Missed meal boluses and poorer glycemic control impact on neurocognitive function may be associated with white matter integrity in adolescents with type 1 diabetes.

Background: The notion that pediatric type 1 diabetes impacts brain function and structure early in life is of great concern. Neurological manifestations, including neurocognitive and behavioral symptoms, may be present from childhood, initially mild and undetectable in daily life. Despite intensive management and technological therapeutic interventions, most pediatric patients do not achieve glycemic control targets for HbA1c. One of the most common causes of such poor control and frequent transient hyperglycemic episodes may be lifestyle factors, including missed meal boluses. Objective: The aim of this study was to assess the association between specific neurocognitive accomplishments-learning and memory, inhibition ability learning, and verbal and semantic memory-during meals with and without bolusing, correlated to diffusion tensor imaging measurements of major related tracts, and glycemic control in adolescents with type 1 diabetes compared with their healthy siblings of similar age. Study design and methods: This is a case-control study of 12- to 18-year-old patients with type 1 diabetes (N = 17, 8 male patients, diabetes duration of 6.53 ± 4.1 years) and their healthy siblings (N = 13). All were hospitalized for 30 h for continuous glucose monitoring and repeated neurocognitive tests as a function of a missed or appropriate pre-meal bolus. This situation was mimicked by controlled, patient blinded manipulation of lunch pre-meal bolus administration to enable capillary glucose level of <180 mg/dl and to >240 mg/d 2 hours after similar meals, at a similar time. The diabetes team randomly and blindly manipulated post-lunch glucose levels by subcutaneous injection of either rapid-acting insulin or 0.9% NaCl solution before lunch. A specific neurocognitive test battery was performed twice, after each manipulation, and its results were compared, along with additional neurocognitive tasks administered during hospitalization without insulin manipulation. Participants underwent brain imaging, including diffusion tensor imaging and tractography. Results: A significant association was demonstrated between glycemic control and performance in the domains of executive functions, inhibition ability, learning and verbal memory, and semantic memory. Inhibition ability was specifically related to food management. Poorer glycemic control (>8.3%) was associated with a slower reaction time. Conclusion: These findings highlight the potential impairment of brain networks responsible for learning, memory, and controlled reactivity to food in adolescents with type 1 diabetes whose glycemic control is poor.

Quantitative Magnetization EXchange MRI Measurement of Liver Fibrosis Model in Rodents.

BACKGROUND: Quantitative MRI can elucidate the complex microstructural changes in liver disease. The Magnetization EXchange (MEX) method estimates macromolecular fraction, such as collagen, and can potentially aid in this task. HYPOTHESIS: MEX sequence, and its derived quantitative macromolecular fraction, should correlate with collagen deposition in rodents liver fibrosis model. STUDY TYPE: Prospective. ANIMAL MODEL: Sixteen adults Sprague-Dawley rats and 13 adults C57BL/6 strain mice given carbon tetrachloride (CCl4 ) twice weekly for 6 or 8 weeks. FIELD STRENGTH/SEQUENCE: A 7 T scanner. MEX sequence (selective suppression and magnetization exchange), spin-echo and gradient-echo scans. ASSESSMENT: Macromolecular fraction (F) and T1 were extracted for each voxel and for livers' regions of interest, additional to calculating the percentage of F > 0.1 pixels in F maps (high-F). Histology included staining with hematoxylin and eosin, picrosirius red and Masson trichrome, and inflammation scoring. Quantitative collagen percentage calculated using automatic spectral-segmentation of the staining. STATISTICAL TESTS: Comparing CCl4 -treated groups and controls using Welch's t-test and paired t-test between different time points. Pearson's correlation used between ROI MEX parameters or high-F fraction, and quantitative histology. F or T1 , and inflammation scores were tested with one-sided t-test. P < 0.05 was deemed significant. RESULTS: Rats: F values were significantly different after 6 weeks of treatment (0.10 ± 0.02) compared to controls (0.080 ± 0.003). After 8 weeks, F significantly increased (0.11 ± 0.02) in treated animals, while controls are not significant (0.0814 ± 0.0008, P = 0.079). F correlated with quantitative histology (R = 0.87), and T1 was significantly different between inflammation scores (1: 1332 ± 224 msec, 2: 2007 ± 464 msec). Mice: F was significantly higher (0.062 ± 0.006) in treatment group compared to controls (0.042 ± 0.006). F and high-F fraction correlated with quantitative histology (R = 0.88; R = 0.84). T1 was significantly different between inflammation scores (1:1366 ± 99 msec; 2:1648 ± 45 msec). DATA CONCLUSION: MEX extracted parameters are sensitive to collagen deposition and inflammation and are correlated with histology results of mouse and rat liver fibrosis model. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Effects of hyperbaric oxygen therapy on functional and structural connectivity in post-COVID-19 condition patients: A randomized, sham-controlled trial.

INTRODUCTION: Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. Abnormalities in brain connectivity were found in recovered patients compared to non-infected controls. This study aims to evaluate the effect of hyperbaric oxygen therapy (HBOT) on brain connectivity in post-COVID-19 patients. METHODS: In this randomized, sham-controlled, double-blind trial, 73 patients were randomized to receive 40 daily sessions of HBOT (n = 37) or sham treatment (n = 36). We examined pre- and post-treatment resting-state brain functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) scans to evaluate functional and structural connectivity changes, which were correlated to cognitive and psychological distress measures. RESULTS: The ROI-to-ROI analysis revealed decreased internetwork connectivity in the HBOT group which was negatively correlated to improvements in attention and executive function scores (p < 0.001). Significant group-by-time interactions were demonstrated in the right hippocampal resting state function connectivity (rsFC) in the medial prefrontal cortex (PFWE = 0.002). Seed-to-voxel analysis also revealed a negative correlation in the brief symptom inventory (BSI-18) score and in the rsFC between the amygdala seed, the angular gyrus, and the primary sensory motor area (PFWE = 0.012, 0.002). Positive correlations were found between the BSI-18 score and the left insular cortex seed and FPN (angular gyrus) (PFWE < 0.0001). Tractography based structural connectivity analysis showed a significant group-by-time interaction in the fractional anisotropy (FA) of left amygdala tracts (F = 7.81, P = 0.007). The efficacy measure had significant group-by-time interactions (F = 5.98, p = 0.017) in the amygdala circuit. CONCLUSIONS: This study indicates that HBOT improves disruptions in white matter tracts and alters the functional connectivity organization of neural pathways attributed to cognitive and emotional recovery in post-COVID-19 patients. This study also highlights the potential of structural and functional connectivity analysis as a promising treatment response monitoring tool.

Hyperbaric oxygen therapy in children with post-concussion syndrome improves cognitive and behavioral function: a randomized controlled trial.

Persistent post-concussion syndrome (PPCS) is a common and significant morbidity among children following traumatic brain injury (TBI) and the evidence for effective PPCS treatments remains limited. Recent studies have shown the beneficial effects of hyperbaric oxygen therapy (HBOT) in PPCS adult patients. This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT) on children (age 8-15) suffering from PPCS from mild-moderate TBI events six months to 10 years prior. Twenty-five children were randomized to receive 60 daily sessions of HBOT (n = 15) or sham (n = 10) treatments. Following HBOT, there was a significant increase in cognitive function including the general cognitive score (d = 0.598, p = 0.01), memory (d = 0.480, p = 0.02), executive function (d = 0.739, p = 0.003), PPCS symptoms including emotional score (p = 0.04, d = - 0.676), behavioral symptoms including hyperactivity (d = 0.244, p = 0.03), global executive composite score (d = 0.528, p = 0.001), planning/organizing score (d = 1.09, p = 0.007). Clinical outcomes correlated with significant improvements in brain MRI microstructural changes in the insula, supramarginal, lingual, inferior frontal and fusiform gyri. The study suggests that HBOT improves both cognitive and behavioral function, PPCS symptoms, and quality of life in pediatric PPCS patients at the chronic stage, even years after injury. Additional data is needed to optimize the protocol and to characterize the children who can benefit the most.

Hyperbaric oxygen therapy improves neurocognitive functions and symptoms of post-COVID condition: randomized controlled trial.

Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. The mechanism can be related to brain tissue pathology caused by virus invasion or indirectly by neuroinflammation and hypercoagulability. This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT or HBO2 therapy) on post-COVID-19 patients with ongoing symptoms for at least 3 months after confirmed infection. Seventy-three patients were randomized to receive daily 40 session of HBOT (n = 37) or sham (n = 36). Follow-up assessments were performed at baseline and 1-3 weeks after the last treatment session. Following HBOT, there was a significant group-by-time interaction in global cognitive function, attention and executive function (d = 0.495, p = 0.038; d = 0.477, p = 0.04 and d = 0.463, p = 0.05 respectively). Significant improvement was also demonstrated in the energy domain (d = 0.522, p = 0.029), sleep (d = - 0.48, p = 0.042), psychiatric symptoms (d = 0.636, p = 0.008), and pain interference (d = 0.737, p = 0.001). Clinical outcomes were associated with significant improvement in brain MRI perfusion and microstructural changes in the supramarginal gyrus, left supplementary motor area, right insula, left frontal precentral gyrus, right middle frontal gyrus, and superior corona radiate. These results indicate that HBOT can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition. HBOT's beneficial effect may be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles.

Hyperbaric oxygen therapy improves symptoms, brain's microstructure and functionality in veterans with treatment resistant post-traumatic stress disorder: A prospective, randomized, controlled trial.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is characterized by changes in both brain activity and microstructural integrity. Cumulative evidence demonstrates that hyperbaric oxygen therapy (HBOT) induces neuroplasticity and case-series studies indicate its potentially positive effects on PTSD. The aim of the study was to evaluate HBOT's effect in veterans with treatment resistant PTSD. METHODS: Veterans with treatment resistant PTSD were 1:1 randomized to HBOT or control groups. All other brain pathologies served as exclusion criteria. Outcome measures included clinician-administered PTSD scale-V (CAPS-V) questionnaires, brief symptom inventory (BSI), BECK depression inventory (BDI), brain microstructural integrity evaluated by MRI diffuse tensor imaging sequence (DTI), and brain function was evaluated by an n-back task using functional MRI (fMRI). The treatment group underwent sixty daily hyperbaric sessions. No interventions were performed in the control group. RESULTS: Thirty-five veterans were randomized to HBOT (N = 18) or control (n = 17) and 29 completed the protocol. Following HBOT, there was a significant improvement in CAPS-V scores and no change in the control (F = 30.57, P<0.0001, Net effect size = 1.64). Significant improvements were also demonstrated in BSI and BDI scores (F = 5.72, P = 0.024 Net effect size = 0.89, and F = 7.65, P = 0.01, Net effect size = 1.03). Improved brain activity was seen in fMRI in the left dorsolateral prefrontal, middle temporal gyri, both thalami, left hippocampus and left insula. The DTI showed significant increases in fractional anisotropy in the fronto-limbic white-matter, genu of the corpus callosum and fornix. CONCLUSIONS: HBOT improved symptoms, brain microstructure and functionality in veterans with treatment resistant PTSD.

Hyperbaric oxygen treatment for long coronavirus disease-19: a case report.

BACKGROUND: The coronavirus disease 2019 pandemic has resulted in a growing population of individuals who experience a wide range of persistent symptoms referred to as "long COVID." Symptoms include neurocognitive impairment and fatigue. Two potential mechanisms could be responsible for these long-term unremitting symptoms: hypercoagulability, which increases the risk of blood vessel occlusion, and an uncontrolled continuous inflammatory response. Currently, no known treatment is available for long COVID. One of the options to reverse hypoxia, reduce neuroinflammation, and induce neuroplasticity is hyperbaric oxygen therapy. In this article, we present the first case report of a previously healthy athletic individual who suffered from long COVID syndrome treated successfully with hyperbaric oxygen therapy. CASE PRESENTATION: A previously healthy 55-year-old Caucasian man presented 3 months after severe coronavirus disease 2019 infection with long COVID syndrome. His symptoms included a decline in memory, multitasking abilities, energy, breathing, and physical fitness. After evaluation that included brain perfusion magnetic resonance imaging, diffusion tensor imaging, computerized cognitive tests, and cardiopulmonary test, he was treated with hyperbaric oxygen therapy. Each session included exposure to 90 minutes of 100% oxygen at 2 atmosphere absolute pressure with 5-minute air breaks every 20 minutes for 60 sessions, 5 days per week. Evaluation after completing the treatment showed significant improvements in brain perfusion and microstructure by magnetic resonance imaging and significant improvement in memory with the most dominant effect being on nonverbal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking. The improved cognitive functions correlated with the increased cerebral blood flow in brain regions as measured by perfusion magnetic resonance imaging. With regard to physical capacity, there was a 34% increase in the maximum rate of oxygen consumed during exercise and a 44% improvement in forced vital capacity. The improved physical measurements correlated with the regain of his pre-COVID physical capacity. CONCLUSIONS: We report the first case of successfully treated long COVID symptoms with hyperbaric oxygen therapy with improvements in cognition and cardiopulmonary function. The beneficial effects of hyperbaric oxygen shed additional light on the pathophysiology of long COVID. As this is a single case report, further prospective randomized control studies are needed.

An in vivo implementation of the MEX MRI for myelin fraction of mice brain.

OBJECTIVE: Magnetization EXchange (MEX) sequence measures a signal linearly dependent on the myelin proton fraction by selective suppression of water magnetization and a recovery period. Varying the recovery period enables extraction of the percentile fraction of myelin bound protons. We aim to demonstrate the MEX sequence sensitivity to the fraction of protons associated with myelin in mice brain, in vivo. METHODS: The cuprizone mouse model was used to manipulate the myelin content. Mice fed cuprizone (n = 15) and normal chow (n = 8) were imaged in vivo using MEX sequence. MR images were segmented into corpus callosum and internal capsule (white matter) and cortical gray matter, and fitted to the recovery equation. Results were analyzed with correlation to MWF and histopathology. RESULTS: The extracted parameters show significant differences in the corpus callosum between the cuprizone and control groups. The cuprizone group exhibited reduced myelin fraction 26.5% (P < 0.01). The gray matter values were less affected, with 13.5% reduction (P < 0.05); no changes were detected in the internal capsule. Results were validated by MWF scans and good correlation to the histology analysis (R2 = 0.685). CONCLUSION: The results of this first in vivo implementation of the MEX sequence provide a quantitative measure of demyelination in brain white matter.

Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer's disease mouse model and in elderly patients.

Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer's disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging.

Regulatory effect of lithium on hippocampal blood-brain barrier integrity in a rat model of depressive-like behavior.

OBJECTIVES: Recent evidence has associated mood disorders with blood-brain barrier (BBB)/ neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin-4 (AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigated the effects of lithium on BBB integrity and NVU-related protein expression in chronic mild stress (CMS) rat model of depressive-like behavior. METHODS: Male Wistar rats were exposed for 5 weeks to unpredictable mild stressors with daily co-administration of lithium chloride to half of the stressed and unstressed groups. Sucrose preference and open field tests were conducted to validate the depressive-like phenotype, and dynamic contrast-enhanced MRI analysis was utilized to assess BBB integrity in brain regions relevant to the pathophysiology of depression. Hippocampal AQP4 and claudin-5 expression were studied using immunofluorescence, western blot, and enzyme-linked immunosorbent assays. RESULTS: Lithium administration to the stressed rats prevented the reductions in sucrose preference and distance traveled in the open field, and normalized the stress-induced hippocampal BBB hyperpermeability, whereas lithium administration to the unstressed rats increased hippocampal BBB permeability. Additionally, lithium treatment attenuated the decrease in hippocampal AQP4 to glial fibrillary acidic protein immunoreactivity ratio in the stressed rats and upregulated hippocampal claudin-5 and BDNF proteins expression. CONCLUSIONS: Our findings suggest that lithium administration in a rat CMS model of depressive-like behavior is associated with attenuation of stressed-induced hippocampal BBB/NVU disruption. These protective effects may be relevant to the mode of action of lithium in depression.

Cognitive enhancement of healthy older adults using hyperbaric oxygen: a randomized controlled trial.

More than half of community-dwelling individuals sixty years and older express concern about declining cognitive abilities. The current study's aim was to evaluate hyperbaric oxygen therapy (HBOT) effect on cognitive functions in healthy aging adults.A randomized controlled clinical trial randomized 63 healthy adults (>64) either to HBOT(n=33) or control arms(n=30) for three months. Primary endpoint included the general cognitive function measured post intervention/control. Cerebral blood flow (CBF) was evaluated by perfusion magnetic resonance imaging.There was a significant group-by-time interaction in global cognitive function post-HBOT compared to control (p=0.0017). The most striking improvements were in attention (net effect size=0.745) and information processing speed (net effect size=0.788).Voxel-based analysis showed significant cerebral blood flow increases in the HBOT group compared to the control group in the right superior medial frontal gyrus (BA10), right and left supplementary motor area (BA6), right middle frontal gyrus (BA6), left middle frontal gyrus (BA9), left superior frontal gyrus (BA8) and the right superior parietal gyrus (BA7).In this study, HBOT was shown to induce cognitive enhancements in healthy aging adults via mechanisms involving regional changes in CBF. The main improvements include attention, information processing speed and executive functions, which normally decline with aging.

Evaluation of White Matter Integrity Utilizing the DELPHI (TMS-EEG) System.

OBJECTIVE: The aim of this study was to evaluate brain white matter (WM) fibers connectivity damage in stroke and traumatic brain injury (TBI) subjects by direct electrophysiological imaging (DELPHI) that analyzes transcranial magnetic stimulation (TMS)-evoked potentials (TEPs). METHODS: The study included 123 participants, out of which 53 subjects with WM-related pathologies (39 stroke, 14 TBI) and 70 healthy age-related controls. All subjects underwent DELPHI brain network evaluations of TMS-electroencephalogram (EEG)-evoked potentials and diffusion tensor imaging (DTI) scans for quantification of WM microstructure fractional anisotropy (FA). RESULTS: DELPHI output measures show a significant difference between the healthy and stroke/TBI groups. A multidimensional approach was able to classify healthy from unhealthy with a balanced accuracy of 0.81 ± 0.02 and area under the curve (AUC) of 0.88 ± 0.01. Moreover, a multivariant regression model of DELPHI output measures achieved prediction of WM microstructure changes measured by FA with the highest correlations observed for fibers proximal to the stimulation area, such as frontal corpus callosum (r = 0.7 ± 0.02), anterior internal capsule (r = 0.7 ± 0.02), and fronto-occipital fasciculus (r = 0.65 ± 0.03). CONCLUSION: These results indicate that features of TMS-evoked response are correlated to WM microstructure changes observed in pathological conditions, such as stroke and TBI, and that a multidimensional approach combining these features in supervised learning methods serves as a strong indicator for abnormalities and changes in WM integrity.

Continuous positive airway pressure alters brain microstructure and perfusion patterns in patients with obstructive sleep apnea.

OBJECTIVES: To assess the effects of continuous positive airway pressure (CPAP) treatment on brain structure and function in patients with obstructive sleep apnea (OSA). METHODS: A prospective study of seven OSA patients recruited from the sleep center at our institution was carried out. Patients were treated with six weeks of CPAP treatment. Pre-treatment and post-treatment magnetic resonance imaging (MRI) perfusion scans were obtained and compared to assess for treatment-induced changes. Microstructural changes were quantified using functional anistrophy (FA) and mean diffusivity (MD), and brain perfusion was quantified using cerebral blood flow (CBF) and cerebral blood volume (CBV). RESULTS: Of the seven patients included the in study, six (85.7%) were male, and the mean age was 51 years (standard deviation = 13.14). Increased FA and decreased MD were found in the hippocampus, temporal lobes, fusiform gyrus, and occipital lobes. Decreased FA and increased MD were found in frontal regions for all patients (p < 0.05). Increased CBF and CBV were also observed following treatment (p < 0.05). CONCLUSION: In addition to symptom resolution, CPAP treatment may allow for healing of OSA-induced brain damage as seen by restoration of brain structure and perfusion.

Hyperbaric Oxygen Therapy Can Induce Angiogenesis and Regeneration of Nerve Fibers in Traumatic Brain Injury Patients.

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.

Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post-concussion syndrome due to traumatic brain injury.

PURPOSE: Recent clinical studies present convincing evidence that hyperbaric oxygen therapy (HBOT) may be the coveted neurotherapeutic method for brain repair. One of the most interesting ways in which HBOT can induce neuroplasticity is angiogenesis. The objective in this study was to assess the neurotherapeutic effect of HBOT in post TBI patients using brain perfusion imaging and clinical cognitive functions. METHODS: Retrospective analysis of patients suffering from chronic neuro-cognitive impairment from TBI treated with HBOT. The HBOT protocol included 60 daily HBOT sessions, 5 days per week. All patients had pre and post HBOT objective computerized cognitive tests (NeuroTrax) and brain perfusion MRI. RESULTS: Ten post-TBI patients were treated with HBOT with mean of 10.3±3.2 years after their injury. After HBOT, whole-brain perfusion analysis showed significantly increased cerebral blood flow and cerebral blood volume. Clinically, HBOT induced significant improvement in the global cognitive scores (p = 0.007). The most prominent improvements were seen in information processing speed, visual spatial processing and motor skills indices. CONCLUSION: HBOT may induce cerebral angiogenesis, which improves perfusion to the chronic damage brain tissue even months to years after the injury.

Nano-Drugs Based on Nano Sterically Stabilized Liposomes for the Treatment of Inflammatory Neurodegenerative Diseases.

The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of ß-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.

Neurodegeneration of lateral habenula efferent fibers after intermittent cocaine administration: implications for deep brain stimulation.

Deep brain stimulation (DBS) is an emerging technique for effective, non-pharmacological intervention in the course of neurological and neuropsychiatric diseases. Several brain targets have been suggested as suitable for DBS treatment of drug addiction. Previously, we showed that DBS of the lateral habenula (LHb) can reduce cocaine intake, facilitate extinction and attenuate drug-induced relapse in rats trained to self-administrate cocaine. Herein, we demonstrated that cocaine self-administration dose-dependently decreased connectivity between the LHb and midbrain, as shown by neurodegeneration of the main LHb efferent fiber, the fasciculus retroflexus (FR). FR degeneration, in turn, may have caused lack of response to LHb stimulation in rats trained to self-administer high-dose cocaine (1.5 mg/kg; i.v.). Furthermore, we show that the micro-structural changes caused by cocaine can be non-invasively detected using magnetic resonance imaging and diffusion tensor imaging. Detection of cocaine-induced alterations in FR anatomy can aid the selection of potential responders to LHb stimulation for treatment of drug addiction.

The CONNECT project: Combining macro- and micro-structure.

In recent years, diffusion MRI has become an extremely important tool for studying the morphology of living brain tissue, as it provides unique insights into both its macrostructure and microstructure. Recent applications of diffusion MRI aimed to characterize the structural connectome using tractography to infer connectivity between brain regions. In parallel to the development of tractography, additional diffusion MRI based frameworks (CHARMED, AxCaliber, ActiveAx) were developed enabling the extraction of a multitude of micro-structural parameters (axon diameter distribution, mean axonal diameter and axonal density). This unique insight into both tissue microstructure and connectivity has enormous potential value in understanding the structure and organization of the brain as well as providing unique insights to abnormalities that underpin disease states. The CONNECT (Consortium Of Neuroimagers for the Non-invasive Exploration of brain Connectivity and Tracts) project aimed to combine tractography and micro-structural measures of the living human brain in order to obtain a better estimate of the connectome, while also striving to extend validation of these measurements. This paper summarizes the project and describes the perspective of using micro-structural measures to study the connectome.

White matter correlates of cognitive domains in normal aging with diffusion tensor imaging.

The ability to perform complex as well as simple cognitive tasks engages a network of brain regions that is mediated by the white matter fiber bundles connecting them. Different cognitive tasks employ distinctive white matter fiber bundles. The temporal lobe and its projections subserve a variety of key functions known to deteriorate during aging. In a cohort of 52 healthy subjects (ages 25-82 years), we performed voxel-wise regression analysis correlating performance in higher-order cognitive domains (executive function, information processing speed, and memory) with white matter integrity, as measured by diffusion tensor imaging (DTI) fiber tracking in the temporal lobe projections [uncinate fasciculus (UF), fornix, cingulum, inferior longitudinal fasciculus (ILF), and superior longitudinal fasciculus (SLF)]. The fiber tracts were spatially registered and statistical parametric maps were produced to spatially localize the significant correlations. Results showed that performance in the executive function domain is correlated with DTI parameters in the left SLF and right UF; performance in the information processing speed domain is correlated with fractional anisotropy (FA) in the left cingulum, left fornix, right and left ILF and SLF; and the memory domain shows significant correlations with DTI parameters in the right fornix, right cingulum, left ILF, left SLF and right UF. These findings suggest that DTI tractography enables anatomical definition of region of interest (ROI) for correlation of behavioral parameters with diffusion indices, and functionality can be correlated with white matter integrity.