Steinmetz, P. N., Wait, S., Lekovic, G. P., Rekate, H. L., Kerrigan, J. F.

SYNCHRONOUS FIRING IN TWO POPULATIONS OF NEURONS IN HUMAN
EPILEPTIC HYPOTHALAMIC HAMARTOMAS
3.337
x
Steinmetz, P. N., Wait, S., Lekovic, G. P., Rekate, H. L., Kerrigan, J. F.
Barrow Neurological Institute, Carolina Neurosurgery and Spine Associates, House Ear Institute, Chiari Institute
40
Firing Rate (sp/s)
firing,
20
0.56
0.5
0.44
0.38
0.31
10
0.25
0.19
0.12
p<10-7.
0.06
0
0
10
20
30
40
60
Spike Rate(sp/s)
60
80
B
80
12. 8 of 222 (4%) neurons had firing rates
which evolved over the course of the
recording session, showing periods of
increasing firing rate on the scale of
10-20 seconds.
Spike Rate(sp/s)
0.0
Neuron A
0.4
0.6
0.8
1.0
0.01
0
Example of burst firing (A) versus more regular firing
(B).
200
Monte Carlo Simulation - Random Order
100
Value In Normal Order
10 20 30 40 50
Time (ms)
Neuron A
Neuron B
0
0.005
0.010
0.015
0.020
Height of peak at 0
Significant peaks were detected by computing the
empirical distribution of peak height when 2 second
intervals were shuffled and then ranking the observed
height.
7. We recorded 222 neurons in 37 fiveminute recording sessions in 14 patients.
9 female patients, mean age 15.7 (2.2-40.2),
7 with seizure onset in first month of life.
Hartigan's dip test for lack of unimodality, p<10-5.
10. 417 of 812 (51%) of pairs of neurons
recorded during a single session showed
a significant level of synchronous firing.
There were a variety of peak types. Some positive and
very large, others smaller and even negative.
C
B
A
Coincidences (sp2/s)
0.00
0
100
200
300
Time (s)
300
Neuron B
Density
Coincidences (sp2/s)
0.2
burst ratio
0.02
0
0
Normal Order
Coincidences (sp2/s)
An endoscopic approach
through the 3rd ventricle is
used to resect the tumor.
0.62
0
Distribution When Shuffled
3. We used intra-operative microwire
recordings to characterize the firing of
individual HH neurons in an intact
network within the tumor.
0.69
Firing rate 1 (spikes/s)
2
1
0.75
40
6. Synchrony between pairs of neurons
was measured by computing the crosscorrelogram and determining the height
of the peak at zero delay.
0.81
0
A
3
0.88
30
20
9. The tendency to fire in bursts was
assessed as the ratio of interspike
intervals < 10 ms to those > 10 ms and
this ratio divided the neurons into three
groups.
0.94
40
30
1
20
20
Fraction
Significant
40
Firing rate 2 (spikes/s)
80
20
10
0.10
0.05
0.00
0
10 20 30 40 50
Time (ms)
0.02
0.01
0.00
0
10 20 30 40 50
Time (ms)
Coincidences (sp2/s)
Small neurons: 90% of HH neurons are small,
GABAergic neurons with local projections and
intrinsic firing in-vitro.
Large neurons: 10% of HH neurons are larger , with
more distal projections, and are quiescent.
p<10-5.
0
Average waveform
shape of events in a
cluster on two scales,
fixed.
Raw signal before
filtering.
Fisher's Exact
Test for class of
pairs of firing
rates affecting
likelihood of
having
synchronous
Hartigan's dip test for
lack of unimodality,
Density
2. Prior patch clamp recordings in excised
human HH tissue have shown two
populations of neurons divided by size
and intrinsic firing properties.
11. Pairs of neurons where both neurons
were in the higher firing rate group were
significantly more likely to fire
synchronously than pairs containing a
neuron from the lower firing rate group.
0
HH associated with epilepsy occurs in 1 in 200,000
children.
Gelastic (laughing) seizures normally occur several
times each day.
Co-morbid features include cognitive deficits and
paychiatric symptoms, including rage behaviors.
5. The firing of single neurons was
identified by filtering and sorting
extracellular waveform events into
clusters of similar shape.
60
A depth electrode was
used as a guide for the
microwires and inserted
through the working
channel of the endoscope.
8. Firing rates of the neurons divided into 2
groups, one group with a mean rate of
0.7 spikes/s and another with a mean
rate of 14.9 spikes/s.
40
4. 38 micron diameter microwires were
inserted into the tumor through the
endoscope prior to excision in order to
record extracellular potentials.
Frequency
1. Hypothalamic hamartomas (HH) are
congenital tumors which can cause
medically refractory gelastic seizures.
0
100
200
300
Time (s)
Summary
A) Single neurons in intact hypothalamic
hamartomas appear to fall into at least two
distinct classes, with firing rates ~0.7 spikes/
s and ~15 spikes/s.
B) Synchronous firing between pairs of neurons
in HH tumors is more likely to occur when
both neurons in the pair have high firing
rates.
0.005
0.000
0
10 20 30 40 50
Time (ms)
Acknowlegements: We would first like to thank all the patients and parents who
participated in this study and Elaine Cabrales for technical assistance. Funding was
provided by the Barrow Neurological Foundation.