Subgenual cingulate cortical activity predicts the efficacy of electroconvulsive therapy.

Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its mechanism of action is unknown. Our goal was to investigate the neurobiological underpinnings of ECT response using longitudinally collected resting-state functional magnetic resonance imaging (rs-fMRI) in 16 patients with treatment-resistant depression and 10 healthy controls. Patients received bifrontal ECT 3 times a week under general anesthesia. We acquired rs-fMRI at three time points: at baseline, after the 1st ECT administration and after the course of the ECT treatment; depression was assessed with the Hamilton Depression Rating Scale (HAM-D). The primary measure derived from rs-fMRI was fractional amplitude of low frequency fluctuation (fALFF), which provides an unbiased voxel-wise estimation of brain activity. We also conducted seed-based functional connectivity analysis based on our primary findings. We compared treatment-related changes in HAM-D scores with pre- and post-treatment fALFF and connectivity measures. Subcallosal cingulate cortex (SCC) demonstrated higher BOLD signal fluctuations (fALFF) at baseline in depressed patients, and SCC fALFF decreased over the course of treatment. The baseline level of fALFF of SCC predicted response to ECT. In addition, connectivity of SCC with bilateral hippocampus, bilateral temporal pole, and ventromedial prefrontal cortex was significantly reduced over the course of treatment. These results suggest that the antidepressant effect of ECT may be mediated by downregulation of SCC activity and connectivity. SCC function may serve as an important biomarker of target engagement in the development of novel therapies for depression that is resistant to treatment with standard medications.

Cerebral white matter disruption in Creutzfeldt-Jakob disease.

BACKGROUND AND PURPOSE: Human prion diseases are known to cause gray matter degeneration in specific cerebral structures, but evidence for white matter involvement is scarce. We used DTI to test the hypothesis that white matter integrity is disrupted in human CJD during the early stages of the disease. MATERIALS AND METHODS: Twenty-one patients with the E200K variant of CJD and 19 controls participated in DTI studies conducted on a 1.5T MR imaging scanner. The data were quantitatively analyzed and mapped with a voxelwise TBSS method. RESULTS: We found significant reductions of FA in patients with CJD in distinct and functionally relevant white matter pathways, including the corticospinal tract, internal capsule, external capsule, fornix, and posterior thalamic radiation. Moreover, these FA deficits increased with disease duration, and were mainly determined by increase of radial diffusivity, suggesting elevated permeability of axonal membranes. CONCLUSIONS: The findings suggest that some of the symptoms of CJD may be caused by a functional dysconnection syndrome, and that the leukoencephalopathy is progressive and detectable fairly early in the course of the disease.

Enhanced detection of diffusion reductions in Creutzfeldt-Jakob disease at a higher B factor.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) is sensitive to the cerebral manifestations of human prion diseases. The magnitude of diffusion weighting, termed "b factor," has only been evaluated at the standard b = 1000 s/mm(2). This is the first rigorous evaluation of b = 2000 s/mm(2) in Creutzfeldt-Jakob Disease (CJD). MATERIALS AND METHODS: We compared DWI characteristics of 13 patients with CJD and 15 healthy controls at b = 1000 s/mm(2) and b = 2000 s/mm(2). Apparent diffusion coefficients (ADC) were computed and analyzed for the whole brain by voxel-wise analysis (by SPM5) as well as in anatomically defined volumes of interest (by FSL FIRST). RESULTS: Measured ADC was significantly lower (by approximately 5%-15%) at b = 2000 s/mm(2) than at b = 1000 s/mm(2) and significantly lower in patients than in controls. The differences between patients and controls were greater and more extensive at b = 2000 s/mm(2) than at b = 1000 s/mm(2) in the expected regions (thalamus, putamen, and caudate nucleus). CONCLUSIONS: Because higher b factors change the absolute value of observed ADC, as well as lesion detection, care should be taken when combining studies using different b factors. While the clinical application of high b factors is currently limited by a low signal intensity-to-noise ratio, it may offer more information in questionable cases, and our results confirm and extend the central role of diffusion imaging in human prion diseases.

Effect of increased repetition time TR on precision of inversion-recovery T(1) measurements.

The effect of increased repetition time, TR, on the precision of inversion-recovery measurements of the spin-lattice relaxation time, T(1), was calculated theoretically, simulated numerically, and measured experimentally. All three methods yielded similar results. With constant inversion times, the T(1) precision was independent of TR. Therefore, 1) multiple-slice inversion-recovery fast-spin-echo T(1) maps should be made one slice at a time, not with interleaved acquisition, and 2) once the longest inversion time t(i) has been set, TR should be set just enough longer than the longest t(i) to allow data acquisition.

Correcting for incomplete saturation and off-resonance effects in multiple-site saturation-transfer kinetic measurements.

The effects of incomplete saturation and off-resonance irradiation on nuclear magnetic resonance saturation-transfer measurements of three-site chemical-exchange rates are discussed. A new method that uses double-saturation measurements is compared with two published methods, one that uses single-saturation measurements and one that uses a single-saturation measurement and a double-saturation measurement. Several formulas are compared for measuring the exchange rate constant k(DE) for exchange from a detected spin D to an exchanging spin E in the presence of exchange from spin D to a competing spin C. For each method, formulas are derived with corrections for incomplete saturation or off-resonance effects, with both corrections, and with neither correction. Exact formulas are available for three exchanging sites with incomplete saturation if there are no off-resonance effects. Off-resonance corrections are imperfect even with complete saturation.

Stroke in children: genetic and metabolic issues.

The study of genetic and metabolic etiologies of pediatric stroke, both vascular and metabolic, allows an understanding of the causes of acute focal neurologic deficits in childhood. Here, the mendelian and mitochondrial genetic causes of pediatric stroke syndromes are reviewed. This approach elucidates the etiology of childhood stroke and illustrates many of the genetic risk factors that are found in adult-onset cerebrovascular disease. Therefore, the study of childhood stroke serves as a model to elucidate the potential risk factors for all stroke. Ultimately this will serve to develop a more rational preventive and therapeutic approach for all cerebrovascular disease.

Corrections for off-resonance effects and incomplete saturation in conventional (two-site) saturation-transfer kinetic measurements.

The effects of off-resonance irradiation and incomplete saturation on saturation-transfer measurements of chemical-exchange rates are discussed. With off-resonance effects there is no exact formula for the exchange rate constant from spin D to spin E, k(DE), in terms of observable signal intensities and relaxation rates. However, k(DE) can be estimated by measuring the effective spin-lattice relaxation rate constant of spin D when spin E is saturated, *R(1), plus signal intensities with no RF irradiation, M(0D) and M(0E); with irradiation of a control position, M'(D) and M'(E); and with saturation of spin E, *M(D) and *M(E). Several formulas are compared and the best formula for calculating k(DE) appears to be either k(DE) = *R(1) [(M'(D)- *M(D))/M(0D)]/[(M'(E) - *M(E))/M(0E)], or the same formula with M(0D) and M(0E) replaced by M'(D) and M'(E). These formulas are exact with incomplete saturation and no off-resonance effects, and are better than previously published formulas when off-resonance effects are present. More accurate formulas are available if signal intensities and relaxation rates can be measured while the exchange process is stopped. Magn Reson Med 43:810-819, 2000.

Correlation of basal ganglia magnetic resonance spectroscopy with Apgar score in perinatal asphyxia.

BACKGROUND: Brain metabolite levels are measured by proton magnetic resonance spectroscopy (1H MRS) and include N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate and the ratios NAA to Cho and Cr (NAA-ChoCr), NAA-Cr, NAA-Cho, and Cho-Cr. Brain metabolite levels may correlate with the degree of neonatal asphyxia. OBJECTIVE: To determine which brain metabolite ratios have the strongest correlation with the Apgar scores in infants with possible asphyxia; whether the correlation is stronger with basal ganglia (BG) or anterior border-zone metabolites; and whether a combined approach using routine MR imaging (MRI), diffusion-weighted MRI, and MRS can be used to evaluate the severity of neonatal asphyxia. METHODS: Twenty infants with 1-minute Apgar scores of 6 or less were studied at 2 to 28 days of age. The MRS variables were compared with routine and diffusion-weighted brain MRI. Clinical variables and MRS findings were subjected to factor analysis and stepwise multiple regressions to determine interrelationships. RESULTS: The BG region NAA-Cho and NAA-ChoCr ratios correlated with the 1-minute (P<.001) and 5-minute (P = .01 for NAA-Cho; P = .006 for NAA-ChoCr). There was no correlation between metabolite levels and the 10-minute Apgar scores. The stongest predictions exist between the 1-minute Apgar scores and the NAA-Cho and NAA-ChoCr ratios. In the anterior border zone, the only correlation was between the 1-minute Apgar score and the NAA-Cho ratio, but there was a strong age effect in these data. Lactate was found in the BG of 3 infants, all of whom had 5-minute Apgar scores of 6 or less. Three patients had focal lesions on MRI; 2 of these had elevated lactate levels in the abnormal region; and the third, who had an intrauterine stroke, had no lactate in the region. CONCLUSIONS: Correlations between NAA-Cho and NAA-ChoCr ratios and the 1- and 5-minute Apgar scores are stronger in the BG region than in the frontal border zone. The presence or absence of lactate may indicate the severity of the brain insult, and the combination of MRS, MRI, and diffusion-weighted MRI may assist in localizing and predicting a long-term brain injury.

Correction of errors caused by imperfect inversion pulses in MR imaging measurement of T1 relaxation times.

Spin-lattice (T1) relaxation times were measured by an inversion-recovery magnetic resonance imaging method with a slice-selective inversion pulse (SIP), a non-selective rectangular inversion pulse (RIP), or a B1-insensitive adiabatic inversion pulse (AIP). Data analysis either assumed perfect inversion (two-parameter fit) or allowed for imperfect inversion (three-parameter fit). Imperfect inversion pulses caused low T1 values in phantoms with a two-parameter fit, while three-parameter T1 estimates were accurate over the range 430-2670 ms. A difference of approximately 10% between two-parameter and three-parameter T1 values in normal human brain tissue was attributed to B1 inhomogeneity with the slice-selective inversion pulse and rectangular inversion pulse, to the slice profile with the slice-selective inversion pulse, and to T2 effects for the adiabatic inversion pulse. Any T1 method that relies on accurate flip angles may have a significant systematic error in vivo. Phantom accuracy does not ensure accuracy in vivo, because phantoms may have a more homogeneous B1 field and a longer T2 than do biological samples.

Magnetic resonance spectroscopy: use in monitoring MELAS treatment.

BACKGROUND: Sodium dichloroacetate has been used to treat patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Magnetic resonance spectroscopy (MRS) has been used to assess cerebral metabolism in MELAS, but to our knowledge, the findings of serial MRS studies performed after therapeutic intervention of strokelike episodes have not been reported. METHODS: Proton MRS was serially used to measure brain metabolites in strokelike regions and in clinically uninvolved brain regions in a patient with MELAS. PATIENT: A patient with MELAS and a strokelike episode clinically improved after treatment with sodium dichloroacetate. An elevated lactate-creatine ratio in the "stroke" region decreased on MRS studies after treatment. After a second episode, the lactate-creatine ratio increased from baseline in a region of the brain that was normal on magnetic resonance imaging scans. CONCLUSIONS: To our knowledge, this is the first study to assess the response to treatment of a MELAS strokelike episode and the first to show an increase in the lactate-creatine ratio in a brain region that was associated with a clinical abnormality, even though it appeared normal on magnetic resonance imaging. We conclude that MRS may help to monitor therapeutic efficacy in mitochondrial encephalomyopathies.

Quantitative MRI of the brain in children with sickle cell disease reveals abnormalities unseen by conventional MRI.

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.

Age-related changes in the pediatric brain: quantitative MR evidence of maturational changes during adolescence.

PURPOSE: To determine whether a quantitative MR imaging method to map spin-lattice relaxation time (T1) can be used to characterize maturational changes in the normal human brain. METHODS: An inversion-recovery technique was used to map T1 transversely at the level of the basal ganglia in a study population of 19 healthy children (4 to 10 years old) and 31 healthy adolescents (10 to 20 years old), and in a normative population of 20 healthy adults (20 to 30 years old). RESULTS: Nonparametric analysis of variance showed that T1 decreases with age in the genu, frontal white matter, caudate, putamen, anterior thalamus, pulvinar nucleus, optic radiation, cortical gray matter (all P < .0001), and occipital white matter. There was a significant reduction in T1 between childhood (mean age, 7.1 +/- 1.4) and adolescence (mean age, 13.5 +/- 2.6) in all brain structures, but there was also a significant reduction in T1 between adolescence (mean age, 13.5 +/- 2.6) and adulthood (mean age, 26.5 +/- 3.4) in all brain structures except occipital white matter. Regression shows that T1 declines to within the range (mean +/- 2 SD) of young adult T1 values by about 2 years in the occipital white matter, by about 4 years in the genu, by 11 years in the cortical gray matter, by 11 years in the frontal white matter, and by 13 years in the thalamus. CONCLUSION: Brain structures mature at strikingly different rates, yet the ratio of gray matter T1 to white matter T1 does not change significantly with age. Thus, conventional MR imaging methods based on inherent contrast are insensitive to these changes. Age-related changes tend to reach completion sooner in white matter than in gray matter tracts. Such normative data are essential for studies of specific pediatric disorders and may be useful for assessing brain maturation in cases of developmental delay.

Clinical value of proton magnetic resonance spectroscopy for differentiating recurrent or residual brain tumor from delayed cerebral necrosis.

PURPOSE: Delayed cerebral necrosis (DN) is a significant risk for brain tumor patients treated with high-dose irradiation. Although differentiating DN from tumor progression is an important clinical question, the distinction cannot be made reliably by conventional imaging techniques. We undertook a pilot study to assess the ability of proton magnetic resonance spectroscopy (1H MRS) to differentiate prospectively between DN or recurrent/residual tumor in a series of children treated for primary brain tumors with high-dose irradiation. METHODS AND MATERIALS: Twelve children (ages 3-16 years), who had clinical and MR imaging (MRI) changes that suggested a diagnosis of either DN or progressive/recurrent brain tumor, underwent localized 1H MRS prior to planned biopsy, resection, or other confirmatory histological procedure. Prospective 1H MRS interpretations were based on comparison of spectral peak patterns and quantitative peak area values from normalized spectra: a marked depression of the intracellular metabolite peaks from choline, creatine, and N-acetyl compounds was hypothesized to indicate DN, and median-to-high choline with easily visible creatine metabolite peaks was labeled progressive/recurrent tumor. Subsequent histological studies identified the brain lesion as DN or recurrent/residual tumor. RESULTS: The patient series included five cases of DN and seven recurrent/residual tumor cases, based on histology. The MRS criteria prospectively identified five out of seven patients with active tumor, and four out of five patients with histologically proven DN correctly. Discriminant analysis suggested that the primary diagnostic information for differentiating DN from tumor lay in the normalized MRS peak areas for choline and creatine compounds. CONCLUSIONS: Magnetic resonance spectroscopy shows promising sensitivity and selectivity for differentiating DN from recurrent/progressive brain tumor. A novel diagnostic index based on peak areas for choline and creatine compounds may provide a simple discriminant for differentiating DN from recurrent or residual primary brain tumors.

Magnetic field gradients and coherence-pathway elimination.

The amount of residual transverse magnetization after the application of a pulsed magnetic-field gradient (PFG) is calculated for a homogeneous volume of interest (VOI) with three orthogonal pairs of sides and for VOIs that deviate from this idealized case. Many of the results can be understood in terms of the Fourier-transform relationship between the VOI intensity profile as a function of position, I(x), and the residual signal as a function of net PFG strength, S(k). Dephasing of transverse magnetization is more effective with imperfect slice-selection profiles, a circular sample cross section, or decreased B1 intensity near the edges of a sample than in the idealized case. When two or more orthogonal PFGs are applied, the net amount of dephasing depends on the source of intensity variation (sample geometry or slice-selective radiofrequency pulse profiles) and the orientation of the PFGs. If a gradient is parallel to one side of a VOI with rectangular cross sections, dephasing is more effective if a second, orthogonal gradient of equal intensity is added than if the original intensity is doubled. In contrast, if a PFG is orthogonal to the axis of an NMR tube with a circular cross section, addition of a second gradient orthogonal to the tube axis provides only slightly greater dephasing and is less effective than doubling the original intensity.

Precise and accurate measurement of proton T1 in human brain in vivo: validation and preliminary clinical application.

Precise and accurate inversion-recovery (PAIR) magnetic resonance (MR) measurements of T1 were obtained in eight brain regions and cerebrospinal fluid of 26 healthy volunteers. Accuracy of the technique was assessed by measuring T1 in small fluid volumes with the PAIR technique and with two independent spectroscopic techniques. The mean difference between T1 measured with PAIR and with the two spectroscopic techniques was 3.1% +/- 1.3. The precision (reproducibility) of measurements with the PAIR technique was excellent. The coefficient of variation (CV) across 16 measurements in a head phantom was 2.0%, compared with a CV of 2.7% across 45 separate measurements in a single subject. The within-subject CV was 1.8% +/- 0.6 in white matter and 1.4% +/- 1.0 in basal ganglia. The between-subject CV in 26 healthy volunteers was 3.6% +/- 0.6 in white matter and 4.1% +/- 1.9 in basal ganglia. Comparison between a patient with an active recurrent brain tumor and an age-matched patient with an inactive brain tumor showed that T1 was significantly elevated throughout the brain of the active-tumor patient, especially in white matter tracts, even though no tumor or edema was detected in the white matter on standard MR images. Comparisons between five brain tumor patients and four healthy volunteers of similar age showed that T1 was significantly and substantially elevated throughout the white matter tracts and in the caudate nucleus, putamen, and thalamus. These results are consistent with the hypothesis that white matter tracts are selectively vulnerable to edema and that T1 increases in white matter are a sensitive indicator of patient status or tumor aggressiveness.

Metabolic loss of deuterium from isotopically labeled glucose.

The isotopically substituted molecule (6-13C, 1, 6, 6-2H3)glucose was evaluated to determine whether metabolic 2H loss would prevent its use in quantitating pentose phosphate pathway (PPP) activity. PPP activity causes the C1 of glucose to be lost as CO2, while C6 can appear in lactate. 2H NMR analysis of the lactate produced from this glucose can distinguish (3-2H)-lactate (from C1 of glucose) from (3-13C, 3, 3-2H2)lactate (from C6 of glucose). 2H NMR spectroscopic analysis of medium containing (6-13C, 1, 6, 6-2H3)glucose after incubation with cultured rat 9L glioma cells suggested a 30.8 +/- 2.1% PPP activity as compared with 6.0 +/- 0.8% from separate, parallel incubations with (1-13C)glucose and (6-13C)glucose. Subsequent experiments with other isotopically labeled glucose molecules suggest that this discrepancy is due to selective loss of 2H from the C1 position of glucose, catalyzed by phosphomannose isomerase. Failure to consider 2H exchange from the C1 and C6 positions of glucose can lead to incorrect conclusions in metabolic studies utilizing this and other deuterated or tritiated glucose molecules.

Measurement of pentose phosphate-pathway activity in a single incubation with [1,6-13C2,6,6-2H2]glucose.

The isotopically substituted molecule D-[1,6-13C2,6,6-2H2]glucose is introduced for measuring the relative activities of the pentose phosphate pathway (PPP) and glycolysis in a single incubation. PPP activity in cultured cells was determined by gas chromatography/mass spectrometric analysis of lactate produced by cells incubated with [1,6-13C2,6,6-2H2]glucose. Two other isotopes, [1,5,6-13C3]glucose and [6-13C,1,6,6-2H3]glucose, were not satisfactory for measurements of this activity. This method has four advantages over the traditional one in which 14CO2 production from [1-14C]glucose and [6-14C]glucose is compared: (1) repeated measurements can be made on a single set of cells, (2) only a single incubation is required, (3) extensive CO2 production by Krebs-cycle activity does not interfere with the measurements and (4) it is not necessary to measure the amount of glucose consumed in order to calculate relative activities of the PPP and glycolysis. Preliminary observation indicates that rat brain PPP activity may be measured in vivo with [1,6-13C2,6,6-2H2]glucose when combined with microdialysis techniques.

WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy.

Suppression of the water signal during 1H magnetic resonance spectroscopy by repeated sequences of a frequency-selective radiofrequency pulse and a gradient dephasing pulse requires nulling of the longitudinal component of the water magnetization and is therefore affected by T1 relaxation, RF-pulse flip angles (which depend on B1), and sequence timing. In in vivo applications, T1 and B1 inhomogeneity within the sample may cause spatially inhomogeneous water suppression. An improved water-suppression technique called WET (water suppression enhanced through T1 effects), developed from a Bloch equation analysis of the longitudinal magnetization over the T1 and B1 ranges of interest, achieves T1- and B1-insensitive suppression with four RF pulses, each having a numerically optimized flip angle. Once flip angles have been optimized for a given sequence, time-consuming flip-angle adjustments during clinical examinations are eliminated. This water-suppression technique was characterized with respect to T1 variations, B1 variations, off-resonance effects, and partial saturation effects and was compared to similar techniques. Effective water suppression has been achieved with this new technique in single-voxel spectroscopy examinations of more than 50 brain tumor patients at 1.5 T.

Scalar coupling and zero-quantum coherence relaxation in STEAM: implications for spectral editing of lactate.

Accurate values were obtained for the lactate zero-quantum coherence frequency, omega ZQ identical to omega 1-omega s = CH3 - CH chemical shift difference, and scalar coupling constant, J, by using the methyl signal's amplitude modulation during the TM period of a STEAM sequence, 90 degrees - TE/2 - 90 degrees - TM - 90 degrees - TE/2 - Acquire. Although most previous work has used J = 7.35 Hz, or 1/J = 136 ms, the actual value is J = 6.93 +/- 0.05 Hz or 1/J = 144.3 +/- 1 ms. In addition, the CH3 - CH chemical shift difference = 2.7956 +/- 0.0005 ppm, and the relaxation time for zero-quantum coherence, TZQ, was much shorter than either T2 or T1 for the methyl resonance. A small component of the signal with TE = 144 ms, which was not modulated at the zero-quantum coherence frequency or by scalar coupling, was assigned to longitudinal two-spin order magnetization (IzSz) created by imperfect radio frequency pulse profiles. This information will allow improved editing of the lactate signal and more accurate quantitation of lactate concentrations.