Rationale for Movement Disorder Surgery

2 Rationale for Movement Disorder Surgery

Cameron C. McIntyre, Christopher R. Butson, Benjamin L. Walter, and Jerrold L. Vitek

Surgical interventions for movement disorders have been practiced for decades, beginning with early studies that used lesions to eliminate activity in localized brain regions. Later, deep brain stimulation (DBS) grew out of observations during such surgery. Surgeons using stimulating/ recording electrodes for target confirmation during ablative surgery found that stimulation of the brain had effects similar to lesioning, specifically that high frequency stimulation (> 100 Hz) of the motor thalamus produced tremor arrest.1 These early studies eventually proved that functional neurosurgery for movement disorders can alleviate symptoms and improve the quality of life for disabling diseases such as Parkinson disease (PD), essential tremor (ET), and dys-tonia in appropriately selected patients. Although these surgeries were initially based on empirical observations, the advancement of scientific understanding and medical technology has allowed for an evolution from empirically to rationally based surgical strategies. Current surgical approaches incorporate magnetic resonance imaging (MRI)-based stereotactically and neurophysiologically guided targeting where the selection of the target(s) is based on pathophysiological understanding of the disorder.

Of the three major movement disorders for which surgical efficacy has been demonstrated (PD, ET, and dystonia), each has significant differences in the underlying pathophysiology. The cardinal symptoms of PD include resting tremor, rigidity, bradykinesia, and akinesia, as well as postural and gait disturbances.^2,3 The pathological hallmark of PD is the degeneration of dopaminergic cells within the substantia nigra with deposition of cytoplasmic eosinophilic inclusions (Lewy bodies) and subsequent dopamine depletion of the striatum. Clinical manifestations of PD occur when nigrostriatal dopamine loss reaches ~60%.⁴ Dopamine denervation of the striatum triggers a cascade of events within the basal ganglia that impairs its ability to appropriately interact with the rest of the nervous system. Medical treatment of PD with levodopa is not the panacea it was initially thought to be due to the late complications of levodopa-induced dyskinesias and increased motor fluctuations. Even with molecular and genetically based therapies on the horizon aimed at slowing the progression of PD, there is and will be for the foreseeable future a large population of patients significantly burdened by this neurodegenerative disease.

Approximately 4% of the population > 40 years of age exhibit symptoms of ET.^5,6 Most ET patients have mild symptoms that can be controlled with medication. However, a significant number of patients are refractory to medication, have significant disability, and are unable to perform simple activities of daily living or maintain employment. Although the neurophysiological origin of tremor remains debated within the scientific community, there remains a sustained need to address the limitations of current pharmacological approaches to the treatment of ET.

Dystonia is characterized by sustained muscle contractions, leading to twisting, repetitive movements, and abnormal postures. It can be focal, involving a single body region, segmental, involving two or more adjacent regions, or generalized, involving both legs plus at least one other region. Dystonia can be a symptom of destructive disease processes and in such cases is termed secondary dystonia. Dystonia with no obvious pathology is called primary dystonia. Some of these patients have now been found to have an inherited gene mutation, and there are now over 14 gene loci identified in association with dystonia. DYT1 dystonia, the most common of these, typically starts focally with one limb in early childhood and slowly generalizes to involve other body regions. Other genetic loci responsible for primary generalized dystonia include DYT2, 4, 6, 7, and 13.⁷

Reports of neuropathological examination of patients with suspected primary generalized dystonia are limited, and standard MRI scans have been reported as normal. Until recently no neuropathological changes have been reported in the brains of DYT1 patients.⁸ However, a recent study found perinuclear inclusion bodies that stain positive for ubiquitin, torsinA, and lamin A/C in the pedunculopontine nucleus, cuneiform nucleus, and griseum centrale mesencephal.⁹ Clinicopathological studies in patients with secondary dystonia indicate that the most common site in which a lesion can be identified is in the striatum, or pallidum.¹⁰ Thalamic lesions, although less common, have also been observed in patients with dystonia.¹¹ Dystonia is a particularly disabling condition, and although many patients with focal dystonias involving small muscle groups may respond to botulinum toxin, others with more diffuse involvement or involvement of larger muscle groups have limited success with traditional medical therapies.

PD, ET, and dystonia each represent especially debilitating diseases that affect significant numbers of patients who do not adequately respond to pharmacological interventions. In turn, functional neurosurgery has been employed in each disease state with substantial degrees of success. The combination of basic science understanding, advancing medical technology, and clinical acceptance has allowed the development of successful surgical practices and clinical centers. Currently there are two forms of surgical intervention for movement disorders that are used most commonly (ablation and DBS), and three general anatomical targets [thalamus, subthalamic nucleus (STN), and globus pallidus (GP)] to which these approaches are applied. Thalamic DBS for intractable tremor has virtually replaced ablative lesions of the thalamus.12 Similarly, DBS of the STN or internal segment of the globus pallidus (GPi) has largely replaced pallidotomy in the treatment of the cardinal motor features of PD (resting tremor, rigidity, bradykinesia).¹³ In addition, multiple pilot studies have begun to examine the utility of DBS for dystonia,^14,15 epilepsy,¹⁶ and obsessive—compulsive disorder (OCD).¹⁷ As data from larger controlled trials become available, neurologists and neurosurgeons will be able to tailor the therapy for their patient based on the patient’s disease characteristics (i.e., appropriate choice of target site and mode of treatment, ablation, or stimulation). Furthermore, we will be able to better predict the degree of clinical benefit and risk of adverse side effects based on characteristics of the patient’s disease, age, and other clinical variables.

Anatomy and Physiology of the Basal Ganglia and Thalamus

The basal ganglia (BG) are located in the basal telencephalon and consist of four interconnected nuclei: the striatum, GP, substantia nigra, and STN (Fig. 2.1). The thalamus is a large, oval-shaped structure that constitutes the dorsal portion of the diencephalon and acts as the gateway to the cortex. All sensory pathways (except olfaction) relay in the thalamus en route to the cerebral cortex as well as many of the anatomical circuits of the cerebellum, BG, and limbic structures.

The striatum is the main input structure of the BG; the GPi and the substantia nigra pars reticulata (SNr) are the output nuclei.¹⁸ Glutamatergic projections from virtually all cortical areas, as well as dopaminergic inputs from the substantia nigra pars compacta (SNc), converge onto spiny projection neurons in the striatum. Striatal output typically consists of low-frequency activity (~10 Hz), which is transmitted to the output nuclei (GPi and SNr) via either a direct or an indirect pathway.^18–20 In the direct pathway, one subpopulation of spiny neurons projects directly to the output nuclei (GPi and SNr) of the BG. A separate subpopulation of striatal neurons follows an indirect pathway, first projecting to the external segment of the globus pallidus (GPe), which projects to the STN, which in turn sends projections to the GPi and SNr. The subpopulations of spiny neurons that give rise to the direct and indirect pathways are characterized by their selective expression of neuropeptide and dopamine receptor subtypes.²¹ Although all striatal spiny neurons use gamma-amino butyric acid (GABA) as their main neurotransmitter, the subpopulation that gives rise to the direct pathway preferentially express the D1 subtype of the dopamine receptor (primarily excitatory), and the subpopulation that gives rise to the indirect pathway preferentially express the D2 subtype of the dopamine receptor (primarily inhibitory).²⁰ In turn, dopaminergic inputs from the SNc can explicitly modulate the transmission of neural activity through the direct and indirect pathways (Fig. 2.1).

The GPe, GPi, and SNr are each composed primarily of projection neurons that typically exhibit a consistent high-frequency (~60 Hz) firing pattern and use GABA as their main neurotransmitter. The inhibitory GPe output is transmitted to the GPi and STN. The STN is composed primarily of projection neurons that typically exhibit a consistent midfrequency (~40 Hz) firing pattern and use glutamate as their main neurotransmitter. Excitatory STN output makes a feedback loop with GPe and also projects to GPi and SNr. In addition, the STN receives direct excitatory cortical inputs that can modulate its firing rate and pattern. The direct and indirect pathways both project to the GPi and SNr, which sends inhibitory projections to the thalamus (Fig. 2.1).

By virtue of the neurotransmitters and baseline activity of neurons in the BG network, activation of the direct or indirect pathways can produce functionally opposite effects on thalamic output.²⁰ Corticostriatal neurons, thalamocortical neurons, and neurons of the STN are excitatory, utilizing glutamate as a neurotransmitter. All other neurons in the BG network are inhibitory, using GABA as their main neurotransmitter. Under resting conditions, the activity of the output neurons of the striatum is low compared with that of tonically active neurons in the GPe and STN. Activation of the corticostriatal pathway leads to increased firing of striatal neurons. Increased activity of striatal neurons in the direct pathway (striatum → GPi/SNr) leads to inhibition of the output nuclei (GPi and SNr). A reduction in tonic activity of the neurons in GPi/SNr leads to a reduction in the inhibition of neurons in the thalamus and increased thalamocortical output. In contrast, activation of the indirect pathway (striatum → GPe → STN → GPi/SNr), leads to the opposite functional effect on the thalamus. Increased activity of the striatal output neurons inhibits the tonically active neurons in the GPe. Inhibition of the neurons in GPe disinhibits neurons in the STN. Increased activity of the excitatory neurons of the STN leads to increased firing of neurons in GPi and SNr. An increase in the tonic activity of the neurons in GPi and SNr leads to an increase in the inhibition of neurons in the thalamus and a reduction in thalamocortical output (Fig. 2.1).

The thalamus is composed of nuclei most commonly classified into four groups (anterior, medial, ventrolateral, and posterior) based on the anatomical divisions created by the internal medullary lamina. The ventrolateral thalamus constitutes nearly all the nuclei intimately involved in sensorimotor function. The motor thalamus can be further subdivided into distinct relays for BG and cerebellar afferents. These channels in turn gain access to different functional regions of the cerebral cortex.²² Anatomical tracing studies in nonhuman primates show that pallidal and cerebellar receiving areas in the thalamus are largely segregated. GPi projects to the anterior part of the ventrolateral thalamus (human—Voa/Vop; monkey—VLo), which predominantly projects to the supplementary motor cortex. The cerebellum predominantly projects to the posterior part of the ventrolateral thalamus (human—Vim/Voi; monkey—VPLo), which then projects to the motor cortex (area 4) and arcuate premotor area.^23,24

Fig. 2.1 Basal—ganglia—thalamo—cortical network. (A) Simplified circuit diagram of the basal ganglia. Relative thickness of the lines indicates degree of activation, arrows represent excitatory synapses, squares represent inhibitory synapses, and line color indicates neurotransmitter [white, dopamine; gray, glutamate; black, gamma-amino butyric acid (GABA)]. Cortical information that reaches the striatum is conveyed to the basal ganglia output structures [internal segment of the globus pallidus (GPi) and the substantia nigra pars re-ticulata (SNr)] via two pathways, a direct inhibitory projection from the striatum to the GPi/SNr, and an indirect network that involves an inhibitory projection from the striatum to the external segment of the globus pallidus (GPe), an inhibitory projection from the GPe to the subthalamic nucleus (STN), an inhibitory projection from the GPe to the GPi/SNr, and an excitatory projection from the STN to the GPi/SNr. The information is then transmitted back to the cerebral cortex via a relay in the thalamus. (B) In Parkinson disease, the dopaminergic cell loss of the substantia nigra pars compacta (SNc) causes a cascade of alterations affecting all the other components of the circuit. The final result is the increased activity of the GABAergic output nuclei GPi/SNr, which causes increased inhibition of the motor thalamus. By contrast, hyperkinetic disorders such as dystonia result in increased inhibition of GPi/SNr, resulting in decreased inhibition of thalamus and overactivity of thalamic projections to cortex. (C) Examples of rasters of spontaneous neuronal activity in a normal monkey (top), a patient with Parkinson disease (PD) (middle), and a patient with dystonia (bottom). These illustrate the firing rates in GPi are reduced in dystonia and increased in PD.93,94 In both PD and dystonia there are abnormal, irregular grouped discharges in GPi, whereas in normal primates GPi has a more tonic regular firing pattern.⁹³ (Sources: Alexander GE, Crutcher MD, DeLong MR. “Basal ganglia—thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions.” In: Uylings HBM, Van Eden CG, De Bruin JPC, Corner MA, Feenstra MGP, eds. Progress in Brain Research. New York: Elsevier Science Publishers; 1990 and Smith Y, Bevan MD, Shink E, Bolam JP. Microcircuitry of the direct and indirect pathways of the basal ganglia. Neuroscience 1998;86:353–387.)

The majority of neurons within the various thalamic nuclei are thalamocortical projection neurons that use glutamate as their primary neurotransmitter. These neurons typically exhibit a relatively low frequency tonic firing pattern (~20 Hz). However, thalamic neurons transition from a tonic firing pattern to a low-frequency burst firing pattern (~4 to 8 Hz interburst interval) dependent on the behavioral state, which determines the synaptic input conditions.25,26 Another major component of the thalamic network consists of a thin sheet of inhibitory neurons, known as the reticular nucleus (nRt). The nRt forms the anterior lateral and a portion of the dorsal surfaces of the thalamus. Reticular neurons provide widespread inhibitory input to cells in the entire thalamus. In addition, thalamocortical projection neurons provide direct inputs to reticular thalamic neurons, generating tightly linked feedback loops. In turn, the interaction of the thalamocortical and reticular neurons provides an additional degree of information processing within both motor and nonmotor circuits of the thalamocortical system²⁷ (Fig. 2.1).

The rate-based block diagram of the BG—thalamocortical network is a highly Simplified representation. The feedback interaction between the STN and GPe,^28,29 direct cortical inputs to the STN,³⁰ and the interaction of additional nuclei such as the pedunculopontine nucleus³¹ and reticular thalamus²⁰ complicate our understanding of this network. In addition, this model does not take into account the pattern and/or synchrony of neural activity in each of the interacting nuclei. Although the rate-based model does not capture all of the important details pertinent to this understanding of the pathophysiological basis underlying the development of hypokinetic and hyperkinetic movement disorders, it has provided a great deal of scientific and clinical insight that has led to testable hypotheses and the development of alternate models that take these new observations into account.

Pathophysiological Basis of Movement Disorders

Our understanding of the pathophysiological basis of hypo- and hyperkinetic movement disorders has increased significantly over the last decade. The physiology of the normal brain relative to hyper- and hypokinetic disease states is summarized in Fig. 2.1, which highlights the neuronal activity changes that take place in the BG and thalamus in these disease states. Sensorimotor, associative, oculomotor, and limbic circuits originate in specific cortical areas, pass through distinct portions of the BG and thalamus, and project back to their cortical area of origin. These circuits are anatomically and functionally segregated throughout the BG—thalamo—cortical network, and disruption of the motor circuit is of primary interest in analysis of movement disorders. Both neuronal firing rates and patterns of activity within the BG network are now considered important in the genesis of movement disorders. In addition, the contribution of altered receptive fields and changes in synchrony are just now being appreciated. These scientific advances are providing a rationale for the selection of anatomical targets for ablative or DBS movement disorder surgery.

The pathophysiological basis underlying the development of PD has been developed from electrophysiological studies in animal models of PD as well as from humans with idiopathic PD undergoing functional neurosurgical procedures. The loss of dopamine from the SNc in PD is proposed to lead to differential changes in neuronal activity of striatal cells in the direct and indirect pathway. In the direct pathway, loss of dopamine at striatal excitatory D1 receptors leads to a decrease of inhibitory activity from the striatum to GPi. In the indirect pathway, there is loss of dopamine at inhibitory D2 receptors leading to increased activity of inhibitory striatal neurons projecting to GPe causing a reduction of GPe activity. The decrease in inhibitory output from GPe to STN leads to excessive excitation from the STN to the GPi. Thus there is an increase in inhibitory activity from the GPi to the thalamus and brain stem, via both the direct and the indirect pathways (Fig. 2.1B), which has been implicitly implicated as the change in neuronal circuits that underlies the development of the hypokinetic features associated with PD.³² Changes in mean firing rates of neurons in GPe, GPi, STN, and VLo in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of PD, and in GPe and GPi in patients with idiopathic PD, show a decrease in mean discharge rates in GPe and VLo and an increase in mean discharge rates in STN and GPi.^32–35 These changes are consistent with predictions from the rate-based block diagram of PD. Similarly, a loss or lowering of inhibitory input from GPi to the thalamus has been proposed as the basis for the development of the hyperkinetic movements associated with drug-induced dyskinesias and other hyperkinetic disorders (e.g., dystonia and hemiballismus).

Changes in neuronal firing rates alone, however, are not sufficient to explain the pathophysiology of PD or hyperkinetic movement disorders. Lesions within the motor thalamus do not exacerbate or induce parkinsonian motor signs, but instead, are reported to improve or abolish parkinsonian tremor, rigidity, and drug-induced dyskinesias.^36,37 Similarly, lesions in the GPi do not induce hyperkinetic movement disorders, but instead have been reported to abolish drug-induced dyskinesias as well as the involuntary movements associated with dystonia and hemiballismus. These results suggest that a decrease in activity of thalamicneurons cannot by itself account for the development of parkinsonian motor signs, nor can a reduction in the rate of GPi neurons account for the development of drug-induced dyskinesias, dystonia, or hemiballismus.38,39 These contradictions of the rate model have led to the incorporation of additional hypotheses to explain the pathophysiology of hypokinetic and hyperkinetic movement disorders.

In addition to the changes in neuronal firing rate, movement disorders are also associated with altered patterns of neuronal activity, changes in somatosensory responsiveness, and the degree of synchrony of neurons within the BG and thalamus (Fig. 2.1). The physiological basis for the development of PD has been a much debated issue. However, it appears likely that PD motor symptoms arise from a combination of changes in both rate and pattern. Observations of increased bursting and rhythmic oscillatory patterns within the BG and thalamus are common in both parkinsonian monkeys and humans with PD.^19,40 Bursting activity of thalamic neurons in the cerebellar receiving area of the thalamus is strongly correlated with tremor in PD, as well as ET.⁴¹ In addition, oscillatory activity, changes in somatosensory responsiveness, and degree of synchronization of pallidal and STN neurons are considered prominent features of PD pathophysiology.²⁹

Pathophysiologically, dystonia can be viewed as either a hypo- or hyperkinetic movement disorder. Dystonia may be a presenting symptom in parkinsonian patients who are not taking antiparkinsonian medications (“off”-dystonia)or alternatively may appear as a consequence of L-dopa treatment (peak dose dystonia). Electrophysiological recordings of pallidal neurons in patients with idiopathic dystonia demonstrate a decrease in the mean discharge rates of GPi neurons, consistent with predictions based on the “rate” model for hyperkinetic movement disorders.^42–44 However, in addition to decreased mean discharge rates, neuronal activity in the BG of dystonic patients have also demonstrated altered patterns of activity and widened receptive fields.⁴⁴ Uncontrolled changes in synchronization of neuronal populations in GPi may also occur and have been suggested to play an important role in the development of dystonia.⁴⁵ However, the exact relationship between changes (rate and pattern) in neural activity and the development of dystonia remains unclear.

The clear clinical improvements in movement disorder symptoms after thalamotomy, subthalamotomy, pallidotomy, or DBS are difficult to reconcile based solely on regularization of firing rate because each intervention should result in a different effect on rate. Therefore, given the pathophysiological characteristics of neuronal firing patterns in movement disorders, it has been suggested that the therapeutic effects of the treatment are dictated primarily by effects on the firing pattern. Based on this hypothesis, both ablation and DBS are effective in the treatment of movement disorders because they replace pathological neuronal activity with either no activity (ablation) or a highly regular firing pattern (DBS).^46–48

Editor’s Comments

For most of the last century, the basal ganglia was viewed as a collection of deep brain nuclei interconnected with the thalamus to form the extrapyramidal system, which, when disrupted, produced diseases quite apart from the pyramidal system. It was not until the 1980s when integration of the basal ganglia, thalamus, and cortex began to emerge from the work of Albin, Alexander, Delong, and colleagues.^95,96 The critical finding in this work was that of a network of basal ganglia/thalamocortical circuits that subserved five separate functions, each segregated from the other, and involved projections from specific cortical areas to separate areas within the subcortical structures that projected recurrently in a closed loop manner back to the original cortical areas through specific thalamic relay nuclei.

In large part, our understanding of these loops relates to many factors, including multiple advances in the neurosciences, but is especially indebted to the MPTP monkey model of Parkinson disease, which allowed the opportunity to characterize biochemical, electrophysiological, and behavioral changes in the basal ganglia as they relate to the parkinsonian state.³² Of the cortico—striato—pallido—thalamocortical loops, the motor loop is that which is most relevant to movement disorders. Widespread involvement of the nonmotor circuits, such as the oculomotor, dorsolateral prefrontal (executive function), associative, and limbic, may explain many of the nonmotor symptoms that characterize Parkinson disease. But it is the motor circuit that helps us understand the cardinal features of Parkinson disease.⁹⁷ Within the motor loop there are the direct (striatum—GPi) and the indirect (striatum—GPe—STN—GPi) projections to the thalamus that have opposite functional effects and are the basis of what has been widely referred to as the Alexander and Delong model of the basal ganglia.

The original model was a wire diagram, very simplistic in its anatomical and physiological construction. The key is that the direct and indirect pathways not only have opposite functions but are driven by different dopaminergic receptors. Thus the most powerful affect of dopamine in normal humans is mediated through the direct pathway. But in Parkinson disease, the dominant effect shifts to the indirect pathway.³² These alterations were used to explain the various movement disorders and specifically Parkinson disease. In support of the model, there is a tremendous amount of experimental evidence from microelectrode recording, anatomical tracing, and metabolic studies.^32,96,97 Later, there was additional strong support from intraoperative patient recordings, imaging studies with both PET and functional MRI, pharmacological studies, and surgical outcome from lesioning of the basal ganglia, all of which supported the concept of increased basal ganglia inhibition to the thalamus as a major feature of the parkinsonian state in this model.

Despite the tremendous support for this initial model, it obviously could not explain comprehensively all of the functions of the basal ganglia, either normal or abnormal. This led to rounds of criticisms that the model was limited in its usefulness, if not flawed.98–100 Although these criticisms were being made, the model was, in fact, continuing to undergo evolution. Fig. 2.1 represents the accumulation of some of these refinements, although incomplete. There is an increased understanding of the microcircuitry developing into an extremely complex interaction among the various nuclei. It is now clear that the GPe does not simply project to STN but has reciprocal innervation from STN and direct projections GPi/SNr.¹⁰¹ This loop within the loop may help explain some of the oscillatory behavior of the system.

In addition, direct cortical projections from primary motor cortex, supplementary motor cortex, and premotor cortex to both striatum and STN have also been described and may be important in relaying information into the basal ganglia and synchronizing oscillatory activity. Reciprocal corticothalamic projections occur between Vim and motor cortex as well as VL and VA to secondary motor cortex. The model now includes connections to other networks outside of the basal ganglia. Foremost of these are projections to the pedunculopontine nucleus (PPN) and midbrain extrapyramidal area (MEA), which may have significant effects on balance and gait difficulties.¹⁰² Failure to affect these nuclei could explain why these symptoms are not well controlled by STN or GPi lesions or stimulation. Cortical projections may also reach the striatum through the central median and parafasicularis (CM/PF) thalamic complex, which has reciprocal connections and, in addition, receives excitatory input from PPN/MEA. The CM/PF is an old stereotactic target for movement disorders. GPe has inhibitory projections directly to the thalamus nucleus reticularis and PPN/MEA, suggesting a more widespread effect outside the indirect pathway. The newer anatomical circuits allow for a much richer evaluation of the basal ganglia, thalamic, and cortical interactions with now thalamic output through the striatum allowing for further synchronization along oscillatory pathways.

Along with the need for additional anatomical understanding is the need for additional understanding of the electrophysiology. The main concept initially was one of changes in rate. Although this allows adequate descriptions of classic hypokinetic (PD) and hyperkinetic (dystonia) disorders, it was soon clear that rate alone could not explain many of the subtleties of the disorders. There is a need to explain the difference symptomatologies between hemichorea/ballism, dysto-nia, and levodopa-induced dyskinesias that all share a common final pathophysiological mechanism.^44,45,91 Although related, there are differences that are more than just the degree of symptomatology and that strongly suggest the need for revision of the rate model. Another deficiency of the rate model is explaining lesions that would produce the so-called Marsden and Obeso paradox.¹⁰³ Although many others have described this, these authors crystallized the apparent paradox that if Parkinson disease and hypokinetic disorders represent overly inhibited thalamic motor nuclei, then how can thalamotomy improve parkinsonian symptomatology? It should make it worse. Similarly, why does not pallidotomy increase dyskinesias rather than diminish them? Why do not lesions in general produce adverse motor effects? The effects of DBS can be questioned in the same manner.

The answer came very early on through clinical studies that, not only was rate important but also the alteration in the pattern of activity (Fig. 2.2). Thus in Parkinson disease there is within STN, GPi, and Vim a greater tendency to discharge in bursts with a high degree of synchronization with neighboring neurons.⁹⁷ The projections from GPe to the thalamus as well as GPi to the PPN should amplify the tendency of the neuronal pools to fire synchronously and in an oscillatory fashion along with their widespread connections to other thalamic subnuclei and cortical regions, thus creating a substantial change in the burst and synchronic activity within the basal ganglia—thalamic complex. If, along with the observation that there is an abnormally wide receptive field in both the MPTP parkinsonian model and Parkinson disease, there is then a suggestion that the oscillatory activity could be erroneously interpreted as excessive sensory feedback. Thus the motor cortex would have a diminished picture of the actual velocity, amplitude, and acceleration of movement activities. This in turn could lead to slowing (bradykinesia) or premature arrest of ongoing motor activity (freezing), and the like. The widened receptive fields and irregular activity may laterally inhibit competing normal motor programs.¹⁰⁴

Because there is indeed a series of somatotopic representations each of which projects to different cortical areas, multiple differences in symptoms could result from varying degrees of disease within the different subpathways. How specific symptoms develop still remains difficult to resolve with the current model. Parkinsonian tremors are treated by using high frequency stimulation in the thalamus, subthalamus, or globus pallidus. Tremor cells are identified in each of these nuclei; yet neurons in the Vim do not receive afferents from the basal ganglia. All of the long loops that include pacemaker oscillatory bursting activity from elements of the basal ganglia have not yet been established. It is difficult to demonstrate the importance of both rate and frequency in a cartoon (Fig. 2.2).

Rigidity likewise is quite difficult to explain with its myriad of manifestations. If the manifestation is at a spinal cord level, again long loop aberrations have been invoked for the symptom. The symptoms may be tied together through thalamocortical dysrhythmia, which would be manifest at the cortical level and could produce these positive symptoms of Parkinson disease.¹⁰⁵ Another alternative, however, includes the identification of PPN and MEA circuitry, which may represent important relays between the thalamus and spinal cord. Lesions of the PPN can induce akinesia, and its importance in balance and gait suggest that this is a tempting target for intervention in Parkinson disease. In fact, stimulation studies have suggested excellent responses with DBS in PPN.^106,107

Another way of evaluating this problem is to look at it from a totally different model system. Here each loop is a neural optimal control system, which includes a model of object behavior and an error distribution system.¹⁰⁸ In this model, the error distribution system would include the dopaminergic neurons that are necessary to tune the model system to have control by the neural optimal control system (cortex). In such a model, Parkinson disease would be considered a disease of the error distribution system. As a consequence, the system incorrectly predicts the state of the motor system in these patients. The controlling system would then treat the incorrect predictions as if the controlled object were perturbed by an unaccounted for external force and in turn tries to adjust for the error in the next step. In an attempt to correct for the perceived rather than the actual patient’s position, the control then introduces specific symptoms such as tremor. Thus at the cortical level, the irregular bursting activity may attempt to be controlled and result in an overshoot rather than an equilibrium.

An important recent finding is that there are multiple oscillatory frequency bands in the local field potentials (LFPs) in STN that relate to disease and treatment. The LFPs are pleomorphic, focal, and synchronized current oscillations produced by local neuronal populations. There are low (13 to 20 Hz) and high (20 to 35 Hz) as well as some very high frequency (70 to 300 Hz) rhythms. The movement-and levodopa-dependent 300 Hz frequency may reflect the normal processing in the basal ganglia and provides support of the excitatory mechanism of high-frequency stimulation.109 The gamma frequency (70 to 100 Hz) may represent synchronous activity in the upper STN.¹¹⁰ It is the β (8 to 30 Hz) frequency activity that is abnormal in PD. In the off state or within minutes of turning off the DBS, the frequency dominates and inversely correlates with the akinesia.^111–113 In the on state or with high frequency DBS, the higher frequencies in the gamma range return to dominate, but dyskinesias are marked by an increase in low-frequency bands (4 to 10 Hz).^113,114 Understanding how these LFPs are formed could clarify our modeling of the electrophysiology of the basal ganglia.

The mechanism or mechanisms by which DBS modulates neuronal network function remain controversial. Most likely all of the mechanisms discussed in the chapter are activated. If there is a gradient current density, clearly both inhibitory and excitatory effects must occur.⁴⁷ The stimulation is from a high-voltage cathode pulse. The polarization block therefore must occur proximal to this lead. However, at a distance somewhat greater, the cathode pulses will preferentially stimulate axons (of passage or from the depolarized neurons) resulting in both orthodromal and antidromal propagation. Unlike the somata, the axons can follow the high frequency firing rates, and this activation of distal neural elements may lead to the reestablishment of appropriate synchronization that is believed to be the key element to the mechanism of DBS stimulation. Stimulation of presynaptic GABAergic terminals could increase inhibition in this area and potentially stimulate some inhibitory interneurons, but this is probably a trivial mechanism.

In addition, imaging is increasingly suggesting more excitatory evidence rather than inhibitory evidence. The combination of the two may be necessary but the excitatory effects are predominant. Thus several studies have shown that DBS in STN has a net effect of increasing firing rates in GPi rather than decreasing them. But as this chapter points out, the model is not only rate but also pattern. The effect of DBS then is one of increased synchronization rather than the irregular burst activity, which appears to be so disruptive to the cortex. One concept is that this is a stochastic resonance and it is the normal signal that had been lost in the noise and is suddenly revealed by this constructive interference paradigm.⁷¹ There is something about going from beta to gamma activity in STN that is important, and the same may be true of other nuclei. Even direct stimulation of the motor cortex may help parkinsonian symptoms.¹¹⁵

Lesioning has very different effects on local and distant circuitry and imaging than DBS, but a common effect of both is increased activity in the motor cortex.^116,117 Lesioning may simply be a different means of removing the disruptive rhythms. It would be interesting to know what happens to the LFPs in lesioning. Meanwhile, it is no longer popular to say that DBS acts as a “functional lesion.” However, the bottom line is that, as far as we know, both DBS and lesioning produce identical net effects on movement disorder symptoms.

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