Linewidth-related bias in modelled concentration estimates from GABA-edited 1H-MRS.

J-difference-edited MRS is widely used to study GABA in the human brain. Editing for low-concentration target molecules (such as GABA) typically exhibits lower signal-to-noise ratio (SNR) than conventional non-edited MRS, varying with acquisition region, volume and duration. Moreover, spectral lineshape may be influenced by age-, pathology-, or brain-region-specific effects of metabolite T2, or by task-related blood-oxygen level dependent (BOLD) changes in functional MRS contexts. Differences in both SNR and lineshape may have systematic effects on concentration estimates derived from spectral modelling. The present study characterises the impact of lineshape and SNR on GABA+ estimates from different modelling algorithms: FSL-MRS, Gannet, LCModel, Osprey, spant and Tarquin. Publicly available multi-site GABA-edited data (222 healthy subjects from 20 sites; conventional MEGA-PRESS editing; TE = 68 ms) were pre-processed with a standardised pipeline, then filtered to apply controlled levels of Lorentzian and Gaussian linebroadening and SNR reduction. Increased Lorentzian linewidth was associated with a 2-5% decrease in GABA+ estimates per Hz, observed consistently (albeit to varying degrees) across datasets and most algorithms. Weaker, often opposing effects were observed for Gaussian linebroadening. Variations are likely caused by differing baseline parametrization and lineshape constraints between models. Effects of linewidth on other metabolites (e.g., Glx and tCr) varied, suggesting that a linewidth confound may persist after scaling to an internal reference. These findings indicate a potentially significant confound for studies where linewidth may differ systematically between groups or experimental conditions, e.g. due to T2 differences between brain regions, age, or pathology, or varying T2* due to BOLD-related changes. We conclude that linewidth effects need to be rigorously considered during experimental design and data processing, for example by incorporating linewidth into statistical analysis of modelling outcomes or development of appropriate lineshape matching algorithms.

GABA, glutamatergic dynamics and BOLD contrast assessed concurrently using functional MRS during a cognitive task.

A recurring issue in functional neuroimaging is how to link task-driven haemodynamic blood oxygen level dependent functional MRI (BOLD-fMRI) responses to underlying neurochemistry at the synaptic level. Glutamate and γ-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters respectively, are typically measured with MRS sequences separately from fMRI, in the absence of a task. The present study aims to resolve this disconnect, developing acquisition and processing techniques to simultaneously assess GABA, glutamate and glutamine (Glx) and BOLD in relation to a cognitive task, at 3 T. Healthy subjects (N = 81) performed a cognitive task (Eriksen flanker), which was presented visually in a task-OFF, task-ON block design, with individual event onset timing jittered with respect to the MRS readout. fMRS data were acquired from the medial anterior cingulate cortex during task performance, using an adapted MEGA-PRESS implementation incorporating unsuppressed water-reference signals at a regular interval. These allowed for continuous assessment of BOLD activation, through T2 *-related changes in water linewidth. BOLD-fMRI data were additionally acquired. A novel linear model was used to extract modelled metabolite spectra associated with discrete functional stimuli, building on well established processing and quantification tools. Behavioural outcomes from the flanker task, and activation patterns from the BOLD-fMRI sequence, were as expected from the literature. BOLD response assessed through fMRS showed a significant correlation with fMRI, specific to the fMRS-targeted region of interest; fMRS-assessed BOLD additionally correlated with lengthening of response time in the incongruent flanker condition. While no significant task-related changes were observed for GABA+, a significant increase in measured Glx levels (~8.8%) was found between task-OFF and task-ON periods. These findings verify the efficacy of our protocol and analysis pipelines for the simultaneous assessment of metabolite dynamics and BOLD. As well as establishing a robust basis for further work using these techniques, we also identify a number of clear directions for further refinement in future studies.

fMRI fluctuations within the language network are correlated with severity of hallucinatory symptoms in schizophrenia.

Although schizophrenia (SZ) represents a complex multiform psychiatric disorder, one of its most striking symptoms are auditory verbal hallucinations (AVH). While the neurophysiological origin of this pervasive symptom has been extensively studied, there is so far no consensus conclusion on the neural correlates of the vulnerability to hallucinate. With a network-based fMRI approach, following the hypothesis of altered hemispheric dominance (Crow, 1997), we expected that LN alterations might result in self-other distinction impairments in SZ patients, and lead to the distressing subjective experiences of hearing voices. We used the independent component analysis of resting-state fMRI data, to first analyze LN connectivity in three groups of participants: SZ patients with and without hallucinations (AVH/D+ and AVH/D-, respectively), and a matched healthy control (HC) group. Then, we assessed the fMRI fluctuations using additional analyses based on fractional Amplitude of Low Frequency-Fluctuations (fALFF), both at the network- and region of interest (ROI)-level. Specific LN nodes were recruited in the right hemisphere (insula and Broca homologous area) for AVH/D+ , but not for HC and AVH/D-, consistent with a left hemisphere deficit in AVH patients. The fALFF analysis at the ROI level showed a negative correlation between fALFF Slow-4 and P1 Delusions PANSS subscale and a positive correlation between the fALFF Slow-5 and P3 Hallucination PANSS subscale for AVH/D+ only. These effects were not a consequence of structural differences between groups, as morphometric analysis did not evidence any group differences. Given the role of language as an emerging property resulting from the integration of many high-level cognitive processes and the underlying cortical areas, our results suggest that LN features from fMRI connectivity and fluctuations can be a marker of neurophysiological features characterizing SZ patients depending on their vulnerability to hallucinate.

Neurobiological mechanisms of ECT and TMS treatment in depression: study protocol of a multimodal magnetic resonance investigation.

BACKGROUND: Noninvasive neurostimulation treatments are increasingly being used to treat major depression, which is a common cause of disability worldwide. While electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are both effective in treating depressive episodes, their mechanisms of action are, however, not completely understood. ECT is given under general anesthesia, where an electrical pulse is administered through electrodes placed on the patient's head to trigger a seizure. ECT is used for the most severe cases of depression and is usually not prescribed before other options have failed. With TMS, brain stimulation is achieved through rapidly changing magnetic fields that induce electric currents underneath a ferromagnetic coil. Its efficacy in depressive episodes has been well documented. This project aims to identify the neurobiological underpinnings of both the effects and side effects of the neurostimulation techniques ECT and TMS. METHODS: The study will utilize a pre-post case control longitudinal design. The sample will consist of 150 subjects: 100 patients (bipolar and major depressive disorder) who are treated with either ECT (N = 50) or TMS (N = 50) and matched healthy controls (N = 50) not receiving any treatment. All participants will undergo multimodal magnetic resonance imaging (MRI) as well as neuropsychological and clinical assessments at multiple time points before, during and after treatment. Arterial spin labeling MRI at baseline will be used to test whether brain perfusion can predict outcomes. Signs of brain disruption, potentiation and rewiring will be explored with resting-state functional MRI, magnetic resonance spectroscopy and multishell diffusion weighted imaging (DWI). Clinical outcome will be measured by clinician assessed and patient reported outcome measures. Memory-related side effects will be investigated, and specific tests of spatial navigation to test hippocampal function will be administered both before and after treatment. Blood samples will be stored in a biobank for future analyses. The observation time is 6 months. Data will be explored in light of the recently proposed disrupt, potentiate and rewire (DPR) hypothesis. DISCUSSION: The study will contribute data and novel analyses important for our understanding of neurostimulation as well as for the development of enhanced and more personalized treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05135897.

Similarities and differences between intermittent and continuous resting-state fMRI.

Introduction: Functional Magnetic Resonance Imaging (fMRI) block-design experiments typically include active ON-blocks with presentation of cognitive tasks which are contrasted with OFF- blocks with no tasks presented. OFF-blocks in between ON-blocks can however, also be seen as a proxy for intermittent periods of resting, inducing temporary resting-states. We still do not know if brain activity during such intermittent periods reflects the same kind of resting-state activity as that obtained during a continuous period, as is typically the case in studies of the classic Default Mode Network (DMN). The purpose of the current study was therefore to investigate both similarities and differences in brain activity between intermittent and continuous resting conditions. Methods: There were 47 healthy participants in the 3T fMRI experiment. Data for the intermittent resting-state condition were acquired from resting-periods in between active task-processing periods in a standard ON-OFF block design, with three different cognitive tasks presented during ON-blocks. Data for the continuous resting-state condition were acquired during a 5 min resting period after the task-design had been presented. Results and discussion: The results showed that activity was overall similar in the two conditions, but with some differences. These differences were within the DMN network, and for the interaction of DMN with other brain networks. DMN maps showed weak overlap between conditions in the medial prefrontal cortex (MPFC), and in particular for the intermittent compared to the continuous resting-state condition. Moreover, DMN showed strong connectivity with the salience network (SN) in the intermittent resting-state condition, particularly in the anterior insula and the supramarginal gyrus. The observed differences may reflect a "carry-over" effect from task-processing to the next resting-state period, not present in the continuous resting-state condition, causing interference from the ON-blocks. Further research is needed to fully understand the extent of differences between intermittent and continuous resting-state conditions.

Electroconvulsive therapy triggers a reversible decrease in brain N-acetylaspartate.

Introduction: Based on previous research on electroconvulsive therapy (ECT) we have proposed a model where disruption, potentiation, and rewiring of brain networks occur in sequence and serve as the underlying therapeutic mechanism of ECT. This model implies that a temporary disturbance of neuronal networks (disruption) is followed by a trophic effect (potentiation), which enables the rewiring of neuronal circuits to a more euthymic functioning brain. We hypothesized that disruption of neuronal networks could trigger biochemical alterations leading to a temporary decrease in N-acetylaspartate (tNAA, considered a marker of neuronal integrity), while choline (a membrane component), myo-Inositol (mI, astroglia marker), and glutamate/glutamine (Glx, excitatory neurotransmitter) were postulated to increase. Previous magnetic resonance spectroscopy studies, reporting diverse findings, have used two different referencing methods - creatine ratios and tissue corrected values referenced to water - for the quantification of brain metabolites. Changes in creatine during ECT have also been reported, which may confound estimates adopting this as an internal reference. Methods: Using MR spectroscopy, we investigated 31 moderately to severely depressed patients and 19 healthy controls before, during, and after ECT or at similar time points (for controls). We tested whether biochemical alterations in tNAA, choline, mI, and Glx lend support to the disrupt, potentiate, and rewire hypothesis. We used both creatine ratios and water-scaled values for the quantification of brain metabolites to validate the results across referencing methods. Results: Levels of tNAA in the anterior cingulate cortex decreased after an ECT treatment series (average 10.6 sessions) by 6% (p = 0.007, creatine ratio) and 3% (p = 0.02, water referenced) but returned to baseline 6 months after ECT. Compared to after treatment series tNAA levels at 6-month follow-up had increased in both creatine ratio (+6%, p < 0.001) and water referenced data (+7%, p < 0.001). Findings for other brain metabolites varied and could not be validated across referencing methods. Discussion: Our findings suggest that prior research must be interpreted with care, as several referencing and processing methods have been used in the past. Yet, the results for tNAA were robust across quantification methods and concur with relevant parts of the disrupt, potentiate, and rewire model.

Neural Activation in the Ventromedial Prefrontal Cortex Precedes Conscious Experience of Being in or out of a Transient Hallucinatory State.

BACKGROUND AND HYPOTHESES: Auditory verbal hallucinations (AVHs) is not only a common symptom in schizophrenia but also observed in individuals in the general population. Despite extensive research, AVHs are poorly understood, especially their underlying neuronal architecture. Neuroimaging methods have been used to identify brain areas and networks that are activated during hallucinations. A characteristic feature of AVHs is, however, that they fluctuate over time, with varying frequencies of starts and stops. An unanswered question is, therefore, what neuronal events co-occur with the initiation and inhibition of an AVH episode. STUDY DESIGN: We investigated brain activation with fMRI in 66 individuals who experienced multiple AVH-episodes while in the scanner. We extracted time-series fMRI-data and monitored changes second-by-second from 10 s before to 15 s after participants indicated the start and stop of an episode, respectively, by pressing a hand-held response-button. STUDY RESULTS: We found a region in the ventromedial prefrontal cortex (VMPFC) which showed a significant increase in activation initiated a few seconds before participants indicated the start of an episode, and a corresponding decrease in activation initiated a few seconds before the end of an episode. CONCLUSIONS: The consistent increase and decrease in activation in this area in advance of the consciously experienced presence or absence of the "voice" imply that this region may act as a switch in turning episodes on and off. The activation is unlikely to be confounded by motor responses. The findings could have clinical implications for brain stimulation treatments, like transcranial magnetic stimulation.

Default mode network alterations underlie auditory verbal hallucinations in schizophrenia.

Although alterations of the default mode network (DMN) in schizophrenia (SZ) have been largely investigated, less research has been carried out on DMN alterations in different sub-phenotypes of this disorder. The aim of this pilot study was to compare DMN features among SZ patients with and without auditory verbal hallucinations (AVH). Three groups of 17 participants each were considered: patients with hallucinations (AVH-SZ), patients without hallucinations (nAVH-SZ) and age-matched healthy controls (HC). The DMN spatial pattern was similar between the nAVH-SZ and HC, but the comparison between these two groups and the AVH-SZ group revealed alterations in the left Angular Gyrus (lAG) node of the DMN. Using a novel approach based on normalized fractional Amplitude of Low-Frequency Fluctuations (fALFF), the AVH-SZ subgroup showed altered spectral activity in the DMN compared with the other two groups, especially in the lower-frequency bands (0.017-0.04 Hz). Significant positive correlations were found for both SZ groups collapsed, and for the nAVH-SZ group alone between delusional scores (PANSS-P1) and slow fALFF bands of the DMN. Narrowing the analysis to the ROI centered on the lAG, significant correlations were found in the AVH-SZ group for hallucination scores (PANSS-P3) and Slow-5 and Slow-4 (both positive), and Slow-3 (negative) fALFF bands. Our results reveal the central role of the lAG in relation to hallucinations, an important cortical area connecting auditory cortex with several hubs (including frontal linguistic centers) and involved in auditory process monitoring.

Comparison of seven modelling algorithms for γ-aminobutyric acid-edited proton magnetic resonance spectroscopy.

Edited MRS sequences are widely used for studying γ-aminobutyric acid (GABA) in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multisite study. GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate. After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors' hardware, presenting across algorithms. Scale differences across algorithms were also observed. Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An interclass correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases. Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.

Negative valence of hallucinatory voices as predictor of cortical glutamatergic metabolite levels in schizophrenia patients.

OBJECTIVES: Negative emotional valence of auditory verbal hallucinations (AVHs) in schizophrenia can be a source of distress and is considered a strong predictor of illness severity. Previous studies have found glutamate to mediate AVH severity in frontal and temporal brain regions, however, they do not specifically address emotional valence of AVH. The role of glutamate for the experience of negative- versus positive emotional valence of AVH is therefore unknown and was investigated in the current study. METHODS: Using magnetic resonance spectroscopy (MRS), 37 schizophrenia patients had Glx (glutamate+glutamine) measured in the left superior temporal gyrus (STG), and additionally in the anterior cingulate cortex (ACC) and the right STG, or in the left inferior frontal gyrus (IFG). Self-reported emotional valence in AVH was measured with the Beliefs About Voices Questionnaire (BAVQ-R). RESULTS: Results from linear mixed models showed that negative emotional valence was associated with reduced Glx levels across all four measured brain regions in the frontal and temporal lobe. More specifically, voices that were experienced to be omnipotent (p = 0.04) and that the patients attempted to resist (p = 0.04) were related to lower Glx levels. Follow-up analysis of the latter showed that voices that evoked emotional resistance (i.e., fear, sadness, anger), rather than behavioral resistance, was a significant predictor of reduced glutamate (p = 0.02). CONCLUSION: The findings could indicate aberrant glutamatergic signaling, or increased NMDA-receptor hypoactivity in patients who experience their voices to be more emotionally negative. Overall, the study provides support for the glutamate hypothesis of schizophrenia.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Simultaneous Measurement of the BOLD Effect and Metabolic Changes in Response to Visual Stimulation Using the MEGA-PRESS Sequence at 3 T.

The blood oxygen level dependent (BOLD) effect that provides the contrast in functional magnetic resonance imaging (fMRI) has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy (MRS) and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the linewidth of the unsuppressed water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate (measured as Glx) and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex (OCC) of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods.

Magnetic Resonance Spectroscopy in Depressed Subjects Treated With Electroconvulsive Therapy-A Systematic Review of Literature.

Electroconvulsive therapy (ECT) is considered to be the most effective acute treatment for otherwise treatment resistant major depressive episodes, and has been used for over 80 years. Still, the underlying mechanism of action is largely unknow. Several studies suggest that ECT affects the cerebral neurotransmitters, such as gamma-aminobutyric acid (GABA) and glutamate. Magnetic resonance spectroscopy (MRS) allows investigators to study neurotransmitters in vivo, and has been used to study neurochemical changes in the brain of patients treated with ECT. Several investigations have been performed on ECT-patients; however, no systematic review has yet summarized these findings. A systematic literature search based on the Prisma guidelines was performed. PubMed (Medline) was used in order to find investigations studying patients that had been treated with ECT and had undergone an MRS examination. A search in the databases Embase, PsycInfo, and Web of Science was also performed, leading to no additional records. A total of 30 records were identified and screened which resulted in 16 original investigations for review. The total number of patients that was included in these studies, ignoring potential overlap of samples in some investigations, was 325. The metabolites reported were N-acetyl aspartate, Choline, Myoinositol, Glutamate and Glutamine, GABA and Creatine. The strongest evidence for neurochemical change related to ECT, was found for N-acetyl aspartate (reduction), which is a marker of neuronal integrity. Increased choline and glutamate following treatment was also commonly reported.

Glutamate- and GABA-Modulated Connectivity in Auditory Hallucinations-A Combined Resting State fMRI and MR Spectroscopy Study.

Background: Auditory verbal hallucinations (AVH) have been linked to aberrant interhemispheric connectivity between the left and the right superior temporal gyrus (STG), labeled the interhemispheric miscommunication theory. The present study investigated if interhemispheric miscommunication is modulated at the neurochemical level by glutamate (Glu) and gamma-aminobutyric acid (GABA) concentrations in temporal and prefrontal lobe areas, as proposed by the theory. Methods: We combined resting-state fMRI connectivity with MR spectroscopy (MRS) in a sample of 81 psychosis patients, comparing patients with high hallucination severity (high-AVH) and low hallucination severity (low-AVH) groups. Glu and GABA concentrations were acquired from the left STG and the anterior cingulate cortex (ACC), an area of cognitive control that has been proposed to modulate STG functioning in AVH. Results: Functional connectivity showed significant interaction effects between AVH Group and ACC-recorded Glu and GABA metabolites. Follow-up tests showed that there was a significant positive association for Glu concentration and interhemispheric STG connectivity in the high-AVH group, while there was a significant negative association for GABA concentration and interhemispheric STG connectivity in the low-AVH group. Conclusion: The results show neurochemical modulation of STG interhemispheric connectivity, as predicted by the interhemispheric miscommunication hypothesis. Furthermore, the findings are in line with an excitatory/inhibitory imbalance model for AVH. By combining different neuroimaging modalities, the current results provide a more comprehensive insight into the neural correlates of AVH.

Combined fMRI Region- and Network-Analysis Reveal New Insights of Top-Down Modulation of Bottom-Up Processes in Auditory Laterality.

Dichotic listening along with the right-ear advantage (REA) has been a standard method of investigating auditory laterality ever since it was first introduced into neuropsychology in the early 1960s. Beginning in the 1980s, authors reported that it was possible to modulate the bottom-up driven perceptual REA by instructing subjects to selectively attend to and report only from the right or left ear. In the present study, we investigated neuronal correlates of both the bottom-up and top-down modulation of the REA through two fMRI analysis approaches: a traditional region approach and a network connectivity approach. Blood-Oxygenation-Level-Dependent (BOLD) fMRI data were acquired while subjects performed the standard forced-attention paradigm. We asked two questions, could the behavioral REA be replicated in unique brain markers, and second if the profound instruction-induced modulation of the REA found in behavioral data would correspond to a similar modulation of brain activation, both region- and network-specific modulations. The subjects were 70 healthy adult right-handers, about half men and half women. fMRI data were acquired in a 3T MR scanner, and the behavioral results replicated previous findings with a REA in the non-forced (NF) and forced-right (FR) conditions, and a tendency for a left-ear advantage (LEA) in the FL-condition. The fMRI data showed unique activations in the speech perception areas of the left temporal lobe when directly contrasted with activations in the homologous right side. However, there were no remaining unique activations when the FR- and FL-conditions were contrasted against each other, and with the NF-condition, using a conservative significance thresholding. The fMRI results are conceptualized within a network connectivity frame of reference, especially with reference to the extrinsic mode network (EMN). The EMN is a generalized task-positive network that is upregulated whenever the task demands exceed a certain threshold irrespective of the specifics and demands of the task. This could explain the similarity of activations for the FR- and FL-conditions, despite the clear differences in behavior.

Dynamic switching between intrinsic and extrinsic mode networks as demands change from passive to active processing.

In this study we report on the relationship between default and extrinsic mode networks across alternating brief periods of rest and active task processing. Three different visual tasks were used in a classic fMRI ON-OFF block design where task (ON) blocks alternated with equal periods of rest (OFF) blocks: mental rotation, working memory and mental arithmetic. We showed the existence of a generalized task-positive network, labelled the extrinsic mode network (EMN) that is anti-correlated with the default mode network (DMN) as processing demands shifted from rest to active processing. We then identified two key regions of interest (ROIs) in the supplementary motor area (SMA) and precuneus/posterior cingulate cortex (PCC) regions as hubs for the extrinsic and intrinsic networks, and extracted the time-course from these ROIs. The results showed a close to perfect anti-correlation for the SMA and Precuneus/PCC time-courses for ON- and OFF-blocks. We suggest the existence of two large-scale networks, an extrinsic mode network and an intrinsic mode network, which are up- and down-regulated as environmental demands change from active to passive processing.

Anterior cingulate gamma-aminobutyric acid concentrations and electroconvulsive therapy.

OBJECTIVE: The anticonvulsant hypothesis posits that ECT's mechanism of action is related to enhancement of endogenous anticonvulsant brain mechanisms. Results of prior studies investigating the role of the inhibitory neurotransmitter gamma-aminobutyric acid ("GABA+", GABA and coedited macromolecules) in the pathophysiology and treatment of depression remain inconclusive. The aim of our study was to investigate treatment-responsive changes of GABA+ in subjects with a depressive episode receiving electroconvulsive therapy (ECT). METHODS: In total, 41 depressed subjects (DEP) and 35 healthy controls (HC) were recruited at two independent sites in Norway and the USA. MEGA-PRESS was used for investigation of GABA+ in the anterior cingulate cortex. We assessed longitudinal and cross-sectional differences between DEP and HC, as well as the relationship between GABA+ change and change in depression severity and number of ECTs. We also assessed longitudinal differences in cognitive performance and GABA+ levels. RESULTS: Depressive episode did not show a difference in GABA+ relative to HC (t71  = -0.36, p = .72) or in longitudinal analysis (t36  = 0.97, p = .34). Remitters and nonremitters did not show longitudinal (t36  = 1.12, p = .27) or cross-sectional differences in GABA+. GABA+ levels were not related to changes in antidepressant response (t35  = 1.12, p = .27) or treatment number (t36  = 0.05, p = .96). An association between cognitive performance and GABA+ levels was found in DEP that completed cognitive effortful testing (t18  = 2.4, p = .03). CONCLUSION: Our results failed to support GABA as a marker for depression and abnormal mood state and provide no support for the anticonvulsant hypothesis of ECT. ECT-induced change in GABA concentrations may be related to change in cognitive function.

Hallucinating schizophrenia patients have longer left arcuate fasciculus fiber tracks: a DTI tractography study.

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on the constrains for interaction between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer reconstructed tracks along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer tracks in the left compared to the right side. In addition, there were significant positive correlations between PANSS scores and track length, track volume, and number of track streamlines for the posterior AF segment on the left side. It is concluded that the present DTI results may have implications for interpretations of functional imaging results.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia.

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their "voices" through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs.