Localizing Movement Disorders in Childhood

Summary

The diagnosis and management of movement disorders in children can be improved by understanding the pathways, neurons, ion channels, and receptors involved in motor learning and control. In this review, we use a localization approach to examine the anatomy, physiology, and circuitry of the basal ganglia and highlight the mechanisms that underlie some of the major movement disorders seen in children. We begin by reviewing the connections between the basal ganglia and the thalamus and cortex. We address the basic clinical definitions of movement disorders and then place diseases within an anatomic/physiologic framework that highlights our current understanding of basal ganglia function. We discuss how new pharmacological, behavioral, and electrophysiological approaches may benefit the child by modifying synaptic function. A better understanding of the mechanisms underlying movement disorders allows improved diagnostic and treatment decisions.

Introduction

The basal ganglia consist of several collections of neurons that fine tune motor movements and behaviors through complex interconnections utilizing a variety of neurochemicals. Plasticity in these connections is responsible for motor learning and habit formation, while more severe perturbations of this system can produce movement disorders and neuropsychological diseases. In response to sensory information, the basal ganglia receive “thoughtful” instructions from the cortex and “reflexive” signals from the centromedian/parafascicular nucleus of the thalamus (figure 1).¹ These signals may compete for dominance during their integration in the striatum where “Go,” or “No-Go” responses are selected. This information processing relies upon complex circuitry, which is modified by dopamine and other neuromodulators in response to experience. While such plasticity is required for motor learning, excessive changes in neurocircuitry, ion channel function, or neurotransmitter availability can result in abnormal striatal processing and dysfunctional movements. Tics, the prototypical hyperkinetic movement disorder, are thought to be mediated through subcortical circuits within the basal ganglia. Movement disorders can also be caused by genetic, acquired, and immunological diseases. While the underlying cellular mechanisms are often unclear, we highlight how downstream changes in basal ganglia function can promote disturbances in movement and how pharmacological, surgical, and behavioral interventions can modify these abnormalities, leading to clinical improvement.

Figure 1:

Sagittal section of a mouse brain illustrating the thalamostriatal feedback network (solid red arrows) and the corticostriatal–thalamic-cortical feedback pathway (dotted blue arrows). Typical sites for deep brain stimulation are illustrated.

The role of the basal ganglia in motor learning

Motor movements, generated in the cortex, are modified by cortical–basal ganglionic–thalamo–cortical circuits.² Most cortical areas and the thalamus send excitatory glutamatergic afferents to the striatum, forming synapses on spiny projection neurons (SPNs). SPNs also receive signals from midbrain neurons that fire and release dopamine in response to novel stimulation. This tripartite circuit is essential for the control and learning of complex motor and behavioral tasks (figure 2A). Dopamine and glutamate also modify a relatively small but influential collection of striatal interneurons; their nuclei, dendrites, and axon collaterals remain within the striatum. While representing only 3–4% of striatal neurons, interneurons have a broad impact on behavior; they are excited by glutamate and modulated by dopamine and in turn modify SPN firing. Striatal interneurons include the tonically-active cholinergic interneurons (ChIs) and assorted GABAergic interneurons. Both receive dopamine signalling and modify SPN activity, but their glutamatergic inputs differ. GABAergic interneurons are mostly excited by glutamatergic afferents from the cortex, while ChIs are almost exclusively activated by inputs from the thalamus. Both types of interneurons are essential; a decrease in the number of GABAergic interneurons promotes abnormal behaviors in rodents exposed to prenatal cocaine,³ while ChIs have been implicated in drug dependence and movement disorders including levodopa-induced dyskinesia.^4–8

Figure 2:

Simplified striatal circuitry in motor learning and movement disorders. Possible interventions are shown in red. (A) SPNs are excited by the cortex and thalamus and modulated by dopamine from midbrain neurons. (B) Striatal signal processing. AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid. CB1=cannabinoid type 1. CBIT=cognitive behavioural intervention for tics. D1R=D1-type dopamine receptor. D2R=D2-type dopamine receptor. GABA=γ-aminobutyric acid. NMDA=N-methyl-D-aspartate. SPN=spiny projection neuron.

SPNs are classified by the type of dopamine receptor expressed. D1-type receptor-expressing SPNs (D1R-SPNs) promote a Go signal by exciting the thalamus and the cortex, while D2-type receptor-expressing SPNs (D2R-SPNs) inhibit the thalamus and cortex and provide a No-Go signal. How do the SPNs know when to provide a Go or No-Go signal? Evidence suggests that D1R-SPNs fire when glutamate and dopamine arrive coincidently at the SPN (figure 2B).⁵ Projections from the cortex release glutamate that binds to AMPA and NMDA receptors on the SPN. Dopamine released by midbrain neurons in response to novel stimulation⁹ binds to D1-type receptors (D1Rs) or D2-type receptors (D2Rs) on the SPN. SPNs express either D1Rs or D2Rs in roughly equal numbers⁵ and are relatively quiescent at rest, given their prominent hyperpolarizing potassium currents and tonic inhibition that is provided by endocannabinoids.¹⁰ Glutamate excites the cell when it interacts with AMPA and NMDA receptors and cell depolarization becomes more likely when dopamine indirectly activates the NMDA receptor on D1R-SPNs.¹⁰ D1Rs activate the SPN by increasing intracellular cAMP, while D2Rs inhibit cell activity by decreasing cAMP. Therefore, coincident glutamate and dopamine release would act to favor D1R-SPN firing and a Go signal.

The mechanisms underlying action selection are far more complex than this simple postsynaptic model illustrates and involves secondary and retrograde messengers that modulate presynaptic activity (figure 2B). Cortical projections to the striatum may express excitatory D1 and nicotinic acetylcholine receptors, as well as inhibitory GABA, muscarinic, D2, adenosine A1A, and cannabinoid CB1 receptors. When the SPN fires, glutamate release from the cortex is subdued by adenosine and endocannabinoids that are putatively produced by the activated SPN. Similarly, presynaptic D2Rs filter cortical information by reducing exocytosis from boutons with a low probability of release. When dopamine is present, D2Rs depress excitatory signaling arriving at the D2R-SPN and tilt the balance between these two neurons in favor of D1-SPNs, thereby providing a net Go signal to the thalamus and cortex.

Our knowledge of presynaptic modulation is confined mainly to the processing of cortically-generated signals entering the striatum. Experiments in rodents with too much or too little dopamine have shown that the striatal circuit is capable of programming complex motor movements.^5,9,11,12 Evidence suggests that the activity of D1R-SPNs and D2R-SPNs remains relatively balanced. A small shift in favor of one or the other determines action outcome and promotes normal function, while too much in either direction may result in motor and behavioral disorders .^5,12–14 Experiments in rodents have shown that contingent use of psychostimulants may produce habits by shifting the balance between SPNs.^5,6 Through a technique called intracranial self-stimulation (ICSS), rats will press a lever repeatedly to deliver an electrical pulse train to a brain region that produces a reward.¹⁵ In well trained rats, the cue increases the activity of D2R-SPNs and then D1R-SPNs are activated during the motor response needed to achieve the reward (figure 3).¹⁶ If similar in humans, then the acquisition of habits may result from an intermittent and repetitive imbalance between SPN subtypes.⁵ In a similar manner, genetic or acquired changes in ion channels, neurotransmitter availability, or receptors would be expected to modify signal processing and promote disorders of movement and thought.

Figure 3:

The role of SPNs in habits and movement disorders. (A) Habits are related to dynamic, time-dependent changes in the balance of D1R-SPNs and D2R-SPNs: the time course of D1R-SPN and D2R-SPN responses in the rat ventral striatum (nucleus accumbens) during an intracranial self-stimulation trial consisting of cue presentation, followed 2 s later by lever extension then a subsequent lever press, which delivers an electrical stimulation to dopamine cell bodies. Shaded areas represent the relative predominance of D1R-SPN and D2R-SPN firing; red and blue lines represent the SPN balance; dashed lines represent time-dependent activation of D1R-SPNs (green) and D2R-SPNs (purple). (B) Some movement disorders might occur in response to a static imbalance in SPN activity: autoantibodies produce an imbalance in striatal function, with D1R-SPNs firing at a greater rate than D2R-SPNs. Panel A was reproduced from Bamford et al,⁵ by permission of Elsevier. D1R=D1-type dopamine receptor. D2R=D2-type dopamine receptor. SPN=spiny projection neuron.

Movement disorders caused by abnormal signal processing

Motor tics are sudden, repetitive, and involuntary movements that involve the face and cervical muscles; they are extremely common in children. The movements wax and wane in character and severity and may travel from one body area to another. These movements may involve the larynx and result in rudimentary sounds and utterances. Like the sounds and movements of new-borns, they are simplistic and primitive in nature. Younger children may not notice them until the emergence of self-awareness that occurs during the latter half of the first decade. Older patients often recognize an unpleasant premonitory sensation or urge immediately preceding the movement. The urge is often vague, described as a primitive feeling of itch, pain, or burn that may be generated by the thalamus.¹⁷ If ignored, the urge returns, increasing in intensity until quenched by the release of a tic.

Tics were first investigated and described by Georges Albert Édouard Brutus Gilles de la Tourette as “maladie des tics,” under the tutelage of the great Jean-Martin Charcot at Salpêtriêre Hospital in Paris.¹⁸ Brain scans, receptor binding studies, genetic linkage studies, and pathological assays have shown variable results without identifying the underlying pathophysiology of this disorder.¹⁹ The corticostriatal pathway was implicated when dopamine receptor antagonists were found to be efficacious in treatment and its role is supported by functional magnetic resonance imaging.²⁰ The building urge and subsequent movement have all the hallmarks of habit formation caused by psychostimulants.⁵ This suggests that tics might localize to subcortical circuits, including the striatum and thalamus, that encode motor learning, habits, and drug dependence.^5,21

The thalamo-striatal circuit was introduced in Neurographia universalis by the seventeenth century French anatomist Raymond Vieussens (1635–1715) and is conserved across species from lamprey up to humans.²² Early work in birds linked instinctive, automatic actions to the primitive connection between the thalamus and striatum.²³ These primitive sub-cortical connections linking the thalamus and striatum promote swift instinctive and reflexive movements, whereas cortical projections to the striatum promote slower planned and volitional motor movements and thoughtful, rational behaviors (figure 1).²¹

The primitive movements that characterize tics and the ability to transiently control them suggest an imbalance between thalamic and cortical inputs to the striatum.²¹ Cortical afferents to the striatum use the vesicular glutamate transporter 1 (VGLUT1) for packaging glutamate in synaptic vesicles (figure 2A).²⁴ Thalamic projections to the striatum utilize VGLUT2, with a higher probability of release compared to VGLUT1.²⁴ The expression of different VGLUT isoforms by these two excitatory pathways suggests distinct modes of neurotransmission that may differentially affect timing and strength of signalling. Therefore, two simultaneous signals, one arriving from the thalamus and the other from the cortex, may compete for dominance. Given the faster kinetics of VGLUT2, the thalamic signal containing the reflexive or primitive response to stimulation may dominate temporarily but can be overridden by the cortical signal that promotes rational and thoughtful behavior.²¹ As such, repetitive reflexive movements such as tics can dominate when the cortex is relatively quiescent.

Many different medications and therapies have been used to treat tics and invariably modify striatal function. The first drugs found to be useful for tics were the neuroleptics that block D2Rs and shift the balance between D1R- and D2R-SPNs in favour of a No-Go response. While useful for children with some co-morbid psychiatric conditions, these medications may carry a heavy burden of untoward effects. Medications such as the α₂-adrenergic agonists clonidine or guanfacine strengthen prefrontal cortical functions²⁵ enhancing cortical excitation of the striatum (figure 2B);²⁶ they are especially useful when tics and co-morbid attention deficit hyperactivity disorder (ADHD) co-exist. The non-stimulant atomoxetine can be used to treat co-morbid tics and ADHD. By inhibiting presynaptic norepinephrine reuptake in the prefrontal cortex, atomoxetine may strengthen corticostriatal activation²⁷ through an α-adrenergic receptor-dependent mechanism.²⁸ Topiramate is an anticonvulsant agent with a broad spectrum of pharmacological properties and can significantly reduce the frequency of tics at very low doses.²⁹ By blocking AMPA receptors,³⁰ topiramate likely reduces excitation of both types of SPNs.^9,31 Tetrabenazine can improve tics and co-morbid symptoms in up to 80% of patients.³² Tetrabenazine reversibly inhibits vesicular monoamine transporter 2 (VMAT2), resulting in decreased uptake of monoamines into synaptic vesicles, thereby depleting dopamine, serotonin, norepinephrine, and histamine. The consequent reduction in dopamine availability would modify SPN activity in favor of the No-Go pathway. Dopamine’s effect on the thalamostriatal pathway is less clear, perhaps explaining why tetrabenazine reduces the tic but not the urge. Cannabinoid type 1 (CB1) receptors are expressed ubiquitously throughout the brain but are co-expressed with presynaptic D2 receptors on glutamatergic afferents, where they specifically inhibit the excitation of D2R-SPNs.¹⁰ While several anecdotal reports promise a reduction of tics and associated behaviour problems, appropriate clinical trials are needed.³³ Other medications used to reduce tics and ADHD include donepezil which is used to treat patients with mild to moderate Alzheimer’s disease, but has low tolerability in children (figure 2A). Donepezil increases acetylcholine delivery by reversibly inhibiting acetylcholinesterase,³⁴ thereby altering the balance between thalamostriatal and corticostriatal pathways.

The response to these pharmacological agents varies between children, but their efficacy suggests that small changes in dopamine availability promoted through learning can have similar therapeutic effects on striatal activity. Indeed, cognitive behavioral intervention for tics (CBIT) is now recommended as a first-line intervention for tics.^33,35 CBIT provides a novel competing response, so it may increase dopamine release and strengthen the cortical input to shift the balance of activity away from the thalamic input (figure 2B). The efficacy of CBIT is similar to pharmacological therapy but with life-long benefits without, untoward clinical effects.^35,36 This intervention may work when children are old enough to participate and when trained therapists are available. Like habit reversal therapy, this approach relies upon recognition of the premonitory urge to teach a competing response to substitute for the expected motor movement. In theory, the substituted volitional movement is cortically driven and therefore competes with the automatic movement (tic) putatively generated by the thalamus. Training would theoretically release dopamine to reprogram striatal function.

It is becoming clear that pharmacological modulation or behavioral modification of the striatum can modify the urge, the tic, or both. Conditions that may occur with tics include ADHD, obsessive-compulsive disease (OCD), and anxiety. These co-morbid disorders require treatment as they may exacerbate tics by modifying dopamine release or prefrontal cortical signals.^37–39 Serotonin reuptake inhibitors are useful for children with OCD and anxiety and have secondary effects on dopamine production. The α₂-adrenergic agonists and stimulants such as methylphenidate are the drugs of choice for clinicians treating combined ADHD and tics.³³ Stimulants work well over time and don’t lead to worsening of tic severity as shown by comprehensive systematic reviews.³³ By releasing dopamine, stimulants would tilt the balance between the Go and No-Go pathway and modify presynaptic filtering in favor of cortical information entering the striatum. CBIT is also recommended for children with comorbid conditions.³³

While CBIT seeks to disassociate the urge and motor response, a key target is the urge; in the absence of an urge, there is no need for a response. The urge might be prevented by targeting the thalamus directly using neuromodulation via deep brain stimulation (DBS),⁴⁰ and by strengthening cortical signaling via transcranial direct current stimulation (tDCS)⁴¹ or by transcranial magnetic stimulation (TMS);⁴² all show promise in the treatment of tics, but additional studies are required.⁴³

Neuromodulation relies on current delivered by direct application through implanted or scalp electrodes, or by current generated through changing magnetic fields. The activation of various cells is mediated by proximity to the electrode, current strength, and their 3-dimensional orientation to the stimulus,⁴⁴ making pathway understanding and localization extremely important. Attempts to treat tics by stimulating various subcortical structures have been tried via DBS, which requires electrode implantation (figure 1).⁴⁰ Stimulation of the centromedian/parafascicular nucleus of the thalamus excites and modulates SPNs and ChIs within the striatum.¹ Similarly, stimulation of other subcortical structures, including the anterior limb of the internal capsule, nucleus accumbens, globus pallidus, and subthalamic nuclei have direct and indirect effects on SPNs and ChIs. DBS programming reflects the need to find the frequency, amplitude, and signal strength necessary to modulate the correct neuron or interneuron population, with stimulation causing either a net Go or No-Go signal, depending on the location and cell population.

Transcranial stimulation, whether by TMS or tDCS forms of neuromodulation, provides a non-invasive means of influencing neuronal activity. In TMS this is done by application of a repetitive brief magnetic field inducing a focal electric current in the brain.⁴⁵ TMS requires specialized equipment and, ideally, co-registration with brain magnetic resonance imaging. Stimulation of the supplementary motor area using tDCS has shown efficacy in preliminary studies and is portable.⁴¹ In this treatment, electrodes are used to either inhibit or excite focal cortical regions via application of a weak direct current. The resulting microelectric field may modulate cortical afferents by altering the neuron’s resting membrane potential.⁴⁶ Prolonged effects on cellular activity up to several months may be mediated by plasticity at glutaminergic, dopaminergic, serotonergic, and GABAergic synapses.⁴⁷ TMS and tDCS likely modulate SPNs signaling, changing the balance to allow either the cortical signal to predominate or reprograming of the circuit to override the thalamic signal.

Movement disorders produced by channelopathies

Channelopathies constitute important movement disorders in children. Ion channels are necessary for normal cellular function and are genetically encoded. Channelopathies largely affect postsynaptic function and promote abnormal paroxysmal movements that in many instances are difficult to discriminate from cortical seizures. There may be a brief period of behavioral arrest subsequent to or preceding the dyskinesia, which might be followed by a prolonged period of weakness or dystonia. The clinician is alerted to a movement disorder when an electroencephalogram is normal during an dyskinesia event.

The neuron uses sodium, calcium, and potassium channels to produce an action potential (figure 4). When sufficiently excited by glutamate, sodium channels open to produce cell depolarization. Ca²⁺ channels open and determine the shape of the action potential spike. After the cell is depolarized, sodium channels close and potassium channels open, bringing the neuron back to a hyperpolarized or inactive state. At this point, the Na⁺-K⁺ pump is activated and driven by Na⁺-K⁺ ATPase. By exchanging 3 Na⁺ ions for 2 K⁺, the cell slowly depolarizes, returning to its resting state. As shown in figure 4E, D1Rs increase adenyl cyclase (AC) and cAMP, while D2 receptors are inhibitory. Some pacemaking cells contain hyperpolarization-activated cation (HCN) channels that produce rapid cell firing. HCN channels open when the cell becomes hyperpolarized. Na⁺, K⁺, and Ca²⁺ enter, and the cells depolarizes. The activity of HCN channels are modified by D1 and D2 receptors through cAMP, a cyclic nucleotide-binding domain protein (CNDB), and an auxiliary subunit, TRIP8b.

Figure 4:

The production of an action potential by sodium, calcium, and potassium channels. The activity of ion channels in the cell membrane at each stage of the production of an action potential. (A) When sufficiently excited by glutamate, the sodium channel opens to produce cell depolarization. (B) Calcium channels open and determine the shape of the action potential spike. (C) After the cell is depolarized, sodium channels close and potassium channels open, bringing the neuron back to a hyperpolarized or inactive state. (D) The sodium–potassium pump is activated, driven by sodium–potassium ATPase, which is altered in alternating hemiparesis of childhood. By exchanging three sodium ions for two potassium ions, the cell slowly returns to its resting state. (E) Some pacemaking cells contain HCN channels that produce rapid cell firing. HCN channels open when the cell becomes hyperpolarized. Sodium, potassium, and calcium enter, and the cell depolarizes. The activity of of HCN channels is modified by D1Rs and D2Rs, through cyclic AMP, a CNDB, and an auxillary subunit, TRIP8b. D1Rs increase adenylyl cyclase and cyclic AMP, whereas D2Rs are inhibitory. The image for (E) was reproduced from McKinley et al, (ref 4) by permission of Elsevier. Inset: The contribution of each different ion channel to each stage of a neuronal action potential. AC=adenylyl cyclase. CNDB=cyclic nucleotide-binding domain protein. D1R=D1-type dopamine receptor. D2R=D2-type dopamine receptor. HCN channel=hyperpolarization activated cation channel. Pi=inorganic phosphate

Many channelopathies including paroxysmal dyskinesias, alternating hemiparesis of childhood (AHC), periodic paralyses, and episodic ataxias have been described, and some can be diagnosed genetically. These diseases may arise de novo or through dominant or recessive inheritance. The pathophysiological mechanisms that underlie most paroxysmal dyskinesias remain unknown. While the gene responsible for the movement disorder can provide clues about the affected channel, it is often unclear whether the abnormal gene produces a hyperactive or hypoactive channel. Many Na⁺, K⁺, and Ca²⁺ channel subtypes exist and are produced in various quantities within neurons. This variation in channel quantity may help to explain the phenotypic diversity in patients with seemingly similar genotypes. Some genetically-identified movement disorders like AHC can produce epilepsy and ataxia, indicating that the channelopathy affects other neurons outside of the basal ganglia. Since the channel cannot be repaired by standard treatments, pharmacology is often directed towards modifying other channels that control cell firing (figure 4).

Children with paroxysmal dyskinesia present with epileptic-like movements. For simplicity, they have been lumped into three main categories. 1) paroxysmal kinesigenic dyskinesia (DYT10; PKD) follows a certain volitional movement, 2) paroxysmal non-kinesigenic dyskinesia (DYT8; PKND) occurs spontaneously while at rest and following caffeine or alcohol consumption, and 3) paroxysmal exertion-induced dyskinesia (DYT18) occurs during or following repetitive movement. All three dyskinesias present with a self-limiting movement, characterized by rigid, dystonic posturing of one or more limbs. PKD is often accompanied by a defect in the PRRT2 gene that encodes the proline-rich transmembrane protein 2 (PRRT2). PRRT2 interacts with the 25-kDa synaptosomal-associated protein (SNAP25), which is expressed in the rodent basal ganglia and is required for dopamine release and normal motor function.^48,49 PKD responds to low-dose carbamazepine, a voltage-gated sodium channel blocker. The heightened response to carbamazepine suggests that Na⁺ channel blockade may prevent abnormal SPN activity that would otherwise occur in response to the paroxysmal release of striatal dopamine. Similar to PKD, the gene PKND encodes the novel protein (PKND) that regulates dopamine signalling. PKND interacts with the presynaptic proteins Rab3-interacting molecule (RIM)1 and RIM2 to inhibit calcium-triggered neurotransmitter release.⁵⁰ In PKND knockout mice, RIM levels and neurotransmitter release are reduced, while overexpression of PKND may produce the opposite effect.⁵⁰ PKND can be difficult to treat; anticonvulsants or benzodiazepines should be attempted. The dystonia-associated muscle contractures can be treated with baclofen and botulinum toxin. The identification of additional genes that cause these disorders and their pathophysiology may lead to targeted therapies.

A related clinical condition is alternating hemiparesis of childhood (AHC) (DYT12; ATP1A3), produced by an abnormal Na⁺-K⁺-transporting ATPase subunit alpha-3 polypeptide (figure 4E) that is needed to repolarize neurons. The dystonia and hemiparesis seen in AHC seems to imply that both inhibitory and excitatory neurons are temporarily inactivated by failure of the cell’s Na⁺/K⁺ pump, which promotes transient dysregulation in dopamine producing neurons, as well as both D1R-SPNs and D2R-SPNs. Like other channelopathies, the disorder can present in early childhood as a seizure mimic. Behavioral arrest and dystonic posturing with ipsilateral gaze version may be followed by a period of hemiparesis lasting minutes to weeks in duration. Treatment relies on the modulation of unaffected channels that regulate cell excitability.

Torsion dystonia is defined as involuntary muscle contractions that cause repetitive, patterned, and twisting movements or postures. The most common cause of dystonia in children is brain injury or infection. Dystonia which does not respond to levodopa should raise suspicion for a genetic dystonia such as early-onset primary dystonia (DYT1; TOR1A), myoclonus dystonia (DYT11; SGCE), glucose-1 transporter deficiency (SLC2A1), or Wilson’s disease (ATP7B). The function of TOR1A remains unclear but is likely involved in dopamine homeostasis. SGCE encodes the epsilon-sarcoglycan protein that may increase dopamine release and reduce D2 receptors, promoting a Go response at striatal circuits.⁵¹ These diseases may present with abnormalities in walking or writing and involve other body regions over time. As a dopamine-depleter, tetrabenazine acts centrally to control SPN firing. Anticholinergics (trihexyphenidyl), benzodiazepines (clonazepam), and GABA-B receptor antagonists (baclofen) have peripheral and perhaps unwanted central actions, while botulinum toxin reduces activity at the neuromuscular junction. Patients with early-onset primary dystonia respond favourably to deep brain stimulation,⁵² copper chelation is necessary for those with Wilson’s disease,⁵³ and the ketogenic diet provides an alternative fuel source for those with glucose-1 transporter deficiency.⁵⁴

Novel genetic treatments for children with genetically-defined movement disorders are being developed. The editing of abnormal genes in the central nervous system have moved through a variety of vectors that aim to remove the abnormal DNA sequence, while simultaneously placing a sequence that provides an adequate production of normal proteins in key brain regions. For example, lentiviral gene therapy has now been used successfully to promote normal immunological function in children with X-linked severe combined immunodeficiency.⁵⁵ Adeno-associated virus (AAVs) has been used to implant reporter genes in mice. In the laboratory, these AAVs have reasonable efficacy in transplanting cre sequences into specific cells. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 represents the latest technology which removes and replaces the abnormal gene for another.⁵⁶ Challenges in this latest technique include off-target gene delivery and an autoimmune reaction that may limit or prevent subsequent treatments. The concurrent use of immunomodulators requires further investigation.

Together, the channelopathies represent a class of movement disorders that are caused by specific gene/protein abnormalities, which modify the regulation, localization, or interaction with other proteins that are required for normal cell activity. Cell homeostasis may provide adequate compensation between attacks, while episodic dysfunction in dopamine release and/or striatal neurons would promote erratic Go and No-Go responses.

Movement disorders produced by changes in neurotransmitter availability

Parkinson’s disease is characterized by bradykinesia, postural instability, and resting tremor. The disease is caused by progressive death of dopamine-producing cells in the midbrain substantia nigra pars compacta which provides dopamine for the dorsal striatum. Parkinsonism in children is rare and most often caused by a genetic defect that prevents the normal production of dopamine and sometimes other biogenic amines: norepinephrine, epinephrine, histamine, and serotonin. The disorder may also be acquired by immunological disease, stroke, or tumour. Rodent studies have shown that dopamine production and dopamine receptor expression occurs late in neurodevelopment,^31,57 perhaps explaining why children with parkinsonism present with progressive symptoms at some point following birth. Children may display reduced facial expression, rigidity, dystonia, spasticity, and poor fine motor movements. The classical resting tremor seen in adults is generally absent. Motor delay is common as normal dopamine release is needed to acquire new skills.⁵⁸

Dopa-responsive dystonia may account for 5–10% of primary dystonias in childhood.⁵⁹ The diurnal variation in symptoms that worsen with activity and as the day progresses is a classic feature. The diagnosis can be challenging, especially in neonates, and the diagnosis may rely upon genetic analysis or a trial of levodopa, the precursor of dopamine that can cross the blood brain barrier. The analysis of biogenetic amines within spinal fluid may suggest a certain defective enzyme⁶⁰ and, when possible, should be performed before treatment initiation. Like in many other movement disorders, brain imaging in dopa-responsive dystonia is normal. A deficiency in enzymes needed to create biogenic amines — including tyrosine hydroxylase (DYT5b; TH), GTP cyclohydrolase (Segawa disease; DYT5a; GCH1), and sepiapterin reductase (SPR) — can produce a wide range of symptoms, many responding to treatment with levodopa in combination with carbidopa or another peripheral decarboxylase inhibitor. Prominent levodopa-induced dyskinesia may occur in children.⁶¹ Therefore, when the diagnosis is suspected, very low-doses of levodopa should be used initially and the dose slowly increased.

The mechanism underlying levodopa-induced dyskinesia is unclear. However, research has suggested that this disorder might be caused by plasticity in striatal cholinergic interneurons (ChIs).⁸ Like other pacemaking cells, ChIs contain HCN channels that rapidly repolarize the cell following each action potential (figure 4E).⁶² ChIs contain choline acetyltransferase (ChAT), the rate limiting enzyme responsible for producing acetylcholine (ACh), and are the major source of striatal acetylcholine.⁴ Acetylcholine modulates the striatal network via numerous subtypes of excitatory nicotinic receptors and inhibitory muscarinic receptors.⁷ Studies in the 1980s suggested that an increase in acetylcholine availability accompanies dopamine deficiency.⁶³ Recent work in mice has shown that the “seesaw” theory holds true for the ratio, but not the availability of these two neuromodulators.⁴

ChIs express excitatory D1Rs and inhibitory D2Rs (figure 5). In normal, untreated mice dopamine tightly regulates the firing rate of these interneurons. When dopamine is released the firing rate decreases and vice versa.⁷ In mice with chronic progressive dopamine deficiency the expression of HCN channels and ChAT declines, causing a reduction in both striatal acetylcholine and dopamine. However, the decrease in acetylcholine is less than the reduction in dopamine, so the acetylcholine to dopamine ratio increases.⁴ When dopamine is released from residual axon terminals with the aid of levodopa, excitation via D1Rs predominates; the ChI increases firing, and the acetylcholine to dopamine ratio increases further, exacerbating the imbalance between the two neuromodulators, potentially leading to levodopa-induced dyskinesia. The effect on acetylcholine production becomes more pronounced as the degree of parkinsonism progresses.⁴ Acute dopamine deficiency has less effect on ChI firing and acetylcholine production⁴ and, perhaps similar to the tardive dyskinesias, can produce a rapid increase in dopamine receptor sensitivity.⁹ This may explain why young children with more complete dopamine deficiency are more likely to develop levodopa-induced dyskinesia than older children and adults with parkinsonism.

Figure 5:

The effect of prolonged dopamine deficiency on the acetylcholine to dopamine ratio. Reproduced from McKinley et al,(Ref4) by permission of Elsevier. The dashed line distinguishes baseline acetylcholine (left) from acetylcholine release following provoked dopamine release (right). (A) The striatal cholinergic interneuron expresses HCN channels and D1Rs and D2Rs, and contains ChAT, the rate-limiting enzyme that produces acetylcholine. HCN channels allow the interneuron to fire repetitively, and dopamine provided by midbrain neurons modifies the firing rate. In normal mice, inhibition by the D2R predominates and dopamine release reduces cell firing. (B) In mice with moderate, progressive dopamine deficiency, the expression of HCN channels and ChAT declines and the firing rate of the cell is diminished. The reduction in acetylcholine release (yellow dots) is less than the reduction in dopamine (blue dots) and the acetylcholine-to-dopamine ratio increases. Dopamine excitation by the D1R predominates so that dopamine release from any remaining axon boutons increases interneuron firing, and the acetylcholine-to-dopamine ratio increases further. (C) As dopamine deficiency progresses, the effects described in (B) become more pronounced. ChAT=choline acetyltransferase. D1R=D1-type dopamine receptor. D2R=D2-type dopamine receptor. HCN channel=hyperpolarisation-activated cation channel.

Therefore, while small changes in pre- and postsynaptic striatal activity can modify Go and No-Go responses to cortical and thalamic input, progressive and long-lasting alterations in dopamine create downstream plasticity that can be difficult to treat by simple replacement therapy. There is evidence that TMS may improve motor symptoms in parkinsonism,⁴³ but the efficacy of neurostimulation in childhood-onset disease requires additional data.

Movement disorders caused by immunologically-mediated mechanisms

Alterations in D1-SPN and D2R-SPN activity may also arise though acquired diseases. Movement disorders are a feature of many antibody-associated disorders and represent potentially treatable conditions. Dystonia, dyskinesias, and chorea are associated with antibodies directed towards cell surface antigens, such ion channels and AMPA, NMDA or GABA receptors.⁶⁴ Perhaps one of the first and best-known immunologically-mediated diseases is Sydenham’s chorea.⁶⁵ Antibodies produced against group-A streptococcus can result in systemic and neurological dysfunction. Historically referred to as St. Vitus’ dance, the chorea is characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands, and feet that cease with sleep. The diagnosis is suspected by behavioral changes and the sudden onset of choreiform movements with evidence of a recent (within 6–9 months) streptococcal infection. Localization to a brain region, cell type, salt channel, or receptor has been challenging despite the identification of anti-DNase beta and antistreptolysin O antibodies, and the elevation of inflammatory markers (erythrocyte sedimentation rate and c-reactive protein). However, using molecular mimicry to streptococcal antigens, antibodies may target dopamine receptors⁶⁶ within the caudate nucleus⁶⁷ and the neuropsychological symptoms can positively correlate with the anti-D2 receptor to anti-D1 receptor ratio (figure 3B),⁶⁸ indicating that these antibodies promote an imbalance in striatal output. The choreiform movements are generally self-limited in duration, so therapy is directed towards eradicating the bacteria and symptomatic relief of the chorea. Long-acting benzodiazepines, clonidine, valproic acid, or carbamazepine are typically used. D2 receptor blocking drugs are useful, since they would promote No-Go actions generated by D2R-SPNs, but there is a high incidence of tardive dyskinesia when using these drugs. Immunotherapy with intravenous immunoglobulin, plasma exchange, or steroids should be considered but their efficacy requires further evaluation.⁶⁹ The behavioral changes and obsessive-compulsive behaviors in Sydenham’s chorea have been associated with antibody-mediated group-A streptococcus.⁷⁰

Another syndrome, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) can present with tics and/or a psychological component and occurs much earlier, days to weeks after the infection rather than 6–9 months later.⁷¹ In the absence of a streptococcal infection, a related disorder pediatric acute-onset neuropsychiatric syndrome (PANs) has been described, where children present with obsessive compulsive symptoms and/or severe eating restrictions, along with other cognitive, behavioral, or neurological symptoms. Work in several laboratories has found evidence of antibody medicated disease,⁷¹ while others have been unable to replicate the results, leading to a lack of consensus with reference to diagnosis and treatment.^72,73 The diagnosis of movement disorders caused by immunologically-mediated mechanisms can be contentious, especially when a child presents with a long history of obsessive-compulsive behaviors or tics and the family presentation implies a genetically-inherited condition not previously identified or acknowledged.

Directions of further investigation

The classification of movement disorders has historically relied upon the clinical manifestations of disease and their response to treatment. The repurposing of drugs that were initially developed for other human diseases has largely led the way to symptom relief, but such are hampered by the lack of specificity with off-target and untoward clinical effects. Fortunately, there are multiple on-going clinical trials for movement disorders that will determine outcomes in response to novel drugs, new rehabilitation techniques, brain stimulation, and real-time computer- and PET-assisted biofeedback (table 1). Registries and programs that seek out genotype-phenotype correlations are essential for diagnosis, clinical care, and prognosis. Given the significant variability between genotype and phenotype, large-scale improvements in treatment will rely upon the proper identification of both the key genetic and pathophysiological mechanisms of each disease. Such investigations in humans and animal models are expected to lead to novel pharmacology that can specifically target the synapses and intracellular biology in certain sets of cells. The expanding use of DBS will allow concurrent in vivo measures of brain activity in humans. For example, new microelectrode studies in children undergoing DBS can highlight differences in the firing rates of neurons within the globus pallidus that project Go and No-Go signals onto the thalamus.⁷⁴ As an added level of complexity, acquired and genetically-determined diseases will inevitably modify downstream neural networks and systems that may require reintegration once the underlying cause is found and corrected. Understanding these processes require basic science investigations in cellular and molecular physiology and the creation of novel animal and computer-assisted models.

Table1.

Ongoing clinical trials for the treatment of paediatric movement disorders (Recruiting as of September 2019; HTTPs://clinicaltrials.gov).

	CliniclTrials. gov identifier	Movement disorder	Sponsor or collaborator	Age of participants	Last Update	Locations
Surface electromyography biofeedback for children with cerebral palsy	NCT01681888	Cerebral palsy, dystonia, hypertonia, spasticity	University of Southern California	≤ 21 years	September 7, 2018	Children’s Hospital of Los Angeles, Los Angeles, CA, USA
A study of TEV-50717 (deutetrabenazine) for the treatment of dyskinesia in cerebral palsy in children and adolescents	NCT03813238	Cerebral palsy, dyskinesia	Teva Branded Pharmaceutical Products, R&D Inc.	6–18 years	August 16, 2019	Teva Investigational Sites in the United States, Canada, and Russia
Efficacy and safety of deep brain stimulation in patients with primary dystonia	NCT03017586	Dystonia	Beijing Pins Medical Co., Ltd	6–60 years	March 15, 2018	Beijing XieHe Hospital, Beijing, Beijing, China; Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Clinical outcomes for deep brain stimulation	NCT03992625	Parkinson’s disease, essential tremor, dystonia	Washington University School of Medicine; National Institute for Biomedical Imaging and Bioengineering, National Institute of Neurological Disorders and Stroke	Child, adult, older adult	June 20, 2019	Washington University in St Louis, Saint Louis, MO USA
Efficacy of proprioceptive focal stimulation (EQUISTASI) on gait parameters in Parkinson’s. Italian multicentric study	NCT02641405	Parkinson’s disease	I.R.C.C.S. Fondazione Santa Lucia|Istituto Auxologico Italiano; IRCCS National Neurological Institute “C. Mondino” Foundation; Ospedale S. Raffaele Arcangelo, Fatebenefratelli; University of Genova; IRCCS San Raffaele	Child, adult, older adult	August 22, 2017	IRCCS Santa Lucia, Rome, Lazio, Italy; IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy; Istituto Auxologico Italiano, Oggebbio, Verbano-Cusio-Ossola, Italy; IRCCS San Raffaele, Cassino, Italy; University of Genova, Genova, Italy; Ospedale S. Raffaele Arcangelo, Fatebenefratelli, Venezia, Italy
Internet-delivered behaviour therapy for children and adolescents with Tourette’s disorder	NCT03916055	Tourette Disorder, Persistent Motor or Vocal Tic Disorder	Karolinska Institutet; Stockholm Health Care Services, Stockholm County Council, Uppsala University	9–17 years	May 1, 2019	Child and Adolescent Psychiatry Research Center, BUP Klinisk forskningsenhet, Stockholm, Sweden
Internet-based cognitive behavioural intervention for children with chronic tics	NCT04087616	Tourette Syndrome, Chronic Tic Disorder	Tel Aviv Medical Center	8–17 years	September 12, 2019	Interdisciplinary Center, Herzliya, Israel; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Extinction learning in youth with Tourette’s syndrome	NCT03765463	Tourette Syndrome, Habit Reversal Training, Tics	Johns Hopkins University	8–17 years	March 4, 2019	Johns Hopkins University School of Medicine, Baltimore, MD, USA
Response inhibition in Tourette’s syndrome	NCT03628703	Tourette Syndrome	Children’s Hospital Medical Center, Cincinnati	10–17 years	May 6, 2019	Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Multi-site transcranial magnetic stimulation therapy of the supplementary motor area in children with Tourette’s syndrome	NCT03642951	Tourette Syndrome	Keith Coffman, The Methodist Hospital System, Cornell University, Children’s Mercy Hospital Kansas City	8–20 years	June 12, 2019	Children’s Mercy Hospital, Kansas City, MO, USA
Evaluation of a cognitive psychophysiological treatment for Tourette’s syndrome and tic disorders	NCT03225430	Tourette’s syndrome, tic disorder, chronic motor or vocal disorder	Centre de Recherche de l’Institut universitaire en sante mentale de Montreal; Canadian Institutes of Health Research	8–65 years	August 22, 2019	Centre de Recherche de l’Institut universitaire en sante mentale de Montreal, QC, Canada
Transcranial direct current stimulation in Tourette’s (TIC-TDCS)	NCT03401996	Tourette’s syndrome	University of Calgary	≥16 years	April 23, 2019	Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
Thalamic deep brain stimulation for the treatment of refractory Tourette’s syndrome	NCT01817517	Tourette’s syndrome	Johns Hopkins University	≥15 years	May 22, 2019	The Johns Hopkins Hospital, Baltimore, MD, USA
Natural history of Wilson’s disease	NCT03334292	Wilson’s disease	Yale University	Child, adult, older adult	May 24, 2019	Yale University, New Haven, CT, USA; Baylor College of Medicine, Houston, TX, USA

Conclusion

Movement disorders are defined by a heterogeneous constellation of signs and symptoms and are challenging to diagnose in children. Identification of the affected circuitry is needed to guide treatments that would have a beneficial effect on the patient. Many of the available data on the mechanisms underlying movement disorders are supplied by rodent studies. The “classic” symptoms related to a specific gene can vary widely amongst patients and often change as the child develops. Seemingly small variations in genes can cause changes in the classification of disease; e.g. from epilepsy to movement disorder or from one class of movement disorder to another. Phenotypic variations suggest that mutations are localized to specific neuronal populations, regulated by genetic promotors and enhancers, and/or modified by developmental plasticity that alter the disease manifestation.⁷⁵ Similarly, patients with differing genotypes may have surprisingly similar clinical presentations. Therefore, while a genetic evaluation may offer important insights, understanding the synaptic, cellular, and/or molecular mechanism that underlies each disorder is also essential for treatment. A better understanding of how particular movements are mediated by alterations in basal ganglia circuitry, cellular physiology, and neurotransmitter availability will lead to a targeted approach that produces clinical improvement and reduces adverse effects.

Key Messages.

• Understanding the basal ganglia circuitry allows a targeted approach when treating children with movement disorders.

• Motor learning and movement disorders are produced by plasticity within the basal ganglia that tilts the balance between Go and No-Go circuits.

• Afferents from the cortex can override subcortical inputs to the basal ganglia that generate reflexive movements and habits.

• The accurate identification of abnormal movement types and their sources improves treatment.

• Acute and chronic dopamine deficiency differentially affect basal ganglia circuitry.

• An accurate diagnosis may require genetic investigations and cerebrospinal fluid studies in disorders of monoamine metabolism.

• Cognitive behavioral intervention for tics (CBIT), may be the best initial therapy for motor tics and co-morbid conditions.

• Neuromodulation and genetic manipulation are expected to offer novel treatments for children with common movement disorders.