- 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.
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- 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. [...]
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- 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.
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- 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.
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- 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.
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