Download Summary of Resources - Gemstone Honors Program

GEMS202 Summary of Resources
Team RITALIN
1. Brian Barnett
2. Team RITALIN
3. Eagle, D. M., & Baunez, C. (2010). Is there an inhibitory-response-control system in the rat?
Evidence from anatomical and pharmacological studies of behavioral inhibition. Neurosci
Biobehav Rev, 34(1), 50-72. doi: S0149-7634(09)00100-6 [pii]10.1016/j.neubiorev.2009.07.003
4. Literature review article
5. a. The purpose of this study is to compile and evaluate a collection of recent research articles
on the topic of behavioral inhibition.
b. The research question asks if there is a body of evidence indicative of an inhibitory-responsecontrol system in humans and rats that spans multiple brain regions and neurotransmitter
pathways. The researchers hypothesize that the papers under review serve to establish a
rudimentary system of inhibition control in the brain.
c. This paper reviews a large quantity of articles that have been published, which means that each
paper reviewed affects the conclusion of the authors. The topics of the reviewed articles range
from establishing the function of brain regions like the subthalamic nucleus, orbitofrontal cortex,
and dorsal medial striatum to observing the effect of drugs like methylphenidate and atomexetine
on neurotransmitter pathways. Each of the above brain regions is tied to specific aspects of
behavioral inhibition such as the speed of the inhibition processes. Lesioning these regions helps
to establish a causal relationship between their activity and the ability to stop and reevaluate
decisions. By performing this analysis, the reviewers are able to point the direction of future
research into focused and specific areas such as neural recording of the orbitofrontal cortex or
functional magnetic resonance imaging of subthalamic nucleus.
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GEMS202 Summary of Resources
Team RITALIN
d. This paper concludes that there is a strong body of evidence for a model of inhibition control
that draws from both anatomical and pharmacological studies but further research should attempt
to bridge the gaps in this model. The subthalamic nucleus and dorsal medial striatum provide a
general model of inhibition of behavioral control. The orbitofrontal cortex seems to be an
outstanding candidate for further research because of its prominent role in inhibitory
management and its place at the forefront of the noradrenaline neurotransmitter pathway.
e. The review effectively assembles the conclusions of disparate studies into a cohesive model of
behavioral inhibition and details how to improve upon this model, which is definitely a
successful answer to the above research questions. The researchers accumulated a surprisingly
large number of papers to review and were able to logically and efficiently tie them together.
f. This review provides our project with an outline of methodologies including rat behavioral
tasks, lesioning models, and neurotransmitter pathways. We can feasibly use any of these
research methods in our study of ADHD and the review establishes a compilation of resources to
help us design our own tasks. We can choose between the stop-signal task, the 5 choice serial
reaction time task, or the delay-discounting task to observe rat inhibition behavior; furthermore,
we can choose between recording and lesioning of nine areas of the brain and manipulating three
major neurotransmitters to evaluate their role in inhibition.
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GEMS202 Summary of Resources
Team RITALIN
1. Brian Barnett
2. Team RITALIN
3. Aron, A. R. & Poldrack, R. A. (2005). The cognitive neuroscience of response inhibition:
relevance for genetic research in attention-deficit/hyperactivity disorder. Biol Psychiatry, 57(11),
1285-92. doi: S0006-3223(04)01106-0[pii]10.1016/j.biopsych.2004.10.026
4. Literature review article
5. a. The purpose of this study is to review existing research that evidences the existence of
endophenotypes for ADHD and behavioral inhibition in general.
b. The research question of this paper asks if response inhibition serves as a strong
endophenotype for ADHD and if it can be incorporated into future genetic and behavioral
studies.
c. Previous research in behavior and neuroimaging of adults has been subject to a meta-analysis
by the authors. The results lend credibility to the idea that the right inferior frontal cortex region
of the brain plays a significant role in the success of response inhibition. In addition, studies of
ADHD patients show that deficits in response inhibition are correlated with dysfunctional action
of right inferior frontal cortex. Research also shows that response inhibition deficiency is
heritable across generations and can be localized to a single gene, DRD4.
d. The authors conclude that while response inhibition capacity is in no way a determinant of
ADHD, its ability to distinguish ADHD patients from control subjects and its genetic heritability
allow it to serve as a potential endophenotype for ADHD. The right inferior frontal cortex and
noradrenaline neurotransmitter pathways are very important aspects of response inhibition and
the genes that control their development and activation should be studied thoroughly.
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GEMS202 Summary of Resources
Team RITALIN
e. The authors do answer their hypothesis through their research. According to their definition of
an endophenotype (a function that lies between genotype and expressed phenotype), response
inhibition is a useful marker for bridging the gap between genes and symptoms of disorders such
as ADHD.
f. This study goes in a different direction than our planned research outline because it deals with
genetics, but cross-disciplinary connections can be made between the identification of
endophenotypes of inhibition and neural bases of ADHD. Both seek to create an empirical
definition of behavioral inhibition and ADHD though tests such as the stop-signal task. This
review provides evidence for the right inferior frontal cortex as a large influence in successful
stop-signal behavioral inhibition, which means that we can attempt to study it in our research
project. In addition, this paper provides a basis for the means with which to perform
neuroimaging studies, which we can utilize in our research as an additional route for determining
the neural basis of ADHD.
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GEMS202 Summary of Resources
Team RITALIN
1. Valerie Cohen
2. Team RITALIN
3. Ray Li, C.-S., Huang, C., Constable, R. T., & Sinha, R. (2006). Imaging Response Inhibition
in a Stop-Signal Task: Neural Correlates Independent of Signal Monitoring and Post-Response
Processing. The Journal of Neuroscience, 26(1), 186-192. doi:10.1523/JNEUROSCI.374105.2006
4. Original research study
5. a. The purpose of this study is to determine the neural basis of response inhibition during a
stop-signal task in humans.
b. How has subjects’ post-response processing affected the results of previous stop-signal task
studies? The hypothesis is that by also examining faster and slower reaction times, instead of just
successful and unsuccessful tasks, the variable of post-response processing will be removed, and
the areas of the brain that directly affect response inhibition can be isolated.
c. Previous research has determined many localized brain regions that are associated with
response inhibitions in stop-signal tasks, particularly the right inferior frontal cortex (IFC).
However, this research did not account for subjects’ emotional responses to failing the previous
tests. By comparing those who were successful with shorter response times to those who were
successful with longer response times, this research aimed to remove that variable from its
results.
d. The researchers found little difference in activation of brain area use between the subjects who
had longer reaction times and the ones who had shorter reaction times.
e. They did answer their question, but the results were different from what they expected.
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GEMS202 Summary of Resources
Team RITALIN
f. This study reveals that the subjects’ processing of their previous response may show up while
we’re measuring brain activity. While these were human subjects, we also need to examine how
these variables might affect rats. This study also suggests specific brain regions (the prefrontal
and central cortex) that may be integral to response inhibition. These suggestions are helpful as
we try to narrow down which regions of the brain we wish to focus on. Lastly, this study looked
for a linear correlation between reaction time of the subjects and increased activation in the
relevant brain areas. This suggestion might be a good approach for analyzing our own data, since
we wish to establish a direct correlation between certain regions of the brain and response
inhibition.
g. One limitation of this study was that only 24 subjects were tested. This makes it difficult to
account for how genetic variability plays into the study. Research with more subjects would be
needed to ensure that genetic variability is not affecting this study.
h. This study had qualitative and quantitative components. The quantitative component was
putting the subjects through stop-signal tasks, while measuring their brain activity with an fMRI.
The qualitative component was a survey administered to subjects on which they ranked their
frustration over their performance on the tasks.
i. The primary method for collecting data was the use of the functional magnetic resonance
imaging on the subjects being studied. Subjects were also surveyed after their third block of tasks
to rate their frustration on a Likert scale from 1 to 10.
j. Statistical Parametric Mapping Version 2 was used to analyze the data. After mean functional
image volumes were calculated, they were normalized to a Montreal Neurological Institute EPI
template with affine registration. They then ran a t-test, correcting for functional discovery
response.
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GEMS202 Summary of Resources
Team RITALIN
1. Valerie Cohen
2. Team RITALIN
3. Verbruggen, F., & Logan, G. D. (2009). Models of response inhibition in the stop-signal and
stop-change paradigms. Neurosci Biobehav Rev, 33(5), 647-661. doi: S0149-7634(08)00144-9
[pii] 10.1016/j.neubiorev.2008.08.014
4. Literature review article
5. a. The purpose of this review is to examine different models for measuring response inhibition
in the stop-signal task (SST).
b. What are the most important measures of inhibitory control in the stop-signal model? The
hypothesis is that the independent horse-race model of Logan and Cowan is particularly effective
in explaining the data from SSTs.
c. A lot of research has been done into stop-signal tasks and analysis of the results of these tasks.
Scientists have already determined time parameters for effectively measuring SSTs. Established
quantitative systems for measuring the subjects’ reactions in SSTs have been developed. This
review sought to compare the most common systems for analyzing stop-signal tasks and consider
on the systems for analyzing SSTs that are currently in development.
d. This review found that the independent horse-race model seemed to best account for the stop
and go processes in the brain. Only when the stop process finishes before the go process does the
subject inhibit reactions. The reviewers also clarified the best method for determining stop-signal
reaction time (SSRT) and functions of inhibition, which are necessary for showing compatibility
between different tasks and reactions. The review found that the newer, more complex horserace models, which at certain points lacked the generality of the independent horse-race model,
were worth pursuing.
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GEMS202 Summary of Resources
Team RITALIN
e. They met their goal of reviewing different models for measuring response inhibition, and their
argument regarding horse-race models was persuasive.
f. This review suggested that there is a point at which launched processes in the brain cannot be
inhibited. This idea is critical to understanding how the brain works during a stop-signal task and
the method we plan on using to examine the neural correlates of ADHD. The independent horserace model is a good model to use when analyzing the data from an SST because it is crucial that
we interpret our data carefully. However, this review also warns against assuming too much
about the independence of these functions. In most behavioral studies, the stop and go processes
are functionally dependent. This is relevant to our team because even though the horse-race
model is useful in interpreting our data, we cannot rely on it too much. While it correlates with
the data from SSTs, it does not account for the connectivity of the brain.
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GEMS202 Summary of Resources
Team RITALIN
1. Taylor Hearn
2. Team RITALIN
3. Pliszk, S. R., Glahn, D. C., Semrud-Clikeman, M., Franklin, C., Perez III, R., Xiong, J., &
Liotti, M. (2006). Neuroimaging of inhibitory control areas in children with attention deficit
hyperactivity disorder who were treatment naive or in long-term treatment. The American
Journal of Psychology, 163(6), 8.
4. Original research study
5. a. The purpose of this study is to determine if the prefrontal and cingulate brain regions differ
in their activity in ADHD children relative to healthy comparison subjects.
b. Is the anterior cingulate cortex is involved in error detection and behavioral adjustment? Is
there a difference in neural activity between treatment-naïve ADHD subjects and those treated in
the long term? Researchers hypothesized that the healthy subjects would show an increase in
activity in the right dorsolateral prefrontal cortex as well as anterior cingulate cortex on stop
trials of a stop-signal task (SST), but subjects with ADHD would not.
c. It is already known that children with ADHD demonstrate a lack of inhibitory control, and
there is a network of brain regions, including the anterior cingulate and prefrontal cortexes, that
is involved in inhibitory control.
d. ADHD subjects had a greater activation of the right dorsolateral prefrontal cortex on stop
trials, but both subject groups showed activation. Healthy subjects activated the anterior
cingulate cortex when inhibition was unsuccessful, but ADHD subjects did not. Also, there was
no significant difference between the treatment naive and long term treatment patients.
e. The study found that, during unsuccessful inhibition, activity was observed in the anterior
cingulate cortex in control subjects but not in ADHD subjects. However, researchers did not
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GEMS202 Summary of Resources
Team RITALIN
expect both subject groups to have increased activation in the right dorsolateral prefrontal cortex
during the SSTs.
f. The study found that ADHD subjects did not show activation of the anterior cingulate cortex
nor the left ventrolateral prefrontal cortex after unsuccessful inhibition, which presents two brain
regions we could possibly study. The study also focuses on noninvasive brain imaging
techniques during trials, a method we may consider due to its less invasive nature. The
researchers also incorporated an SST into their study. We are highly considering this activity for
our study so we may want to model our SST after theirs.
g. One limitation of the study was that their stop-signal task did not include a “null event” so
there was no way to examine the effects of the “go” stimuli on their own. Also, the researchers
were not able to consider the effects of age or gender because of the small sample size.
h. Researchers studied a two subject groups, fifteen healthy subjects and seventeen with ADHD.
The ADHD subjects were then broken down into a group of eight treatment naïve subjects and
nine subjects who had undergone long-term treatment but were medication-free at the time of the
brain scans. Subjects consisted of both males and females ages nine to fifteen. Each subject
performed the stop-signal task while monitored by the fMRI.
i. The study utilized a GE/Elscin 2T Prestige system for all scans and tools with this package for
functional image analysis.
j. The researchers used multiple programs from the fMRI of the Brain Software Library to
analyze the fMRI scans as well as MANOVA and ANOVA statistical tests to examine
differences between treatment-naive and previously treated patients
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GEMS202 Summary of Resources
Team RITALIN
1. Taylor Hearn
2. Team RITALIN
3. Tian, L., Jiang, T., Wang, Y., Zang, Y., He, Y., Liang, M., ... Zhuo, Y. (2006). Altered restingstate functional connectivity patterns of anterior cingulate cortex in adolescents with attention
deficit hyperactivity disorder. Neurosci Lett, 400(1-2), 39-43. doi: S0304-3940(06)00151-0 [pii]
4. Original research study
5. a. The purpose of this study was to investigate the resting-state functional connectivity pattern
differences of dorsal anterior cingulate cortex (dACC) in adolescents with and without ADHD.
b. Researchers hypothesized that either the functional connectivities between dorsal anterior
cingulate cortex and cognitive control related brain regions, or those between dACC and
autonomic control related brain regions, or both kinds of these connectivities, would be abnormal
in ADHD patients.
c. It is already believed that abnormalities in the fronto-striatal network are the core deficits of
ADHD. However, this study used fMRI scans during resting-state as opposed to task-based
studies, which makes it more comparable across different patient groups.
d. The dACC had more significant resting-state functional connectivities with several other brain
regions in the ADHD patients as compared to the controls, which may indicate abnormalities of
autonomic control functions.
e. These results do supports support the study’s hypothesis, and builds upon it by advocating the
practicality and noninvasiveness of fMRI scans as a means for pathology analysis.
f. This study suggests a brain area (dACC) that shows promise for having a neural correlate to
ADHD. It also recommends a practical diagnostic method for ADHD, which we may be able to
build upon as a way to further our research. The article also describes several regions that have
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GEMS202 Summary of Resources
Team RITALIN
functional connectivities with the dACC, which may be useful for our group to at least consider
studying.
g. The major limitation of the study would be is the sample size, 12 ADHD patients and 12
controls. However, we would not be able to improve upon this by much due to our limited
resources.
h. This study had an ADHD and a control group whose dACCs were quantitatively studied using
fMRI scans while the subjects were in a conscious, resting-state. Subjects were ages 11-15, male,
right-handed, and had an IQ>80 on the Wechsler Intelligence Scale for Children.
i. The researchers used a SIEMENS TRIO 3-Tesla scanner to image the subjects, who were told
to not to concentrate on any particular thing, relax, and close their eyes.
j. Researchers used a random-effect two-tailed two-sample t-test to analyze the data after using
various techniques such as Statistical Parametric Mapping to normalize their brain images.
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GEMS202 Summary of Resources
Team RITALIN
1. Emily Jones
2. Team RITALIN
3. Bari, A., Robbins, T. W., & Hagan, J. J. (2011). Animal Models of ADHD. In J. J. Hagan
(Eds.), Molecular and Functional Models in Neuropsychiatry (Vol. 7, pp. 149-185). Heidelberg,
Berlin: Springer-Verlag.
4. Literature review article
5. a. The purpose of this book chapter is to describe the most common animal models of ADHD
induced by genetic, physical, or chemical methods. The author’s goal was to analyze how
effectively each model exhibits the three traits of ADHD (inattention, hyperactivity, and
impulsivity) through the lens of face, predictive, and construct validity.
b. Which animal models of ADHD most closely resemble the human aetiology by presenting
neuroanatomical, neurochemical, method of origin, and behavioral similarities? The selection of
rats from a sample population that exhibit higher magnitudes of ADHD categorized behaviors
rather than the artificial generation of traits will most likely yield the best models according to
dimensional and multi-deficit approaches when analyzed for predictive and construct validity.
c. Animal models of ADHD symptoms have been produced for decades, generated by
identifying genes or brain structures that cause behavioral deficits in ADHD patients and
removing them in laboratory rodents. However, no complete model which presents all three
behavioral features (inattention, hyperactivity, and impulsivity) with constructive validity has yet
been proposed. Furthermore, the study provides an analysis of current animal models of ADHD,
which elucidates what methods should be adapted in future experiments to create a model that
could match human ADHD aetiology and the DSM-IV definition of ADHD. This would allow
more in-depth studies of ADHD pathology than clinical studies with human patients could.
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GEMS202 Summary of Resources
Team RITALIN
d. The study concluded that there are multiple aetiological and pathological pathways for
developing an ADHD phenotype in animal models, and that this could explain the heterogeneity
in ADHD patient behavior types. No single pathway can replicate ADHD in humans: lesion
studies are effective but assume that neural circuits and neurotransmitter systems work in a
vacuum, knock-out studies do not account for gene interaction or environmental factors, and
trauma and toxin studies only account for rare human ADHD cases. Therefore, selecting for an
ADHD phenotype in rats and then cross-breeding these individuals to naturally create an ADHD
genotype will allow neural, genetic, and behavioral abnormalities to be examined together and
will better reflect ADHD in humans. Furthermore, multiple translational neuropsychological
tasks (tests which can be used to measure ADHD behaviors in humans and in animal models)
should be employed to accurately classify the ADHD phenotype, in concurrence with a multidimensional diagnostic approach.
e. The results did answer the research question and matched the researchers’ hypothesis. They
analyzed which models were the most effective and predicted that selection for a phenotype
would be the best model, although they could not validate this claim as studies involving such
models from their laboratory are not yet published.
f. The study found that impulsivity on delay discounting and stop-signal tasks classify 90% of
patients with ADHD; we could better analyze if our rat model of ADHD has predictive validity
by testing the rats in both types of tasks. They further classify ADHD along three behavioral
dimensions, which could help us define our rat model according to its subphenotype. Finally,
they named the orbitofrontal cortex, dorsal-medial prefrontal cortex, and dorsal-medial striatum
as the brain regions controlling stop-signal task impulsivity; we will therefore consider lesioning
these areas in our model.
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GEMS202 Summary of Resources
Team RITALIN
1. Emily Jones
2. Team RITALIN
3. Winstanley, C. A., Eagle, D. M., & Robbins, T. W. (2006). Behavioral models of impulsivity
in relation to ADHD: translation between clinical and preclinical studies. Clin Psychol Rev,
26(4), 379-395. doi: S0272-7358(06)00002-X [pii] 10.1016/j.cpr.2006.01.001
4. Literature review article
5. a. The purpose of this review article is to define the nature of impulsivity and to examine how
experiments can analyze the various aspects of this multi-dimensional trait through translational
neuropsychological tasks and develop behavioral models through neuroanatomical and
neurochemical modifications.
b. How can the multiple facets of impulsivity exhibited in ADHD be defined through
categorization, modeled through lesions and neurotransmitter antagonists, and examined through
delay discounting and reaction time tasks? Impulsivity can be defined by identifying common
themes from psychological questionnaires; structural abnormalities present in the prefrontal
cortex and ventral striatum and neurotransmitter abnormalities of the dopamine and serotonin
systems can be used to develop a laboratory model of ADHD; reaction time tasks will measure
impulsive action while delay discounting tasks will measure impulsive choice.
c. Impulsivity as it is exhibited in ADHD has already been broadly defined, but no one has yet
taken associated behaviors measured in clinical studies and converted them into operational
categories that can be measured in lab models. Various translational tasks and animal models of
ADHD are also well established, but have not been analyzed for efficacy and purpose.
d. This review determined that impulsive behaviors can be grouped into two categories:
impulsive action and impulsive choice. Impulsive action can be measured by go/no-go, stop-
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GEMS202 Summary of Resources
Team RITALIN
signal, and five-choice serial reaction time tasks. Impulsive choice can be measured by delaydiscounting paradigms. The prefrontal cortex is responsible for both categories of impulsivity –
most importantly impulsive choice – while the ventral striatum is responsible mainly for
impulsive action due to its presence in the limbic-motor interface. Both the serotonin and the
dopamine system affected impulsive action.
e. The study’s results did answer the research question; the hypothesis was confirmed. They
grouped features of impulsivity to form an operational definition, and found that the most
common translational tasks and areas of neuroanatomical study could be classified according to
this system. However, the study did not examine the effects of the dopamine and serotonin
systems on impulsive choice, most likely due to lack of prior studies.
f. The study also classifies two ADHD subphenotypes: the “thought and action” pathway and the
“motivational style” pathway. We can better classify what dimension of impulsivity expressed in
ADHD we are studying by focusing on the basal ganglia, striatum, and mesocortical
dopaminergic system implicated in the “thought and action” pathway. The study also observes
that stop-signal reaction time (SSRT) tasks are not sufficient for analyzing impulsivity, as the
“horse-race” analysis model used to calculate SSRTs does not account for changes in response
strategy, and increased SSRTs are not unique to the ADHD phenotype. We should be cautious in
our application and analysis of our own SSRT results with this in mind. Finally, the study
implicates frontal-striatal activation and the caudate nucleus in impulsive action; we can consider
these areas for lesioning in our experiments.
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GEMS202 Summary of Resources
Team RITALIN
1. Reshma Kariyil
2. Team RITALIN
3. Ito, S., Stuphorn, V., Brown, J. W., & Schall, J. D. (2003). Performance monitoring by the
anterior cingulate cortex during saccade countermanding. Science, 302(5642), 120-122. doi:
302/5642/120 [pii] 10.1126/science.1087847
4. Original research study
5. a. The purpose of this study is to see how the anterior cingulated cortex (ACC) is involved in
controlling goal-directed behavior.
b. What is the function of the ACC in controlling behavior directed towards a goal? The
researchers formulated two hypotheses. First, they hypothesized that the ACC is involved in
signaling between intended and actual responses and reinforcement. Second, they proposed that
the ACC is involved in signaling conflict when opposing responses occur at the same time,
causing error.
c. It is already known that the ACC is involved in monitoring performance in goal-directed
behavior, but how it does so is uncertain. This study adds to the literature by studying neurons in
the ACC involved with error, reinforcement, and conflict.
d. There was not as much activity in error-related neurons during canceled stop-signal trials as
there was during latency-matched no stop-signal trials. The researchers concluded that those
neurons in the ACC were not active when neurons from the supplementary eye field (SEF) were
signaling conflict. When reinforcement was omitted, many error-related neurons became active.
Reinforcement–related neurons were active during reinforcement, but not after errors were made.
There was no activation in conflict-related neurons in the ACC.
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GEMS202 Summary of Resources
Team RITALIN
e. The researchers were able to find that the ACC plays a role in comparing predicted and actual
consequences, but is not involved in signaling conflict. Through this, the researchers were able to
answer their question.
f. This study incorporated a stop-signal task, which is a task we will use, into the saccade
countermanding task. In this study, the anterior cingulate cortex region of the brain was studied,
which we may study as well. Saccades are associated with our topic of study, ADHD, because
antisaccades, movements of the eyes away from a stimulus, are common in those with ADHD. If
possible, we can incorporate a saccade-countermanding task into our project as well.
g. One major limitation of this study is that there were only two monkeys used as subjects. In
addition, there may be differences in the signaling pathways of monkeys and humans, which
leads to the possibility of obtaining different results if human subjects are used.
h. Two macaque monkeys were used in this study. They both performed the saccadecountermanding task in which their ability to withhold intended saccades was tested. During the
task, recordings were taken from error-related, reinforcement-related, and conflict-related
neurons from the anterior cingulated cortex.
i. The researchers used a PDP 11/83, a minicomputer, to present the stimuli and record the eye’s
position. A Plexon system was used to record spikes.
j. The data was analyzed by creating plots of neuron activity and diagrams of the locations of
neurons in the monkeys’ brains. Mean latencies of activities were calculated.
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GEMS202 Summary of Resources
Team RITALIN
1. Reshma Kariyil
2. Team RITALIN
3. Acheson, A., Farrar, A. M., Patak, M., Hausknecht, K. A., Kieres, A. K., Choi, S., ... Richards,
J. B. (2006). Nucleus accumbens lesions decrease sensitivity to rapid changes in the delay to
reinforcement. Behav Brain Res, 173(2), 217-228. doi: S0166-4328(06)00346-9 [pii]
10.1016/j.bbr.2006.06.024
4. Original research study
5. a. The purpose of this study is to examine the role of the nucleus accumbens (NAC) in
affecting delay and probability discounting.
b. What is the neurological basis for delay discounting? How does the NAC affect delay
discounting? Are delay and probabilistic reinforcement controlled by the same region of the
brain? The researchers hypothesized that lesions to the NAC would create deficits in adapting to
delay reinforcement changes.
c. One characteristic of ADHD is impulsivity, or delay discounting. However, there is little
evidence for a neurological basis of delay discounting. This study adds to existing literature by
examining the effects of lesions to the NAC on delay discounting.
d. When the delay to the reward was unchanged across trials, there was no effect on delay
discounting in the lesioned or sham group. When the delay was increased, the lesioned group had
higher indifference points, meaning they were less impulsive. The lesioned group was not as
sensitive to changes in the delay and amount of the reward, which suggests that the ability to
adapt to such changes was impaired. Because probability discounting was not affected on the
adjusting amount procedure task, the researchers concluded that probability and delay
discounting are controlled by different pathways in the brain.
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GEMS202 Summary of Resources
Team RITALIN
e. Since there was no effect on delay discounting when the delay was unchanged, the researchers
did not completely answer their question about what the neurological basis of delay discounting
is. Since the rats’ ability to adapt to changes was impaired, they saw that the NAC may play a
role in adapting to changes in delay. They also found that different neural pathways are involved
in delay and probabilistic reinforcement.
f. This study solely focused on the NAC, which is one of the regions of the brain that we will be
focusing on in our study. We can use a similar methodology for the delay discounting task to use
as a behavioral component to our project. The researchers in this study used Neuronal Nuclei, or
NeunN, staining to confirm lesion damage, which we might consider using to confirm lesion
damage in our rats’ brains.
g. As stated by the researchers, the delays used in this study were significantly shorter than those
in a similar study, which could have affected the outcomes. In this study, both the core and shell
regions of the NAC were damaged, thereby requiring additional research to determine the effects
on delay discounting of each individual region.
h. Forty-eight male Holtzman Sprague-Dawley rats were trained for the delay discounting and
probability discounting tasks. They were randomly put into lesion or sham groups, and 0.15 M
quinolinic acid was used to lesion the NAC of the lesion group. The tasks were performed before
and after surgery. Indifference points were determined for both pre-surgery and post-surgery
tasks.
i. Adjusting amount procedure apparatuses/chambers were constructed with infrared detectors to
detect nose pokes into water dispensers.
j. The researchers used NeuN staining to analyze the lesions and constructed discount and
probability curves to analyze the data from the tasks.
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GEMS202 Summary of Resources
Team RITALIN
1. Alice Kunin
2. Team RITALIN
3. Risterucci, C., Terramorsi, D., Nieoullon, A., & Amalric, M. (2003). Excitotoxic lesions of the
prelimbic-infralimbic areas of the rodent prefrontal cortex disrupt motor preparatory processes.
Eur J Neurosci, 17(7), 1498-1508. doi: 2541 [pii]
4. Original research study
5. a. The purpose of this study is to explore how the medial prefrontal cortex’s (mPFC) ability to
process information affects reaction time and motor planning in rats.
b. Does lesioning the prelimbic-infralimbic (PL-IL) region of the mPFC alter rodent control of
forelimb movement in a reaction time task? Risterucci et al. hypothesized that for rodents to
perform a rapid movement after the presentation of a sensory cue, regions of the mPFC must be
intact to process the stimulus and react accordingly.
c. It is already known that the mPFC is in engaged in humans when subjects must react to
sensory stimuli and plan actions. However, many brain regions are not conserved between rats
and humans, so the researchers aimed to test if the cortical bases underlying motor control were
the same in rats so that rats may be used as testable models for human mPFC dysfunctions.
d. This study found that when the PL-IL region mPFC was lesioned, rats gave significantly fewer
correct responses on reaction time tasks, and were also much more likely to respond prematurely
rather than to wait for the sensory cue to attempt to receive the reward. Overall, these results
indicate the PL-IL area of the mPFC in rats regulates motor readiness, controls impulsive
responsiveness, and may be involved in adjusting behavior when one’s response must be
delayed. This indicates that PL-IL lesioned rats can be used to reproduce deficits observed in
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humans with disinhibitory behaviors, such as those observed in humans who have attention
deficit hyperactivity disorder (ADHD).
e. These findings answered the study’s research question and the researchers’ hypothesis was
correct.
f. This study describes in detail how the rats were lesioned excitotoxically by flooding the mPFC
with excessive stimulation by neurotransmitters to destroy brain cells in that region. This is an
effective way to deactivate brain regions of interest, and we may need to use this method in our
experiment. It also provides us with a brain region for further study; if the PL-IL is involved in
motor preparatory processes, we may study this region’s efferents and afferents to determine
what other brain structures are involved in this information processing. Further, it also gives a
detailed procedure for examining the rat brains after testing to determine that the lesions did, in
fact, occur in the area of interest. This will help us validate our data.
g. This study was forced to assume that rats were prematurely responding because their reaction
times were too short for them to have accurately processed the sensory cue. However, the exact
time it takes individual rats to process these signals is unknown and must be estimated, which
may have caused quickly-reacting rats to be recorded as premature and impulsive.
h. This study excitotoxically lesioned a group of rats and compared them with sham-operated
controls. The reaction time task required the rats to depress a lever until the sensory cue was
presented until they could receive the reward. The amount of time before the cue was presented
varied. After the study, the rats’ brains were frozen and dissected to confirm lesion damage.
i. Microcomputers were attached to operant boxes to record rat movement, lever depression, and
rat nose-pokes into the reward box.
j. Data was analyzed using analysis of variance (ANOVA), t-tests, and the Newman-Keuls test.
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GEMS202 Summary of Resources
Team RITALIN
1. Alice Kunin
2. Team RITALIN
3. Uslaner, J. M., & Robinson, T. E. (2006). Subthalamic nucleus lesions increase impulsive
action and decrease impulsive choice - mediation by enhanced incentive motivation? Eur J
Neurosci, 24(8), 2345-2354. doi: EJN5117 [pii] 10.1111/j.1460-9568.2006.05117.x
4. Original research study
5. a. The purpose of this study was to determine the subthalamic nucleus’ (STN) role in
mediating impulsivity, as well as the effects of food restriction and amphetamine (Ritalin) use in
subjects with dysfunctional STN.
b. Does lesioning the STN in rats affect impulsive action and impulsive decision making? Does
amphetamine use or food restriction further affect the impulsivity of STN lesioned rats? Uslaner
and Robinson predicted that lesioning the STN would increase both impulsive action and
impulsive choice, and that amphetamine and food restriction would exacerbate these effects.
c. STN was already known to play a role in motor control but its role in impulse control was
uncertain. While some studies showed increased impulsive behavior after STN lesions, others
reported decreased impulsivity. They hoped to find an explanation for these discrepancies.
d. The study found that STN lesions increased impulsive action since the rats responded very
quickly to reward stimuli. Food restriction and amphetamines exacerbated these effects in STN
lesioned rats, but not in controls. In addition, STN lesions decreased impulsive choice since the
lesioned rats were more willing to wait in a delay-discounting task to receive larger rewards
rather than small, immediate rewards. Amphetamines and food restriction further decreased the
lesioned rats’ impulsive choice. They concluded that rather than affecting impulsivity, lesions to
the STN magnified the incentive value of rewards so the rats appeared more impulsive by
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responding quickly, and less impulsive by choosing to wait when a larger reward was at stake.
They proposed that the STN plays a role in inhibiting inappropriate responding for incentives.
e. The study answered the research question of the STN’s role in impulsivity, although their
hypothesis was not supported by the data.
f. This study tested the effects of amphetamines on the lesioned rats. Ritalin is structurally
similar to amphetamines and our team has considered administering Ritalin to rats after lesioning
to determine if it helps their condition. The study also provides detailed instructions of how to
train rats for delay discounting tasks, which our team may use since these tasks are a common
method for assessing impulsive behaviors. Also, since many brain areas are involved in
impulsivity, this study will help us narrow our search to particularly looking at the afferents and
efferents of the STN and how they also affect impulsivity.
g. Only 17 rats in the study were found to have fully lesioned STN and were included in the data,
so this small sample size may have made the data less accurate than a larger sample of rats
would. Also, the rats were only studied for two weeks so it is unknown if longer administration
of amphetamines would have altered their performance, since some medications take several
weeks for full expression of the chemical to occur.
h. The study used two tasks, the DRL-30-s which measures behavioral disinhibition, as well as a
delay discounting task to measure impulsive choice. A group of sham rats served as controls.
After testing, rats’ brains were removed and dissected to verify that lesions were in the STN.
i. Data was collected by using microcomputers to record the time taken for rats to depress the
reward levers.
j. Mixed model ANOVA as well as t-tests and the Bonferroni procedure were used to analysis
data and control for multiple comparisons.
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GEMS202 Summary of Resources
Team RITALIN
1. Sae In Kwak
2. Team RITALIN
3. Depue, B. E., Burgess, G. C., Willcutt, E. G., Ruzic, L. L., & Banich, M. T. (2010). Inhibitory
Control of Memory Retrieval and Motor Processing Associated with the Right Lateral Prefrontal
Cortex: Evidence from Deficits in Individuals with ADHD. Neuropsychologia, 48(13), 39093917.
4. Original research study
5. a. The purpose of the study was to determine whether ADHD patients have dysfunction in
memory retrieval rather than the motor domain of their brain by examining inhibitory function.
b. The individuals with ADHD will have low ability to process inhibit memory retrieval, thus
they will have significantly low activity in rostrolateral prefrontal cortex (rLPFC), which
regulates the posterior parts of brain that support memory.
c. There have been a number of studies done on inhibitory control in the motor domain of the
ADHD individuals; however, additional research is required to determine the effects in
psychological or cognitive domains such as memory inhibition. According to previous studies,
there is substantial evidence that shows rLPFC regions become active when the subjects are
requested to inhibit an emotional response. It is possible that rLPFC may support inhibition
across different domains.
d. Prefrontal brain regions of right middle frontal gyrus (rMFG) in the control group showed
significantly greater activity than the ADHD individuals during inhibition over memory retrieval.
This reveals that ADHD individuals’ reduced activation in prefrontal regions, especially rMFG,
as compared to increased activation in posterior significantly demonstrate their inability to
suppress inhibitory memory function.
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e. Yes; even though they did not specifically focus on rLPFC, they found that there is a negative
relationship between the prefrontal and posterior region of the brain, especially about their
crucial role in controlling inhibitory emotional memory. This supports their hypothesis, since
rLPFC is included in prefrontal region of the brain, where it shows a significant decrease when
the ADHD patients are asked to stop thinking about irrelevant information.
f. This study gives a general idea of what brain regions we can lesion to simulate ADHD.
According to the study, there is a negative relationship between prefrontal and posterior regions
of the brain, which are in charge of representing memory, and controlling inhibitory emotional
memory respectively. Also, rMFG and rLPFC can be further studied by using the rats, since only
the humans were tested in this study. In addition, the stop-signal task that was used in this study
can be modified and utilized to measure the significance of artificial ADHD symptoms.
g. The ADHD individuals used in this study were volunteers, so there would have been some
bias among the participants. Also, some of the ADHD patients were on medication, which would
have affected the data.
h. Think/no-think test uses face-picture pairs to measure the ability of memory retrieval of the
subjects. Also, stop-signal task was used in this study only on the ADHD patients. The participant
was instructed to press either the X or O key as rapidly as possible for each trial, but to follow
the instructions of the audio when presented.
i. The individuals were evaluated using the think/no-think test, and the stop-signal task, as
explained in part h.
j. Image analysis was used in this study. Percent signal change analyses were performed using
FSL’s Featquery signal change processing tool. Featquery was used to interrogate the percent
signal change of regions of interest defined for the control individuals the ADHD individuals.
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GEMS202 Summary of Resources
Team RITALIN
1. Sae In Kwak
2. Team RITALIN
3. Hsu, J., Lee, L., Chen, R., Yen, C., Chen, Y., & Tsai, M. (2010). Striatal volume changes in a
rat model of childhood attention-deficit/hyperactivity disorder. Psychiatry Research, 179(3),
338-341. doi:10.1016/j.psychres.2009.08.008
4. Original research study
5. a. Previous studies show that the striatum is reported to be abnormal in size in ADHD patients,
but it is still not clear how it changes during developmental stages.
b. There will be the greatest abnormal growth in striatum during the puberty stage.
c. A number of previous volumetric imaging studies have shown the importance of basal
ganglia’s role as a pathophysiological factor in ADHD. The basal ganglia receives input from the
neocortex through the striatum and sends processed information to the prefrontal cortex, which is
in charge of motor planning, learning, and execution. Correspondingly, significantly low activity
of striatal region was found in the individuals with ADHD. Previous studies found that the
pallidum and caudate volumes of ADHD patients correlated with severe ADHD symptoms and
poor cognitive performance. Based on this information, volumetric differences of the caudate
nucleus may be related to hyperactivity or impulsivity with ADHD individuals.
d. The time interval which yields the maximum striatal volume change was at the age of 5 weeks
in spontaneous hypertensive rats (SHRs), which corresponds to approximately 7-9 years in
humans. Also, the striatal volumes of SHRs were significantly smaller than those of the controls,
which corresponds to a previous study that found that ADHD individuals have smaller caudate
nucleus volumes than the controls.
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e. Yes. This study found that there was a significant growth in striatal volume at the age of 5
week among the SHRs, which is equivalent to right before the puberty stage in humans.
f. This study specifically focused on volumetric changes of striatum during developmental stages
of the SHRs and Wistar-Kyoto (WKY) rats. It demonstrated that the maximum change in the
volume of stratum appears in the 5th week in SHRs, which is equivalent to 7-9 years in humans.
Based on this study, we can focus on the area around the striatum and investigate whether the
nuclei compartments surrounding striatum contribute to this change. Also, when artificially
creating ADHD symptoms in the rats, we can lesion the striatum, since the study indicated that
the ADHD individuals have a smaller striatal volume. In addition, we could consider as a followup study measuring methods to increase striatal volume as a treatment for ADHD.
g. In this study, the researchers use SHRs and WKY rats to investigate the significant growth of
striatal volumes in each stage of growth. However, rats’ and humans’ ages differ significantly, so
we may need to consider a discrepancy in growth patterns.
h. SHRs and WKYs were used to study volume differences of the striatum at various stages of
age. Micrographs of Nissl-stained serious sections in both rats at the ages of 4 to 10 weeks were
used to measure volumes of the bilateral striatum.
i. In order to calculate the cross-sectional area of the striatum and the volume of the striatum of
the subjects, researchers used the Cavalieri estimator. Also, Nissl-staining was used to stain the
cell body of striatum.
j. A two-tailed t-test was utilized to analyze the data. The paired t-test was used to compare the
right and left striatal volumes in a rat. In addition, the unpaired t-test was used to compare the
striatal volumes between WKY rats and SHRs.
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GEMS202 Summary of Resources
Team RITALIN
1. Jessica Lee
2. Team RITALIN
3. Rubia, K., Smith, A., & Taylor, E. (2007). Performance of children with attention deficit
hyperactivity disorder (ADHD) on a test battery of impulsiveness. Child Neuropsychol, 13(3),
276-304. doi: 777240805 [pii] 10.1080/0929704060077076
4. Original research study
5. a. This study analyzed the performances of children with ADHD on six tasks measuring
cognitive control, cognitive inhibition, sustained attention, and time discrimination.
b. Do children with ADHD have deficits in all inhibitory, motivational, attentional, and time
management domains, or mostly in a specific domain? The researchers hypothesized that these
deficits, such as increased intrasubject variability and premature responses, would be apparent in
all six cognitive tasks and be a main feature of impulsivity.
c. It is already known that impulsivity in ADHD patients results from an inability to inhibit
responses; it is characterized by problems in self-control functions and timing behavior.
Researchers administered a Maudsley Attention and Response Suppression (MARS) task battery
to determine whether any specific task domain showed deficits in cognitive control functions.
d. Inconsistent and premature responses in patients with ADHD were task-independent; ADHD
patients also showed problems with time estimation, motor inhibitory control, and sustained
attention. These cognitive tasks were correlated with each other and with impulsivity; however,
cognitive inhibition did not seem to play a role in impulsiveness, and the presence of a reward in
the motivational task did not improve deficits.
e. This study did answer the study’s research question. The different tasks supported the theory
that ADHD is primarily characterized by deficits in motor rather than cognitive inhibition.
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f. This study suggests that deficits in motor inhibition deficits are more prevalent than deficits in
cognitive inhibition in ADHD patients, which will help our team to focus primarily on areas of
the brain that are geared towards motor processes. Although our team is using rats as models,
this article provides a variety of methods that could be used in human subjects, which we would
implement if we were to do clinical testing in the future in conjunction with the Psychology
Department. In addition, this study uses the same statistical t-tests that we will be using to
analyze our own data.
g. This study had a relatively small sample size (only 32 ADHD patients and 34 healthy control
patients), which hindered the data’s statistical power. In addition, the positive predictive value
(PPV) was rather low because of its dependence on the prevalence of the disorder. The PPV is
the fraction of patients who show positive test results and are diagnosed correctly.
h. This methodology was both qualitative and quantitative. Patients had to have scored above the
threshold for hyperactivity in the Strengths and Difficulties questionnaire (SDQ), which is based
on a scale of 0-10. They also took a Raven Progressive Matrices IQ test, where ADHD
participants scored above the 5th percentile. Both groups participated in six tasks--Go/No-Go,
Stop, Stroop, Switch, Rewarded CPT, and Time Discrimination tasks--set up in that order. These
tasks were all quantitative, determining mean reaction times.
i. This experimental study used the SDQ and IQ tests to determine which subjects would be
placed into the ADHD and control groups. These tests involved a screen displaying pictures, and
subjects’ responses were recorded using a 4-button gamepad.
j. Researchers used the statistical t-test to show that no significant differences existed in the data
for gender, handedness, IQ, or age and the Pearson correlation analysis to investigate correlations
between variables.
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GEMS202 Summary of Resources
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1. Jessica Lee
2. Team RITALIN
3. Cardinal, R. N., Pennicott, D. R., Sugathapala, C. L., Robbins, T. W., & Everitt, B. J. (2001).
Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science, 292(5526),
2499-2501. doi: 1060818 [pii] 10.1126/science.1060818
4. Original research study
5. a. This study analyzed the neuroanatomical basis of impulsivity in the nucleus accumbens and
its cortical afferents.
b. Does lesioning the nucleus accumbens (AcbC) and its cortical afferents, the anterior cingulate
cortex (ACC) and medial prefrontal cortex (mPFC), cause rats to make more impulsive choices?
The researchers hypothesized that the AcbC, ACC, and mPFC play a key role in affecting
impulsivity in the delay-discounting task.
c. The nucleus accumbens is a crucial part of the brain that helps regulate choices. Also, ADHD
patients have shown abnormal functions in the ACC and mPFC; however, this study specifically
focuses on the neuroanatomical basis of impulsivity in the AcbC, ACC, and mPFC.
d. Lesioning the AcbC of the rats’ brains made them hyperactive and affected the rats’ ability to
choose a large delayed reinforcer because the rats were more likely to make an impulsive choice
in favor of the smaller, immediate reinforcer. Lesioning the ACC and the mPFC of the rats’
brains did not affect the rats’ ability to choose the delayed reinforcer.
e. The results of this study did answer the research questions appropriately because they
determined that the nucleus accumbens may play a role in ADHD symptoms, specifically in
impulsivity. They were concise with their research and findings. Their hypothesis was
confirmed.
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f. The delay discounting task that the researchers administered to their lesioned rats is very
similar to the task that our team plans to use on our rats (stop-signal task). This study provides us
with information about the nucleus accumbens, which will help our team to determine a specific
part of the brain to focus on. In addition, this article shows that the delay discounting task is a
good task to use when analyzing impulsivity and delays in rewards. This will help tremendously
when we are determining possible correlations in impulsivity and neurological bases.
g. This study does not identify the sample size used. This is a shortcoming because we do not
know whether or not the sample size was large enough for the results to be significant.
h. The rats were trained in a delayed reinforcement choice task in which they had to choose
between a small, immediate food reinforcer and a large, delayed food reinforcer. Then, the rats
had their AcbC, ACC, or mPFC lesioned. The data was mostly quantitative, because they
recorded the time it took for the rats to pick the different reinforcers. The differences in the rats
were observed, based on which part of their brain was lesioned.
i. To collect the data, the researchers observed the behaviors of the rats in the delayed
reinforcement choice task and recorded how many times each rat selected each reinforcer option.
j. The researchers created graphs of the pre-operative, post-operative, and delay omission tests
for the AcbC lesions, ACC lesions, and the mPFC lesions, which compared the delay to large
reinforcers in seconds with the percentage of choice of large reinforcers. The graphs showed that
the rats showed less preference for the larger reinforcer when there was more delay.
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GEMS202 Summary of Resources
Team RITALIN
1. Brooke Lubinski
2. Team RITALIN
3. Chambers, C. D., Garavan, H., & Bellgrove, M. A. (2009). Insights into the neural basis
of response inhibition from cognitive and clinical neuroscience. Neurosci Biobehav Rev., 33,
631-646.
4. Literature review article
5. a. The purpose of this review is to provide a comprehensive analysis of numerous studies
in order to identify the contribution of cognitive and clinical neuroscience, and molecular
genetics in regards to response inhibition.
b. To what degree do neural architecture, genetics, cognition, and individual differences
influence response inhibition? The authors suggest that each of these factors play a significant
role in determining how response inhibition is regulated in the brain.
c. It is already known that the right inferior frontal gyrus (IFG) is imperative for successful
response inhibition in stop-signal task trials. The authors seek to synthesize the information
gathered from numerous studies related to inhibition response, in order to determine the degree
to which different factors appear to regulate inhibition and suggest additional research.
d. The authors concluded that both the IFG and supplementary motor area (SMA/Pre-SMA)
appear to deter normal response inhibition. They also determined that there is a close relationship
between cognitive processes such as working memory and attention, and response inhibition.
Additionally, they suggested that ADHD and OCD appear to be familial, and that they are the
results of immature development of frontostriatal circuitry. Finally, they proposed that inhibitory
control is highly dependent on learning and neural plasticity.
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e. After reviewing lesion and clinical studies, TMS results, and additional evidence regarding
impulsivity, the researchers appear to answer their research question as well as offer insight to
additional factors that may influence inhibition. These additional factors should be the focus of
future research.
f. The authors discuss structural abnormalities of the prefrontal cortex, caudate nucleus and
globus pallidus in individuals with ADHD, suggesting three additional brain regions we could
study. The authors evaluate various methods used to measure inhibition, including go/no-go and
stop-signal tasks, which we can possibly use to measure impulsivity in our own research. The
authors’ review of the strong relationship between motivation, memory and inhibition is
something we should consider when we formulate our methods in order to ensure that our results
are based on impulsivity rather than confounding factors.
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GEMS202 Summary of Resources
Team RITALIN
1. Brooke Lubinski
2. Team RITALIN
3. Bari, A., Mar, A.C., Theobald, D.E., Elands, S.A., Oganya, K.C., Eagle, D.M. & Robbins,
T.W. (2011) Prefrontal and monoaminergic contributions to stop-signal task performance in rats.
J Neurosci, 31, 9254-9263.
4. Original research study
5. a. The purpose of this study is to determine the effect of temporarily inactivating different
prefrontal subregions in rats using muscimol microinfusions on their stop-signal task (SST)
performance and to identify the neural substrates of the noradrenaline reuptake inhibitor
atomoxetine.
b. What are the neural substrates of response inhibition, and what are the sites in the prefrontal
cortex (PFC) that decrease impulsivity due to the regulation by atomoxetine? Are the effects of
atomoxetine mediated by dopamine or norepinephrine?
c. It is known that lesions of the orbitofrontal cortex (OFC) create longer stop-signal reaction
time (SSRT) in rats; however, this effect is not observed when the prelimbic or infralimbic
cortices were lesioned. The researchers want to determine if the rat anterior cingulate cortex
(ACC) and other regions affected SST performance. It is also known that norepinephrine
neurotransmission is important in the regulation of prefrontal areas during response inhibition, so
the researchers seek to identify the specific neural substrates in rodents that are involved when
given atomoxetine, a drug used to treat ADHD.
d. Inactivation of the ACC or dorsal prelimbic cortex prolonged SSRT, and decreased stop
accuracy (i.e. the percentage of stop trials in which the go response was correctly inhibited). The
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researchers determined that atomoxetine decreases impulsivity during SST due to its interaction
with norepinephrine in the dorsal prelimbic cortex and OFC.
e. The results of the study answer the research questions. By temporarily inactivating portions of
the prefrontal cortex, and by reviewing the interactions of atomoxetine with various
catecholamines, the researchers also significantly advanced the scientific community’s
understanding of the neural circuitry and systems associated with response inhibition.
f. Impairment of the dorsomedial PFC increased the rats’ impulsivity thereby suggesting it may
have a neural correlate associated with ADHD. Our team should consider the role norepinephrine
has in determining inhibitory control because it is identified as a mediator in impulsivity due to
its interactions with atomoxetine. The paper describes how to inactivate brain regions utilizing
muscimol microinfusion, which our team may utilize in our research.
g. The researchers note that temporary inactivation of the OFC created a disruption in general
performance. Thereby, the SSRT estimates may not be accurate, thus preventing the researchers
from concluding to what degree manipulation of the OFC affects reaction time.
h. The methodology was quantitative. Rats initially underwent SST training. After gaining
baseline measurements, the rats were divided into groups based on their performance and
implanted with cannulae targeted towards the ACC, PFC, and OFC. Rats received intracerebral
microinjections and were then assessed on their performance on SST.
i. Data was collected by observing the rats’ performance in SST by determining their SSRT. The
rats were eventually euthanized and had their brains removed in order to determine the
placement of the cannulae.
j. The researchers analyzed their data using repeated-measures ANOVA as well as Mauchly’s
test and SME analysis. For post hoc testing, they used Fisher’s least significant difference.
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Team RITALIN
1. Gautam Rao
2. Team RITALIN
3. Boehler, C.N, Appelbaum, L.G, Krebs, R.M., Hopf, J.M., & Woldorff, M.G. (2010), Pinning
down response inhibition in the brain — Conjunction analyses of the Stop-signal task,
Neuroimage, 52, 1621-1632.
4. Original research study
5. a. The purpose of this study is to determine a function comparison between human brain
fMRI’s of response-related-inhibition and performance on stop-signal tasks
b. The present research question is to find a compromise between the two types of measuring
inhibition-related brain activity, Stop-trials and Go-trials, through conjugation analyses of fMRI
responses during each task. The results of this investigation will help to find neural processes
that link successful and unsuccessful stop-trials compared to those where the stop-trial did not
work (trials without response inhibition).
c. This article discusses how other works relating to response-inhibition and neural networks are
more conservative and do not fully explain response-inhibition related brain activity. This paper
uses conjugated analysis (using both sets of data rather than only one set) of Go-Trials and StopTrials coupled with Stop-relevant and Stop-irrelevant blocks to re-evaluate the areas of the brain
that are active during these tests. The paper gives a clear network of brain areas that are active
during Stop-signal tasks (SST), and possibly a new standard of how SSTs should be run.
d. The results of this paper include a series of brain areas that are active such as the occipital
lobe, parietal cortex, temporal-parietal junction, thalamus, caudate nucleus, and sub thalamic
nucleus, and anterior insula, which is interesting because without the use of conjugation we are
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able to see more regions of the brain activate during different parts of the test (i.e. the stop and
go signals).
e. The results do answer the research question. The question was to find brain areas that are
active during response related inhibition using successful and unsuccessful stop-trials, and this
was accomplished. The new areas that were seen active were only seen because of the
conjugated analysis which was the entire reason for the experiment.
f. As a team we could use the same conjugated analysis system on our stop-signal task with
successful and unsuccessful trials, which would mean that our team would have a broader area of
brain activity and brain areas to see the neurons. We could use the brain areas that are already
mapped in this article and see if other articles have similar ones and use these areas for testing
the stop-signal tasks. We could see if the same areas in the rats are similar in humans to make
sure the stop-signal task is working.
g. A limitation of the study is that it only studies normal humans, or ones that do not have
ADHD, so although the areas of the brain were mapped out, there was no relationship to the
brains of ADHD patients.
h. The methodology is a qualitative measure of the activity of brain areas in response to a stopsignal task and a quantitative measure of subject accuracy.
i. An fMRI machine was used to measure the brain activity and relate it to other parts of the brain
in different activity levels. The accuracy was determined on whether the subject was successful
in the stop-signal task or not.
j. The researchers analyzed data using a conjugated analysis which utilized both the successful
and unsuccessful trials and compared brain activity levels to create a clear network of brain areas
used in stop-signal tasks.
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GEMS202 Summary of Resources
Team RITALIN
1. Gautam Rao
2. Team RITALIN
3. Eagle, D. M., Baunez, C., Hutcheson, D.M., Lehmann, O., Shah, A.P., Robbins, T.W., (2007),
Stop-Signal Reaction-Time Task Performance: Role of Prefrontal Cortex and Subthalamic
Nucleus, Cerebral Cortex, 18, 178-188.
4. Original research study
5. a. The purpose of this research is to see the effect of lesioning different parts of the brain,
orbitofrontal cortex (OF), infralimbic cortex (IF), and subthalamic nucleus (STN), on SSRT
(stop-signal response tasks) and Go signal response tasks (GoRT).
b. The research question of this study is what areas of the brain are involved in a neural pathway
that controls a stop-response.
c. Other research shows that lesioning the brain causes a change in the SSRT overall. This
research proves that lesions of the prefrontal cortex can impair the rat's ability to stop a Go
response once it has been initiated.
d. The results of this study are that lesioning the OF causes the rats to have a slower SSRT
reaction time and lesioning the STN causes a faster GoRT as well as an impaired stopping ability
when there is no delay between the start of the Go signal and Stop signal. The study supports the
existence of discrete regions of dissociation that are beyond the cortex.
e. The results do answer the research questions because the question was concerned about the
effects of lesioning different areas and how the rats respond in different tasks.
f. As a team, we could try using a GoRT as well as an SSRT in our behavioral task construction.
We could also try to lesion the same parts of the brain and compare the neuron firing to the
results found in this paper. Finally, we could try lesioning different areas of the brain in different
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hemispheres. For example we could lesion the STN in the right and the OF in the left and see the
effect on SSRT and GoRT.
g. A limitation of this study is that it took a long time to train the rats for both the types of tests.
We would have to ensure that our research is not slowed by tasks such as these. We could lesion
different areas of the brain in different hemispheres, such as lesioning the STN in the right and
the OF in the left and seeing what effect it has on SSRT and GoRT response times.
h. The methodology of this paper is a quantitative measure of the accuracy of the rats performing
the tasks and the time it took to recognize a stop signal pre and post-surgery.
i. The accuracy was tested by how many tests the rats got right. The time was tested by
measuring how long it took to go from the first to the second lever.
j. The researchers compared results of the SSRTs and GoRTs of the pre-surgery to the postsurgery rats to see if there was a difference due to the lesioning of brain areas.
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GEMS202 Summary of Resources
Team RITALIN
1. Ashley Zhan
2. Team RITALIN
3. Sun, H., Green, T. A., Theobald, D.E., Birnbaum, S. G., Graham, D. L., Zeeb, F.
D.,...Winstanley, C. A. (2010). Yohimbine increases impulsivity through activation of cAMP
response element binding in the orbitofrontal cortex. Biol Psychiatry, 67(7), 649-656. doi:
S0006-3223(10)00009-0 [pii]
4. Original research study
5. a. The purpose of this study is to examine the effects of the pharmacological stressor
yohimbine on motor impulsivity and on the phosphorylation of cAMP response element binding
(CREB) activity in the areas of the brain - the orbitofrontal cortex (OFC) and the nucleus
accumbens (NAc) - that control impulsivity.
b. The research hypothesis is that activation of the norepinephrine pathways in the brain can
increase impulsivity.
c. Clinically, yohimbine has been proven to trigger impulsivity in human patients. The OFC and
the NAc have been indicated as areas of the brain that affect impulsivity. This experiment
presents novel information by examining the effects of yohimbine on specific areas of the brain
and on the NE-CREB pathway in a preclinical setting.
d. The results showed that yohimbine increased response impulsivity in the rats used in the
experiments as well as the phosphorylation of CREB within the OFC. Likewise, overexpression
of CREB in the OFC facilitated the effects of yohimbine. There was, however, no selective
increasing of CREB phosphorylation within the NAc.
e. The results support the hypothesis as it applies to the OFC. This study further contributes to
the understanding of neurological pathways and the treatment of mental disorders. The study also
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GEMS202 Summary of Resources
Team RITALIN
showed that the NAc did not reveal the same results as the OFC, indicating that there is a
significant difference between the two areas of the brain as they relate to measuring impulsivity.
f. This study indicates that the OFC may be a better area of the brain for us to study than the
NAc. The experiment also used the five-choice serial reaction time task (5CSRT) to measure the
rat's behavior, proving that this method is another viable option for our own experiments.
Analyzing tissue samples of the brain may be another possible component of our experiment that
we can consider applying.
g. In one of the experiments, two of the rats were excluded from the study due to poor health. At
other times, there were low numbers of completed trials by some of the rats, so data was omitted
from the analyses. Therefore, the results of the study may have been affected.
h. This study was quantitative. When using the 5CSRT task, 16 rats were trained and tested in 8
standard five-hole chambers. When determining the effects of yohimbine on CREB signaling in
areas of the brain, 12 rats were given yohimbine and then sacrificed for their samples after 30
minutes.
i. The study measured impulsive responding through 5CSRT tasking. Tissue samples from the
rat's brains were also taken, dissected, frozen on dry ice, and then processed for western blotting.
j. For the 5CSRT tasks, they analyzed variables such as the percentage of correct trials, incorrect
and premature responses, the percentage of completed and omitted trials, and latency in
collecting rewards. Effects in the brain areas were analyzed by ANOVA in 5-day bins. NIH
image software was used to determine the density of protein bands.
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GEMS202 Summary of Resources
Team RITALIN
1. Ashley Zhan
2. Team RITALIN
3. Sun, H., Cocker, P. J., Zeeb, F. D., & Winstanley, C. A. (2011). Chronic atomoxetine
treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats
and alters markers of synaptic plasticity in the orbitofrontal cortex. Psychopharmacology (Berl).
doi: 10.1007/s00213-011-2419-9
4. Original research study
5. a. The purpose of this study is to determine the long-term effects of treatment with
atomoxetine, a drug used to treat ADHD, during adolescence on impulsive choice and impulsive
action, and whether any changes in mRNA or protein levels in the frontal cortices of the brain
occur.
b. The hypothesis is that atomoxetine treatment will have long-lasting effects and decrease
impulsive action and choice during adulthood when it is administered in adolescence.
c. Most people are diagnosed with ADHD during childhood or adolescence when the brain is still
maturating. Acute atomoxetine has been shown to increase the flow of norepinephrine and
dopamine in the frontal cortices, and decrease both types of impulsivity in adulthood. This study
aims to study the effects of atomoxetine treatment when administered in adolescence in order to
examine the effects of treatment as it would be administered in clinical populations.
d. The results showed that atomoxetine treatment in adolescence caused a decrease in impulsive
choice in adulthood but not in impulsive action. Chronic atomoxetine treatment also decreased
the phosphorylation of CREB and extracellular signal regulated kinase (an upstream regulator) in
the orbitofrontal cortex, and decreased mRNA.
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GEMS202 Summary of Resources
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e. The results showed that atomoxetine might be able to treat impulsivity in choice in the longterm, but not impulsivity in action. Atomoxetine has merit in being an effective drug for treating
ADHD, based on its effects on CREB activity, but it might not be the best choice when
administered clinically.
f. This study gives us insight into how treating ADHD can be affected by age, since the brain
(particularly the areas that control impulsivity) continues to develop throughout adolescence. We
can take this factor into account when analyzing our own data. The study further supports the use
of behavioral testing as an effective means of measuring impulsivity. We can also consider
separating impulsive behavior into impulsive choice and impulsive action when we measure the
effects of lesions in the brain.
g. The dosage of the drug that the rats were given was altered to fit the physiology of the animal.
When the drug is administered in human patients, the dosage is different. Therefore, there might
be slight differences in the effects of the drug.
h. The rats received daily atomoxetine treatment during adolescence and performed tasks—
delay-discounting test or five-choice serial reaction time task—after maturation. This
methodology was quantitative.
i. Data was collected by observing the behavior of the rats in the tasks, and by sacrificing the rats
and taking samples of their brain tissue. Tissue samples were frozen on dry ice and processed
using the quantitative polymerase chain reaction technique (for mRNA) and western blotting (for
protein levels).
j. Up-regulation was quantified by measuring protein volumes with image analysis; this was
correlated to drug dosage using Student’s T-test.
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