Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Jul:269:242-52.
doi: 10.1016/j.expneurol.2015.04.015. Epub 2015 May 1.

T2 relaxation time post febrile status epilepticus predicts cognitive outcome

Jeremy M Barry  1 , ManKin Choy  2 , Celine Dube  2 , Ashlee Robbins  3 , Andre Obenaus  4 , Pierre Pascal Lenck-Santini  5 , Rod C Scott  6 , Tallie Z Baram  2 , Gregory L Holmes  5
Affiliations

T2 relaxation time post febrile status epilepticus predicts cognitive outcome

Jeremy M Barry et al. Exp Neurol. 2015 Jul.

Abstract

Evidence from animal models and patient data indicates that febrile status epilepticus (FSE) in early development can result in permanently diminished cognitive abilities. To understand the variability in cognitive outcome following FSE, we used MRI to measure dynamic brain metabolic responses to the induction of FSE in juvenile rats. We then compared these measurements to the ability to learn an active avoidance spatial task weeks later. T2 relaxation times were significantly lower in FSE rats that were task learners in comparison to FSE non-learners. While T2 time in whole brain held the greatest predictive power, T2 in hippocampus and basolateral amygdala were also excellent predictors. These signal differences in response to FSE indicate that rats that fail to meet metabolic and oxygen demand are more likely to develop spatial cognition deficits. Place cells from FSE non-learners had significantly larger firing fields and higher in-field firing rate than FSE learners and control animals and imply increased excitability in the pyramidal cells of FSE non-learners. These findings suggest a mechanistic cause for the spatial memory deficits in active avoidance and are relevant to other acute neurological insults in early development where cognitive outcome is a concern.

Keywords: Cognition; Febrile status epilepticus; MRI; Place cells.

PubMed Disclaimer

Conflict of interest statement

We declare no conflicts of interest.

Figures

Figure 1
Figure 1
Illustration of the active avoidance task and behavioral results: A) Rats were tethered to a shock cable connected to a pin that was subcutaneously implanted on the back of the rat’s neck. An LED at the end of the shock cable (indicated by green crosshair) was used to signal the rat’s position in the room frame while the arena rotated counter-clockwise. The rat’s path is indicated by black lines. When the rat entered the shock zone (gray sector in southern position), the rat received a mild electrical shock (indicated by open red circles); B) Dwell-time maps during habituation and training sessions. Red colors indicate more time while bluer colors indicate less time. The top row shows examples of avoidance behavior over several sessions (left to right) from a rat that learned to avoid (L=Learner). Note that over the course of training the rat spends more time in a more circumscribed region of the arena, far from the shock zone. The bottom row shows examples over several sessions from a rat that did not learn to avoid (Non-learner=NL). The final training session on the far right looks similar to the habituation session; C) The percentage of learners (L) and non-learners (NL) in the control (left) and FSE (right) groups.
Figure 2
Figure 2
MRI T2 relaxation times are lower in FSE than control rats. A) The left side of the figure shows the MRI T2 relation time in a coronal section from the brain of a control animal at co-ordinates −2.3 mm AP. The area of the basolateral amygdala is indicated with a black circle. The right side shows the same scan for an FSE animal. Note the generally low T2 throughout the section and in the vicinity of amygdala; B) The left side of the figure shows T2 from the same animals as above at co-ordinates −2.6 mm AP. The area of the Hippocampus is indicated with a black rectangle. The right side shows the same scan for an FSE animal. Note the generally low T2 throughout the section and in the vicinity of the hippocampus.
Figure 3
Figure 3
MRI T2 relaxation time post-FSE is lower for febrile learners: A) The average and standard error of MRI T2 relaxation time from control rats (blue) and FSE rats (red) for all regions of interest and whole brain. The T2 levels were universally lower in FSE animals than control animals (Dhippo=dorsal hippocampus; BLA=basolateral amygdala; Mthal=medial thalamus; MEA=medial nucleus of the amygdala; Cblm=Cerebellum; Prlm Ctx=prelimbic cortex; Aud Ctx=auditory cortex; Brain=whole brain); B) Cox regression for control and FSE rats shows that there was no significant difference between the two groups with regard to the number of sessions to criterion; C) When separated into learners and non-learners, T2 levels were significantly lower in FSE learners than non-learners in the dorsal hippocampus, the basolateral amygdala and whole brain; Scatterplots of T2 relaxation time in the whole brain (D), hippocampus (E) and basolateral amygdala (F) for each individual rat in the FSE and CTRL group. Non-learners are indicated with a black circle. Febrile non-learners tend to have T2 levels that are above the average for FSE animals (red line) while there is no relationship between T2 levels and the average for control animals (blue line).
Figure 4
Figure 4
Cox regression survival analysis adjusted for T2 relaxation time in the whole brain (A), dorsal hippocampus (B) and basolateral amygdala (C). In all three cases analyses revealed that control rats were more likely to learn the task than FSE rats. For any given T2 relaxation time, control rats were better at avoiding the shock zone than FSE rats. Similar results were found for the dorsal hippocampus (B) and basolateral amygdala (C).
Figure 5
Figure 5
Examples of place cell firing fields from control learners (Top Row), a control non-learner (Second Row), FSE learners (Third Row) and FSE non-learners (Bottom Row). The firing fields of control and FSE learners were similar while the fields of FSE non-learners appeared to be larger and less circumscribed.
Figure 6
Figure 6
Average and standard error of firing field properties calculated per animal in each group. As place cells were recorded from only one rat in the control non-learner group, this group was not included from statistical analysis: A) In-field firing rate (Hz) per rat was significantly faster for firing fields recorded from FSE non-learners; B) Field size (pixels) per rat was significantly larger for firing fields recorded from FSE non-learners; C) While fields from FSE non-learners were more coherent than control learners, this can be accounted for by their higher firing rate and larger field size.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med. 1987;316:493–498. - PubMed
    1. Barnes CA, Suster MS, Shen J, McNaughton BL. Multistability of cognitive maps in the hippocampus of old rats. Nature. 1997;388:272–275. - PubMed
    1. Bassan H, Barzilay M, Shinnar S, Shorer Z, Matoth I, Gross-Tsur V. Prolonged febrile seizures, clinical characteristics, and acute management. Epilepsia. 2013;54:1092–1098. - PubMed
    1. Bender RA, Dube C, Gonzalez-Vega R, Mina EW, Baram TZ. Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures. Hippocampus. 2003;13:399–412. - PMC - PubMed
    1. Cacucci F, Yi M, Wills TJ, Chapman P, O’Keefe J. Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model. Proc Natl Acad Sci U S A. 2008;105:7863–7868. - PMC - PubMed

Publication types