Randy L. Gollub

Acute Effects of Cocaine on Human Brain Activity and Emotion

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.

Reproducibility of Quantitative Tractography Methods Applied to Cerebral White Matter

Tractography based on diffusion tensor imaging (DTI) allows visualization of white matter tracts. In this study, protocols to reconstruct eleven major white matter tracts are described. The protocols were refined by several iterations of intra- and inter-rater measurements and identification of sources of variability. Reproducibility of the established protocols was then tested by raters who did not have previous experience in tractography. The protocols were applied to a DTI database of adult normal subjects to study size, fractional anisotropy (FA), and T2 of individual white matter tracts. Distinctive features in FA and T2 were found for the corticospinal tract and callosal fibers. Hemispheric asymmetry was observed for the size of white matter tracts projecting to the temporal lobe. This protocol provides guidelines for reproducible DTI-based tract-specific quantification.

Reliability in multi-site structural MRI studies: Effects of gradient non-linearity correction on phantom and human data

Longitudinal and multi-site clinical studies create the imperative to characterize and correct technological sources of variance that limit image reproducibility in high-resolution structural MRI studies, thus facilitating precise, quantitative, platform-independent, multi-site evaluation. In this work, we investigated the effects that imaging gradient non-linearity have on reproducibility of multi-site human MRI. We applied an image distortion correction method based on spherical harmonics description of the gradients and verified the accuracy of the method using phantom data. The correction method was then applied to the brain image data from a group of subjects scanned twice at multiple sites having different 1.5 T platforms. Within-site and across-site variability of the image data was assessed by evaluating voxel-based image intensity reproducibility. The image intensity reproducibility of the human brain data was significantly improved with distortion correction, suggesting that this method may offer improved reproducibility in morphometry studies. We provide the source code for the gradient distortion algorithm together with the phantom data.

Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects.

Acupuncture, an ancient therapeutic technique, is emerging as an important modality of complementary medicine in the United States. The use and efficacy of acupuncture treatment are not yet widely accepted in Western scientific and medical communities. Demonstration of regionally specific, quantifiable acupuncture effects on relevant structures of the human brain would facilitate acceptance and integration of this therapeutic modality into the practice of modern medicine. Research with animal models of acupuncture indicates that many of the beneficial effects may be mediated at the subcortical level in the brain. We used functional magnetic resonance imaging (fMRI) to investigate the effects of acupuncture in normal subjects and to provide a foundation for future studies on mechanisms of acupuncture action in therapeutic interventions. Acupuncture needle manipulation was performed at Large Intestine 4 (LI 4, Hegu) on the hand in 13 subjects [Stux, 1997]. Needle manipulation on either hand produced prominent decreases of fMRI signals in the nucleus accumbens, amygdala, hippocampus, parahippocampus, hypothalamus, ventral tegmental area, anterior cingulate gyrus (BA 24), caudate, putamen, temporal pole, and insula in all 11 subjects who experienced acupuncture sensation. In marked contrast, signal increases were observed primarily in the somatosensory cortex. The two subjects who experienced pain instead of acupuncture sensation exhibited signal increases instead of decreases in the anterior cingulate gyrus (BA 24), caudate, putamen, anterior thalamus, and posterior insula. Superficial tactile stimulation to the same area elicited signal increases in the somatosensory cortex as expected, but no signal decreases in the deep structures. These preliminary results suggest that acupuncture needle manipulation modulates the activity of the limbic system and subcortical structures. We hypothesize that modulation of subcortical structures may be an important mechanism by which acupuncture exerts its complex multisystem effects. Hum Brain Mapp 9:13–25, 2000.

Functional brain mapping of the relaxation response and meditation.

&NA; Meditation is a conscious mental process that induces a set of integrated physiologic changes termed the relaxation response. Functional magnetic resonance imaging (fMRI) was used to identify and characterize the brain regions that are active during a simple form of meditation. Significant (p <10−7) signal increases were observed in the group‐averaged data in the dorsolateral prefrontal and parietal cortices, hippocampus/parahippocampus, temporal lobe, pregenual anterior cingulate cortex, striatum, and pre‐ and post‐central gyri during meditation. Global fMRI signal decreases were also noted, although these were probably secondary to cardiorespiratory changes that often accompany meditation. The results indicate that the practice of meditation activates neural structures involved in attention and control of the autonomic nervous system.

Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance

BACKGROUND Working memory (WM) deficits in schizophrenia have been associated with dorsolateral prefrontal cortex (DLPFC) dysfunction in neuroimaging studies. We previously found increased DLPFC activation in schizophrenic versus normal subjects during WM performance (Manoach et al 1999b). We now have investigated whether schizophrenic subjects recruit different brain regions, particularly the basal ganglia and thalamus, components of frontostriatal circuitry thought to mediate WM. METHODS We examined regional brain activation in nine normal and nine schizophrenic subjects during WM performance using functional magnetic resonance imaging. Subjects performed a modified version of the Sternberg Item Recognition Paradigm that included a monetary reward for correct responses. We compared high and low WM load conditions to each other and to a non-WM baseline condition. We examined activation in both individual subjects and averaged group data. RESULTS Relative to normal subjects, schizophrenic subjects exhibited deficient WM performance, at least an equal magnitude of right DLPFC activation, significantly greater left DLPFC activation, and increased spatial heterogeneity of DLPFC activation. Furthermore, only the schizophrenic group activated the basal ganglia and thalamus, even when matched for task performance with the normal group. CONCLUSIONS Aberrant WM performance and brain activation in schizophrenia may reflect dysfunction of frontostriatal circuitry that subserves WM. Future studies will elucidate the contribution of the anatomical components of this circuitry to WM deficits.

MRI-derived measurements of human subcortical, ventricular and intracranial brain volumes: Reliability effects of scan sessions, acquisition sequences, data analyses, scanner upgrade, scanner vendors and field strengths

Automated MRI-derived measurements of in-vivo human brain volumes provide novel insights into normal and abnormal neuroanatomy, but little is known about measurement reliability. Here we assess the impact of image acquisition variables (scan session, MRI sequence, scanner upgrade, vendor and field strengths), FreeSurfer segmentation pre-processing variables (image averaging, B1 field inhomogeneity correction) and segmentation analysis variables (probabilistic atlas) on resultant image segmentation volumes from older (n=15, mean age 69.5) and younger (both n=5, mean ages 34 and 36.5) healthy subjects. The variability between hippocampal, thalamic, caudate, putamen, lateral ventricular and total intracranial volume measures across sessions on the same scanner on different days is less than 4.3% for the older group and less than 2.3% for the younger group. Within-scanner measurements are remarkably reliable across scan sessions, being minimally affected by averaging of multiple acquisitions, B1 correction, acquisition sequence (MPRAGE vs. multi-echo-FLASH), major scanner upgrades (Sonata-Avanto, Trio-TrioTIM), and segmentation atlas (MPRAGE or multi-echo-FLASH). Volume measurements across platforms (Siemens Sonata vs. GE Signa) and field strengths (1.5 T vs. 3 T) result in a volume difference bias but with a comparable variance as that measured within-scanner, implying that multi-site studies may not necessarily require a much larger sample to detect a specific effect. These results suggest that volumes derived from automated segmentation of T1-weighted structural images are reliable measures within the same scanner platform, even after upgrades; however, combining data across platform and across field-strength introduces a bias that should be considered in the design of multi-site studies, such as clinical drug trials. The results derived from the young groups (scanner upgrade effects and B1 inhomogeneity correction effects) should be considered as preliminary and in need for further validation with a larger dataset.

Brain Activity Associated with Expectancy-Enhanced Placebo Analgesia as Measured by Functional Magnetic Resonance Imaging

In this study, a well established expectancy manipulation model was combined with a novel placebo intervention, a validated sham acupuncture needle, to investigate the brain network involved in placebo analgesia. Sixteen subjects completed the experiment. We found that after placebo acupuncture treatment, subjective pain rating reduction (pre minus post) on the placebo-treated side was significantly greater than on the control side. When we calculated the contrast that subtracts the functional magnetic resonance imaging (fMRI) signal difference between post-treatment and pretreatment during pain application on placebo side from the same difference on control side [e.g., placebo (post – pre) – control (post – pre)], significant differences were observed in the bilateral rostral anterior cingulate cortex (rACC), lateral prefrontal cortex, right anterior insula, supramarginal gyrus, and left inferior parietal lobule. The simple regression (correlation) analysis between each subjects fMRI signal difference of post-treatment and pretreatment difference on placebo and control side and the corresponding subjective pain rating difference showed that significant negative correlation was observed in the bilateral lateral/orbital prefrontal cortex, rACC, cerebellum, right fusiform, parahippocampus, and pons. These results are different from a previous study that found decreased activity in pain-sensitive regions such as the thalamus, insula, and ACC when comparing the response to noxious stimuli applied to control and placebo cream-treated areas of the skin. Our results suggest that placebo analgesia may be configured through multiple brain pathways and mechanisms.

Acupuncture De Qi, from Qualitative History to Quantitative Measurement

De qi is an important traditional acupuncture term used to describe the connection between acupuncture needles and the energy pathways of the body. The concept is discussed in the earliest Chinese medical texts, but details of de qi phenomenon, which may include the acupuncturists and/or the patients experiences, were only fully described in the recent hundred years. In this paper, we will trace de qi historically as an evolving concept, and review the literature assessing acupuncture needle sensations, and the relationship between acupuncture-induced de qi and therapeutic effect. Thereafter, we will introduce the MGH Acupuncture Sensation Scale (MASS), a rubric designed to measure sensations evoked by acupuncture stimulation as perceived by the patient alone, and discuss some alternative statistical methods for analyzing the results of this questionnaire. We believe widespread use of this scale, or others like it, and investigations of the correlations between de qi and therapeutic effect will lead to greater precision in acupuncture research and enhance our understanding of acupuncture treatment.

Working memory and DLPFC inefficiency in schizophrenia: The FBIRN study

BACKGROUND The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.