Biomedical Engineering Reference
In-Depth Information
variability. Stability refers to a level, linear evolution of minute means in time, preferably
with a zero or very shallow slope. This is called the network reference mean and is assigned
a standard deviation (SD). Variability refers to the positive and negative excursions of the
minute means about the reference mean. A high variability of the minute means yields a
large SD and low sensitivity. A steep slope indicates failure of life support and a permanent
or temporary loss of the network for sensing. Shallow slopes can be tolerated. A detection
event occurs when the mean network activity drops out of the
1 SD reference state for a
period of several minutes. Effective toxicants affect neural tissues over a long period of
time, and a single movement of a minute mean outside the SD box is generally insufficient
for reliable detection. This is illustrated in Figure 6.16 with a network response to
tetrodotoxin. Transient response decreases appear to be caused by a lack of proper mixing
of the toxicant with the medium.
Detection in terms of multiples of the reference SD (often called z -score) immediately allows
classification into two road categories: inhibition and excitation. If burst analysis is included
in the detection variables, then it is also possible to read out “disinhibition,” a response to the
blocking of inhibitory circuitry that leads to burst coordination and burst oscillation. All com-
pounds that cause epileptiform activity are in the “disinhibitory” category. Figure 6.17 shows
a pattern transition to trimethylolpropane phosphate (TMPP) where the spike rate is mini-
mally affected but a major reorganization of spikes into bursts occurs. Hence, although spike
rate is a dominant variable, it is necessary but not sufficient for detection.
Figure 6.18 summarizes a simple numbering scheme that can be used for an initial com-
pound identification. It takes into consideration classification into four categories: excita-
tory, inhibitory, biphasic, and disinhibitory, as well as the speed of the response, the
reversibility of the response, and the manner in which the activity dies. Biphasic responses
are almost always excitation followed by inhibition whereas disinhibition generates coordi-
nated burst oscillation. Response speed is somewhat qualitative and has been given 5 num-
bers with “5” being the fastest response such as is seen with tetrodotoxin and “1” the
slowest as is seen with botulinum toxin. The characterization of activity death is not trivial
as different affected mechanisms create different activity decay profiles. These categories are
presently (1) burst period death (BPD), (2) burst duration death (BDD), (3) spike amplitude
death (SAD), and cytotoxic death (CTD). This vector is open and will allow addition of other
variables or replacement of variables if they are not compatible with automated detection
schemes. Using this approach, the inhibitory transmitter GABA, or its analog muscimol,
would be identified by the number sequence 1, 5, 1, 1. These molecules are reversibly
inhibitory, act very fast, and create a decrease in burst period without appreciably affecting
the burst duration. Breakaway bursts, even if the period is as long as minutes, generally look
600
Reference activity
550
2 nM
4 nM
7 nM
10 nM
13 nM
500
450
400
350
300
250
Detection
range
200
150
100
50
0
0
100
120
140
160
180
200
220
240
260
280
300
320
340
FIGURE 6.16
Response of a frontal cortex culture to tetrodotoxin in terms of network spike production. The dashed horizon-
tal line represents the network reference mean and the dashed box the
1SD detection reference.
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