Charles C. Martin

Cingulate function in depression: A potential predictor of treatment response

THE relationship between pretreatment regional cerebral glucose metabolism and eventual antidepressant drug response was measured using positron emission tomography (PET) in hospitalized patients with unipolar depression. Rostral anterior cingulate metabolism uniquely differentiated eventual treatment responders from non-responders. Hypometabolism characterized non-responders when compared with controls, in contrast to responders who were hypermetabolic. Metabolism in no other region discriminated the two groups, nor did associated demographic, clinical or behavioral measures, including motor speed, cognitive performance, depression severity or illness chronicity. Cingulate hypermetabolism may represent an important adaptive response to depression and failure of this response may underlie poor outcome. A critical role for rostral cingulate area 24a/b in the limbic-cortical network involved in abnormal mood states is proposed.

Imaging human intra-cerebral connectivity by PET during TMS

NON-INVASIVE imaging of human inter-regional neural connectivity by positron emission tomography (PET) during transcranial magnetic stimulation (TMS) was performed. The hand area of primary motor cortex (M1) in the left cerebral hemisphere was stimulated with TMS while local and remote effects were recorded with PET. At the stimulated site, TMS increased blood flow (12–20%) in a highly focal manner, without an inhibitory surround. Remote covariances, an index of connectivity with M1, were also focal. Connectivity patterns established in non-human species were generally confirmed. Excitatory connectivity (positive covariance) was observed in ipsilateral primary and secondary somatosensory areas (S1 and S2), in ipsilateral ventral, lateral premotor cortex (M2) and in contralateral supplementary motor area (SMA). Inhibitory connectivity (negative covariance) was observed in contralateral M1.

Retinotopic organization of early visual spatial attention effects as revealed by PET and ERPs

Cerebral blood flow PET scans and high‐density event‐related potentials (ERPs) were recorded (separate sessions) while subjects viewed rapidly‐presented, lower‐visual‐field, bilateral stimuli. Active attention to a designated side of the stimuli (relative to passive‐viewing conditions) resulted in an enhanced ERP positivity (P1 effect) from 80–150 msec over occipital scalp areas contralateral to the direction of attention. In PET scans, active attention vs. passive showed strong activation in the contralateral dorsal occipital cortex, thus following the retinotopic organization of the early extrastriate visual sensory areas, with some weaker activation in the contralateral fusiform. Dipole modeling seeded by the dorsal occipital PET foci yielded an excellent fit for the P1 attention effect. In contrast, dipoles constrained to the fusiform foci fit the P1 effect poorly, and, when the location constraints were released, moved upward to the dorsal occipital locations during iterative dipole fitting. These results argue that the early ERP P1 attention effects for lower‐visual‐field stimuli arise mainly from these dorsal occipital areas and thus also follow the retinotopic organization of the visual sensory input pathways. These combined PET/ERP data therefore provide strong evidence that sustained visual spatial attention results in a preset, top‐down biasing of the early sensory input channels in a retinotopically organized way. Hum. Brain Mapping 5:280–286, 1997.

Quantitative PET with positron emitters that emit prompt gamma rays

The purpose of this work was to determine the feasibility of using positron emitting isotopes that emit prompt gammas to acquire quantitative positron emission tomography (PET) data using standard PET instrumentation. Prompt gammas can contaminate PET data by increasing dead time, converting singles into invalid coincidences, and producing multiple coincidences which can lead to the replacement of valid coincidences by invalid coincidences. The measurements in this work were made by scanning point sources containing F-18, Na-22, and Co-60 and studying the effects of the prompt gammas on the PET data, We found that for the Na-22 point source, the annihilation photon coincidence rate was about 25 times the prompt gamma-annihilation photon coincidence rate in the entire active volume of the scanner. With scatter, the Na-22 prompt gamma-annihilation photon coincidence rate was 1.3 times higher than the F-18 scatter coincidence rate. The most significant effect of the prompt gamma was to increase dead time; the dead time correction factor for Cu-60 was 2.4 times higher than the correction factor for N-13 for the same source activity. We conclude that, in many cases, quantitative PET data can be readily obtained with isotopes that emit prompt gammas, using standard PET 2-D instrumentation. However there are some cases, such as 3-D PET, where prompt gammas could significantly contaminate the PET data.

A tool for comparison of PET and fMRI methods: Calculation of the uncertainty in the location of an activation site in a PET image

A technique for calculating the uncertainty in the location of an activation site in a PET image, without performing repeated measures, is presented. With the development of new fMRI methods for measuring cerebral hemodynamics, demonstration of the efficacy of these techniques will be critical to establish clinical utility. Comparisons with PET are a powerful tool for validating these new fMRI techniques. In addition to the fact that PET techniques are well-established methods for making physiological measurements in vivo, PET methods are also free of the geometric distortions and nonuniform signal-to-noise artifacts (due to signal dropout) common in fMRI techniques. Comparisons reported previously have been limited by the large number of trials acquired in single-subject fMRI studies and the small number of trials in a PET study (due to the radiation dose to the patient or the interscan delays for tracer decay). Our method calculates both the center of mass (CM) of a predefined region of interest and the uncertainty in the location of the CM using the preimage PET data (sinograms). Results of phantom studies demonstrate that our method is an unbiased measurement equivalent to that of repeated measures with a large number of images. Extension of this technique to estimate the uncertainty in the location of an activation site in a PET statistical parametric map will permit precise rigorous comparisons of PET and fMRI methods in single subjects without the constraints imposed by the relatively small number of PET measurements.

Synthesis of the fluorine-18 labeled inhalation anesthetics

Fourteen compounds (fluoroalkanes and fluoroethers), including the two most utilized inhalation anesthetics Isoflurane (CF3CHClOCF2H) and Halothane (CF3CHBrCl), have been labeled with fluorine-18 via a facile 18F-for-19F exchange reaction. The compounds include ten inhalation anesthetics which span a ten-fold range in potency and four structurally related non-anesthetics. All the compounds possess a trifluoromethyl group (CF3) adjoining a carbon atom with an acidic alpha-hydrogen and at least one halogen or a strong electron withdrawing group (X), [CF3CHXR]. We postulate the isotopic fluoride exchange reaction proceeds through a carbanion transition state resulting from alpha-proton transfer to base. The carbanion stability is attributed to the inductive effect of the CF3 group and the electron withdrawing capability of X. Compounds labeled in dimethyl sulfoxide (DMSO) at 125 degrees C in 15 min include Isoflurane-CF3CHClOCF2H (1) (97% [18F]fluorine incorporation, 99% radiochemical purity, respectively), Sevoflurane-CF3CHCF3OCFH2 (2) [98%, 99%], CF3CHBrOCF2H (3) [85%, 80%], Desflurane-CF3CHFOCF2H (4) [50%, 99%], Fluroxene-CF3CH2OCH = CH2 (5) [25%, 99%], Fluothyl-CF3CH2OCH2CF3 (6) [60%, 10% at a temperature of 175 degrees C], Halothane-CF3CHBrCl (7) [98%, 95%], CF3CH2I (8) [99%, 98%], CF3CH2Br (9) [18%, 98%], CF3CHCl2 (10) [95%, 98%], CF3CH2Cl (11) [90%, 20%], CF3CHClCF3 (12) [95%, 99%], (CF3)3CH (13) [99%, 99%] and HF-134a-CF3CFH2 (14) (15%, 93% at a temperature of 175 degrees C).

Effect of partition coefficient, permeability surface product, and radioisotope on the signal-to-noise ratio in PET functional brain mapping: A computer simulation

In this work we use a computer simulation to estimate the magnitude of improvement in the signal‐to‐noise ratio of PET functional brain mapping studies as a function of partition coefficient and permeability surface product for O‐14, F‐17, and O‐15 labeled flow tracers. A model for signal‐to‐noise ratio is derived from the Kety model for inert diffusible blood flow tracers. The results of the simulation suggest that moderate increases in partition coefficient and permeability surface product compared with water would lead to an increase in signal‐to‐noise ratio of a factor of about 3. Hum. Brain Mapping 7:151‐160, 1999.

A method for comparison of spatial distributions of activations measured using two different techniques and application to comparisons with PET

Objectives In many of the previous comparisons of PET and fMR1 brain maps, investigators reported, for activations appearing in both the PET and fMRI brain maps, that the activations were very similar in appearance (1-2). In addition, many investigators routinely compare the activation maps from different fMRI techniques to investigate new imaging strategies. It is the purpose of this work to report a general method to compare, within subject and in a statistically rigorous manner, the spatial distributions of brain activations measured using two different imaging techniques. In addition, we address additional statistical issues involved in performing comparisons with PET.