Blaise deB. Frederick

Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence.

BACKGROUND Developing the means to identify smokers at high risk for relapse could advance relapse prevention therapy. We hypothesized that functional magnetic resonance imaging (fMRI) reactivity to smoking-related cues, measured before a quit attempt, could identify smokers with heightened relapse vulnerability. METHODS Before quitting smoking, 21 nicotine-dependent women underwent fMRI during which smoking-related and neutral images were shown. These smokers also were tested for possible attentional biases to smoking-related words using a computerized emotional Stroop (ES) task previously found to predict relapse. Smokers then made a quit attempt and were grouped based on outcomes (abstinence vs. slip: smoking > or = 1 cigarette after attaining abstinence). Prequit fMRI and ES measurements in these groups were compared. RESULTS Slip subjects had heightened fMRI reactivity to smoking-related images in brain regions implicated in emotion, interoceptive awareness, and motor planning and execution. Insula and dorsal anterior cingulate cortex (dACC) reactivity induced by smoking images correlated with an attentional bias to smoking-related words. A discriminant analysis of ES and fMRI data predicted outcomes with 79% accuracy. Additionally, smokers who slipped had decreased fMRI functional connectivity between an insula-containing network and brain regions involved in cognitive control, including the dACC and dorsal lateral prefrontal cortex, possibly reflecting reduced top-down control of cue-induced emotions. CONCLUSIONS These findings suggest that the insula and dACC are important substrates of smoking relapse vulnerability. The data also suggest that relapse-vulnerable smokers can be identified before quit attempts, which could enable personalized treatment, improve tobacco-dependence treatment outcomes, and reduce smoking-related morbidity and mortality.

Time lag dependent multimodal processing of concurrent fMRI and near-infrared spectroscopy (NIRS) data suggests a global circulatory origin for low-frequency oscillation signals in human brain

Low frequency oscillations (LFOs), characterized by frequencies in the range 0.01-0.1 Hz are commonly observed in blood-related brain functional measurements such as near-infrared spectroscopy (NIRS) and functional magnetic resonance imaging (fMRI). While their physiological origin and implications are not fully understood, these signals are believed to reflect some types of neuronal signaling, systemic hemodynamics, and/or cerebral vascular auto-regulation processes. Here, we examine a new method of integrated processing of concurrent NIRS and fMRI data collected on six human subjects during a whole brain resting state acquisition. The method combines the high spatial resolution offered by fMRI (approximately 3mm) and the high temporal resolution offered by NIRS (approximately 80 ms) to allow for the quantitative assessment of temporal relationships between the LFOs observed at different spatial locations in fMRI data. This temporal relationship allowed us to infer that the origin of a large proportion of the LFOs is independent of the baseline neural activity. The spatio-temporal pattern of LFOs detected by NIRS and fMRI evolves temporally through the brain in a way that resembles cerebral blood flow dynamics. Our results suggest that a major component of the LFOs arise from fluctuations in the blood flow and hemoglobin oxygenation at a global circulatory system level.

Prefrontal and limbic resting state brain network functional connectivity differs between nicotine-dependent smokers and non-smoking controls

BACKGROUND Brain dysfunction in prefrontal cortex (PFC) and dorsal striatum (DS) contributes to habitual drug use. These regions are constituents of brain networks thought to be involved in drug addiction. To investigate whether networks containing these regions differ between nicotine dependent female smokers and age-matched female non-smokers, we employed functional MRI (fMRI) at rest. METHODS Data were processed with independent component analysis (ICA) to identify resting state networks (RSNs). We identified a subcortical limbic network and three discrete PFC networks: a medial prefrontal cortex (mPFC) network and right and left lateralized fronto-parietal networks common to all subjects. We then compared these RSNs between smokers and non-smokers using a dual regression approach. RESULTS Smokers had greater coupling versus non-smokers between left fronto-parietal and mPFC networks. Smokers with the greatest mPFC-left fronto-parietal coupling had the most DS smoking cue reactivity as measured during an fMRI smoking cue reactivity paradigm. This may be important because the DS plays a critical role in maintaining drug-cue associations. Furthermore, subcortical limbic network amplitude was greater in smokers. CONCLUSIONS Our results suggest that prefrontal brain networks are more strongly coupled in smokers, which could facilitate drug-cue responding. Our data also are the first to document greater reward-related network fMRI amplitude in smokers. Our findings suggest that resting state PFC network interactions and limbic network amplitude can differentiate nicotine-dependent smokers from controls, and may serve as biomarkers for nicotine dependence severity and treatment efficacy.

Cerebellar Vermis Involvement in Cocaine-Related Behaviors

Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II–III and VIII–IX) has been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [11C]altropane accumulated in those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II–III and VIII–IX in cocaine users, and, at early time points after ligand administration, we found appreciable [11C]altropane accumulation in lobules VIII–IX, possibly indicating DAT presence in this region. These data suggest that parts of cerebellar vermis mediate cocaines persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine- and other incentive-related behaviors.

Influence of baseline hematocrit and hemodilution on BOLD fMRI activation

Current understanding of blood oxygenation level dependent (BOLD) fMRI physiology predicts a close relationship between BOLD signal and blood hematocrit level. However, neither this relationship nor its effect on BOLD percent activation (BPA) has been empirically examined in man. To that end, BPA in primary visual cortex in response to photic stimulation was determined in a group of 24 normal subjects. A positive linear relationship between BPA and hematocrit was seen, particularly in men. To evaluate the effect of change in hematocrit on BPA, 9 men were studied before and following isotonic saline hemodilution, resulting in an average 6% reduction in hematocrit and an 8-31% reduction in BPA. No significant change in the number of activated pixels was seen. A model of predicted BPA as a function of hematocrit and vessel size was developed, and results from this model closely mirrored the empiric data. These results suggest that hematocrit significantly influences the magnitude of BPA and that such baseline factors should be accounted for when comparing BOLD data across groups of subjects, particularly in the many instances in which hematocrit may vary systematically. Such instances include several disease states as well as studies involving sex differences, drug administration, stress and other factors. Finally, the robust agreement between predicted and empiric data serves to validate a semiquantitative approach to the analysis of BOLD fMRI data.

Neural Substrates of Attentional Bias for Smoking-Related Cues: An fMRI Study

Attentional bias for drug-related stimuli, as measured by emotional Stroop (ES) tasks, is predictive of treatment outcomes for tobacco smoking and other abused drugs. Characterizing relationships between smoking-related attentional bias and brain reactivity to smoking images may help in identifying neural substrates critical to relapse vulnerability. To this end, we investigated putative relationships between interference effects in an offline smoking ES task and functional MRI (fMRI) measures of brain reactivity to smoking vs neutral images in women smokers. Positive correlations were found between attentional bias and reactivity to smoking images in brain areas involved in emotion, memory, interoception, and visual processing, including the amygdala, hippocampus, parahippocampal gyrus, insula, and occipital cortex. These findings suggest that smokers with elevated attentional biases to smoking-related stimuli may more readily shift attention away from other external stimuli and toward smoking stimuli-induced internal states and emotional memories. Such attentional shifts may contribute to increased interference by smoking cues, possibly increasing relapse vulnerability. Treatments capable of inhibiting shifts to drug cue-induced memories and internal states may lead to personalized tobacco dependence treatment for smokers with high attentional bias to smoking-related stimuli.

In vivo proton magnetic resonance spectroscopy of the temporal lobe in Alzheimer's disease

PURPOSE Prior proton magnetic resonance spectroscopy (MRS) studies have consistently reported decreased brain n-acetyl aspartate (NAA) levels and increased myo-inositol (mI) levels in subjects with Alzheimers disease (AD) relative to healthy comparison subjects. These studies have usually been conducted in small and homogeneous populations of patients with established Alzheimers disease. Few studies have tested the usefulness of this finding in a general population seeking evaluation for memory loss and other cognitive declines. We designed a study to evaluate the significance of single-voxel proton MRS findings in these patients with memory loss and other cognitive declines. GENERAL METHOD: Thirty-five subjects with a primary complaint of memory loss and other cognitive declines were consecutively referred over a period of 13 months to a specialty clinic. Patients with a diagnosis of mild to moderate probable Alzheimers disease (N = 22), non-Alzheimers dementia (depression, multiinfarct dementia, Parkinsons Disease, Korsakoffs Psychosis, and bipolar disorder; N = 13), and healthy comparison subjects (N = 18) were examined with respect to possible differences in metabolites using proton MRS in a 3.4-ml anterior temporal lobe voxel. FINDINGS The Alzheimers disease group had 10.7% lower NAA/creatine (Cr) ratios relative to the healthy comparison group and 9.4% lower NAA/creatine relative to the non-Alzheimers dementia group (15.0% lower NAA/creatine relative to the depression subgroup of the non-Alzheimers dementia group). There were no significant differences in choline (Cho) or myo-inositol ratios among the groups. There were significant correlations between NAA/creatine ratios and mini-mental status exam (MMSE) scores in subjects with Alzheimers disease (t = 2.41, p = 0.032) but not in subjects with non-Alzheimers dementia or in its depression subgroup. CONCLUSIONS This study found a reduction in the neuronal marker NAA in the anterior temporal lobe of patients diagnosed with probable Alzheimers disease, using a short add-on proton MRS exam. This change was not observed in patients whose memory loss and other cognitive declines were not attributed to Alzheimers disease, suggesting that it may aid in the diagnosis or detection of Alzheimers disease.

Brain fMRI reactivity to smoking-related images before and during extended smoking abstinence.

Reactivity to smoking-related cues may play a role in the maintenance of smoking behavior and may change depending on smoking status. Whether smoking cue-related functional MRI (fMRI) reactivity differs between active smoking and extended smoking abstinence states currently is unknown. We used fMRI to measure brain reactivity in response to smoking-related versus neutral images in 13 tobacco-dependent subjects before a smoking cessation attempt and again during extended smoking abstinence (52 +/- 11 days) aided by nicotine replacement therapy. Prequit smoking cue induced fMRI activity patterns paralleled those reported in prior smoking cue reactivity fMRI studies. Greater fMRI activity was detected during extended smoking abstinence than during the pre-quit [corrected] assessment subcortically in the caudate nucleus and cortically in prefrontal (BA 6, 8, 9, 10, 44, 46), [corrected] primary somatosensory (BA 1, 2, 3), temporal (BA 22), [corrected] parietal (BA 5, 7, 40), occipital (BA 17, 18), [corrected] and posterior cingulate (BA 31) cortex. These data suggest that during extended smoking abstinence, fMRI reactivity to smoking versus neutral stimuli persists in brain areas involved in attention, somatosensory processing, motor planning, and conditioned cue responding. In some brain regions, fMRI smoking cue reactivity is increased during extended smoking abstinence in comparison to the prequit state, which may contribute to persisting relapse vulnerability.

Two‐dimensional, J‐resolved spectroscopic imaging of GABA at 4 Tesla in the human brain

A method for measuring brain gamma‐amino butyric acid (GABA) levels is presented that combines 2D J‐resolved magnetic resonance spectroscopy (J‐MRS) techniques with chemical‐shift imaging (2D‐JMRSI) at 4 Tesla (T). The results of phantom and in vivo experiments agree well in demonstrating that the 2CH2 GABA resonance situated at 2.97 ppm can be resolved from the neighboring creatine (Cr) resonance at 3.03 ppm and quantified. Single‐voxel, J‐resolved standard and metabolite‐nulled in vivo experiments on six healthy subjects reveal a broad component from the underlying macromolecules (MM) that resonates at and around 3.00 ppm, which is estimated to contribute approximately 15% to the J‐resolved GABA resonance in this large voxel at a repetition time (TR) of 4.5 s. With our 2D‐JMSRI at 1.25 s TR, the macromolecule resonance contribution to our GABA measurements is approximated to be 12%. Six healthy human subjects underwent scanning at 4T with this sequence, yielding a global brain GABA concentration of 0.76 ± 0.20 mM after correction for 12% macromolecule contribution. Magn Reson Med, 2005.

Sex differences in response to red and blue light in human primary visual cortex: a bold fMRI study

Studies using a variety of investigative methods, including functional brain imaging and electroencephalography (EEG), have suggested that changes in central nervous system (CNS) dopamine function result in altered visual system processing. The discovery of abnormal retinal blue cone, but not red cone, electroretinogram in association with cocaine withdrawal and Parkinsons disease suggests that visual system response to blue light might be a marker for CNS dopamine tone. As there are numerous sex-related differences in central nervous system dopamine function, we predicted that blue and red light stimulation would produce sex-specific patterns of response in primary visual cortex when studied using the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) technique. We analyzed the BOLD response to red and blue light in male and female human volunteers (N=20). Red and blue light responses in primary visual cortex (V1) to stepped intensities of red and blue light were compared by sex for threshold to detectable BOLD signal increase and for stimulus intensity vs. BOLD signal response. Near threshold, males and females showed similar BOLD signal change to red light, but males showed a threefold greater increase (0.52%) to blue light stimulation when compared to females (0.14%). Log-linear regression modeling revealed that the slope coefficients for the red light stimulus intensity vs. signal change curve were not significantly different for males and females (z=0.995, P=0.320), whereas the slope coefficients for the blue light stimulus intensity vs. signal change curve were significantly larger in males (z=2.251, P=0.024). These findings support a sex and color-dependent differential pattern of primary visual cortical response to photic stimulation and suggest a method for assessing the influence of specific dopamine agonist/antagonist medications on visual function.