Resting-state functional connectivity following a single dose treatment with CB1 neutral antagonist tetrahydrocannabivarin (THCv) in healthy volunteers

BACKGROUND: The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown. METHOD: We examined the effects of a single 10mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales. RESULTS: Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv. CONCLUSION: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions

Enhanced neural response to anticipation, effort and consummation of reward and aversion during Bupropion treatment

Background We have previously shown that the selective serotonergic re-uptake inhibitor, citalopram, reduces the neural response to reward and aversion in healthy volunteers. We suggest that this inhibitory effect might underlie the emotional blunting reported by patients on these medications. Bupropion is a dopaminergic and noradrenergic re-uptake inhibitor and has been suggested to have more therapeutic effects on reward-related deficits. However, how bupropion affects the neural responses to reward and aversion is unclear. Methods 17 healthy volunteers (9 female, 8 male) received 7 days of bupropion (150 mg/day) and 7 days of placebo treatment, in a double-blind crossover design. Our functional Magnetic Resonance Imaging task consisted of 3 phases; an anticipatory phase (pleasant or unpleasant cue), an effort phase (button presses to achieve a pleasant taste or to avoid an unpleasant taste) and a consummatory phase (pleasant or unpleasant tastes). Volunteers also rated wanting, pleasantness and intensity of the tastes. Results Relative to placebo, bupropion increased activity during the anticipation phase in the ventral medial prefrontal cortex (vmPFC) and caudate. During the effort phase, bupropion increased activity in the vmPFC, striatum, dorsal anterior cingulate cortex and primary motor cortex. Bupropion also increased medial orbitofrontal cortex, amygdala and ventral striatum activity during the consummatory phase. Conclusions Our results are the first to show that bupropion can increase neural responses during the anticipation, effort and consummation of rewarding and aversive stimuli. This supports the notion that bupropion might be beneficial for depressed patients with reward-related deficits and blunted affect

Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin (THCv) on food reward and aversion in healthy volunteers

Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders. We previously showed that the cannabis receptor subtype (CB1) inverse agonist rimonabant, an antiobesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses (Horder et al., 2010). Unlike rimonabant, tetrahydrocannabivarin is a neutral CB1 receptor antagonist (Pertwee, 2005) and may therefore produce different modulations of the neural reward system. We hypothesized that tetrahydrocannabivarin would, unlike rimonabant, leave intact neural reward responses but augment aversive responses. Methods: We used a within-subject, double-blind design. Twenty healthy volunteers received a single dose of tetrahydrocannabivarin (10mg) and placebo in randomized order on 2 separate occasions. We measured the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (picture of moldy strawberries and/or a less pleasant strawberry taste) using functional magnetic resonance imaging. Volunteers rated pleasantness, intensity, and wanting for each stimulus. Results: There were no significant differences between groups in subjective ratings. However, tetrahydrocannabivarin increased responses to chocolate stimuli in the midbrain, anterior cingulate cortex, caudate, and putamen. Tetrahydrocannabivarin also increased responses to aversive stimuli in the amygdala, insula, mid orbitofrontal cortex, caudate, and putamen. Conclusions: Our findings are the first to show that treatment with the CB1 neutral antagonist tetrahydrocannabivarin increases neural responding to rewarding and aversive stimuli. This effect profile suggests therapeutic activity in obesity, perhaps with a lowered risk of depressive side effects. Keywords: reward, THCv, obesity, fMRI, cannabinoi

Attention-dependent modulation of cortical taste circuits revealed by granger causality with signal-dependent noise

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention

Optimized, automated shimming procedure for improved experimental cardiac magnetic resonance imaging and spectroscopy at ultra-high magnetic fields

Background: As técnicas de ressonância magnética cardíaca por imagem (MRI) e espetroscopia (MRS) são ferramentas usadas para caraterizar, de forma não invasiva, modelos de rato com doenças cardíacas humanas. As experiências são tipicamente conduzidas em sistemas de Ressonância Magnética (MR) equipados com magnetos de elevada intensidade (≥ 7 Tesla). Um requisito fundamental da MR é a homogeneidade do campo magnético estático, B0 (Grutter, 1993), e as flutuações (inomogeneidades) do campo magnético principal na região de imagem devem ser menores a três partes por milhão (3 ppm). Inserindo uma amostra aumenta-se a inomogeneidade do campo (devido a diferentes graus de magnetização ao longo da amostra como resposta a B0 ("suscetibilidade magnética")), a qual necessita de ser compensada (Crijns et al, 2011; Koch et al, 2006). Homogeneizar (shimming) o campo magnético estático é uma tarefa crucial em qualquer experiência de MR para maximizar a resolução e a razão entre sinal e ruído. Isto é particularmente importante em campos magnéticos de elevada intensidade devido à dependência linear da suscetibilidade magnética com B0. O ajuste manual das bobinas de shim é laborioso e subjetivo. Para além disso, este processo é particularmente desafiante onde vários tecidos (por exemplo, osso, fluxo de sangue, entre outros) estão numa vizinhança próxima dentro do tórax, tendo cada um diferentes suscetibilidades magnéticas e movimentos relativos. Métodos automáticos de shimming, como o FASTMAP ou FASTERMAP (Shen et al, 1997), estão experimental e clinicamente bem estabelecidos no tecido cerebral mas falham no coração devido à fase de sinal mal definida de MR, particularmente no interior dos ventrículos. Com base numa técnica previamente implementada para o cérebro humano, foi investigada a implementação de uma nova abordagem para corações de ratos, in vivo, capaz de homogeneizar B0 na região de interesse, com uma forma aleatória. Objetivo: O objetivo deste projeto é investigar os parâmetros ótimos de digitalização e pós-processamento, por forma a otimizar e alcançar um procedimento automático de shimming, potenciando, assim, as técnicas de MRI e MRS cardíacas. Métodos: Diversos ratos (n=5) foram submetidos à técnica de MR, realizada num magneto horizontal de 9.4 Tesla (T). A aquisição de imagem foi conduzida através de sequências rápidas echo variando os seguintes parâmetros: resolução, compensação de fluxo (on / off), orientação (short-axis / axial) e dimensão (multi-cortes 2D vs 3D). Três diferentes configurações de bobinas de shim foram investigadas e a sequência ótima de MR foi avaliada. Resultados: O nível de 17% de threshold demonstrou ser aceitável para a remoção das discontinuidades de fase. A análise quantitativa do desempenho das diferentes abordagens de phase unwrapping mostrou que a abordagem 3D é a mais eficaz na resolução das discontinuidades de fase presentes nos mapas de campo. A aplicação de orientação axial, os dados de maior resolução, a ausência de compensação de fluxo e a introdução de bobinas de shim de maiores ordens demonstraram um peso significativo na redução das inomogeneidades de B0, quando aplicados. Conclusões: Este projeto permitiu estabelecer parâmetros ótimos de aquisição e opções de pós-processamento que melhoram a homogeneidade de B0, importantes na validação de futuros estudos complementares.Background: Cardiac magnetic resonance imaging and spectroscopy are tools to non-invasively characterize rodent models of human heart disease. The experiments are typically carried out on dedicated MR systems equipped with ultra-high field magnets (≥ 7 Tesla). One fundamental requirement of MR is the homogeneity of the static magnetic field B0 (Grutter, 1993), and fluctuations of the main magnetic field (B0 inhomogeneities) within the scan region should be less than three parts per million (3 ppm). Inserting a sample inherently increases the field inhomogeneity (due to different degree of magnetization across the sample in response to the B0 field (“magnetic susceptibility”)), which needs to be compensated for (Crijns et al, 2011; Koch et al, 2006). Homogenizing (i.e. shimming) the static magnetic field is crucial for any MR experiment in order to maximize resolution and signal-to-noise. This is particularly important at ultra-high magnetic fields due to linear dependence of magnetic susceptibility. Adjusting the three linear and typically up to 14 higher order shims manually is laborious and subjective. Moreover, this process is particularly challenging where various tissues (i.e. heart and skeletal muscle, bone, lungs and flowing blood) are in close vicinity within the chest, each having different magnetic susceptibilities and relative motions. Auto-shim methods such as FASTMAP or FASTERMAP (Shen et al, 1997), are clinically and experimentally well established in brain tissue, but inevitably fail in the heart due to the ill-defined phase of the MR-signal, particularly inside the ventricles. Based on a technique, previously applied to human brain – implemented a novel approach for the application to mouse hearts in vivo, that is able to homogenize the B0-field in an arbitrarily shaped, but connected region of interest. Aim: The aim of this project is to investigate optimal scan parameters and post-processing approach to optimize and advance an automated shimming procedure for improved experimental cardiac magnetic resonance imaging and spectroscopy at ultra-high magnetic fields. Methods: Mice (n = 5) underwent MR experiments carried out in a 9.4 Tesla (T) horizontal magnet. The image acquisition was performed using fast gradient echo sequences varying the following parameters: resolution, flow compensation on / off, orientation (short-axis / axial), and dimension (2D multislice vs 3D). Three different shim coils’ configurations (shim coils up to the third order) were investigated and optimal MR sequence was assessed. Results: The threshold level of 17% proved to be acceptable for removal of phase discontinuities and hence it was used in subsequent studies. Quantitative analysis of the performance of different phase unwrapping approaches showed that the 3D approach is the most effective in resolving phase discontinuities present in field maps. The application of axial orientation, highest resolution data, absence of compensation flow and the introduction of higher order shim coils showed a significant reduction of B0 inhomogeneities when applied. Conclusions: This project established optimal acquisition parameters and post-processing options to improve the homogeneity of B0, and will aid the validation process in further follow-up studies

The Impact of Echo Time Shifts and Temporal Signal Fluctuations on BOLD Sensitivity in Presurgical Planning at 7 T.

OBJECTIVES: Gradients in the static magnetic field caused by tissues with differing magnetic susceptibilities lead to regional variations in the effective echo time, which modifies both image signal and BOLD sensitivity. Local echo time changes are not considered in the most commonly used metric for BOLD sensitivity, temporal signal-to-noise ratio (tSNR), but may be significant, particularly at ultrahigh field close to air cavities (such as the sinuses and ear canals) and near gross brain pathologies and postoperative sites. MATERIALS AND METHODS: We have studied the effect of local variations in echo time and tSNR on BOLD sensitivity in 3 healthy volunteers and 11 patients with tumors, postoperative cavities, and venous malformations at 7 T. Temporal signal-to-noise ratio was estimated from a 5-minute run of resting state echo planar imaging with a nominal echo time of 22 milliseconds. Maps of local echo time were derived from the phase of a multiecho GE scan. One healthy volunteer performed 10 runs of a breath-hold task. The t-map from this experiment served as a criterion standard BOLD sensitivity measure. Two runs of a less demanding breath-hold paradigm were used for patients. RESULTS: In all subjects, a strong reduction in the echo time (from 22 milliseconds to around 11 milliseconds) was found close to the ear canals and sinuses. These regions were characterized by high tSNR but low t-values in breath-hold t-maps. In some patients, regions of particular interest in presurgical planning were affected by reductions in the echo time to approximately 13-15 milliseconds. These included the primary motor cortex, Broca's area, and auditory cortex. These regions were characterized by high tSNR values (70 and above). Breath-hold results were corrupted by strong motion artifacts in all patients. CONCLUSIONS: Criterion standard BOLD sensitivity estimation using hypercapnic experiments is challenging, especially in patient populations. Taking into consideration the tSNR, commonly used for BOLD sensitivity estimation, but ignoring local reductions in the echo time (eg, from 22 to 11 milliseconds), would erroneously suggest functional sensitivity sufficient to map BOLD signal changes. It is therefore important to consider both local variations in the echo time and temporal variations in signal, using the product metric of these two indices for instance. This should ensure a reliable estimation of BOLD sensitivity and to facilitate the identification of potential false-negative results. This is particularly true at high fields, such as 7 T and in patients with large pathologies and postoperative cavities

A cross-linguistic evaluation of script-specific effects on fMRI lateralization in late second language readers

Behavioral and neuroimaging studies have provided evidence that reading is strongly left lateralized, and the degree of this pattern of functional lateralization can be indicative of reading competence. However, it remains unclear whether functional lateralization differs between the first (L1) and second (L2) languages in bilingual L2 readers. This question is particularly important when the particular script, or orthography, learned by the L2 readers is markedly different from their L1 script. In this study, we quantified functional lateralization in brain regions involved in visual word recognition for participants' L1 and L2 scripts, with a particular focus on the effects of L1–L2 script differences in the visual complexity and orthographic depth of the script. Two different groups of late L2 learners participated in an fMRI experiment using a visual one-back matching task: L1 readers of Japanese who learnt to read alphabetic English and L1 readers of English who learnt to read both Japanese syllabic Kana and logographic Kanji. The results showed weaker leftward lateralization in the posterior lateral occipital complex (pLOC) for logographic Kanji compared with syllabic and alphabetic scripts in both L1 and L2 readers of Kanji. When both L1 and L2 scripts were non-logographic, where symbols are mapped onto sounds, functional lateralization did not significantly differ between L1 and L2 scripts in any region, in any group. Our findings indicate that weaker leftward lateralization for logographic reading reflects greater requirement of the right hemisphere for processing visually complex logographic Kanji symbols, irrespective of whether Kanji is the readers' L1 or L2, rather than characterizing additional cognitive efforts of L2 readers. Finally, brain-behavior analysis revealed that functional lateralization for L2 visual word processing predicted L2 reading competency

Quality data assessment and improvement in pre-processing pipeline to minimize impact of spurious signals in functional magnetic imaging (fMRI)

In the recent years, the field of quality data assessment and signal denoising in functional magnetic resonance imaging (fMRI) is rapidly evolving and the identification and reduction of spurious signal with pre-processing pipeline is one of the most discussed topic. In particular, subject motion or physiological signals, such as respiratory or/and cardiac pulsatility, were showed to introduce false-positive activations in subsequent statistical analyses. Different measures for the evaluation of the impact of motion related artefacts, such as frame-wise displacement and root mean square of movement parameters, and the reduction of these artefacts with different approaches, such as linear regression of nuisance signals and scrubbing or censoring procedure, were introduced. However, we identify two main drawbacks: i) the different measures used for the evaluation of motion artefacts were based on user-dependent thresholds, and ii) each study described and applied their own pre-processing pipeline. Few studies analysed the effect of these different pipelines on subsequent analyses methods in task-based fMRI.The first aim of the study is to obtain a tool for motion fMRI data assessment, based on auto-calibrated procedures, to detect outlier subjects and outliers volumes, targeted on each investigated sample to ensure homogeneity of data for motion. The second aim is to compare the impact of different pre-processing pipelines on task-based fMRI using GLM based on recent advances in resting state fMRI preprocessing pipelines. Different output measures based on signal variability and task strength were used for the assessment

Fast Event-Related Mapping of Population Fingertip Tuning Properties in Human Sensorimotor Cortex at 7T

fMRI studies that investigate somatotopic tactile representations in the human cortex typically use either block or phase-encoded stimulation designs. Event-related (ER) designs allow for more flexible and unpredictable stimulation sequences than the other methods, but they are less efficient. Here we compared an efficiency-optimized fast ER design (2.8s average intertrial interval, ITI) to a conventional slow ER design (8s average ITI) for mapping voxelwise fingertip tactile tuning properties in the sensorimotor cortex of 6 participants at 7 Tesla. The fast ER design yielded more reliable responses compared to the slow ER design, but with otherwise similar tuning properties. Concatenating the fast and slow ER data, we demonstrate in each individual brain the existence of two separate somatotopically-organized tactile representations of the fingertips, one in the primary somatosensory cortex (S1) on the post-central gyrus, and the other shared across the motor and pre-motor cortices on the pre-central gyrus. In both S1 and motor representations, fingertip selectivity decreased progressively, from narrowly-tuned Brodmann areas 3b and 4a respectively, towards associative parietal and frontal regions that responded equally to all fingertips, suggesting increasing information integration along these two pathways. In addition, fingertip selectivity in S1 decreased from the cortical representation of the thumb to that of the pinky

Computing the social brain connectome across systems and states

Social skills probably emerge from the interaction between different neural processing levels. However, social neuroscience is fragmented into highly specialized, rarely cross-referenced topics. The present study attempts a systematic reconciliation by deriving a social brain definition from neural activity meta-analyses on social-cognitive capacities. The social brain was characterized by meta-analytic connectivity modeling evaluating coactivation in task-focused brain states and physiological fluctuations evaluating correlations in task-free brain states. Network clustering proposed a functional segregation into (1) lower sensory, (2) limbic, (3) intermediate, and (4) high associative neural circuits that together mediate various social phenomena. Functional profiling suggested that no brain region or network is exclusively devoted to social processes. Finally, nodes of the putative mirror-neuron system were coherently cross-connected during tasks and more tightly coupled to embodied simulation systems rather than abstract emulation systems. These first steps may help reintegrate the specialized research agendas in the social and affective sciences