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mise à jour du
21 mars 2010
Arch Gene Psychiatry aug 2000;57:741-748
lexique
A Functional Neuroanatomy of Tics
in Tourette Syndrome
Emily Stern, David A Silbersweig et al.
Department of psychiatry Weill medical college of Cornell University New York

Chat-logomini

A Cursing Brain? the histories of Tourette Syndrome. Kushner HI 1999 
Georges Gilles de la Tourette
 
Tourette syndrome (TS) is a classic neuropsychiatrie disorder characterized by multiple motor and vocal tics. Tourette syndrome is seen worldwide, with typical onset in childhood, and a prevalence of approximately 5 per 10 000. Comorbid obsessivecompulsive, attention-deficit, and learning disorder features have been described as well. There is a significant genetic component in TS, with a suggestion of autosomal dominant transmission, although there have been no significant linkage findings to date. Autoimmune mechanisms have also been implicated in some cases.
 
Tics, the defining symptom of TS, are sudden, brief, stereotyped actions. They may be simple vocalizations (such as grunting or sniffing), or movements of individual muscle groups. Alternatively, they may be complex in nature, comprising whole words (including curses [coprolalia]) or clusters of movements. Mild tics can be unintentional, involuntary actions that can occur without a patient's awareness. However, the more severe or complex tics are often intentional, "unvoluntary" actions, in that they are briefly suppressible, performed to relieve a local tension, sometimes preceded or provoked by an uncomfortable sensation, or performed compulsively in association with irresistible urges. In these cases, the subjective sense of free will is disrupted: tics are performed against the patient's will, or the will to act is not under the patient's control. Therefore, TS provides a model of one type of disordered human volition.
 
The neural correlates of these striking symptoms of volitional disruption are not well defined. Basal ganglia dysfunction has been suggested by the occurrence of tics in pathological conditions that affect these deep structures, such as carbon monoxide poisoning and encephalitis lethargica." The dopaminergic system has been implicated in TS because dopaminergic medication can induce tics, while blockade of dopaminergic neurotransmission can be effective in their suppression. Most in vivo radioligand imaging and postmortem histochemical studies of TS have therefore focused on presynaptic and postsynaptic dopaminergic function in the basal ganglia, although a number of other brain regions and neurochemical (including peptide and second messenger) systems have been examined. Recent structural magnetic resonance irnaging studies have demonstrated abnormalities of volume and lack of normal asymmetry in the basal ganglia. A possible role for the anterior cingulate and midbrain in the generation of tics bas also been suggested. Single-photon emission computed tomography and fludeoxyglucose F 18 positron emission tomography (PET) studies in the "resting" baseline state have produced variable results, with decreased or increased activity described in regions such as the striatum and thalamus, and premotor, sensorimotor, and paralimbic cortices. Disordered interactions between subcortical, paralimbic, and sensorimotor brain regions have also been postulated. A recent functional magnetic resonance imaging study focusing on the suppression of tics found that increased severity of tics outside the scanner was associated with less of a suppression-related decrease in ventral globus pallidus, putamen, and midthalamus activity (and less of a corresponding increase in midfrontal, lateral temporal, inferior occipital, and head of caudate activity).
 
To date, the functional neuroimaging experiments of TS have provided extremely valuable information, but have not measured (or, in some cases, controlled for) tic occurrence during scanning, and therefore have not generated an image of the brain state specifically associated with tics. We have developed and validated methods of PET image acquisition and analysis that can isolate patterns of brain activity associated with transient, randomly occurring neuropsychiatric states. These methods have been used to study the functional neuroanatomy of hallucinations (involuntary perception) in schizophrenia. In this study, they were used to examine the pathophysiology of tics (unvoluntary/involuntary action) in TS. [...]
 
Comment : These results define a distributed neural system in which abnormal activity is associated with the spontaneous initiation of, or failure to suppress, motor and vocal behavioral repertoires in this group of TS patients. Prominent activity was noted in primary motor and Broca's areas, corresponding to the modality-specific outflow pathways of behavioral expression in motor and vocal tics. Striatal activity was also noted, supporting the involvement of basal ganglia circuits that are emphasized in iraditional pathophysiological models of TS. The extensive activity in executive and premotor regions may be particularly notable, and may help to extend our understanding of disordered action and volition in TS, because these regions have traditionally been associated with the selection, preparation, and initiation of behavior.
 
Activity detected in the striatum can be seen in the context of cortico-striato-pallido-thalamo-cortical circuits that modulate activity in parallel brain systems underlining discrete psychomotor functions with specific functional and somatotopic organization. Within these circuits, the direct and indirect basal ganglia pathways provide a balance of excitation and inhibition that may be disrupted in TS. A failure of inhibition in motor cortex of TS patients, due to subcortical afferent disinhibition and/or to failure of intracortical inhibition, has been suggested by a transcranial magnetic stimulation study. The findings of the current study implicate 3 of the corticostriato-pallido-thalamo-cortical circuits in particular: the motor, dorsolateral prefrontal, and anterior cingulate circuits. These circuits are involved in the selection, programming, initiation, and control of movement. Dopaminergic projections front the midbrain tegmentum, a region where activation was noted at a threshold of P<.005 (uncorrected), are involved in the modulation of these circuits.This modulation may provide a mechanism of symptom formation (excess dopamine) and treatment effect (dopamine blockade) in TS.
 
For particular tics, the specific cortical and subcortical regions that are activated may determine the phenomenology of the behavior. In the individual analysis, coprolalia (which comprised more than 90% of the vocal tics) was associated with activation in the region of the Broca's area and the frontal operculum, known to be involved in the generation of speech. Activation was also noted in the hcad of the caudate, which has recently been identified by lesion methods as a critical component of the network underlying language. The other language regions noted (including posterior superior temporal gyrus, middle temporal gyrus, and supramarginal gyrus) may have been involved in the generation or the subsequent hearing of the self-generated linguistic material. Activation in the posterior cingulate gyrus has recently been described in association with emotional linguistic material. The thalamic and cerebellar activations are consistent with the roles of these structures in modulating outflow of the cortical-subcortical circuits implicated. In contrast to the vocal tics, motor tics were associated with notable sensorimotor cortex activation. It is likely that activations of somatotopically specific subregions in sensorimotor cortices would be associated with movements in specific corresponding muscle groups.
 
Activity in anterior cingulate, premotor, and supplementary motor areas, and dorsolateral prefrontal cortex, detected in the current study, has been described in tasks involving conscious, volitional behavior, and is thought to be involved in the selection, preparation, and initiation of action . Activity in the supplementary motor area bas also been noted in the performance of over learned (automatic) motor sequences. Activation of medial premotor association cortices bas been associated with self-generated movements and activation of lateral premotor association cortices bas been associated with externally cued volumary movements.The striking activation of both medial and lateral premotor systems in this study suggests that both systems can be implicated in unvoluntary internally generated action. The involvement of the lateral premotor system may reflect the response to internal sensations, which are now known to be a common component of tics in TS. One study bas reported a lack of normal premovement potentials associated with simple tics, while another study found that premotor potentials were prescrit during tics in sortie patients. In either event, tics may differ from externally cued, planned movement in the timing, sequence, coherence, or distribution of premotor activity, and complex tics might be expected to involve more premotor activity than simple tics. A study of electroencephalogram microstates suggested differences between TS patients and normal subjects during simple and complex moveinents. While the purpose of this study was to characterize the functional neuroanatomy of tics, future comparisons of tics vs volitional movements in TS patients, and of volitional movements in TS patients vs normal subjects, may help to clarify these issues.
 
The lesion and stimulation literature is also relevant to the interpretation of the findings in ibis study. Lesions or failure of activation of the medial frontal premotor system, prommently activated in this study, have been associated with the inability to initiate voluntary action. Conversely, stimulation of, or seizure activity in, these regions can produce complex vocal and motor automatisms (sometimes associated with urges and emotions) resembling tics. This is particularly the case with the anterior cingulate, which is part of the rostral limbic systern, and integrates affective cues with executive functions for the selection of context-dependent behavior. The prominently activated insula is also involved in the integration of internal rnotivational states, with behavior appropriate for the extrapersonal world (entailing behavioral triggering or inhibition functions), in the imparting of affective tone to experience and behavior, and in somatosensory, linguistic, and self-generated motor functions. Like the cingulate, it performs these roles by serving as a convergence point with widespread multimodal, limbic, and basal ganglia connections. Dysfunction (including abnormal gating) in these phylogenetically older paralimbic regions may contribute to the primitive, uninhibited behavior of TS. The maxima of some of the activations in the insular region were centered on the claustrum. While such a small localization must be considered with caution, it is worth noting that the claustrum bas connectivity with sensoriniotor, premotor, and anterior cingulate regions, and is involved in the performance of movements.
 
The predommantly dorsal location ofanterior cingulate activation, rostral location of supplementary motor activation and dorsolateral location of prefrontal activation associated with tics in this study represents interminent increased activity of executive components of the motor system (althouggh supplementary motor cortex overall is considered premotor, and the cingulate also contains direct corticospinal projections). Executive dysfunction has been noted in neuropsychological tests of patients with TS. Tonic overactivity of frontal executive systems, coupled with hypoactivity in primary sensorimotor cortices, has been implicated in idiopathic dystonia, characterized by involumary motor posturing and slowing. Increased activity in orbitofrontal cortex and anterior cingulate cortex, aud their subcortical connections (including the head of the caudate), bas been implicated in obsessive-compulsive symptomatology characterized by involumary thoughts and complex actions, and seen with increased frequency in patients with TS. Given the differential prefrontal projections to various regions of the striatum (premotor to putamen and prefrontal to head of caudate), it might be expected that putamen dysfunction would be associated with a greater degree of motor symptomatology, whereas caudate dysfunction would be associated with a greater degree ofcognitive symptomatology.
 
The results of this state study of tics in TS may also be seen in the context of prior "trait" studiesof TS. When the variable results of the previous trait studies are taken together, they suggest a tome dysregulation of a number of the regions in which increased activity was detected in this symptom-state examination.
 
The decreased activity noted in some of the previous studies may reflect inhibition of tics during those study sessions (such inhibition is unlikely in the current study, as patients were reminded not to supress tics before cach scan and had frequent tics during each scan, with which brain activity was directly correlated). It is also possible that tonic decreased activity alternates with intermittent increased activity during tics in the regions implicated in TS. Although tics are not frank seizures, such a temporal pattern would be similar to that described in PET studies of epileptic foci and consistent with an imbalance of excitation and inhibition.
 
The results of this study may help to expand the interpretation of the results of a previous functional magnetic resonance imaging study that examined tic suppression in TS. That study compared a condition in which tics were suppressed with a condition in which tics were expressed. The authors interpreted their findings with an emphasis on the issue of suppression, and make the reasonable suggestion that failure to inhibit tics in TS may result from an impaired ability to alter subcortical neuronal activity. While they noted that the higher rate of spontaneous tics in their control condition was a possible confounding factor, they felt that this was unlikely because they expected that the higher rate of tics would produce a greater change in magnetic resonance imaging signal intensity during successful tic suppression, and correlate positively (not negatively, as observed) with severity of tic symptoms (measured outside of the scanner). However, this would not be the case in regions active during both tics and (possibly to a different degree in) their suppression. in the current study, tics were not suppressed, and were counted and characterized during the scans and differences in numbers of tics, and possibly urge, are not an issue. The results of these 2 studies can therefore be taken together, possibly suggesting that anterior cingulate and midfrontal activity is common to both tics and their suppression, and that putamen and sensorimotor cortex (motor outflow) activity is higher during tics and lower during suppression. While the pattern of increased activity noted in the current study could be primary, it is also quit, possible that it could result from failure of inhibition.
 
Although these statistically significant results represcrit a sampling of hundreds of tics in 72 images from multiple subjects, the population studied is still relatively small, the analysis applies for just this group of subjects, and further studies will be necessary to replicate, extend, and assess the generalizability of these findings. Possible medication effect in 4 of the subjects also has to be considered as a potential limitation, although a number of points make this issue less likely to affect the results: the target symptom (tics), and therefore the neural firing underlying it, was active despite medication in the 4 medicated patients (2 were unmedicated); the analysis determines the variance induced by tics in a constant pharmacodynamic/pharmacokinetic setting over the course of the study session; and subject-specific effects, including medication and dosage (chlorpromazine equivalents), were partialed out in the analysis. Despite the 2 videotapes and throat microphone, it is possible that extremely subtle tics may have been missed, although patients with known severe, stereotypical tics were studied. Regarding timing, it should be kept in mind that the temporal discrimination achieved with this technique is not due to direct temporal resolution, the timing measures were to the nearest second, possible subcomponents of tics cannot be resolved, and it is not possible to say where the activation in the identified systems begins, or whether it occurs in parallel. Future analyses and studies can examine these issues, as well as similarities and differences between subtypes of tics, within and between individual unmedicated patients.
 
In conclusion, activity was noted specifically during tics in motor/vocalization, paralimbic, premotor, and executive frontal-subcortical brain systems. Autonomous activity in these regions may account for the striking motor and vocal acts of TS patients, and may contribute to the "unvoluntary" experience of an irresistible urge that often accompanies these acts. Indeed, tics may represcrit a paradoxical state in which brain regions important for motivational aspects of behavior, and normally associated with a subjective sense of volition as they initiate action, are not operating under the volitional control of the patient. This suggested systems-level pathophysiology of TS is consistent with observations of behavioral changes associated with lesions and stimulation in medial frontal regions, and these findings may contribute to a framework for future studies.