Introduction
The notion that functional brain disorders can be treated by modulating the activity of subcortical brain regions is as old as modern neurosurgery. Meyers is credited with performing the first transventricular lesions of the basal ganglia , but it was not until the invention of ventriculography and the human stereotactic frame that surgical approaches to deep brain targets became routine. Ablation represents the simplest means by which to modulate neural activity but, given the risks associated with creating irreversible brain lesions, the horrific experience of trans-orbital frontal lobotomy in America, and the introduction of chlorpromazine in the 1950s and levodopa in the 1960s, neuroablative procedures fell into disfavor until their resurrection in the late 1980s.
Over the last two decades, the field of deep cerebral neuromodulation has developed rapidly ( Table 3.1 ). Chronic electrical deep brain stimulation (DBS) has supplanted neuroablation as the primary neuromodulatory technique and has become a standard treatment for medically refractory essential tremor, Parkinson’s disease, and primary dystonia. The treatment of obsessive–compulsive disorder (OCD) with DBS has been approved in the USA and pivotal trials of DBS for epilepsy and major depressive disorder (MDD) are either completed or in progress. In addition, alternatives to electrical neuromodulation are being developed including gene therapy directed at both neuroprotection/restoration and neuromodulation. In this chapter, we provide an overview of the various deep cerebral targets currently being employed for neuromodulatory therapy. The scientific/physiologic rationale for modulating these targets will be discussed and key clinical research findings will be highlighted. Due to space constraints, we will focus on electrical neuromodulation as this is currently the most widely employed modality, but any of these sites may be targeted with novel neuromodulatory techniques in the future.
Disease/disorder | Target |
---|---|
Pain Nocioceptive Neuropathic | Periventricular/periaqueductal gray (PVG/PAG) Ventrocaudal thalamus |
Tremor Essential tremor * Parkinsonian tremor * Intention tremor | Ventrolateral thalamus # Zona incerta/pre-lemniscal radiation |
Parkinson’s disease * Rigidity Bradykinesia Levodopa-induced dyskinesia Motor fluctuations Tremor Gait akinesia and postural instability | Posteroventral globus pallidus pars internus # Subthalamic nucleus # Pedunculoponinte nucleus (PPN) |
Dystonia Primary generalized dystonia * Secondary dystonia | Posteroventral globus pallidus pars iInternus # Subthalamic nucleus # Ventolateral tThalamus |
Epilepsy Remote from the epileptogenic focus At the epileptogenic focus | Cerebellum Centromedian nucleus of the thalamus Anterior nucleus of the thalamus Subthalamic nucleus Head of the caudate nucleus Cortical Mesial temporal lobe (MTL) |
Tourette’s syndrome | Centromedian nucleus of the thalamus Posteroventral globus pallidus pars interna Anteromedial globus pallidus pars interna Nucleus accumbens (NAc) and anterior limb of internal capsule (IC) |
Obsessive–compulsive disorder * | Ventral capsule/ventral striatum (VC/VS) # Nucleus accumbens |
Depression | Subgenual cingulate cortex (Brodmann’s area 25) Rostral cingulate cortex (Brodmann’s area 24a) Ventral striatum/nucleus accumbens Inferior thalamic peduncle Lateral Habenula |
Addiction | Nucleus accumbens |
Obesity | Ventromedial hypothalamus |
* Indicates an approved indication.
# Indicates an approved target for the given indication. (NB: Dystonia and obsessive–compulsive disorder are approved in the USA under a ‘Humanitarian Device Exemption’)
The thalamus
Following the pioneering work of Hassler in Germany , Cooper in the USA , and Narabayashi in Japan , the thalamus was the favored target of functional neurosurgeons in the pre-computed tomography (CT), pre-microelectrode, pre-levodopa era. The reasons are obvious:
- 1.
in structures such as the ventrocaudal (Vc) and ventrolateral (VL) nuclei, neurons are arranged in a clear topographic manner, simplifying electrophysiological mapping with the cruder macroelectrode techniques of the day
- 2.
the effects of stimulation at these targets typically are immediate, allowing the surgeon to feel comfortable about electrode position prior to performing an irreversible ablation
- 3.
functions are relatively compartmentalized in the thalamus so that one may treat movement, for example, without affecting sensation.
Today, the thalamus is targeted less frequently than other deep cerebral structures, but a working knowledge of thalamic anatomy and physiology remains essential. The interested reader is directed to Dr Ronald Tasker’s classic work on thalamic physiology and Dr Patrick Kelly’s detailed description of his ventrolateral thalamotomy technique, employing semi-microelectrode recording .
Pain
Deep brain stimulation-derived analgesia was first observed and reported by Pool and Heath who found that stimulating the septal nuclei, including the diagonal band of Broca anterolateral to the forniceal columns, resulted in significant pain relief in psychiatric patients. Mazars reported that thalamic stimulation produces paresthesias with simultaneous long-lasting relief of deafferentation pain . As a direct extension of Melzack and Wall’s ‘Gate theory’ , Reynolds reported on the analgesic effect of aqueductal stimulation in rats . Analogous work by Hosobuchi and Richardson first demonstrated the efficacy of thalamic and periventricular/periaqueductal gray (PVG/PAG) stimulation for the relief of pain. Since then, the Vc and PVG/PAG have been the most studied sites of DBS for pain in humans.
The mechanisms underlying pain relief via stimulation at these sites appear to be different yet are still not completely understood. Hosobuchi proposed that pain relief derived from PVG/PAG stimulation is mediated by opioid release following the observation that stimulation-induced analgesia at this site is blocked with naloxone . Current thought maintains that the analgesic effect of PVG/PAG stimulation is mediated by multiple opioid- and biogenic amine-dependent supraspinal descending pain modulatory systems. In addition, ascending pathways from the PVG to the medial dorsal nucleus of the thalamus, an area associated with the limbic system and with extensive connections to the amygdala and cingulate cortex, have been identified, raising the possibility that stimulation of the PVG may also modify the patient’s emotional response to pain . Consequently, the majority of PVG stimulation studies have concentrated on its utility in treating intractable nociceptive rather than neuropathic pain. The results of many individual studies and pooled meta-analyses of PVG/PAG DBS for nociceptive pain have demonstrated success rates as high as 63%, depending on the etiology .
In contrast, pain relief from Vc thalamic stimulation is thought to be mediated by activation of the nucleus raphe magnus of the rostro-ventral medulla as well as descending inhibitory pain pathways . Ventrocaudal thalamic stimulation has been applied most frequently in the setting of neuropathic/deafferentation pain syndromes, including anesthesia dolorosa, post-stroke pain, brachial plexus avulsion, post-herpetic neuralgia, and post-cordotomy dysesthesia. In general, deafferentation pain syndromes respond less well to stimulation than do nociceptive syndromes, with relief in a mean of 47% of patients . Of these, 31% of patients with a central pain etiology (e.g. thalamic post-stroke pain) respond to thalamic DBS, while 51% of those with a peripheral etiology (e.g. post-herpetic neuralgia) experience a meaningful response. Interestingly, the rate of long-term pain alleviation is highest in those patients undergoing DBS of the PVG/PAG alone (79%), or the PVG/PAG plus the thalamus (87%). Stimulation of the thalamus alone is less effective (58%) than stimulation of the PVG/PAG ± thalamus ( P < 0.05) . Many studies have thus concluded that DBS is more effective in treating nociceptive pain syndromes and that stimulation at both the PVG/PAG and thalamus may be most effective . Presently, DBS is not approved in the USA at either target for the treatment of refractory pain.
Tremor
Tremor is a rhythmic, involuntary oscillation of the musculature that can affect the head, extremities, and/or trunk. Tremor is characterized by its clinical manifestations (i.e. resting, postural, action, and/or intention) and may be caused by multiple neurological disorders including Parkinson’s disease (PD), essential tremor (ET), traumatic brain injury, stroke, and multiple sclerosis. In the 1950s, Cooper serendipitously discovered that ligation of the anterior choroidal artery ameliorated tremor, though paresis could also result . Further research by Narabayashi , Hassler , Cooper , and others identified the ventrolateral nucleus of the thalamus as the primary target for eliminating tremor and employed ventriculography-based stereotaxis to ablate this site directly. Thereafter, thalamotomy remained the most commonly performed procedure for involuntary movement disorders until the late 1980s when Benabid developed DBS .
The junction of the ventral intermediate (Vim) and ventral oralis posterior (Vop) subnuclei of the VL thalamus is the most commonly targeted site for treating disabling parkinsonian and essential tremor with DBS . The Vim and Vop are histologically distinct subnuclei located posteriorly in the VL nucleus. The Vim receives excitatory cerebellar input and projects to the motor cortex. The zona incerta, which is often included in the stimulaton field, contains the thalamic fasciculus and is partly made up of dentatothalamic and pallidothalamic projections.
Multicenter trials in North America and Europe as well as smaller case series report excellent results with unilateral and bilateral thalamic DBS for tremor. Taken together, these studies report significant improvement of hand tremor in up to 75% of unilaterally and 95% of bilaterally stimulated patients, respectively . Axial tremor (head, voice) is improved in up to 50% and 100% of unilaterally and bilaterally stimulated patients, respectively . These effects appear to be long lasting, though tremor recurrence due to stimulation tolerance has been reported. Studies comparing DBS to radiofrequency thalamotomy demonstrate equivalent tremor suppression but a lower risk of neurological complications in patients treated with DBS . The most common deficits related to thalamic interventions are hemiparesis, dysarthria, ataxia, and sensory deficits, most of which abate over time. Suppression of tremor results in significant reductions in functional disability in patients with ET . In contrast, patients with advanced PD do not realize significant functional improvements following thalamic DBS because their other more disabling symptoms (e.g. rigidity, bradykinesia, motor fluctuations, levodopa-induced dyskinesia, and gait disturbance) are not improved. Consequently, DBS at other targets is more commonly employed for patients with advanced PD (see below).
Epilepsy
By its very nature, epilepsy would appear to be the ideal disorder to treat with electrical neurostimulation and, in particular, intermittent responsive stimulation. Toward that end, neurosurgeons have targeted a number of deep cerebral, cerebellar, and brainstem sites with the hope of controlling seizure disorders. These include the corpus callosum, caudate nucleus, centromedian thalamus, posterior hypothalamus, subthalamic nucleus and the hippocampus. Stimulation at these targets has often appeared efficacious in small open-label studies, but failed to achieve significant seizure control when tested in a controlled fashion . Consequently, most of these deep brain stimulation strategies have been abandoned and the substantial population of medically refractory epilepsy patients who are not candidates for resective/ablative surgery are currently treated with vagus nerve stimulation. Nevertheless, two neurostimulation strategies, one ‘open-loop’ and one responsive, are in advanced stages of clinical testing and might be commercially available by the time this textbook is published.
Anterior nucleus of the thalamus (ANT)
The ANT is a component of Papez’ circuit and is thought to play a central role in the propagation of seizure activity. Its small size, surgical accessibility, and direct connection to limbic structures, make it an attractive target for neuromodulation. High frequency stimulation of the ANT has been found to raise seizure thresholds in animal models of epilepsy and preliminary open-label clinical trials have demonstrated significant reductions in seizure frequency in small numbers of patients . Based on these successes, a 110-patient, double-blind, multicenter trial of ANT DBS for medically refractory epilepsy was completed in 2008 . Cycled stimulation at the ANT resulted in a statistically significant 40% reduction in the median seizure frequency of the treatment group versus a 14% seizure reduction in the control group. After 2 years of open-label stimulation, the median seizure frequency was reduced 56%, with 54% of patients achieving seizure frequency reductions of 50% or more . Based on these results a United States Food and Drug Administration (FDA) advisory board has recommended approval of ANT DBS for the treatment of medically refractory complex partial epilepsy.
Responsive neurostimulation (RNS)
A second approach to therapeutic neurostimulation for epilepsy involves the use of a ‘closed loop’ or responsive system, which detects seizures before they manifest clinically, and disrupts them with a short burst of electrical stimulation. Neuropace, Inc. recently presented the results of their multicenter, double-blind trial in which 191 patients with medically refractory partial epilepsy were randomized to therapeutic or sham stimulation for a 3-month period following implantation of the device . At the conclusion of the 3-month blinded phase of the study, patients who received therapeutic stimulation experienced a mean 29% reduction in disabling seizures versus a 14% reduction in the sham-stimulation control group (interestingly, the identical placebo response observed in the ANT/DBS trial ). A ruling from the FDA is pending.
Tourette’s syndrome
Tourette’s syndrome (TS) is a chronic complex neuropsychiatric disorder characterized by sudden, repetitive, stereotyped motor or vocal tics. Tourette’s syndrome is often co-morbid with OCD, attention deficit hyperactivity disorder (ADHD), and/or self-injurious behavior . Similar to Parkinson’s disease (see below), disordered cortico-striato-pallido-thalamo-cortical circuitry may be responsible for the motor and non-motor manifestations of TS. Hyperactivity within the dopaminergic system may lead to excessive thalamocortical drive, resulting in hyperexcitability of cortical motor areas and the release of tics. Hyperactivity in Broca’s area, the frontal operculum, and the caudate nucleus may underlie vocal tics, while abnormal activation of the orbitofrontal region (as is observed in OCD), may underlie the compulsions that patients with TS experience .
Based on Hassler and Dieckmann’s success with thalamic lesioning for TS , Visser-Vandewalle et al (1999) performed the first thalamic DBS for TS in a 42-year-old male, achieving complete resolution of his tics one year postoperatively . Since then, several small series have reported success with DBS for TS at four different targets:
- 1.
the centromedian nucleus including either the substantia periventricularis and nucleus ventro-oralis internus (CM–SPv–Voi) or the parafascicular nucleus (CM-Pf)
- 2.
the posteroventral globus pallidus pars interna (GPi)
- 3.
the anteromedial GPi
- 4.
the nucleus accumbens (NAc) and anterior limb of internal capsule (IC) .
Preliminary data suggest that the efficacy of thalamic versus pallidal DBS in TS is similar, though pallidal stimulation may attenuate tics more abruptly and thalamic stimulation may yield better effects on mood and impulsivity . According to a recent review by Porta et al, tic reduction ranging from 25 to 100% has been reported in a total of 39 TS patients with follow-up periods of 3–60 months . Additional research will be necessary to determine whether an optimal target for TS exists and whether efficacy can be demonstrated in larger case series.
Globus pallidus pars internus (GPi)
Spiegel and Wycis may be credited with inventing electrical pallidotomy (or rather ansotomy) for the treatment of parkinsonian tremor and rigidity in 1947 . Their groundbreaking work was independently confirmed by Narabayashi, who performed procaine oil-induced transient pallidotomies in a series of PD patients . Over the next decade, Fenelon, Leksell, Guiot, and Cooper all advocated mesial pallidotomy and ansotomy for the treatment of tremor and rigidity . Interestingly, Cooper noted superior results from pallidotomy in patients with dystonia musculorum deformans (now known as DYT1-associated torsion dystonia) . In 1960, Svennilson reported improved results for pallidotomy in Parkinson’s disease when the lesion was placed more ventrally, posteriorly, and laterally in the GPi . A quarter century later, DeLong and colleagues employed microelectrode recording techniques to demonstrate that the neurons in the posteroventral GPi subserve sensorimotor functions, and that this region becomes hyperactive in primates with MPTP-induced parkinsonism . These findings provided the scientific underpinnings for the resurgence of posteroventral pallidotomy for medically refractory PD, which was championed by Laitinen and colleagues in Sweden . Moreover, DeLong and colleagues’ work resulted in the more widespread use of microelectrode recording as a localization technique during stereotactic targeting in patients. Though controversial, microelectrode techniques provide useful information that macroelectrode techniques do not, and may impact targeting in a significant proportion of pallidal interventions .
Posteroventral pallidotomy effectively alleviates tremor, rigidity, bradykinesia, and levodopa-induced dyskinesias in the contralateral hemibody of PD patients, however, the performance of bilateral procedures may be associated with serious speech, swallowing, and cognitive complications, so that the overall utility of pallidotomy in patients with advanced symmetric disease, severe motor fluctuations, and gait disturbance is limited . However, the successes of both unilateral pallidotomy and thalamic DBS as a replacement for thalamotomy set the stage for the use of bilateral DBS at both the GPi and the subthalamus (see below) for the treatment of Parkinson’s disease and primary generalized dystonia.
Parkinson´s disease
The serendipitous discovery that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) poisoning can induce a parkinsonian state in humans and non-human primates has contributed greatly to our current understanding of PD and basal ganglia physiology as it pertains to motor function. In the classic model proposed by DeLong and Crutcher , the striatum (caudate nucleus and putamen) receives broad input from the cortex and the intralaminar nuclei of the thalamus as well as dopaminergic input from the substantia nigra pars compacta (SNc). The globus pallidus pars interna (GPi) and substantia nigra pars reticulata (SNr) generate the dominant motor output of the basal ganglia, extending projections to the ventroanterior and ventrolateral (VA/VL) nuclei of the thalamus via the ansa lenticularis and fasciulus lenticularis ( Fig. 3.1 ). The VA/VL nuclei, in turn, project to supplemental motor regions anterior to the primary motor cortex. In addition, there exist projections from the GPi/SNr to the pedunculopontine nucleus (PPN), which is important in locomotion, and to the superior colliculus, which is involved with eye movements. The striatum modulates output from the GPi/SNr via direct inhibitory axonal projections and an indirect pathway via the globus pallidus par externus (GPe) and the subthalamic nucleus (STN).
