Fundamentals and Clinics of Deep Brain Stimulation: An Interdisciplinary Approach

By Alfonso Fasano

This book provides a state-of-the-art overview of our current understanding of deep brain stimulation (DBS) for the treatment of neurological and psychiatric disorders. With a broad multidisciplinary scope, it presents contributions from leading experts in the field from Europe and America, who share not only their knowledge, but their experience as well. The book focuses both on basic and theoretical aspects of DBS, as well as clinical and practical aspects. It follows an evidence-based approach, and where possible offers clinical recommendations based on published guidelines.

It starts with a general section, which discusses basic principles and general considerations. This is followed a sections dedicated to neurological disorders, and psychiatric disorders, in which only accepted indications are discussed. All experimental indications are discussed in the final chapter. The text is supplemented with numerous illustrations.

Intended for medical specialists and residents involved in the treatment of patients with DBS, it also appeals to other professionals working with DBS patients, such as psychologists, nurses, physiotherapists, as well as basic and clinical neuroscientists.

• Language: English
• Publisher: Springer
• Release date: Mar 24, 2020
• ISBN: 9783030363468

Book preview

Part IGeneral Section

© Springer Nature Switzerland AG 2020

Y. Temel et al. (eds.)Fundamentals and Clinics of Deep Brain Stimulationhttps://doi.org/10.1007/978-3-030-36346-8_1

1. The History of Deep Brain Stimulation

J. D. Hans Speelman¹   and Rick Schuurman²  

(1)

Department of Neurology, UMC Amsterdam, Amsterdam, The Netherlands

(2)

Department of Neurosurgery, UMC Amsterdam, Amsterdam, The Netherlands

J. D. Hans Speelman (Corresponding author)

Rick Schuurman

Email: [e-mail]

Abstract

Deep brain stimulation (DBS) is a medical treatment that aims at obtaining therapeutic effects by applying chronic electrical impulses in specific brain structures. The saga started in 1947 with the development of a stereotactic device for application in the human brain and the publication of reliable stereotactic brain atlases. These developments made it possible to induce precision lesions in deep brain structures solely through a burr hole in the skull. Following this, lesion surgery was replaced by chronic high-frequency electrical stimulation. DBS had been used since the 1950s for treatment of psychiatric patients, but this practice was abandoned due to ethical objections, as well as the introduction of neuroleptics. In the 1960s, the technique had been introduced for treatment of movement disorders. In 1993, DBS had been acknowledged for the treatment of tremors and thereafter for the treatment of Parkinson’s disease, dystonias, obsessive–compulsive disorder and epilepsy.

Keywords

Deep brain stimulationHistory

This chapter is a translated and slightly adapted version of Speelman H. DBS in historisch perspectief [DBS in historical perspective]. In: Temel Y, Leentjens AFG, de Bie RMA (eds). Handboek diepe hersenstimulatie bij neurologische en psychiatrische aandoeningen [Handbook of deep brain stimulation for neurological and psychiatric disorders]. Bohn Stafleu van Loghum, Houten 2016; pp 1–9.

Introduction

Deep brain stimulation (DBS) aims at obtaining symptomatic improvement of certain neurological or psychiatric disorders by chronically applying high-frequency electrical impulses to a specific subcortical nucleus or tract. The electrical stimulation is performed by means of a flexible electrode implanted into the intracranial target structure, which, through a small burr hole in the skull, is connected with a subcutaneously implanted pulse generator. By this technique it becomes possible to influence both pathophysiological nerve activities therapeutically, such as in the case of movement disorders, as well as to influence normal physiological activity in other indications, such as in the treatment of chronic pain.

Special equipment for positioning the electrode in the brain, with a precision of 0.5–1.0 mm, the so-called stereotactic frame, has been developed and refined in time (Guiot et al. 1962). Moreover, essential parts of the surgery are the detailed visualization of the intracranial structures for the determination of the position of the intracerebral structures in relation to the stereotactic frame, and the possibility of neurophysiological control of the position of the tip of the electrode. The advancements in these fields have been the important conditions for the development of DBS as a treatment option for neurological and psychiatric conditions.

First Developments

From 1905 the Clarke–Horsley stereotactic apparatus, named after both creators, was used by the British neurosurgeon Victor Horsley for his study of the function of deep-seated brain structures in animals. This instrument appeared to enable the induction of lesions in anatomically determined intracerebral structures in animals (Fig. 1.1) (Horsley and Clarke 1908). Clarke, a physician and pioneer physiologist, and the designer of the stereotactic instrument, proposed already before 1920 to apply this stereotactic frame for surgery of brain tumor in humans, inducing electrolytic lesions or implantation of radium, as well as for the treatment of chronic pain (Schurr and Merrington 1978). The Canadian neurologist and neurophysiologist Aubrey Mussen made an adaptation of the Clarke–Horsley stereotactic apparatus for the surgical treatment of deep-sited brain tumors in man. However, at that time, no surgeon was willing to apply this technique (Olivier et al. 1983). The problem was the great variance of the position of intracerebral structures in relation to external skull characteristics and the lack of a reliable stereotactic neuroanatomical atlas. It lasted until 1947 before this technique was used in a human patient with an adapted stereotactic apparatus (Spiegel et al. 1947).

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Fig. 1.1

Stereotactic frame designed by Clarke and Horsley. (a) frontal view and (b) lateral view, with also at the right the instrument for stereotactic punctures in the spinal cord

Neurosurgery Before 1947

Surgical Treatment of Psychiatric Disorders

It was the Swiss psychiatrist Gottlieb Burckhardt, who, in 1888, started neurosurgical procedures in six psychiatric patients with psychoses and behavioral disturbances (Burckhardt 1891). These procedures for psychiatric patients were very much disputed at the time. After the second World Congress for Neurology, in 1935 in London, neurosurgical interventions for psychiatric disorders, also called psychosurgery, were accepted as a medical treatment (Heller et al. 2006). In the same year the Portuguese neurologist Egas Moniz performed the first bilateral frontal lobotomy in a patient with psychosis, together with the neurosurgeon Almeida Lima. Moniz had been rewarded with the Nobel prize for Physiology or Medicine, shared with Rudolf Walter Hess, in 1949 for the discovery of the therapeutic value of leucotomy in certain psychoses (Mashour et al. 2005). In 1936, Walter Freeman, a neurologist at the George Washington University in Washington, DC, started the prefrontal lobotomy project together with the neurosurgeon James Watts (Heller et al. 2006; Mashour et al. 2005). He introduced the transorbital frontal lobotomy, also called the ice pick lobotomy, which made the presence of the neurosurgeon superfluous. This procedure had been applied in the USA in more than 40,000 persons with psychoses and/or behavioral disturbances (Shorter 1997). The results of 5000 lobotomies had been reported at the 1948 International Congress of Psychosurgery in Lisbon, Portugal. This procedure had been seriously criticized, because it was still considered an experimental procedure. Moreover, the indications had not been clearly delineated, there was a lack of a proper preoperative screening, and there was no uniform surgical technique (Freed et al. 1949).

Neurosurgery for Movement Disorders

In 1890 Horsley performed the first neurosurgical procedure for the treatment of movement disorders by removing parts of the motor cortex in a patient with hemi-athetosis, with a favorable result. Unfortunately, this result had been buried in oblivion (Fig. 1.2) (Horsley 1890, 1909; Kandel and Schavinsky 1972). In 1912 the first publication appeared reporting the improvements of rigidity in a case of paralysis agitans, by means of cutting afferent cervical roots (Leriche 1912). This was followed by publications about the effects of intersection of extrapyramidal tracts at various levels of the spinal cord with some, mostly transient, improvements in athetosis and dystonia, but not in parkinsonism (Speelman and Bosch 1998).

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Fig. 1.2

The English neurosurgeon Sir Victor Alexander Haden Horsley (1867–1916)

In 1937, a period started in which surgical lesioning in the course of the corticospinal tract was applied. This involved the (pre)motor cortex, the internal capsule, the brainstem (mesencephalic pedunculotomy) and the spinal cord (Speelman and Bosch 1998). Of these, only the pedunculotomy still was performed until the beginning of the 1950s. Eventually this surgical procedure was also abandoned, because the surgical relief of extrapyramidal dyskinesias seems to boil down to the artificial production of a paralysis and no improvement was achieved of the parkinsonian rigidity and bradykinesia (Figs. 1.3 and 1.4) (Speelman and Bosch 1998; Redfern 1989). In 1939, Russell Meyers, a neurosurgeon at the State University at Iowa (USA), started his experimental neurosurgery for movement disorders by systemic surgery in the basal ganglia. The first patient was a woman with a unilateral postencephalitic rest tremor of 7 years duration. She did not improve after contralateral premotor cortectomy, but after an additional extirpation of the anterior part of the caudate nucleus, the tremor disappeared permanently without neurological side effects (Meyers 1940). In 1951 Meyers published the surgical results for 58 patients with paralysis agitans (Table 1.1). He concluded that the optimal improvement of tremor and rigidity had been obtained by transection of the pallidofugal fibers and/or the extirpation of the anterior part of the caudate nucleus with simultaneous transection of the anterior leg of the internal capsule. However, about half of the patients showed transient memory disturbances for periods of 3 months to a year, and the surgical mortality of 15.7% was too high (Meyers 1951a, b).

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Fig. 1.3

Schematic drawing of the surgical procedures of Parkinson’s disease (Speelman and Bosch 1998). (1) Extirpation of cortical premotor and motor areas; (2) cutting of the corticospinal tract at the level of the oval center; (3) cutting at the level of the internal capsule; (4) pallido(anso)tomy, GPi-DBS; (5) thalamotomy; (6) campotomy (Cooper and Bravo 1958); (7) ligation of the choroidal anterior artery (Cooper 1953); (8) pedunculotomy; (9) cutting of the rubrospinal and tegmental tracts in the medulla oblongata; (10) cutting of the cortical spinal tract in the spinal cord; and (11) lateral cervical cordotomy (Leriche 1912)

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Fig. 1.4

Cutting of pallidal fugal fiber tracts, as approached by Russell Meyers (M). The French neurosurgeon M. F. Fénelon introduced a blind cutting of these fiber tracts (F) (Fénelon 1950)

Table 1.1

Overview of the experimental surgeries for paralysis agitans by Russell Meyers (1951a)

1947: Introduction of the Stereotactic Neurosurgery in Clinical Practice

In 1947 Ernest A. Spiegel, a neurologist at Temple University Medical Center (Philadelphia, Pennsylvania) (Fig. 1.5), H. T. Wycis, a neurosurgeon in the same department, and collaborators wrote: exposure of subcortical brain areas necessitates rather extensive operations. It seemed desirable, therefore, to adapt the stereotactic technique for use in the human brain, and this apparatus is being used for psychosurgery. They continued: further applications are under study, for example, interruption of the spinothalamic tract in certain types of pain or phantom limb, production of pallidal lesions in involuntary movements, and aspiration of cystic fluids from tumours (Spiegel et al. 1947). Two years later the authors published the results of stereotactically induced lesions in the thalamic dorsomedian nucleus of 38 patients, and most of them were institutionalized in a psychiatric asylum because of schizophrenia, depression or severe compulsive symptoms. They reported that by thalamotomy, improvements could be obtained without the risks of changes of personality or epileptic fits, as can occur after frontal lobotomy (Freed et al. 1949; Spiegel et al. 1949).

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Fig. 1.5

Ernst. A. Spiegel (1895–1985)

Two developments were essential for the application of stereotaxy, or encephalotomy as Spiegel et al. named it, in clinical practice: the possibility to relate brain structures to intracranial structures by means of x-rays, and the development of a stereotactic atlas of the brain (Talairach et al. 1950; Spiegel and Wycis 1952). Spiegel and Wycis used calcifications in the pineal gland and the commissura habenularum, as well as air ventriculography to indicate the posterior commissure, in order to determine the position of the thalamus and globus pallidus (GPi) (Schurr and Merrington 1978). Jean Tailarach, a psychiatrist and neurosurgeon in Paris, also used ventriculography and introduced the line interconnecting the anterior commissure (CA), or foramen of Monro (FM) and the posterior commissure (CP), as a reference for the intracerebral structures (Talairach et al. 1949). In 1952, Spiegel and Wycis published the first stereotactic atlas of the human brain (Spiegel et al. 1949; Spiegel and Wycis 1952). Thereafter, the stereotactic neurosurgery was started in various other centers and further developed (Talairach et al. 1949; Leksell 1949; Riechert and Wolff 1951; Hayne and Meyers 1950; Narabayashi et al. 1956). Stereotactic neurosurgery was still considered an experimental procedure, which also gave opportunities to study in vivo the physiology of the human brain and brain disorders.

Based upon the experimental surgery approach of Russell Meyers (see before), initially, the globus pallidus and its efferent tracts, the ansa lenticularis and fasciculus lenticularis were indicated as target structures for stereotactic surgical procedures for movement disorders, such as Parkinson’s disease, chorea, athetosis and dystonias (Leksell 1949; Narabayashi et al. 1956; Fénelon 1950; Spiegel and Wycis 1950; Guiot and Brion 1953). In 1953 Irving Cooper, a neurosurgeon at the St Barnabas Hospital in New York City, reported two parkinsonian patients with improvement of motor symptoms after ligation of the anterior choroidal artery. He interpreted this as a consequence of necrosis of the globus pallidus (Cooper 1953). These results supported the choice of the globus pallidus and/or the ansa lenticularis as a target structure in the surgery for movement disorders. Spiegel mentioned that in the period from 1948 till 1961, almost 6000 operations had been performed for the treatment of extrapyramidal disorders, with 90% stereotactic pallidotomies/ansotomies in about 80 centers around the world, compared with 302 surgical procedures for these indications before 1948 (Spiegel and Wycis 1962).

It was the work of Rolf Hassler, a neuroanatomist in Freiburg (Germany), and Irving Cooper that led to the replacement of the globus pallidus by the thalamus as preferred target for the neurosurgical treatment of tremors and Parkinson’s disease (Hassler and Riechert 1954; Cooper and Bravo 1958). Other brain areas as well, such as the subthalamic structures (zona incerta and the fields of Forel) with sparing of the subthalamic nucleus (STN) , were explored for the treatment of these indications (Heller et al. 2006; Bertrand 1958; Spiegel et al. 1963; Andy et al. 1963; Spiegel 1969).

In 1968, more than 37,000 stereotactic operations had been performed, most frequently for the treatment of Parkinson’s disease. It was the opinion that only 12–15% of patients with Parkinson’s disease were candidates for stereotaxy. More strict guidelines for patient selection and surgical technique had been formulated, and stereotactic brain atlases were now available (Speelman and Bosch 1998; Spiegel 1969).

The Introduction of Levodopa

The introduction of levodopa for the treatment of Parkinson’s disease in 1969 caused a dramatic reduction in the number of patients referred for stereotaxy, as well as in the number of centers active in this field, worldwide (Redfern 1989). Nevertheless, in 1970 the European Society for Stereotactic and Functional Neurosurgery (ESSFN) had been founded with the aim of further development of the stereotactic surgical technique. Progress in the field of the radiodiagnostics, especially the CT scan, and of the computer techniques enhanced the possibilities for the diagnostics and treatments of intracranial deep-seated brain tumors. The advances in intracerebral microrecording and macrostimulation increased the therapeutic opportunities for pain, spasticity, as well as epilepsy (Redfern 1989).

Revival of Stereotaxy

In the beginning of the 1980s, there was a revival of interest in stereotactic neurosurgery for Parkinson’s disease, due to the shortcomings and side effects of levodopa therapy. Initially, thalamotomy had been performed for the treatment of tremor and rigidity in Parkinson’s disease in combination with levodopa therapy (Siegfried 1980; Gildenberg 1984). The Finnish–Swedish Lauri Laitinen, a neurosurgeon in Umeå and Stockholm, and co-workers continued performing pallidotomies according to the coordinates of the Swedish neurosurgeon Leksell, and published their favorable results of pallidotomy for parkinsonian motor symptoms and levodopa-induced dyskinesias in 1992 (Fig. 1.6) (Laitinen et al. 1992a, b). As a consequence, the internal segment of the globus pallidus (GPi) became the preferred target for the treatment of Parkinson’s disease, chorea and dystonias. The thalamus remained the target structure for patients with pharmacotherapy-resistant tremors.

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Fig. 1.6

Neurosurgeon Lauri Laitinen (1928–2005) left, and right Marwan Hariz (1953), his pupil and formal neurosurgeon in London and Umeå (Sweden)

Deep Brain Stimulation

From the introduction of stereotaxy in clinical practice, in 1947, electrical stimulation had been applied to verify the correct position of the surgical probe in the target structure. When symptomatic improvement was observed without undesirable side effects, a lesion (-tomy) was induced by heating, freezing, chemically, electrolytically, or mechanically (Schurr and Merrington 1978; Albe-Fessard et al. 1953). Apart from that, neurophysiological brain research in vivo could be performed (Gildenberg 2005). Initially chronic therapeutic application of DBS had been performed by externalized electrode wires. External electrical stimulation was applied for months, even up to one and a half years, while the patient was ambulatory. Thereafter, eventually a lesion was induced, because suitable pulse generators were still not available (Blomstedt and Hariz 2010; Hariz et al. 2010).

Psychiatric Indications

In the 1950s DBS had been used for the search for mechanisms and therapeutic effects in patients with behavioral disturbances and psychoses (Delgado et al. 1952; Sem-Jacobsen 1959). At the time Robert C. Heath, a psychiatrist at the Tulane University in New Orleans (USA), started with chronic deep brain stimulation research for the treatment of psychiatric patients, as well as in patients suffering from pain and epileptic seizures (Heath 1963). His publication titled Modulation of Emotion With a Brain Pacemaker: Treatment for Intractable Psychiatric Illness in 1977 caused extensive discussions about the ethical aspects of psychosurgery (Baumeister 2000). These discussions as well as the introduction of neuroleptics had been the reason that neurosurgery for psychiatric indications was considered obsolete until the end of the 1990s (Hariz et al. 2010; Baumeister 2000; Krack et al. 2010).

Pain

Since the introduction of the stereotaxy, chronic pharmacotherapy-resistant pain had been the object of neurophysiological research, stereotactic neurosurgery, and later on also DBS (Schurr and Merrington 1978; Iskander and Nashold 1995). Initially, treatment of pain had been focused on influencing the emotional process of pain by inducing lesions and chronic stimulation of medial and preseptal thalamic structures. However, in the 1960s these target structures had been replaced by the somatosensory thalamus (Tasker 1982; Hosobuchi et al. 1973) and the periaqueductal and periventricular grey matter (Hosobuchi et al. 1973; Akil et al. 1978).

Movement Disorders

Chronic deep brain stimulation as a therapy for movement disorders had been started in the late 1960s by Natalia Petrovna Bechtereva, a neurophysiologist and neuroscientist working in Leningrad (nowadays called St Petersburg) (Blomstedt and Hariz 2010). Bechtereva performed chronic electrical high-frequency stimulation of the basal ganglia and motor thalamus by multiple electrodes, which had been externalized, even up to periods of 1.5 years. She frequently observed long-lasting improvements of symptoms during stimulation-free intervals. Finally, she often induced a microlesion through the most favorable electrode, because of the unavailability of implantable pulse generators (Bechtereva et al. 1975).

From the beginning of the 1970s chronic electrical stimulation of deep intracerebral structures became possible by transcutaneous activation of a subcutaneous implanted receiver by an external antenna and transmitter (Blomstedt and Hariz 2010; Heath 1963; Iskander and Nashold 1995; Gildenberg 2006; Sarem-Aslani and Mullett 2011). In 1980, Irving Cooper published his results of chronic electrical stimulation of the thalamus and globus pallidus for various movement disorders (Cooper et al. 1980). In the same year Brice, a neurosurgeon from Southampton (UK), and collaborators reported suppression of tremor by chronic electrical stimulation of the thalamus for two patients with multiple sclerosis and severe intention tremor (Brice and McLellan 1980). Orlando J. Andy, a neurosurgeon at the University of Mississippi School of Medicine (USA), reported favorable results of thalamic deep brain stimulation in nine patients with movement disorders, five of whom suffered from a parkinsonian rest tremor (Andy 1983). Jean Siegfried (Zürich, Switzerland) reported reduction of pain as well as suppression of dyskinetic symptoms by chronic electrical stimulation of the sensory thalamic nucleus in five patients with a syndrome thalamique (Siegfried 1986). These results were previously reported by the French neurosurgeon G. Mazars (Paris) and colleagues (Tasker 1982).

From 1980 Until the Present Time

DBS with high-frequency stimulation is effective in chronic suppression of certain neurological and psychiatric symptoms. The outcomes are comparable with the induction of lesions, but DBS has the advantage that the effects, positive and negative, are reversible after interrupting the stimulation, and implantable pulse generators with high-frequency stimulation (>100 Hz) are now available. The main indication was at the time the treatment of chronic pain.

In 1987 a new era in the history of DBS started after the publication of Alim Benabid (Fig. 1.7) and colleagues from Grenoble (France) of their results with continuous thalamic stimulation for the treatment of tremor in Parkinson’s disease. They described four patients, one with continuous thalamic stimulation, who previously had a thalamotomy on the contralateral side, and three patients with unilateral chronic thalamic stimulation. In all four patients the electrodes had been positioned in the nucleus ventralis intermedius (Vim) of the thalamus (Benabid et al. 1987). Because of the positive results of the ventroposterolateral pallidotomy in the treatment of Parkinson’s disease, this still remained the surgical treatment of choice for most clinicians (Laitinen et al. 1992b; Svennilson et al. 1960). The Grenoble group published their outcomes of long-term thalamic Vim DBS in 26 patients with Parkinson’s disease and six patients with essential tremor in 1991 (Benabid et al. 1991). Based on these positive results, the multicentre European thalamic DBS-study was initiated in 1992, in which 14 centers participated (Limousin et al. 1999). At that time Jean Siegfried et al. reported that the results of GPi DBS equalled those of pallidotomy, but that bilateral implantation of electrodes could be performed safely, even in the same surgical session (Siegfried and Lippitz 1994).

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Fig. 1.7

Prof. Alim-Louis Benabid (1942), a neurosurgeon-neurobiologist in Grenoble (France)

The real breakthrough of the DBS in the treatment of Parkinson’s disease had been the publication in 1995 of the favorable outcome of chronic DBS with the subthalamic nucleus (STN) as a target structure (Limousin et al. 1995). The choice of the STN as a surgical target was based on the knowledge of the physiology of intracerebral networks, obtained by neurophysiological registrations from deeply seated intracerebral structures during DBS procedures and animal experiments (Bergman et al. 1990; Aziz et al. 1991; Kringelbach et al. 2007; Benazzouz et al. 1993).

Important developments thereafter had been the improvement of stimulation equipment, and expanding knowledge in the field of ICT. The magnetic resonance imaging (MRI) scan and the fusion technique of the preoperative MRI scan with a CT scan improved the calculations of the coordinates of the target structure became more reliable. Moreover, it was possible to visualize postoperatively the position of the stimulation electrodes in relation to the intended target structures. The introduction of the micro electrode recording (MER) technique had been an improvement of the neurophysiological support in determining the position intracerebral structures , especially the STN.

Nowadays, more than 170,000 patients worldwide have obtained a uni- or bilateral electrode implantation for a DBS procedure. Eighty percent of these are patients with a movement disorder, mainly Parkinson’s disease, followed by tremors and dystonias. For these indications, DBS has been acknowledged by the Food and Drug Administration (FDA) and the Conformité Européenne (CE) as a regular treatment, based upon randomized clinical studies (Table 1.2). In addition, DBS is approved for treatment of obsessive–compulsive disorder and epilepsy.

Table 1.2

Registration of DBS treatment for various indications in Europe and the USA

CE Conformité Européenne, FDA Food and Drug Administration, Vim nucleus ventriculo-intermedius of the thalamus, STN subthalamic nucleus, GPi internal globus pallidus, HDE humanitarian device exemption

Current developments are the reintroduction of lesioning by means of stereotactic radiosurgery (gamma knife), transcranial high-intensity focused ultrasound therapy, further technical improvement of DBS electrodes and devices (see Chap. 5), the necessity of microrecording (MER) during the surgical procedure (see Chap. 6) and the possibility of performing the complete surgical procedure under general anesthesia (see also Chap. 7) (Hariz 2017; Elaime et al. 2010; Wang et al. 2015).

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Y. Temel et al. (eds.)Fundamentals and Clinics of Deep Brain Stimulationhttps://doi.org/10.1007/978-3-030-36346-8_2

2. Anatomy of Targets for Deep Brain Stimulation

Ali Jahanshahi¹, ²  , Juergen K. Mai³   and Yasin Temel¹, ²  

(1)

Department of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands

(2)

Maastricht University-MHeNS School for Mental Health and Neuroscience, Maastricht, The Netherlands

(3)

Institute for Anatomy, Heinrich-Heine-University, Duesseldorf, Germany

Ali Jahanshahi (Corresponding author)

Email: [e-mail]

Juergen K. Mai

Email: [e-mail]

Yasin Temel

Email: [e-mail]

Abstract

The purpose of Deep Brain Stimulation (DBS) is to modulate the activity of specific anatomical areas in the brain and thereby manage the symptoms of neurological and/or psychiatric disorders. Essential to this surgical management is an understanding of the anatomy and physiology of the target regions. The basal ganglia and the thalamus are the main target areas for DBS. These structures are connected to higher (cortical) and lower (brainstem) areas through both partially parallel and partly integrated projections. These projections are primarily responsible not only for motor control, but also for other functions such as motor learning, associative functions, and emotions. According to the classical basal ganglia model, information flows through the basal ganglia back to the cortex through two pathways, while new models show that parallel circuits subserve the classical functions of the basal ganglia engaging associative and limbic territories. The current targets of DBS for movement disorders are the dorsolateral part of the subthalamic nucleus, the posterior ventrolateral part of the internal globus pallidus, and the ventrolateral nuclei of the thalamus. For psychiatric disorders, relevant targets are the ventral striatum, including the nucleus accumbens, the ventral part of the internal capsule, the ventromedial part of the subthalamic nucleus, the anterior part of the internal globus pallidus, and the medial nuclei of the thalamus. The anterior nucleus of the thalamus is part of the Papez circuit and has been targeted in patients with treatment-resistant epilepsy. The anatomical details of these targets are discussed in this chapter.

Keywords

Deep brain stimulationBasal gangliaAnatomyTargetingNeurological disorders

Introduction

DBS aims to modulate the activity of localized anatomical areas, thereby reducing symptoms of specific neurological and/or psychiatric disorders. DBS has evolved to be an important therapeutic application in patients with specific disorders, including Parkinson’s disease (PD) (Deuschl et al. 2006), essential tremor (Benabid et al. 1993; Hubble et al. 1996), dystonia (Krauss et al. 1999), epilepsy (Fisher et al. 2010), as well as obsessive compulsive disorder (OCD) (Nuttin et al. 1999; Denys et al. 2010). Furthermore, the effects of DBS in managing the clinical symptoms of severe depression, Gilles de la Tourette syndrome (GTS) and various other psychiatric disorders have been explored (Bewernick et al. 2010; Lozano et al. 2012; Ackermans et al. 2011). Although three decades have passed since the introduction of DBS, neurophysiological correlates underlying the therapeutic effects of DBS remain to be clarified (Gradinaru et al. 2009). Knowing how DBS results in therapeutic effects in neurological or psychiatric disorder will be critical to our understanding of not only how DBS works, but also how to make it work better and how to apply it effectively to other neurological disorders. The essence of any mechanistic research, even ones that inherently seeks to unravel the mechanisms behind the therapy or pathophysiology, is one of anatomy. DBS needs to target the regions that have efficient access to anatomic networks involved in disease symptoms. Even though anatomical models relevant to core aspects of psychopathology continue to develop, it is conceivable that anatomic relationships of the basal ganglia, thalamus, and other cortical and subcortical structures are vital for gaining insight into the application of DBS in managing the neurological and psychiatric symptoms. An accurate implantation of the electrodes in DBS operations is therefore essential to obtain the desired effects. In fact, with a clear insight on the anatomy, a large part of therapeutic effects and side effects of DBS can be explained. This chapter aims to elaborate on the anatomy of the most commonly used DBS targets that have been thought to underlie the therapeutic effects of DBS. The focus will be mainly on the basal ganglia and the thalamus anatomy in the context of neurological and to psychiatric disorders. The cortico-basal ganglia-thalamocortical circuits and the individual areas are discussed below.

The Cortico-Basal Ganglia-Thalamocortical Circuits

The basal ganglia consist of the pallidal complex, the striatum, the substantia nigra, and the subthalamic nucleus (STN) (Alexander and Crutcher 1990). The motor loop computes the processes between the motor cortex and basal ganglia by direct, indirect, and hyperdirect pathways to determine overall thalamic activity. The cortical projections reach the basal ganglia via two major input structures. First is the striatum, which consists of the putamen and caudate nuclei in the dorsal striatum, and the nucleus accumbens (NAc) in the ventral striatum. The second input pathway enters the basal ganglia through the STN.

The striatum has been known as input structure for some time (Albin et al. 1989), but the STN as input structure is a more recent concept (Nambu et al. 2002). This cortico-subthalamic projection is known as the hyperdirect pathway and is glutamatergic, hence excitatory (Fig. 2.1). The cortico-striatal efferents enter the caudate, putamen, and accumbens nuclei to be processed further within the basal ganglia circuit. Cortico-striatal projections arise from the entire ipsilateral and contralateral cortical areas. These pathways are excitatory in nature and use glutamate as neurotransmitter at their synaptic terminals with the spines of striatal neurons, and are topographically organized (Gerfen 1984; Donoghue and Herkenham 1986). Cortico-striatal projections are classified into (1) pyramidal tract neurons, which project through the cortico-pyramidal tract and innervate the striatum ipsilateraly: these pathways mainly innervate the striatal neurons, giving rise to the indirect pathway, and (2) the intra-telencephalic neurons, which provide bilateral input to the striatal neurons in the direct pathway (Lei et al. 2004).

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Fig. 2.1

The cortico-basal ganglia-thalamocortical projections can be subdivided into three major functional pathways, namely the motor, associative, and limbic pathways. The connections of the motor pathway are described above. As for associative pathway, the cortico-striatal projections mainly innervate the caudate nucleus. The other connections of this pathway are very similar to those of the motor pathway. The cortical efferents from limbic areas enter the basal ganglia via the STN and the ventral striatum. The output projects through the ventral pallidum to the medial part of the thalamus (Alexander et al. 1990) and from there back to the related cortical areas. STN subthalamic nucleus, GPe globus pallidus externa, GPi globus pallidus interna, SNc substantia nigra pars compacta, SNr substantia nigra pars reticulata. (Figure reproduced with permission from Temel et al. 2005)

The thalamo-striatal projection is the second major source of innervation to the striatum, which had been largely neglected in the past years. These projections mainly arise from the midline and intralaminar thalamic nuclei (Berendse and Groenewegen 1990) as well as from the ventral thalamic motor nuclei (McFarland and Haber 2001). Thalamo-striatal efferents follow a similar path as the cortico-striatal pathway.

These projections descend on the dorsal striatum to the pallidal complex and feed two major striatal pathways. Via the direct pathway, these projections reach the output structures of the basal ganglia: the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). The direct pathway arises from medium spiny neurons (MSNs) that project monosynaptically to the GPi and SNr. These MSNs preferentially express dopamine D1 receptors. The indirect pathway arises from MSNs that express dopamineD2 receptors. Via the indirect pathway, the striatal projections first reach the external globus pallidus (GPe), then the STN, and via the STN, the signals pass on to the output nuclei (GPi and SNr). The indirect pathway involves direct projections from the GPe to the GPi as well. Apart from cortico-striatal and thalamo-striatal projections, the amygdaloid complex also provides glutamatergic input to the striatum (Ragsdale and Graybiel 1988). The GPi and SNr project mainly to the ventrolateral nuclei of the thalamus which, in turn, project back to the cerebral cortex (mainly the frontal lobe). The thalamic projections to the cortex are again excitatory. The efferent GPi and SNr pathways interact with different target structures through axon collaterals (Parent and Hazrati 1995; Parent et al. 2000). All projections within the basal ganglia are inhibitory and use GABA as neurotransmitter, except the STN neurons, which expresses glutamate as a neurotransmitter and is therefore the only excitatory nucleus. From the output nuclei, the projections reach the ventrolateral nuclei of the thalamus, and via the thalamus to the cortex; for more in-depth review, see Lanciego et al. (2012).

The monoaminergic neurotransmitter systems play an important role in modulating the functions of basal ganglia. A normal functioning of the basal ganglia system is highly dependent on intact dopamine release to the input nuclei. The nigro-striatal dopaminergic efferents arise mainly from the A9 group of dopaminergic neurons in the substantia nigra pars compacta (SNc) neurons and to lesser extent from A8 neurons, which are situated in retrorubral field (Dahlstrom and Fuxe 1964). The SNc projects to the motor and associative parts of the striatum as well as the STN. The mesostriatal and mesolimbic dopaminergic projections arise from the A10 group of dopaminergic cells in the ventral tegmental area (VTA) and project to the ventral striatum (e.g., the NAc) and the ventromedial part of the STN. Perturbed dopamine release is associated with several basal ganglia disorders such as the Parkinsonism, dystonia, chorea, and tics. In addition to dopaminergic projections, the serotonergic cells in the brainstem’s raphe nuclei also project to the dorsal and ventral striatum (Anden et al. 1966). However, the exact function of these projections remains unknown, as experimental data are controversial.

Anatomical Structures

The Striatum

The striatum is a heterogeneous structure with a diverse range of neuronal phenotypes and neurotransmitters. Several histochemical and immunohistochemical stains have revealed the presence of two major compartments named striosomes and matrix. The striosomes and matrix are differentiated into discrete territories and are well characterized to differ in their expression of neurochemical markers. For instance, histochemical staining using antibody against acetylcholinesterase enzyme (AChE) (Graybiel and Ragsdale 1978) has revealed the presence of scattered areas showing weak AChE labeling (striosomes) within a more intensely stained background (matrix). Immunocytochemical staining of number of other markers such as substance P, GABA, and neurotensin has also shown a preferential expression of these markers within these two compartments (Pert et al. 1976; Graybiel et al. 1981; Gerfen 1984; Desban et al. 1995). The local axon collaterals and dendritic arborization of MSNs are restricted within the striatal compartment in which they are positioned in either striosome or matrix. For instance, dendrites from striosomal MSNs do not enter the neighboring matrix and vice versa (Penny et al. 1988; Fujiyama et al. 2011). On top of exerting differences in afferent and efferent connectivity, the striosome and matrix compartments have also been suggested to play distinct roles in a range of neurological diseases. MSNs located in the matrix compartment project to the GPe, GPi, and SNr, while striosomal MSNs primarily innervate the SNc. However, these same cells form axon collaterals that reach the GPe, GPi, and SNr (Gerfen 1984; Bolam et al. 1988; Kawaguchi et al. 1989; Gimenez-Amaya and Graybiel 1990; Fujiyama et al. 2011). With regard to the input pathways, glutamatergic projections arising from the cerebral cortex and thalamus as well as dopaminergic fibers originating from the SNc mainly innervate the matrix compartment, while cortical limbic areas and amygdala preferentially project to the striosomes (Graybiel 1984; Donoghue and Herkenham 1986; Ragsdale and Graybiel 1988; Gerfen 1992; Sadikot et al. 1992a, b; Kincaid and Wilson 1996). The exact functional outcomes of striosome-matrix organization remain to be determined (Lanciego et al. 2012).

Striatal Neurons

The striatum contains two different types of neurons: projection or striatofugal neurons (90%) and interneurons (10%). Since projection neurons have a small-to-medium cell body (20 μm in diameter), they are also called medium-sized spiny neurons. These neurons are multipolar and their dendritic processes are covered by postsynaptic specializations called dendritic spines. All striatal MSNs are inhibitory neurons and express GABA as neurotransmitter. MSNs are divided further based on their projection pattern, including GPe innervating neurons and those that innervate the GPi and SNr. Striatal MSNs projecting to the GPe express the dopamine D2 receptor (D2R), forming the inhibitory indirect pathway (striato-GPe-STN-GPi/SNr) and thus inhibit the target neurons. In contrast, striatal MSNs, which directly innervate the GPi and SNr, express dopamine subtype 1 receptors (D1R), giving rise to the excitatory direct pathway (striato-pallidal) that stimulates target neurons. Another key difference between the direct and the indirect pathways is that source neurons in the direct pathway express the neuropeptide substance P, while the indirect pathway neurons contain the neuropeptides enkephalin and dynorphin (Wichmann et al. 2002). The striatum also contains several different types of interneurons, unlike MSNs all of which show smooth dendrites. These interneurons are classified into four groups according to their neurochemical phenotype and morphological features (Kawaguchi et al. 1995). These cell groups are as follows: (1) cholinergic neurons, which express acetylcholine as neurotransmitter and are the largest in size and most abundant among the other groups; according to their electrophysiological fingerprint, these neurons exhibit tonic firing pattern; (2) GABAergic and also contain parvalbumin with fast-spiking activity in electrophysiological recording; (3) GABAergic interneurons containing calretinin; and (4) another type of GABAergic interneurons, known as nitrergic interneurons which express nitric oxide as the neurotransmitter. These interneurons together with MSNs form a complex intra-striatal circuit. For instance, both tonic and fast-spiking GABAergic interneurons are under dopaminergic control, and in turn, modulate the activity of MSNs’ neurons; meanwhile, calretinin-expressing and nitrergic interneurons innervate tonic and fast-spiking GABAergic interneurons (for review, see Lanciego et al. 2012).

The Ventral Striatum

The ventral striatum consists of the nucleus accumbens, the ventromedial part of the caudate nucleus and the spined cell part of the olfactory tubercles (Nauta 1979; Parent and Hazrati 1995; Nakano 2000). The most important part of the ventral striatum is the nucleus accumbens (NAc) (Basar et al. 2010). The NAc is located anterior to the posterior border of the anterior commissure (AC) and lies parallel to the midline. It lies ventral and medial of the caudate nucleus and extends dorsolaterally into the putamen (Fig. 2.2). The NAc is more visible in coronal than in sagittal, and more in sagittal than transverse MR images. In T2-weighted MR images, the NAc shows more intense signaling compared with the caudate nucleus and putamen, which leads to easier distinction of the boundaries of the NAc with the caudate and putamen. Unlike the rest of the striatum, the NAc can be divided into a core and a shell, each of which has unique features. The