Cerebral Intracellular Lactic Alkalosis Persisting Months after Neonatal Encephalopathy Measured by Magnetic Resonance Spectroscopy


We have found that cerebral lactate can be detected later than 1 month of age after neonatal encephalopathy (NE) in infants with severe neurodevelopmental impairment at 1 y. Our hypothesis was that persisting lactate after NE is associated with alkalosis and a decreased cell phosphorylation potential. Forty-three infants with NE underwent proton and phosphorus-31 magnetic resonance spectroscopy at 0.2-56 wk postnatal age. Seventy-seven examinations were obtained: 25 aged <2 wk, 16 aged ≥ 2 to ≤ 4 wk, 25 aged >4 to ≤ 30 wk, and 11 aged >30 wk. Neurodevelopmental outcome was assessed at 1 y of age: 17 infants had a normal outcome and 26 infants had an abnormal outcome. Using univariate linear regression, we determined that increased lactate/creatine plus phosphocreatine (Cr) was associated with an alkaline intracellular pH (pHi) (p < 0.001) and increased inorganic phosphate/phosphocreatine (Pi/PCr) (p < 0.001). This relationship was significant, irrespective of outcome group or age at time of study. Between outcome groups, there were significant differences for lactate/Cr measured at <2 wk (p = 0.005) and >4 to ≤ 30 wk (p = 0.01); Pi/PCr measured at <2 wk (p < 0.001); pHi measured at <2 wk (p < 0.001), ≥ 2 to ≤ 4 wk (p = 0.02) and >4 to ≤ 30 wk (p = 0.03); and for N-acetylaspartate/Cr measured at ≥ 2 to ≤ 4 wk (p = 0.03) and >4 to ≤ 30 wk (p = 0.01). Possible mechanisms leading to this persisting cerebral lactic alkalosis are a prolonged change in redox state within neuronal cells, the presence of phagocytic cells, the proliferation of glial cells, or altered buffering mechanisms. These findings may have implications for therapeutic intervention.


Perinatal asphyxia is reputed to be the most important cause of acute neurologic injury in the newborn and occurs in 6 per 1000 term live births(1,2). It is a major cause of neonatal death, brain injury, and neuromotor and intellectual impairment, and 10-20% of survivors suffer from mental retardation, cerebral palsy, and seizure disorder later in childhood(3,4).

Studies of animal models have suggested that whereas some neuronal loss may occur during the hypoxic-ischemic insult, a cascade of processes is also initiated that may result in the attainment of critical thresholds, hours or days later, which will trigger damage and further expression of cell injury and death(5).

The evolution of cerebral energy metabolism during and after HI has been studied in vivo by means of MRS(6). During HI in animal models, there was impairment of oxidative phosphorylation with an increase in the concentration of Pi and a reduction in the concentration of PCr in the brain, an increase in the cerebral concentration of lactate, and an acidic pHi(79). Pi/PCr is a surrogate measure of ADP concentration ([ADP]) which accumulates as ATP concentration ([ATP]) falls, and which stimulates glycolysis and oxidative phosphorylation(10). Pi/PCr thus reflects intracellular phosphorylation potential(11,12). After resuscitation, these variables briefly normalized, but despite adequate oxygen and substrate supply to the brain, a period of "delayed energy failure" began 8-24 h later, characterized by a second reduction in phosphorylation potential and increase in lactate, but with a rise in pHi(8,9,13).

In newborn infants who suffered severe birth asphyxia, there was a similar delayed decline in cerebral high energy phosphates, an increase in brain lactate, and an alkaline pHi during the days subsequent to birth(14,15). The severity of this delayed energy failure(16) correlated with subsequent severity of adverse outcome and reduced head growth at 1 and 4 y of age(17,18); similarly elevated cerebral lactate within 18 h of birth asphyxia predicted adverse outcome at 1 y of age(15).

Recent studies have suggested that the metabolic consequences of HI can persist for much longer than this in infants who develop neurodevelopmental impairment. Lactate was detected in the brain after 4 wk of age in seven of eight infants with abnormal neurodevelopmental outcome at 1 y after perinatal asphyxia; none of the infants with normal outcome at 1 y showed evidence of persisting lactate(19). One infant demonstrated an alkalotic pHi in the brain for 10 months after severe perinatal asphyxia(20).

The present study therefore addressed the hypothesis that after NE thought to be secondary to perinatal HI, cerebral energy metabolism remains abnormal for a prolonged period, with increased lactate concentrations that are accompanied by increased pHi and decreased cell phosphorylation potential. A secondary aim was to determine whether there was any difference in these variables between the normal and abnormal neurodevelopmental outcome groups.


Permission for this prospective study was granted by the Hammersmith Hospital Research Ethics Committee (no. 93/4047), and parental consent was obtained for every examination.

Subjects. Forty-three infants, born at median (range) gestational age 39.5 wk (36-42 wk) and birth weight 3340 g (2290-4450 g), were selected by the following criteria: clinical suspicion of birth asphyxia based upon a history of fetal distress (late decelerations on cardiotocography, meconium-stained liquor, acidemia (i.e.. pH < 7.1 and/or base deficit > 12 mmol/L) in umbilical cord blood or arterial blood within 30 min of birth), and abnormal postnatal neurologic signs consistent with NE(21). Six infants were small for gestational age. In all cases, appearances on magnetic resonance imaging at 2-14 d of age were consistent with hypoxia-ischemia damage(22), and findings included one or more of the following: brain swelling, loss of the posterior limb of the internal capsule, abnormal signal in the posterior lentiform nucleus and thalamus, cortical highlighting, and/or loss of gray/white matter differentiation.

1H and 31P MRS. To measure Pi, PCr, and pHi phosphorus-31 (31P) MRS was used. The peak area ratios of lactate/Cr and NAA/Cr were measured with proton (1H) MRS. Cr was chosen as the metabolite of reference because of its relative stability after HI, and so lactate/Cr is a reflection of lactate concentration(23). Brain volumes always encompassing the basal ganglia, an area particularly susceptible to damage after HI, were assessed(24).

1H and 31P MRS was performed after sedation with oral or rectal chloral hydrate (50-75 mg/kg-1). Throughout each examination, the infants were monitored by MRS-compatible pulse oximetry and ECG and were supervised by a pediatrician experienced in neonatal resuscitation and MRS.

A total of 77 examinations were obtained from the patient group: 25 infants were less than 2 wk old; 16 were more than or equal to 2 wk and less than or equal to 4 wk; 25 were more than 4 wk and less than or equal to 30 wk; and 11 were more than 30 wk old. Eighteen of the infants were studied more than once. Proton data from subject no. 30 at 48 wk of age have been reported previously(19).

Cerebral MR data were obtained with a Picker prototype 1.5 Tesla MRS system (Picker International, Cleveland, OH), using a double-tuned pediatric birdcage coil. Data were collected between June 1996 (when the double-tuned pediatric birdcage coil became available) and December 1997 (when the system was upgraded to a Picker Eclipse configuration). A set of localized 1H MR spectra were obtained from a 16 × 16 or 32 × 16 grid covering a transverse plane at the level of the basal ganglia by using three-dimensional chemical shift imaging in the spin-echo data acquisition mode with TE of 130 ms and 270 ms(25). The nominal voxel size was 4.5 cm3. To process data, cosine filtering was used in each spatial domain and an exponential line-broadening filter function of 1.2 Hz in the spectral domain before three-dimensional Fourier transformation. A knowledge-based algorithm was used for the removal of the water residuum and for baseline flattening(26). A set of localized 31P MR spectra were then collected by two-dimensional chemical shift imaging. Data were collected from planes including the basal ganglia, each nominally 20 mm thick, with TR 1 s, pulse angle 45°, and 32 data collections at each gradient permutation. This data set was filtered with a cosine filter in the spatial domain and an exponential filter of 5.3 Hz in the spectral dimension.

Peak areas of lactate, Cr, and NAA were measured in the 1H MR spectra using inverse polynomial lineshape functions in NMR1 (New Methods Research Inc, Syracuse, NY). The criteria for lactate detection were an inverted peak at TE 130 ms, centered at 1.3 ppm; doublet structure (J-coupling 7 Hz) if adequate spectral resolution; and a phase change of 180° at TE 270 ms, allowing assignment of lactate to be confirmed when there was ambiguity as to the extent of peak overlap with lipid signals. Lactate/Cr and NAA/Cr were generally measured from four spectra localized to the basal ganglia, and the results were averaged to give a single value for each subject. Lactate was considered detected when lactate/Cr was greater than 0.05.

Pi/PCr was determined by fitting the peaks to Lorentzian lineshape functions using NMR1. pHi was measured from the difference in the chemical shifts of Pi and PCr(27).

Statistical considerations. Infants were grouped according to normal and abnormal outcome at 1 y of age. Data collected during three time periods were compared: <2 wk, ≥ 2 to ≤ 4 wk, >4 to ≤ 30 wk. The data were not normally distributed, and thus lactate/Cr, NAA/Cr, Pi/PCr, and pHi were transformed to normality by using log (x-k), where k was -0.02, -0.50, 0.50, and 6.88, respectively(28). Normality was confirmed for each transformed variable by the skewness/kurtosis test for normality(29). Linear and multiple regression analyses were used to define the relationship between the transformed variables for the group overall. Regression analyses were then performed to compare the normal and abnormal outcome groups at the different time points. Robust regression methods were used to take account of multiple measurements in some infants(30).

Neurodevelopmental outcome. Neurodevelopmental outcome was assessed at 1 y of age, using Griffith's development scales(31) and a detailed neurologic examination. Neurologic signs were quantified with an optimality score(32,33). This score includes items for tone, posture, passive and elicited motility and tone, interaction, reflexes, and vision and hearing responses. The maximum possible optimality score was 21.

Neurodevelopmental outcome was categorized as normal or abnormal. Infants were classified as normal if they had no abnormal neurologic signs and achieved a Griffith's DQ of >85. All other infants were regarded as having an abnormal neurodevelopmental outcome. MRS data were compared between normal and abnormal groups, but for illustrative purposes, the severity of neurodevelopmental impairment was classified as mild, moderate, severe, or no discernible development. Infants with minor neurologic signs, such as hypotonia or asymmetry of tone but normal development (DQ > 85), were classified as mildly abnormal. Infants with DQ 75-84 were classified as mild, those with a DQ of 50-74 as moderate, those with a DQ of 20-50 as severe, and those with DQ <20 as having no detectable development. All infants who died did so because of neurologic problems, and in this study, they were considered together with those with severe neurologic impairment.


Exclusions. In addition to the studies reported, data from 19 examinations of 12 of the study infants were not of analyzable quality or the study protocol could not be completed, generally because of motion artefact. These data were consequently excluded. This included four infants with normal outcome (one examination in the neonatal period, three examinations of three infants between 4 and 30 wk, and two examinations of two infants after 30 wk) and eight infants with abnormal outcome (four examinations of four infants in the neonatal period, six examinations of five infants between 4 and 30 wk, and three infants after 30 wk). No data from infants with normal outcome aged >30 wk were obtained, so a comparison between data from infants with normal and abnormal outcome could be made only up to 30 wk of age.

Neurodevelopmental outcome. The perinatal clinical details, Griffith's General Quotient, and Optimality Score from 17 asphyxiated infants with normal outcome at 1 y are shown in Table 1.

Table 1 Clinical details of birth-asphyxiated infants with normal outcome at 1 y

The perinatal clinical details, Griffith's General Quotient, and Optimality Score of 26 asphyxiated infants with abnormal outcome (mild, moderate, severe, and no detectable development) at 1 y, or those who died, are shown in Table 2.

Table 2 Clinical details of birth-asphyxiated infants with abnormal outcome at 1 y or who died (ordered by outcome)

One infant with a normal outcome and five infants with an abnormal outcome were small for gestational age.

Spectroscopy findings. Fig. 1 (A and B) provides an illustrative example of proton and phosphorus spectra from one infant after severe NE, showing the presence of lactate coinciding with elevated Pi/PCr and alkaline pHi at 2 d of age. Fig. 1 (C and D) shows the persistence of lactate and an alkaline pHi at 9 wk of age in the same infant.

Figure 1

Representative 1H (A, C) and 31P MR (B, D) spectra from a term infant with severe birth asphyxia. The 1H MRS data were collected with TE 130 ms. At 2 d of age (A, B) lactate was obviously present (mean lactate/Cr from four spectra in the basal ganglia was 0.8), Pi/PCr was 2.44, and pHi was 7.23. At 9 wk of age (C, D), lactate was still present (mean lactate/Cr in the basal ganglia was 0.26), Pi/PCr was decreased to 0.86, and pHi was less alkaline (7.08). At 0.3 wk of age, a signal was detected from propan-1,2-diol (pd), a carrier for phenobarbitone.

The spectral data from the two outcome groups are summarized in Fig. 2 (a and b) and in Fig. 3. Lactate, Pi/PCr, and pHi were most abnormal at 0-2 wk and decreased with increasing age. Univariate linear regression revealed highly significant relationships, lactate/Cr to pHi (p < 0.001) and lactate/Cr to Pi/PCr (p < 0.001), for the group as a whole. These relationships were also significant considering separately the normal outcome group [lactate/Cr to pHi (p = 0.004) and lactate/Cr to Pi/PCr (p < 0.001)] and the abnormal outcome groups [lactate/Cr to pHi (p < 0.001) and lactate/Cr to Pi/PCr (p < 0.001)]. Adding either Pi/PCr or age to the regression equation predicting lactate/Cr from pHi did not significantly improve the fit (p = 0.17, 0.46, respectively).

Figure 2

Lactate/Cr plotted against pHi for normal (a) and abnormal (b) outcome. Each baby is identified by the patient number. Linear regression analysis showed a significant relationship between lactate/Cr and pHi. The relationship was the same, irrespective of outcome.

Figure 3

Mean and 95% confidence intervals of data collected at the different time periods for the spectral parameters, lactate/Cr, pHi, Pi/PCr, and NAA/Cr in the normal and abnormal outcome groups. The p values obtained by comparing the means of the normal and abnormal outcome groups at different time periods are also illustrated. NS = not statistically significant.

For the lactate/Cr to pHi relationship, the regression lines were similar in the normal and abnormal outcome groups with similar intercepts (R2 = 0.52). For the lactate/Cr to Pi/PCr relationship, the regression lines of the two groups were parallel (R2 = 43%), but the intercepts were significantly different (p = 0.003), differing by 0.81. In other words, despite the very strong relationship between these variables, for a given Pi/PCr, the lactate/Cr was higher in the abnormal group than in the normal group.

In our comparison of the means of the normal and abnormal outcome groups at different time periods (Fig. 3), lactate/Cr was significantly higher in the abnormal group at <2 wk (p = 0.005) and >4 to ≤ 30 wk (p = 0.01). Pi/PCr was significantly higher in the abnormal outcome group at <2 wk (p < 0.001), but there was no significant difference beyond this time. pHi was significantly more alkaline in the abnormal outcome group at <2 wk (p < 0.001) and 2-4 wk (p = 0.02), and >4 to ≤ 30 wk (p = 0.03). There was no significant difference between groups for NAA/Cr in the first 2 wk of age; beyond this time NAA/Cr was significantly higher in the normal outcome group (p = 0.02, p = 0.03).


The major finding of the study was that the increased lactate in the basal ganglia of infants months after NE was associated with an alkaline pHi and an increased Pi/PCr. These findings decreased with increasing time after the insult but could be detected for up to 1 y after the hypoxic-ischemic insult. The relationship between these variables was significant in both the abnormal and normal outcome groups.

The 1H MR data were obtained from a nominal 4.5 cm3 volume encompassing the basal ganglia, whereas the 31P MR data were obtained from a much larger volume, a transverse plane nominally 2 cm thick at the level of the basal ganglia. The volumes could not be matched because of the lower sensitivity of 31P MRS compared with 1H MRS. Cr was selected as the 1H metabolite of reference, because its concentration is thought to remain unaltered immediately after HI injury(23), although it is not clear how the Cr concentration changes in the months subsequent to birth asphyxia. It is important that the infants are adequately still during the MR examination, because motion would cause a decreased signal-to-noise ratio in the spectra and maybe uncertainty as to the accuracy of the metabolite ratios. Data from 19 additional examinations of 12 of the study infants were excluded generally because of motion.

Cerebral lactate concentrations in neonates have been shown to increase with the degree of growth restriction and to be inversely related to gestational age(34). However, infants whose birthweight is appropriate for gestational age and those who are small for gestational age have similar phosphorus metabolites and pHi(35). Cerebral lactate has been shown to be elevated during various pediatric neurologic diseases such as stroke(36), hypoxia-ischemia(25), metabolic and mitochondrial disorders(37), CNS injury(38), and in near-drowning(39). Neonates, infants, and children with acute CNS insults and elevated lactate peaks detected acutely by 1H MRS were more likely to have a poor long-term neurologic outcome than were those in whom lactate was not detected(40).

In adults, several studies have demonstrated persisting lactate in the chronic stage of brain infarction - in one case, as late as 2 y after a middle cerebral artery infarct(4148). Patients with large and persistent elevations of cerebral lactate in the acute to subacute phase had significant neurologic impairment, whereas those with lesser changes had a more benign course(45,49). The progression from intracellular acidosis during the acute phase to alkalosis during the subacute/chronic phase of adult ischemic brain injury in humans and in animal models has been illustrated by several groups(5054). Positron emission tomography has also confirmed this crossover from acute acidosis to alkalosis subsequent to adult stroke; a significant pHi increase in subacute to chronic infarcts correlated with a reduced oxygen extraction fraction and blood perfusion exceeding metabolic demand (i.e., luxury perfusion), causing alkalosis by removing excess CO2(5558). In the months after perinatal HI, this rebound alkalosis has also been demonstrated in one infant followed serially until the age of 10 months: however, it was not possible to measure cerebral lactate levels at the time of this study(20).

Possible mechanisms leading to lactic alkalosis. There are several mechanisms that could explain the chronic lactic alkalosis seen in our infants in the months after NE. One possibility is that lactate is a stagnant pool produced during the acute phase of injury and that it diminishes gradually with time. This, however, is unlikely, according to the physiologic estimates of lactate washout after ischemia(59), blood brain barrier permeability to lactate(60), and the well- characterized biphasic response of lactate after HI(9). After adult stroke, such lactate has been shown to be actively produced in the stroke region by the formation of lactate from 13C-labeled glucose(61). The lactate seen during the period of secondary energy failure therefore must be due to a renewed production.

The second possibility is that persisting lactic alkalosis is attributable to ongoing ischemia. This too is unlikely. Levels of cerebral blood flow after perinatal HI have been shown to be high(6264) and to be associated with low oxygen extraction(62,65). Positron emission tomography scans demonstrate a period of localized increased glucose uptake or hypermetabolism in the early post-asphyxial period (2-5 d) in areas that go on to develop an infarct(66). After this acute period, there is a local decrease in cerebral blood flow in the parasagittal regions(67) and a halving of the cerebral metabolic rate for glucose(68). In subacute to chronic adult infarcts, an alkaline pHi correlated with a reduced oxygen extraction fraction and blood perfusion exceeding metabolic demand, i.e., luxury perfusion(55,56,69).

A more likely explanation for the persisting lactic alkalosis is an altered redox state caused by inability to regenerate NAD+. Lactate and its redox partner pyruvate have a central position as the terminal metabolites of glycolysis within the cytosol, and pyruvate as the initial substrate for the mitochondrial tricarboxylic acid cycle(70). Lactate is both formed and used by lactate dehydrogenase in a near equilibrium reaction: [lactate]+[NAD+]= [pyruvate]+[NADH]+[H+] or Equation 1 where [NADH] = dihydronicotinamide adenine dinucleotide concentration, [NAD+] = nicotinamide adenine dinucleotide concentration, [H+] = hydrogen ion concentration, and K = equilibrium constant for lactate dehydrogenase.

A decrease in NAD+ or an increase in NADH causes a shift in the equilibrium either toward lactate formation, or a fall in [H+], or both. Consequently, a persisting reduction of the redox potential will lead to increased lactate and an alkaline pHi. Mitochondrial impairment could exacerbate this decreased NAD+/NADH by leading to increased [ADP] which will drive glycolysis and produce NADH, and by an inability to regenerate NAD+ from NADH along the electron transport chain. Further evidence of mitochondrial damage is that children with inborn errors of mitochondrial metabolism have increased levels of cerebral lactate(71,72). The pHi and phosphorylation potential of mitochondrial disorders have not been explored fully; however, a study (with a mouse model) determined the brain pHi to be alkaline, by 31P MRS(73). This situation may be analogous to that occurring in the months that follow perinatal asphyxia(74). Interventional strategies that use dichloroacetate are being developed at present for mitochondrial disorders-dichloroacetate having been shown experimentally to lower lactate levels and improve morbidity by accelerating the oxidation of glucose, lactate, and pyruvate to acetyl-CoA(75).

Activation of poly (ADP-ribose) (PARP) by cellular injury will also consume NAD+ as a substrate to transfer ADP-ribose groups to nuclear proteins in an attempt to effect repair(7678). Excessive activation of PARP and depletion of its NAD+ might contribute to cell death through consequent depletion of ATP, inasmuch as four molecules of ATP are needed to generate one molecule of NAD+. In vitro studies have shown that inhibition of PARP activity spares the cell from energy loss, thus providing neuroprotection(79). In vivo administration of a PARP inhibitor led to a significant reduction in infarct volume in focal ischemia(80), and genetic deletion of PARP or inhibition of PARP attenuates tissue injury and conserves NAD+(81).

A fourth possibility is that tissue alkalosis enhances glycolysis and lactate production(82). The major regulator of glycolysis is phosphofructokinase which has an alkaline pHi optimum(83). Glycolysis of glucose to pyruvate generates NADH which shifts the cytosolic redox state toward lactate formation. Lactate production, therefore, could be stimulated by alkalosis. Brain lactate increases during hypocapnia in animals(84) and humans(85). However, in severe hypocapnia, oxygen delivery is reduced and may be insufficient to maintain oxidative metabolism, and thus the lactate increase may result from cerebral ischemia(86). The alkalosis resulting from hypocapnia may further limit oxygen delivery to the brain by shifting the oxygen dissociation curve to the left.

A fifth possibility that could explain the lactic alkalosis is the presence of phagocytes. Phagocytic cells have a high rate of anaerobic glycolysis which leads to elevated lactate(87). Brain macrophages (microglia, astrocytes, and leukocytes) have been shown to appear 1-3 d after an infarction and slowly disappear over many months(88). Histopathology of 10- and 15-d-old strokes has confirmed the presence of macrophages with few other cells throughout the infarction core center, blending into border zones of reactive astrocytes(89).

A sixth possible cause of intracerebral alkalosis is proliferation of glial cells to replace necrotic or apoptotic neurons after perinatal HI. Alkalosis may be associated with the stimulation of glial cell growth, as growth factor reportedly increases the pHi in fibroblasts(90). Increased pHi has also been reported in glial cell tumors(91).

Finally, cerebral alkalosis that follows NE may be due to altered buffering mechanisms in the remaining cells. All vertebrate cells, including neurons and glia, contain a Na+/H+ antiporter system and ischemia and associated acute lactic acidosis could cause an adaptive increase in brain buffering by this system. In some cells, Na+ influx and growth factor have been seen to stimulate the Na+/H+ antiporter to increase pHi(92): thus it is possible that this mechanism could contribute to the alkalosis.

This persisting lactic alkalosis therefore may be consistent with an altered redox state, the presence of phagocytic cells, gliosis, and/or altered buffering mechanisms. However, the relative influence of each of these factors is as yet unknown.

It is not known whether lactate is beneficial or detrimental to brain tissue after HI. Some studies suggest a possible role for lactate in supporting synaptic function after hypoxia(93). Several years ago it was demonstrated that brain tissue can respire when lactate is the substrate(94,95), and in vivo studies have shown that brain tissue produces lactate aerobically, especially under stimulating conditions(96101). Schurr et al. has recently shown that lactate is preferred over glucose for recovery of synaptic function after HI(102). Based on studies with astrocytic and neuronal cultures, it has been hypothesized that glutamate uptake by astrocytes stimulates the production of glycolytic lactate and its aerobic utilization by neurons(103).

Relationship of MRS findings to neurodevelopmental outcome. As expected from previous work(15,104), in our study there was a significant relationship between Lac/Cr in the first 2 wk after birth, and the outcome. We have also confirmed a difference in Lac/Cr after 4 wk of age in the normal and abnormal groups(19).

pHi was significantly different between outcome groups at <2 wk (p < 0.001) and between ≥ 2 to ≤ 4 wk (p = 0.02) and >4 to ≤ 30 wk (p = 0.03). pHi appeared to be the strongest predictor of outcome at all times up to 30 wk postnatal age.

Confirming previous studies(16), the Pi/PCr ratio (in some studies expressed as PCr/Pi) was significantly different in the normal and abnormal groups at <2 wk (p < 0.001), and after this time was not significantly different. As discussed before, Pi/PCr is a surrogate measure of [ADP], which accumulates as [ATP] falls, and which stimulates glycolysis and oxidative phosphorylation. The significant difference between normal and abnormal groups only in the first 2 wk implies that a reduced phosphorylation potential may not be essential in the development of persistent lactic alkalosis.

NAA/Cr was not significantly different between outcome groups until <2 wk, after which time there was a significant difference between normal and abnormal outcome groups at ≥ 2 to ≤ 4 wk (p = 0.03) and >4 to ≤ 30 wk (p = 0.01). Other investigators have suggested that a reduced NAA/Cho was indicative of a poor prognosis after perinatal asphyxia, both neonatally (mean age 7 d)(104), at 3 mo(104), and at 14 d(105). However, a further study in infants at an earlier stage (median age 1.3 d, range 0.1-4.5 d) with age-matched controls showed no convincing reduction in NAA/Cho(106).

NAA is an amino acid found exclusively in the nervous system and is synthesized in brain mitochondria from acetyl-CoA and aspartate by the enzyme L-aspartate N-acetyl transferase. NAA has been used as a neuronal marker, because apart from oligodendrocyte type 2 cells, NAA is present primarily in neurons(107). However, the functions and roles of this amino acid remain unknown. NAA can be detected in the cerebral cortex and white matter of fetuses as early as 16 wk gestation(108) and shows an age-dependent increase in synthetic rate that is reflected in total brain levels of NAA(109,110). As demonstrated in animal and human adults, NAA/Cho ratios decline hours to days after HI(111), and this is reflected in our findings.

Conclusion. This study shows that, in the months after NE, there is a significant relationship between increased cerebral lactate levels and an alkaline pHi. In the infants with abnormal neurodevelopmental outcome at 1 y, lactate/Cr and pHi are generally significantly higher at >2 wk, compared with those infants with a normal neurodevelopmental outcome. Phosphorylation potential, however, is not significantly different between groups at >2 wk, which implies that a reduced phosphorylation potential may not be essential in the development of persistent lactic alkalosis. Further understanding of the mechanisms leading to these prolonged changes may lead us to other modalities of intervention, with the aim of improving outcome.



magnetic resonance spectroscopy


neonatal encephalopathy






inorganic phosphate


creatine plus phosphocreatine




intracellular pH


echo time


developmental quotient


poly ADP-ribose


  1. 1

    Robertson CMT, Finer NN, Grace MGA 1989 School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 114: 753–760.

  2. 2

    Bax M, Nelson KB 1993 Birth asphyxia: a statement. World Federation of Neurology Group. Dev Med Child Neurol 35: 1022–1024.

  3. 3

    Nelson KB 1988 What proportion of cerebral palsy is related to birth asphyxia?. [editor's column] J Pediatr 112: 572–574.

  4. 4

    Hull JD, Dodd K 1991 What is birth asphyxia?. Br J Obstet Gynaecol 98: 953–955.

  5. 5

    Gluckman PD, Williams CE 1992 When and why do brain cells die?. Dev Med Child Neurol 34: 1010–1014.

  6. 6

    Azzopardi D, Edwards AD 1995 Magnetic resonance spectroscopy in neonates. Curr Opin Neurol 8: 145–149.

  7. 7

    Hope PL, Cady EB, Chu A, Delpy DT, Gardiner RM, Reynolds EOR 1987 Brain metabolism and intracellular pH during ischaemia and hypoxia: an in vivo31P and 1H nuclear magnetic resonance study in the lamb. J Neurochem 49: 75–82.

  8. 8

    Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD, Peebles DM, Wylezinska M, Owen-Rees H, Kirkbride V, Cooper C, Aldridge RF, Roth SC, Brown G, Delpy DT, Reynolds EOR 1994 Delayed ('secondary') cerebral energy failure following acute hypoxia-ischaemia in the newborn piglet: continuous 48-hour studies by 31P magnetic resonance spectroscopy. Pediatr Res 36: 699–706.

  9. 9

    Penrice J, Lorek A, Cady EB, Amess P, Wylezinska M, Cooper CE, D'Souza P, Brown GC, Kirkbride V, Edwards AD, Wyatt JS, Reynolds EOR 1997 Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet. Pediatr Res 41: 795–802.

  10. 10

    Radda GK 1992 Control, bioenergetics, and adaptation in health and disease: noninvasive biochemistry from nuclear magnetic resonance. NMR Biomed 6: 3032–3038.

  11. 11

    Siesjö BK 1978. Brain Energy Metabolism. John Wiley, London, 178–202.

  12. 12

    Chance B, Leigh JS, Clarke BJ, Maris J, Kent J, Niioka S, Smith D 1985 Control of oxidative metabolism and oxygen delivery in human skeletal muscle: a steady state analysis of the work/energy cost transfer function. Biochemistry 82: 8384–8388.

  13. 13

    Blumberg RM, Cady EB, Wigglesworth JS, McKenzie JE, Edwards AD 1996 Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia ischaemia in the developing brain. Exp Brain Res 113: 130–137.

  14. 14

    Hope PL, Costello AM, Cady EB, Delpy DT, Tofts PS, Chu A, Hamilton PA, Reynolds EO, Wilkie DR 1984 Cerebral energy metabolism studied with phosphorus NMR spectroscopy in normal and birth-asphyxiated infants. Lancet 2: 366–370.

  15. 15

    Hanrahan D, Cox IJ, Azzopardi D, Cowan F, Sargentoni J, Bell JD, Bryant DJ, Edwards AD 1999 Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at one year of age. Dev Med Child Neurol 41: 76–82.

  16. 16

    Azzopardi D, Wyatt JS, Cady EB, Delpy DT, Baudin J, Stewart AL, Hope PL, Hamilton PA, Reynolds EOR 1989 Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 25: 445–451.

  17. 17

    Roth SC, Edwards AD, Cady EB, Delpy DT, Wyatt JS, Azzopardi D, Baudin J, Townsend J, Stewart AL, Reynolds EOR 1992 Relation between cerebral oxidative metabolism following birth asphyxia and neurodevelopmental outcome and brain growth at one year. Dev Med Child Neurol 34: 285–295.

  18. 18

    Roth SC, Baudin J, Cady E, Johal K, Townsend JP, Wyatt JS, Reynolds EOR, Stewart AL 1997 Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol 39: 718–725.

  19. 19

    Hanrahan D, Cox IJ, Edwards AD, Cowan F, Sargentoni J, Bell JD, Bryant DJ, Rutherford MA, Azzopardi D 1998 Persistent increases in cerebral lactate concentration after birth asphyxia. Pediatr Res 44: 304–311.

  20. 20

    Laptook AR, Corbett RJ, Uauy R, Mize C, Mendelsohn D, Nunnally RL 1989 Use of 31P magnetic resonance spectroscopy to characterize evolving brain damage after perinatal asphyxia. Neurology 39: 709–712.

  21. 21

    Sarnat HB, Sarnat MS 1976 Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Ann Neurol 33: 696–705.

  22. 22

    Rutherford MA, Pennock JM, Schwieso JE, Cowan F, Dubowitz LM 1995 Hypoxic-ischaemic encepalopathy: early magnetic resonance imaging findings and their evolution. Neuropediatrics 26: 183–191.

  23. 23

    Cady EB, Amess P, Penrice J, Wylezinska M, Sams V, Wyatt J 1997 Early cerebral metabolite quantification in perinatal hypoxic-ischaemic encephalopathy by proton and phosphorus magnetic resonance spectroscopy. Magn Reson Imag 15: 605–611.

  24. 24

    Rutherford MA, Pennock JM, Schweiso J, Cowan F, Dubowitz L 1996 Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child 75: F145–F151.

  25. 25

    Hanrahan D, Sargentoni J, Azzopardi D, Manji K, Cowan F, Rutherford MA, Cox IJ, Bell JD, Bryant D, Edwards AD 1996 Cerebral metabolism within 18 hours of birth asphyxia: a proton magnetic resonance spectroscopy study. Pediatr Res 39( 4): 584–590.

  26. 26

    Saeed N 1995 A knowledge-based approach to deconvolve the water component in in vivo proton MR spectroscopy. J Comput Assist Tomogr 19: 830–837.

  27. 27

    Petroff OAC, Pritchard JW, Behar KL, Alger JR, den Hollander JA 1985 Cerebral intracellular pH by 31P magnetic resonance spectroscopy. Neurology 35: 781–788.

  28. 28

    Box GEP, Cox DR 1964 An analysis of transformations. J R Statist Soc 26: 211–252.

  29. 29

    D' Agostino RB, Belanger A, D'Agostino RBJ 1990 A suggestion for using powerful and informative tests for normality. Am Statist 44: 316–321.

  30. 30

    STATA release 5 1997 Estimation and post-estimation commands. User's Guide, Stata Press, Texas, U.S.A 235: 239

  31. 31

    Griffiths R 1970 The Abilities of Babies. University of London Press, London

  32. 32

    Rutherford MA, Pennock JM, Counsell SJ, Mercuri E, Cowan FM, Dubowitz LM, Edwards AD 1998 Abnormal magnetic resonance signal in the internal calsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischaemic encephalopathy. Pediatrics 102: 323–328.

  33. 33

    Keunzle C, Baenziger O, Martin E, Thun-Hohenstein L, Steinlin M, Good M 1994 Prognostic value of early MR imaging in term infants with severe perinatal asphyxia. Neuropediatrics 4: 191–200.

  34. 34

    Leth H, Toft PB, Pryds O, Peitersen B, Lou HC, Henriksen O 1995 Brain lactate in preterm and growth-retarded neonates. Acta Paediatr 84: 495–499.

  35. 35

    Azzopardi D, Wyatt JS, Hamilton PA, Cady EB, Delpy DT, Hope PL, Reynolds EOR 1989 Phosphorus metabolites and intracellular pH in the brains of normal and small for gestational age infants investigated by magnetic resonance spectroscopy. Pediatr Res 25: 440–444.

  36. 36

    Groenendaal F, van der Grond J, Witkamp TD, de Vries LS 1995 Proton magnetic resonance spectroscopic imaging in neonatal stroke. Neuropediatrics 26: 243–248.

  37. 37

    Wang Z, Zimmerman RA, Sauter R 1996 Proton MR spectroscopy of the brain: clinically useful information obtained in assessing CNS diseases in children. AJR 167: 191–199.

  38. 38

    Auld KL, Ashwal S, Holshouser BA, Tomasi LG, Perkin RM, Ross BD, Hinshaw DBJ 1995 Proton magnetic resonance spectroscopy in children with acute central nervous system injury. PaediatrNeurol 12: 323–334.

  39. 39

    Kreis R, Arcinue E, Ernst T, Shonk TK, Flores R, Ross BD 1996 Hypoxic encephalopathy after near-drowning studied by quantitative 1H-magnetic resonance spectroscopy. J Clin Invest 97: 1142–1154.

  40. 40

    Ashwal S, Holshouser BA, Tomasi LG, Shu S, Perkin RM, Nystrom GA, Hinshaw DB 1997 1H-magnetic resonance spectroscopy-determined cerebral lactate and poor neurological outcome in children with central nervous system disease. Ann Neurol 41: 470–481.

  41. 41

    Graham GD, Blamire AM, Howsman AM, Rothman DL, Fayad PB, Brass LM, Petroff OAC, Shulman RG, Pritchard JW 1992 Proton magnetic resonance spectroscopy of cerebral lactate and other metabolites in stroke patients. Stroke 23: 333–340.

  42. 42

    Sappey-Marinier D, Calabrese G, Hetherington HP, Fisher SNG, Deicken R, Van Dyke C, Fein G, Weiner MW 1992 Proton magnetic resonance spectroscopy of human brain: applications to normal white matter, chronic infarction, and MRI white matter signal hyperintensities. Magn Reson Med 26: 313–327.

  43. 43

    Duijn JH, Matson GB, Maudsley AA, Hugg JW, Weiner MW 1992 Human brain infarction:proton MR spectroscopy. Radiology 183: 711–718.

  44. 44

    Gideon P, Sperling B, Arlien-Soborg P, Olsen TS, Henriksen O 1994 Long-term follow-up of cerebral infarction patients with proton magnetic resonance spectroscopy. Stroke 25: 967–973.

  45. 45

    Federico F, Simone IL, Lucivero V, Giannini P, Laddomada G, Mezzapesa DM, Tortorella C 1998 Prognostic value of proton magnetic resonance spectroscopy in ischaemic stroke. Arch Neurol 55: 489–494.

  46. 46

    Houkin K, Kamada K, Kamiyama H, Iwasaki Y, Abe H, Kashiwaba T 1993 Longitudinal changes in proton magnetic resonance spectroscopy in cerebral infarction. Stroke 24: 1316–1321.

  47. 47

    Lanfermann H, Kugel H, Heindel W, Herholz K, Heiss W, Lackner K 1995 Metabolic changes in acute and subacute cerebral infarctions: findings at proton MR spectroscopic imaging. Radiology 196: 203–210.

  48. 48

    Hugg JW, Duijn JH, Matson GB, Maudsley AA, Tsuruda JS, Gelinas DF, Weiner MW 1992 Elevated lactate and alkalosis in chronic human brain infarction observed by 1H and 31P MR spectroscopic imaging. J Cereb Blood Flow Metab 12: 734–744.

  49. 49

    Graham GD, Kalvach P, Blamire AM, Brass LM, Fayad PB, Pritchard JW 1995 Clinical correlates of proton magnetic resonance spectroscopy findings after acute cerebral infarction. Stroke 26: 225–229.

  50. 50

    Levine SR, Welsh KMA, Helpern JA, Chopp M, Bruce R, Selwa J, Smith MB 1988 Prolonged deterioration of ischaemic brain energy metabolism and acidosis associated with hyperglycaemia:human cerebral infarction studied by serial 31P NMR spectroscopy. Ann Neurol 23: 416–418.

  51. 51

    Chopp M, Chen H, Vande Linde AMQ, Brown E, Welch KMA 1990 Time course of postischaemic intracellular alkalosis reflects the duration of ischaemia. J Cereb Blood Flow Metab 10: 860–865.

  52. 52

    Chopp M, Vande Linde AM, Chen H, Knight R, Helpern JA, Welch KM 1990 Chronic cerebral intracellular alkalosis following forebrain ischemic insult in rats. Stroke 21: 463–4660.

  53. 53

    Nakada T, Hankin K, Hida K, Kwee IL 1991 Rebound alkalosis and persistent lactate: multinuclear (1H, 13C, 31P) NMR spectroscopic studies in rats. Magn Reson Med 18: 9–14.

  54. 54

    Levine SR, Helpern JA, Welsh KMA, Vande Linde AMQ, Sawaya KL, Brown EE, Ramadan NM, Deveshwar RK, Ordridge RJ 1992 Human focal cerebral ischaemia: Evaluation of brain pH and energy metabolism with 31P NMR spectroscopy. Radiology 185: 537–544.

  55. 55

    Syrota A, Castaing M, Rougemont D, Berridge M, Baron JC, Bousser MG, Pocidalo JJ 1983 Tissue acid-base balance and oxygen metabolism in human cerebral infarction studied by positron emission topography. Ann Neurol 14: 419–428.

  56. 56

    Hakim AM, Pokrupa RP, Villanueva J, Diksic M, Evans AC, Thompson CJ, Meyer E, Yamamoto YC, Feindel WH 1987 The effect of spontaneous reperfusion on metabolic function in early human cerebral infarcts. Ann Neurol 21: 279–289.

  57. 57

    Senda M, Alpert NM, Mackay BC, Buxton RB, Correlia JA, Weise SB, Ackerman RH, Doer D, Buonanno FS 1989 Evaluation of the 11CO2 positron emission tomographic method for measuring brain pH. II: Quantitative pH mapping in patients with ischaemic cerebrovascular disease. J Cereb Blood Flow Metab 9: 859–873.

  58. 58

    Fox PT, Raichle ME, Mintum MA, Dence C 1988 Nonoxidative glucose consumption during focal physiologic neural activity. Science 241: 462–464.

  59. 59

    Zimmer R, Lang R 1975 Rates of lactic acid permeation and utilization in the isolated dog brain. Am J Physiol 229: 432–437.

  60. 60

    Olendorf WH 1971 Blood brain permeability to lactate. Eur Neurol 6: 49–55.

  61. 61

    Rothman DL, Howsman AM, Graham GD, Petroff O, Lantos G, Fayad PB, Brass LM, Shulman GI, Shulman RG, Pritchard JW 1991 Localised proton NMR observation of [3:13C] lactate in stroke after [1-13C] glucose infusion. Magn Reson Med 21: 302–307.

  62. 62

    Frewen TC, Kissoon N, Kronick J, Fox M, Lee R, Bradwin N, Chance G 1991 Cerebral blood flow, cross-brain oxygen extraction and fontanelle pressure after hypoxic-ischaemic injury in newborn infants. J Pediatr 118: 265–271.

  63. 63

    Friis-Hansen B 1985 Perinatal brain injury and cerebral blood flow in newborn infants. Acta Pediatr Scand 74: 323–331.

  64. 64

    Pryds O, Greisen G, Lou H 1990 Vasoparalysis is associated with brain damage in asphyxiated term infants. J Pediatr 117: 119–125.

  65. 65

    Griesen G 1997 Cerebral blood flow and energy metabolism in the newborn. Clin Perinatal 24( 3): 531–546.

  66. 66

    Blennow M, Ingvar M, Lagercrantz H, Stone Elander S, Eriksson L, Forssberg H, Ericson K, Flodmark O 1995 Early [18F]FDG positron emission tomography in infants with hypoxic-ischaemic encephalopathy shows hypermetabolism during the postasphyctic period. Acta Paediatr 84: 1289–1295.

  67. 67

    Volpe J, Herscovitch P, Perlman JM, Kreusser KL, Raichle ME 1985 Positron emission tomography in the asphyxiated term newborn: parasagittal impairment in cerebral blood flow. Ann Neurol 17: 287–296.

  68. 68

    Suhonen Polvi H, Kero P, Korvenranta H, Ruotsalainen U, Haaparanta M, Bergman J, Simell O, Wegelius U 1993 Repeated fluorodeoxyglucose positron emission tomography of the brain in infants with suspected hypoxic-ischaemic brain injury. Eur J Nucl Med 20: 759–765.

  69. 69

    Syrota A, Samson Y, Boullais C, Wajnberg C, Loc'h C, Crouzel C, Maziere B, Soussaline F, Baron JC 1985 Tomographic mapping of brain intracellular pH and extracellular water space in stroke patients. J Cereb Blood Flow Metab 5: 358–368.

  70. 70

    Veech RL 1991 The metabolism of lactate. NMR Biomed 4: 53–58.

  71. 71

    Grodd W, Krageloh-Mann I, Klose U, Sauter R 1991 Metabolic and destructive brain disorders in children: findings with localised proton MR spectroscopy. Radiology 181: 173–181.

  72. 72

    Krageloh-Mann I, Grodd W, Schoning M, Maquard K, Nagele T, Ruitenbeek W 1993 Proton spectroscopy in five patients with Leigh's disease and mitochondrial enzyme deficiency. Dev Med Child Neurol 35: 769–776.

  73. 73

    Tracey I, Dunn JF, Radda GK 1997 A 31P magnetic resonance spectroscopy and biochemical study of the mo (vbr) mouse: potential model for the mitochondrial encephalomyopathies. Muscle-Nerve 20: 1352–1359.

  74. 74

    Nelson C Silverstein FS 1994 Acute disruption of cytochrome oxidase activity in brain in a perinatal rat stroke model. Pediatr Res 36: 12–19.

  75. 75

    Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS 1997 Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 77: 535–541.

  76. 76

    Zhang J, Dawson VL, Dawson TM, Snyder SH 1994 Nitric oxide activation of poly (ADP-ribose) synthetase in neurotoxicity. Science 263: 687–689.

  77. 77

    Lindahl T, Satoh MS, Poirier GG, Klungland A 1998 Post-translational modification of poly (ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci 20: 405–411.

  78. 78

    De Murcia G, Menissier de Murcia J 1994 Poly (ADP-ribose) polymerase: a molecular nick-sensor [published erratum appears in Trends Biochem Sci 1994 Jun 19(6):250]. Trends Biochem Sci 19: 172–176.

  79. 79

    Eliasson MJL, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang Z-Q, Dawson TM, Snyder S, Dawson VL 1997 Poly (ADP) ribose polymerase gene disruption renders mice resistant to cerebral ischaemia. Nature Med 3: 1089–1095.

  80. 80

    Takahashi K, Greenberg JH, Jackson P, Maclin K, Zhang J 1997 Neuroprotective effects of inhibiting poly (ADP-ribose) synthetase on focal cerebral ischemia in rats. J Cereb Blood Flow Metab 17: 1137–1142.

  81. 81

    Endres M, Wang Z-Q, Namura S, Waeber C, Moskowitz MA 1997 Ischemic brain injury is mediated by the activation of poly (ADP-ribose) polymerase. J Cereb Blood Flow Metab 17: 1143–1151.

  82. 82

    Ui M 1966 A role of phosphofructokinase in pH-dependent regulation of glycolysis. Biochim Biophys Acta 124: 310–322.

  83. 83

    Kemp R G Foe LG 1983 Allosteric regulatory properties of muscle phosphofructokinase. Mol Cell Biochem 57: 147–154.

  84. 84

    Petroff OAC, Pritchard JW, Behar KL, Rothman DL, Alger JR, Shulman RG 1985 Cerebral metabolism in hyper-and hypocarbia: 31P and 1H nuclear magnetic resonance studies. Neurology 35: 1681–1688.

  85. 85

    van Rijen PC, Luyten PR, Berkelbach van der Sprenkel JW 1989 1H and 31P NMR measurement of cerebral lactate, high energy phosphate levels, and pH during voluntary hyperventilation: associated EEG, capnographic and doppler findings. Magn Res Med 10: 182–193.

  86. 86

    Gotoh F, Meyer JS, Takagi Y 1965 Cerebral effects of hyperventilation in man. Arch Neurol 12: 410–423.

  87. 87

    Karonvsky ML 1962 Metabolic basis of phagocytic activity. Physiol Rev 42: 143–168.

  88. 88

    Garcia JH, Kamijyo Y 1974 Cerebral infarction:evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J Neuropathol Exp Neurol 33: 408–421.

  89. 89

    Petroff OA, Graham GD, Blamire AM, al-Rayess M, Rothman DL, Fayad PB, Brass LM, Shulman RG, Prichard JW 1992 Spectroscopic imaging of stroke in humans: histopathology correlates of spectral changes. Neurology 42: 1349–1355.

  90. 90

    Schuldiner S, Rozengurt E 1982 Na+/H+ antiport and Swiss 3T3 cells. Mitogenic stimulation leads to cytoplasmic alkalinization. Proc Natl Acad Sci USA 79: 7778–7782.

  91. 91

    Hubesch B, Sappey-Marinier D, Roth K, Meyerhoff DJ, Matson GB, Weiner MW 1990 P-31 MR spectroscopy of normal human brain and brain tumours. Radiology 174: 401–409.

  92. 92

    Sardet C, Counillon L, Franchi A, Pouyssegur J 1990 Growth factors induce phosphorylation of the Na+/H+ antiporter, a glycoprotein of 110kD. Science 247: 723–726.

  93. 93

    Schurr A, Payne RS, Miller JJ, Rigor BM 1997 Brain lactate, not glucose fuels the recovery of synaptic function from hypoxia upon reoxygenation: an in vitro study. Brain Res 744: 105–111.

  94. 94

    McIlwain H 1953 Glucose level, metabolism and response to electrical impulses in cerebral tissues from man and laboratory animals. J Biochem 55: 618–624.

  95. 95

    McIlwain H 1953 Substances which support respiration and metabolic response to electrical impulses in human cerebral tissues. J Neurol Neurosurg Psychiatry 16: 257–266.

  96. 96

    Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW 1992 Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab 12: 584–592.

  97. 97

    Fellows LK, Boutelle MG, Fillenze M 1993 Physiological stimulation increases nonoxidative glucose metabolism in the brain of the freely moving rat. J Neurochem 60: 1258–1263.

  98. 98

    Fox PT, Raichle ME, Mintun MA, Dence C 1988 Non-oxidative glucose consumption during focal physiologic neural activity. Science 241: 462–464.

  99. 99

    Lear JL 1990 Glycolysis:link between PET and proton MR spectroscopic studies of the brain. Radiology 174: 328–330.

  100. 100

    Prichard J, Rothman D, Novotny E, Petroff O, Kuwabara T, Avison M, Howseman A, Hanstock C, Schulman R 1991 Lactate rise detected by 1H NMR in the human visual cortex during physiologic stimulation. Proc Natl Acad Sci USA 88: 5829–5831.

  101. 101

    Raichle ME 1991 The metabolic requirements of functional activity in the human brain: a positron emission tomographic study. Adv Exp Med Biol 291: 1–4.

  102. 102

    Schurr A, Payne RS, Miller JJ, Rigor BM 1997 Brain lactate is an obligatory aerobic energy substrate for functional recovery after hypoxia: further in vitro validation. J Neurochem 62: 423–426.

  103. 103

    Pellerin L, Magistretti PJ 1996 Excitatory amino acids stimulate aerobic glycolysis in astrocytes via activation of the Na+/K+ ATPase. Dev Neurosci 18: 336–342.

  104. 104

    Groenendaal F, Veenhoven RH, van der Grond J, Jansen GH, Witkamp TD, de Vries LS 1994 Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy. Pediatr Res 35: 148–151.

  105. 105

    Peden CJ, Rutherford MA, Sargentoni J, Cox IJ, Bryant DJ, Dubowitz LM 1993 Proton spectroscopy of the neonatal brain following hypoxic-ischaemic injury. Dev Med Child Neurol 35: 502–510.

  106. 106

    Penrice J, Cady E, Lorek A, Wylezinska M, Amess P, Aldridge R, Stewart A, Wyatt JS, Reynolds EOR 1996 Proton magnetic resonance spectroscopy of the brain in normal preterm and term infants, and early changes after perinatal hypoxia-ischaemia. Pediatr Res 40: 6–14.

  107. 107

    Urenjak J, Williams SR, Gadian DG, Noble M 1992 Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type 2 astrocyte progenitors and immature oligodendrocytes in vitro. J Neurochem 59: 55–61.

  108. 108

    Kato T, Nishina M, Matsushita K, Hori E, Mito T, Takashima S 1997 Neuronal maturation and N-acetyl-L-aspartic acid development in human fetal and child brains. Brain Dev 19: 131–133.

  109. 109

    Patel TB, Clark JB 1979 Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/cytosolic carbon transport. Biochem J 184: 539–546.

  110. 110

    Williams SR, Gadian DG, Bell JD, Small RK, Iles RA 1989 1H NMR study of cerebral development in the rat. NMR Biomed 2: 225–229.

  111. 111

    Gideon P, Henriksen O, Sperling B, Christiansen P, Olsen TS, Jorgensen HS, Arlien-Soborg P 1992 Early time course of N-acetylaspartate, creatine and phosphocreatine, and compounds containing choline in the brain after acute stroke. Stroke 23: 1566–1572.

Download references


The authors thank Dr. Daniella Ricci and Dr. Christine Salmaso for help in obtaining data on neurodevelopmental assessment, and Dr. Caroline Dore for statistical advice.

Author information

Correspondence to A David Edwards.

Additional information

Supported by Picker International, the British Heart Foundation (grant number PG/95149), the Weston Foundation, and the Medical Research Council (grant number 9202316).

Rights and permissions

Reprints and Permissions

About this article

Further reading