Neurobiology Of Tourette Syndrome

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Despite a preponderance of evidence suggesting an organic rather than psychogenic origin for Tourette syndrome, the precise neurobiological abnormality remains speculative.

Neuroanatomically, there is increasing evidence confirming that cortico-striato-thalamo-cortical (CSTC) pathways represent the site of origin not only for tics but also for accompanying neuropsychiatric problems. Pathophysiolog-ical hypotheses are generally based on either A, excess thalamic excitation or impaired intracortical inhibition, or B, involvement of a specific neurotransmitter or synaptic component. Therefore, an animal model that displays altered synaptic circuitry or an altered neurotransmitter system may lead to the development of behavioral problems similar to those seen in TS.

There has been great difficulty in generating an animal model for TS, in part because the etiology of the underlying abnormalities is unclear. An animal model of TS should demonstrate dysfunction in brain regions causally affected by the disorder, should reflect the type of immune response thought to be active in the diseased brain, and should show abnormalities in neurotransmitter systems or second messengers or both that are inferred from human studies.

One unifying hypothesis for the pathogenesis of TS suggests that it is a developmental disorder resulting in dopaminergic hyperinnervation of the ventral striatum and the associated limbic system. The association between basal ganglia and limbic system structures may help explain the link between tics and complex behavioral problems. An abnormality in developmentally regulated, presumably genetically programmed, apoptosis may underlie the persistence of these dopaminergic projections, although the genetic basis for this is unknown.

Until such time that a genetic model for the disease can be generated, animal models will need to be developed through alterations of synaptic circuitry through microlesions, electrical stimulation, pharmacologic manipulation, or molecular biological alterations of neurotransmitter systems. These in vitro models will need to replicate the alterations expressed in TS patients if the animals are to express the phenotype themselves.

A. Neuroanatomic Localization 1. Circuitry

A series of parallel cortico-striato-thalamo-cortical (CSTC) circuits that link specific regions of the frontal cortex to subcortical structures66-68 provide a unifying framework for understanding the interconnected neurobio-logical relationships that exist in TS. Five distinct parallel circuits have been described in primates, with each subserving a different function. Although presented as distinct pathways, there is evidence to suggest that these circuits may be more integrated than was previously thought.69 This multiple convergent and divergent organization provides the capacity for integration and transformation of cortical information.70

The motor circuit, a potential site for generation of tics, originates primarily from the supplementary motor cortex and projects to the putamen in a somatotopic distribution. The oculomotor circuit, a potential site of origin for ocular tics, begins principally in the frontal eye fields and connects to the central region of the caudate. The dorsolateral prefrontal circuit links Brodmann's areas 9 and 10 with the dorsolateral head of the caudate and appears to be involved with executive function and motor planning. Dysfunction of this pathway could lead to attentional difficulties and poor results on Letter Word Fluency Testing.71 The lateral orbitofrontal circuit originates in the inferolateral prefrontal cortex and projects to the ventromedial caudate. Orbitofrontal injury is associated with OCD, personality changes, disinhibition, irritability, and mania. Lastly, the anterior cingulate circuit arises in the anterior cingulate gyrus and projects to the ventral striatum (olfactory tubercle, nucleus accumbens, and ventral medial aspect of the caudate and putamen), which receives additional input from the amygdala, hippocampus, and entorhinal and perirhinal cortex. Mutism, apathy, and OCD are associated with this circuit. Dysfunction of the CSTC circuit may explain the loss of impulse control and apparent global disinhibition typically expressed by TS patients.

Abnormal activation of motor cortex via basal ganglia-thalamocortical circuits would be expected to cause relatively simple motor patterns, such as those observed in simple tics. Abnormal activation of premotor, supplementary motor, and cingulate motor areas would be expected to cause more elaborate motor patterns, similar to those observed in complex tics. Abnormal activation of the orbitofrontal cortex would be expected to cause even more elaborate motor patterns observed as compulsions. The premonitory symptoms would likewise be associated with abnormal activity of these areas. Thus, abnormal activation of motor areas may be associated with specific or nonspecific sensations, and activation of orbitofrontal areas may be associated with obsessions. Finally, abnormal disinhibition of dorsolateral prefrontal mechanisms may be associated with attention deficits. Although these proposed mechanisms for dysfunctional basal ganglia circuits and the consequent TS symptomatology are hypothetical, newer techniques of biochemistry, pharmacology, electrophysiol-ogy, molecular biology, and functional neuroimaging may stimulate formulation of more specific hypotheses to be tested, both in individuals with TS and in animal models of this disease.

2. Evidence Supporting A CSTC Anatomical Localization

Initial studies in TS focused primarily on the basal ganglia. Functional imaging studies identified abnormalities in glucose metabolism and perfusion of the basal ganglia, especially on the left.72-74 In the HMPAO SPECT study of Moriarty et al.,75 tic severity correlated with changes in the left lenticular nuclei. Volumetric MRI studies in TS showed significant differences in the symmetry of the putamen and lenticular region in children76 and a reduction in the size of these structures in adults.77 On the basis of a quantitative MRI study of monozygotic twins, other investigators have suggested that, rather than an abnormality of the lenticular region, the caudate may be the important site.78 Transcranial magnetic stimulation (TMS) in children with tic disorders identified a shortened cortical silent period,79 suggesting a deficiency of motor inhibition believed to be at the level of the basal ganglia. Lastly, in preliminary functional MRI studies, Peterson et al.80 compared images acquired during periods of voluntary tic suppression with those acquired when subjects were allowed spontaneous expression of their tics. Significant changes in signal intensity were seen in the basal ganglia and thalamus as well as in connected cortical regions.

Complementing these TMS experiments, stimulation of the putamen by electrical or chemical means can provoke motor movements and tic-like vocal responses. Alexander and DeLong 81 showed that myostimulation of discrete striatal sites in the putamen of awake monkeys results in stereotyped movements of specific body parts, with increasing stimulation resulting in enhanced, but still stereotyped, muscle contraction. These data suggest that repeated activation of discrete sets of striatal matrisomes can produce repeated stereotyped movements. In contrast, microstimulation of the STN, GPi, or SNpr does not evoke movement. If a discrete population of striatal neurons becomes active due to excessive cortical or thalamic input to the striatum, or insufficient inhibition within the striatum, a stereotyped tic may result. Voluntary movement would be facilitated in a normal fashion but might be accompanied by unwanted facilitation of other motor patterns, resulting in tics accompanying the desired motor pattern (Mink, 2003). Interestingly, high-frequency stimulation of the median and rostral intralaminar thalamic nuclei produced a decrease in tics, implicating a role of these nuclei in the output of tonically active neurons in the striatum.

Large lesions of GPi or SNpr can disinhibit both desired and unwanted motor patterns, allowing not only normal initiation of the desired movement, but also inappropriate activation of competing motor patterns, resulting in involuntary movements. Thus, voluntary as well as involuntary movements are generated. Although smaller lesions of putamen, GPi, SNpr, or STN can produce unwanted motor output pat terns, these patterns are not stereotyped and differ from tics. More work is needed in these areas to distinguish what features of the cortical and subcortical circuits give rise specifically to tic-like involuntary movements that can be modeled and examined more closely in the laboratory setting. In addition, further anatomical explanation of OCD and ADHD are required for the development of animal models.

More recent studies have emphasized and provided evidence for significant cortical dysfunction. Volumetric MRI studies have shown larger volumes of the dorsolateral pre-frontal region in children with TS, but significantly smaller volumes in adults with the disorder.82 Cortical white matter in children with TS is increased in the right frontal lobe83 and decreased in the deep left frontal region.84 Midsagittal measurements of the corpus callosum, which interconnect homologous cortical areas, have identified variable alterations in the size of this structure.85'86 Functional MR imaging, in which images acquired during periods of voluntary tic suppression were compared with those during spontaneous expression of tics, suggests that tic suppression involves activation of the prefrontal cortex.80 Event-related [15O]H2O PET combined with time-synchronized audio and videotaping identified aberrant activity in interrelated sen-sorimotor, language, executive, and paralimbic circuits.87 Lastly, transcranial magnetic stimulation studies have suggested that tics may originate from impaired inhibition directly at the level of the motor cortex.8889

B. Excess Striato-Thalamic Excitation or Abnormal Intracortical Inhibition?

1. Pathways

The striato-thalamic circuit is commonly subdivided into two pathways from the striatum to globus pallidus interna (GPi) and substantia nigra pars reticulata (SNpr) ("direct" and "indirect") and one extending from these neurons to the thalamus (Figure 1). The direct pathway transmits striatal information monosynaptically to the GPi and SNpr, whereas the indirect system conveys information to these same regions via a disynaptic relay from globus pallidus externa (GPe) to the subthalamic nucleus (STN). These parallel pathways have opposing effects on GABAergic GPi/SNpr output neurons (i.e., the direct pathway inhibits and the indirect pathway stimulates) and, in turn, a reverse effect on thalamocortical (VA-VL) neurons. Both the GPi and SNpr receive innervation in a somatotopic organization: head and eyes represented in SNpr, and the rest of the body in the GPi. The thalamic targets of GPi/SNpr project to the frontal lobe, with the VA-VL thalamic complex providing excitatory innervation to motor-related cortical areas. Topographic representation noted in the striatum and globus pallidus are maintained within the thalamus and subsequent projections to the premotor and motor cortex.

Neurobiology Tourette Syndrome

figure 1 Diagram of C-S-T-C pathways. Proposed physiological mechanisms for tic symptoms include: a) disruption of the tonically active inhibitory GPi/SNpr output on excitatory thalamic nuclei, leading to excess excitement of cortical neurons, and b) excess excitement of frontal cortical neurons due to other causes, such as impaired inhibition or excessive dopaminergic innervation.

Abbreviations: GABA, gamma-aminobutyric acid; glu, glutamate; GPe, globus pallidus externa; GPi, globus pallidus interna; SNpr, substantia nigra pars reticulate; STN, subthalamic nucleus; THAL, thalamus.

figure 1 Diagram of C-S-T-C pathways. Proposed physiological mechanisms for tic symptoms include: a) disruption of the tonically active inhibitory GPi/SNpr output on excitatory thalamic nuclei, leading to excess excitement of cortical neurons, and b) excess excitement of frontal cortical neurons due to other causes, such as impaired inhibition or excessive dopaminergic innervation.

Abbreviations: GABA, gamma-aminobutyric acid; glu, glutamate; GPe, globus pallidus externa; GPi, globus pallidus interna; SNpr, substantia nigra pars reticulate; STN, subthalamic nucleus; THAL, thalamus.

A second model, known as the "center-surround" system, has also been proposed as a pathway that could disrupt striato-thalamic signals.90 In this latter system, rapid direct and diffuse excitatory cortical inputs to subthalamic nucleus (STN) and slower more focused cortico-striatal pathways have a differential effect on the GPi/SNpr. As proposed, cortical initiation of a movement generates an excitatory signal to the STN, which then diffusely excites the GPi/SNpr, causing inhibition of the thalamocortical/brainstem motor mechanism (i.e., stimulates the brake). In parallel, inputs from cortical areas projecting to the striatum are transferred to a focused, slower, more powerful, context-dependent direct output pathway that inhibits specific neurons in the GPi/SNpr. The effect of this inhibition is to disinhibit selectively the desired motor pattern (i.e., selectively releasing the brake). Lastly, the indirect pathway acts to further focus the activity. In summary, the braking/acceleration of motor patterns enables the desired specific action while simultaneously inhibiting any competing movements.

2. Site of Abnormality

The basic pathobiological principle in all of the proposed pathways (direct-indirect, center-surround system, and stri-atal striosome-matrix compartment model, which was not discussed)91 is a disruption of the tonically active inhibitory GPi/SNpr output on excitatory thalamic nuclei that, in turn, influences generation of motor patterns in the cortex or brain stem. Nevertheless, despite proposals of a primary subcortical abnormality, it is also possible that impaired inhibition occurs directly at the level of the motor cortex, or both.

Evidence supporting intracortical inhibitory pathways includes results from neurophysiological and transcranial magnetic stimulation (TMS) studies. Prepulse inhibition of the startle reflex, a measure of inhibitory sensorimotor gating, is deficient in TS.92 Event-related brain potentials (ERPs), time-locked small voltage fluctuations recorded from the scalp that vary in amplitude as a function of stimulus perception or cognitive processes, have supported hypotheses of altered inhibitory processes or difficulties sustaining the process.93-97 Results from studies of two response-locked ERPs, Bereitschaft and motor potentials, suggest that the inhibitory impairment involves abnormal modulation of motor excitation/inhibition circuits.98 In TMS, the two most common measures are pre-pulse inhibition (PPI), also known as intracortical inhibition (ratio of amplitude of motor action potential generated by a suprathresh-old stimulus to that after a conditioning paradigm that uses a subthreshold stimulus followed by a standard suprathresh-old stimulus) and cortical silent period (period of electrical silence after the TMS-evoked motor excitation potential in a voluntarily contracted muscle). Although the results are somewhat variable among TS studies, all showed either reduced PPI and/or shortened cortical silent period.79,89,99

C. Abnormality of Synaptic Neurotransmission

The distribution of classical neurotransmitters within CSTC circuits raises the possibility that a variety of transmitters are involved in the pathobiology of TS. In general, current hypotheses are based on extrapolations from clinical trials evaluating the response to specific medications; from studies of CSF, blood, and urine in relatively small numbers of patients; from SPECT and PET investigations; and from neurochemical assays on a limited number of postmortem brain tissues. Genetic linkage has also been analyzed in an attempt to identify specific candidate genes that relate to components of neurotransmission.

The dopaminergic, GABAergic, cholinergic, serotoniner-gic, noradrenergic, and opioid systems have all been inves tigated to varied degrees.100-102 Which, if any, of these proposals represents the primary pathologic factor remains to be determined. Since many transmitter systems are interrelated in the production of complex actions, it is indeed possible, if not probable, that imbalances exist among several transmitter systems. Moreover, investigators must vigorously pursue mechanisms that could unify findings of alterations within multiple transmitter systems, i.e., such possibilities as second-messenger pathways, vesicle release proteins, channelopathies, or synaptic membrane dysfunction. Furthermore, any hypotheses about specific neuro-transmitter deficiencies must account for variability in tic manifestations, fluctuating symptoms, and potential resolution in adulthood.

The possibility of a dopaminergic abnormality in TS continues to receive strong consideration, because of the therapeutic response to neuroleptics, data from postmortem studies, and a variety of nuclear imaging protocols. If TS is associated with excess nigrostriatal dopaminergic activity, whether via postulated supersensitive dopamine receptors, dopamine hyperinnervation, abnormal presynaptic terminal function, increased vesicular dopamine release, or increased responsiveness to dopamine receptor activation, the result would be the disinhibition of excitatory neurons in the thalamus (see102 for review).

On the basis of finding increased densities of prefrontal D2 receptor protein in postmortem tissue from three individuals with TS (two typical and one adult onset), we have recently proposed a prefrontal-dopaminergic model for this disorder.103 That is, excess activation of postsynaptic pyramidal dopamine receptors would permit these neurons to fire more easily, leading to overstimulation of the striatal target. An excess inhibitory dopaminergic influence on cortical GABAergic interneurons would further increase excitatory pyramidal output. Since the dopamine transporter was also increased in the two typical cases of TS, a second possibility is an increased phasic dopamine release. Specifically, a reduction in tonic (basal) dopamine, postulated to be due to an overactive dopamine transporter system, could result in a system with elevated DA receptors and an excessive phasic release of dopamine. A similar proposal has been used to explain several neurochemical changes in TS, including elevated intrasynaptic dopamine release after a pharmacologic challenge with amphetamine.104 In support of the aforementioned hypothesis, tics can be exacerbated by stimulants that increase DA release and block reuptake and by environmental stimuli (stress, anxiety) that increase phasic DA release. Despite the aforementioned proposals, some investigators have emphasized that abnormalities of dopamine fail to explain many clinical and laboratory observations, including the description of unchanged tics in four adults who developed parkinsonism and received treatment with L-dopa105 and the coexistence of tics and dopa-responsive dystonia.106

D. Neuroimmunological Disorder?

Pathophysiologically, based on a Sydenham chorea (SC) model, an immune-mediated mechanism involving molecular mimicry (i.e., antibodies produced against GABHS cross-react with neuronal tissue in specific brain regions) has been proposed for a subset of children with TS. Labeled as pediatric autoimmune neuropsychiatry disorders associated with streptococcal infection (PANDAS), this entity has attained widespread notoriety in both scientific and lay publications. First formally proposed in 1998,31 diagnostic criteria include the presence of OCD and/or tic disorder; prepubertal age at onset; sudden, "explosive" onset of symptoms and/or a course of sudden exacerbations and remissions; a temporal relationship between symptoms and GABHS; and the presence of neurological abnormalities, including hyperactivity and choreiform movements. The existence of this entity has been supported by several clinical, neuroradiographic, and laboratory studies. More specifically, additional cohorts have been described;107 familial studies have shown that first-degree relatives of children with PANDAS have higher rates of tic disorders and OCD than do those in the general population.108 Furthermore, volumetric analyses in children with PANDAS show that the average size of the caudate, putamen, and globus pallidus is significantly larger in those with PANDAS than in healthy children.109 There are reports of improvement of tics/OCD after plasma exchange or the use of intravenous immunoglobulin,110 and the finding that a trait marker for susceptibility in rheumatic fever (the monoclonal antibody D8/17) has an enhanced expression in individuals with PANDAS.111 Nevertheless, despite these findings, concerns have been raised about the existing clinical criteria used to define this disorder,112113 the failure to identify abnormal antineuronal antibodies,114 and the inability of PANDAS sera to induce stereotypes after infusion into rodent striatum.115116 Taken together, these findings suggest that, although PANDAS is an intriguing hypothesis, convincing evidence supporting an immune-mediated process is not yet available.

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