My jaw is on the floor. Finally something!
Front. Hum. Neurosci., 19 October 2017 |
Frontiers | Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients | Frontiers in Human Neuroscience
Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients
Sigal Tal1,2†, Amir Hadanny1,3,4*†, Efrat Sasson5, Gil Suzin3 and Shai Efrati1,3,6,7*
1Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
2Radiology Department, Assaf Harofeh Medical Center, Zerifin, Israel
3Sagol Center for Hyperbaric Medicine and Research, Assaf Harofeh Medical Center, Zerifin, Israel
4Faculty of Medicine, Bar-Ilan University, Ramat Gan, Israel
5WiseImage, Hod Hasharon, Israel
6Research and Development Unit, Assaf Harofeh Medical Center, Zerifin, Israel
7Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
Background: Recent clinical studies in stroke and traumatic brain injury (TBI) victims suffering chronic neurological injury present evidence that hyperbaric oxygen therapy (HBOT) can induce neuroplasticity.
Objective: To assess the neurotherapeutic effect of HBOT on prolonged post-concussion syndrome (PPCS) due to TBI, using brain microstructure imaging.
Methods: Fifteen patients afflicted with PPCS were treated with 60 daily HBOT sessions. Imaging evaluation was performed using Dynamic Susceptibility Contrast-Enhanced (DSC) and Diffusion Tensor Imaging (DTI) MR sequences. Cognitive evaluation was performed by an objective computerized battery (NeuroTrax).
Results: HBOT was initiated 6 months to 27 years (10.3 ± 3.2 years) from injury. After HBOT, DTI analysis showed significantly increased fractional anisotropy values and decreased mean diffusivity in both white and gray matter structures. In addition, the cerebral blood flow and volume were increased significantly. Clinically, HBOT induced significant improvement in the memory, executive functions, information processing speed and global cognitive scores.
Conclusions: The mechanisms by which HBOT induces brain neuroplasticity can be demonstrated by highly sensitive MRI techniques of DSC and DTI. HBOT can induce cerebral angiogenesis and improve both white and gray microstructures indicating regeneration of nerve fibers. The micro structural changes correlate with the neurocognitive improvements.
Frontiers | Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients | Frontiers in Human Neuroscience
Some highlights I copied:
In the current study, for the first time in humans, DTI changes of chronic TBI were evaluated before and after HBOT. The increase in FA and decrease in MD post HBOT, together with cognitive function improvement of patients in the late chronic stage of TBI, suggest that brain microstructure recovery can be induced by HBOT.
DTI values, FA and MD, were found in our study to correlate with the improvements in cognitive functions in concordance with previous studies (Sugiyama et al., 2009; Wada et al., 2012; Arenth et al., 2014; Haberg et al., 2015). Memory, executive function and information processing speed were all significantly improved. In correlation with these cognitive improvements, MD decreased in most of the frontal lobe white matter, such as the prefrontal cortex that enables executive control (Miller and Cohen, 2001) and the anterior cingulate gyrus involved in error detection, especially in a Stroop task (Bush et al., 2000). Also, FA increased in most of the long association fibers critical for proper cognitive function:
• SLF–Bi-directional connection of the hemispheric frontal, parietal, temporal and occipital lobes. The SLF plays an important role in high brain functions, particularly language, reflected in information processing speed and executive function tasks (Heilman et al., 1970; Rocha et al., 2005; Sasson et al., 2013). In correlation with those changes, there was a significant improvement in neurocognitive test results in both information processing speed (IPS) and executive functions (EF) (i.e., IPS: 13.1 ± 2.7, p < 0.0001; EF: 11.3 ± 2.7, p < 0.001).
• ILF–Connection between the temporal and occipital lobes on the same hemisphere. The ILF is known to play an important role in visual memory (Bauer and Trobe, 1984; Shinoura et al., 2007). In correlation with those changes, there was a significant improvement in the memory index, which includes a visual memory task (i.e., Memory: 10.5 ± 2.4, p < 0.001).
• Cingulum – A cluster of white matter fibers projecting from the cingulate gyrus in the frontal lobe to the entorhinal cortex in the temporal lobe. The cingulum has been tightly associated with memory disorders (Charlton et al., 2006; Sepulcre et al., 2009). The memory correlates also with the changes in the cingulum.
• Genu of the Corpus Callosum-The largest white matter structure in the brain. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication. Integrity of the corpus callosum is linked to information processing speed and episodic memory (Bucur et al., 2008; Lockhart and DeCarli, 2014). The improvement in information processing speed and memory indices may also correlate with the improvement in the genu of the corpus callosum.
Mechanisms of neuroplasticity and cellular repair by HBOT have been suggested in many animal studies (Hadanny and Efrati, 2016). These include enhanced mitochondrial function and cellular metabolism, improved blood brain barrier and inflammatory reactions, reduced apoptosis, alleviation of oxidative stress, increased levels of neurotrophins and nitric oxide, and up-regulation of axonal guidance agents (Efrati et al., 2013; Efrati and Ben-Jacob, 2014). Moreover, the effects of HBOT on neurons may be mediated indirectly by glial cells. HBOT may also promote neurogenesis of endogenous neural stem cells (Efrati et al., 2013; Efrati and Ben-Jacob, 2014). HBOT may enable the metabolic change simply by supplying the missing oxygen/energy needed for these regeneration processes (Efrati et al., 2013; Efrati and Ben-Jacob, 2014). The ability of HBOT to induce angiogenesis was demonstrated in several different pre-clinical studies (Mu et al., 2011; Lin et al., 2012; Lee et al., 2013; Hu et al., 2014). Hu et al. have demonstrated that HBOT-induced neurogenesis is mediated by ROS/HIF-1α/β-catenin pathway (Hu et al., 2014). In the current study, it is demonstrated that HBOT can induce neuroplasticity in humans even years after the acute insult.
Along with the structural changes, HBOT induces angiogenesis, as shown by the increase of CBF and CBV in this study as well as in our previous study (Tal et al., 2015). The injured areas in the brains post TBI experience hypoxia and hypoperfusion, which serve as a rate-limiting factor for any regenerative process (Graham and Adams, 1971; Graham et al., 1978; Stein et al., 2004; Kim et al., 2010; Ostergaard et al., 2014). HBOT-induced angiogenesis has been amply confirmed in pre-clinical models and can be deduced from brain SPECTs of patients post stroke and post TBI even years after the acute insult (Lin et al., 2012; Boussi-Gross et al., 2013; Efrati et al., 2013; Peng et al., 2014; Duan et al., 2015). The generation of new microvessels renders the local environment non-hypoxic, thus able to induce brain plasticity, enhance neurogenesis and synaptogenesis and foster functional recovery (Chen et al., 2003; Jiang et al., 2005). Unsurprisingly, CBV and CBF increased in the long association fiber tracts discussed above, including corpus callosum, association fibers (SLF, IFOF) and cingulum. Angiogenesis and increased perfusion to the malfunctioning tissue, seen in DSC, serve as infrastructure for the regenerative process and the preservation of newly generated metabolic functioning of the axonal microstructure seen in DTI.
Conclusion
HBOT can induce cerebral angiogenesis and recovery of brain microstructure in patients with chronic cognitive impairments due to TBI months to years after the acute injury. The increased integrity of brain fibers correlates with the functional cognitive improvement. The mechanism by which HBOT can induce brain neuroplasticity can be demonstrated by highly sensitive perfusion MRI and DTI. Further studies, using DTI - MRI, are needed in order to gain better understanding of the neuroplasticity effect of HBOT in a larger cohort of patients with different types of brain injuries.