We thank Erin Douglas, Anna Evans, and Carolyn Bellion for their contributions to participant recruitment and clinical assessment. We also thank Michael Casp, Zoe Englander, Justin Woodlief, and James Carter for their contributions to data collection and analysis, and Robert M. Hamer for consultation on statistical analysis and editing of the manuscript. Finally, we thank the individuals and their families who participated in this study. 
This study was supported by Conte center grant P50 MH064065 from the National Institute of Mental Health. Dr. Hart was supported by T32 HD040127 from the National Institute of Child Health and Human Development.

The research techniques used during this study were approved by the institutional review boards (IRB) of Duke University and the University of North Carolina &#8211; Chapel Hill.
1. Imaging Task Design
<ol>
	<li>Generate an event-based behavioral task that presents infrequent target stimuli (a circle) within a sequence of more-frequent standard stimuli (scrambled images). A schematic of the task is shown in Figure 1. Present the task using CIGAL software10.</li>
<...

<ol>
	<li>Kety, S. S., Rosenthal, D., Wender, P. H., Schulsinger, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mental+illness+in+the+biological+and+adoptive+families+of+adpoted+schizophrenics.">Mental illness in the biological and adoptive families of adpoted schizophrenics.</a> Am J Psyc. 128, 302-306 (1971).</li><li>Weinberger, D. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Implications+of+normal+brain+development+for+the+pathogenesis+of+schizophrenia.">Implications of normal brain development for the pathogenesis of schizophrenia.</a> Arch Gen Psychia. 44, 660-669 (1987).</li><li>Nuechterlein, K. H., Dawson, M. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Information+processing+and+attentional+functioning+in+the+developmental+course+of+schizophrenic+disorders.">Information processing and attentional functioning in the developmental course of schizophrenic disorders.</a> Schizophr Bul. 10, 160-203 (1984).</li><li>Nuechterlein, K. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+vulnerability/stress+model+of+schizophrenic+relapse:+a+longitudinal+study.">The vulnerability/stress model of schizophrenic relapse: a longitudinal study.</a> Acta Psychiatr Scand, Supp. 382, 58-64 .</li><li>Keshavan, M. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Premorbid+cognitive+deficits+in+young+relatives+of+schizophrenia+patients.">Premorbid cognitive deficits in young relatives of schizophrenia patients.</a> Front Hum Neurosc. 3 (62), (2010).</li><li>Kiehl, K. A., Liddle, P. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+event-related+functional+magnetic+resonance+imaging+study+of+an+auditory+oddball+task+in+schizophrenia.">An event-related functional magnetic resonance imaging study of an auditory oddball task in schizophrenia.</a> Schizophr Re. 48, 159-171 (2001).</li><li>Bramon, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Is+the+P300+wave+an+endophenotype+for+schizophrenia?+A+meta-analysis+and+a+family+study.">Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study.</a> Neuroimag. 27, 960-968 (2005).</li><li>Dichter, G. S., Bellion, C., Casp, M., Belger, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Impaired+modulation+of+attention+and+emotion+in+schizophrenia.">Impaired modulation of attention and emotion in schizophrenia.</a> Schizophr Bul. 36, 595-606 (2010).</li><li>Fichtenholtz, H. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Emotion-attention+network+interactions+during+a+visual+oddball+task.">Emotion-attention network interactions during a visual oddball task.</a> Brain Res Cogn Brain Re. 20, 67-80 (2004).</li><li>Voyvodic, J. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Real-time+fMRI+paradigm+control,+physiology,+and+behavior+combined+with+near+real-time+statistical+analysis.">Real-time fMRI paradigm control, physiology, and behavior combined with near real-time statistical analysis.</a> Neuroimag. 10, 91-106 (1999).</li><li>Lang, P. J., Bradley, M. M., Cuthbert, B. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> International affective picture system (IAPS): Digitized photographs, instruction manual and affective ratings. Technical Report A-6. , (2005).</li><li>Smith, S. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advances+in+functional+and+structural+MR+image+analysis+and+implementation+as+FSL.">Advances in functional and structural MR image analysis and implementation as FSL.</a> Neuroimag. 23, 208-219 (2004).</li><li>Smith, S. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fast+robust+automated+brain+extraction.">Fast robust automated brain extraction.</a> Hum Brain Map. 17, 143-155 (2002).</li><li>Jenkinson, M., Bannister, P., Brady, M., Smith, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Improved+optimization+for+the+robust+and+accurate+linear+registration+and+motion+correction+of+brain+images.">Improved optimization for the robust and accurate linear registration and motion correction of brain images.</a> Neuroimag. 17, 825-841 (2002).</li><li>Jenkinson, M., Smith, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+global+optimisation+method+for+robust+affine+registration+of+brain+images.">A global optimisation method for robust affine registration of brain images.</a> Med Image Ana. 5, 143-156 (2001).</li><li>Woolrich, M. W., Ripley, B. D., Brady, M., Smith, S. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Temporal+autocorrelation+in+univariate+linear+modeling+of+FMRI+data.">Temporal autocorrelation in univariate linear modeling of FMRI data.</a> Neuroimag. 14, 1370-1386 (2001).</li><li>Beckmann, C. F., Jenkinson, M., Smith, S. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=General+multilevel+linear+modeling+for+group+analysis+in+FMRI.">General multilevel linear modeling for group analysis in FMRI.</a> Neuroimag. 20, 1052-1063 (2003).</li><li>Woolrich, M. W., Behrens, T. E., Beckmann, C. F., Jenkinson, M., Smith, S. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multilevel+linear+modelling+for+FMRI+group+analysis+using+Bayesian+inference.">Multilevel linear modelling for FMRI group analysis using Bayesian inference.</a> Neuroimag. 21, 1732-1747 (2004).</li><li>Genovese, C. R., Lazar, N. A., Nichols, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Thresholding+of+statistical+maps+in+functional+neuroimaging+using+the+false+discovery+rate.">Thresholding of statistical maps in functional neuroimaging using the false discovery rate.</a> Neuroimag. 15, 870-878 (2002).</li><li>Hart, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Altered+fronto-limbic+activity+in+children+and+adolescents+with+familial+high+risk+for+schizophrenia..">Altered fronto-limbic activity in children and adolescents with familial high risk for schizophrenia..</a> Psychiatry Re. 212, 19-27 (2013).</li><li>Hariri, A. R., Bookheimer, S. Y., Mazziotta, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modulating+emotional+responses:+effects+of+a+neocortical+network+on+the+limbic+system.">Modulating emotional responses: effects of a neocortical network on the limbic system.</a> Neurorepor. 11, 43-48 (2000).</li><li>Gottesman, I. I., Gould, T. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+endophenotype+concept+in+psychiatry:+etymology+and+strategic+intentions.">The endophenotype concept in psychiatry: etymology and strategic intentions.</a> Am J Psyc. 160, 636-645 (2003).</li><li>Glahn, D. C., Thompson, P. M., Blangero, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neuroimaging+endophenotypes:+strategies+for+finding+genes+influencing+brain+structure+and+function.">Neuroimaging endophenotypes: strategies for finding genes influencing brain structure and function.</a> Hum Brain Map. 28, 488-501 (2007).</li></ol>

The modified emotional oddball paradigm in the current study has been shown to elicit differences in neural recruitment during selective attention and emotional processing in children and adolescents at risk for schizophrenia. While existing paradigms using the emotional oddball task have been used to investigate neural changes in adult populations with psychiatric illness8, the current paradigm may be particularly useful for measurement of vulnerability markers in younger age groups. 
<p class='jove_conte...

Schizophrenia is a neurodevelopmental disorder with a known genetic component1,2 and with symptoms including deficits in both executive and emotional processing3,4. First-degree relatives are thought to be at an increased risk of developing schizophrenia, and have been shown to share some of these same neurocognitive deficits in both cognitive and social-emotional domains5. We therefore expect that brain activity in regions associated with executive and emotional processing may be altered in at-risk family members preceding the onset of clinical symptoms. 
Previous studies have indicated that both adults with schizophrenia and adults at familial high risk show aberrant activity within executive and emotional processing networks; however it remains unclear how these changes come about during development. Demonstrating that these changes occur early in life will be a critical first step in understanding the pathophysiology of the disorder. Therefore, this study utilizes an emotional oddball paradigm during functional MRI (fMRI) scanning in order to measure brain activity during the completion of a task that requires both executive and emotional processing in adolescents who are at risk for developing schizophrenia. Oddball paradigms are frequently used to examine the function of fronto-striate circuitry in schizophrenia6 and in individuals with familial high risk7 by measuring selective attention processes allocated to task-relevant target stimuli. Here, a standard oddball task has been modified to include task-irrelevant aversive and neutral stimuli that have been shown to elicit changes in brain activity in patients with schizophrenia8. 
This paper measures functional differences between healthy adolescents and adolescents at high familial risk for schizophrenia using an emotional oddball task. The task design is similar to that used by Fichtenholtz and colleagues9, but the selection of aversive emotional images has been modified to be appropriate for children between the ages of 9-18. The use of this task during functional MRI allowed for the identification of specific brain regions that showed patterns of hyperactivation and hypoactivation in children and adolescents with FHR for schizophrenia, in addition to age-related changes in neural activity during adolescent development.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td class="xl63">3T MRI scanner</td>
			<td class="xl63">GE</td>
			<td class="xl63"></td>
			<td class="xl63">BIAC 3T scanner (replaced)</td>
		</tr>
	</tbody>
</table>

measurement of fronto-limbic activity using an emotional oddball task in children with familial high risk for schizophrenia

Adolescence is a critical developmental period where the early symptoms of schizophrenia frequently emerge. First-degree relatives of people with schizophrenia who are at familial high risk (FHR) may show similar cognitive and emotional changes. However, the neurological changes underlying the emergence of these symptoms remain unclear. This study sought to identify differences in frontal, striatal, and limbic regions in children and adolescents with FHR using functional magnetic resonance imaging. Groups of 21 children and adolescents at FHR and 21 healthy controls completed an emotional oddball task that relied on selective attention and the suppression of task-irrelevant emotional information. The standard oddball task was modified to include aversive and neutral distractors in order to examine potential group differences in both emotional and executive processing. This task was designed specifically to allow for children and adolescents to complete by keeping the difficulty and emotional image content age-appropriate. Furthermore, we demonstrate a technique for suitable fMRI registration for children and adolescent participants. This paradigm may also be applied in future studies to measure changes in neural activity in other populations with hypothesized developmental changes in executive and emotional processing.

There were no differences between groups based on demographic characteristics20. Behavioral data indicated that the target detection task is at an appropriate level of difficulty for children and adolescents between the ages of 9-18. In the current study, controls correctly identified 82.36% of targets (S.D. = 0.14), and the familial risk group correctly identified 76.8% of targets (S.D. = 0.17). Both groups showed decreased accuracy when identifying emotional pictures compared to neutral pic...

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Measurement of Fronto-limbic Activity Using an Emotional Oddball Task in Children with Familial High Risk for Schizophrenia

This paper describes how to use the emotional oddball task and fMRI to measure brain activation in children and adolescents at familial high risk for schizophrenia (FHR).&#160;FMRI was used to measure differences in fronto-striato-limbic regions during an emotional oddball task. Children with FHR exhibited abnormal functional activation during adolescence.

Adolescence is a critical developmental period where the early symptoms of schizophrenia frequently emerge. First-degree relatives of people with ...

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8.7K visualizações.  University of North Carolina at Chapel Hill School of Medicine. This paper describes how to use the emotional oddball task and fMRI to measure brain activation in children and adolescents at familial high risk for schizophrenia (FHR). FMRI was used to measure differences in fronto-striato-limbic regions during an emotional oddball task. Children with FHR exhibited abnormal functional activation during adolescence.