This is the last of a three-part series to inform
you about the findings from research studies funded by the Juvenile Research
Foundation. The first two
Newsletters described the approach and development of a new perspective on
pediatric bipolar disorder. This Newsletter tells you about the direction that
researchers plan to follow now that the foundation for this novel view is in
place. If you missed either of the first two Newsletters, you can to refer to
them at http://www.bipolarchild.com/Newsletters/. We hope you will be encouraged by the progress and
inspired to believe that the end of this journey is attainable.
The research that we have
brought to your attention is well poised to move on to the next phase of
investigation. The specificity and accuracy with which a subtype of the illness
has been defined improves the chances of success for ensuing studies. To summarize the work to date, researchers
supported by the Juvenile Bipolar Research Foundation (JBRF) has collected
clinical information on a large sample of children who have been diagnosed or
are suspected of having pediatric bipolar disorder. Multiple analyses run on this data generated the following:
- The delineation of a genetically robust trait
called Fear-of-Harm (FOH) that serves to define a subtype of the illness which
has become the focus of our investigation.
- A
highly specific dimensional symptom profile that accompanies the FOH
trait.
This highly heritable
trait makes it an ideal candidate for further genetic study and the dimensional
symptom profile points us to very specific brain pathways that may explain the
biological underpinnings of this subtype.
The dimensional symptom profile also allows us to identify, with 96% accuracy,
children who have the trait. This
is an enormous improvement over the current state of affairs and finally moves
us down a path that could potentially yield more targeted treatment strategies,
including pharmacological, psychological and circadian approaches.
To continue to focus on
this single, hereditary behavior as the basis for future studies undoubtedly
leaves some children who exhibit a bipolar disorder out of the mix. However, given the complexity of the
physiology involved, this dissection of the illness into a very specific slice
is necessary. This is the route
that may better enable researchers to uncover real and useful answers.
This single behavioral
trait is not uncommon. Some degree
of the FOH trait was found to be present in 2/3 of the study population. A full 1/3 of the subjects exhibited
the trait in its pure form. So,
while it does not cover all children, it is very relevant and conclusions drawn
from it are likely to have wide application.
The compilation of evidence-based
not conceptual
information is key to the development of a broad-based body of knowledge that
can move the research agenda forward.
Listed below are the three main research areas that researchers now plan
to pursue as this strong foundation of inquiry has been established.
Genome-wide Association Study
Identification of
susceptibility genes for bipolar disorder is the most direct way to discover
the network of signaling pathways in the brain that regulate specific behaviors
associated with the condition. The
development of treatments which specifically target those pathways can then be
launched.
In a technique called
genome wide association study (GWAS), investigators scan the entire human DNA,
or genome, of many individuals to pick up genetic variations that differ
between healthy individuals and individuals with the disorder of interest.
Of critical importance to
the success of this approach is: 1) the selected cases should be homogeneous
for the target condition, and 2) the sample size must be large enough to
provide statistically significant results.
We believe that the
delineation of the FOH trait and the dimensional, clinical profile of symptoms
associated with it will potentially allow us to gather such a homogeneous
group. The ease and accuracy that
the Child
Bipolar Questionnaire brings to the identification of children with the
FOH trait promises to round up the very large sample of cases needed to proceed
with the scan. JBRF has already
made substantial progress in the process of collecting DNA samples from
children who fit the FOH trait. We
need your participation to gather as many samples as possible. A link for this purpose is at the end
of this News Flash.
Chronobiology Biomarker Study
Chronobiology is the study
of biological rhythms. A biomarker
is a distinctive biological indicator
of a process, event, or condition.
The identification of a biomarker for a specific condition greatly
enhances diagnostic reliability and simultaneously identifies a treatment
target that may reduce the impact of the condition. In this study, investigators seek to explore the
relationship between sleep/activity patterns and thermal regulation in children
with the FOH subtype to determine if some imbalance in the relationship between
these rhythms could be a biomarker of the illness.
Preliminary studies and
longstanding clinical observations tell us that many children at risk for, or
who carry a diagnosis of, pediatric bipolar disorder experience numerous types
of sleep disturbances as well as a dysregulation of activity rhythms. They also feel excessively cold in the
mornings, overheat in the evenings, have a poor thermogenic response to cold,
and sweat profusely during even mild physical exercise. Dimensional analysis revealed that
these phenomenons are represented as parts of behavioral dimensions that
accompany the FOH trait.
Since we know that the relationship between core and outside body
temperature interact with the circadian rhythm of sleep, the onset and offset
of sleep as well as the quality of
sleep, the dysregulation of this relationship may well be a biomarker of the
condition.
Investigators have
launched a study, funded by the National Institute of Mental Health (NIMH), to
explore this phenomenon. While the
study is ongoing, preliminary results indicate that this could indeed turn out
to be a biomarker for the illness.
What's more, the underlying physiology involved in the core versus
outside body temperature relationship also influences other dimensions of the
illness such as anxiety, aggression, sweet cravings, and fear conditioning.
Stem Cell Study: Turning Skin Cells into Brain
Cells
In a remarkable new
process that is only three years old, investigators have the capability to
deprogram a skin cell, return it back to its original stem cell state and then
encourage it to develop again down a completely different developmental path
into a brain cell or "neuron". This novel procedure will allow researchers to
examine differences in gene expression in brain cells through a direct
comparison of the DNA of an individual with pediatric bipolar disorder and a
control subject.
This process could tell us
all sorts of things about how that brain cell functions or malfunctions and how
it will respond in the presence of different medications. Using the FOH
phenotype to identify a clinically homogeneous group of children that represent
a subtype of the illness, investigators are hopeful that they will achieve
meaningful results.
We hope you have found
this discussion interesting and inspiring. We feel that the research conducted so far has done a lot to
correct a fundamental obstacle that prevented the timely progression of
research and development. We look
forward to the mounting body of useful information that this new approach opens
up. Together we can find ourselves further down the path to peace that we and
our children so desperately desire.
Alissa Bronsteen and Demitri Papolos, M.D.
