Markus Sack

Impulsivity and Aggression in Female BPD and ADHD Patients: Association with ACC Glutamate and GABA Concentrations

Borderline personality disorder (BPD) and attention-deficit-hyperactivity disorder (ADHD) are both characterized by high impulsivity and difficulties in controlling anger and aggression. In BPD, comorbid ADHD may further increase impulsivity. For both disorders, altered MR spectroscopy levels of the neurotransmitters glutamate and GABA as well as some correlations with impulsivity were previously reported. The objective of this study was to investigate the neurotransmitters glutamate and GABA in relation to impulsivity and aggression as expressed in the anterior cingulate cortex (ACC) in groups of female patients with BPD and ADHD, respectively. Associations of glutamate and GABA levels with further BPD (symptom severity) and ADHD aspects (hyperactivity and inattention) were exploratively evaluated. 1H MR spectra were acquired at 3T to determine glutamate to total creatine ratios (Glu/tCr) and GABA levels from the ACC in a BPD group (n=26), an ADHD group (n=22), and a healthy control (HC) group (n=30); all participants were females. Both patient groups showed higher scores on self-reported impulsivity, anger, and aggression compared with HCs. ACC GABA levels were significantly lower in ADHD than HC. Although measures of impulsivity were positively related to glutamate and negatively to GABA, for aggression only a negative correlation with GABA could be demonstrated. These data provide human in vivo evidence for the role of ACC Glu/tCr and GABA in impulsivity and aggression. If distinct associations of Glu/tCr and GABA for BPD and ADHD can be confirmed in future studies, this might yield implications for more specific pharmacological treatments.

Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: A MEGA‐PRESS study with symmetric editing pulse frequencies for macromolecule suppression

Despite MEGA‐PRESS being a robust method for editing the GABA resonance, there are macromolecule resonances at the same chemical shift that are coedited with this sequence. Although this is a known problem, it is still often overlooked. We aimed to evaluate the amount of macromolecule signal coedited, as well as the gender and age dependencies for the GABA resonance at 3.01 ppm using MEGA‐PRESS with two different editing pulse frequencies. Forty‐five healthy subjects (21–52 years) were included in an in vivo single voxel MEGA‐PRESS study at 3.0 T. Phantom measurements were conducted to measure the signal loss when switching the editing pulse between 1.5 and 1.9 ppm instead of the mostly used switching between 1.9 and 7.5 ppm. The in vivo GABA signal detected by switching the editing pulse frequencies between 1.5 and 1.9 ppm was only 50% of the mean GABA detected by switching the editing pulse frequencies between 1.9 and 7.5 ppm. No gender differences were detected. A small age dependency was observed for GABA plus macromolecules, but not for GABA, suggesting an age‐dependent macromolecule increase. Magn Reson Med, 2013.

Effects of a high-caloric diet and physical exercise on brain metabolite levels: a combined proton MRS and histologic study.

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS). It has been suggested that one mechanism in this context is the promotion of neuroinflammation. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating the effects of physical exercise in a cafeteria-diet mouse model on CNS metabolites by means of in vivo proton magnetic resonance spectroscopy (1HMRS). In addition postmortem histologic and real-time (RT)-PCR analyses for inflammatory markers were performed. Cafeteria diet induced obesity and hyperglycemia, which was only partially moderated by exercise. It also induced several changes in CNS metabolites such as reduced hippocampal glutamate (Glu), choline-containing compounds (tCho) and N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamic acid (NAAG) (tNAA) levels, whereas opposite effects were seen for running. No association of these effects with markers of central inflammation could be observed. These findings suggest that while voluntary wheel running alone is insufficient to prevent the unfavorable peripheral sequelae of the diet, it counteracted many changes in brain metabolites. The observed effects seem to be independent of neuroinflammation.

Signal-to-noise ratio of a mouse brain (13) C CryoProbe™ system in comparison with room temperature coils: spectroscopic phantom and in vivo results.

MRI and MRS in small rodents demand very high sensitivity. Cryogenic transmit/receive radiofrequency probes (CryoProbes) designed for 1H MRI of mouse brain provide an attractive option for increasing the performance of small‐animal MR systems. As the Larmor frequency of 13C nuclei is four times lower than that for 1H nuclei, an even larger sensitivity improvement is expected for 13C applications. The aim of this work was to evaluate the performance of a prototype 13C CryoProbe™ for mouse brain MRS. To investigate the possible gain of the 13C CryoProbe™, we acquired localized single‐voxel 13C spectra and chemical shift images of a dimethyl sulfoxide phantom with the CryoProbe™, as well as with two room temperature resonators. The cryogenically cooled resonator achieved approximately four‐fold higher signal‐to‐noise ratio in phantom tests when compared with the best‐performing room temperature coil. In addition, we present localized 13C spectra of mouse brain obtained with the CryoProbe™, as well as with one of the room temperature coils, demonstrating the performance in vivo. In summary, the cryogenic cooling technique significantly enhances the 13C signal sensitivity at 9.4 T and enables the investigation of metabolism within mouse brain. Copyright

Big GABA: Edited MR spectroscopy at 24 research sites

Abstract Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter &ggr;‐aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J‐difference spectral editing sequences. Nevertheless, implementations of GABA‐edited MRS remain diverse across research sites, making comparisons between studies challenging. This large‐scale multi‐vendor, multi‐site study seeks to better understand the factors that impact measurement outcomes of GABA‐edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule‐ (MM‐) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM‐suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within‐site, while site‐level differences accounted for comparatively more variance (20%) than vendor‐level differences (8%). For MM‐suppressed GABA data, the variance was distributed equally between site‐ (50%) and participant‐level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM‐suppressed GABA measurements that is attributed in part to differences in site‐to‐site data acquisition. This studys protocol establishes a framework for future methodological standardization of GABA‐edited MRS, while the results provide valuable benchmarks for the MRS community. HighlightsGABA‐edited MEGA‐PRESS data from 272 adults were collected from 24 sites.GABA+ data showed good agreement across vendors and sites.Variability in MM‐suppressed GABA data was attributed in part to B0 field offsets.Multi‐site studies using GABA editing are feasible using a standardized protocol.These results provide valuable benchmarks for the MRS community.

Early effects of a high-caloric diet and physical exercise on brain volumetry and behavior: a combined MRI and histology study in mice

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS) in the long-term. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating early effects of a cafeteria-diet on gray and white brain matter volume by means of voxel-based morphometry (VBM) and region-of-interest (ROI) analysis. Half of the mice performed voluntary wheel running to study if regular physical exercise prevents unfavorable effects of a cafeteria-diet. In addition, histological analyses for myelination and neurogenesis were performed. As expected, wheel running resulted in a significant increase of gray matter volume in the CA1–3 areas, the dentate gyrus and stratum granulosum of the hippocampus in the VBM analysis, while a positive effect of the cafeteria-diet was shown for the whole hippocampal CA1–3 area only in the ROI analysis, indicating a regional volume effect. It was earlier found that hippocampal neurogenesis may be related to volume increases after exercise. Interestingly, while running resulted in a significant increase in neurogenesis assessed by doublecortin (DCX)-labeling, this was not true for cafeteria diet. This indicates different underlying mechanisms for gray matter increase. Moreover, animals receiving cafeteria diet only showed mild deficits in long-term memory assessed by the puzzle-box paradigm, while executive functioning and short term memory were not affected. Our data therefore highlight that high caloric diet impacts on the brain and behavior. Physical exercise seems not to interact with these mechanisms.

ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder

ABSTRACT Impulsivity often develops from disturbed inhibitory control, a function mainly regulated by &ggr;‐Aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) and the fronto‐striatal system. In this study, we combined MRS GABA measurements and fMRI to investigate neurochemical and neurofunctional correlates of interference inhibition, further emphasizing the direct relationship between those two systems, as well as their relations to impulsivity in patients with BPD. In addition to BOLD activation, task‐dependent functional connectivity was assessed by a generalized psychophysiological interactions approach. Full factorial analyses were performed via SPM to examine the main effect (within‐group associations) as well as the interaction term (group differences in the association slope). The UPPS scales were used to evaluate impulsivity traits. Compared to healthy controls (HCs), BPD patients exhibited significantly less ACC‐caudate functional connectivity during interference inhibition. ACC GABA levels in BPD patients but not in HCs were positively related to the magnitude of activation in several fronto‐striatal regions (e.g. ACC, frontal regions, putamen, caudate,) and the strength of ACC‐caudate functional connectivity during interference inhibition. The strength of the correlations of GABA with connectivity significantly differs between the two groups. Moreover, among all the UPPS impulsivity subscales, UPPS sensation seeking in the BPD group was related to GABA and was also negatively related to the task‐dependent BOLD activation and functional connectivity in the fronto‐striatal network. Finally, mediation analyses revealed that the magnitude of activation in the caudate and the strength of ACC‐caudate functional connectivity mediated the relationship between ACC GABA levels and UPPS sensation seeking in patients with BPD. Our findings suggest a disconnectivity of the fronto‐striatal network in BPD patients during interference inhibition, particularly for patients with higher impulsivity. The ACC GABAergic system seems to play a crucial role in regulating regional BOLD activations and functional connectivity in this network, which are further associated with impulsive sensation seeking in BPD. HIGHLIGHTSACC seed based connectivity during interference inhibition is altered in BPD.ACC GABA levels correlate with BOLD activation and ACC connectivity in BPD.Impulsivity trait correlates with BOLD activation and ACC connectivity in BPD.fMRI derived measures mediate the relationship between GABA and impulsivity.

Effects of normal aging and SCN1A risk-gene expression on brain metabolites: evidence for an association between SCN1A and myo-inositol

Previously reported MRS findings in the aging brain include lower N‐acetylaspartate (NAA) and higher myo‐inositol (mI), total creatine (Cr) and choline‐containing compound (Cho) concentrations. Alterations in the sodium channel voltage gated type I, alpha subunit SCN1A variant rs10930201 have been reported to be associated with several neurological disorders with cognitive deficits. MRS studies in SCN1A‐related diseases have reported striking differences in the mI concentrations between patients and controls. In a study on ‘healthy aging’, we investigated metabolite spectra in a sample of 83 healthy volunteers and determined their age dependence. We also investigated a potential link between SCN1A and mI. We observed a significantly negative association of NAA (p = 0.004) and significantly positive associations of mI (p ≤ 0.001), Cr (p ≤ 0.001) and Cho (p = 0.034) with age in frontal white matter. The linear association of Cho ends at the age of about 50 years and is followed by an inverted ‘U’‐shaped curve. Further, mI was higher in C allele carriers of the SCN1A variant rs10930201. Our results corroborated the age‐related changes in metabolite concentrations, and found evidence for a link between SCN1A and frontal white matter mI in healthy subjects. Copyright

Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression

Hyperconnectivity of the default-mode network (DMN) is one of the most widely replicated neuroimaging findings in major depressive disorder (MDD). Further, there is growing evidence for a central role of the lateral habenula (LHb) in the pathophysiology of MDD. There is preliminary neuroimaging evidence linking LHb and the DMN, but no causal relationship has been shown to date. We combined optogenetics and functional magnetic resonance imaging (fMRI), to establish a causal relationship, using an animal model of treatment-resistant depression, namely Negative Cognitive State rats. First, an inhibitory light-sensitive ion channel was introduced into the LHb by viral transduction. Subsequently, laser stimulation was performed during fMRI acquisition on a 9.4 Tesla animal scanner. Neural activity and connectivity were assessed, before, during and after laser stimulation. We observed a connectivity decrease in the DMN following laser-induced LHb perturbation. Our data indicate a causal link between LHb downregulation and reduction in DMN connectivity. These findings may advance our mechanistic understanding of LHb inhibition, which had previously been identified as a promising therapeutic principle, especially for treatment-resistant depression.

Longitudinal Structural and Functional Brain Network Alterations in a Mouse Model of Neuropathic Pain

Neuropathic pain affects multiple brain functions, including motivational processing. However, little is known about the structural and functional brain changes involved in the transition from an acute to a chronic pain state. Here we combined behavioral phenotyping of pain thresholds with multimodal neuroimaging to longitudinally monitor changes in brain metabolism, structure and connectivity using the spared nerve injury (SNI) mouse model of chronic neuropathic pain. We investigated stimulus-evoked pain responses prior to SNI surgery, and one and twelve weeks following surgery. A progressive development and potentiation of stimulus-evoked pain responses (cold and mechanical allodynia) were detected during the course of pain chronification. Voxel-based morphometry demonstrated striking decreases in volume following pain induction in all brain sites assessed - an effect that reversed over time. Similarly, all global and local network changes that occurred following pain induction disappeared over time, with two notable exceptions: the nucleus accumbens, which played a more dominant role in the global network in a chronic pain state and the prefrontal cortex and hippocampus, which showed lower connectivity. These changes in connectivity were accompanied by enhanced glutamate levels in the hippocampus, but not in the prefrontal cortex. We suggest that hippocampal hyperexcitability may contribute to alterations in synaptic plasticity within the nucleus accumbens, and to pain chronification.