: The remission of two patients with treatment-resistant major depression treated with deep brain stimulation of the habenula supported the hypothesis that the habenula is an effective target for deep brain stimulation and initiated a surge of basic science research. This review aims to assess the viability of the deep brain stimulation of the habenula as a treatment option for treatment resistant depression.
Methods: PubMed and the Cochrane Library databases were searched with no chronological restrictions for the identification of relevant articles.
Results: The results of this review are presented in a narrative form describing the functional neuroanatomy of the human habenula, its implications in major depression, findings of electrode implantation of this region and findings of deep brain stimulation of the habenula for the treatment of depression.
Conclusion: Data assessing the hypothesis are scarce. Nonetheless, findings highlight the major role of the habenula in normal, as well as in pathological brain function, particularly in depression disorders. Moreover, findings of studies utilizing electrode implantation in the region of the habenula underscore our growing realization that research in neuroscience and deep brain stimulation complement each other in a reciprocal relationship; they are as self-reliant, as much as they depend on each other.
Keywords: Depression, TRD, habenula, psychosurgery, deep brain stimulation, DBS
Abbreviations/Acronyms: HB = habenula, LHb = lateral habenula, MHb = medial habenula, VTA = ventral tegmental area, SN= Substantia nigra DBS= deep brain stimulation, TRD =Treatment Resistant Depression, ElectroConvulsive Therapy = ECT
Introduction
Advances in functional neuroanatomy, biological psychiatry, neurobiology, functional imaging and stereotaxy are now converging to support a more behaviorally relevant, functional neurosurgical approach to treat psychiatric disorders.1 Moreover, the idea of using neurosurgery as a treatment option for Major Depression Disorder (MDD) has gained support over the last years.2 Major Depression Disorder is a disabling psychiatric disorder with a high incidence.3 Among the characteristics that constitute the diagnostic features established by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) which include depressed mood, anhedonia or loss of interest, appetite changes, sleep disturbances, suicidal ideation and increased guilt, depressed patients also have maladaptive responses to the prediction of and responses to negative events and feedback.4,5 The underlying neuroanatomical and neurocircuitry correlates of depression and stress-like disorders have long been the focus of neuroscientists.6,7 In addition, the habenula has been proposed to be intimately involved in the reward pathways. Consequently, it is believed to contribute to the prediction and response to negative outcomes.5
Although the anatomy of the habenula has been studied throughout the past century, with a noteworthy detailed anatomical study by Marburg in 1944,8 this small conserved part of the epithalamus has been largely ignored until recently. New founded interest in the habenula is attributed to novel findings indicating that the habenula is activated in the stress response, and is connected with other regions that exert direct effects on emotion and behavior.9,10 The habenula is implicated in several emotional and cognitive processes, because of its abundant connections with structures of the prefrontal cortex, basal forebrain, limbic system, basal ganglia and the brainstem monoaminergic neurotransmitter systems.10,11
Treatment-refractory depression (TRD) is defined as “the lack of clinical response after adequate pharmacotherapy has been attempted”12 or the lack of achieving remission after two or more antidepressant schemes.13 Today, DBS of defined anatomical regions, such as the subcallosal cingulate cortex, ventral striatum, ventral capsule and medial forebrain bundle, that have been implicated in the circuitry of depression has been effectively used for the treatment of TRD patients.14 Among the potential targets of DBS for the management of TRD the habenula has been proposed as a viable option, and has resulted in the successful treatment of two patients with severe TRD.15
The aim of this paper is to address the data assessing the viability of the habenula as a target for DBS in the treatment of TRD. To do this, we review the most important features regarding the functional anatomy of the human habenula and discuss the recent patient findings supporting its involvement in the pathophysiology of MDD. A brief history of the neurophysiological findings from animal studies involving surgically implanted electrodes to stimulate the habenula is also presented. These findings have served as the impetus of a recent surge of studies, including the application of DBS in TRD patients and several animal studies aiming to assess the effects of the DBS of the habenula in the treatment of MDD.
Historical Background Examples of efforts to influence human behavior by altering the brain structure have been recorded long before the advent of modern psychosurgery in the 19th century.
Trephinations, which were performed by Shamans to relieve spiritual or psychiatric disturbances, have been documented from the Neolithic Period.16 In 1891, Burckhardt performed the first topectomies in “pathologic” brain areas with the aim to treat behavioral disturbances.17
The beginning of modern psychosurgery was marked by the work of Egas Moniz, a Portuguese neurologist, who conducted a neurosurgical clinical trial for the treatment of psychiatric disorders, including depression, schizophrenia, panic disorder and bipolar disorder, by using the technique of prefrontal leucotomy.18 Based on Moniz’s findings, Walter Freeman and James Watts performed prefrontal lobectomies through bilateral transorbital burr holes (the so-called, transorbital “ice pick lobotomy”). Despite the lack of long-term objective data, Moniz’s study generated considerable interest and enthusiasm, resulting in Moniz receiving the Nobel Prize in Medicine and Physiology in 1949.19 The prefrontal leucotomy was subsequently widely used in the USA, with more than 50,000 procedures being performed in the 1940s and 1950s.19,20 While there was some symptomatic improvement in the broad spectrum of psychiatric patients studied, the crude lesions produced by the procedure resulted in adverse effects and consequently, raised questions regarding the outcomes and ethical concerns.18 With the advent of psychopharmacology, psychosurgery slowly began to decline and despite its controversial evolution, psychosurgery was finally defined in 1976 by the World Health Organization as “the selective surgical removal or destruction of nerve pathways for the purposes of influencing behavior” 21
Studies in neurosurgery continued, focusing on more clearly defined psychiatric conditions, and on more carefully defined and significantly smaller brain lesions such as the anterior cingulotomy, obtained by using more precise instrumentation, such as radiofrequency lesioning or gamma knife irradiations. The main disadvantage of these ablative treatment modalities is that they are irreversible. Because of the reversibility of its effects and the ability to vary both the sites and parameters of stimulation, deep brain stimulation (DBS) has gained support as a possible treatment option for psychiatric disorders. Today, neurosurgeons have gained the ability to safely target regions of the brain smaller than half centimeter through DBS resulting in the remission of specific psychiatric diseases such as major depression disorder.14
Functional neuroanatomy The brain region defined as the habenula (Hb) consists of nuclei located bilaterally on the dorsomedial surfaces of the thalami, lateral to the third ventricle and anterior to the pineal recess. The Hb nuclei are divided into two groups, the lateral Hb (LHb) and the medial Hb (MHb) nuclei, which are interconnected via the habenular commissure. The habenular commissure runs superior to the pineal recess, whereas the posterior commissure runs inferiorly (Fig.1).22
Strategically located in one of the central-most regions of the brain, the habenular nuclei are connected, mainly through the stria medullaris and the fasciculus retroflexus, with the majority of central core of the brain namely the thalamus, the bed nucleus of the stria terminalis, the head of the caudate, the putamen, globus pallidus internus, posterior insular cortex, the amygdalar nuclei, posterior hippocampus, septal nuclei, basal nucleus of Meynert, medial prefrontal cortex, the periaqueductal gray matter, ventral tegmental area (VTA), substantial nigra (SN), dorsal raphe nuclei and interpenducular nucleus, in addition to numerous cortical structures such as the inferior frontal gyrus, the cingulate, retrosplenial and calcarine cortices and Heschl’s gyrus, as revealed by white matter dissections and radiological studies. 23-28 Although animal studies have described the connectivity of the habenula in great detail,9 studies in humans have yet to distinguish which connections are afferent and which are efferent as well as which connections concern the LHb and which the MHb.29 While data on the connectivity of the habenula have derived from both animal and human studies, for the sake of specificity this section is limited in findings coming from human studies.
While the LHb and MHb have been distinguished both in radiological and histological studies, differences in their connectivity with other regions have not been rigorously established in human studies.29 In general, it appears that the LHb seems to be mostly connected with the forebrain and limbic system, while the MHb is mainly connected to the brainstem and habenular commisure30,31
The habenular nuclei are connected to the serotonergic system through the dorsal raphe nucleus, to the dopaminergic system through the VTA and SN, and to the noradrenergic system through the locus ceruleus. The habenular function in the cholinergic system is mediated through its anatomical connectivity to the basal nucleus of Meynert 29 which is regarded as the primary cholinergic projection system to the cortex32.
Besides revealing connectivity, fMRI studies of healthy subjects have also provided most of the findings regarding the functional significance of the habenula by assessing its activation in response to specific tasks or induced stimuli.
Such studies have identified activation of the habenula during multiple learning tasks; therefore, revealing its key role in learning and motivation.33 In addition, evidence supports its participation in the process of error detection and the ability to adjust accordingly through a circuit involving the VTA, SN and the amygdala.24 A similar study in healthy volunteers has disclosed a tight functional correlation of habenular nuclei to the negative reward prediction errors.34 Recent research has also linked the habenula to the processing of aversive stimuli through its connection to the VTA, in a circuit that also involves the dopaminergic projections of the VTA to the putamen and medial prefrontal cortex.25 Finally, a study mapping the activation of the habenula following administration of painful thermal stimuli, suggests that it has a role in the perception of pain.35
Pathophysiological implications Regardless of its small size, the habenula appears to play a central role in the pathophysiology of depression. This has been supported by several animal studies over the last decades.31 There is some, albeit limited evidence in humans, deriving mainly from histological and radiological studies (MRI- fMRI) in patients suffering from MDD, which shows differences in the volume of the habenula in addition to alterations in its activation pattern.
Structural findings Studies assessing the structural changes of the habenula associated with MDD have revealed interesting but also inconsistent findings. A post-mortem brain study investigating the
morphology of the habenula in MDD and schizophrenic patients reported that MDD patients had a smaller habenula volume compared to control subjects; a finding not observed in schizophrenic patients.36 Significantly increased habenula volumes were also found in drug-naive MDD patients in an MRI study that compared habenula volumes among drug-naive, medicated MDD patients and healthy controls.37 In contrast, other studies have reported smaller habenular sizes in MDD patients, as compared to healthy subjects, a finding, however, that was not statistically significant. Nonetheless, their post-hoc analysis showed significantly smaller habenular volumes in female patients suffering from MDD.38,39 Additionally, smaller habenular volumes were found in TRD patients when compared to healthy subjects, as reported in a recent MRI study.40 A radiologic study that sought to compare the habenular volume of MDD patients in different phases of their disease, documented smaller sizes only in female patients undergoing their first depressive episode.36 Interesting findings also derive from a study that assessed the habenular volume of MDD patients before and after ElectroConvulsive Therapy (ECT), which showed a significant increase in the habenular grey matter two weeks following ECT.41
Functional findings The habenula is involved in the serotonergic system by modulating the activity of the median and dorsal raphe nuclei directly through its efferent projection fibers and indirectly via the forebrain, which projects to the habenula and likewise controls the raphe nuclei. These findings implicate this small structure in the pathophysiology of MDD. This suggestion is also supported by radiological studies that document its over-activation in MDD. 42 More specifically, fMRI studies showed increased activity of the habenula and raphe nuclei in induced tryptophan depleted states.42,43 Furthermore, Furman & Gotlib who studied the activation patterns of the LHb in response to negative and to positive feedback, demonstrated a more profound activation of the LHb in negative rather than positive feedback responses in both MDD patients and healthy controls. Surprisingly though, this study also reported a left lateralized hypo-activation in response to negative feedback among the depressed patients when compared to healthy controls.5 A recent report investigating phasic habenula function in MDD patients during anticipation of an aversive stimulus, showed abnormal responses compared to those of healthy volunteers. More specifically, the habenula activation pattern was assessed in a group of MDD patients and a
healthy control group performing classical (Pavlovian) conditioning tasks in which an electric shock was the unconditioned stimulus. Interestingly, habenular responses decreased within the patient group, as the unconditioned stimulus became progressively more shock predicting. In contrast, healthy volunteers showed increased habenular responses as the conditioned stimulus became more shock predicting.44
Surgical applications
Initial data regarding the effects of electrode implantation in the habenula of mice were published in 1989 and 1992. These studies monitored the levels of specific neurotransmitter levels through implanted probes in various brain areas during stimulation of the LHb. In addition, they also explored the means by which habenular stimulation would increase the levels of those neurotransmitters through induced lesions in specific bundles or nuclei. The authors reported that LHb stimulation induced increased serotonin levels in the striatum mediated through the dorsal raphe nucleus, 45 along with increased noradrenaline levels in the hippocampus, 46 medial frontal cortex and nucleus accumbens 47 via fibers of the dorsal noradrenergic bundle and fasciculus retroflexus. 45-47 More recently, a study in primates investigated the effect of habenular electrode implantation in reward circuits, in which stimulation of the habenula inhibited dopaminergic neurons of the subtantia nigra (SN).48
In 2007, Sartorius and colleagues proposed the habenula as a potential target for DBS in the treatment of depression.49 The authors reviewed the pathophysiology of depression in relation to altered serotonin and norepinephrine levels, noting the correlation of habenular function to these neurotransmitters and the general role of the habenula in depression. Furthermore, the authors proposed a set of clinical characteristics of MDD patients which could benefit from treatment with habenular DBS. They have also postulated that the effects of habenular DBS could be demonstrated by a case of a treatment resistant MDD patient who underwent successful DBS of the inferior thalamic peduncle area.50 This hypothesis was based on the fact that this DBS target also resulted in the functional inhibition of the stria medullaris, which is the main afferent tract of the habenula. Finally, the authors claimed that the antidepressive effect of habenular DBS
could be achieved by high frequency stimulation of its afferent projections, since data show that in this way habenular serotonergic projections to the dorsal raphe nucleus are inhibited while GABAergic projections are spared.49 The first case of habenular DBS for the treatment of resistant MDD was reported in 2010.51 A 64 year-old woman who had been suffering from MDD since the age of 18 and for the last nine years was unresponsive both to medical and electroconvulsive therapy underwent bilateral DBS of the habenular region and reportedly had complete remission after 4 months of high frequency stimulation.51 A second case of resistant MDD was also treated with habenular DBS resulting again in its gradual complete remission.52 Notably, the authors state that the electrode trajectory should target the lateral habenular complex, which includes the stria medullaris apart from the LHb, to ensure that this fiber tract is also sufficiently stimulated.52 Thus, it is important to clarify that the treatment effect could be possibly attributed to the stimulation of the stria medullaris and not to the LHb itself. Moreover, the authors state that both patients experienced a rapid relapse when the pacemaker stopped working followed by a slow remission after the stimulation was restored. These findings contradict the immediate effect seen in DBS for neurological disorders and could be attributed to brain plasticity procedures.15 Long term outcome data of these cases or additional reports have not been published since.
Paradoxically, animal studies investigating the role of habenular DBS for the treatment of depression succeeded that of human patients. Aiming to elucidate the underlying mechanism of DBS of the habenula for the treatment of depression, these studies have also aided in understanding the more global effects of DBS on brain function and neuroplasticity.
In 2011 an animal study on models of depression in mice showed that DBS of the LHb ameliorated depressive symptoms, resulting in the reduction of the learned helplessness behaviors. The mechanism underlying this behavioral change induced by the DBS was attributed to the suppression of the habenula’s efferent projections to the VTA.53 In the same direction, another mice study which demonstrated relief of depressive symptoms following DBS of the LHb suggested that this could be attributed to increased monoamine neurotransmitter levels (serotonin, dopamine and noradrenaline) measured in the depressive rats undergoing DBS in
contrast to the lower neurotransmitters levels measured in the non-treated depressed rats.54 Finally, the rationale of habenular DBS for MDD is also supported by a recent study in mice that explored additional molecular mechanisms involving the calcium/calmodulin dependent Kinase Type II, glycogen synthase kinase 3 and AMP-activated protein kinase. Phosphorylation of these proteins was positively correlated with the therapeutic effects of DBS.55
Conclusion While the initial findings support the hypothesis that the habenula may serve as an effective target for DBS in the management of complex neuropsychiatric disorders, such as MMD, data are very scarce (only two patients underwent habenular DBS) and have not been replicated. In addition, long-term outcome data of these two patients have not been published. Moreover, due to the concurrent targeting of the stria medullaris thalami in the aforementioned cases, the treatment effect could also be attributed to stimulation of this specific tract and not to the habenula itself. As such, whether the habenula is an effective target for DBS of patients with TRD remains subject to question. Nevertheless, data in the literature highlight the role of the habenula in normal, as well as pathological brain function and particularly in depression disorders. Thus, more studies are needed in order to enhance our anatomical and functional knowledge of the human habenula and document its potential implication in modern psychosurgery. References
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42. Morris JS, Smith KA, Cowen PJ, Friston KJ, Dolan RJ. Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. NeuroImage. Aug 1999;10(2):163-172. 43. Roiser JP, Levy J, Fromm SJ, et al. The effects of tryptophan depletion on neural responses to emotional words in remitted depression. Biological psychiatry. Sep 01 2009;66(5):441-450. 44. Lawson RP, Nord CL, Seymour B. Disrupted habenula function in major depression. Feb 2017;22(2):202-208. 45. Kalen P, Strecker RE, Rosengren E, Bjorklund A. Regulation of striatal serotonin release by the lateral habenula-dorsal raphe pathway in the rat as demonstrated by in vivo microdialysis: role of excitatory amino acids and GABA. Brain research. Jul 17 1989;492(1-2):187-202. 46. Kalen P, Lindvall O, Bjorklund A. Electrical stimulation of the lateral habenula increases hippocampal noradrenaline release as monitored by in vivo microdialysis. Experimental brain research. 1989;76(1):239-245. 47. Cenci MA, Kalen P, Mandel RJ, Bjorklund A. Regional differences in the regulation of dopamine and noradrenaline release in medial frontal cortex, nucleus accumbens and caudateputamen: a microdialysis study in the rat. Brain research. May 29 1992;581(2):217-228. 48. Matsumoto M, Hikosaka O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature. Jun 28 2007;447(7148):1111-1115. 49. Sartorius A, Henn FA. Deep brain stimulation of the lateral habenula in treatment resistant major depression. Medical hypotheses. 2007;69(6):1305-1308. 50. Jimenez F, Velasco F, Salin-Pascual R, et al. A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery. Sep 2005;57(3):585-593; discussion 585-593. 51. Sartorius A, Kiening KL, Kirsch P, et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biological psychiatry. Jan 15 2010;67(2):e9-e11. 52. Schneider TM, Beynon C, Sartorius A, Unterberg AW, Kiening KL. Deep brain stimulation of the lateral habenular complex in treatment-resistant depression: traps and pitfalls of trajectory choice. Neurosurgery. Jun 2013;72(2 Suppl Operative):ons184-193; discussion ons193. 53. Li B, Piriz J, Mirrione M, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470(7335):535-539. 54. Meng H, Wang Y, Huang M, Lin W, Wang S, Zhang B. Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression. Brain research. Nov 08 2011;1422:32-38. 55. Kim Y, Morath B, Hu C, et al. Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex. Behavioural brain research. Jun 01 2016;306:170-177. Figure 1. (a) A Diffusion Tensor Imaging (DTI) figure demonstrating the trajectory of the stria medullaris i.e. the main afferent and efferent tract of the habenula. (b) Photo of a medial side of a left cerebral hemisphere illustrating the microcircuitry of the habenula. The medial part of the thalamus has been dissected to reveal the stria medullaris. Ant C = anterior commissure, Diagonal Band = diagonal band of Brocca, Gn = genu of the corpus calosum, Hb = habenula Hb C = habenula commissure, MB mamilary bodies, Nucleus Basalis = nucleus basalis of Meyernt,
OC = optic chiasm, P = pineal gland, Post C = posterior commissure, Septal Nuclei = medial septal nuclei Spl = Splenium of the corpus calosum, Stria Medullaris = stria medulllaris thalami.
HIGHLIGHTS
•
The habenula is a small volume region strategically located in one of the central-most regions of the human brain.
•
It is vastly connected with structures of the prefrontal cortex, basal forebrain, limbic system, basal ganglia and the brainstem monoaminergic neurotransmitter systems.
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Its functional implications span from emotional and cognitive processes in normal behavior to the underlying mechanism of the pathophysiology of mental disorders.
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Deep brain stimulation of the habenula in two patients suffering from treatment resistant depression resulted in their remission.