Nobel laureates' letter to President Bush.
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Embryo Disposition↗
Biomedical subjects
N F Ramsey
Publications and source records attributed to N F Ramsey.
Combined analysis of language tasks in fMRI improves assessment of hemispheric dominance for language functions in individual subjects.
Recent advances in functional neuroimaging techniques have prompted an increase in the number of studies investigating lateralization of language functions. One of the problems in relating findings of various studies to one another is the diversity of reported results. This may be due to differences in the tasks that are used to stimulate language processing regions and in the control tasks, as well as differences in the way imaging data are analyzed,in particular the threshold for significance of signal change. We present a simple method to assess language lateralization that allows for some variation of tasks and statistical thresholding, but at the same time yields reliable and reproducible results. Images acquired during a set of word-comprehension and -production tasks are analyzed conjointly. As opposed to the use of any one particular task, this combined task analysis (CTA) approach is geared toward identifying language regions that are involved in generic language functions rather than regions that are involved in functions that are specific to a single task. In two experiments CTA is compared to single-task analysis in healthy right-handed males. In a third experiment left-handed males were examined. Results indicate that CTA: (1) improves detection of language-related brain activity in individual subjects and (2) yields a high language laterality index (LI) in right-handed males with a small variance across subjects. The high LI matches the strong left-hemisphere dominance for language that is typical for these subjects as reported in neuropsychological and clinical tests in other studies. In the left-handed subjects dominance was found either in the left (n = 4) or the right (n = 1) hemisphere or was absent (n = 3). The LI derived from CTA is more consistent across statistical thresholds for significance of signal change in fMRI analysis than in individual-task analysis. Also, the CTA results are very similar to those obtained with conjunction analysis of the same data.
Adult↗
Endogenous opioids and reward.
The discovery of endogenous opioids has markedly influenced the research on the biology of addiction and reward brain processes. Evidence has been presented that these brain substances modulate brain stimulation reward, self-administration of different drugs of abuse, sexual behaviour and social behaviour. There appears to be two different domains in which endogenous opioids, present in separate and distinct brain regions, are involved. One is related to the modulation of incentive motivational processes and the other to the performance of certain behaviours. It is concluded that endogenous opioids may play a role in the vulnerability to certain diseases, such as addiction and autism, but also when the disease is present, such as alcoholism.
Animals↗
Specific versus nonspecific brain activity in a parametric N-back task.
In this study functional magnetic resonance imaging (fMRI) was used to examine cerebral activity patterns in relation to increasing mental load of a working memory task. Aim of the experiment was to distinguish nonspecific task-related processes from specific workload processes analytically. Twelve healthy volunteers engaged in a spatial n-back task with four levels. FMRI data were acquired with the 3D-PRESTO pulse sequence. Analysis entailed a two-step multiple regression algorithm, which was specifically designed to measure and separate load-sensitive and load-insensitive activity simultaneously, while preserving the original high spatial resolution of the fMRI signal. Load-sensitive and load-insensitive activity was found in both dorsolateral-prefrontal and parietal cortex, predominantly bilaterally, and in the anterior cingulate. As expected, the left primary sensorimotor cortex showed predominantly load-insensitive activity. Load-sensitive activity reflects specific working memory functions, such as temporary retention and manipulation of information, while load-insensitive activity reflects supportive functions, such as visual orientation, perception, encoding, and response selection and execution. Good performance was correlated with a large area of load-sensitive activity in anterior cingulate, and with a small area of load-insensitive activity in the right parietal cortex. The findings indicate that nonspecific and specific working memory processes colocalize and are represented in multiple frontal and parietal regions. Implication of this analytical strategy for application in research on psychiatric disorders is discussed.
Adult↗
Cerebral mirror-imaging in a monozygotic twin.
A healthy monozygotic twin of discordant handedness was scanned with functional magnetic resonance imaging during a language and a mental rotation task. Mirror-imaging was found for both cerebral functions.
Brain Mapping↗
Language area localization with three-dimensional functional magnetic resonance imaging matches intrasulcal electrostimulation in Broca's area.
In this study, intraoperative electrocortical stimulation mapping (ioESM), the current gold standard for the localization of critical language areas, is compared with functional magnetic resonance imaging (fMRI) in a 14-year-old girl with medically intractable epilepsy caused by a tumor in the region of Broca's area. Prior to the operation, four different fMRI tasks that target inferior frontal language areas were applied. Prior to the resection, ioESM as well as fMRI detected no language areas at the exposed cortical area. After removal of the tumor, a unique opportunity presented itself, where ioESM could be performed in the depth of a now exposed and intact gyrus. One specific locus that was indicated to be a critical language area by multiple-task fMRI was targeted. IoESM selectively confirmed the location of this language area to within an estimated 3 mm. We propose that the combined use of different fMRI tasks increases the sensitivity and specificity for the detection of essential language areas.
Adolescent↗
Naltrexone affects cocaine self-administration in naïve rats through the ventral tegmental area rather than dopaminergic target regions.
Behavioural studies have shown an involvement of central endogenous opioid systems in experimental cocaine addiction. Seeking to further localize the attenuating effect of opioid blockade on the reinforcing effects of cocaine, naltrexone was administered locally to different regions of the mesocorticolimbic system, which are thought to be critically involved in cocaine self-administration behaviour. Both cell body and nerve terminal regions of this system were targeted. Using a model for the initiation of cocaine self-administration behaviour, no effect of naltrexone was found in caudate, amygdaloid or accumbens nuclei, nor in the medial prefrontal cortex. However, blockade of endogenous opioid receptors in the ventral tegmental area region attenuated cocaine self-administration. With the initiation model, this finding reflects an attenuating effect on the reinforcing effects of cocaine. The attenuation of self-administration was dependent on the naltrexone dose. The present findings suggest that endogenous opioid systems in the ventral tegmental area modulate the reinforcing efficacy of cocaine.
Animals↗
Tactile stimulation during finger opposition does not contribute to 3D fMRI brain activity pattern.
Functional magnetic resonance imaging (fMRI) is a new, non-invasive technique to localize brain activity with a high spatial resolution. Activation of the motor cortex by sequential movement of the thumb to the fingers has been used extensively to validate the fMRI technique. This task, however, combines motor activity (movement of thumb and fingers) with tactile stimulation (touching the finger with the thumb). In this study we examined the contribution of tactile stimulation to the activity pattern. Nine healthy subjects were instructed to touch the fingers with the thumb in a first task, and repeat this movement without touching the fingers in a second task. Comparison of the two activity patterns did not result in a significant difference. Therefore we concluded that the pattern of activity associated with a fingertapping task is not influenced by tactile stimulation, but is caused primarily by motor activation and possibly by proprioceptive activity.
Adult↗
Phase navigator correction in 3D fMRI improves detection of brain activation: quantitative assessment with a graded motor activation procedure.
Motion poses severe problems for BOLD fMRI, particularly in clinical studies, as patients exhibit more involuntary movements than controls. This study focuses on the merits of a motion correction technique incorporated in multishot fMRI scans, so-called phase navigator correction. The technique entails real-time assessment and off-line elimination of signal fluctuations caused by subject motion. The purpose of this study was to quantify and characterize the effect of this type of improvement on 3D fMRI brain activity maps. For imaging, the 3D PRESTO method was used, with a relatively simple finger opposition task. The followed strategy was guided by the notion that application of any fMRI imaging tool in clinical studies requires several qualities, such as high and spatially homogeneous sensitivity to brain activity, and low sensitivity to motion. A graded motor activation protocol in 10 healthy subjects revealed that image stability was improved by approximately 20%, by the use of phase navigator correction. As a result, sensitivity for task-related BOLD signal change was enhanced considerably in the brain activity maps. Implications for use of this fMRI technique in patient studies are discussed.
Adult↗
Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia.
Functional magnetic resonance imaging (fMRI) is a potential paradigm shift in psychiatric neuroimaging. The technique provides individual, rather than group-averaged, functional neuroimaging data, but subtle methodological confounds represent unique challenges for psychiatric research. As an exemplar of the unique potential and problems of fMRI, we present a study of 10 inpatients with schizophrenia and 10 controls performing a novel "n back" working memory (WM) task. We emphasize two key design steps: (1) the use of an internal activation standard (i.e., a physiological control region) to address activation validity, and (2) the assessment of signal stability to control for "activation" artifacts arising from unequal signal variance across groups. In the initial analysis, all but one of the patients failed to activate dorsolateral prefrontal cortex (DLPFC) during the working memory task. However, some patients (and one control) also tended to show sparse control region activation in spite of normal motor performance, a result that raises doubts about the validity of the initial analysis and concerns about unequal subject motion. Subjects were then matched for signal variance (voxel stability), producing a subset of six patients and six controls. In this comparison, the internal activation standard (i.e., motor activation) was similar in both groups, and five of six patients, including two whom were neuroleptic-naive, failed to activate DLPFC. In addition, a tendency for overactivation of parietal cortex was seen. These results illustrate some of the promise and pitfalls of fMRI. Although fMRI generates individual brain maps, a specialized survey of the data is necessary to avoid spurious or unreliable findings, related to artifacts such as motion, which are likely to be frequent in psychiatric patients.
Adult↗
Statistical analysis of functional MRI data in the wavelet domain.
The use of the wavelet transform is explored for the detection of differences between brain functional magnetic resonance images (fMRI's) acquired under two different experimental conditions. The method benefits from the fact that a smooth and spatially localized signal can be represented by a small set of localized wavelet coefficients, while the power of white noise is uniformly spread throughout the wavelet space. Hence, a statistical procedure is developed that uses the imposed decomposition orthogonality to locate wavelet-space partitions with large signal-to-noise ratio (SNR), and subsequently restricts the testing for significant wavelet coefficients to these partitions. This results in a higher SNR and a smaller number of statistical tests, yielding a lower detection threshold compared to spatial-domain testing and, thus, a higher detection sensitivity without increasing type I errors. The multiresolution approach of the wavelet method is particularly suited to applications where the signal bandwidth and/or the characteristics of an imaging modality cannot be well specified. The proposed method was applied to compare two different fMRI acquisition modalities. Differences of the respective useful signal bandwidths could be clearly demonstrated; the estimated signal, due to the smoothness of the wavelet representation, yielded more compact regions of neuroactivity than standard spatial-domain testing.
Adult↗
Modulation of cocaine intravenous self-administration in drug-naive animals by dihydropyridine Ca2+ channel modulators.
The dihydropyridine Ca2+ channel blocker nimodipine and the dihydropyridine Ca2+ channel activator BayK 8644 (1,4-dihydropyridine-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-py ridine- 5-carboxylate) were administered to drug-naive mice and rats that were tested for intravenous cocaine self-administration. A range of cocaine doses was tested to investigate the nature of the effect. The results indicate that nimodipine and BayK 8644 shifted the dose-response curve for cocaine's reinforcing action to the right and left, respectively. Thus, the Ca2+ channel blocker nimodipine decreases the sensitivity of mice and rats to the reinforcing effects of cocaine while the Ca2+ channel activator BayK 8644 makes the animals more sensitive to cocaine reward. The results suggest that a dihydropyridine-sensitive mechanism is implicated in the initiation of cocaine self-administration.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Fast 3D functional magnetic resonance imaging at 1.5 T with spiral acquisition.
A new method to perform rapid 3D fMRI in human brain is introduced and evaluated in normal subjects, on a standard clinical scanner at 1.5 Tesla. The method combines a highly stable gradient echo technique with a spiral scan method, to detect brain activation related changes in blood oxygenation with high sensitivity. A motor activation paradigm with a duration of less than 5 min, performed on 10 subjects, consistently showed significant changes in signal intensity in the area of the motor cortex. In all subjects, these changes survived high statistical thresholds.
Brain↗
Functional mapping of human sensorimotor cortex with 3D BOLD fMRI correlates highly with H2(15)O PET rCBF.
Positron emission tomography (PET) functional imaging is based on changes in regional cerebral blood flow (rCBF). Functional magnetic resonance imaging (fMRI) is based on a variety of physiological parameters as well as rCBF. This study is aimed at the cross validation of three-dimensional (3D) fMRI, which is sensitive to changes in blood oxygenation, with oxygen-15-labeled water (H2(15)O) PET. Nine normal subjects repeatedly performed a simple finger opposition task during fMRI scans and during PET scans. Within-subject statistical analysis revealed significant ("activated") signal changes (p < 0.05, Bonferroni corrected for number of voxels) in contralateral primary sensorimotor cortex (PSM) in all subjects with fMRI and with PET. With both methods, 78% of all activated voxels were located in the PSM. Overlap of activated regions occurred in all subjects (mean 43%, SD 26%). The size of the activated regions in PSM with both methods was highly correlated (rho = 0.87, p < 0.01). The mean distance between centers of mass of the activated regions in the PSM for fMRI versus PET was 6.7 mm (SD 3.0 mm). Average magnitude of signal change in activated voxels in this region, expressed as z-values adapted to timeseries, zt, was similar (fMRI 5.5, PET 5.3). Results indicate that positive blood oxygen level-dependent (BOLD) signal changes obtained with 3D principles of echo shifting with a train of observations (PRESTO) fMRI are correlated with rCBF, and that sensitivity of fMRI can equal that of H2(15)O PET.
Adult↗
Three-dimensional functional magnetic resonance imaging of human brain on a clinical 1.5-T scanner.
Functional magnetic resonance imaging (fMRI) is a tool for mapping brain function that utilizes neuronal activity-induced changes in blood oxygenation. An efficient three-dimensional fMRI method is presented for imaging brain activity on conventional, widely available, 1.5-T scanners, without additional hardware. This approach uses large magnetic susceptibility weighting based on the echo-shifting principle combined with multiple gradient echoes per excitation. Motor stimulation, induced by self-paced finger tapping, reliably produced significant signal increase in the hand region of the contralateral primary motor cortex in every subject tested.
Brain↗
Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat.
The involvement of dopamine D1 receptor systems in the reinforcing properties of opiate reward was studied by examining the effect of the dopamine D1 antagonist SCH23390 on the initiation of heroin self-administration in rats. The D1 antagonist was administered daily systemically or locally in the nucleus accumbens (NAC), after which the animals were allowed to self-administer heroin (IV) in a 3-h session for 5 consecutive days. Systemic treatment with SCH23390 (0.17 and 0.5 mg.kg-1) significantly decreased heroin intake during initiation of heroin self-administration, while a dose of 0.06 mg.kg-1 was not effective. Local administration of SCH23390 (0.5 and 2.5 micrograms/site) in the NAC did not affect heroin intake. Both systemic and intra-accumbal administration of SCH23390 dose dependently decreased motor behavior measured in a small open field. The attenuation of heroin intake during initiation of heroin self-administration by blockade of dopamine D1 receptor systems may be due to a decrease in the reinforcing effects of heroin or more likely to a reduction in non-reinforcement-related behavior. The dopamine D1 receptors present in the NAC are probably not involved in opiate reward.
Animals↗
Emotional but not physical stress enhances intravenous cocaine self-administration in drug-naive rats.
Involvement of stress in the etiology of drug dependence has received little attention. In the present study a number of behavioural manipulations were applied and examined for an effect on intravenous cocaine self-administration in drug-naive rats with no prior training in leverpress responding. Self-administration rate was measured during five consecutive daily sessions. Stress reduction by handling rats daily for two weeks prior to testing for self-administration did not affect cocaine self-administration. Acute physical stress was induced either by a hot plate or by repeated footshocks, and emotional stress was induced by forcing rats to witness another rat being subjected to repeated footshocks. These stressors were applied immediately prior to each cocaine self-administration session. Emotional but not physical stress enhanced the rate of cocaine self-administration. It is concluded that emotional distress may increase the rewarding effects of cocaine and may render an individual more susceptible to development of drug dependence.
Animals↗
Prenatal exposure to morphine enhances cocaine and heroin self-administration in drug-naive rats.
Drugs of abuse putatively exert their rewarding actions by activating specific mechanisms in the brain. Sensitivity of these mechanisms to stimulation by drugs may be a factor in the development of drug dependence. As endogenous opioid systems may be involved in drug reward, manipulation of the functional state of opioid systems may affect this development. In the present study male rats exposed to morphine or placebo during their foetal period were tested for the development of intravenous self-administration of either heroin, cocaine or saline. Heroin and cocaine represent two fundamentally different classes of abused drugs. Prenatal exposure to morphine enhanced rates of heroin and of cocaine, but not of saline self-administration. The data indicate that this was not simply the result of increased motor activity. Given the fact that the unit-doses of heroin and cocaine were threshold doses for the development of intravenous drug self-administration behaviour, it is concluded that the reinforcing efficacy of both drugs is enhanced by prenatal morphine treatment, and that such treatment possibly facilitates development of drug dependence in general.
Animals↗