Brain Function and Pain Interference After Pediatric Intensive Interdisciplinary Pain Treatment.

OBJECTIVES: Intensive interdisciplinary pain treatments (IIPTs) are programs that aim to improve functioning in youth with severe chronic pain. Little is known about how the brain changes after IIPT; however, decreased brain responses to emotional stimuli have been identified previously in pediatric chronic pain relative to healthy controls. We examined whether IIPT increased brain responses to emotional stimuli, and whether this change was associated with a reduction in pain interference. PATIENTS AND METHODS: Twenty youths with chronic pain aged 14 to 18 years were scanned using functional magnetic resonance imaging, pre and post-IIPT. During the functional magnetic resonance imaging, patients were presented with emotional stimuli (ie, faces expressing happiness/fear), neutral expressions, and control (ie, scrambled) images. Patients completed a measure of pain interference pre and post-IIPT. Paired t tests were used to examine differences in brain activation in response to emotional versus neutral stimuli, pre to post-IIPT. Data from significant brain clusters were entered into linear mixed models to examine the relationships between brain activation and impairment pre and post-IIPT. RESULTS: Patients demonstrated a decrease in middle frontal gyrus (MFG) activation in response to emotional stimuli (happy + fear) relative to scrambled images, between pre and post-IIPT ( P < 0.05). Lower MFG activation was associated with lower pain interference, pre and post-IIPT ( P < 0.05). CONCLUSION: Contrary to our hypothesis, IIPT was associated with a reduction in MFG activation to emotional stimuli, and this change was associated with reduced pain interference. The MFG is a highly interconnected brain area involved in both pain chronification and antinociception. With further validation of these results, the MFG may represent an important biomarker for evaluating patient treatment response and target for future pain interventions.

Changes in brain metabolite levels across childhood.

Metabolites play important roles in brain development and their levels change rapidly in the prenatal period and during infancy. Metabolite levels are thought to stabilize during childhood, but the development of neurochemistry across early-middle childhood remains understudied. We examined the developmental changes of key metabolites (total N-acetylaspartate, tNAA; total choline, tCho; total creatine, tCr; glutamate+glutamine, Glx; and myo-inositol, mI) using short echo-time magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC) and the left temporo-parietal cortex (LTP) using a mixed cross-sectional/longitudinal design in children aged 2-11 years (ACC: N = 101 children, 112 observations; LTP: N = 95 children, 318 observations). We found that tNAA increased with age in both regions, while tCho decreased with age in both regions. tCr increased with age in the LTP only. Glx did not show linear age effects in either region, but a follow-up analysis in participants with ≥3 datapoints in the LTP revealed a quadratic effect of age following an inverted U-shape. These substantial changes in neurochemistry throughout childhood likely underlie various processes of structural and functional brain development.

In vivo Glx and Glu measurements from GABA-edited MRS at 3 T.

In vivo quantification of glutamate (Glu) and γ-aminobutyric acid (GABA) using MRS is often achieved using two separate sequences: a short-echo point resolved spectroscopy (PRESS) acquisition for Glu and a Mescher-Garwood PRESS (MEGA-PRESS) acquisition for GABA. The purpose of this study was to examine the agreement of Glu and Glx (the combined signal of glutamate + glutamine) quantified from two different GABA-edited MEGA-PRESS acquisitions (GABA plus macromolecules, GABA+, TE = 68 ms, and macromolecule suppressed, MMSup, TE = 80 ms) with Glu and Glx quantified from a short-echo PRESS (PRESS-35, TE = 35 ms) acquisition. Fifteen healthy male volunteers underwent a single scan session, in which data were acquired using the three acquisitions (GABA+, MMSup and PRESS-35) in both the sensorimotor and anterior cingulate cortices using a voxel size of 3 × 3 × 3 cm3 . Glx and Glu were quantified from the MEGA-PRESS data using both the OFF sub-spectra and the difference (DIFF) spectra. Agreement was assessed using correlation analyses, Bland-Altman plots and intraclass correlation coefficients. Glx quantified from the OFF sub-spectra from both the GABA+ and MMSup acquisitions showed poor agreement with PRESS-35 in both brain regions. In the sensorimotor cortex, Glu quantified from the OFF sub-spectra of GABA+ showed moderate agreement with PRESS-35 data, but this finding was not replicated in the anterior cingulate cortex. Glx and Glu quantified using the DIFF spectra of either MEGA-PRESS sequence were in poor agreement with the PRESS-35 data in both brain regions. In conclusion, Glx and Glu measured from MEGA-PRESS data generally showed poor agreement with Glx and Glu measured using PRESS-35.

Intraventricular hemorrhage in asphyxiated newborns treated with hypothermia: a look into incidence, timing and risk factors.

BACKGROUND: Intraventricular hemorrhage (IVH) is uncommon in term newborns. Asphyxia and hypothermia have been mentioned separately as possible risk factors of IVH, since they might cause fluctuations of cerebral blood flow. The aim of this study was to assess the incidence, the timing, and the risk factors of intraventricular hemorrhage (IVH) in term asphyxiated newborns treated with hypothermia. METHODS: We conducted a prospective cohort study of all term asphyxiated newborns treated with hypothermia from August 2008 to June 2013. The presence or not of IVH was assessed using brain magnetic resonance imaging (MRI) performed after the hypothermia treatment was completed or using head ultrasound during the hypothermia treatment. For these newborns, to determine the timing of IVH, we retrospectively reviewed if they had other brain imaging studies performed during their neonatal hospitalization stay. In addition, we compared their general characteristics with those not developing IVH. RESULTS: One hundred and sixty asphyxiated newborns met the criteria for hypothermia. Fifteen of these newborns developed IVH, leading to an estimate of 9% (95% CI: 5.3-15.0%) of IVH in this population of newborns. Fifty-three percent had hemorrhage limited to the choroid plexus or IVH without ventricular dilatation; 47% had IVH with ventricular dilatation or parenchymal hemorrhage. Sixty-seven percent had an initial normal brain imaging; the diagnostic brain imaging that demonstrated the IVH was obtained either during cooling (in 30%), within 24 h of the rewarming (in 30%), or 24 h after the rewarming (in 40%). Recurrent seizures were the presenting symptom of IVH during the rewarming in 20% of the newborns. Coagulopathy was more frequent in the asphyxiated newborns developing IVH (p < 0.001). The asphyxiated newborns developing IVH also presented more frequently with persistent pulmonary hypertension, hypotension, thrombocytopenia and coagulopathy (p = 0.03). CONCLUSIONS: The asphyxiated newborns treated with hypothermia appear to be at an increased risk of IVH, especially those with significant hemodynamic instability. IVH seems to develop during late hypothermia and rewarming. Efforts should be directed towards maintaining hemodynamic stability in these patients, even during the rewarming.

Evolution of Apparent Diffusion Coefficient and Fractional Anisotropy in the Cerebrum of Asphyxiated Newborns Treated with Hypothermia over the First Month of Life.

The objective of this study was to assess the evolution of diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI) over the first month of life in asphyxiated newborns treated with hypothermia and to compare it with that of healthy newborns. Asphyxiated newborns treated with hypothermia were enrolled prospectively; and the presence and extent of brain injury were scored on each MRI. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured in the basal ganglia, in the white matter and in the cortical grey matter. Sixty-one asphyxiated newborns treated with hypothermia had a total of 126 ADC and FA maps. Asphyxiated newborns developing brain injury eventually had significantly decreased ADC values on days 2-3 of life and decreased FA values around day 10 and 1 month of life compared with those not developing brain injury. Despite hypothermia treatment, asphyxiated newborns may develop brain injury that still can be detected with advanced neuroimaging techniques such as DWI and DTI as early as days 2-3 of life. A study of ADC and FA values over time may aid in the understanding of how brain injury develops in these newborns despite hypothermia treatment.

Angiogenesis dysregulation in term asphyxiated newborns treated with hypothermia.

BACKGROUND: Neonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns. OBJECTIVE: This study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns. DESIGN/METHODS: Twelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns. RESULTS: Compared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns. CONCLUSIONS: These findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery.

Does near-infrared spectroscopy identify asphyxiated newborns at risk of developing brain injury during hypothermia treatment?

OBJECTIVE: The aim of this article is to assess whether near-infrared spectroscopy (NIRS) identifies, during hypothermia treatment, the asphyxiated newborns who later develop brain injury. STUDY DESIGN: In this study, asphyxiated newborns, for whom later brain injury was defined by brain imaging and/or autopsy results, were monitored by NIRS during therapeutic hypothermia. We compared regional cerebral oxygenation saturation (rSO2) measured by NIRS at key time points for newborns who developed or did not develop later brain injury. RESULTS: A total of 18 asphyxiated newborns treated with hypothermia were enrolled. rSO2 was higher in the asphyxiated newborns who developed later brain injury. Sensitivity within the first 10 hours of hypothermia treatment for an adverse outcome was 100% (95% confidence interval [CI], 70-100%) and specificity was 83% (95% CI, 36-99%). CONCLUSIONS: NIRS appears to identify asphyxiated newborns at risk of developing brain injury as early as the first 10 hours of hypothermia treatment. Thus, NIRS may have an important role as an early outcome predictor in this population.

MRI obtained during versus after hypothermia in asphyxiated newborns.

OBJECTIVE: To assess whether the brain MRI results obtained during hypothermia identify the later brain injury observed in asphyxiated newborns after therapy is completed. PATIENTS AND METHODS: Asphyxiated newborns treated with hypothermia were prospectively enrolled in this study if they had at least one MRI performed during hypothermia treatment and then another MRI performed around day 10 of life. RESULTS: A total of 129 MRI scans were obtained from 43 asphyxiated newborns treated with hypothermia. Sixty per cent developed brain injury; all the brain injuries observed on the late scans were already present on day 2-3 of life during hypothermia, and the extent of injury was similar between the early and late scans. The brain MRI on day 2-3 of life had a sensitivity of 100% (95% CI 84% to 100%) and a specificity of 100% (95% CI 77% to 100%) to identify the presence and extent of later brain injury. CONCLUSIONS: The brain MRIs performed during hypothermia already permit an accurate definition of the presence and extent of brain injury that later develop in asphyxiated newborns despite treatment. These results may have research and clinical implications for the care of these newborns.

Measurement of brain perfusion in newborns: pulsed arterial spin labeling (PASL) versus pseudo-continuous arterial spin labeling (pCASL).

BACKGROUND: Arterial spin labeling (ASL) perfusion-weighted imaging (PWI) by magnetic resonance imaging (MRI) has been shown to be useful for identifying asphyxiated newborns at risk of developing brain injury, whether or not therapeutic hypothermia was administered. However, this technique has been only rarely used in newborns until now, because of the challenges to obtain sufficient signal-to-noise ratio (SNR) and spatial resolution in newborns. OBJECTIVE: To compare two methods of ASL-PWI (i.e., single inversion-time pulsed arterial spin labeling [single TI PASL], and pseudo-continuous arterial spin labeling [pCASL]) to assess brain perfusion in asphyxiated newborns treated with therapeutic hypothermia and in healthy newborns. DESIGN/METHODS: We conducted a prospective cohort study of term asphyxiated newborns meeting the criteria for therapeutic hypothermia; four additional healthy term newborns were also included as controls. Each of the enrolled newborns was scanned at least once during the first month of life. Each MRI scan included conventional anatomical imaging, as well as PASL and pCASL PWI-MRI. Control and labeled images were registered separately to reduce the effect of motion artifacts. For each scan, the axial slice at the level of the basal ganglia was used for comparisons. Each scan was scored for its image quality. Quantification of whole-slice cerebral blood flow (CBF) was done afterwards using previously described formulas. RESULTS: A total number of 61 concomitant PASL and pCASL scans were obtained in nineteen asphyxiated newborns treated with therapeutic hypothermia and four healthy newborns. After discarding the scans with very poor image quality, 75% (46/61) remained for comparison between the two ASL methods. pCASL images presented a significantly superior image quality score compared to PASL images (p < 0.0001). Strong correlation was found between the CBF measured by PASL and pCASL (r = 0.61, p < 0.0001). CONCLUSION: This study demonstrates that both ASL methods are feasible to assess brain perfusion in healthy and sick newborns. However, pCASL might be a better choice over PASL in newborns, as pCASL perfusion maps had a superior image quality that allowed a more detailed identification of the different brain structures.