The Development of Cognitive Function in Tourette Syndrome: fMRI Studies

Bradley L. Schlaggar, M.D., Ph.D.

Washington University School of Medicine

Funded in February, 2002: $100000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

back to top

Using Imaging to Explore the Basis of Some Developmental Disorders

Tourette Syndrome is a rare but socially devastating developmental disorder, in which affected children impulsively have inappropriate actions, such as blurting out swear words. Understanding how to treat developmental conditions requires that we gain an understanding of how normal cognitive development occurs and how this is altered in various disease states.

The researchers hypothesize that some developmental disorders such as Tourette Syndrome are associated with faulty cognitive control processes in certain brain regions. The investigators further hypothesize that in healthy children both “brain-state” activities (such as recalling memories) and “item-specific” activities (such as recalling a specific memory) are tied to cognitive control, while in children with Tourette Syndrome, control is tied only to brain-state activities.  They will use fMRI to explore these hypotheses.

ABSTRACT

back to top

The Development of Cognitive Function in Tourette Syndrome: fMRI Studies

Cognitive control generally refers to putative brain processes that serve to link or unify the functions of anatomically distinct cognitive modules (Posner 1978).  Little is known about the functional neuroanatomy of cognitive control in children.  Abnormal cognitive control has substantial clinical relevance. Common pediatric neuropsychiatric disorders are thought to be due, in part, to dysfunction of control. For example, Tourette Syndrome (TS), a genetic neurological disorder with pediatric onset manifest as chronic tics, is associated with impulsivity and aberrant cognitive control. To understand the functional neuroanatomy that underlies the executive dysfunction in TS, further information about the normal development of control processes needs to be obtained.

This proposal has two major components.  First, it addresses a previously unexplored aspect of cognitive development: the timing, location, and pattern of brain regions involved in cognitive control through the use of recently-developed mixed state/item fMRI designs (Donaldson et al. 2001). Brain regions performing cognitive functions can be thought to have both sustained and transient activity, reflecting state- and item-related processing, respectively. Here, “state” refers to a task mode (e.g., the state of recalling memories) and “item” refers to a particular event (recalling a specific memory).  If control is intimately linked to the establishment of a brain-state, then brain regions serving cognitive control may well demonstrate sustained activity during task performance and show state-related interaction effects on item activity. 

Second, this proposal applies the context afforded by our studies on normal subjects to a population of patients (TS) with suspected executive dysfunction.  To date, no published study using functional neuroimaging has explored, across development, the functional neuroanatomy of cognitive control in TS or in any other condition attributable to executive dysfunction. We hypothesize that compared to normal subjects, those with a disorder of cognitive control will demonstrate differential involvement of both state- and item-related activity in the frontal cortex, a brain region widely implicated in cognitive control.

INVESTIGATOR BIOGRAPHIES

back to top
Bradley L. Schlaggar, M.D., Ph.D.

Assistant Professor of Neurology, Radiology, Anatomy & Neurobiology, and Pediatrics

HYPOTHESIS

back to top

Hypothesis:
1. Brain regions in the frontal cortex implicated in controlled cognitive processing in normal adults should demonstrate different developmental profiles when children with Tourette Syndrome (TS) are compared with normal children.
2. Differential involvement of state (i.e., sustained) and item (i.e., transient) -related brain activity will be demonstrable in children with TS, compared to normal children when studied with functional magnetic resonance imaging (fMRI) technology.

Goals
1. To perform developmental studies using recently developed mixed fMRI designs that allow direct imaging of "state" and "item" signals.
2. To apply mixed fMRI designs on patients with TS to test the hypothesis that the fictional neuroanatomy of cognitive control in TS will differ from normal subjects with respect to state and/or item effects.

Methods:
In this study a whole-brain fMRI, using standard EPI and MPRAGE sequences on a 1.5 Tesla (Siemans) scanner, will be employed to generate brain activation images elicited by the performance of lexical processing tasks in normal children and adults, and then in child and adult TS patients.  Subjects are required to apply a rule to a word when it is presented as a stimulus and, in this case, overtly generate a single word response.  These experiments will implement a mixed event- and blocked design.  Subject responses and reaction times will be recorded and measured.  Several types of controlled processing tasks with verbal and button-press responses will be used.

FINDINGS

back to top

Lay Results:
We have found, using fMRI imaging, that adults activate different regions of their brains compared to children when they generate words.  This finding grew out of a Dana-funded study to determine how brain signals control the normal generation of words and how this control malfunctions in children with the developmental disorder called Tourette’s Syndrome, who sometimes utter inappropriate words, such as obscenities.  Using fMRI to learn first how normal cognitive control occurs in healthy children and adults as they generate words, the researchers found that adults activate different brain regions compared to children.  The Dana-funded research has established the validity of fMRI in studying changes in brain activation that occurs over time as the brain matures.

Scientific Results:

  1. The mixed blocked/event-related fMRI design is feasible for directly comparing children and adults (Wenger et al. 2004).
  2. When applied to a cognitive task paradigm, this design can help disambiguate developmental differences seen in prior event-related and blocked paradigms (Burgund et al 2006).
  3. Ongoing analysis of children/teens with Tourette Syndrome versus age-matched controls reveals interesting differences in trial-related and sustained activity.  We are currently applying regions of interest from our meta-analysis of control demanding tasks studied in adults (Dosenbach et al 2006). 
  4. We are also applying resting state functional connectivity approaches to these data (Fair et al 2007).

SELECTED PUBLICATIONS

back to top

Schlaggar B.L. and McCandliss B.D.  Development of neural systems for reading.  Annu Rev Neurosci. 2007;30:475-503.

Fair D.A., Schlaggar B.L., Cohen A.L., Miezin F.M., Dosenbach N.U.F., Wenger K.K., Fox M.D., Snyder A.Z., Raichle M.E., and Petersen S.E.  A method for using blocked and event-related fMRI data to study "resting state" functional connectivity.  Neuroimage. 2007 Mar;35(1):396-405.

Aslin, R.N. and Schlaggar, B.L.  Is myelination the precipitating neural event for language development in infants and toddlers?   Neurology. 2006 Feb 14;66(3):304-5.

Brown T.T., Petersen S.E., and Schlaggar B.L. Does human functional brain organization shift from different to focal with development?  Dev Sci. 2006 Jan;9(1):9-11.

Fair D., Brown T., Petersen S., and Schlaggar B.L.  fMRI reveals novel functional neuroanatomy in a child with perinatal stroke. Neurology. 2006 Dec 26;67(12):2246-9.

Fair D.A., Brown T.T., Petersen S.E., and Schlaggar B.L.  A comparison of analysis of variance and correlation methods for investigating cognitive development with fMRI.   Dev Neuropsychol. 2006;30(1):531-46.

Dosenbach N.U.F., Visscher K.M., Palmer E.D., Miezin F.M., Wenger K.K., Kang H.C., Burgund E.D., Grimes A.L., Schlaggar B.L., and Petersen S.E.   A core system for the implementation of task sets.  Neuron. 2006 Jun 1;50(5):799-812.

Burgund E.D., Lugar H.M., Miezin F.M., Schlaggar B.L., and Petersen S.E.  The development of sustained and transient neural activity.  Neuroimage. 2006 Feb 1;29(3):812-21.

Burgund E.D., Lugar H.M., Schlaggar B.L., and Petersen S.E.  Task demands modulate sustained and transient neural activity during visual-matching tasks.  Neuroimage. 2005 Apr 1;25(2):511-9.

Brown T.T., Lugar H.M., Coalson R.S., Miezin, F.M., Petersen, S.E., and Schlaggar, B.L.  Developmental changes in human cerebral functional organization for word generation  Cereb Cortex. 2005 Mar;15(3):275-90.

Wenger K.K., Visscher K.M., Miezin F.M., Petersen S.E., and Schlaggar B.L.  Comparison of sustained and transient activity in children and adults using a mixed blocked/event-related fMRI design.  Neuroimage. 2004 Jun;22(2):975-85.