244
| BRAIN 2015: 138; 238–245
levodopa-induced dyskinesia? Mov Disord 2012; 27: 339–40. Cerasa A, Messina D, Pugliese P, Morelli M, Lanza P, Salsone M, et al. Increased prefrontal volume in PD with levodopa-induced dyskinesias: a voxel-based morphometry study. Mov Disord 2011; 26: 807–12. Cerasa A, Pugliese P, Messina D, Morelli M, Gioia MC, Salsone M, et al. Prefrontal alterations in Parkinson’s disease with levodopainduced dyskinesia during fMRI motor task. Mov Disord 2012; 27: 364–71. Cerasa A, Koch G, Donzuso G, et al. A network centred on the inferior frontal cortex is critically involved in levodopainduced dyskinesias. Brain 2015; 138: 414–27.
Scientific Commentaries Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000, 47 (Suppl 1): 2–9. Gross RE, Lombardi WJ, Lang AE, Duff J, Hutchison WD, Saint-Cyr JA, et al. Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson’s disease. Brain 1999; 122: 405–16. Lees A, Tolosa E, Olanow CW. Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias and Melvin Yahr. Mov Disord 2015; 30: 3–6. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, DeLong MR, Olanow CW. Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the
current model. Ann Neurol 2000, 47 (4 Suppl 1): 22–32. Page RD, Sambrook MA, Crossman AR. Thalamotomy for the alleviation of levodopa-induced dyskinesia: experimental studies in the 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-treated parkinsonian monkey. Neuroscience 1993; 55: 147–65. Pe´rier C, Tremblay L, Fe´ger J, Hirsch EC. Behavioral consequences of bicuculline injection in the subthalamic nucleus and the zona incerta in rat. J Neurosci 2002; 22: 8711–19. Rascol O, Sabatini U, Brefel C, Fabre N, Rai S, Senard JM, et al. Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia. Brain 1998; 121: 527–33.
This scientific commentary refers to ‘Altered structural connectivity of cortico-striato-pallido-thalamic networks in Gilles de la Tourette syndrome’ by Worbe et al. (doi:10.1093/brain/ awu311). Tourette syndrome is a developmental disorder of childhood onset characterized by the presence of involuntary, recurring movements and utterances known as tics. It is more prevalent in boys than in girls (4:1) and typically follows a developmental time course in which, in the majority of individuals, tics are either absent or mild by early adulthood. Adults with Tourette syndrome can thus be viewed as unrepresentative of the more general Tourette population (i.e. children and adolescents with the disorder), but nevertheless constitute an important group in which the clinical phenotype is stable and the compensatory plastic changes thought to bring about increased control over tic severity during adolescence (Jackson et al., 2011) have either failed to occur or have been ineffective.
While the neurobiology of Tourette syndrome is unclear, it is thought to involve disinhibition of cortico-striatothalamo-cortical (CSTC) circuits, which are a connected set of brain structures involved in the planning and execution of movements (Albin and Mink, 2006) and in the formation of habits (Graybiel, 2008). The responsiveness of neurons in the striatum depends upon the salience of perceived stimuli, which can either be rewarding or aversive (Blazquez et al., 2002), and repeated exposure to the same salient stimuli is thought to result in a particular response being reinforced to produce a habit. It is hypothesized that in Tourette syndrome this habit formation process is over-extended (Graybiel, 2008) with neurons in the striatum becoming active in inappropriate contexts leading to disinhibition within thalamic and cortical target regions and resulting in unwanted actions becoming reinforced as tics (Albin and Mink, 2006). In a new paper published in Brain Worbe et al. (2014) add to our understanding of this process by examining alterations in connectivity
within the CSTC pathways in adults with Tourette syndrome. During the last decade a number of imaging studies have investigated abnormalities in the brain structure of individuals with Tourette syndrome. However, the results from these studies have been mixed, with many inconsistent or seemingly contradictory findings reported (Thomalla et al., 2009; Jackson et al., 2011; Cheng et al., 2014). Several factors are likely to contribute to these mixed results. For instance, previous studies have often drawn conclusions based upon samples with quite different characteristics. These include the presence of co-morbid disorders, differences in medication, and most importantly differences in age. Furthermore, many previous studies have failed to distinguish between alterations in structural connectivity that may be seen as primary causes of Tourette syndrome, and those that should be considered as secondary consequences, associated with compensatory or adaptive changes that aid in the control of clinical symptoms.
Downloaded from by guest on April 30, 2015
Alterations in structural connectivity may contribute both to the occurrence of tics in Gilles de la Tourette syndrome and to their subsequent control
Scientific Commentaries
group with Tourette syndrome, there was enhanced structural connectivity in the white matter tracts linking the striatum and thalamus with cortical structures, including primary motor cortex, primary somatosensory cortex, and supplementary motor area. Importantly, consistent with the previous structural neuroimaging studies of adolescents with Tourette syndrome, this enhanced connectivity of the motor cortex was positively associated with increased motor tic severity. One final intriguing aspect of the study reported by Worbe et al. relates to the gender composition of their sample of adults with Tourette syndrome. As noted above, in child and adolescent samples the ratio of boys to girls is typically 4:1, but in the study by Worbe and colleagues, the ratio of females to males is closer to parity. This observation is consistent with the recent suggestion that the childhood gender bias for boys is attenuated in adulthood (Lichter and Finnegan, 2014). This may indicate that females with Tourette syndrome are less likely to undergo remission of tics during adolescence. It has been proposed that females may experience greater functional interference from tics than males (Lichter and Finnegan, 2014). Consistent with this proposal, Worbe et al. report the novel finding that females with Tourette syndrome have increased connectivity in CSTC pathways compared to males, which may contribute to increased tic severity. Amelia Draper and Stephen R. Jackson School of Psychology, University of Nottingham, Nottingham NG7 2RD
Correspondence to: Stephen R. Jackson, E-mail: stephen.jackson@nottingham. ac.uk
| 245
doi:10.1093/brain/awu338
References Albin RL, Mink JW. Recent advances in Tourette syndrome research. Trends Neurosciences 2006; 29: 175–82. Blazquez PM, Fujii N, Kojima J, Graybiel AM. A network representation of response probability in the striatum. Neuron 2002; 33: 973–82. Cheng B, Braass H, Ganos C, Treszl A, Biermann-Ruben K, Hummel FC, et al. Altered intrahemispheric structural connectivity in Gilles de la Tourette syndrome. Neuroimage Clin 2014; 7: 174–81. Draper A, Stephenson MC, Jackson GM, Pepes S, Morgan PS, Morris PG, et al. Increased GABA contributes to enhanced control over motor excitability in tourette syndrome. Curr Biol 2014; 24: 2343–7. Graybiel AM. Habits, rituals, and the evaluative brain. Ann Rev Neurosci 2008; 31: 359–87. Jackson SR, Parkinson A, Jung J, Ryan SE, Morgan PS, Hollis C, et al. Compensatory neural reorganizaton in tourette syndrome. Curr Biol 2011; 21: 580–5. Lichter DG, Finnegan SG. Influence of gender on Tourette syndrome beyond adolescence. Eur Psychiatr 2014. Advance Access published on September 2, 2014, doi:10.1016/ j.eurpsy.2014.07.003. Plessen JK, Gruner R, Lundervold A, Hirsch JG, Xu D, Bansal R, et al. Reduced white matter connectivity in the corpus callosum of children with Tourette syndrome. J Child Psychol Psychiatr 2006; 47: 1013–22. Thomalla G, Siebner HR, Jonas M, Baumer T, Biermann-Ruben K, Hummel F, et al. Structural changes in the somatosensory system correlate with tic severity in Gilles de la Tourette syndrome. Brain 2009; 132: 765–77. Worbe Y, Marrakchi-Kacem L, Lecomte S, Valabregue R, Poupon F, Guevara P, et al. Altered structural connectivity of corticostriato-pallido-thalamic networks in Gilles de la Tourette syndrome. Brain 2015; 138: 472–82.
Downloaded from by guest on April 30, 2015
One finding that has consistently emerged from studies in children and adolescents with Tourette syndrome is that alterations in the microstructure of white matter pathways projecting to sensorimotor regions of cortex, such as reduced white matter connectivity in the corpus callosum (Plessen et al., 2006) or reduced fractional anisotropy (a measure of white matter microstructure) again in the corpus callosum (Jackson et al., 2011; Draper et al., 2014), are paradoxically associated with reductions in tic severity. These results have most often been interpreted as evidence for compensatory alterations in brain structure that aid in the control of clinical symptoms. By contrast, studies of adults with Tourette syndrome have reported a different pattern of results. Thomalla et al. (2009) described widespread increases in fractional anisotropy values in white matter pathways projecting to primary sensory and motor cortex in adults with the disorder and demonstrated that fractional anisotropy values in these pathways were negatively associated with tic severity. Similarly, Cheng et al. (2014) reported a negative association between white matter integrity and tic severity in pathways that connect the striatum to the supplementary motor area, but they also demonstrated reduced CSTC connectivity in their group of adults with Tourette syndrome. The study by Worbe et al. (2014) provides important new information on this issue. Worbe and colleagues use high-resolution diffusion tensor imaging, together with probabilistic tractography techniques, to examine the connectivity of white matter tracts in a large sample of 49 adults with Tourette syndrome, and a group of individuals without neurological disorders and of comparable age. In the
BRAIN 2015: 138; 238–245
| BRAIN 2015: 138; 238–245
levodopa-induced dyskinesia? Mov Disord 2012; 27: 339–40. Cerasa A, Messina D, Pugliese P, Morelli M, Lanza P, Salsone M, et al. Increased prefrontal volume in PD with levodopa-induced dyskinesias: a voxel-based morphometry study. Mov Disord 2011; 26: 807–12. Cerasa A, Pugliese P, Messina D, Morelli M, Gioia MC, Salsone M, et al. Prefrontal alterations in Parkinson’s disease with levodopainduced dyskinesia during fMRI motor task. Mov Disord 2012; 27: 364–71. Cerasa A, Koch G, Donzuso G, et al. A network centred on the inferior frontal cortex is critically involved in levodopainduced dyskinesias. Brain 2015; 138: 414–27.
Scientific Commentaries Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000, 47 (Suppl 1): 2–9. Gross RE, Lombardi WJ, Lang AE, Duff J, Hutchison WD, Saint-Cyr JA, et al. Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson’s disease. Brain 1999; 122: 405–16. Lees A, Tolosa E, Olanow CW. Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias and Melvin Yahr. Mov Disord 2015; 30: 3–6. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, DeLong MR, Olanow CW. Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the
current model. Ann Neurol 2000, 47 (4 Suppl 1): 22–32. Page RD, Sambrook MA, Crossman AR. Thalamotomy for the alleviation of levodopa-induced dyskinesia: experimental studies in the 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine-treated parkinsonian monkey. Neuroscience 1993; 55: 147–65. Pe´rier C, Tremblay L, Fe´ger J, Hirsch EC. Behavioral consequences of bicuculline injection in the subthalamic nucleus and the zona incerta in rat. J Neurosci 2002; 22: 8711–19. Rascol O, Sabatini U, Brefel C, Fabre N, Rai S, Senard JM, et al. Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia. Brain 1998; 121: 527–33.
This scientific commentary refers to ‘Altered structural connectivity of cortico-striato-pallido-thalamic networks in Gilles de la Tourette syndrome’ by Worbe et al. (doi:10.1093/brain/ awu311). Tourette syndrome is a developmental disorder of childhood onset characterized by the presence of involuntary, recurring movements and utterances known as tics. It is more prevalent in boys than in girls (4:1) and typically follows a developmental time course in which, in the majority of individuals, tics are either absent or mild by early adulthood. Adults with Tourette syndrome can thus be viewed as unrepresentative of the more general Tourette population (i.e. children and adolescents with the disorder), but nevertheless constitute an important group in which the clinical phenotype is stable and the compensatory plastic changes thought to bring about increased control over tic severity during adolescence (Jackson et al., 2011) have either failed to occur or have been ineffective.
While the neurobiology of Tourette syndrome is unclear, it is thought to involve disinhibition of cortico-striatothalamo-cortical (CSTC) circuits, which are a connected set of brain structures involved in the planning and execution of movements (Albin and Mink, 2006) and in the formation of habits (Graybiel, 2008). The responsiveness of neurons in the striatum depends upon the salience of perceived stimuli, which can either be rewarding or aversive (Blazquez et al., 2002), and repeated exposure to the same salient stimuli is thought to result in a particular response being reinforced to produce a habit. It is hypothesized that in Tourette syndrome this habit formation process is over-extended (Graybiel, 2008) with neurons in the striatum becoming active in inappropriate contexts leading to disinhibition within thalamic and cortical target regions and resulting in unwanted actions becoming reinforced as tics (Albin and Mink, 2006). In a new paper published in Brain Worbe et al. (2014) add to our understanding of this process by examining alterations in connectivity
within the CSTC pathways in adults with Tourette syndrome. During the last decade a number of imaging studies have investigated abnormalities in the brain structure of individuals with Tourette syndrome. However, the results from these studies have been mixed, with many inconsistent or seemingly contradictory findings reported (Thomalla et al., 2009; Jackson et al., 2011; Cheng et al., 2014). Several factors are likely to contribute to these mixed results. For instance, previous studies have often drawn conclusions based upon samples with quite different characteristics. These include the presence of co-morbid disorders, differences in medication, and most importantly differences in age. Furthermore, many previous studies have failed to distinguish between alterations in structural connectivity that may be seen as primary causes of Tourette syndrome, and those that should be considered as secondary consequences, associated with compensatory or adaptive changes that aid in the control of clinical symptoms.
Downloaded from by guest on April 30, 2015
Alterations in structural connectivity may contribute both to the occurrence of tics in Gilles de la Tourette syndrome and to their subsequent control
Scientific Commentaries
group with Tourette syndrome, there was enhanced structural connectivity in the white matter tracts linking the striatum and thalamus with cortical structures, including primary motor cortex, primary somatosensory cortex, and supplementary motor area. Importantly, consistent with the previous structural neuroimaging studies of adolescents with Tourette syndrome, this enhanced connectivity of the motor cortex was positively associated with increased motor tic severity. One final intriguing aspect of the study reported by Worbe et al. relates to the gender composition of their sample of adults with Tourette syndrome. As noted above, in child and adolescent samples the ratio of boys to girls is typically 4:1, but in the study by Worbe and colleagues, the ratio of females to males is closer to parity. This observation is consistent with the recent suggestion that the childhood gender bias for boys is attenuated in adulthood (Lichter and Finnegan, 2014). This may indicate that females with Tourette syndrome are less likely to undergo remission of tics during adolescence. It has been proposed that females may experience greater functional interference from tics than males (Lichter and Finnegan, 2014). Consistent with this proposal, Worbe et al. report the novel finding that females with Tourette syndrome have increased connectivity in CSTC pathways compared to males, which may contribute to increased tic severity. Amelia Draper and Stephen R. Jackson School of Psychology, University of Nottingham, Nottingham NG7 2RD
Correspondence to: Stephen R. Jackson, E-mail: stephen.jackson@nottingham. ac.uk
| 245
doi:10.1093/brain/awu338
References Albin RL, Mink JW. Recent advances in Tourette syndrome research. Trends Neurosciences 2006; 29: 175–82. Blazquez PM, Fujii N, Kojima J, Graybiel AM. A network representation of response probability in the striatum. Neuron 2002; 33: 973–82. Cheng B, Braass H, Ganos C, Treszl A, Biermann-Ruben K, Hummel FC, et al. Altered intrahemispheric structural connectivity in Gilles de la Tourette syndrome. Neuroimage Clin 2014; 7: 174–81. Draper A, Stephenson MC, Jackson GM, Pepes S, Morgan PS, Morris PG, et al. Increased GABA contributes to enhanced control over motor excitability in tourette syndrome. Curr Biol 2014; 24: 2343–7. Graybiel AM. Habits, rituals, and the evaluative brain. Ann Rev Neurosci 2008; 31: 359–87. Jackson SR, Parkinson A, Jung J, Ryan SE, Morgan PS, Hollis C, et al. Compensatory neural reorganizaton in tourette syndrome. Curr Biol 2011; 21: 580–5. Lichter DG, Finnegan SG. Influence of gender on Tourette syndrome beyond adolescence. Eur Psychiatr 2014. Advance Access published on September 2, 2014, doi:10.1016/ j.eurpsy.2014.07.003. Plessen JK, Gruner R, Lundervold A, Hirsch JG, Xu D, Bansal R, et al. Reduced white matter connectivity in the corpus callosum of children with Tourette syndrome. J Child Psychol Psychiatr 2006; 47: 1013–22. Thomalla G, Siebner HR, Jonas M, Baumer T, Biermann-Ruben K, Hummel F, et al. Structural changes in the somatosensory system correlate with tic severity in Gilles de la Tourette syndrome. Brain 2009; 132: 765–77. Worbe Y, Marrakchi-Kacem L, Lecomte S, Valabregue R, Poupon F, Guevara P, et al. Altered structural connectivity of corticostriato-pallido-thalamic networks in Gilles de la Tourette syndrome. Brain 2015; 138: 472–82.
Downloaded from by guest on April 30, 2015
One finding that has consistently emerged from studies in children and adolescents with Tourette syndrome is that alterations in the microstructure of white matter pathways projecting to sensorimotor regions of cortex, such as reduced white matter connectivity in the corpus callosum (Plessen et al., 2006) or reduced fractional anisotropy (a measure of white matter microstructure) again in the corpus callosum (Jackson et al., 2011; Draper et al., 2014), are paradoxically associated with reductions in tic severity. These results have most often been interpreted as evidence for compensatory alterations in brain structure that aid in the control of clinical symptoms. By contrast, studies of adults with Tourette syndrome have reported a different pattern of results. Thomalla et al. (2009) described widespread increases in fractional anisotropy values in white matter pathways projecting to primary sensory and motor cortex in adults with the disorder and demonstrated that fractional anisotropy values in these pathways were negatively associated with tic severity. Similarly, Cheng et al. (2014) reported a negative association between white matter integrity and tic severity in pathways that connect the striatum to the supplementary motor area, but they also demonstrated reduced CSTC connectivity in their group of adults with Tourette syndrome. The study by Worbe et al. (2014) provides important new information on this issue. Worbe and colleagues use high-resolution diffusion tensor imaging, together with probabilistic tractography techniques, to examine the connectivity of white matter tracts in a large sample of 49 adults with Tourette syndrome, and a group of individuals without neurological disorders and of comparable age. In the
BRAIN 2015: 138; 238–245
