Functional neuroimaging in Tourette syndrome

Functional neuroimaging in Tourette syndrome

Journal of Psychosomatic Research 67 (2009) 575 – 584 Review article Functional neuroimaging in Tourette syndrome Hugh Rickards⁎ Department of Neuro...

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Journal of Psychosomatic Research 67 (2009) 575 – 584

Review article

Functional neuroimaging in Tourette syndrome Hugh Rickards⁎ Department of Neuropsychiatry, Birmingham University and BSMHFT, Birmingham, United Kingdom Received 24 April 2009; received in revised form 24 June 2009; accepted 28 July 2009

Abstract Functional neuroimaging of neuropsychiatric disorders is a complex discipline requiring skills in medical science, philosophy, and technical physics. This review first examines the broad categories of functional imaging studies that have been utilized in this area, comparing the strengths and weaknesses of each approach. This review then looks at much of the available

literature on functional imaging in Tourette syndrome (TS) and provides a synthesis of data. The review will also examine the different methodologies employed and will suggest which methodologies are most likely to lead to elucidation of the pathophysiology of TS and related conditions. © 2009 Elsevier Inc. All rights reserved.

Keywords: fMRI; Functional neuroimaging; PET; Tourette syndrome

Comparing the different approaches utilized in the functional imaging of TS Studies probing specific neurotransmitter systems Studies of this type can utilize single photon emission computed tomography (SPECT) or positron emission tomography (PET) procedures with ligands that bind to specific receptors in the brain. An example of this is the use of [ 11 C]raclopride to examine the function of dopamine receptors. A variety of neurotransmitter systems have been examined, but most of the studies have focused on the dopamine and serotonin (5HT) systems. The advantage of probing specific neurotransmitter systems is that the technique has the potential to be relatively sensitive and specific, particularly if the disorder in question is related to a specific neurotransmitter system (such as dopamine in Parkinson's disease). However, no clear single neurotransmitter system has so far been clearly

⁎ Department of Neuropsychiatry, Birmingham and Solihull Mental Health Foundation Trust, Barberry Building, 25 Vincent Drive, Edgbaston, Birmingham B15 2FG, UK. E-mail address: [email protected] 0022-3999/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2009.07.024

identified in TS by cerebrospinal fluid and plasma studies. There is a response to dopamine antagonists, but this does not necessarily implicate the dopamine system directly. Participants in these studies are exposed to small amounts of ionizing radiation. Region-of-interest studies Studies of this type can use SPECT or PET procedures. The aim is to examine regional brain activity, usually in relation to glucose metabolism or blood flow. Some studies have focused on specific regions of the brain that have been implicated in the pathogenesis of TS (for instance, the striatum), and other studies have used standard regions of interest that effectively cover the whole brain. Currently, the spatial and temporal resolutions of these types of scan are poor when compared to those of MRI. This leads to problems with signals from adjacent areas to the region of interest and problems with averaging of intraregional differences (for instance, the striatum may contain different systems, some of which are overactive and some of which are underactive. The overall function of this area may then appear to be “normal” in a region-of-interest study). There is a small exposure to ionizing radiation in both PET and SPECT procedures.

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Types of imaging technique PET versus SPECT PET has a resolution greater than that of SPECT (although PET's resolution is poor compared to that of MRI). However, radionuclides in PET are expensive to produce and do not last long (shorter half-life). PET scanners are not so readily available. Some paradigms require radionuclides with a longer half-life, making SPECT a more appropriate investigation tool in some cases. Technetium-99m ( 99m Tc) hexamethylpropyleneamine oxide (HMPAO) SPECT produces differentiation between gray matter and white matter and has been shown to reflect cerebral metabolism in other conditions such as epilepsy [1]. Functional MRI (fMRI) studies fMRI utilizes the differential magnetic properties of blood flow to generate information about functions in specific brain regions. MRI has generally better temporal and spatial resolutions than PET or SPECT. However, MRI cannot currently analyze specific receptor systems. Because of the nature of image acquisition in fMRI, regions or systems of interest normally have to be activated using a specific paradigm, comparing the active state to the resting state. However, fMRI also has the capacity to examine functional connectivity between brain regions, particularly by looking at correlations between activities in one region and another. This potentially powerful methodology relies on relatively complex mathematics and, often, on multiple comparisons. The idea of a “resting state” can be problematic in TS, as a person is usually ticking or suppressing tics. This has been addressed in at least one functional imaging study by using Stage 2 sleep as resting state, creating a number of logistic problems. Activation tasks require the participant to activate a part of the brain that is somehow implicated in the pathophysiology of the disease. Activities may include performing tic-like voluntary movements, voluntary tic suppression, performing tics themselves, or stimulation of a specific system or brain region using either drugs or cognitive tasks, such as the Stroop test. Particular problems with the functional imaging of patients with TS Head movements in the scanner can be problematic for all types of brain imaging. Waxing and waning of tics over a short time can also lead to difficulties. HMPAO is useful as it is taken up rapidly (so you can measure the tics over the short period of HMPAO uptake). It remains in the brain without redistribution long enough to get the person in the scanner, and you could even give the person a sedative at that time to reduce any movement artifact.

The problem with examining the function of the brain at a single point in time in TS is that any change in function might be consequential rather than causal. Changes in brain function may also be epiphenomena. TS is a complex condition, and tics may involve a number of brain processes, including premonitory sensation, awareness of premonitory sensation, attempts to suppress, thinking about suppression, preparation for movement, the tic itself, and relief of premonitory sensation. This list only includes those brain functions that have conscious components. There are likely to be a range of brain functions related to tics that have no conscious component and about which we have little knowledge. Thus, functional changes in the brain may be demonstrating the “TS pathology” itself or may represent the process of tic generation and its accompanying phenomena. These processes are likely to overlap and can take variable amounts of time (in some cases, the whole process can be completed in well under a second). Paradigms for functional neuroimaging studies need to take these factors into account.

Summary of recent studies Studies probing particular neurotransmitter systems Ligand studies aim to use a radioactive compound that binds to a specific receptor in order to examine the function of that receptor system. The first ligand-based studies in TS were aimed at the dopaminergic system. This system was targeted for two main reasons: dopamine was implicated in TS because of response to treatment, and it was technically possible to study the dopaminergic system. In addition, a single postmortem study implicated the dopamine system in TS [2]. Turjanski et al. [3] studied presynaptic and postsynaptic dopaminergic functions in TS using [11F]dopa (to assess the integrity of dopaminergic terminals) and [11C]raclopride (to assess receptor site density) (Table 1). Both of these ligands are positron-emitting, so this was a PET study. This study was limited by the fact that the majority of patients in the [11F]dopa study were medicated with neuroleptic drugs at the time of the study. Despite this, there were no clear differences between patients and controls using either ligand. This study was the sequel to another study from the same group using the same methodology and finding the same results [4], so it is unclear whether it represents a replication or an extension of the original findings. Ernst et al. [5] used a similar ligand ([18F]dopa) to study 11 children with TS and found a higher level of binding in the left striatum of the TS patients compared to matched controls. Wong et al. [6] used the dopamine-blocking ligand [11C]3-N-methylspiperone in a two-stage process. Firstly, they looked at dopamine receptor density in the striatum compared to that in the occipital cortex, and, secondly, they

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Table 1 PET ligand studies Authors

Year Nuclide 11

[ F]Dopa [11C]Raclopride [18F]Dopa [11C]Methylspiperone

N (TS) Result

Comments

10 10 11 20

Majority of patients were medicated Majority of patients were medicated

Turjanski et al. [3] Turjanski et al. [3] Ernst et al. [5] Wong et al. [6]

1994 1994 1999 1997

Singer et al. [8]

2002 [11C]Raclopride

7

Gilbert et al. [9]

2006 [18F]Fallypride

6

Behen et al. [25]

2007 [11C]Methyltryptophan

Albin et al. [23] Albin et al. [23] Haugbol et al. [26] Wong et al. [7]

2009 2009 2007 2008

[11C]Dihydrotetrabenazine [11C]MPH [11F]Altanserin Variety of ligands

26 33 33 20 14

No differences No differences Higher binding in the left striatum Subgroup of four patients with elevated D2 binding

Haloperidol pretreatment; the subgroup with high binding had higher vocal tic scores

Baseline scans showed no difference; amphetamine challenge led to increased binding Widespread lower dopamine binding found

Fallypride is used to examine extrastriatal dopamine binding Decreased uptake in dorsolateral prefrontal cortex Children and increased uptake in thalamus No differences No differences Increased 5HT2A binding in striatum General up-regulation of 5HT systems Increased dopamine binding in the left ventral striatum; changes in midbrain 5HT function; amphetamine challenge increased dopamine release

pretreated subjects with haloperidol in 20 TS patients. The dopamine receptor density was not different between subjects and controls. However, there was a subgroup of four TS patients with significantly elevated dopamine 2 (D2) receptor binding. Clinically, this subgroup was only different in that it had higher vocal tic scores. In a more recent follow-up to this study, Wong et al. [7] studied 14 TS adults and 10 healthy controls. They utilized several scans with different ligands over 3 days to measure a range of parameters around dopamine and 5HT, including receptor density and affinity, transporter binding, and dopamine release following administration of amphetamine. In this study, D2 binding was increased in the left ventral striatum. There were changes in midbrain and striatal 5HT functions (regardless of the presence or the absence of obsessive– compulsive disorder) in TS patients. The amphetamine challenge led to a greater release of striatal dopamine in TS subjects. Singer et al. [8] used [11C]raclopride and a pharmacological paradigm (amphetamine challenge) in seven adults with TS and controls. Like the study of Turjanski et al., the baseline raclopride scans did not differ between patients and controls, but the amphetamine challenge resulted in a greatly increased binding in the TS group compared to controls, replicating the findings of Wong et al. [7] to some extent. More recently, a PET ligand that binds to extrastriatal dopamine receptors ([18F]fallypride) has become available. Gilbert et al. [9] designed a study specifically to look at extrastriatal dopamine activity in six TS adults and controls. Widespread lower dopamine binding was found in the orbitofrontal cortex, primary motor cortex, anterior cingulate, mediodorsal thalamus, and hippocampus. The relevance of these findings is not currently very clear.

[123I]Iodobenzamide (IBZM) is a potent D2 antagonist, and two studies have used this ligand to study postsynaptic dopamine function in TS. Wolf et al. [10] used a discordant monozygotic twin methodology to clarify the relationship between environment and severity of symptoms in TS (Table 2). Five sets of monozygotic twins (all of whom had TS, but of differing severities) were studied in a SPECT scanner. Caudate D2 binding was much greater in all the more severely affected of the twin pairs, although there was strong “within-pair” concordance. The subjects had undergone HMPAO SPECT scanning, which showed no differences in striatal regional cerebral blood flow (rCBF) between subjects and controls, and all subjects had been off medication for an “extended period” prior to the study. These findings suggest that absolute levels of dopamine receptors are genetically determined, but that small changes could be either the cause or the result of symptom severity. Müller-Vahl et al. [11] used the same ligand ([123 I]IBZM) in medicated and unmedicated TS patients and unmedicated controls. In the seven neuroleptic-treated patients, IBZM binding was significantly different from that in controls, but the neuroleptic-naive patients showed no difference from controls. Further subgroup analysis showed that subjects who were advanced in their illness had relatively low IBZM binding in the striatum than controls. Again, this finding must be viewed with caution as it appears post hoc in a study with a low number of subjects with TS (N=17). A further iodine-based isotope [123I]2s-carbomethoxy-3s(4-iodophenyl)-N-(3-fluoropropyl) nortropane (β-CIT) is a SPECT ligand for dopamine transporter (DAT) binding and has been used in three TS studies. Malinson et al. [12] studied five adults with TS and matched controls and found significantly higher striatal [123I]β-CIT binding in the subjects. All subjects had binding higher than that of their

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Table 2 SPECT ligand studies Authors

Year

Nuclide 123

N (TS)

Results

Comments

Caudate D2 binding always higher in the more severely affected twin Neuroleptic-naive patients showed no difference from controls No difference Higher striatal binding No differences

Strong “within-pair” concordance

Wolf et al. [10]

1996

[

I]IBZM

10

Müller-Vahl et al. [11]

2000

[123I]IBZM

17

Hwang et al. [19] Malinson et al. [12] Heinz et al. [13]

2008 1995 1998

[123I]IBZM [123I]β-CIT [123I]β-CIT

10 5 10

Müller-Vahl et al. [15] Stamenkovic et al. [14] Serra-Mestres et al. [16]

2000 2001 2004

[123I]β-CIT [123I]β-CIT [123I]FP-CIT

12 20 10

Cheon et al. [17] Mena et al. [18] Hwang et al. [19] Yeh et al. [20]

2004 2004 2008 2007

[123I]IPT-CIT TRODAT 1-Tc99m TRODAT 1-Tc99m TRODAT 1-Tc99m

9 10 10 8

Bohnen et al. [21] Albin et al. [22] Berding et al. [24]

1999 2003 2004

[11C]Dihydrotetrabenazine [11C]Dihydrotetrabenazine [123I]AM281

8 19 6

Higher striatal binding No differences Dopamine binding higher in caudate and striatum Dopamine binding higher in basal ganglia Increased DAT bilaterally in striatum No differences Less decline in binding in striatum related to MPH challenge No difference Increased ventral striatal binding Ligand detectable in people with TS

matched controls, although there was some overlap in the data taken as a whole. Heinz et al. [13] failed to replicate this finding, using an identical methodology, in 10 TS patients and matched controls. Post hoc findings indicated a negative correlation between tic severity and binding in the midbrain and thalamus (where [123 I]β-CIT binding may reflect serotonergic function). Another replication failure was reported by Stamenkovic et al. [14], who studied 20 TS patients with the same ligand and looked at DAT binding in all brain areas compared to the cerebellum. However, Müller-Vahl et al. [15] also used [123 I]β-CIT in 12 TS patients and controls and found increased striatal activity (compared to occipital values). Serra-Mestres et al. [16] were able to use higher-resolution SPECT scanning and to focus on the different nuclei of the basal ganglia in 10 drug-free TS patients and matched controls. DAT binding (measured using [123I]FP-CIT) was higher in caudate and striatum. In this study, the researchers also considered the effect of the severity of (motor and behavioral) symptoms and found that these did not affect binding. This finding was confirmed by Cheon et al. [17] in nine drug-naive children with “Tourette simplex” (i.e., TS without any associated psychopathology) using a very similar ligand ([123I]PT-SPECT). This group also replicated the finding that binding was not related to severity of symptoms. Technetium “DAT” SPECT scanning has been shown to be a useful tool in the diagnosis of akinetic rigid syndromes. Three studies have utilized this methodology in TS. Mena et al. [18] used TRODAT 1-Tc99m, a newly developed technetium-labeled tropane derivative, in 10 TS patients and normal controls and showed a marked increase in DAT in the striatum bilaterally. However, all patients were being treated with neuroleptics. Hwang et al. [19] captured both

Post hoc finding of reduced binding in midbrain and thalamus

Binding was not affected by symptoms Binding was not affected by symptoms All patients treated with neuroleptics

Preliminary study

presynaptic and postsynaptic dopamine functions in the striatum using both [99mTc]TRODAT-1 and [123I]IBZM SPECT in 10 adult TS patients and healthy controls and found no significant differences between the groups. Yeh et al. [20] examined the effect of methylphenidate (MPH) pretreatment on DAT scanning. Normally MPH would cause a decline in DAT binding, and this was seen to a lesser extent in the TS group only in the right striatum. Bohnen et al. [21] used a type 2 vesicular monoamine transporter ligand ([11C]dihydrotetrabenazine), which binds to monoaminergic neurones in the striatum, in eight adults with TS and matched controls. They found no differences between the groups. Albin et al. [22] replicated the methodology, comparing 19 variously medicated TS patients with 27 controls, and again found no difference between the groups in the dorsal striatum, but an increase in ventral striatal dihydrotetrabenazine binding in the subject group. A second work by Albin et al. [23] used [11C]MPH (which binds to plasmalemmal DAT) and [11C]dihydrotetrabenazine to examine dopamine transport in 33 TS adults and controls. They found no differences between subjects and controls in terms of binding. Berding et al. [24] examined the cannabinoid CB1 ligand [123I]AM281 in six TS patients before and after exposure to Δ9-tetrahydrocannabinol. They found that this ligand was detectable by SPECT in people with TS with an acceptably low exposure to radiation. This ligand may show promise for future studies. A small number of studies have examined the 5HT system in TS. In addition to the study of Wong et al. [7], who found nonspecific changes in 5HT function in the brain of people with TS, Behen et al. [25] used [11C]methyl-L-tryptophan as nuclide to measure general

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5HT function. They studied 29 children with TS and 9 healthy controls and focused their attention mainly on structures within the model of corticostriatothalamocortical (CSTC) circuitry. They showed a decrease in tracer uptake in the dorsolateral prefrontal cortex bilaterally and an increase in tracer uptake in the thalamus bilaterally. Haugbol et al. [26] compared 20 adults with TS and 20 controls. A PET imaging study of [18F]altanserin, which binds to 5HT2A receptors, was performed. This showed increased striatal 5HT2A binding in TS patients compared to controls, but the medication status of the participants was not clear. A post hoc analysis also suggested global upregulation of the 5HT2A system. Summary of ligand studies A number of studies in this area failed to show significant differences between patients and controls, but this may be a reflection of the poor spatial resolution of current scanning procedures. Findings that are starting to emerge include an increased dopamine activity in the left striatal region, which may be more pronounced in the ventral striatal area. Two studies have shown that amphetamine challenge leads to a relatively overactive dopaminergic system in the striatum. None of the studies cited so far has indicated a direction of causation (Are the functional changes causing or reflecting the symptoms, or are both symptoms and functional changes a reflection of a third process?). “Region-of-interest” studies [99Tc]HMPAO SPECT HMPAO is a radionuclide that crosses the blood–brain barrier (around 5% of intravenous HMPAO enters the brain and tends not to redistribute for the first 24 h after injection). HMPAO is taken up in the brain in proportion to blood flow, which in turn varies with the metabolism of the region of interest [27]. Six studies addressed rCBF in TS [28–33]. In the study of Riddle et al. [29], nine TS patients and matched controls were imaged with HMPAO SPECT, and reduced rCBF in the left putamen/globus pallidus was noted (a relative reduction of around 4%) (Table 3). The studies of George et al. [28] and Kleiger et al. [31] used a slightly different methodology; they used the occipital lobe as the comparator area (compared to Riddle et al.'s use of the region of interest/whole brain minus cerebellum ratio). The first work of George et al. [28] showed only an increase in right frontal activity compared with controls, whereas the second work of Kleiger et al. [31] showed findings similar to those of Riddle et al. [29] in 50 patients compared to 20 controls; there were reductions in activity in the left caudate and anterior cingulate gyrus. Moriarty et al. [33] later went on to study whether HMPAO SPECT could generate an endophenotype that could distinguish obsessive–compulsive symptoms from tics in five small Gilles de la Tourette syndrome pedigrees. They studied 20 subjects in all and

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found decreased perfusion in the striatal, frontal, and temporal regions in affected individuals regardless of symptoms or syndrome. A single case reported by Sieg et al. [34] using HMPAO showed a focal reduction in perfusion in the left basal ganglia. This was a clinical case report rather than a controlled study. Kleiger et al. [31] studied six drug-free adults with TS using HMPAO SPECT. The activity was recorded in proportion to cerebellar activity (although the cerebellum has previously been shown to be active in relation to tics). Contrary to previous HMPAO studies, they found hypoperfusion in the right basal ganglia. Chiu et al. [32] used [99mTc]HMPAO brain single-photon emission tomography to try to delineate differences in perfusion between children with chronic tic disorder and children with TS. “Visual interpretation” and “semiquantitative analysis” were used to compare perfusion between the two groups (27 children with TS and 11 children with chronic tics). Visual interpretation of the scans indicated that 82% of patients with TS had abnormal perfusion compared to none of the patients with chronic tics. Abnormalities tended to be located in the left lateral temporal lobe. This study illustrates some of the fundamental issues that hamper functional neuroimaging research. The two categories being studied are not necessarily discrete natural entities, and the imaging studies may reflect symptoms rather than causes. The findings may also be epiphenomena in relation to other factors (particularly comorbid conditions, which were not controlled for in this study). Diler et al. [35] studied 38 children with TS and 18 controls. The group used [99mTc]ethyl cysteinate dimer (ECD) to study regional cerebral perfusion and found a variety of differences between patients and controls, in particular lower perfusion in the left caudate, cingulum, right cerebellum, left dorsolateral prefrontal region, and left orbital region. [11F]Fluorodeoxyglucose (FDG) PET studies PET studies can examine regions of interest, as well as specific receptor ligands. FDG-PET studies measure the glucose uptake of the brain, which is used as a proxy for function or activity. The first recorded study [36] was performed in five patients and found no differences between subjects with TS and controls. A similar group performed the same study with a higher number of participants (n=11) and an improved scanner [37]. This group was the first to identify a reduction of around 15% of activity in the frontal, cingulate, and insular cortices and in the ventral striatum. Braun et al. [38] performed FDG-PET on 16 TS patients who were drug-free. They looked at the function of specific regions of interest, as well as differences in function between regions. Generally, their findings showed a reduction in glucose uptake in the inferior limbic cortex (particularly the insula) and the striatum and a relative hypermetabolism in the sensorimotor cortices. This was

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Table 3 Region-of-interest studies Authors

Date Nuclide

Scanner N (TS)

Riddle et al. [29]

1992 HMPAO

SPECT 9

Compared to cerebellum

George et al. [28] Moriarty et al. [30]

1992 HMPAO 1995 HMPAO

SPECT SPECT

Compared to occipital lobe Compared to occipital lobe

Moriarty et al. [33]

1997 HMPAO

SPECT

Sieg et al. [34] Kleiger et al. [31] Chiu et al. [32]

1993 HMPAO 1997 HMPAO 2001 HMPAO

SPECT SPECT SPECT

Diler et al. [35]

2002 [99mTc]ECD SPECT

Chase et al. [36] Brooks et al. [37]

1984 FDG 1985 FDG

PET PET

Braun et al. [38]

1993 FDG

PET

Stoetter et al. [39]

1992 FDG

PET

Reduced rCBF in left putamen/ globus pallidus 20 Increase in right frontal rCBF 50 Reduced rCBF in left caudate and anterior cingulate 20 Decrease in striatal, frontal, and temporal regions 1 Focal reduction of rCBF in left basal ganglia 6 Hypoperfusion in right basal ganglia 27 TS, 11 CMT Left-sided abnormalities more common in TS 38 Lower left caudate perfusion and other changes 5 No difference 11 15% reduction in frontal cortex, cingulate cortex, insular cortex, and ventral striatum 16 Reduction in limbic cortex and striatum; hypermetabolism of sensorimotor cortex 18 Similar to above finding

Eidelberg et al. [40] 1997 FDG

PET

10

Stern et al. [41]

2000 [15O]H2O

PET

6

Jeffries et al. [43]

2002 FDG

PET

18

Lerner et al. [42]

2007 [15O]H2O

PET

9

Results

Comments

Did not correlate with symptom type or severity Case report (no control) Compared to cerebellum Visual interpretation of scans only

Drug-free patients

May have been a re-publication of the same data set Increase in sensorimotor activity; decrease in Scaled subprofile mapping to caudate and thalamic activity identify “networks” of activity Tics activated the sensorimotor, language, Serial scanning to improve executive, and paralimbic regions temporal resolution Ventral striatal connections were most different from those of controls The main abnormal area in “tic release” Used Stage 2 sleep as control situation was the cerebellum

particularly pronounced in the ventral part of the striatum. A similar finding was reported by the same group [39], but it is unclear whether or not this is a replication of the finding or a republication of the same data set. Turjanski et al. [3] reported on FDG-PET in 15 patients who were also in a raclopride study (vide supra). They specifically looked at caudate and putamen and found no differences between patients and controls. Eidelberg et al. [40] used the same methodology in 10 TS patients and found that, globally, there were no differences between patients and controls. However, they used a technique called Scaled Subprofile Modeling to identify “networks” involved in TS. This method is akin to factor analysis and identified two “factors”: an increase in activity in sensorimotor cortices and midbrain, and a decrease in caudate and thalamic metabolism. PET has also been used to elucidate the pathophysiology of tics themselves. Stern et al. [41] performed serial scanning on six adults with TS. The radionuclide in this study was [15O]H2O. The patients were all videotaped and audiotaped during the scanning process, and each patient was scanned 12 times. Tics produced widespread activation in the sensorimotor, language, executive, and paralimbic regions of the brain. One patient with coprolalia demonstrated that a different group of regions was activated by his coprolalia compared to the group of regions activated by his vocal tics. These regions included

prerolandic and postrolandic language areas, insula, caudate, thalamus, and cerebellum. Lerner et al. [42] used [15O]H2O as PET nuclide to look at the neural mechanisms around tic generation in nine TS patients and matched controls. They used sleep as control to minimize the effect of “wanting to tic” or “tic suppression” as background noise. This condition has previously been used in imaging studies of dystonia. The active paradigm for the patients was “tic release.” The main areas associated with tic release were cerebellum and insula, and the authors go on to suggest that cerebellar abnormality may be the primary problem in TS. They then go on to support their idea by suggesting that the reason that deep brain stimulation in the thalamus may be effective is that it interrupts the major connections between the cerebellum and the striatum. As imaging techniques become more sophisticated, one area of great promise is that of imaging paradigms that examine the relationship between regions of interest. Jeffries et al. [43] used [18F]deoxyglucose and compared 18 TS patients (off drugs) with 16 controls. They were looking particularly at connectivity between regions. Using Pearson Product–Moment Correlation Coefficient, they ascertained which areas of the brain had connectivities that were most unlike those of the controls. Interestingly, the area of the brain that was connected most differently in the TS groups was the ventral striatal area (this was the only area where the connectivity was more than 3 S.D. from the mean of the

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normal distribution in controls). The main differences in striatal connectivity were in relation to motor cortices, but also to the cerebellum, pons, and caudal part of the orbitofrontal cortex. The insula also appeared to be significantly differently connected in the TS group. An overview of the whole study suggests a broad range of differences between the functional connectivity of TS brains and the functional connectivity of normal brains. The fact that the differences were most pronounced in the ventral striatum fits well with the idea of TS being a disorder that crosses over the boundary between motor and emotional functions. In addition, the involvement of the cerebellum in this study casts doubt over the utility of using the cerebellum as a “control” region when looking at the activity of other regions. Summary of region-of-interest studies There are no specific replicated findings in this series of studies. However, a general overview of all studies points towards a general reduction in the activity of the striatum in TS when compared to controls. This applies particularly to the left striatal structures. Two studies indicate increased higher levels of activity in the sensorimotor cortices, which are not particularly surprising in a motor disorder. The connectivity study indicated that the brain areas involved may center on the ventral striatum but include a number of areas and pathways outside the CSTC pathways. fMRI studies There are a number of fMRI studies, all using slightly different but specific paradigms. These are described below. Peterson et al. [44] used the paradigm of tic suppression to study adults with TS using fMRI (Table 4). They found 22

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adults without significant head tics and who could voluntarily suppress their tics. They scanned them during tic suppression and “free expression of tics.” The results showed widespread differences between the “suppression” and the “free expression.” Post hoc analyses of basal ganglia structures indicated decreased activity in the ventral globus pallidus and putamen. Increased activity was seen in the ventral head of the right caudate nucleus. Biswal et al. [45] used a finger-tapping test to examine the organization of the sensorimotor cortex in TS. The task involved tapping the thumb and forefinger together in a rhythmic self-paced fashion. Only the sensorimotor and supplementary motor cortices were examined on a “pixel-bypixel” basis. Only five patients with TS were examined alongside five matched controls, but the TS patients tended to activate more pixels and over a wider geographical area than the controls. It is difficult to see what conclusion can be drawn from these data, except to say that cortical motor organization is somehow different in people with TS. Hershey et al. [46] attempted to stimulate dopaminergic activity in the brain by utilizing the Working Memory Test (WMT), as well as levodopa stimulation, individually and combined. This complicated design showed that brain areas responded differently to the WMT according to whether or not the subject had been pretreated with levodopa, although in only eight patients. In general, levodopa served to normalize the exaggerated WMT responses seen in the TS group, although there were no clear group differences found. Gates et al. [47] studied a single 15-year-old patient with a matched control who had regular phonic tics but no head tics. The control mimicked tics at roughly the same interval as the patient. A variety of areas were preferentially activated by the patient, including caudate, cingulate, cuneus, left angular gyrus, left inferior parietal gyrus, and occipital gyrus. The

Table 4 fMRI studies Authors

Date

N (TS)

Paradigm

Result

Comments

Peterson et al. [44]

1998

22

Tic suppression

Biswal et al. [45]

1998

5

Finger tapping

Hershey et al. [46]

2004

8

WMT±levodopa

Gates et al. [47]

2004

1

Control mimicked tics

Fattaposta et al. [48] Marsh et al. [49]

2005 2007

1 66

Regular and unusual motor tasks Stroop test

Recovery of fMRI 15 s after vocal tics Subject was a skilled kickboxer Cross-sectional study

Bohlhalter et al. [51]

2006

10

Event-related

Baym et al. [52]

2008

18

Cognitive task

Church et al. [53]

2009

33

Functional connectivity

Suppression related to decreased activity in globus pallidus and putamen; increase in ventral right caudate activity Greater activation of sensorimotor cortex with motor task L-Dopa normalized exaggerated WMT responses in TS cases Activation in caudate, cingulate, cuneus, and other areas SMA activation in both tasks in TS patients Subjects failed to activate frontostriatal systems with age Paralimbic and sensory areas associated with urge to tic Activation of direct pathway in TS; prefrontal area activated by task Failure of TS patients to develop age-appropriate connectivity

First image 2 s before tic Not controlled for sex

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researchers used “fuzzy clustering” analysis. Of greater interest were the data about signal decay that this study developed following a vocalization. It took between 10 and 15 s after vocalization for the fMRI to normalize. Another study with a single patient and a control utilized an unusual patient with TS who was also an expert kickboxer [48]. The participants were asked to perform a regular task (index finger tapping) and an unusual task (little finger tapping). The supplementary motor area (SMA) was expected to be activated during relatively unusual tasks. However, the TS patient showed SMA activation in both usual task and unusual task. However, the unusual skills of the subject may have acted as a confounder. The largest fMRI study to date was published by Marsh et al. [49]. They used the Stroop test [50] as an activation task. The rationale behind this choice was that the Stroop test preferentially activates frontostriatal systems, it improves with age, and deactivations of the “default mode” system (governed by the ventral and posterior cingulate cortices) became more prominent with age. The researchers used a cross-sectional sample of 66 people with TS to examine whether the normal changes with age are also seen in the TS group. Their rationale is slightly undermined by the lack of any evidence for impairment in people with TS in the Stroop test. However, there were clear age-related differences between subjects and controls. In particular, the posterior cingulate cortex became relatively deactivated with age in controls, but not in TS patients. Also, the frontostriatal circuits became more activated with age in controls, but not in the subjects, indicating a possible problem with maturation and lending support to their a priori hypothesis. The cross-sectional design of this study limits the validity of the findings, but nevertheless suggests future avenues for research (ideally, serial scanning of a cohort of TS patients into adulthood). Bohlhalter et al. [51] used a creative methodology to ascertain the neural substrate of the period just before tics are clinically apparent. The aim of this study was to look at two time periods (2 s prior to the tic compared to the tic itself). Just prior to the tic, a group of areas, including the anterior cingulate, insula, and parietal operculum, was activated. During the tic itself, the activity was relatively high in the superior parietal area and cerebellum on both sides. One possible criticism of this study is that, clinically, 2 s is quite a long time to experience a premonitory sensation; many people experience premonitory sensations for between 0.5 and 1 s. Baym et al. [52] used a “cognitive control” task to compare subjects with TS to matched controls (although they were not matched for sex). The cognitive task involved set shifting, response selection, and rule representation, and those with severe tics found these tasks to be more difficult. The TS subjects engaged the prefrontal cortex more actively while performing the cognitive tasks than did the controls, although there were no group differences in the striatum.

Recently developed fMRI techniques have enabled functional connectivity between regions to be established. Church et al. [53] looked at resting-state functional connectivity MRI in 33 adolescent TS patients. This is a way of looking at changes in brain “systems” rather than areas. There are two networks involved with “task control.” These are the “cingulo-opercular” network and the ”frontoparietal” network. Control work has shown how these networks mature normally, and this can be used as control data. A general finding from this type of research is that specific brain regions can “move” from one network to another through the process of maturity. According to the study of Church et al., these developmental transitions do not appear to take place in TS; this means that TS brain connectivity looks “younger” than the age of the patient would suggest. A typical adolescent TS brain would have the connectivity of a 7- to 9-year-old. When you compare adolescents with TS to age-matched controls, frontoparietal connectivity is most different between the groups. These differences have also been reported in autism and attention deficit/hyperactivity disorder. Summary of fMRI In the author's view, the fMRI studies do not provide a clear and consistent picture of brain activity in TS. Studies of connectivity implicate regions of the brain well outside those of conventional CSTC circuits and should lead to a reappraisal of these circuits as being central in the pathogenesis of TS. fMRI work that is focused on the developmental aspects of connectivity shows a great deal of promise and indicates that TS brains are “immature.” In an ideal world, serial scanning of at-risk individuals throughout development would provide the clearest “window on the brain,” but this is logistically complex and prohibitively expensive.

Conclusions Generally, functional neuroimaging in TS is in its infancy. Spatial resolution is poor on the whole but improving, particularly with coutilization of functional and structural methodologies. It is unlikely that TS is a manifestation of a specific malfunction of a detectable neurotransmitter or its receptors. Therefore, summary comments are largely restricted to generalities; there is a preponderance of changes on the left side of the brain. Most brain regions have been implicated, but more commonly the striatum, particularly the ventral portion. In general, there is evidence of hypoactivity of the basal ganglia and hyperactivity of the motor/premotor areas, which fits in with structural neuroimaging findings. Within the basal ganglia, there is insufficient acuity of the scanning process to test models such as Mink's model of dysfunctional striatal matrisomes [54]. However, many

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studies contained subtle biases that favored the discovery of basal ganglia abnormalities over abnormalities in other regions (particularly the use of other regions as “control” areas, the specific use of slices that contain predominantly basal ganglia, and the restriction of areas of interest to the basal ganglia only). No clear endophenotype has emerged from scanning studies, which could be correlated to factor analyses of symptom clusters or to genetic data. So far, no single finding has been reliably replicated in this area. TS is a dynamic illness involving different systems of the brain, so studies that use specific pharmacological or cognitive stimulation paradigms are more likely to yield success in the future. Although the pathology of TS may be focal, functional brain changes are widespread, involve many different areas and systems, and are extremely complex. The only study to timelock tics to brain function [37] clearly shows this. Although a number of studies implicate the basal ganglia in the pathogenesis of TS, no study clearly implicates the CSTC circuitry as a whole, and some studies implicate completely different areas such as the cerebellum. Further studies that are likely to yield fruitful results in the future will involve better temporal resolution (to “timelock” tics or tic suppression), better spatial resolution (to subdivide the striatum and other brain areas and to examine pathways that connect regions), and specific targeting of brain systems using cognitive or pharmacological stimulation. It looks likely that MRI will be the most useful scanning modality in the foreseeable future. In the future, these designs may lead to better classification and subgrouping of TS. The design of imaging studies will, in turn, be influenced by the current work on factor analysis, in an iterative process. Clearer clinical phenotypes or endophenotypes could feed into genetic studies. Imaging could lead to better prediction of treatment response and could also be used to explore the neural substrate of people with TS. Finally, multimodal imaging (e.g., fMRI and magnetoencephalography) may increase resolution. However, it may be that our current processes lack sufficient acuity to answer the basic etiological questions about TS. We may still have a long walk through the foothills before the real mountains appear in front of us. Acknowledgments I would like to thank Dr. Andrea Cavanna for help with the discussion and for his endless enthusiasm. References [1] Stefan H, Pawlick G, Bocher-Schwarz HG, et al. Functional and morphological abnormalities temporal lobe epilepsy: a comparison of interictal and ictal EEG. J Neurol 2007;134:377–84. [2] Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in post-mortem striatum from patient's with Tourette syndrome. Ann Neurol 1991;30:558–62.

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