Team RITALIN

Executive Summary

Currently, there is no thoroughly validated animal model of Attention Deficit Hyperactivity Disorder (ADHD). Since the causes of ADHD are multi-faceted, including environmental and genetic effects, it is difficult to recreate conditions in a laboratory that will consistently produce ADHD without other confounding variables. Since women who smoke during pregnancy are three times as likely to have children diagnosed with ADHD, we anticipate that administering nicotine to mothers during gestation will consistently produce ADHD in rat pups. We will confirm this diagnosis by measuring impulsive action during administration of the stop-signal task. We will also conduct single-neuron recordings during the task from the medial prefrontal cortex (mPFC), an area which regulates impulsivity and is known to malfunction in children with ADHD. From these findings, we will determine the validity of fetal nicotine rats as models of ADHD, which could be used to further study the neurological basis of this disease.

Research Questions

  1. Is there a correlation between patterns of neural firing in the mPFC and variations in impulsivity in control rats?
  2. Is this firing disrupted and impulsivity increased in fetal nicotine rats?

Hypotheses

  1. Patterns of neural firing in the mPFC in control rats will reflect the role of the mPFC as an impulsivity control area.
  2. Fetal nicotine rats will show reduced neural firing in the mPFC in response to the stop-signal and increased impulsivity.

Literature Review

ADHD Stop Signal Task Neurophysiology Fetal Nicotine Rats

ADHD

In recent years, there has been a significant increase in the number of diagnoses of ADHD. From 2003 to 2007, there was a 21.8% increase in the reported incidence of ADHD among children/adolescents between the ages of four and seventeen (Center for Disease Control and Prevention). Many of these diagnoses, however, are inaccurate. This is because current methods of diagnosing ADHD, as outlined by The Diagnostic and Statistical Manual-IV (DSM-IV), rely solely on observations of a patient's behavior, with impulsivity, inattention, and hyperactivity being the most commonly observed symptoms (American Psychiatric Association, 1994).

Past studies have suggested that certain environmental factors can cause the onset of ADHD symptoms. Prenatal exposure to teratogens, factors which affect fetal development, such as alcohol and drugs often increases the chance of developing ADHD and often exacerbates ADHD-like symptoms in children. Children who have been prenatally exposed to alcohol, for instance, have been shown to display symptoms associated with ADHD such as hyperactivity, impulsivity, and disruptive behavior. Similarly, the children of mothers who smoked tobacco during pregnancy had a 2.7-fold increase in risk for developing ADHD (Curatolo, D'Agati, & Moavero, 2010). It is important therefore, to take such factors in addition to age, gender, and cultural background into consideration when diagnosing ADHD (Frick & Nigg, 2011).

Dopamine
Noradrenaline

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Stop Signal Task

In clinical studies, the stop-signal task is a procedure that is generally used to measure impulsivity. The task gauges how quickly an initiated response is inhibited (Eagle & Baunez, 2010). We will use the stop-signal task because it provides a quantitative measure of motor inhibition by examining the stop signal reaction time (SSRT) and the stop accuracy. The SSRT is the time needed by the rat to inhibit an initiated response, and the stop accuracy is the percent of stop trials during which the subject correctly inhibits a response (Bari et al., 2011). By obtaining and analyzing a subject's SSRT values upon completion of the SSRT, it is possible to use these values as a basis for measuring inhibitory control and impulsivity, as a longer SSRT and lower stop accuracy would indicate greater impulsivity and lower inhibitory control.

Experts in the fields of clinical psychology and psychopathology have made extensive use of SSRTs to study response inhibition in persons deemed to be generally impulsive, such as those with ADHD. Elevated SSRTs, which suggest that a greater amount of time is needed to inhibit an initiated response, have been associated with children and adult ADHD patients. This relationship has also been demonstrated in animal models of ADHD. A high SSRT value, therefore, is correlated to a lower level of inhibitory control and higher level of impulsivity (Verbruggen & Logan, 2009).

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Neurophysiology

The medial prefrontal cortex of the brain is a homologous area in both humans and rats that functions as an executive control center. The medial prefrontal cortex is a subsection of the prefrontal cortex and projects onto other brain areas, such as the insular cortex, nucleus accumbens, thalamus, amygdala, and brain stem, in top-down processing. The main neurotransmitters we are looking at are dopamine and noradrenaline which are necessary to the control of the medial prefrontal cortex and are decreased in ADHD patients.

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Fetal Nicotine Rats

The fetal nicotine rat model is one proposed animal model of ADHD. Although it is not yet an established model, studies have already shown a correlation between maternal smoking increased rates of ADHD in children. The purpose of our research is to either validate or invalidate the fetal nicotine rat model, by breeding fetal nicotine rats and comparing their performance on the stop-signal task to control rats. The three types of validity that are crucial to developing an animal model are face validity, construct validity, and predictive validity. We aim to establish face validity, by determining if the rat displays the three primary symptoms of ADHD. We also aim to confirm construct validity through measuring neural firings in the brain of the rat, to determine if it follows the pathophysiology of the disease.

Nicotine



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Methodology

Our experimental design will investigate the behavioral, neurological, and pharmacological components of inhibition. A pilot study will evaluate the performance of fetal nicotine rats on a stop-signal task. Rats will perform this task n a recording box with directional light sources and directional reward wells. The rats will learn to associate light with reward direction (i.e., left light leads to reward in left well). These trials will be called go trials; the stop-signal trials consist of a second stimulus dictating the inhibition of the first light flash and a subsequent switch to the opposite well to receive the reward. This task illustrates the behavioral components of the inhibition of action. To add to this information, the neural activity of the medial prefrontal cortex of these rats will be recorded with surgically implanted electrodes. The recording of neural data allows for the analysis of the modulation of neural firing in this brain area during the inhibition of action.

Anticipated Conclusions

ADHD has been deemed a highly controversial disorder due to its reliance on behavioral observations instead of quantitative measures. This method of diagnosing ADHD has led to numerous misdiagnoses, rising medical costs, and incorrect medication prescriptions, which can be detrimental to the health of patients because of possible harmful side effects. An established association of ADHD to a particular brain region would be of great value to health professionals and pharmaceutical companies by delivering drug treatments to specific regions of the brain involved in monitoring ADHD symptoms.

Research has indicated that the medial prefrontal cortex (mPFC) is involved in controlling impulsivity, one of the most common symptoms of ADHD. Additional studies have demonstrated that, Adderall®, an amphetamine-based drug has been shown to increase the amount of dopamine and noradrenaline in the mPFC cortex and, consequentially, reduce impulsivity in rat models of ADHD. We aim to prove that the physiological pathways within the mPFC are disrupted in their inhibition of impulsivity by conducting single-unit recordings of fetal nicotine rats, which are known for their impulsivity, and comparing these to recordings of Long-Evans rats.