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>

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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.

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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...

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Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic Na&#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

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

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14.6K 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 Naïve 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 ...

MALDI Imaging Mass Spectrometry of Neuropeptides in Parkinson's Disease

MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 (Fig.1). A 12 &mu;m thin tissue section is covered with a MALDI matrix, which facilitates desorption and ionization of intact peptides and proteins that can be detected with a mass analyzer, typically using a MALDI TOF/TOF mass spectrometer. Generally hundreds of peaks can be assessed in a single rat brain tissue section. In contrast to commonly used imaging techniques, this approach does not require prior knowledge of the molecules of interest and allows for unsupervised and comprehensive analysis of multiple molecular species while maintaining high molecular specificity and sensitivity2. Here we describe a MALDI IMS based approach for elucidating region-specific distribution profiles of neuropeptides in the rat brain of an animal model Parkinson's disease (PD). 
PD is a common neurodegenerative disease with a prevalence of 1% for people over 65 of age3,4. The most common symptomatic treatment is based on dopamine replacement using L-DOPA5. However this is accompanied by severe side effects including involuntary abnormal movements, termed L-DOPA-induced dyskinesias (LID)1,3,6. One of the most prominent molecular change in LID is an upregulation of the opioid precursor prodynorphin mRNA7. The dynorphin peptides modulate neurotransmission in brain areas that are essentially involved in movement control7,8. However, to date the exact opioid peptides that originate from processing of the neuropeptide precursor have not been characterized. Therefore, we utilized MALDI IMS in an animal model of experimental Parkinson's disease and L-DOPA induced dyskinesia. 
MALDI imaging mass spectrometry proved to be particularly advantageous with respect to neuropeptide characterization, since commonly used antibody based approaches targets known peptide sequences and previously observed post-translational modifications. By contrast MALDI IMS can unravel novel peptide processing products and thus reveal new molecular mechanisms of neuropeptide modulation of neuronal transmission. While the absolute amount of neuropeptides cannot be determined by MALDI IMS, the relative abundance of peptide ions can be delineated from the mass spectra, giving insights about changing levels in health and disease. In the examples presented here, the peak intensities of dynorphin B, alpha-neoendorphin and substance P were found to be significantly increased in the dorsolateral, but not the dorsomedial, striatum of animals with severe dyskinesia involving facial, trunk and orolingual muscles (Fig. 5). Furthermore, MALDI IMS revealed a correlation between dyskinesia severity and levels of des-tyrosine alpha-neoendorphin, representing a previously unknown mechanism of functional inactivation of dynorphins in the striatum as the removal of N-terminal tyrosine reduces the dynorphin's opioid-receptor binding capacity9. This is the first study on neuropeptide characterization in LID using MALDI IMS and the results highlight the potential of the technique for application in all fields of biomedical research.

Dopamine replacement pharmacotherapy using L-DOPA is the most commonly used symptomatic treatment of Parkinson&#x2019;s disease, but is accompanied by side effects including involuntary abnormal movements, termed dyskinesia 1. Here, a protocol for MALDI imaging mass spectrometry is presented that detects changes in rat brain neuropeptide levels related to dyskinesia.

MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 ...

Medicine

Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia

Genetically modified mouse models face limitations, especially when studying movement disorders, where most of the available transgenic rodent models do not present a motor phenotype resembling the clinical aspects of the human disease. Pharmacological mouse models allow for a more direct study of the pathomechanisms and their effect on the behavioral phenotype. Osmotic pumps connected to brain cannulas open up the possibility of creating pharmacological mouse models via local and chronic drug delivery. For the hereditary movement disorder of rapid-onset dystonia-parkinsonism, the loss-of-function mutation in the &#945;3-subunit of the Na+/K+-ATPase can be simulated by a highly specific blockade via the glycoside ouabain. In order to locally block the &#945;3-subunit in the basal ganglia and the cerebellum, which are the two brain structures believed to be heavily involved in the pathogenesis of rapid-onset dystonia-parkinsonism, a bilateral cannula is stereotaxically implanted into the striatum and an additional single cannula is introduced into the cerebellum. The cannulas are connected via vinyl tubing to two osmotic pumps, which are subcutaneously implanted on the back of the animals and allow for the chronic and precise delivery of ouabain. The pharmacological mouse model for rapid-onset dystonia-parkinsonism carries the additional advantage of recapitulating the clinical and pathological features of asymptomatic and symptomatic mutation carriers. Just like mutation carriers of rapid-onset dystonia parkinsonism, the ouabain-perfused mice develop dystonia-like movements only after additional exposure to stress. We demonstrate a mild stress paradigm and introduce two modified scoring systems for the assessment of a motor phenotype.

We provide a protocol to generate a pharmacological DYT/PARK-ATP1A3 dystonia mouse model via implantation of cannulas into basal ganglia and cerebellum connected to osmotic pumps. We describe the induction of dystonia-like movements via application of a motor challenge and the characterization of the phenotype via behavioral scoring systems.

Genetically modified mouse models face limitations, especially when studying movement disorders, where most of the available transgenic rodent models do ...

Neuroscience

Standardized Data Acquisition for Neuromelanin-Sensitive Magnetic Resonance Imaging of the Substantia Nigra

The dopaminergic system plays a crucial role in healthy cognition (e.g., reward learning and uncertainty) and neuropsychiatric disorders (e.g., Parkinson's disease and schizophrenia). Neuromelanin is a byproduct of dopamine synthesis that accumulates in dopaminergic neurons of the substantia nigra. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a noninvasive method for measuring neuromelanin in those dopaminergic neurons, providing a direct measure of dopaminergic cell loss in the substantia nigra and a proxy measure of dopamine function. Although NM-MRI has been shown to be useful for studying various neuropsychiatric disorders, it is challenged by a limited field-of-view in the inferior-superior direction resulting in the potential loss of data from the accidental exclusion of part of the substantia nigra. In addition, the field is lacking a standardized protocol for the acquisition of NM-MRI data, a critical step in facilitating large-scale multisite studies and translation into the clinic. This protocol describes a step-by-step NM-MRI volume placement procedure and online quality control checks to ensure the acquisition of good-quality data covering the entire substantia nigra.

This protocol shows how to acquire neuromelanin-sensitive magnetic resonance imaging data of the substantia nigra.

The dopaminergic system plays a crucial role in healthy cognition (e.g., reward learning and uncertainty) and neuropsychiatric disorders (e.g., ...

Induction and Assessment of Levodopa-induced Dyskinesias in a Rat Model of Parkinson's Disease

Levodopa (L-DOPA) remains the gold-standard therapy used to treat Parkinson&#39;s disease (PD) motor symptoms. However, unwanted involuntary movements known as L-DOPA-induced dyskinesias (LIDs) develop with prolonged use of this dopamine precursor.&#160;It is estimated that the incidence of LIDs escalates to approximately 90% of individuals with PD within 10&#8211;15 years of treatment. Understanding the mechanisms of this malady and developing both novel and effective anti-dyskinesia treatments requires consistent and accurate modeling for pre-clinical testing of therapeutic interventions. A detailed method for reliable induction and comprehensive rating of LIDs following 6-OHDA-induced nigral lesioning in a rat model of PD is presented here. Dependable LID assessment in rats provides a powerful tool that can be readily utilized across laboratories to test emerging therapies focused on reducing or eliminating this common treatment-induced burden for individuals with PD.

This article describes methods to induce and evaluate levodopa-induced dyskinesias in a rat model of Parkinson&#39;s disease. The protocol offers detailed information regarding the intensity and frequency of a range of dyskinetic behaviors, both dystonic and hyperkinetic, providing a reliable tool to test treatments targeting this unmet medical need.

Levodopa (L-DOPA) remains the gold-standard therapy used to treat Parkinson&#39;s disease (PD) motor symptoms. However, unwanted involuntary movements ...

Digital Handwriting Analysis of Characters in Chinese Patients with Mild Cognitive Impairment

An increasing amount of evidence shows that cognitive deficits and movement dysfunctions are not separated. Patients with mild cognitive impairment (MCI) can manifest fine motor disorders of the upper extremities. Handwriting is a complex and unique human activity involving both motor and cognitive coordination. Researchers from western countries have discovered that patients with MCI have abnormal handwriting features. However, no relevant studies have been conducted in the Chinese population. Owing to the cross-culture phenomenon of handwriting, the aim of this study is to find new handwriting tasks to demonstrate the differences in handwriting features between elderly patients with MCI and age-matched healthy individuals.

This study proposed a digital handwriting analysis of characters in individuals with mild cognitive impairment to find more information than is revealed by traditional pencil&#8211;paper handwriting analysis.

An increasing amount of evidence shows that cognitive deficits and movement dysfunctions are not separated. Patients with mild cognitive impairment (MCI) ...

Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.

Rodent models of L-DOPA-induced dyskinesias are invaluable tools to identify therapeutic interventions to attenuate the development or alleviate the manifestations that emerge due to the repeated administration of L-DOPA. This protocol demonstrates how to induce and analyze dyskinetic-like movements in the unilaterally 6-OHDA-lesioned rat model of Parkinson's disease.

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). ...

Biology

Induction of Levodopa-Induced Dyskinesias in a Rat Model of Parkinson's Disease

Source: Caulfield, M. E., et al. <a href="https://app.jove.com/v/62970">Induction and Assessment of Levodopa-induced Dyskinesias in a Rat Model of Parkinson&#39;s Disease.</a> J. Vis. Exp. (2021).
This video demonstrates the process of inducing levodopa-induced dyskinesias in a Parkinson&#39;s rat model by administering levodopa alongside a dopamine conversion inhibitor. Repeated injections overstimulate the brain neurons, resulting in motor dysfunction.

All procedures involving animal models have been reviewed by the local institutional animal care committee and the JoVE veterinary review board.&#160;
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Handwriting Analysis Indicates Spontaneous Dyskinesias in Neuroleptic Naïve Adolescents at High Risk for Psychosis

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