Reversal of neuromotor and cognitive dysfunction in an enriched environment combined with multimodal early onset stimulation after traumatic brain injury in rats.

This study was designed to investigate the additional benefits of a multimodal early onset stimulation (MEOS) paradigm when combined with enriched environment (EE) versus EE only and standard housing (SH) on the recovery after experimental traumatic brain injury (TBI). Male Sprague- Dawley rats were subjected to moderate lateral fluid percussion (LFP) brain injury (n = 40) or sham operation (n = 6). Thereafter, the injured and sham/EE + MEOS and EE only groups were placed into a complex EE consisting of tunnel-connected wide-bodied cages with various beddings, inclining platforms, and toys. Along with group living and environmental complexity, injured and sham/EE + MEOS animals were additionally exposed to a standardized paradigm of multimodal stimulation including auditory, visual, olfactory, and motor stimuli. In contrast, injured and sham/SH groups were housed individually without stimulation. A standardized composite neuroscore (NS) test was used to assess acute post-traumatic neuromotor deficits (24 h after injury) and recovery on days 7 and 15; recovery of cognitive function was assessed on days 11-15 using the Barnes maze. Neuromotor impairment was comparable in all injured animals at 24 h post-injury, but braininjured EE + MEOS rats performed significantly better than both brain-injured SH and EE groups when tested on post-injury days 7 and 15 (p = 0.004). Similarly, latencies to locate the hidden box under the Barnes maze platform were significantly shortened in EE + MEOS animals at day 15 (p = 0.003). These results indicate that the reversal of neuromotor and cognitive dysfunction after TBI can be substantially enhanced when MEOS is added to EE.

Multimodal MR imaging of acute and subacute experimental traumatic brain injury: Time course and correlation with cerebral energy metabolites.

BACKGROUND: Traumatic brain injury (TBI) is one of the leading causes of death and permanent disability world-wide. The predominant cause of death after TBI is brain edema which can be quantified by non-invasive diffusion-weighted magnetic resonance imaging (DWI). PURPOSE: To provide a better understanding of the early onset, time course, spatial development, and type of brain edema after TBI and to correlate MRI data and the cerebral energy state reflected by the metabolite adenosine triphosphate (ATP). MATERIAL AND METHODS: The spontaneous development of lateral fluid percussion-induced TBI was investigated in the acute (6 h), subacute (48 h), and chronic (7 days) phase in rats by MRI of quantitative T2 and apparent diffusion coefficient (ADC) mapping as well as perfusion was combined with ATP-specific bioluminescence imaging and histology. RESULTS: An induced TBI led to moderate to mild brain damages, reflected by transient, pronounced development of vasogenic edema and perfusion reduction. Heterogeneous ADC patterns indicated a parallel, but mixed expression of vasogenic and cytotoxic edema. Cortical ATP levels were reduced in the acute and subacute phase by 13% and 27%, respectively, but were completely normalized at 7 days after injury. CONCLUSION: The partial ATP reduction was interpreted to be partially caused by a loss of neurons in parallel with transient dilution of the regional ATP concentration by pronounced vasogenic edema. The normalization of energy metabolism after 7 days was likely due to infiltrating glia and not to recovery. The MRI combined with metabolite measurement further improves the understanding and evaluation of brain damages after TBI.

Late effects of enriched environment (EE) plus multimodal early onset stimulation (MEOS) after traumatic brain injury in rats: Ongoing improvement of neuromotor function despite sustained volume of the CNS lesion.

Recently we showed that the combination between MEOS and EE applied to rats for 7-15 days after traumatic brain injury (TBI) was associated with reduced CNS lesion volume and enhanced reversal of neuromotor dysfunction. In a continuation of this work, we tested whether these effects persisted for longer post-operative periods, e.g. 30 days post-injury (dpi). Rats were subjected to lateral fluid percussion (LFP) or to sham injury. After LFP, one third of the animals (injured and sham) was placed under conditions of standard housing (SH), one third was kept in EE-only, and one third received EE+MEOS. Standardized composite neuroscore (NS) for neurological functions and computerized analysis of the vibrissal motor performance were used to assess post-traumatic neuromotor deficits. These were followed by evaluation of the cortical lesion volume (CLV) after immunostaining for neuron-specific enolase, caspase 3 active, and GFAP. Finally, the volume of cortical lesion containing regeneration-associated proteins (CLV-RAP) was determined in sections stained for GAP-43, MAP2, and neuronal class III beta-tubulin. We found (i) no differences in the vibrissal motor performance; (ii) EE+MEOS rats performed significantly better than SH rats in NS; (iii) EE-only and EE+MEOS animals, but not SH rats, showed better recovery at 30 dpi than at 15 dpi; (iv) no differences among all groups in CLV (larger than that at 15 dpi) and CLV-RAP, despite a clear tendency to reduction in the EE-only and EE+MEOS rats. We conclude that EE+MEOS retards, but cannot prevent the increase of lesion volume. This retardation is sufficient for a continuous restoration of neurological functions.

Multimodal early onset stimulation combined with enriched environment is associated with reduced CNS lesion volume and enhanced reversal of neuromotor dysfunction after traumatic brain injury in rats.

This study was designed to determine whether exposure to multimodal early onset stimulation (MEOS) combined with environmental enrichment (EE) after traumatic brain injury (TBI) would improve neurological recovery and to elucidate its morphological correlates. Male Sprague-Dawley rats were subjected to lateral fluid percussion (LFP) brain injury or to sham operation. After LFP, one-third of the animals (injured and sham) were placed under conditions of standard housing (SH), one-third were kept in EE only, and one-third received EE + MEOS. Assessment of neuromotor function 24 h post-injury using a standardized composite neuroscore test revealed an identical pattern of neurological impairment in all animals subjected to LFP. Neuromotor dysfunction in SH animals remained on a similar level throughout the experiment, while improvements were noted in both other groups 7 days post-injury (dpi). On 15 dpi, reversal of neuromotor dysfunction was significantly better in EE + MEOS animals vs. SH- and EE-only groups. In parallel, the comparison of lesion volume in EE + MEOS- vs. EE-only vs. SH rats revealed that animals exposed to EE + MEOS had consistently the lowest values (mm3, mean +/- SD; n = 6 rats in each group) as measured in serial brain sections immunostained for neuron-specific enolase (5.2 +/- 3.4 < or = 5.5 +/- 4.1 < 9.5 +/- 1.9), caspase 3-active/C3A (5.9 +/- 4.0 < or = 6.4 +/- 3.9 < 10.3 +/- 1.8) and glial fibrillary acidic protein (6.0 +/- 3.4 < or = 6.5 +/- 4.3 < 10.7 +/- 1.2). This first report on the effect of EE + MEOS treatment strongly indicates that the combined exposure reduces CNS scar formation and reverses neuromotor deficits after TBI in rats.