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- Hello, I'm Cindy Forehand,
Dean of the Graduate College

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at the University of Vermont.

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We're here this afternoon
to welcome you to the first

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of four university scholars lectures

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for this academic year,
in what is the 40th year

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of our University Scholars Productions.

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As always, we're here to celebrate
the high value UVM places

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on research, scholarship and creativity.

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The University Scholar
Award Program recognizes

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outstanding faculty
members each academic year

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for sustained excellence in research,

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scholarship and creative arts.

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Today, we recognize one of
this year's award recipients,

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professor Gregory Holmes, a
colleague in the Department

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of Neurological Sciences within

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the Larner College of Medicine.

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Greg Holmes is chair of the Department

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of Neurological Sciences and a Professor

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of Neurological Sciences and Pediatrics.

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He is an internationally
renowned pediatric neurologist

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with an expertise in pediatric epilepsy.

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His research in the laboratory and clinic

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has resulted in an understanding

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of the pathophysiologic basis
of cognitive impairments

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and other comorbidities
in children with epilepsy.

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Dr. Holmes studied at
Washington and Lee university

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for his bachelor's
degree and the University

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of Virginia School of Medicine for his MD,

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followed by residencies
in Pediatrics at Yale

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and Pediatric Neurology at
Boston Children's Hospital

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and Harvard Medical School, where in 1996,

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he became Professor of Neurology

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and was bestowed an honorary M.A degree.

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Prior to becoming Chair of
Neurological Sciences at UVM,

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in 2013, Dr. Holmes was Inaugural Chair

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of Neurology at Dartmouth Medical School.

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His research is inspired by his
patients and their families.

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He has over 500 peer
reviewed research articles,

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books, book chapters and review articles.

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He's enjoyed continuous funding for more

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than 40 years from federal
agencies, primarily the NIH.

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Dr. Holmes served on the
editorial boards of 12 epilepsy

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and neurology journals and has been

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on multiple NIH Study Sections
and FDA Advisory Committees.

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He is a past President of
the American Epilepsy Society

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and has received many honors,
including research awards

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from the American Epilepsy Society, NIH,

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American Clinical Neurophysiology Society,

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International League Against Epilepsy

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and The Child Neurology Society.

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From 2010 to 2012, he was a member

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of the National Academy of
Science sponsored committee

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on the public health
dimensions of the epilepsies,

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culminating in the book
Epilepsies Across The Spectrum.

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On the lighter side, Dr. Holmes is known

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for a large collection of ties featuring

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the classic Disney character Mickey Mouse,

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and also for a frame toilet
seat hanging in his office,

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which was gifted to him
by a prior institution.

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I am pleased now to introduce
professor Gregory Holmes

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for his inaugural university
scholar lecture, titled,

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Construction and Disruption
of Spatial Memory

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Networks During Development,
attendees may submit questions

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through the chat at any
time throughout the lecture.

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And professor Holmes will
answer questions for about

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10 minutes at the conclusion
of the talk, professor Holmes.

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- Okay thank you very much Dr. Forehand.

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I really appreciate that
wonderful introduction.

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And again, I wanna
reiterate, I'm just so proud

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to receive this award,
when you look at the number

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of people over the last 40
years, who've gotten this award,

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it's really nice to be
in the same category

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of my predecessors here,
so I really do appreciate

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the committee that picked me.

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I also appreciate Dr. Rod
Scott and Margaret Vizard

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for writing a letter of nomination.

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So again, I'm very happy to be here.

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When I heard about this talk,
I was told that I was gonna

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be speaking in front
of an empty auditorium

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and that's not actually true,
I have a five people here

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and that's probably five
more than I usually get it

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at most of my lectures, I often
have trouble getting my wife

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to come to my lecture, so
this to me is a big crowd.

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So I appreciate you guys for being here.

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So I'm gonna talk a
little bit about epilepsy

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and some of the research we are doing,

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and you know, this is a broad audience.

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So just a few definitions,
a seizure is considered

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the clinical manifestation
of abnormal excessive

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and hypersynchronized neuronal discharges

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and focal or widespread brain areas,

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resulting in an abnormal behavior.

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Now what's fascinating about epilepsy

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is that abnormal behavior
can be quite varied.

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It can be children just
have simple staring attacks,

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absence seizures or they can have more

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cause severe generalized
tonic-clonic seizures,

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often called convulsions.

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Now epilepsy is a spectrum
of neurological disorders

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characterized by spontaneous
recurrent seizures.

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So if you have a child like I did,

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who had a febrile seizure,

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that's not really considered a epilepsy.

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'Cause that was a provoked seizures,

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epilepsy is really unprovoked seizures.

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Now I trained at a
children's hospital in Boston

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and ran the epilepsy program
there for many years.

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The person that founded
the epilepsy program

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was William Gordon Lennox,
and a classic book in 1960.

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He talked about the many
myriad aspects of epilepsy

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recognizing that this
is a spectrum disorder.

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What's interesting, he talked
about mental impairment

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in patients with epilepsy
and in this figure here,

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what you can see is that, he looked at

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the lifetime accumulation of people

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that had grand mal or generalized
tonic-clonic seizures,

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and found that if you had a thousand

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or more during your lifetime, your chances

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of having cognitive
impairment were over 60%.

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If you had petit mal or absence seizure,

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the incidents of having
cognitive impairment

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was actually quite low.

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So this is a pretty dramatic
finding written in 1960.

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What's been shown over the
years is that epilepsy,

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especially in young children
can be quite devastating.

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Now I will say at the onset that most kids

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and most adults that have
epilepsy actually do quite well,

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but there's a subset of
kids and that if they

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start having seizures early in life

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and they do not get controlled,

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that means they're pharmacoresistant,

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the medications do not work.

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The chances of them having normal

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cognitive function is very low.

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So if you look at
children, say at age two,

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who do not achieve
control of their seizures,

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the chances of them having

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cognitive impairment
is really, really high.

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Only a 20% will have an 80 score

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on the Vineland, which
is administered yearly.

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So what we see here is
that early life seizures,

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especially if they're not controlled

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with medications can be quite detrimental

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and quite devastating to the children.

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Now, if you started in an older age,

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it really doesn't matter
if you get control or not.

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We usually don't see any cognitive

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deterioration in those children.

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Now there is a group of epilepsies

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that are really devastating.

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And these are called the
epileptic encephalopathies.

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And this refers to a group of disorders

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in which there's unremitting,
epileptic seizures.

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These children have severe
cognitive behavioral impairment,

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and this occurs over and beyond what

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can be expected from the
underlying pathology.

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So epilepsy is not normal
so it's often caused

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by a variety of different brain injuries

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and those brain injuries themselves

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can lead to cognitive impairment,

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but there's indication
at least in some children

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that the seizures themselves can lead

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to cognitive impairment or
further the cognitive impairment.

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In addition to frequent
seizures, the children often go

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from a normal EEG here to one
that's quite disorganized,

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very slow with a lot of
epileptiform activity.

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So epileptic encephalopathies are really

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a devastating condition and it's tragic

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to follow these children over time.

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Now I've been working with
a person named Susan Axelrod

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for over 20 years, a couple of decades.

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And Susan, you may recognize

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that she's married to David Axelrod.

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Susan's story began when she
had a seven month old child,

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Lauren who's pictured here and Lauren

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was fine at birth, doing well
and then developed epilepsy

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and had very severe seizures.

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And just did not do well at all.

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She's now an adopt, she is in a group home

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and she's functioning well,
but she has a very low IQ

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and has a lot of social difficulties

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as well as intellectual problems.

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So Susan, when she had
this, she went to website,

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she looked into the Epilepsy Foundation.

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And what she read about
epilepsy was that, you know,

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it's a pretty benign condition, you know,

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often in the epilepsy foundation website,

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you would have these
cute kids that probably

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had petit mal absence seizures
and looked absolutely fine.

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And she, you know, she said,

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this is not what I've been going through.

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My child is not fine, my
child is doing terrible.

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And so she founded what's called CURE.

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And this is an organization
that's been incredible

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over the years, emphasizing that epilepsy

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is not a nice disorder to have,

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looking at the number of
people around the world

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that have epilepsy, 50
million and also pointed out,

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and this was coming about
when she formed CURE that

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it can be a lethal disease
that patients can die,

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either during a seizure,
even in between seizures

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at a much higher risk than
the population in general.

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So as Susan and I were talking one day,

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we were at a grant
meeting talking together

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and she was talking about Lauren.

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I was telling about my experience

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with taking care of patients
and almost simultaneously,

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we both said at the same time,
the problem with epilepsy

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is that it really I'll say stinks,

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but you know what, I'll not.

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So it's a bad disorder,
it's not nice to have.

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Okay, so the problem that most of the kids

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have with epilepsy that
have cognitive problems

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are ones of learning and memory.

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So just a little primer on memory,

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we break it down into declarative memory

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and then non-declarative memory.

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Declarative memory is like somatic memory,

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this is like how you
remember general information.

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Episodic memory would be
personally experienced events.

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So declarative memory
really comes from the part

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of the brain called the
hippocampus, which is here.

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So this type of memory
is hippocampo dependent.

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It's often referred to as explicit memory.

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And then there's non-declarative memory.

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And this is information
you cannot describe.

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So this would be, you know,
you learn to ride a bike

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and you can remember how to ride the bike

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and you can't describe how you learned

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how to ride the bike, but you learned

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how to ride the bike and habits.

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And these non-declarative
memory comes from

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a part of the cerebellum and
the basal ganglion, excuse me.

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So there is a concept
called infantile amnesia.

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Excuse me, just a second here.

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And this was actually
described by Sigmund Freud.

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Okay, thank you.

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In which he noted that children, infants,

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did not have much memory
when they got older.

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So there is infantile and
there's childhood amnesia.

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The infantile amnesia is described

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as children before the age of two,

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who cannot form autobiographical events

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that happened in a
spatial temporal context.

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And then childhood amnesia
is three to five years of age

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where the children are remember less

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than you would expect
from simple forgetting.

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So knowing this, I always tell my parents

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that they're absolutely wasting their time

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taking their four year old to Disneyland

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and spending a fortune 'cause
the kid's not gonna remember

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anything about it when they're older.

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So we can also look at
memory, how it develops.

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And so there's both an egocentric

255
00:12:51,200 --> 00:12:53,433
and an allocentric spatial memory.

256
00:12:54,730 --> 00:12:59,090
So egocentric, that refers
to your body and you know,

257
00:12:59,090 --> 00:13:01,190
you go to your right
or you go to your left.

258
00:13:01,190 --> 00:13:03,630
It's based on what you're doing.

259
00:13:03,630 --> 00:13:07,530
Allocentric memory is
that you look at objects

260
00:13:07,530 --> 00:13:10,892
in the environment and
then you figure out that

261
00:13:10,892 --> 00:13:14,450
the where of the, what,
where and when is based

262
00:13:14,450 --> 00:13:17,470
on this information
where you can encode it

263
00:13:17,470 --> 00:13:20,690
and ascertain from these different cues

264
00:13:20,690 --> 00:13:23,200
where the object really is,
it has nothing to do with you,

265
00:13:23,200 --> 00:13:25,660
it's these objects around
you that you can then

266
00:13:25,660 --> 00:13:29,540
put together to develop
allocentric memory,

267
00:13:29,540 --> 00:13:31,140
so you can remember the fire hydrant

268
00:13:31,140 --> 00:13:34,000
is between the car and the bike here,

269
00:13:34,000 --> 00:13:36,800
whereas egocentric, you
just know that to find

270
00:13:36,800 --> 00:13:38,320
the fire hydrant you have to go, right

271
00:13:38,320 --> 00:13:40,120
or you have to go right or left.

272
00:13:40,120 --> 00:13:42,870
You're not using any other
cues around the environment.

273
00:13:44,640 --> 00:13:47,760
Now I'm not gonna be cutting up baby,

274
00:13:47,760 --> 00:13:50,800
babies have amnesia and that doesn't

275
00:13:50,800 --> 00:13:52,093
mean babies aren't smart.

276
00:13:53,660 --> 00:13:58,660
If you do a paired visual
comparison test to assess memory,

277
00:13:59,785 --> 00:14:03,650
what you do is you have the
child look at two objects,

278
00:14:03,650 --> 00:14:07,090
for example, that are the same,

279
00:14:07,090 --> 00:14:09,963
then you substitute an
object that's different.

280
00:14:10,950 --> 00:14:13,690
And then you substitute another
one, maybe different color,

281
00:14:13,690 --> 00:14:18,070
different facial figuration
and a normal baby,

282
00:14:18,070 --> 00:14:22,880
will look at the novel object
more than the familiar object.

283
00:14:22,880 --> 00:14:25,680
And so babies can learn to remember things

284
00:14:26,850 --> 00:14:28,863
during the first year of life,

285
00:14:29,840 --> 00:14:32,290
but this isn't considered to
be non-declarative in type,

286
00:14:32,290 --> 00:14:34,763
so it doesn't depend upon the hippocampus.

287
00:14:37,030 --> 00:14:41,050
Beautiful work by
Rovee-Collier and colleagues,

288
00:14:41,050 --> 00:14:44,590
who'd take babies and they
had put them in a crib

289
00:14:44,590 --> 00:14:49,590
and then they'd have a mobile
and if the child came in,

290
00:14:51,747 --> 00:14:53,920
they'd put a string on the child's leg,

291
00:14:53,920 --> 00:14:58,100
connected to the mobile
and if the child kicked

292
00:14:58,100 --> 00:15:00,610
the leg, nothing would happen.

293
00:15:00,610 --> 00:15:02,690
On day two, you come in
and put the same thing

294
00:15:02,690 --> 00:15:04,470
on the child and the child kicks the leg

295
00:15:04,470 --> 00:15:08,930
and all of a sudden this mobile is moving.

296
00:15:08,930 --> 00:15:10,517
And then your third day is you take it

297
00:15:10,517 --> 00:15:12,780
and it doesn't move again
when the child kicks.

298
00:15:12,780 --> 00:15:16,290
So you compare the
amount of kicking between

299
00:15:16,290 --> 00:15:20,330
this day and this day and if
they kick more on this day

300
00:15:20,330 --> 00:15:23,780
than the first day,
that means they remember

301
00:15:23,780 --> 00:15:28,513
that kicking will cause the
mobile to start moving around.

302
00:15:29,400 --> 00:15:31,990
If you do the same thing
with the train here,

303
00:15:31,990 --> 00:15:33,620
you can just have the child push a button,

304
00:15:33,620 --> 00:15:35,510
nothing happens next
day, you push a button,

305
00:15:35,510 --> 00:15:37,940
the train moves, third day he comes in

306
00:15:37,940 --> 00:15:40,320
and he pushes the button, nothing happens,

307
00:15:40,320 --> 00:15:45,050
subtract this from this and
it demonstrates learning.

308
00:15:45,050 --> 00:15:46,680
The child remembers
that pushing the button

309
00:15:46,680 --> 00:15:49,460
will cause the train to go forward.

310
00:15:49,460 --> 00:15:50,590
And these are my kind of tests

311
00:15:50,590 --> 00:15:53,163
because I think even I could handle them.

312
00:15:54,480 --> 00:15:57,220
So another way to look at the development

313
00:15:57,220 --> 00:16:00,930
of memory is to do a test
and where you take a child

314
00:16:00,930 --> 00:16:04,930
and you put them in a room
and you have all these plates

315
00:16:04,930 --> 00:16:09,290
on the ground and if the
child picks the right plate,

316
00:16:09,290 --> 00:16:12,713
there's a little toy or a
piece of candy under the plate.

317
00:16:13,620 --> 00:16:15,630
So the child has to go into the room

318
00:16:15,630 --> 00:16:18,660
at different angles, at different
entrances in other words,

319
00:16:18,660 --> 00:16:22,740
and this particular
experiment, they put a marker

320
00:16:22,740 --> 00:16:25,990
on top of the plate in
which the toy was located.

321
00:16:25,990 --> 00:16:27,950
So all the child had to
do is know to go right

322
00:16:27,950 --> 00:16:30,900
to that marker, pick up the
plate and he would get the toy.

323
00:16:31,810 --> 00:16:35,010
The next step and that's
local cue learning.

324
00:16:35,010 --> 00:16:36,710
That's egocentric learning.

325
00:16:36,710 --> 00:16:39,430
The next time you'd bring the child in

326
00:16:39,430 --> 00:16:41,870
and you don't Mark any of the plates.

327
00:16:41,870 --> 00:16:44,580
So the child has to
remember where the plate is

328
00:16:44,580 --> 00:16:47,170
based on cues around the room.

329
00:16:47,170 --> 00:16:49,453
So this is an example
of allocentric memory.

330
00:16:50,290 --> 00:16:53,610
And so allocentric memory as
I told you is hippocampus.

331
00:16:53,610 --> 00:16:56,790
Local cue memory is non-hippocampus.

332
00:16:56,790 --> 00:17:00,440
And it turns on at
around a 43 to 46 months,

333
00:17:00,440 --> 00:17:03,970
children learn to do the
allocentric learning,

334
00:17:03,970 --> 00:17:08,520
but not before then, another
test, similar design,

335
00:17:08,520 --> 00:17:13,100
fewer markers, if the plate is queued,

336
00:17:13,100 --> 00:17:14,863
children learn that very early.

337
00:17:15,960 --> 00:17:17,750
If the plate is not cued and you have

338
00:17:17,750 --> 00:17:22,750
to use allocentric cues, it
takes again 25, 43 months.

339
00:17:23,230 --> 00:17:27,710
So we think that in children,
the hippocampus kicks in

340
00:17:27,710 --> 00:17:32,063
around 43 months and allows
allocentric learning to occur.

341
00:17:33,380 --> 00:17:36,720
So why is it this change that's occurring

342
00:17:36,720 --> 00:17:40,850
in the hippocampus as for
pretty much non-functioning

343
00:17:40,850 --> 00:17:45,023
in young children, but
develops in older children?

344
00:17:45,920 --> 00:17:48,198
The brain is just an absolutely wonderful,

345
00:17:48,198 --> 00:17:52,460
and we're gonna look at, during pregnancy,

346
00:17:52,460 --> 00:17:55,790
you go from just a small number of cells

347
00:17:55,790 --> 00:17:59,070
to a well-functioning
developing hemisphere.

348
00:17:59,070 --> 00:18:03,250
And a lot of that
development is based on genes

349
00:18:03,250 --> 00:18:04,664
as well as to a certain degree,

350
00:18:04,664 --> 00:18:08,620
environment, that's okay, thanks.

351
00:18:08,620 --> 00:18:11,810
Now as the child gets older, we have

352
00:18:11,810 --> 00:18:14,683
what's called activity
dependent plasticity.

353
00:18:15,630 --> 00:18:20,630
So as you learn things, you
increase excitation cells learn

354
00:18:20,700 --> 00:18:24,620
to develop mature,
connect with one another,

355
00:18:24,620 --> 00:18:29,270
and learning drives that
connectivity with maturation.

356
00:18:29,270 --> 00:18:31,330
So there's environmental factors

357
00:18:31,330 --> 00:18:34,363
that take place after birth.

358
00:18:35,770 --> 00:18:38,330
So again, I don't want you to need

359
00:18:38,330 --> 00:18:40,605
and learn a lot of anatomy,
but I just wanna talk

360
00:18:40,605 --> 00:18:41,870
a little bit about the hippocampus

361
00:18:41,870 --> 00:18:46,780
'cause it's so important
and memory and learning,

362
00:18:46,780 --> 00:18:49,340
and keep in mind, there's
a lot of information

363
00:18:49,340 --> 00:18:52,020
that flows into the
hippocampus, primarily from what

364
00:18:52,020 --> 00:18:55,250
is called the entorhinal
cortex of the brain.

365
00:18:55,250 --> 00:18:58,520
And this flows into the hippocampus,

366
00:18:58,520 --> 00:19:01,730
a number of different
neuronal ensembles here,

367
00:19:01,730 --> 00:19:05,550
code this information and
then send this information out

368
00:19:05,550 --> 00:19:07,550
to widespread areas of the brain.

369
00:19:07,550 --> 00:19:11,730
So very, very important
in learning and memory.

370
00:19:11,730 --> 00:19:13,420
If you don't have a hippocampus,

371
00:19:13,420 --> 00:19:16,300
if you remove both hippocampi,
which was done surgically

372
00:19:16,300 --> 00:19:19,170
on a patient named H.M. you have

373
00:19:19,170 --> 00:19:20,963
devastating problems with memory.

374
00:19:22,190 --> 00:19:24,560
So our lab has been very
interested in this development

375
00:19:24,560 --> 00:19:28,210
of memory and we use
single cell recordings.

376
00:19:28,210 --> 00:19:30,630
And what'd you do here is you take a rat

377
00:19:30,630 --> 00:19:35,630
and you put in 64, 128 electrodes,

378
00:19:36,340 --> 00:19:38,690
and you put them into the hippocampus

379
00:19:38,690 --> 00:19:40,757
and then you can record single cells.

380
00:19:40,757 --> 00:19:42,630
And when I say it records single cell,

381
00:19:42,630 --> 00:19:45,800
people call this units
and these are actually

382
00:19:45,800 --> 00:19:48,400
action potentials that you're recording.

383
00:19:48,400 --> 00:19:50,550
And the beauty of this
system is you can rack

384
00:19:50,550 --> 00:19:52,020
and run around and learn the tasks

385
00:19:52,020 --> 00:19:54,873
while you're recording
on a single cell level.

386
00:19:56,960 --> 00:20:01,010
So we put a light on top
of the rat's head here,

387
00:20:01,010 --> 00:20:05,330
put them in a chamber and then
through some nice techniques,

388
00:20:05,330 --> 00:20:07,650
you can actually look at
action potentials and wreak

389
00:20:07,650 --> 00:20:09,240
and figure out how many cells

390
00:20:09,240 --> 00:20:10,640
are firing these action potentials.

391
00:20:10,640 --> 00:20:14,170
So we can identify using
electrophysiological techniques,

392
00:20:14,170 --> 00:20:19,170
individual cells that are
causing those action potentials.

393
00:20:21,710 --> 00:20:26,420
So these are pretty incredible
cells because an investigator

394
00:20:26,420 --> 00:20:29,833
named O'Keeffe put an
animal once in a chamber.

395
00:20:30,720 --> 00:20:33,000
The chamber had a cue card here.

396
00:20:33,000 --> 00:20:36,680
So the animal could orient
where he was in space.

397
00:20:36,680 --> 00:20:40,900
And Keith was listening to
these action potentials.

398
00:20:40,900 --> 00:20:42,090
You can just turn up your amplifier

399
00:20:42,090 --> 00:20:44,640
and you can actually
listen to action potentials

400
00:20:44,640 --> 00:20:47,090
and found that when the
animal is running around,

401
00:20:47,090 --> 00:20:49,270
there would be certain
cells that fired in certain

402
00:20:49,270 --> 00:20:54,270
locations and this is a cell
that fires around five o'clock.

403
00:20:55,970 --> 00:20:59,350
And these are the action
potentials from the tetrodse.

404
00:20:59,350 --> 00:21:02,350
Here's a cell that fires around noon

405
00:21:02,350 --> 00:21:03,900
and you can see the action potentials.

406
00:21:03,900 --> 00:21:06,040
And here's a cell that fires everywhere

407
00:21:06,040 --> 00:21:09,820
and this would be an
inter-neuron, a fast spiking cell,

408
00:21:09,820 --> 00:21:13,770
which is a GABAergic or inhibitory cell.

409
00:21:13,770 --> 00:21:16,940
So here we have a situation,
a place cells in which

410
00:21:16,940 --> 00:21:19,720
you have a single cell can help predict

411
00:21:19,720 --> 00:21:21,570
where the animal is in space.

412
00:21:21,570 --> 00:21:24,640
You take the animal out and
bring them back the next day,

413
00:21:24,640 --> 00:21:27,620
the animal goes to this
area, the cell fires again.

414
00:21:27,620 --> 00:21:31,250
So these are place cells an
incredible discovery by O'Keefe

415
00:21:31,250 --> 00:21:36,183
that led to him getting
the Nobel Prize recently.

416
00:21:37,570 --> 00:21:39,810
Now place cells are very interesting

417
00:21:39,810 --> 00:21:43,850
because here's an animal running around.

418
00:21:43,850 --> 00:21:45,400
And as he goes through
these different areas,

419
00:21:45,400 --> 00:21:48,743
certain place cells and colors here, fire.

420
00:21:49,640 --> 00:21:51,820
Now and here's an example, when the animal

421
00:21:51,820 --> 00:21:54,620
is what running on a linear track, you see

422
00:21:54,620 --> 00:21:56,910
all these action potentials
and they're lined up

423
00:21:56,910 --> 00:22:00,870
in the order they fired and
so the action potentials

424
00:22:00,870 --> 00:22:05,240
are occurring as a rat goes
into different locations.

425
00:22:05,240 --> 00:22:08,550
Now, when rats stop and rest,

426
00:22:08,550 --> 00:22:11,673
you see what's called a sharp wave-ripple.

427
00:22:13,170 --> 00:22:16,380
And this is just a slow way
with a lot of fast activity.

428
00:22:16,380 --> 00:22:20,830
And what happens during
a sharp wave-ripple,

429
00:22:20,830 --> 00:22:25,070
the cells that fire while this
animal is running fire again,

430
00:22:25,070 --> 00:22:27,460
but they fire in rapid succession.

431
00:22:27,460 --> 00:22:29,750
So the animal who's cells are
firing is as animal's running

432
00:22:29,750 --> 00:22:32,210
across different cells, different colors,

433
00:22:32,210 --> 00:22:35,910
animal stops and they
fire again spontaneously,

434
00:22:35,910 --> 00:22:38,250
even though the animal's not moving.

435
00:22:38,250 --> 00:22:41,030
Same thing with here,
if the animal is awake,

436
00:22:41,030 --> 00:22:45,260
when the animal goes to sleep,
you get this replay of cells.

437
00:22:45,260 --> 00:22:48,340
So this replay of cells
is felt to represent or be

438
00:22:48,340 --> 00:22:53,110
a physiological mechanism where
one can consolidate memory.

439
00:22:53,110 --> 00:22:56,763
So you're replaying this
information from what you just did.

440
00:22:59,490 --> 00:23:02,040
So and then there's another
cell you need to know about,

441
00:23:02,040 --> 00:23:03,990
in the entorhinal cortex,
remember I told you

442
00:23:03,990 --> 00:23:07,440
the entorhinal cortex
flows into the hippocampus.

443
00:23:07,440 --> 00:23:09,780
Now this is a single
cell, but this cell fires

444
00:23:09,780 --> 00:23:14,780
in a grid-like pattern and
so they're called grid cells,

445
00:23:14,850 --> 00:23:19,683
which then help the
animal location in space,

446
00:23:19,683 --> 00:23:23,430
and then feed into the hippocampus<

447
00:23:23,430 --> 00:23:25,750
these are entorhinal
cortex in the hippocampus

448
00:23:25,750 --> 00:23:27,860
and you get these place cells on here.

449
00:23:27,860 --> 00:23:31,951
So place is down here, grid cell here,

450
00:23:31,951 --> 00:23:35,623
entorhinal cortex, hippocampus here.

451
00:23:37,980 --> 00:23:42,600
So these cells are really
pretty cool to look at.

452
00:23:42,600 --> 00:23:46,110
And the thing is that these cells

453
00:23:46,110 --> 00:23:48,813
are not firing just randomly.

454
00:23:49,760 --> 00:23:53,810
The cells are firing based
on brain oscillations.

455
00:23:53,810 --> 00:23:57,040
And so we talk a lot about theta in rats,

456
00:23:57,040 --> 00:24:00,800
and we have theta in humans,
this is the frequency.

457
00:24:00,800 --> 00:24:02,120
When rats running around, they have

458
00:24:02,120 --> 00:24:04,900
this very nice theta activity.

459
00:24:04,900 --> 00:24:07,050
When they rest, they
have these sharp waves

460
00:24:07,050 --> 00:24:08,730
and the EEG slows down while

461
00:24:08,730 --> 00:24:11,520
they're trying to consolidate the memory.

462
00:24:11,520 --> 00:24:14,773
So we can look at the
cells firing and not only

463
00:24:14,773 --> 00:24:18,880
will they fire and low
space, but also how they fire

464
00:24:18,880 --> 00:24:22,160
in relationship to the theta activity.

465
00:24:22,160 --> 00:24:24,670
So this is called temporal coding,

466
00:24:24,670 --> 00:24:29,353
the timing of the cell in
relationship to the theta.

467
00:24:30,810 --> 00:24:33,250
And so that's interesting,
but who really caters?

468
00:24:33,250 --> 00:24:37,460
Well, it's very important
because the cells fire

469
00:24:37,460 --> 00:24:40,330
on the theta dependent upon
what the animal is doing.

470
00:24:40,330 --> 00:24:41,960
For example, here's an
animal that's just running

471
00:24:41,960 --> 00:24:44,790
around chasing food and here's an animal

472
00:24:44,790 --> 00:24:47,860
that's in a test called
the active avoidance,

473
00:24:47,860 --> 00:24:51,760
where the animal has to remember
where the shock zone is.

474
00:24:51,760 --> 00:24:54,930
He can't see it, but based
on cues around the room,

475
00:24:54,930 --> 00:24:59,280
the animal has to learn
to avoid the shock zone

476
00:24:59,280 --> 00:25:02,150
and the cells fire at
different places there,

477
00:25:02,150 --> 00:25:05,093
you can plot these out, you
know, when you think thetas

478
00:25:05,093 --> 00:25:07,900
it's 360 degrees and you can figure out

479
00:25:07,900 --> 00:25:11,203
where the cells fire in
relationship to the theta.

480
00:25:12,917 --> 00:25:17,190
And when cells fire synchronously
or fire on the same stage

481
00:25:17,190 --> 00:25:20,260
if they are in different cells
that can really affect how

482
00:25:20,260 --> 00:25:23,170
much neurotransmitter is
released and so it can be

483
00:25:23,170 --> 00:25:27,960
a pretty powerful way
to send messages from

484
00:25:27,960 --> 00:25:29,710
one area of the brain to the other.

485
00:25:30,930 --> 00:25:33,550
So what you can do when
you're bored at night

486
00:25:33,550 --> 00:25:36,430
is go out and buy yourself two metronomes

487
00:25:36,430 --> 00:25:38,970
and then you take the metronomes
and you put it on a board

488
00:25:38,970 --> 00:25:42,793
and then you put some
beer cans under the board.

489
00:25:43,810 --> 00:25:46,070
If you're a faculty member at UVM

490
00:25:46,070 --> 00:25:50,930
you would use Heady Topper,
if you're an undergrad

491
00:25:50,930 --> 00:25:54,820
of drinking age, you would
probably buy Pabst Blue Ribbon.

492
00:25:54,820 --> 00:25:57,230
But anyhow, you put these
beer cans under here

493
00:25:57,230 --> 00:25:59,770
and you set the metronomes off,

494
00:25:59,770 --> 00:26:02,170
so they're not firing together.

495
00:26:02,170 --> 00:26:05,170
What'll happen over time
is that metronomes will,

496
00:26:05,170 --> 00:26:06,920
through different torque pressures,

497
00:26:09,320 --> 00:26:11,880
will start to become synchronous.

498
00:26:11,880 --> 00:26:13,400
And as they become synchronous,

499
00:26:13,400 --> 00:26:16,160
this board will move back and forth.

500
00:26:16,160 --> 00:26:19,010
So there's a lot of power in two areas

501
00:26:19,010 --> 00:26:23,240
that are in sync, can cause
significant movement here

502
00:26:24,100 --> 00:26:26,830
to neurons that are in sync, it can cause

503
00:26:26,830 --> 00:26:29,370
increased neurotransmitter release

504
00:26:29,370 --> 00:26:32,050
when they're in the same phase.

505
00:26:32,050 --> 00:26:33,520
So this is a powerful mechanism

506
00:26:33,520 --> 00:26:37,883
by which neural transmission
occurs in the brain.

507
00:26:39,230 --> 00:26:44,230
So we're back to development. And the rat,

508
00:26:44,270 --> 00:26:49,270
this allocentric memory
that occurs will depend

509
00:26:49,920 --> 00:26:54,920
upon a lot of things coming
in line, your rhythms,

510
00:26:55,310 --> 00:26:58,650
theta rhythm, a faster
rhythm, gamma rhythm,

511
00:26:58,650 --> 00:27:03,430
which really drives input
into the dendrites of cells,

512
00:27:03,430 --> 00:27:05,400
your grid cells, boundary cell,

513
00:27:05,400 --> 00:27:07,112
which I didn't talk
about are cells that fire

514
00:27:07,112 --> 00:27:12,112
at a boundary when the animal's
in a cylinder or a square.

515
00:27:14,180 --> 00:27:16,240
And then you have the sharp wave-ripples,

516
00:27:16,240 --> 00:27:18,303
which is important for consolidation.

517
00:27:19,260 --> 00:27:21,910
So, you know, I just think of these things

518
00:27:21,910 --> 00:27:24,287
all coming together,
being all very important.

519
00:27:24,287 --> 00:27:27,260
And the timing of when
they develop is important.

520
00:27:27,260 --> 00:27:30,340
When I refer to P here,
I'm talking about rats

521
00:27:30,340 --> 00:27:33,770
that are postnatal day
seven, postnatal day 21,

522
00:27:33,770 --> 00:27:37,240
which is a current equivalent to P10 rat

523
00:27:37,240 --> 00:27:39,143
is equivalent to about a term infant.

524
00:27:40,400 --> 00:27:44,480
So think of this as a
orchestra where everything

525
00:27:44,480 --> 00:27:47,950
has to come together,
timing has to be perfect.

526
00:27:47,950 --> 00:27:51,270
And you can think of the
percussion system here.

527
00:27:51,270 --> 00:27:55,633
That percussion section is
driving the theta activity.

528
00:27:57,350 --> 00:28:00,850
The basses you can think
of boundary cells here.

529
00:28:00,850 --> 00:28:03,497
You can think of the string section,

530
00:28:03,497 --> 00:28:06,470
and the violas, the violins, cellos,

531
00:28:06,470 --> 00:28:11,470
perhaps representing grid
cells and place cells.

532
00:28:13,700 --> 00:28:16,300
And then you can think
of the flute section,

533
00:28:16,300 --> 00:28:19,110
the woodwind section, the brass section

534
00:28:19,110 --> 00:28:21,140
as being the different types of rhythms

535
00:28:21,140 --> 00:28:22,770
that have to come together.

536
00:28:22,770 --> 00:28:26,670
So everything has to
work beautifully in sync.

537
00:28:26,670 --> 00:28:31,670
Timing is great and you
get a beautiful music

538
00:28:31,810 --> 00:28:35,720
from the orchestra and it's
the same thing with the brain.

539
00:28:35,720 --> 00:28:39,230
If everything is in sync, you have a child

540
00:28:39,230 --> 00:28:43,473
or you have an animal that
can learn and learn quickly.

541
00:28:44,900 --> 00:28:49,100
Okay, so and again these are
important developmental steps.

542
00:28:49,100 --> 00:28:52,930
They occur in waves and the
timing is absolutely critical

543
00:28:52,930 --> 00:28:56,750
of when these different wave form

544
00:28:56,750 --> 00:29:01,750
I talked about join up
together and this maturation

545
00:29:02,070 --> 00:29:06,290
of these different cells
goes from an leads to,

546
00:29:06,290 --> 00:29:09,920
in a child from egocentric
memory to allocentric memory.

547
00:29:09,920 --> 00:29:11,810
And we said earlier
that allocentric memory

548
00:29:11,810 --> 00:29:13,290
is around four or five years.

549
00:29:13,290 --> 00:29:15,460
So we were talking about the hippocampus.

550
00:29:15,460 --> 00:29:17,000
So this is the period
where you really start

551
00:29:17,000 --> 00:29:20,563
to see allocentric memory come into play.

552
00:29:22,060 --> 00:29:25,300
So what about rats?

553
00:29:25,300 --> 00:29:28,700
Well, it turns out that the
equivalent to declarative memory

554
00:29:28,700 --> 00:29:32,410
in children is the
spatial cognition in rats.

555
00:29:32,410 --> 00:29:34,300
And there's a number of ways you can look

556
00:29:34,300 --> 00:29:37,320
at spatial cognition in rats and one

557
00:29:37,320 --> 00:29:40,180
is the famous Morris water maze,

558
00:29:40,180 --> 00:29:42,569
where you drop a rat into the water.

559
00:29:42,569 --> 00:29:45,070
There's a platform here
that's under the water.

560
00:29:45,070 --> 00:29:48,970
The water is opaque, you
put milk or latex paint

561
00:29:49,920 --> 00:29:52,470
in the water, they can't see the platform.

562
00:29:52,470 --> 00:29:55,670
Rats are great swimmers and
they don't really like it.

563
00:29:55,670 --> 00:29:58,763
So if they accidentally
will find the platform.

564
00:30:00,000 --> 00:30:02,640
If you keep doing the same
test, as long as you have cues

565
00:30:02,640 --> 00:30:05,820
around the room, allocentric cues,

566
00:30:05,820 --> 00:30:09,620
the rat will quickly learn to
swim right to the platform.

567
00:30:09,620 --> 00:30:11,150
And that's called the Morris water maze.

568
00:30:11,150 --> 00:30:13,790
One of the most famous and well-used tests

569
00:30:13,790 --> 00:30:17,360
in spatial cognition in rodents

570
00:30:17,360 --> 00:30:19,560
and the sight declarative memory.

571
00:30:19,560 --> 00:30:22,430
So if you take rats and
you give them a bunch

572
00:30:22,430 --> 00:30:26,840
of seizures early in life
in the newborn period,

573
00:30:26,840 --> 00:30:29,623
and then you look at them versus controls,

574
00:30:30,490 --> 00:30:32,733
we're talking about
early life seizures here,

575
00:30:33,640 --> 00:30:36,937
you can see and this is
the number of trials here.

576
00:30:36,937 --> 00:30:41,370
And we do the testing over
days, four days typically.

577
00:30:41,370 --> 00:30:43,100
And you can see that
in early life seizures,

578
00:30:43,100 --> 00:30:46,713
the animals really never learn the task.

579
00:30:47,710 --> 00:30:50,750
And the control animals over time,

580
00:30:50,750 --> 00:30:52,663
quickly learned the task here.

581
00:30:53,740 --> 00:30:57,613
So early life seizures
cause cognitive impairment.

582
00:30:59,440 --> 00:31:02,420
And if you do the active
avoidance test here,

583
00:31:02,420 --> 00:31:06,820
so the rat can't see this,
but this is avoidance,

584
00:31:06,820 --> 00:31:09,770
he gets a shock if the rat enters here.

585
00:31:09,770 --> 00:31:12,920
So if you take a control rat,
the rat will quickly learn

586
00:31:12,920 --> 00:31:16,190
using this dwell map here to stay away,

587
00:31:16,190 --> 00:31:19,000
as far away from that
shock zone as possible.

588
00:31:19,000 --> 00:31:23,130
And this arena is rotating, so the animal

589
00:31:23,130 --> 00:31:24,830
as he's setting in here is he knows,

590
00:31:24,830 --> 00:31:26,220
he's getting close to that shock zone,

591
00:31:26,220 --> 00:31:29,230
will turn around and run back.

592
00:31:29,230 --> 00:31:31,870
So it's a rotating arena with a shock zone

593
00:31:31,870 --> 00:31:34,110
and he has to use clues around the room

594
00:31:34,110 --> 00:31:36,210
to know where that shock zone is.

595
00:31:36,210 --> 00:31:37,760
Here's a rat that had early life seizures.

596
00:31:37,760 --> 00:31:40,480
You can see just by the
path the rat is taking,

597
00:31:40,480 --> 00:31:42,770
he runs through that shock zone a lot.

598
00:31:42,770 --> 00:31:44,993
Control animal stays away from it.

599
00:31:46,160 --> 00:31:49,450
So this is another good
test of spatial avoidance

600
00:31:49,450 --> 00:31:52,870
and rats that have early life seizures

601
00:31:52,870 --> 00:31:55,610
just have a great deal
of difficulty learning

602
00:31:55,610 --> 00:31:58,803
what that shock zone is.

603
00:32:00,080 --> 00:32:03,720
So that's interesting, but
what's going on physiologically?

604
00:32:03,720 --> 00:32:06,223
I told you the importance of place cells,

605
00:32:07,110 --> 00:32:09,112
theta coming in line, all these different

606
00:32:09,112 --> 00:32:12,557
physiological parameters,
well, if you take a rat

607
00:32:12,557 --> 00:32:14,370
and you give them a bunch of seizures

608
00:32:14,370 --> 00:32:18,790
and just very brief seizures actually,

609
00:32:18,790 --> 00:32:21,260
and then you wait a while
and then you test them

610
00:32:21,260 --> 00:32:26,260
in the just the kind of
single cell recording

611
00:32:26,760 --> 00:32:28,790
just looking at place cells, you can see

612
00:32:28,790 --> 00:32:30,450
that the figures on top here,

613
00:32:30,450 --> 00:32:33,300
these place cells are very precise.

614
00:32:33,300 --> 00:32:35,690
The dark colors are the
higher firing rates,

615
00:32:35,690 --> 00:32:37,570
and you can see that
they're really precise

616
00:32:37,570 --> 00:32:40,870
and the firing occurs in
a very limited fashion.

617
00:32:40,870 --> 00:32:43,147
If you look at rats that
have had recurrent seizures,

618
00:32:43,147 --> 00:32:47,660
the place maps are all over
the place, very disorganized,

619
00:32:47,660 --> 00:32:52,660
very poorly modulated, not very precise.

620
00:32:52,880 --> 00:32:55,230
And they may actually even change position

621
00:32:55,230 --> 00:32:57,650
from one section to the
next, so as are looking

622
00:32:57,650 --> 00:33:01,080
at four sections and that
corresponds beautifully

623
00:33:01,080 --> 00:33:02,890
with how they do in the Morris water maze.

624
00:33:02,890 --> 00:33:05,750
So animals that have aberrant place cells

625
00:33:05,750 --> 00:33:08,560
do very poorly in the Morris water maze.

626
00:33:08,560 --> 00:33:12,030
So it's a good indication
on a single cell level

627
00:33:12,030 --> 00:33:15,150
of cognition and this is impaired

628
00:33:15,150 --> 00:33:17,823
with rats with developmental seizures.

629
00:33:19,300 --> 00:33:22,680
Now a very important thing
is that a lot of people think

630
00:33:22,680 --> 00:33:26,450
and this is true in
adults, but not children.

631
00:33:26,450 --> 00:33:31,450
And certainly adult rats and
not pediatrics, not baby rats,

632
00:33:31,520 --> 00:33:34,930
that you have a seizure, the
rat convulses, they get blue,

633
00:33:34,930 --> 00:33:37,770
they get cyanotic and you think, well,

634
00:33:37,770 --> 00:33:40,930
maybe this is just due to
cell loss, the cells die.

635
00:33:40,930 --> 00:33:43,283
And that's why there's
cognitive impairment.

636
00:33:44,470 --> 00:33:49,010
And that's not the case
and animal literature

637
00:33:49,010 --> 00:33:52,870
suggested years ago that rats, baby rats,

638
00:33:52,870 --> 00:33:56,410
will have frequent seizures
and you cut the brains

639
00:33:56,410 --> 00:33:59,123
and you look at them and
you see no cell loss.

640
00:34:01,091 --> 00:34:05,883
And so the implication was
that seizures are harmless

641
00:34:06,770 --> 00:34:09,870
in the developing animal
because you don't see cell loss.

642
00:34:09,870 --> 00:34:13,260
And it just shows the important
cell loss is not everything.

643
00:34:13,260 --> 00:34:16,960
And so animals can have
significant deficits

644
00:34:16,960 --> 00:34:20,310
without actually cells dying and what we

645
00:34:20,310 --> 00:34:23,170
and some of our colleagues
have shown is that you can get

646
00:34:23,170 --> 00:34:26,580
with early life seizures,
you can see, not cell loss,

647
00:34:26,580 --> 00:34:31,160
but you can see changes in
these neurons and decreases

648
00:34:31,160 --> 00:34:35,600
in the synapses, the spines,
the dendritic arborization here

649
00:34:37,110 --> 00:34:40,180
and if you do functional MRI on these rats

650
00:34:40,180 --> 00:34:43,120
with early life seizures,
you can actually see changes

651
00:34:43,120 --> 00:34:47,890
in how the current flow
in this region occurs.

652
00:34:47,890 --> 00:34:52,740
So here's a example of a
diffusion tensor imaging,

653
00:34:52,740 --> 00:34:55,290
looking at CA1 of the hippocampus,

654
00:34:55,290 --> 00:34:57,520
this is part of the hippocampus.

655
00:34:57,520 --> 00:34:59,960
This is a control rat, this is a rat

656
00:34:59,960 --> 00:35:03,860
that's had a long seizure and you can see

657
00:35:03,860 --> 00:35:07,890
that there's difference
in the track profile

658
00:35:07,890 --> 00:35:10,780
in these animals and how current flow

659
00:35:10,780 --> 00:35:13,970
through these animals is
different in these animals.

660
00:35:13,970 --> 00:35:16,780
So these animals have
impairment and we think a lot

661
00:35:16,780 --> 00:35:18,230
of this impairment has to do with

662
00:35:18,230 --> 00:35:22,910
that dendritic arborization that occurs.

663
00:35:22,910 --> 00:35:25,900
And if you then look at
oscillations in the hippocampus,

664
00:35:25,900 --> 00:35:30,350
we see in the gamma region
abnormalities in CA1

665
00:35:30,350 --> 00:35:34,300
that correspond to the
MRI findings as well.

666
00:35:34,300 --> 00:35:37,210
So seizures are going something
structurally to the brain,

667
00:35:37,210 --> 00:35:39,683
but they're not killing brain cells.

668
00:35:41,120 --> 00:35:44,207
So we've had recently and
this is just from this year,

669
00:35:44,207 --> 00:35:48,430
I've been very interested
in what it is about seizures

670
00:35:48,430 --> 00:35:50,160
and the developing animal that leads

671
00:35:50,160 --> 00:35:53,270
to so much cognitive
impairment and which leads

672
00:35:53,270 --> 00:35:58,270
to aberrant place cells leads
to spatial cognitive function.

673
00:35:58,340 --> 00:36:03,013
And what is it about the
seizure per se, that occurs?

674
00:36:04,630 --> 00:36:07,720
What I told you earlier that there's this,

675
00:36:07,720 --> 00:36:09,690
as you develop allocentric memory

676
00:36:10,750 --> 00:36:13,120
in rodents and presumably humans,

677
00:36:13,120 --> 00:36:15,760
these different processes come in line

678
00:36:15,760 --> 00:36:19,090
and they're driven by brain oscillations.

679
00:36:19,090 --> 00:36:22,660
So we've said, why not look at animals

680
00:36:22,660 --> 00:36:25,730
during the critical period
of spatial cognition

681
00:36:25,730 --> 00:36:29,390
and this would be corresponding
to a child as I mentioned,

682
00:36:29,390 --> 00:36:31,160
that's when they develop
allocentric memory,

683
00:36:31,160 --> 00:36:35,410
we use the same age in
rats, give them seizures

684
00:36:35,410 --> 00:36:40,140
during the critical period
and then when you follow

685
00:36:40,140 --> 00:36:43,120
these animals, they are
impaired cognitively.

686
00:36:43,120 --> 00:36:44,670
But we said, what if we
don't give them seizures?

687
00:36:44,670 --> 00:36:48,260
What if we just changed
their oscillatory pattern?

688
00:36:48,260 --> 00:36:52,220
So here's a normal rat, very young rat,

689
00:36:52,220 --> 00:36:54,343
and they have this beautiful theta rhythm.

690
00:36:55,350 --> 00:36:57,610
We decided to take rats and we would use

691
00:36:57,610 --> 00:37:01,230
this a technique called
optogenetic-induction

692
00:37:01,230 --> 00:37:04,373
in which you can stick what's called

693
00:37:04,373 --> 00:37:07,400
a channelrhodopsin in the medial septum

694
00:37:07,400 --> 00:37:11,890
and we can then control
oscillations in the hippocampus.

695
00:37:11,890 --> 00:37:15,060
And so what we did is not cause
seizures, but we just said,

696
00:37:15,060 --> 00:37:19,960
let's just throw in junk
oscillations, nothing pathological,

697
00:37:19,960 --> 00:37:23,093
normal oscillations, but not seizures.

698
00:37:24,020 --> 00:37:28,083
So the process here is
that you take a rat,

699
00:37:29,160 --> 00:37:33,500
you put a electrode and you put a virus

700
00:37:33,500 --> 00:37:35,650
which contains channelrhodopsin,

701
00:37:35,650 --> 00:37:40,380
which will be taken up by
the cells and in these cells,

702
00:37:40,380 --> 00:37:42,770
when you shine a bright light,

703
00:37:42,770 --> 00:37:45,170
a blue light, that cells will fire,

704
00:37:45,170 --> 00:37:49,990
when you shine a yellow light,
the cells will not fire.

705
00:37:49,990 --> 00:37:52,910
So the medial septum is
in the middle of the brain

706
00:37:52,910 --> 00:37:55,210
and it projects to both of the hippocampi.

707
00:37:55,210 --> 00:38:00,210
So it's a midline structure,
goes to both hippocampi.

708
00:38:00,800 --> 00:38:02,630
So we put electrodes in the medial septum,

709
00:38:02,630 --> 00:38:04,580
we put electrodes in the hippocampus

710
00:38:05,550 --> 00:38:08,000
and then we checked to make sure

711
00:38:08,000 --> 00:38:10,180
that we were actually inducing changes

712
00:38:10,180 --> 00:38:13,420
in the hippocampus with
medial septum stimulation.

713
00:38:13,420 --> 00:38:16,440
And so here, we had
stimulated five, six, seven,

714
00:38:16,440 --> 00:38:18,640
eight, nine, 10, 11, 12 hertz.

715
00:38:18,640 --> 00:38:20,070
You can see in this spectrogram,

716
00:38:20,070 --> 00:38:23,563
which shows the power of the wave form.

717
00:38:24,550 --> 00:38:26,830
You can see very nice as you go up,

718
00:38:26,830 --> 00:38:28,600
we're getting what we said we would get

719
00:38:28,600 --> 00:38:31,210
and you get beautiful,
what we would call driving

720
00:38:31,210 --> 00:38:32,890
of the hippocampus so we can control

721
00:38:32,890 --> 00:38:34,580
the hippocampal oscillations

722
00:38:34,580 --> 00:38:36,453
through medial stapal stimulation.

723
00:38:37,430 --> 00:38:39,080
Then we say, well let's
take some rats in which

724
00:38:39,080 --> 00:38:42,460
we can do this and let's
just give them nonsense.

725
00:38:42,460 --> 00:38:45,030
Let's just give them oscillations varying

726
00:38:45,030 --> 00:38:48,550
from a 100 hertz to one
hertz and you can see here,

727
00:38:48,550 --> 00:38:51,000
this is over on at least an hour,

728
00:38:51,000 --> 00:38:55,100
you can see different
oscillatory patterns in the rat.

729
00:38:55,100 --> 00:38:59,660
And then we test them in
the active avoidance test

730
00:39:01,060 --> 00:39:03,130
and here, so we're not giving seizures,

731
00:39:03,130 --> 00:39:06,220
we're giving normal oscillations,

732
00:39:06,220 --> 00:39:10,000
but in an aberrant temporal fashion.

733
00:39:10,000 --> 00:39:12,450
And just to show you how
beautiful this works,

734
00:39:12,450 --> 00:39:14,530
the people in my lab are just fantastic

735
00:39:14,530 --> 00:39:18,160
at getting quality, here's
baseline, rat has temporal.

736
00:39:18,160 --> 00:39:20,520
You start to stimulate then at six hertz,

737
00:39:20,520 --> 00:39:24,670
this is just showing power here.

738
00:39:24,670 --> 00:39:27,690
And this is an amplitude synchrony,

739
00:39:27,690 --> 00:39:30,218
basically amplitude correlations,

740
00:39:30,218 --> 00:39:31,860
but you can see it is six hertz,

741
00:39:31,860 --> 00:39:33,700
You get exactly what you want, six hertz.

742
00:39:33,700 --> 00:39:37,470
There's some normal
rhythms in there as well.

743
00:39:37,470 --> 00:39:39,830
12 hertz, you get beautiful 12 hertz,

744
00:39:39,830 --> 00:39:42,200
and it's reflected here
and in the spectrogram,

745
00:39:42,200 --> 00:39:44,940
which shows the frequency,
this is a crane rate

746
00:39:44,940 --> 00:39:49,110
at six hertz and this is
re occurring at 12 hertz.

747
00:39:49,110 --> 00:39:50,010
What's interesting you can see

748
00:39:50,010 --> 00:39:51,800
what's called harmonics as well.

749
00:39:51,800 --> 00:39:54,810
So if you stimulate it six, you can see

750
00:39:54,810 --> 00:39:57,970
also some activity at 12 and so on.

751
00:39:57,970 --> 00:40:00,900
So it works, it works very, very well.

752
00:40:00,900 --> 00:40:03,430
And lo and behold, we did
this, these rats look fine.

753
00:40:03,430 --> 00:40:05,620
You know, we did stimulate
them for four days during

754
00:40:05,620 --> 00:40:09,540
the critical period, then we
put them in active avoidance.

755
00:40:09,540 --> 00:40:12,680
And whether we gave them
a one hour of stimulation

756
00:40:13,880 --> 00:40:18,880
a day or five hours a day, these animals

757
00:40:19,670 --> 00:40:22,620
had pretty significant impairment.

758
00:40:22,620 --> 00:40:24,390
So these are number of shocks

759
00:40:24,390 --> 00:40:26,750
and these are the trial numbers here.

760
00:40:26,750 --> 00:40:29,920
And even though our
ends were pretty small,

761
00:40:29,920 --> 00:40:33,190
our statistics were so
strong that we went ahead

762
00:40:33,190 --> 00:40:35,830
and got this published and showing

763
00:40:35,830 --> 00:40:39,460
that hippocampus oscillations during

764
00:40:39,460 --> 00:40:41,510
the critical period of
brain development results

765
00:40:41,510 --> 00:40:45,283
in substantial deficits
in spatial cognition.

766
00:40:46,510 --> 00:40:49,160
And just to show you an example of this,

767
00:40:49,160 --> 00:40:52,590
this is again, a dwell
map, active avoidance here.

768
00:40:52,590 --> 00:40:55,168
Here's the shock zone
which the animal can't see,

769
00:40:55,168 --> 00:40:58,330
these are animals that
had no light stimulation,

770
00:40:58,330 --> 00:41:00,249
or these are animals
that had yellow light,

771
00:41:00,249 --> 00:41:04,680
that will not activate the
channelrhodopsin nothing happens.

772
00:41:04,680 --> 00:41:07,220
But these are animals that
had blue light and you can see

773
00:41:07,220 --> 00:41:09,430
like this animal just ran through

774
00:41:09,430 --> 00:41:12,270
the shock zone, pay no attention to it.

775
00:41:12,270 --> 00:41:14,160
This animal had a
different kind of strategy.

776
00:41:14,160 --> 00:41:17,210
Just kind of did his own circle inside

777
00:41:17,210 --> 00:41:18,920
and he was getting shocked a little less,

778
00:41:18,920 --> 00:41:23,713
but was quite impaired in this testing.

779
00:41:24,710 --> 00:41:28,210
So the question was
that, although we thought

780
00:41:28,210 --> 00:41:30,910
we were putting in normal
oscillatory activity,

781
00:41:30,910 --> 00:41:34,840
but just kind of random
noise into the system,

782
00:41:34,840 --> 00:41:38,090
could this cause any
damage, could this be,

783
00:41:38,090 --> 00:41:42,010
you know, could this be
frying the neurons, et cetera?

784
00:41:42,010 --> 00:41:45,330
But so we did some pretty
nice histology here.

785
00:41:45,330 --> 00:41:50,280
What I'm showing you here is
the channelrhodopsin expressed

786
00:41:50,280 --> 00:41:54,510
in the medial septum here
and the medial septum, again,

787
00:41:54,510 --> 00:41:59,510
projects to the hippocampus
and you can see the axons

788
00:42:01,890 --> 00:42:06,720
and the terminals of the
medial septum neurons here.

789
00:42:06,720 --> 00:42:09,400
This is CA1 of the hippocampus,

790
00:42:09,400 --> 00:42:13,770
here this is a stain just to show cells.

791
00:42:13,770 --> 00:42:17,010
Here's the dentate gyrus
here, but these fibers

792
00:42:17,010 --> 00:42:19,330
weren't right where we expected them to.

793
00:42:19,330 --> 00:42:22,560
And this is a new N,
Michelle Klok in the lab,

794
00:42:22,560 --> 00:42:26,530
did a new N which shows neurons here.

795
00:42:26,530 --> 00:42:29,803
And when you do extensive cell
counting on these animals,

796
00:42:30,730 --> 00:42:32,583
really, there's no cell loss.

797
00:42:35,015 --> 00:42:38,290
So and this optogenetic
stimulation just by kind

798
00:42:38,290 --> 00:42:41,653
of putting a normal activity
in at the wrong time,

799
00:42:42,650 --> 00:42:46,390
it really can disrupt the
development of spatial cognition

800
00:42:46,390 --> 00:42:51,390
and lead to long-standing
deficits in spatial cognition.

801
00:42:52,520 --> 00:42:56,010
So we think that the
body of the work recently

802
00:42:56,010 --> 00:42:57,840
what we're doing is that
it's not necessarily

803
00:42:57,840 --> 00:43:01,570
the seizures that are causing
the problems in these kids,

804
00:43:01,570 --> 00:43:05,860
it's the abnormal rhythms
that are going into the brain.

805
00:43:05,860 --> 00:43:07,770
And as I mentioned earlier, the children

806
00:43:07,770 --> 00:43:12,490
with the epileptic encephalopathies
have terrible EEGs.

807
00:43:12,490 --> 00:43:14,670
So 24 hours a day, seven days a week,

808
00:43:14,670 --> 00:43:17,120
they're having aberrant activity.

809
00:43:17,120 --> 00:43:19,090
They may not be having seizures,

810
00:43:19,090 --> 00:43:22,570
but the brain is not, the temporal coding,

811
00:43:22,570 --> 00:43:25,330
the information going
to the hippocampus based

812
00:43:25,330 --> 00:43:29,040
on the oscillatory
activity is just not right.

813
00:43:29,040 --> 00:43:33,660
So there's more and more
evidence that the children

814
00:43:33,660 --> 00:43:38,660
that have cognitive impairment
with early life seizures,

815
00:43:38,860 --> 00:43:43,347
it may be more related to
the dysrhythmia of the brain,

816
00:43:44,870 --> 00:43:47,260
the alterations and the oscillations,

817
00:43:47,260 --> 00:43:50,690
more so than the actual seizures per se.

818
00:43:50,690 --> 00:43:54,960
So the EEG may be more
predictive of outcome

819
00:43:54,960 --> 00:43:57,509
in these kids with the
epileptic encephalopathies,

820
00:43:57,509 --> 00:44:02,509
than the actual seizures themselves.

821
00:44:03,750 --> 00:44:07,873
So again, the brain is a magical organ.

822
00:44:09,510 --> 00:44:14,410
It's the timing is everything
and I think that the brain

823
00:44:14,410 --> 00:44:18,010
is a, you know, musical
orchestra, where everything

824
00:44:18,010 --> 00:44:21,750
has to come together and
a perfectly timed pattern

825
00:44:21,750 --> 00:44:26,750
for the children to develop
a normal spatial cognition,

826
00:44:28,300 --> 00:44:30,680
and which would be declarative
memory in children.

827
00:44:30,680 --> 00:44:34,050
So, in conclusion is I just wanna note,

828
00:44:34,050 --> 00:44:36,800
and I hope with the one
take-home message for you

829
00:44:36,800 --> 00:44:41,150
is that epilepsy is
far more than seizures.

830
00:44:41,150 --> 00:44:45,160
Our children have cognitive
impairment to a high degree,

831
00:44:45,160 --> 00:44:48,890
the ones with severe seizures
and early life seizures.

832
00:44:48,890 --> 00:44:51,530
They're more prone for
sleep disorders, depression,

833
00:44:51,530 --> 00:44:53,560
attention deficit disorder, et cetera.

834
00:44:53,560 --> 00:44:56,060
So it really is a spectrum disorder.

835
00:44:56,060 --> 00:44:59,290
And we, as clinicians need
to spend more time trying

836
00:44:59,290 --> 00:45:03,463
to work on the cognitive
and on the comorbidities

837
00:45:03,463 --> 00:45:05,690
than we may need to do on the seizures.

838
00:45:05,690 --> 00:45:08,960
Many parents have told
me that the seizures

839
00:45:08,960 --> 00:45:11,273
are just a small part of the
problem with their child.

840
00:45:11,273 --> 00:45:16,240
They have so many other issues
they can handle the seizures,

841
00:45:16,240 --> 00:45:19,970
but they have trouble handling
the other things that occur.

842
00:45:19,970 --> 00:45:22,860
And it's heartbreaking such as
with Susan Axelrod's daughter

843
00:45:22,860 --> 00:45:26,673
to see her decline so rapidly over time.

844
00:45:28,020 --> 00:45:29,500
Children are particularly vulnerable

845
00:45:29,500 --> 00:45:34,100
to the adverse effects of
seizures, so timing is everything.

846
00:45:34,100 --> 00:45:37,350
And so at a time when
the brain is very plastic

847
00:45:37,350 --> 00:45:39,700
and you're trying to
develop the hippocampus

848
00:45:39,700 --> 00:45:43,580
so that you can develop
a declarative memory,

849
00:45:43,580 --> 00:45:45,180
during that time you're being bombarded

850
00:45:45,180 --> 00:45:49,575
with seizures or aberrant oscillations,

851
00:45:49,575 --> 00:45:54,575
that can be really quite vulnerable.

852
00:45:54,920 --> 00:45:56,450
And there's a critical period of time,

853
00:45:56,450 --> 00:45:59,300
in work that we haven't done,
but other people have done

854
00:45:59,300 --> 00:46:01,340
is that if you can shut off activity

855
00:46:02,460 --> 00:46:04,200
or cause abberent activity during

856
00:46:04,200 --> 00:46:07,480
the critical period of time
of spatial development,

857
00:46:07,480 --> 00:46:09,190
and that in children would be during

858
00:46:09,190 --> 00:46:13,790
the first four years of life
and you have the insight

859
00:46:13,790 --> 00:46:16,510
and do the same thing in an older child,

860
00:46:16,510 --> 00:46:19,510
much less likely to have
that cognitive impairment.

861
00:46:19,510 --> 00:46:22,170
I told you earlier that
children that are older

862
00:46:22,170 --> 00:46:25,370
and start having seizures
are much less likely

863
00:46:25,370 --> 00:46:29,170
to be impaired than children that

864
00:46:30,750 --> 00:46:32,910
are very young when they
start having seizures.

865
00:46:32,910 --> 00:46:37,520
So we really have to work hard on stopping

866
00:46:37,520 --> 00:46:39,620
the seizures in the young children.

867
00:46:39,620 --> 00:46:42,110
And I think the seizures may
adversely effect the rhythms

868
00:46:42,110 --> 00:46:43,820
of the brain and therefore result

869
00:46:43,820 --> 00:46:47,530
in longstanding cognitive impairment.

870
00:46:47,530 --> 00:46:51,470
So with that, I would like to thank people

871
00:46:51,470 --> 00:46:55,280
for listening to this
in the late afternoon

872
00:46:55,280 --> 00:46:58,810
and I have so many people to thank.

873
00:46:58,810 --> 00:47:01,390
But I'm just really concentrating
this list on the people

874
00:47:01,390 --> 00:47:04,140
I've been working with
over the last couple

875
00:47:04,140 --> 00:47:08,690
of years here at UVM in my lab here,

876
00:47:08,690 --> 00:47:11,963
we work very close with
Tallie Baram at UC Irvine,

877
00:47:13,330 --> 00:47:17,200
I did a sabbatical in Paris
and still maintain contact

878
00:47:17,200 --> 00:47:20,520
and rich collaborations
with the people there.

879
00:47:20,520 --> 00:47:23,440
And then we've had
post-docs, I had a post-doc

880
00:47:23,440 --> 00:47:25,567
from the Ukraine who
I'm still working with

881
00:47:25,567 --> 00:47:27,540
and we just published a paper recently.

882
00:47:27,540 --> 00:47:31,210
But all these people and
as I mentioned before,

883
00:47:31,210 --> 00:47:36,210
in the ceremony that, you
know, I'm the type of person

884
00:47:36,750 --> 00:47:38,650
that goes around and giving the talks,

885
00:47:39,990 --> 00:47:42,380
getting the wards like this
one, but these are the people

886
00:47:42,380 --> 00:47:45,540
that do all the heavy lifting
and are in the lab every day,

887
00:47:45,540 --> 00:47:49,178
are working very hard and so I really have

888
00:47:49,178 --> 00:47:52,970
a very good group, so with
that, I thank you very much

889
00:47:52,970 --> 00:47:55,363
and be glad to take some questions.

890
00:47:59,710 --> 00:48:01,133
- Thank you, Dr. Holmes.

891
00:48:03,030 --> 00:48:05,760
I wanna open this up
right now for questions,

892
00:48:05,760 --> 00:48:08,040
but I wanna first just
say thank you very much.

893
00:48:08,040 --> 00:48:09,800
And if you didn't have a room with only

894
00:48:09,800 --> 00:48:11,130
the five people helping you do this,

895
00:48:11,130 --> 00:48:12,690
you would hear us all applauding for you.

896
00:48:12,690 --> 00:48:15,760
So I will take a second
for you to appreciate that.

897
00:48:15,760 --> 00:48:17,910
The questions will come from me,

898
00:48:17,910 --> 00:48:19,530
they're being published from the audience.

899
00:48:19,530 --> 00:48:21,703
So I have a beginning question for you,

900
00:48:22,820 --> 00:48:24,790
comes from Jerry Herrera and it says,

901
00:48:24,790 --> 00:48:27,920
very fascinating talk,
I really enjoyed it.

902
00:48:27,920 --> 00:48:30,700
Do kids with seizures,
suffering cognitive impairment,

903
00:48:30,700 --> 00:48:33,190
have any issues with
control of bodily functions

904
00:48:33,190 --> 00:48:35,563
like urination, voiding and bowel control?

905
00:48:36,759 --> 00:48:40,830
- Yes, so that's often
one of the major problems

906
00:48:41,700 --> 00:48:42,723
with the children and those are the kids

907
00:48:42,723 --> 00:48:45,373
that are usually pretty impaired.

908
00:48:47,160 --> 00:48:48,860
So and yeah, the answer is yes.

909
00:48:48,860 --> 00:48:53,482
And that's one of the things
I always ask my parents

910
00:48:53,482 --> 00:48:55,610
just talked to a patient today, you know,

911
00:48:55,610 --> 00:48:58,650
and going through the
developmental milestones,

912
00:48:58,650 --> 00:49:01,230
the child has severe
epilepsy and, you know,

913
00:49:01,230 --> 00:49:04,270
you ask the parents about
toilet skills and that

914
00:49:04,270 --> 00:49:07,470
is so critical, so hard to take care

915
00:49:07,470 --> 00:49:08,780
of some of these kids are so impaired,

916
00:49:08,780 --> 00:49:10,640
but the toilet skills is the big thing.

917
00:49:10,640 --> 00:49:14,040
It keeps them out of school,
it's just a terrible thing.

918
00:49:14,040 --> 00:49:16,623
And yes, it's a major problem with that.

919
00:49:17,550 --> 00:49:19,887
There's also the issue of,
you know, during seizures,

920
00:49:19,887 --> 00:49:22,230
you can have, certainly one of the things

921
00:49:22,230 --> 00:49:24,820
I always ask patients, did
they urinate during the seizure

922
00:49:24,820 --> 00:49:26,640
and you can even defecate
during a seizure.

923
00:49:26,640 --> 00:49:29,040
So it can be a problem, but usually

924
00:49:29,040 --> 00:49:33,350
in the more impaired kids do we see it.

925
00:49:33,350 --> 00:49:37,630
We also see there's a
pretty high association

926
00:49:37,630 --> 00:49:40,650
with epilepsy and autism
and we're not saying

927
00:49:40,650 --> 00:49:43,640
epilepsy causes autism,
but they're comorbidities

928
00:49:43,640 --> 00:49:46,120
and the children with autism tend

929
00:49:46,120 --> 00:49:48,240
to have these toilet skills as well.

930
00:49:48,240 --> 00:49:51,260
But that may be a different
mechanism than some

931
00:49:51,260 --> 00:49:54,323
of the kids with more
cognitive complaints, yes.

932
00:49:56,430 --> 00:49:59,690
- Great, thank you, there's
another question coming through.

933
00:49:59,690 --> 00:50:01,813
I don't have it yet, hold on, here it is,

934
00:50:02,760 --> 00:50:04,650
from Cory Trcicia, are the phenotypes

935
00:50:04,650 --> 00:50:06,440
that you observed sexually dimorphic,

936
00:50:06,440 --> 00:50:08,680
is the epilepsy itself sexually dimorphic

937
00:50:08,680 --> 00:50:10,893
either in incidents or severity?

938
00:50:11,930 --> 00:50:14,963
- Really, really good question,
that's a great question.

939
00:50:18,760 --> 00:50:20,450
One of the things we're
just doing in the lab,

940
00:50:20,450 --> 00:50:25,377
and we just finished two
with Rhys Niedecker is he did

941
00:50:29,150 --> 00:50:31,960
a nice study and we're
getting ready to publish it.

942
00:50:31,960 --> 00:50:34,220
He's a medical student now,
he spent a couple of years

943
00:50:34,220 --> 00:50:36,460
in the lab, he's a first
year medical student

944
00:50:36,460 --> 00:50:39,963
and we deducted a study in which, well,

945
00:50:39,963 --> 00:50:42,900
first of all at the NIH,
we used to always be,

946
00:50:42,900 --> 00:50:45,380
chauvinistically, we always
used to use male rats,

947
00:50:45,380 --> 00:50:48,220
'cause we said less variability
and blah, blah, blah.

948
00:50:48,220 --> 00:50:49,560
And that was really the wrong thing.

949
00:50:49,560 --> 00:50:53,220
NIH said you now have to use
sex as a biological variable.

950
00:50:53,220 --> 00:50:54,630
And they were absolutely right.

951
00:50:54,630 --> 00:50:56,490
So Rhys did a study in which we looked

952
00:50:56,490 --> 00:51:01,120
at male rats and female
rats pups that had seizures.

953
00:51:01,120 --> 00:51:05,340
And it turned out that the
female pups did much better

954
00:51:06,240 --> 00:51:10,610
in outcome than the male
pups that had seizures.

955
00:51:10,610 --> 00:51:13,310
So I'm looking at this now clinically

956
00:51:13,310 --> 00:51:15,350
because that's not been really reported

957
00:51:15,350 --> 00:51:19,150
whether the prepubescent children,

958
00:51:19,150 --> 00:51:20,970
whether you're male or
female end up having

959
00:51:20,970 --> 00:51:23,930
more severe seizures and worse outcome.

960
00:51:23,930 --> 00:51:27,010
Our lab data would indicate and Rhys did

961
00:51:27,010 --> 00:51:29,060
a great job in controlling for, you know,

962
00:51:29,900 --> 00:51:32,080
the pain threshold and
the active avoidance,

963
00:51:32,080 --> 00:51:34,440
all the right things,
looked at estrous cycles

964
00:51:34,440 --> 00:51:36,410
in the adult animals and
really didn't see much there.

965
00:51:36,410 --> 00:51:39,580
But so, yeah, so even
in prepubescent rats,

966
00:51:39,580 --> 00:51:41,560
we were finding that
there's a big difference

967
00:51:41,560 --> 00:51:43,890
between male and females
and it is much better

968
00:51:43,890 --> 00:51:46,623
to be a female rat as far as outcome.

969
00:51:50,690 --> 00:51:54,690
- Thank you, a follow-up
on the voiding question.

970
00:51:54,690 --> 00:51:57,010
Do you see this defective
voiding in the rats

971
00:51:57,010 --> 00:51:59,433
where you introduce
optogenetic dysrhythmia?

972
00:52:00,350 --> 00:52:04,120
- We do not, I shouldn't
say that we didn't

973
00:52:04,120 --> 00:52:06,230
really look very hard, it's not something

974
00:52:06,230 --> 00:52:11,230
we observed spontaneously,
but we did not see that.

975
00:52:11,470 --> 00:52:14,623
But I can't say for sure, we
really weren't monitoring that.

976
00:52:16,407 --> 00:52:20,600
- Okay, I don't have
another one at the moment,

977
00:52:20,600 --> 00:52:23,100
but I do have a question
to ask you myself.

978
00:52:23,100 --> 00:52:26,480
So when you're looking at this disruption

979
00:52:26,480 --> 00:52:29,720
of the rhythm by all
this abnormal activity,

980
00:52:29,720 --> 00:52:31,357
do you think it's the abnormal activity

981
00:52:31,357 --> 00:52:33,550
and the abnormal rhythm or the loss

982
00:52:33,550 --> 00:52:36,360
of the normal rhythm
that's actually involved

983
00:52:36,360 --> 00:52:38,623
in the disruption of the memory formation?

984
00:52:40,040 --> 00:52:43,910
- Very good question and I don't know.

985
00:52:43,910 --> 00:52:46,010
I think one of the things one could do

986
00:52:46,010 --> 00:52:49,220
is just simply turn off the medial stuff.

987
00:52:52,660 --> 00:52:56,340
It's been done before, actually
in the mammillary bodies,

988
00:52:56,340 --> 00:52:58,590
which flows into the medial septum.

989
00:52:58,590 --> 00:53:01,970
And if you do that acutely in adult rats

990
00:53:01,970 --> 00:53:03,450
and you test them in the water maze,

991
00:53:03,450 --> 00:53:07,150
they cannot learn it when
the theta has been stopped.

992
00:53:07,150 --> 00:53:10,320
What hasn't been addressed yet is whether

993
00:53:10,320 --> 00:53:12,810
if you knock off either developmentally,

994
00:53:12,810 --> 00:53:16,570
would you have cognitive
impairment later on?

995
00:53:16,570 --> 00:53:18,410
And the answer is probably yes,

996
00:53:18,410 --> 00:53:20,230
there's been one genetic
study where they knocked

997
00:53:20,230 --> 00:53:21,680
out a gene that was important

998
00:53:22,737 --> 00:53:26,090
in synaptic scaffolding and connectivity.

999
00:53:26,090 --> 00:53:28,870
And I forget the name of the
gene and when they knocked

1000
00:53:28,870 --> 00:53:33,210
that off in the young
rats and they actually

1001
00:53:33,210 --> 00:53:35,850
had decreased theta, those animals

1002
00:53:35,850 --> 00:53:38,880
did have impairment cognitively later on.

1003
00:53:38,880 --> 00:53:41,180
If they did it in older
rats and knocked it out,

1004
00:53:41,180 --> 00:53:43,510
conditional knockout, it
did not have any effects.

1005
00:53:43,510 --> 00:53:44,990
So it was during the critical period

1006
00:53:44,990 --> 00:53:47,220
that seemed to have an
effect, so I would think that

1007
00:53:47,220 --> 00:53:50,770
it may be a combination
of both, good point.

1008
00:53:50,770 --> 00:53:54,600
- Great, thank you, I
have another follow-up on,

1009
00:53:54,600 --> 00:53:56,090
now we're gonna bounce back and forth,

1010
00:53:56,090 --> 00:53:58,440
the problem with chats is
the follow-ups are delayed.

1011
00:53:58,440 --> 00:54:00,560
So the follow-up on the sexual dimorphism

1012
00:54:00,560 --> 00:54:03,050
is epilepsy in humans sexually dimorphic

1013
00:54:03,050 --> 00:54:05,740
with respect to incidents or severity?

1014
00:54:05,740 --> 00:54:09,200
- Yeah and because of what we found,

1015
00:54:09,200 --> 00:54:13,530
I have gone and started to
look at that, I have it.

1016
00:54:13,530 --> 00:54:17,690
It's not clear from
the clinical literature

1017
00:54:17,690 --> 00:54:20,850
whether that's true or not but
it hasn't been really studied

1018
00:54:20,850 --> 00:54:25,850
that well and I think these large studies,

1019
00:54:26,230 --> 00:54:27,840
I haven't seen any significant

1020
00:54:27,840 --> 00:54:30,240
difference in cognitive outcome.

1021
00:54:30,240 --> 00:54:31,920
You know, one of the problems you get into

1022
00:54:31,920 --> 00:54:35,890
with clinical, when you
try to go to the clinical

1023
00:54:35,890 --> 00:54:40,020
from the lab is that you
get so much variability

1024
00:54:40,020 --> 00:54:44,420
in the clinical arena, different
severities of seizures,

1025
00:54:44,420 --> 00:54:46,760
different age of onset,
different medications

1026
00:54:46,760 --> 00:54:49,560
that have been given,
different seizure types.

1027
00:54:49,560 --> 00:54:54,290
So it's often hard to dissect that out.

1028
00:54:55,540 --> 00:54:57,170
It's much easier to do it in an animal

1029
00:54:57,170 --> 00:54:59,030
where you have control of everything,

1030
00:54:59,030 --> 00:55:01,340
but it's something I'm
looking at right now.

1031
00:55:01,340 --> 00:55:03,023
And again, based on Rhys' data.

1032
00:55:04,850 --> 00:55:09,340
- Great, thank you, another
question from Karen Lounsbury,

1033
00:55:09,340 --> 00:55:11,800
somewhat similar to mine,
is there a toxic effect of

1034
00:55:11,800 --> 00:55:15,020
the seizures themselves that
leads to cognitive impairment

1035
00:55:15,020 --> 00:55:17,600
or is it the lack of
normal neuronal activity?

1036
00:55:17,600 --> 00:55:20,943
Can you simulate the
deficit with other toxins?

1037
00:55:22,350 --> 00:55:26,260
- Yeah, so, I mean, one of
the things people have done

1038
00:55:28,470 --> 00:55:33,103
years ago is one condition that
both in children and adults,

1039
00:55:34,140 --> 00:55:36,720
more so in adults, is
called status epilepticus.

1040
00:55:36,720 --> 00:55:41,687
So if you cause a patient
have a prolonged seizure,

1041
00:55:41,687 --> 00:55:43,480
and when I say prolonged,
we're usually talking about

1042
00:55:43,480 --> 00:55:46,360
an hour or more of
constant seizure activity,

1043
00:55:46,360 --> 00:55:49,000
those patients have pretty
significant cell loss

1044
00:55:49,000 --> 00:55:51,430
and have cognitive impairment.

1045
00:55:51,430 --> 00:55:55,440
So people used toxins in the
past, so one that we used

1046
00:55:55,440 --> 00:55:59,577
and other people used is
pilocarpine kainic acid.

1047
00:55:59,577 --> 00:56:03,820
And so the question came up
and that causes stutters.

1048
00:56:03,820 --> 00:56:07,770
So if you stick pilocarpine or kainic acid

1049
00:56:07,770 --> 00:56:09,440
in the hippocampus, the animals will have

1050
00:56:09,440 --> 00:56:13,680
a very severe seizure and
they will have cell loss.

1051
00:56:13,680 --> 00:56:16,930
And the question was, well,
is it due to the toxin

1052
00:56:16,930 --> 00:56:18,380
or is it due to the seizure?

1053
00:56:18,380 --> 00:56:22,243
So the professor I did my sabbatical with,

1054
00:56:23,945 --> 00:56:28,945
is Professor Ben-Ari in
Paris answered that question.

1055
00:56:29,210 --> 00:56:32,970
So he gave kainic acid
into the hippocampus

1056
00:56:32,970 --> 00:56:36,440
and he followed that with
an injection of diazepam

1057
00:56:36,440 --> 00:56:39,310
or Valium which is a good
drug to stop seizures.

1058
00:56:39,310 --> 00:56:42,600
What he saw was virtually no damage,

1059
00:56:42,600 --> 00:56:46,260
so it was a pilocarpine
causing the seizure damage.

1060
00:56:46,260 --> 00:56:48,870
As far as how that
occurs, most people think,

1061
00:56:48,870 --> 00:56:52,700
the most common theory is
it's excitable toxicity.

1062
00:56:52,700 --> 00:56:55,103
So when you have this massive seizure,

1063
00:56:55,980 --> 00:56:58,320
you're releasing all this glutamate,

1064
00:56:58,320 --> 00:57:01,030
glutamate can be very toxic to cells

1065
00:57:01,030 --> 00:57:04,220
and can lead to cell death.

1066
00:57:04,220 --> 00:57:08,803
So that's the thinking
there, but, you know,

1067
00:57:10,355 --> 00:57:11,360
you're not really asking this question,

1068
00:57:11,360 --> 00:57:13,170
but one point I actually
really think should be made

1069
00:57:13,170 --> 00:57:16,100
is that and I didn't emphasize it enough,

1070
00:57:16,100 --> 00:57:18,410
is that whatever causes the seizures,

1071
00:57:18,410 --> 00:57:20,260
it has to be taken into consideration

1072
00:57:20,260 --> 00:57:23,590
of any cognitive impairment, so, you know,

1073
00:57:23,590 --> 00:57:27,130
children that have
hypoxic-ischemic encephalopathy

1074
00:57:27,130 --> 00:57:31,000
and have birth asphyxia
and they have seizures,

1075
00:57:31,000 --> 00:57:33,820
the seizures may contribute
to cognitive impairment,

1076
00:57:33,820 --> 00:57:37,300
but those kids, the issue is
the cause of the seizures,

1077
00:57:37,300 --> 00:57:39,530
other being the hypoxic-ischemic injury.

1078
00:57:39,530 --> 00:57:42,000
So etiology is clearly important

1079
00:57:42,000 --> 00:57:43,500
when you're seeing patients trying

1080
00:57:43,500 --> 00:57:45,810
to determine what's causing the epilepsy.

1081
00:57:45,810 --> 00:57:49,660
We'll give you a good
idea of what the outcomes

1082
00:57:49,660 --> 00:57:52,080
are gonna be, but seizures can add

1083
00:57:52,080 --> 00:57:56,360
to that impairment or, you know, cause it

1084
00:57:56,360 --> 00:58:00,450
in people with like idiopathic
epilepsy, but etiology,

1085
00:58:00,450 --> 00:58:03,383
the cause of the seizures
is also very important.

1086
00:58:04,557 --> 00:58:09,500
- Great, thank you, I think
we don't have another question

1087
00:58:09,500 --> 00:58:11,450
at the moment, I'm just
gonna wait a second or two,

1088
00:58:11,450 --> 00:58:16,080
but I think that this is
absolutely perfect timing

1089
00:58:16,080 --> 00:58:19,340
on a talk and question,
so I thank you for that.

1090
00:58:19,340 --> 00:58:23,800
And hopefully you've
enjoyed your time doing this

1091
00:58:23,800 --> 00:58:25,830
in this very strange presentation

1092
00:58:25,830 --> 00:58:28,205
to the crew, thank you very much.

1093
00:58:28,205 --> 00:58:30,538
- Okay, thank you very much.