Cocaine addiction is characterized by overwhelming craving for the substance, which drives its escalating use despite adverse consequences. Animal models suggest a disrupted glutamate homeostasis in ...the nucleus accumbens to underlie addiction-like behavior. After chronic administration of cocaine, rodents show decreased levels of accumbal glutamate, whereas drug-seeking reinstatement is associated with enhanced glutamatergic transmission. However, due to technical obstacles, the role of disturbed glutamate homeostasis for cocaine addiction in humans remains only partially understood, and accordingly, no approved pharmacotherapy exists. Here, we applied a tailored proton magnetic resonance spectroscopy protocol that allows glutamate quantification within the human nucleus accumbens. We found significantly reduced basal glutamate concentrations in the nucleus accumbens in cocaine-addicted (N = 26) compared with healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared with baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on 2 days). Taken together, our findings reveal a disturbed accumbal glutamate homeostasis as a key neurometabolic feature of cocaine addiction also in humans. Therefore, we suggest the glutamatergic system as a promising target for the development of novel pharmacotherapies, and in addition, as a potential biomarker for a personalized medicine approach in addiction.
•Amygdalar neurometabolites were measured reliably with high anatomical specificity.•Glutamate and other neurometabolites did not differ between smokers and non-smokers.•Glutamine levels in smokers ...were decreased in satiation compared to baseline.•Glx levels were negatively associated with nicotine quantity and duration.•More severe nicotine addiction may be associated with altered glutamate homeostasis.
Tobacco smoking is one of the main causes of premature death worldwide and quitting success remains low, highlighting the need to understand the neurobiological mechanisms underlying relapse. Preclinical models have shown that the amygdala and glutamate play an important role in nicotine addiction. The aims of this study were to compare glutamate and other metabolites in the amygdala between smokers and controls, and between different smoking states. Furthermore, associations between amygdalar metabolite levels and smoking characteristics were explored.
A novel non-water-suppressed proton magnetic resonance spectroscopy protocol was applied to quantify neurometabolites in 28 male smokers (≥15 cigarettes/day) and 21 non-smoking controls, matched in age, education, verbal IQ, and weekly alcohol consumption. Controls were measured once (baseline) and smokers were measured in a baseline state (1–3 h abstinence), during withdrawal (24 h abstinence) and in a satiation state (directly after smoking). Baseline spectroscopy data were compared between groups by independent t-tests or Mann-Whitney-U tests. Smoking state differences were investigated by repeated-measures analyses of variance (ANOVAs). Associations between spectroscopy data and smoking characteristics were explored using Spearman correlations.
Good spectral quality, high anatomical specificity (98% mean gray matter) and reliable quantification of most metabolites of interest were achieved in the amygdala. Metabolite levels did not differ between groups, but smokers showed significantly higher glutamine levels at baseline than satiation. Glx levels were negatively associated with pack-years and smoking duration.
In summary, this study provides first insights into the neurometabolic profile of the amygdala in smokers with high anatomical specificity. By applying proton magnetic resonance spectroscopy, neurometabolites in smokers during different smoking states and non-smoking controls were quantified reliably. A significant shift in glutamine levels between smoking states was detected, with lower concentrations in satiation than baseline. The negative association between Glx levels and smoking quantity and duration may imply altered glutamate homeostasis with more severe nicotine addiction.
Display omitted
Purpose
The detection and quantification of metabolites relevant for the diagnosis of fatal metabolic disorders by proton magnetic resonance spectroscopy (1H-MRS) was recently demonstrated. This ...prospective study aimed to compare the concentrations of beta-hydroxybutyrate (BHB), glucose (GLC), and lactate (LAC) derived from both biochemical analyses and 1H-MRS for the diagnosis of fatal metabolic disorders.
Methods
In total, 20 cases with suspected fatal metabolic disorders were included in the study. For the agreement based on thresholds, the concentrations of BHB and GLC in the vitreous humor (VH) from the right vitreous and in cerebrospinal fluid (CSF) from the right lateral ventricle were derived from 1H-MRS and biochemical analyses. The predefined thresholds for pathological elevations were 2.5 mmol/l for BHB and 10 mmol/l for GLC based on the literature. In addition, concentrations of the same metabolites in white matter (WM) tissue from the corona radiata of the right hemisphere were analyzed experimentally using both methods. To enable the biochemical analysis, a dialysate of WM tissue was produced. For all three regions, the LAC concentration was determined by both methods.
Results
The conclusive agreement based on thresholds was almost perfect between both methods with only one disagreement in a total of 70 comparisons due to the interference of a ferromagnetic dental brace. The differences in the concentrations between both methods showed high standard deviations. Confidence intervals of the bias not including 0 were found in CSF-GLC (− 3.1 mmol/l), WM-GLC (1.1 mmol/l), and WM-LAC (− 6.5 mmol/l).
Conclusion
Despite a considerable total error attributable to both methods, MRS derives the same forensic conclusions as conventional biochemical analyses. An adaptation of the protocol to reduce the detected errors and more data are needed for the long-term validation of MRS for the diagnosis of fatal metabolic disorders. The production of WM dialysates cannot be recommended due to high glycolytic loss.
In a case of a fatal traffic accident, a suspicious finding was identified in the muscular tissue of the left thigh by whole-body postmortem computed tomography. To better interpret the finding, the ...lower extremities were investigated by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (
1
H-MRS). MRI revealed the presence of an evenly distributed intramuscular fluid and
1
H-MRS of a volume within the fluid detected concentrations of acetate and lactate. The fluid was assumed to be an extravasation of an intraosseous infusion, erroneously administered to the intermediate vastus of the left thigh during resuscitation, which was later confirmed when access to resuscitation protocols was granted. Further ex situ
1
H-MRS investigations of five different infusion fluids showed the possible discrimination of the fluids and further indicated the unknown fluid to be a Ringer’s acetate solution. This paper presents the case-based application of postmortem intramuscular 1H-MRS and introduces the possibility of its use to differentiate exo- and endogenic fluids for forensic interpretation. Further research for this method regarding problems in forensic pathology is needed.
Background
The
in situ
classification of bullets is of interest in forensic investigations when the bullet cannot be removed. Although computed tomography (CT) is usually performed on shooting ...victims, visual assessment, or caliber measurements using CT can be challenging or infeasible if the bullets are deformed or fragmented. Independent from the bullet’s intactness, x-ray attenuation values (CT numbers) may provide information regarding the material of the bullet.
Methods
Ethical approval was not required (animal cadavers) or waived by the ethics committee (decedents). Copper and lead bullets were fired into animal cadavers, which then underwent CT scanning at four energy levels (80, 100, 120, and 140 kVp). CT numbers were measured within regions of interest (ROIs). In addition to comparing CT numbers, the dual-energy index (DEI), representing the ratio between the CT numbers of two energy levels, was calculated. The most appropriate method was applied for decedents with fatal gunshot wounds.
Results
CT numbers demonstrated no significant difference between copper and lead bullets, and false classifications can easily occur. DEI calculations revealed significant differences between the two groups of bullets. The 120/140 DEIs calculated from the maximum CT numbers obtained from ROIs at the edge of copper
versus
lead bullets presented a significant difference (
p
= 0.002) and a gap between the CT numbers of copper and lead bullets and was successfully applied for the decedents.
Conclusions
This study presents a viable method for distinguishing copper and lead bullets
in situ
via CT and highlights the potential pitfalls of incorrect classifications.
An important contribution of the thalamus to the transition from wakefulness to sleep is a consistent finding in animal studies. In humans, only little is currently known about the specific role of ...the thalamus in regulating wake-sleep transitions. Although changes in thalamic blood flow and activity have been reported, the underlying molecular mechanisms have not been investigated. Knowledge about neurotransmitter changes at the wake-to-sleep transition would be indispensable for a better translation of basic animal research findings to humans. Here, we start to fill this important scientific gap. More specifically, we benefit from recent advances in magnetic resonance spectroscopy (MRS), which allow for the non-invasive, local-specific and high-quality detection of naturally occurring metabolite changes in the human brain. We demonstrate in 9 young adults able to produce consolidated sleep in the MRS scanner a specific decrease in thalamic glutamate concentration from wakefulness to N2 sleep (t = 3.74, p < 0.01). The magnitude of this decrease was highly correlated with individual N2 sleep duration (r = 0.84, p = 0.005). When 5 participants were kept awake in a separate control condition, no decrease in thalamic glutamate levels occurred. The study highlights for the first time in humans that dynamic changes in distinct brain metabolites can be reliably detected at the transition from waking to sleep. The reported methodology to simultaneously acquire MRS and neurophysiological signals offers great potential for investigating the molecular mechanisms underlying the gating and maintenance of sleep and wake in humans.
The detection and assessment of cerebral lesions and traumatic brain injuries are of particular interest in forensic investigations in order to differentiate between natural and traumatic deaths and ...to reconstruct the course of events in case of traumatic deaths. For this purpose, computed tomography (CT) and magnetic resonance imaging (MRI) are applied to supplement autopsy (traumatic death) or to supplant autopsy (natural deaths). This approach is termed “virtual autopsy.” The value of this approach increases as more microlesions and traumatic brain injuries are detected and assessed. Focusing on these findings, this article describes the examination of two decedents using CT, 3-T, and 7-T MRI. The main question asked was whether there is a benefit in using 7-T over 3-T MRI. To answer this question, the 3-T and 7-T images were graded regarding the detectability and the assessability of coup/contrecoup injuries and microlesions using 3-point Likert scales. While CT missed these findings, they were detectable on 3-T and 7-T MRI. However, the 3-T images appeared blurry in direct comparison with the 7-T images; thus, the detectability and assessability of small findings were hampered on 3-T MRI. The potential benefit of 7-T over 3-T MRI is discussed.
•A multimodal imaging study captures craving-related changes in cocaine use disorder.•rs-fMRI assessed functional connectivity (FC) during cue-induced craving states.•MRS measured glutamate levels in ...the nucleus accumbens (NAcc) in craving states.•Craving states were characterized by increased NAcc-prefrontal and NAcc-thalamic FC.•NAcc-thalamic FC was linked to glutamate changes in the NAcc and craving intensity.
Craving is a core symptom of cocaine use disorder and a major factor for relapse risk. To date, there is no pharmacological therapy to treat this disease or at least to alleviate cocaine craving as a core symptom. In animal models, impaired prefrontal-striatal signalling leading to altered glutamate release in the nucleus accumbens appear to be the prerequisite for cocaine-seeking. Thus, those network and metabolic changes may constitute the underlying mechanisms for cocaine craving and provide a potential treatment target. In humans, there is recent evidence for corresponding glutamatergic alterations in the nucleus accumbens, however, the underlying network disturbances that lead to this glutamate imbalance remain unknown. In this state-dependent randomized, placebo-controlled, double-blinded, cross-over multimodal study, resting state functional magnetic resonance imaging in combination with small-voxel proton magnetic resonance spectroscopy (voxel size: 9.4 × 18.8 × 8.4 mm3) was applied to assess network-level and associated neurometabolic changes during a non-craving and a craving state, induced by a custom-made cocaine-cue film, in 18 individuals with cocaine use disorder and 23 healthy individuals. Additionally, we assessed the potential impact of a short-term challenge of N-acetylcysteine, known to normalize disturbed glutamate homeostasis and to thereby reduce cocaine-seeking in animal models of addiction, compared to a placebo. We found increased functional connectivity between the nucleus accumbens and the dorsolateral prefrontal cortex during the cue-induced craving state. However, those changes were not linked to alterations in accumbal glutamate levels. Whereas we additionally found increased functional connectivity between the nucleus accumbens and a midline part of the thalamus during the cue-induced craving state. Furthermore, obsessive thinking about cocaine and the actual intensity of cocaine use were predictive of cue-induced functional connectivity changes between the nucleus accumbens and the thalamus. Finally, the increase in accumbal-thalamic connectivity was also coupled with craving-related glutamate rise in the nucleus accumbens. Yet, N-acetylcysteine had no impact on craving-related changes in functional connectivity. Together, these results suggest that connectivity changes within the fronto-accumbal-thalamic loop, in conjunction with impaired glutamatergic transmission, underlie cocaine craving and related clinical symptoms, pinpointing the thalamus as a crucial hub for cocaine craving in humans.
Recently, a special bullet shooting stunner for heavy cattle has been developed that fires a bullet instead of a bolt. In the search for a suitable ammunition, the following criteria must be met: ...First, the energy of the bullet must be sufficient to penetrate the thick frontal bones of heavy cattle. Second, the injury potential at the corresponding penetration depth should preferably be large in order to damage brain tissue relevant to stunning. Third, the bullet must not perforate the occipital bone (over-penetration).
Four different bullet types
, and a common full metal jacket (
) bullet were evaluated in a series of experiments on soap blocks and removed bone plates followed by computed tomography examinations. Penetration potential was evaluated in terms of kinetic energy relative to the caliber of the bullet, i.e., mean energy density (
). Injury potential was evaluated by the mean extent of the cavity volume (
) at the relevant penetration depth of 5.5 to 7.5 cm in the soap block.
All four bullet types passed through the frontal bone plate. The
was 17.50 J/mm
(
), 17.46 J/mm
(
), 13.47 J/mm
(
), and 13.47 J/mm
(
). The
and the
each fragmented heavily. The
was excluded after three experiments due to over-penetrations. The
was
= 3.77 cm
(
), 2.71 cm
(
), and 1.31 cm
(
), with a significant difference (
= 0.006) between the
and the
.
For use in heavy cattle, the
and the
are recommended due to the larger
than the
.
Abstract Background The injection of muscle precursor cells (MPC) into the external urinary sphincter muscle (EUS) is a promising therapeutic option for regenerative treatment of stress urinary ...incontinence (SUI). The objective of the present project was to conduct a pre-clinical trial to investigate the feasibility and accuracy of ultrasound (US) guided, transurethral injections into the EUS of female cadavers. Methods This is a prospective, anatomical, interventional and radiological cadaveric laboratory investigation. Two urologists performed transurethral US-guided injections to deliver nano-iron particles into the EUS. The intervention was performed in three unfixed, fresh female cadavers. Each cadaver received MRI before and CT as well as MRI of the pelvis after the injections. Results The precision and accumulation of nano-iron particles in the EUS was compared using a rating scale to evaluate left versus right and anterior versus posterior distribution in axial and sagittal orientation with US, MRI and CT. The accuracy of our US-guided injections into the anterior target region yielded 4 points on the rating scale. Adequate precision and accumulation of particles in the left versus right EUS were also demonstrated (3 vs. 3.33 points, respectively). Signal intensity in MRI revealed a mean ratio of 0.33 before and after injection. CT scans showed no relevant artefacts impairing the assessment. Conclusion US-guided, transurethral injection into the EUS is feasible and imaging reveals a precise accumulation in the target region. Our method provides an appropriate approach to deliver MPC in the EUS muscle for a regenerative treatment of SUI in the near future.
PDF
