This work was supported by National Institute of Health Grants R01MH094650 to Dr. Mittal.

1. Participants
<ol>
	<li>Provide approval for the protocol and informed consent procedures from the University Institutional Review Board.</li>
	<li>Recruit adolescent and young adult UHR participants by using Craigslist (i.e. local classified advertisements on the internet), email postings, newspaper ads, and community professional referrals.</li>
	<li>Recruit healthy control participants by craigslist, flyers and newspaper announcements.
	<ol>
		<li>Advertise that the study looks at healthy development for volunteers with no family history of psychosis and no psychiatric symptoms.</li>
		<li>Exclude healthy controls based on the presence of any category of Axis I disorder or a psychotic disorder in a 1st degree relative. 
		Note: A psychotic disorder in a first degree relative is intended as exclusion criteria for healthy controls because of the familial or genetic risk of psychosis1.</li>
	</ol>
	</li>
	<li>Exclude all participants based on criteria consisting of a history of head injury, the presence of a neurological disorder, substance dependence, or a history of taking neuroleptic medication.
	<ol>
		<li>Exclude UHR participants based on the presence of an Axis I psychotic disorder (e.g.&#160;schizophrenia, schizoaffective disorder, schizophreniform).</li>
	</ol>
	</li>
</ol>
2. Clinical Interviews
<ol>
	<li>Train interviewers to administer the Structured Interview for Prodromal Syndromes (SIPS) to diagnose a prodromal syndrome and the Structured Clinical Interview for Axis-I DSM IV Disorders (SCID) over a 2&#160;month period.
	<ol>
		<li>Establish inter-rater reliabilities on clinical interviews to exceed the minimum study criterion of Kappa &#8805;80.</li>
	</ol>
	</li>
	<li>Define criteria for a prodromal or high-risk syndrome by moderate levels of positive symptoms and/or a decline in global functioning accompanying the presence of schizotypal personality disorder and/or a family history of schizophrenia.</li>
	<li>Compute a total sum score for each category as an indicator of the respective dimensions of symptomatology. 
	Note: The SIPS gauges several distinct categories of prodromal symptom domains including positive, negative, and disorganized dimensions.</li>
	<li>Administer the Structured Clinical Interview for Axis-I DSM-IV Disorders (SCID) to rule out a psychotic disorder diagnosis. 
	Note: This measure has been demonstrated to have excellent inter-rater reliability in adolescent populations and has been used in several previous studies focusing on adolescent populations with schizophrenia spectrum disorders.</li>
	<li>Assess the participant&#39;s nicotine usage during the past month. Rate tobacco usage on a 0-5 scale with 0 = abstinent and 5 = 20+ cigarettes per day.</li>
</ol>
3. Handwriting Task
<ol>
	<li>Run Neuroscript MovAlyzeR software with a tablet computer and a noninking pen.</li>
	<li>Create an example of LLeeLLee on a notecard (see Figure 1). 
	Note: The software and stimulus are described previously and have been shown to be valid tools for detecting movement abnormalities in schizophrenia patients and Parkinson&#39;s patients15-17.</li>
</ol>
<img alt="Figure 1" src="/files/ftp_upload/50852/50852fig1.jpg" /> 
Figure 1.&#160;Example of the test condition. Participants are instructed to write the word LLeeLLee in cursive in the MID section. It is helpful to have an example such as this to show the participant so that they understand the instructions.
<ul style="margin-left: 40px;">
	<li>Leave the example notecard visible to the participant throughout the experiment. Note: The notecard will help the participant understand the experiment.</li>
</ul>
<ol start="3">
	<li>Orient tablet into landscape mode to provide a writing space of 18 cm x 28 cm with a resolution of 1,280 x 800 pixels.</li>
	<li>Allow participants to position computer screen into a comfortable writing position.</li>
	<li>Set the sampling rate in the software to the measured sampling rate (e.g.&#160;100-200 Hz).</li>
	<li>Instruct participant to write the word LLeeLLee in cursive in the 2 cm guidelines with the dominant hand. 
	Note: The condition is programmed to divide the writing surface into 4 regions. There are horizontal lines measuring 1 cm, 2 cm, and 4 cm. The 1 cm region is marked TOP. The 2 cm region is marked MID, and the 4 cm region is marked BOT. Participants will use the MID section for all three trials.</li>
	<li>Keep instructions visible during each trial. 
	Note: The instructions for the task are displayed at the top of the monitor and are as follows: &#34;DH lleellee MID Normal Speed&#34;. The participant should be told prior to starting the program that these instructions mean to write the word LLeeLLee in the MID section with the dominant hand and at a comfortable handwriting speed. Also note that the software will redo trial automatically if the participant makes an error while writing.</li>
</ol>
4. Processing Trials
<ol>
	<li>Process trials using a Fast Fourier Transform Low Pass 12 Hz filter, with a 1.75 Sharpness, 1 Lump decimates sample, and 1 Up-sample Factor. Remove trailing pen lift and rotate to horizontal baseline. Set additional counter clockwise rotation when segmenting at vertical velocity to zero radians. 
	Note: The handwriting analysis software will automatically incorporate these processing steps if they are selected within the program options.</li>
	<li>Summarize the absolute values of target variables LLeeLLee at two centimeters for Average Normalized Jerk (ANJ) per Trial. Collapse across trial and stroke.</li>
</ol>
Note: The ANJ is a measure of movement dysfluency. Higher ANJ indicates greater dysfluency (See Figure 2). The dysfluency measure is based on the vertical component of the jerk (in cm/sec3), i.e.&#160;the 3rd time derivative of vertical position of the pen tip. Dysfluencies are caused by sudden changes in force. The 2nd time derivative, which is acceleration, is proportional to the net muscle force (if friction is neglected). Therefore, the 3rd time derivative is proportional to the force changes. To obtain an overall measure of dysfluency the vertical jerk is squared and integrated across the duration of a stroke (unit is cm2/sec5). To make this measure independent upon the duration and the vertical size of the stroke, multiply the integral by the 5th power of stroke duration (unit is sec5) and the inverse of the vertical size squared (unit is 1/cm2). The result is therefore unitless. Normalized jerk describes the shape of the acceleration curve irrespective of width and height. Take the square root of the end result to make ANJ proportional with jerk
<img alt="Equation 1" fo:src="/files/ftp_upload/50852/50852eq1highres.jpg" src="/files/ftp_upload/50852/50852eq1.jpg" /> 
The ANJ of a trial is defined by the average of the normalized jerk estimates across all up and down strokes of a trial&#160;23.
<img alt="Figure 2" fo:content-width="5in" fo:src="/files/ftp_upload/50852/50852fig2highres.jpg" src="/files/ftp_upload/50852/50852fig2.jpg" /> 
Figure 2. Trial from a control participant. Each trial is divided into 16 strokes. The segmentation of stroke for analysis of average normalize jerk is illustrated with the first pen stroke (in blue). A blue bracket outlines the stroke, and circles denote the start and stop of the stroke segment. <a href="https://www.jove.com/files/ftp_upload/50852/50852fig2large.jpg" target="_blank"> Click here to view larger figure</a>.
5. Statistical Analysis
<ol>
	<li>Employ independent two tailed t-tests and chi-square tests to examine differences between groups in continuous and categorical demographic variables, respectfully. If necessary, adjust for inequalities of variance by Levene&#39;s test.</li>
	<li>Employ an analysis of covariance (ANCOVA) controlling for nicotine use and gender with group (UHR and Control) as the independent variable and ANJ collapsed across trial.</li>
</ol>

<ol>
	<li>Cannon, T. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prediction+of+psychosis+in+youth+at+high+clinical+risk:+a+multisite+longitudinal+study+in+North+America.">Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America.</a> Arch. Gen. Psychiatry. 65, 28-37 (2008).</li><li>Yung, A. R., Phillips, L. J., Yuen, H. P., McGorry, P. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Risk+factors+for+psychosis+in+an+ultra+high-risk+group:+psychopathology+and+clinical+features.">Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features.</a> Schizophr. Res. 67, 131-142 (2004).</li><li>Miller, T. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prodromal+assessment+with+the+structured+interview+for+prodromal+syndromes+and+the+scale+of+prodromal+symptoms:+predictive+validity,+interrater+reliability,+and+training+to+reliability.">Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability.</a> Schizophr. Bull. 29, 703-715 (2003).</li><li>Cornblatt, B. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+schizophrenia+prodrome+revisited:+a+neurodevelopmental+perspective.">The schizophrenia prodrome revisited: a neurodevelopmental perspective.</a> Schizophr. Bull. 29, 633-651 (2003).</li><li>Mittal, V. A., Dean, D. J., Pelletier, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dermatoglyphic+asymmetries+and+fronto-striatal+dysfunction+in+young+adults+reporting+non-clinical+psychosis.">Dermatoglyphic asymmetries and fronto-striatal dysfunction in young adults reporting non-clinical psychosis.</a> Acta Psychiatr. Scand. 126, 290-297 (2012).</li><li>Mittal, V. A., Neumann, C., Saczawa, M., Walker, E. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Longitudinal+progression+of+movement+abnormalities+in+relation+to+psychotic+symptoms+in+adolescents+at+high+risk+of+schizophrenia.">Longitudinal progression of movement abnormalities in relation to psychotic symptoms in adolescents at high risk of schizophrenia.</a> Arch. Gen. Psychiatry. 65, 165-171 (2008).</li><li>Mittal, V. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Abnormal+movements+are+associated+with+poor+psychosocial+functioning+in+adolescents+at+high+risk+for+psychosis.">Abnormal movements are associated with poor psychosocial functioning in adolescents at high risk for psychosis.</a> Schizophr. Res. 130, 164-169 (2011).</li><li>Mittal, V. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Markers+of+basal+ganglia+dysfunction+and+conversion+to+psychosis:+neurocognitive+deficits+and+dyskinesias+in+the+prodromal+period.">Markers of basal ganglia dysfunction and conversion to psychosis: neurocognitive deficits and dyskinesias in the prodromal period.</a> Biol. Psychiatry. 68, 93-99 (2010).</li><li>Walker, D., Diforio, <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Schizophrenia:+a+neural+diathesis-stress+model.">Schizophrenia: a neural diathesis-stress model.</a> Psychol. Rev. 104, 667-685 (1997).</li><li>Walker, E. F., Savoie, T., Davis, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Neuromotor+precursors+of+schizophrenia.">Neuromotor precursors of schizophrenia.</a> Schizophr. Bull. 20, 441-451 (1994).</li><li>Mittal, V. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Striatal+volumes+and+dyskinetic+movements+in+youth+at+high-risk+for+psychosis.">Striatal volumes and dyskinetic movements in youth at high-risk for psychosis.</a> Schizophr. Res. 123, 68-70 (2010).</li><li>Bechdolf, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Interventions+in+the+initial+prodromal+states+of+psychosis+in+Germany:+concept+and+recruitment.">Interventions in the initial prodromal states of psychosis in Germany: concept and recruitment.</a> Br. J. Psychiatry Suppl. 48, s45-s48 (2005).</li><li>Mittal, V. A., Dean, D. J., Pelletier, A., Caligiuri, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Associations+between+spontaneous+movement+abnormalities+and+psychotic-like+experiences+in+the+general+population.">Associations between spontaneous movement abnormalities and psychotic-like experiences in the general population.</a> Schizophr. Res. 132, 194-196 (2011).</li><li>Mittal, V. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=BDNF+Val66Met+and+spontaneous+dyskinesias+in+non-clinical+psychosis.">BDNF Val66Met and spontaneous dyskinesias in non-clinical psychosis.</a> Schizophr. Res. 140, 65-70 (2012).</li><li>Caligiuri, M. P., Teulings, H. L., Dean, C. E., Niculescu, A. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Handwriting+movement+analyses+for+monitoring+drug-induced+motor+side+effects+in+schizophrenia+patients+treated+with+risperidone.">Handwriting movement analyses for monitoring drug-induced motor side effects in schizophrenia patients treated with risperidone.</a> Hum. Mov. Sci. 28, 633-642 (2009).</li><li>Caligiuri, M. P., Teulings, H. L., Dean, C. E., Niculescu, A. B., 3rd, J. B., Lohr, <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Handwriting+movement+kinematics+for+quantifying+extrapyramidal+side+effects+in+patients+treated+with+atypical+antipsychotics.">Handwriting movement kinematics for quantifying extrapyramidal side effects in patients treated with atypical antipsychotics.</a> Psychiatry Res. 177, 77-83 (2010).</li><li>Caligiuri, M. P., Teulings, H. L., Filoteo, J. V., Song, D., Lohr, J. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+measurement+of+handwriting+in+the+assessment+of+drug-induced+parkinsonism.">Quantitative measurement of handwriting in the assessment of drug-induced parkinsonism.</a> Hum. Mov. Sci. 25, 510-522 (2006).</li><li>Schizophr Bull, . <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> 19, 303-315 (1993).</li><li>Andersson, K., Fuxe, K., Agnati, L. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+single+injections+of+nicotine+on+the+ascending+dopamine+pathways+in+the+rat.+Evidence+for+increases+of+dopamine+turnover+in+the+mesostriatal+and+mesolimbic+dopamine+neurons.">Effects of single injections of nicotine on the ascending dopamine pathways in the rat. Evidence for increases of dopamine turnover in the mesostriatal and mesolimbic dopamine neurons.</a> Acta Physiol. Scand. 112, 345-347 (1981).</li><li>Lane, R. D., Glazer, W. M., Hansen, T. E., Berman, W. H., Kramer, S. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+tardive+dyskinesia+using+the+Abnormal+Involuntary+Movement+Scale.">Assessment of tardive dyskinesia using the Abnormal Involuntary Movement Scale.</a> J. Nerv. Ment. Dis. 173, 353-357 (1985).</li><li>Zhang, X. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Smoking+and+tardive+dyskinesia+in+male+patients+with+chronic+schizophrenia.">Smoking and tardive dyskinesia in male patients with chronic schizophrenia.</a> Prog. Neuropsychopharmacol. Biol. Psychiatry. 35, 1765-1769 (2011).</li><li>Tucha, O., Lange, K. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+nicotine+chewing+gum+on+a+real-life+motor+task:+a+kinematic+analysis+of+handwriting+movements+in+smokers+and+non-smokers.">Effects of nicotine chewing gum on a real-life motor task: a kinematic analysis of handwriting movements in smokers and non-smokers.</a> Psychopharmacology. 173, 49-56 (2004).</li><li>Teulings, H. L., Contreras-Vidal, J. L., Stelmach, G. E., Adler, C. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Parkinsonism+reduces+coordination+of+fingers,+wrist,+and+arm+in+fine+motor+control.">Parkinsonism reduces coordination of fingers, wrist, and arm in fine motor control.</a> Exp. Neurol. 146, 159-170 (1997).</li><li>Lin, C. Y., Yeh, C. H., Chang, T. T., Kao, C. H., Tsai, S. Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Smoking,+dopamine+transporter,+and+hand+tremor.">Smoking, dopamine transporter, and hand tremor.</a> Clin. Nucl. Med. 37, 35-38 (2012).</li><li>Van Gemmert, A. W., Teulings, H. L. <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+graphonomics:+studies+on+fine+motor+control,+its+development+and+disorders.">Advances in graphonomics: studies on fine motor control, its development and disorders.</a> Hum. Mov. Sci. 25, 447-453 (2006).</li><li>Gharabawi, G. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Abnormal+Involuntary+Movement+Scale+(AIMS)+and+Extrapyramidal+Symptom+Rating+Scale+(ESRS):+cross-scale+comparison+in+assessing+tardive+dyskinesia.">Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS): cross-scale comparison in assessing tardive dyskinesia.</a> Schizophr. Res. 77, 119-128 (2005).</li><li>Cortese, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Relationship+of+neuromotor+disturbances+to+psychosis+symptoms+in+first-episode+neuroleptic-naive+schizophrenia+patients.">Relationship of neuromotor disturbances to psychosis symptoms in first-episode neuroleptic-naive schizophrenia patients.</a> Schizophr. Res. 75, 65-75 (2005).</li><li>Howes, O. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Elevated+striatal+dopamine+function+linked+to+prodromal+signs+of+schizophrenia.">Elevated striatal dopamine function linked to prodromal signs of schizophrenia.</a> Arch. Gen. Psychiatry. 66, 13-20 (2009).</li><li>Van Gemmert, A. W., Teulings, H. L., Contreras-Vidal, J. L., Stelmach, G. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Parkinson's+disease+and+the+control+of+size+and+speed+in+handwriting.">Parkinson's disease and the control of size and speed in handwriting.</a> Neuropsychologia. 37, 685-694 (1999).</li></ol>

The authors Derek J. Dean, Michael Caligiuri, and Vijay A. Mittal declare they have no competing financial interests. The author, Hans-Leo Teulings is the owner of NeuroScript who developed and markets the MovAlyzeR software to record and analyze pen movements.

This study found significant evidence of more dysfluent pen movements and the presence of dyskinesia in an UHR sample using a handwriting analysis program to examine movement abnormalities.
Traditionally, observer based rating scales have been utilized to measure movement abnormalities in order to monitor drug side effects15-17. However, the observer ratings suffer from significant drawbacks including long training times for raters, experimenter error, and suboptimal reliability<sup...

The period preceding the onset of psychosis is of clinical and research interest as it may shed light on formal psychosis (prior to when a number of third variable confounds such as medication obfuscate our understanding), and also serves as a viable point of intervention (roughly &#8531; of youth showing a prodromal syndrome go on to develop schizophrenia in a 2 year period, and several studies suggest that psychosocial, cognitive training, and pharmacological interventions may ameliorate the course of illness)1. This prodromal period is marked by attenuated positive symptoms (perceptual abnormalities, suspiciousness, feelings of grandiosity, or unusual thoughts) and a decline in functioning2. Individuals who report a moderate degree of positive symptoms during a structured clinical interview, and/or a decline in functioning accompanying the presence of schizotypal personality disorder and/or a family history of schizophrenia are considered to have a prodromal or ultra high-risk (UHR) syndrome1-3. Current etiological conceptions of psychosis suggest that it is a neurodevelopmental disorder that affects an individual during late adolescence or early adulthood4. Constitutional factors such as genetics and prenatal insults result in vulnerability for psychosis4. Movement abnormalities are of keen interest to this model, as the same mechanisms believed to be contributing to psychotic symptoms are also responsible for governing the motor system5. Researchers argue that by understanding movement behavior prior to the onset of schizophrenia, we may improve our ability to predict, understand, and intervene in the development of schizophrenia6.
It is well known that individuals who later go on to develop schizophrenia often show subtle movement abnormalities prior to the onset of illness7,8. Walker and colleagues collected videotapes of patients with schizophrenia during childhood and rated the videos for movement abnormalities, showing that movement abnormalities are present long before the onset of illness and are indicative of a neurological constitutional vulnerability9,10. Research suggests that the basal ganglia may be implicated in this neurological constitutional vulnerability, as UHR individuals show impaired neural development and neurocognitive deficits related to basal ganglia function8,11. Additionally, Mittal and colleagues have used observer ratings to show that movement abnormalities, closely linked to basal ganglia function, could successfully classify UHR individuals likely to convert to psychosis8,12. Another at risk group, nonclinical psychosis&#160;individuals who report having a psychotic-like experience at least once a year,&#160;show dyskinesia during a finger force stability task5,13,14. These findings provide strong evidence for the idea that movement abnormalities may be a core feature of risk of psychosis. Clearly, research that can improve detection and understanding of movement abnormalities is crucial for the understanding of the etiology of psychosis and for preventive efforts.
Efforts to understand medication side-effects that affect dopamine regulation in schizophrenia and Parkinson&#39;s patients have guided technological improvements, such as the development of computerized tablets for handwriting analysis, in measuring movement abnormalitie15-17. Antipsychotic medication may lead to the development of tardive dyskinesia, characterized by slow involuntary repetitive movements18. Nicotine use has also been shown to affect dopamine regulation and handwriting kinematics19-21. For example, Tucha and Lange showed that pen movement fluency improved during a computerized handwriting task when healthy participants were given chewing gum containing nicotine22. During assessment, participants generally write in a western cursive handwriting with larger and smaller vertical strokes. Western cursive handwriting is optimal for examining pen movement smoothness because of the predominance of vertical strokes that require complex coordination of muscles to perform well23. Dysfluent pen movements result when the muscles that coordinate the movement receive disregulated signals from the basal ganglia15,16.
The software segments and analyzes pen movements per stroke and extracts a variable that is thought to be a proximal measure of dyskinesia, called average normalized jerk15-17. Jerk is defined as the change in acceleration over time per stroke23. Because of the different lengths in vertical strokes in most western style handwritings, jerk is normalized across strokes. Within each stroke, dysfluent pen movements are characterized by a greater number of acceleration peaks over a given distance. Thus, dysfluent pen movements are characterized by a lack of smoothness, a greater number of acceleration peaks, and a larger value of jerk.
The improvement of measures used to rate movement abnormalities in UHR youth is critical for improving our etiological conceptions of the illness and our understanding of movement disorders in general. In that effort to understand movement disorders in those at risk for psychosis, we examined handwriting kinematics from 36 neuroleptic na&#239;ve research participants using handwriting analysis software. Despite its wide use in investigating dyskinesia in Parkinson&#39;s and schizophrenia patients, this is surprisingly the first study to report on handwriting kinematics in an ultra-high-risk group for psychosis. We hypothesized that the UHR individuals would show more dysfluent pen movements, characterized by a larger value of jerk, when asked to write on a tablet computer than a group of healthy controls.

<table border="1">
 <tbody>
		 <tr>
			<td>Material Name</td>
			<td>Company</td>
			<td></td>
			<td>Website </td>
		 </tr>
		 <tr>
			<td>Fujitsu Lifebook T901 Tablet Computer</td>
			<td>Fujitsu Ltd. </td>
			<td></td>
			<td><a href="http://www.shopfujitsu.com/store/" target="_blank">http://www.shopfujitsu.com/store/</a></td>
		 </tr>
		 <tr>
			<td>Neuroscript MovAlyzeR</td>
			<td>Neuroscript LLC</td>
			<td></td>
			<td><a href="http://www.neuroscript.net/movalyzer.php" target="_blank">http://www.neuroscript.net/movalyzer.php</a></td>
		 </tr>
 </tbody>
 </table>

handwriting analysis indicates spontaneous dyskinesias in neuroleptic na&#239;ve adolescents at high risk for psychosis

Growing evidence suggests that movement abnormalities are a core feature of psychosis. One marker of movement abnormality, dyskinesia, is a result of impaired neuromodulation of dopamine in fronto-striatal pathways. The traditional methods for identifying movement abnormalities include observer-based reports and force stability gauges. The drawbacks of these methods are long training times for raters, experimenter bias, large site differences in instrumental apparatus, and suboptimal reliability. Taking these drawbacks into account has guided the development of better&#160;standardized and more efficient procedures to examine movement abnormalities through handwriting analysis software and tablet. Individuals at&#160;risk for psychosis showed significantly more dysfluent pen movements (a proximal measure for dyskinesia) in a handwriting task. Handwriting kinematics offers a great advance over previous methods of assessing dyskinesia, which could clearly be beneficial for understanding the etiology of psychosis.

There were no significant differences between groups on demographic characteristics including age, years of education, or parental education (see Table 1 for a demographic breakdown of the participants). Chi Square tests revealed significant differences between groups on gender &#967;2 (1, N = 36) = 5.46, p&#8804;0.05, with more males in the UHR group and more females in the control group. There was a significant group differences in tobacco usage frequency, t(22.9) = 2.15, p&#8804;0.05, showi...

Watch this Scientific Journal Video about Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic NaÃ¯ve Adolescents at High Risk for Psychosis at JoVE.com

Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic Na&amp;#239;ve Adolescents at High Risk for Psychosis

Handwriting analysis software significantly improves upon existing instruments measuring movement disorders. Individuals at&#160;risk for psychosis and healthy controls completed handwriting tasks to test for dyskinesia. Results suggest that youth at&#160;risk for psychosis exhibit dyskinesia and that handwriting analysis could significantly contribute to wider dissemination of early identification efforts

Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic Na&#239;ve Adolescents at High Risk for Psychosis

Growing evidence suggests that movement abnormalities are a core feature of psychosis. One marker of movement abnormality, dyskinesia, is a result of ...

handwriting-analysis-indicates-spontaneous-dyskinesias-neuroleptic

Research

Education

JoVE Core

JoVE Journal

Nursing

Behavior

Unit 1

Introduction to Health

SCIENTISTS IN ACTION

14.5K Views.  University of Colorado Boulder. Handwriting analysis software significantly improves upon existing instruments measuring movement disorders. Individuals at risk for psychosis and healthy controls completed handwriting tasks to test for dyskinesia. Results suggest that youth at risk for psychosis exhibit dyskinesia and that handwriting analysis could significantly contribute to wider dissemination of early identification efforts

Video: Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic Na&#239;ve Adolescents at High Risk for Psychosis

Assessment and Evaluation of the High Risk Neonate: The NICU Network Neurobehavioral Scale

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant. The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. These are infants who are at increased risk for poor developmental outcome because of insults during prenatal development, such as substance exposure or prematurity or factors such as poverty, poor nutrition or lack of prenatal care that can have adverse effects on the intrauterine environment and affect the developing fetus. The NNNS assesses the full range of infant neurobehavioral performance including neurological integrity, behavioral functioning, and signs of stress/abstinence. The NNNS is a noninvasive neonatal assessment tool with demonstrated validity as a predictor, not only of medical outcomes such as cerebral palsy diagnosis, neurological abnormalities, and diseases with risks to the brain, but also of developmental outcomes such as mental and motor functioning, behavior problems, school readiness, and IQ. The NNNS can identify infants at high risk for abnormal developmental outcome and is an important clinical tool that enables medical researchers and health practitioners to identify these infants and develop intervention programs to optimize the development of these infants as early as possible. The video shows the NNNS procedures, shows examples of normal and abnormal performance and the various clinical populations in which the exam can be used.

The NICU Network Neurobehavioral Scale (NNNS) was developed as an assessment for the at-risk infant. The purpose of this article is to describe the NNNS, provide video examples of the NNNS procedures and discuss the ways in which the exam has been used.

There has been a long-standing interest in the assessment of the neurobehavioral integrity of the newborn infant.  The NICU Network Neurobehavioral Scale ...

Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice

The contextual and cued fear conditioning test is one of the behavioral tests that assesses the ability of mice to learn and remember an association between environmental cues and aversive experiences. In this test, mice are placed into a conditioning chamber and are given parings of a conditioned stimulus (an auditory cue) and an aversive unconditioned stimulus (an electric footshock). After a delay time, the mice are exposed to the same conditioning chamber and a differently shaped chamber with presentation of the auditory cue. Freezing behavior during the test is measured as an index of fear memory. To analyze the behavior automatically, we have developed a video analyzing system using the ImageFZ application software program, which is available as a free download at http://www.mouse-phenotype.org/. Here, to show the details of our protocol, we demonstrate our procedure for the contextual and cued fear conditioning test in C57BL/6J mice using the ImageFZ system. In addition, we validated our protocol and the video analyzing system performance by comparing freezing time measured by the ImageFZ system or a photobeam-based computer measurement system with that scored by a human observer. As shown in our representative results, the data obtained by ImageFZ were similar to those analyzed by a human observer, indicating that the behavioral analysis using the ImageFZ system is highly reliable. The present movie article provides detailed information regarding the test procedures and will promote understanding of the experimental situation.

This article presents a protocol for a contextual and cued fear conditioning test using a video analyzing system to assess fear learning and memory in mice.

The contextual and cued fear conditioning test is one of the behavioral tests that assesses the ability of mice to learn and remember an association ...

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.

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 ...

Cortical Source Analysis of High-Density EEG Recordings in Children

EEG is traditionally described as a neuroimaging technique with high temporal and low spatial resolution. Recent advances in biophysical modelling and signal processing make it possible to exploit information from other imaging modalities like structural MRI that provide high spatial resolution to overcome this constraint1. This is especially useful for investigations that require high resolution in the temporal as well as spatial domain. In addition, due to the easy application and low cost of EEG recordings, EEG is often the method of choice when working with populations, such as young children, that do not tolerate functional MRI scans well. However, in order to investigate which neural substrates are involved, anatomical information from structural MRI is still needed. Most EEG analysis packages work with standard head models that are based on adult anatomy. The accuracy of these models when used for children is limited2, because the composition and spatial configuration of head tissues changes dramatically over development3.&#160;
In the present paper, we provide an overview of our recent work in utilizing head models based on individual structural MRI scans or age specific head models to reconstruct the cortical generators of high density EEG. This article describes how&#160;EEG recordings are acquired, processed, and analyzed with pediatric populations at the London Baby Lab, including laboratory setup, task design, EEG preprocessing, MRI processing, and EEG channel level and source analysis.&#160;

In recent years, there has been increasing interest in estimating the cortical sources of scalp measured electrical activity for cognitive neuroscience experiments. This article describes how high density EEG is acquired and how recordings are processed for cortical source estimation in children from the age of 2 years at the London Baby Lab.

EEG is traditionally described as a neuroimaging technique with high temporal and low spatial resolution. Recent advances in biophysical modelling and ...

Design and Implementation of an fMRI Study Examining Thought Suppression in Young Women with, and At-risk, for Depression

Ruminative brooding is associated with increased vulnerability to major depression. Individuals who regularly ruminate will often try to reduce the frequency of their negative thoughts by actively suppressing them. We aim to identify the neural correlates underlying thought suppression in at-risk and depressed individuals. Three groups of women were studied; a major depressive disorder group, an at-risk group (having a first degree relative with depression) and controls. Participants performed a mixed block-event fMRI paradigm involving thought suppression, free thought and motor control periods. Participants identified the re-emergence of &#8220;to-be-suppressed&#8221; thoughts (&#8220;popping&#8221; back into conscious awareness) with a button press. During thought suppression the control group showed the greatest activation of the dorsolateral prefrontal cortex, followed by the at-risk, then depressed group. During the re-emergence of intrusive thoughts compared to successful re-suppression of those thoughts, the control group showed the greatest activation of the anterior cingulate cortices, followed by the at-risk, then depressed group. At-risk participants displayed anomalies in the neural regulation of thought suppression resembling the dysregulation found in depressed individuals. The predictive value of these changes in the onset of depression remains to be determined.

We aim to identify the neural correlates underlying sustained and transient thought suppression, and thought re-emergence in controls, at-risk and depressed individuals. Activation was greatest for controls compared to the at-risk and the depressed group in the dorsolateral prefrontal cortex during thought suppression and anterior cingulate cortex during thought re-emergence.

Ruminative brooding is associated with increased vulnerability to major depression. Individuals who regularly ruminate will often try to reduce the ...

A Novel Method for Involving Women of Color at High Risk for Preterm Birth in Research Priority Setting

Involvement of patients and the public is now recognized to be essential for the good conduct of research. Patient and public involvement in research priority setting and funding decisions is only beginning to be recognized as important, and methods for doing so are nascent. This protocol describes the Research Prioritization by Affected Communities (RPAC) protocol and findings from its use with women at high socio-demographic risk for preterm birth. The goal was to directly involve these women in identifying and prioritizing their unanswered questions about pregnancy, birth and neonatal care, and treatment so that their views could be included in research priority setting by funders and researchers. The RPAC protocol may be used to meaningfully involve under-represented groups at high-risk for specific health problems, or those who face disproportionate burden of disease, in research strategy and funding priority setting.

This manuscript describes the Research Prioritization by Affected Communities (RPAC) protocol and findings from its use with women at risk for preterm birth. Using the protocol, women identified and prioritized their unanswered questions about pregnancy, birth and neonatal care aimed at influencing research priority setting by funders and researchers.

Involvement of patients and the public is now recognized to be essential for the good conduct of research. Patient and public involvement in research ...

Systematic Assessment of Well-Being in Mice for Procedures Using General Anesthesia

In keeping with the 3R Principle (Replacement, Reduction, Refinement) developed by Russel and Burch, scientific research should use alternatives to animal experimentation whenever possible. When there is no alternative to animal experimentation, the total number of laboratory animals used should be the minimum needed to obtain valuable data. Moreover, appropriate refinement measures should be applied to minimize pain, suffering, and distress accompanying the experimental procedure. The categories used to classify the degree of pain, suffering, and distress are non-recovery, mild, moderate, or severe (EU Directive 2010/63). To determine which categories apply in individual cases, it is crucial to use scientifically sound tools.
The well-being-assessment protocol presented here is designed for procedures during which general anesthesia is used. The protocol focuses on home cage activity, the Mouse Grimace Scale, and luxury behaviors such as burrowing and nest building behavior as indicators of well-being. It also uses the free exploratory paradigm for trait anxiety-related behavior. Fecal corticosterone metabolites as indicators of acute stress are measured over the 24-h post-anesthetic period.
The protocol provides scientifically solid information on the well-being of mice following general anesthesia. Due to its simplicity, the protocol can easily be adapted and integrated in a planned study. Although it does not provide a scale to classify distress in categories according to the EU Directive 2010/63, it can help researchers estimate the degree of severity of a procedure using scientifically sound data. It provides a way to improve the assessment of well-being in a scientific, animal-centered manner.

We developed a protocol to assess well-being in mice during procedures using general anesthesia. A series of behavioral parameters indicating levels of well-being as well as glucocorticoid metabolites were analyzed. The protocol can serve as a general aid to estimate the degree of severity in a scientific, animal-centered manner.

In keeping with the 3R Principle (Replacement, Reduction, Refinement) developed by Russel and Burch, scientific research should use alternatives to animal ...

Behavioral Assessments of Spontaneous Locomotion in a Murine MPTP-induced Parkinson's Disease Model

Parkinson&#8217;s disease (PD) is a common neurodegenerative disorder disease, causing the phenomenon of shaking, rigidity, slowness of movement and dementia. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can lead to some Parkinson&#8217;s-like symptoms by destroying dopaminergic neurons in the substantia nigra of the brain. It has been thus used to establish PD models in various animal studies. Here, mice receive MPTP injections (20 mg/kg/day) for seven days and the behavioral tests are performed on the eighth day. This model is adapted efficiently in the study of PD. The behavioral tests here include the cylinder test and the open field test. The cylinder experiment is used to detect the animals&#8217; ability to lift their front paws when put into a different environment. As the PD model mice show arching&#8212;the mouse arches its back&#8212;the number of paw liftings decrease. This test is easy to execute. The open field test is used to detect the amount of time the mice spend on running, walking, and remaining immobile. We analyze animals&#8217; movements in open field using software and obtain data. Lastly, we use L-DOPA, one of the most commonly used PD drugs, as one example to show how to apply this model to the study of PD drugs. Our results indicate that MPTP neurotoxicity induces motor deficit which can be mitigated by L-DOPA.

Behavioral Assessments of Spontaneous Locomotion in a Murine MPTP-induced Parkinson&#039;s Disease Model

We describe establishment of a murine model for Parkinson's disease using MPTP, and behavioral assessments using cylinder and open field tests to measure motor function. We then use L-DOPA as one example to show how to apply this model in the study of PD drugs.

Parkinson&#8217;s disease (PD) is a common neurodegenerative disorder disease, causing the phenomenon of shaking, rigidity, slowness of movement and ...

Short Session High Intensity Interval Training and Treadmill Assessment in Aged Mice

High intensity interval training (HIIT) is emerging as a therapeutic approach to prevent, delay, or ameliorate frailty. In particular short session HIIT, with regimens less than or equal to 10 min is of particular interest as several human studies feature routines as short as a few minutes a couple times a week. However, there is a paucity of animal studies that model the impacts of short session HIIT. Here, we describe a methodology for an individually tailored and progressive short session HIIT regimen of 10 min given 3 days a week for aged mice using an inclined treadmill. Our methodology also includes protocols for treadmill assessment. Mice are initially acclimatized to the treadmill and then given baseline flat and uphill treadmill assessments. Exercise sessions begin with a 3 min warm-up, then three intervals of 1 min at a fast pace, followed by 1 min at an active recovery pace. Following these intervals, the mice are given a final segment that starts at the fast pace and accelerates for 1 min. The HIIT protocol is individually tailored as the speed and intensity for each mouse are determined based upon initial anaerobic assessment scores. Additionally, we detail the conditions for increasing or decreasing the intensity for individual mice depending on performance. Finally, intensity is increased for all mice every two weeks. We previously reported in this protocol enhanced physical performance in aged male mice and here show it also increases treadmill performance in aged female mice. Advantages of our protocol include low administration time (about 15 min per 6 mice, 3 days a week), strategy for individualizing for mice to better model prescribed exercise, and a modular design that allows for the addition or removal of the number and length of intervals to titrate exercise benefits.

Short session (&#8804;10 min) high intensity interval training (HIIT) is emerging as an alternative to longer exercise modalities, yet the shorter variants are rarely modeled in animal studies. Here, we describe a 10 min, 3 day a week, uphill treadmill HIIT protocol that enhances physical performance in male and female aged mice.

High intensity interval training (HIIT) is emerging as a therapeutic approach to prevent, delay, or ameliorate frailty. In particular short session HIIT, ...

Evaluating Skilled Prehension in Mice Using an Auto-Trainer

We describe a method to introduce na&#239;ve mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that permits the mouse to reach out of its cage and retrieve food pellets. Minimal food restriction is employed to encourage the mice to perform the food retrieval from the slot. As the mice begin to associate coming to the slot for food, the pellets are manually pulled away to stimulate extension and pronation of their paw to grasp and retrieve the pellet through the frontal slot. When the mice begin to reach for the pellets as they arrive at the slot, the behavioral assay can be performed by measuring the rate at which they successfully grasp and retrieve the desired pellet. They are then introduced to an auto-trainer that automates both the process of providing food pellets for the mouse to grasp, and the recording of successful and failed reaching and grasping attempts. This allows for the collection of reaching data for multiple mice with minimal effort, to be used in experimental analysis as appropriate.

Method to assess the impact of training on motor skills is a useful tool. Unfortunately, most behavioral assessments can be labor intensive and/or expensive.We describe here a robotic method of assessing prehension (reach-to-grasp) skill in mice.

We describe a method to introduce na&#239;ve mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that ...