Suppression of thalamocortical oscillations following traumatic brain injury in rats

Laboratory investigation

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Traumatic brain injury (TBI) often causes an encephalopathic state, corresponding amplitude suppression, and disorganization of electroencephalographic activity. Clinical recovery in patients who have suffered TBI varies, and identification of patients with a poor likelihood of functional recovery is not always straightforward. The authors sought to investigate temporal patterns of electrophysiological recovery of neuronal networks in an animal model of TBI. Because thalamocortical circuit function is a critical determinant of arousal state, as well as electroencephalography organization, these studies were performed using a thalamocortical brain slice preparation.

Methods

Adult rats received a moderate parietal fluid-percussion injury and were allowed to survive for 1 hour, 2 days, 7 days, or 15 days prior to in vitro electrophysiological recording. Thalamocortical brain slices, 450-μm thick, were prepared using a cutting angle that preserved reciprocal connections between the somatosensory cortex and the ventrobasal thalamic complex.

Results

Extracellular recordings in the cortex of uninjured control brain slices revealed spontaneous slow cortical oscillations (SCOs) that are blocked by (2R)-amino-5-phosphonovaleric acid (50 μM) and augmented in low [Mg2+]o. These oscillations have been shown to involve simultaneous bursts of activity in both the cortex and thalamus and are used here as a metric of thalamocortical circuit integrity. They were absent in 84% of slices recorded at 1 hour postinjury, and activity slowly recovered to approximate control levels by Day 15. The authors next used electrically evoked SCO-like potentials to determine neuronal excitability and found that the maximum depression occurred slightly later, on Day 2 following TBI, with only 28% of slices showing evoked activity. In addition, stimulus intensities needed to create evoked SCO activity were elevated at 1 hour, 2 days, and 7 days following TBI, and eventually returned to control levels by Day 15. The SCO frequency remained low throughout the 15 days following TBI (40% of control by Day 15).

Conclusions

The suppression of cortical oscillatory activity following TBI observed in the rat model suggests an injury-induced functional disruption of thalamocortical networks that gradually recovers to baseline at approximately 15 days postinjury. The authors speculate that understanding the processes underlying disrupted thalamocortical circuit function may provide important insights into the biological basis of altered consciousness following severe head injury. Moreover, understanding the physiological basis for this process may allow us to develop new therapies to enhance the rate and extent of neurological recovery following TBI.

Abbreviations used in this paper:ACSF = artificial CSF; EEG = electroencephalographic; SCO = slow cortical oscillation; TBI = traumatic brain injury.

Article Information

Address correspondence to: Chris Kao, M.D., Ph.D., Department of Neurological Surgery, Room T-4224, Medical Center North, Vanderbilt University Medical Center, Nashville, Tennessee 37232. email: chris.kao@vanderbilt.edu.

Please include this information when citing this paper: published online May 25, 2012; DOI: 10.3171/2012.4.JNS111170.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Diagram of the fluid-percussion model of brain injury in the rat, as previously described. Reproduced with permission from Dixon CE, Lyeth BG, Povlishock JT, Findling RL, Hamm RJ, Marmarou A, et al: A fluid percussion model of experimental brain injury in the rat. J Neurosurg 67:110–119, 1987.

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    Photograph of a thalamocortical slice acquired in an injured rat obtained 1 hour following fluid-percussion injury. Note the thalamocortical fiber tracts (arrows) are visible in these adult male Sprague-Dawley rats (in contrast, thalamocortical fiber tracts are often translucent in young rats). Hip = hippocampal area.

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    Simultaneous intracellular (upper) and extracellular (lower) SCO recordings obtained in a sham control somatosensory cortex in vitro slice. The inset depicts intracellular (upper) and extracellular (lower) tracings at high resolution. Note that the spontaneous activity of intracellular action potentials and extracellular field potentials are time locked with the same frequency. Asterisks denote extracellular field potentials.

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    Examples of recordings acquired after histological staining of slices at 15 days post-TBI. In these slices (fixed with 4% paraformaldehyde and cut with a vibratome into 40-μm sections), an array of histological markers indicates the intact tissue structures of the recording slices. A: Cresyl violet staining of the rat brain slice (cortex [a and b]; thalamus [c]). Original magnification × 5. Thal = thalamus. Inset: In higher power view (original magnification × 20), arrow indicates the hemorrhage in white matter after fluid-percussion injury, and arrowheads indicate intact neuronal somata in the thalamus. B–D: Cortical neurons and thalamic neurons are clearly visualized. MAP2, original magnification × 20 (B) and × 10 (C and D). E: The thalamocortical slice visualized with Timm silver staining showing the bundle of connection tracts (white arrows). Original magnification × 2. F and G: The profile of cortical astrocytes. At 15 days after fluid-percussion TBI, the astrocytes are morphologically similar to those in noninjured control ones. GFAP, original magnification × 10 (F) and × 20 (G). IHC = immunohistochemistry.

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    Incidence of SCOs in slices obtained in both control and injured rats. The incidence of SCO in injured rats decreased after TBI, as measured by the percentage of slices or percentage of animals, and then gradually increased to approximate slices from the sham-injured rats by Day 15 postinjury. d = day; h = hour.

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    A and B: The peak amplitude and area of visible SCOs were found to be significantly depressed at 1 hour, 2 days, and 7 days postinjury, but they demonstrated a time-dependent recovery and were essentially normalized by postinjury Day 15. C: A TBI-induced alteration in SCO frequency persisted through 15 days postinjury. Asterisk signifies a difference, compared with control, that was found to be statistically significant (p < 0.05).

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    Time-dependent changes of evoked SCO-like potentials and stimulating threshold currents in TBI slices. A: All control slices exhibited evoked responses. However, following TBI, a time-dependent suppression of evoked SCO-like potentials was observed. B: The intensity required to produce SCOs was found to significantly increase following TBI (error bars in B represent the standard deviation).

References

1

Agmon AConnors BW: Thalamocortical responses of mouse somatosensory (barrel) cortex in vitro. Neuroscience 41:3653791991

2

Alves OLBullock RClausen TReinert MReeves TM: Concurrent monitoring of cerebral electrophysiology and metabolism after traumatic brain injury: an experimental and clinical study. J Neurotrauma 22:7337492005

3

Arrieta-Cruz IPfaff DW: Definition of arousal and mechanistic studies in intact and brain-damaged mice. Ann N Y Acad Sci 1157:24312009

4

Baker AJPhan NMoulton RJFehlings MGYucel YZhao M: Attenuation of the electrophysiological function of the corpus callosum after fluid percussion injury in the rat. J Neurotrauma 19:5875992002

5

Clarkson ANHuang BSMacisaac SEMody ICarmichael ST: Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468:3053092010

6

Clauss RPNel WH: Effect of zolpidem on brain injury and diaschisis as detected by 99mTc HMPAO brain SPECT in humans. Arzneimittelforschung 54:6416462004

7

Conti ACRaghupathi RTrojanowski JQMcIntosh TK: Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J Neurosci 18:566356721998

8

Coulter DALee CJ: Thalamocortical rhythm generation in vitro: extra- and intracellular recordings in mouse thalamocortical slices perfused with low Mg2+ medium. Brain Res 631:1371421993

9

Dawson LADjali SGonzales CVinegra MAZaleska MM: Characterization of transient focal ischemia-induced increases in extracellular glutamate and aspartate in spontaneously hypertensive rats. Brain Res Bull 53:7677762000

10

Dixon CELyeth BGPovlishock JTFindling RLHamm RJMarmarou A: A fluid percussion model of experimental brain injury in the rat. J Neurosurg 67:1101191987

11

Gaetz M: The neurophysiology of brain injury. Clin Neurophysiol 115:4182004

12

Hall SDYamawaki NFisher AEClauss RPWoodhall GLStanford IM: GABA(A) alpha-1 subunit mediated desynchronization of elevated low frequency oscillations alleviates specific dysfunction in stroke—a case report. Clin Neurophysiol 121:5495552010

13

Hartings JATemereanca SSimons DJ: State-dependent processing of sensory stimuli by thalamic reticular neurons. J Neurosci 23:526452712003

14

Jermakowicz WJCasagrande VA: Neural networks a century after Cajal. Brain Res Brain Res Rev 55:2642842007

15

Kao CForbes JAStayman ASun DACarron RBenabid AL: High-frequency cortical stimulation augments recovery of thalamocortical oscillations from hypoxia in rat brain slices. Neuromodulation 14:1041102011

16

Kao CQCoulter DA: Physiology and pharmacology of corticothalamic stimulation-evoked responses in rat somatosensory thalamic neurons in vitro. J Neurophysiol 77:266126761997

17

Kao CQGoforth PBEllis EFSatin LS: Potentiation of GABA(A) currents after mechanical injury of cortical neurons. J Neurotrauma 21:2592702004

18

Kilinc DGallo GBarbee KA: Mechanically-induced membrane poration causes axonal beading and localized cytoskeletal damage. Exp Neurol 212:4224302008

19

Littlejohns LBader MK: Prevention of secondary brain injury: targeting technology. AACN Clin Issues 16:5015142005

20

Llinás RRibary UContreras DPedroarena C: The neuronal basis for consciousness. Philos Trans R Soc Lond B Biol Sci 353:184118491998

21

Luhmann HJ: Ischemia and lesion induced imbalances in cortical function. Prog Neurobiol 48:1311661996

22

Nilsson GELutz PL: Release of inhibitory neurotransmitters in response to anoxia in turtle brain. Am J Physiol 261:R32R371991

23

Nuwer MRHovda DASchrader LMVespa PM: Routine and quantitative EEG in mild traumatic brain injury. Clin Neurophysiol 116:200120252005

24

Povlishock JT: Pathophysiology of neural injury: therapeutic opportunities and challenges. Clin Neurosurg 46:1131262000

25

Reeves TMKao CQPhillips LLBullock MRPovlishock JT: Presynaptic excitability changes following traumatic brain injury in the rat. J Neurosci Res 60:3703792000

26

Reinert MKhaldi AZauner ADoppenberg EChoi SBullock R: High level of extracellular potassium and its correlates after severe head injury: relationship to high intracranial pressure. J Neurosurg 93:8008072000

27

Rumpl ELorenzi EHackl JMGerstenbrand FHengl W: The EEG at different stages of acute secondary traumatic midbrain and bulbar brain syndromes. Electroencephalogr Clin Neurophysiol 46:4874971979

28

Schiff NDGiacino JTKalmar KVictor JDBaker KGerber M: Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448:6006032007. (Erratum in Nature 452:120 2008)

29

Silva LRAmitai YConnors BW: Intrinsic oscillations of neocortex generated by layer 5 pyramidal neurons. Science 251:4324351991

30

Tanaka YTanaka YFuruta TYanagawa YKaneko T: The effects of cutting solutions on the viability of GABAergic interneurons in cerebral cortical slices of adult mice. J Neurosci Methods 171:1181252008

31

Timofeev IGrenier FBazhenov MSejnowski TJSteriade M: Origin of slow cortical oscillations in deafferented cortical slabs. Cereb Cortex 10:118511992000

32

Zhu JHamm RJReeves TMPovlishock JTPhillips LL: Postinjury administration of L-deprenyl improves cognitive function and enhances neuroplasticity after traumatic brain injury. Exp Neurol 166:1361522000

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