When "more for others, less for self" leads to co-benefits: A tri-MRI dyad-hyperscanning study.

Unselfishness is admired, especially when collaborations between groups of various scales are urgently needed. However, its neural mechanisms remain elusive. In a tri-MRI dyad-hyperscanning experiment involving 26 groups, each containing 4 participants as two rotating pairs in a coordination game, we sought to achieve reciprocity, or "winning in turn by the two interacting players," as the precursor to unselfishness. Due to its critical role in social processing, the right temporal-parietal junction (rTPJ) was the seed for both time domain (connectivity) and frequency domain (i.e., coherence) analyses. For the former, negative connectivity between the rTPJ and the mentalizing network areas (e.g., the right inferior parietal lobule, rIPL) was identified, and such connectivity was further negatively correlated with the individual's final gain, supporting our task design that "rewarded" the reciprocal participants. For the latter, cerebral coherences of the rTPJs emerged between the interacting pairs (i.e., within-group interacting pairs), and the coupling between the rTPJ and the right superior temporal gyrus (rSTG) between the players who were not interacting with each other (i.e., within-group noninteracting pairs). These coherences reinforce the hypotheses that the rTPJ-rTPJ coupling tracks the collaboration processes and the rTPJ-rSTG coupling for the emergence of decontextualized shared meaning. Our results underpin two social roles (inferring others' behavior and interpreting social outcomes) subserved by the rTPJ-related network and highlight its interaction with other-self/other-concerning brain areas in reaching co-benefits among unselfish players.

Distinct cerebral coherence in task-based fMRI hyperscanning: cooperation versus competition.

This study features an functional magnetic resonance imaging (fMRI) hyperscanning experiment from 2 sites, 305 km apart. The experiment contains 2 conditions: the dyad collaborated to win and then split the reward in the cooperation condition, whereas the winner took all the reward in the competition condition, thereby resulting in dynamic strategic interactions. To calculate the cerebral coherence in such jittered event-related fMRI tasks, we first iteratively estimated the feedback-related blood oxygenation level-dependent responses of each trial, using 8 finite impulse response functions (16 s) and then concatenated the beta volume series. With the right temporal-parietal junction (rTPJ) as the seed, the interpersonal connected brain areas were separately identified: the right superior temporal gyrus (rSTG) (cooperation) and the left precuneus (lPrecuneus) (competition), both peaking at the designated frequency bin (1/16 s = 0.0625 Hz), but not in permuted pairs. In addition, the extended coherence analyses on shorter and longer concatenated volumes verified that only in the optimal trial frequency did the rTPJ-rSTG and rTPJ-lPrecuneus couplings peak. In sum, our approach both showcases a flexible analysis method that widens the applicability of interpersonal coherence in the rapid event-related fMRI hyperscanning and reveals a context-based inter-brain coupling between interacting pairs during cooperation and during competition.

Epinephrine modulates memory of latent learning in an inhibitory avoidance task.

The present study examined the memory modulatory effect of epinephrine on latent learning of an inhibitory avoidance task. Male Sprague-Dawley rats on the first day were subjected to one of three conditions (no, short or long) in pre-exposure to the task apparatus. One day or several days later, they received the typical inhibitory avoidance training with a 0.5 mA/0.5 s foot shock. Memory of the inhibitory avoidance response was tested one day after the foot-shock training. The long pre-exposure group showed better memory than the no or short pre-exposure group, and this latent memory could last for 6 days: Retention scores of the long pre-exposure group were significantly better than those of the no pre-exposure group if the shock training was given 3 or 6 days, but not 12 or 21 days, after the pre-exposure. Epinephrine injected after the pre-exposure training modulated the latent memory in a dose- and time-dependent manner: 0.01 mg/kg given shortly after the short pre-exposure enhanced the memory, but 0.5 mg/kg given shortly after the long pre-exposure impaired it. Epinephrine injected 4 h after the pre-exposure had no effect, neither did that given to rats pre-exposed to a different context. Epinephrine (0.01 mg/kg) also made the latent memory lasting longer as the rats treated with it showed significant avoidance behavior when they had the shock training at 12 or 21 days after the pre-exposure. These findings suggest that epinephrine could modulate memory formed in the latent learning.

Deciphering laminar-specific neural inputs with line-scanning fMRI.

Using a line-scanning method during functional magnetic resonance imaging (fMRI), we obtained high temporal (50-ms) and spatial (50-µm) resolution information along the cortical thickness and showed that the laminar position of fMRI onset coincides with distinct neural inputs in rat somatosensory and motor cortices. This laminar-specific fMRI onset allowed us to identify the neural inputs underlying ipsilateral fMRI activation in the barrel cortex due to peripheral denervation-induced plasticity.

Functional connectivity MRI tracks memory networks after maze learning in rodents.

Learning and memory employs a series of cognitive processes which require the coordination of multiple areas across the brain. However in vivo imaging of cognitive function has been challenging in rodents. Since these processes involve synchronous firing among different brain loci we explored functional connectivity imaging with resting-state fMRI. After 5-day training on a hidden platform watermaze task, notable signal correlations were seen between the hippocampal CA3 and other structures, including thalamus, septum and cingulate cortex, compared to swim control or naïve animals. The connectivity sustained 7 days after training and was reorganized toward the cortex, consistent with views of memory trace distribution leading to memory consolidation. These data demonstrates that, after a cognitive task, altered functional connectivity can be detected in the subsequently sedated rodent using in vivo imaging. This approach paves the way to understand dynamics of area-dependent distribution processes in animal models of cognition.

Wireless amplified nuclear MR detector (WAND) for high-spatial-resolution MR imaging of internal organs: preclinical demonstration in a rodent model.

PURPOSE: To assess the feasibility of imaging deep-lying internal organs at high spatial resolution by imaging kidney glomeruli in a rodent model with use of a newly developed, wireless amplified nuclear magnetic resonance (MR) detector. MATERIALS AND METHODS: This study was approved by the Animal Care and Use Committee at the National Institutes of Health/National Institute of Neurologic Disorder and Stroke. As a preclinical demonstration of this new detection technology, five different millimeter-scale wireless amplified nuclear MR detectors configured as double frequency resonators were chronically implanted on the medial surface of the kidney in five Sprague-Dawley rats for MR imaging at 11.7 T. Among these rats, two were administered gadopentetate dimeglumine to visualize renal tubules on T1-weighted gradient-refocused echo (GRE) images, two were administered cationized ferritin to visualize glomeruli on T2*-weighted GRE images, and the remaining rat was administered both gadopentetate dimeglumine and cationized ferritin to visualize the interleaved pattern of renal tubules and glomeruli. The image intensity in each pixel was compared with the local tissue signal intensity average to identify regions of hyper- or hypointensity. RESULTS: T1-weighted images with 70-µm in-plane resolution and 200-µm section thickness were obtained within 3.2 minutes to image renal tubules, and T2*-weighted images of the same resolution were obtained within 5.8 minutes to image the glomeruli. Hyperintensity from gadopentetate dimeglumine enabled visualization of renal tubules, and hypointensity from cationic ferritin enabled visualization of the glomeruli. CONCLUSION: High-spatial-resolution images have been obtained to observe kidney microstructures in vivo with a wireless amplified nuclear MR detector.

Functional connectivity changes during consolidation of inhibitory avoidance memory in rats: a manganese-enhanced MRI study.

Consolidation of memory involves transfer of encoded information into a durable neural representation, but how this is transacted in the nervous system remains elusive. It has been proposed that memory consolidation is subserved by formation of a cell assembly due to coincidence of pre- and post-synaptic activity therein after learning. To capture such off-line changes, manganese-enhanced magnetic resonance imaging (MEMRI) was used to trace brain activity during the memory consolidation period. Male Wistar rats were trained on the one-trial inhibitory avoidance task and received intraventricular infusion of manganese ion shortly after training. The MEMRI taken 1 day later showed that brain areas including the prelimbic, insular and anterior pirifrom cortices of the learning group had significantly lower memory-related MEMRI signal than those of the control group. The functional network was revealed by correlating the MEMRI signals among regions followed by graph theoretical analysis. Learning sculpted the non-discriminative connectivity among many brain regions in the controls into a network in the trained rats with selected connectivity among regions implicated in inhibitory avoidance learning. The network could be organized into three clusters presumably subserving different functions. The results suggest that the brain prunes excessive functional connectivity in a cell assembly to consolidate new memory.

3D mapping of somatotopic reorganization with small animal functional MRI.

There are few in vivo noninvasive methods to study neuroplasticity in animal brains. Functional MRI (fMRI) has been developed for animal brain mapping, but few fMRI studies have analyzed functional alteration due to plasticity in animal models. One major limitation is that fMRI maps are characterized by statistical parametric mapping making the apparent boundary dependent on the statistical threshold used. Here, we developed a method to characterize the location of center-of-mass in fMRI maps that is shown not to be sensitive to statistical threshold. Utilizing centers-of-mass as anchor points to fit the spatial distribution of the BOLD response enabled quantitative group analysis of altered boundaries of functional somatosensory maps. This approach was used to study cortical reorganization in the rat primary somatosensory cortex (S1) after sensory deprivation to the barrel cortex by follicle ablation (F.A.). FMRI demonstrated an enlarged nose S1 representation in the 3D somatotopic functional maps. This result clearly demonstrates that fMRI enables the spatial mapping of functional changes that can characterize multiple regions of S1 cortex and still be sensitive to changes due to plasticity.

Detection of nighttime melatonin level in Chinese Original Quiet Sitting.

BACKGROUND/PURPOSE: Some research has shown that melatonin levels increase after meditation practices, but other research has shown that they do not. In our previous functional magnetic resonance imaging study, we found positive activation of the pineal body during Chinese Original Quiet Sitting (COQS). To find other supporting evidence for pineal activation, the aim of this study was to evaluate the effect of COQS on nighttime melatonin levels. METHODS: Twenty subjects (11 women and 9 men, aged 29-64 years) who had regularly practiced daily meditation for 5-24 years participated in this study. All subjects served alternately as participants in the mediation and control groups. COQS was adopted in this study. Tests were performed during two nighttime sessions. Saliva was sampled at 0, 10, 20, 30, 45, 60 and 90 minutes after COQS and tested for level of melatonin. Time period effect analysis and mixed effect model analysis were preceded by paired t test analysis. RESULTS: In the meditation group (n = 20), the mean level of melatonin was significantly higher than the baseline level at various times post-meditation (p < 0.001). Within the control group (n = 20), the mean level of melatonin at various times was not significantly different compared with baseline (p>0.05). These results suggested that the melatonin level was statistically elevated in the meditation group and almost unchanged in the control group after nighttime meditation. The urine serotonin levels detected by measuring 5-hydroxy-indole-3-acetic acid levels were also studied, but no detectable difference between the groups was found. CONCLUSION: Our results support the hypothesis that meditation might elevate the nighttime salivary melatonin levels. It suggests that COQS can be used as a psychophysiological stimulus to increase endogenous secretion of melatonin, which in turn, might contribute to an improved sense of well-being.

A brain network that supports consensus-seeking and conflict-resolving of college couples' shopping interaction.

One of the typical campus scenes is the social interaction between college couples, and the lesson couples must keep learning is to adapt to each other. This fMRI study investigated the shopping interactions of 30 college couples, one lying inside and the other outside the scanner, beholding the same item from two connected PCs, making preference ratings and subsequent buy/not-buy decisions. The behavioral results showed the clear modulation of significant others' preferences onto one's own decisions, and the contrast of the "shop-together vs. shop-alone", and the "congruent (both liked or disliked the item, 68%) vs. incongruent (one liked but the other disliked, and vice versa)" together trials, both revealed bilateral temporal parietal junction (TPJ) among other reward-related regions, likely reflecting mentalizing during preference harmony. Moreover, when contrasting "own-high/other-low vs. own-low/other-high" incongruent trials, left anterior inferior parietal lobule (l-aIPL) was parametrically mapped, and the "yield (e.g., own-high/not-buy) vs. insist (e.g., own-low/not-buy)" modulation further revealed left lateral-IPL (l-lIPL), together with left TPJ forming a local social decision network that was further constrained by the mediation analysis among left TPJ-lIPL-aIPL. In sum, these results exemplify, via the two-person fMRI, the neural substrate of shopping interactions between couples.

Post-training infusion of glutamate into the bed nucleus of the stria terminalis enhanced inhibitory avoidance memory: an effect involving norepinephrine.

This study examined an interaction between glutamate and norepinephrine in the bed nucleus of the stria terminalis (BNST) in modulating affective memory formation. Male Wistar rats with indwelling cannulae in the BNST were trained on a one-trial step-through inhibitory avoidance task and received pre- or post-training intra-BNST infusion of glutamate, norepinephrine or their antagonists. Results of the 1-day test indicated that post-training intra-BNST infusion of DL-2-amino-5-phosphonovaleric acid (APV) impaired retention in a dose- and time-dependent manner, while infusion of glutamate had an opposite effect. Co-infusion of 0.2microg glutamate and 0.02microg norepinephrine resulted in marked retention enhancement by summating non-apparent effects of the two drugs given at a sub-enhancing dose. The amnesic effect of 5.0microg APV was ameliorated by 0.02microg norepinephrine, while the memory enhancing effect of 1.0microg glutamate was attenuated by 5.0microg propranolol. These findings suggest that training on an inhibitory avoidance task may alter glutamate neurotransmission, which by activating NMDA receptors releases norepinephrine to modulate memory formation via beta adrenoceptors in the BNST.

Infusion of lidocaine into the dorsal hippocampus before or after the shock training phase impaired conditioned freezing in a two-phase training task of contextual fear conditioning.

Learning in a contextual fear conditioning task involves forming a context representation and associating it with a shock. The dorsal hippocampus (DH) is implicated in representing the context, but whether it also has a role in associating the context and shock is unclear. To address this issue, male Wistar rats were trained on the task by a two-phase training paradigm, in which rats learned the context representation on day 1 and then reactivated it to associate with the shock on day 2; conditioned freezing was tested on day 3. Lidocaine was infused into the DH at various times in each of the two training sessions. Results showed that intra-DH infusion of lidocaine shortly before or after the context training session on day 1 impaired conditioned freezing, attesting to the DH involvement in context representation. Intra-DH infusion of lidocaine shortly before or after the shock training session on day 2 also impaired conditioned freezing. This deficit was reproduced by infusing lidocaine or APV (alpha-amino-5-phosphonovaleric acid) into the DH after activation of the context memory but before shock administration. The deficit was not due to drug-induced state-dependency, decreased shock sensitivity or reconsolidation failure of the contextual memory. These results suggest that in contextual fear conditioning integrity of the DH is required for memory processing of not only context representation but also context-shock association.

The capacity constraint in the prefrontal and parietal regions for coordinating dual arithmetic tasks.

Using a dual-serial-arithmetic paradigm, we examined whether a capacity limitation constrains the neural activation that underlies dual-task performance. Six conditions were run in the experiment (the baseline, single-addition, single-subtraction, dual-addition, dual-subtraction, and the dual-operation condition). In the baseline condition, participants were asked to remember the initial pair of numbers and ignore subsequent stimuli. In the single-addition and single-subtraction conditions, participants had to calculate a running total over a series of stimuli. In the dual-addition and dual-subtraction conditions, they had to do two arithmetic tasks involving the same operand (e.g., + 2 and + 7, - 3 and - 5). Participants performed one addition and one subtraction task (e.g., + 2 and - 7, - 3 and + 5) in the dual-operation condition. The functional magnetic resonance imaging results showed strict left prefrontal and parietal regions in the single-addition condition and bilateral activation in the single-subtraction condition. Greater activation in the prefrontal and parietal regions was observed in both the dual-operation condition and the dual-addition condition in comparison to the single-addition condition. No greater activation was observed in either the dual-operation condition or dual-subtraction condition in comparison to the single-subtraction condition. These results suggest a constraint imposed by a limit in capacity for the neural activity subserving dual-task performance when one of the tasks places high resource demands on the executive network.

Resting state functional connectivity data supports detection of cognition in the rodent brain.

Learning is a process which induces plastic changes in the synapses and connections across different regions of the brain. It is hypothesized that these new connections can be tracked with resting state functional connectivity MRI. While most of the evidence of learning-induced plasticity arises from previous human data, data from sedated rats that had undergone training for either 1 day or 5 days in a Morris Watermaze is presented. Seed points were taken from the somatosensory and visual cortices, and the hippocampal CA3 to detect connectivity changes. The data demonstrates that 5-day trained rats showed increased correlations between the hippocampal CA3 and thalamus, septum and cingulate cortex, compared to swim control or naïve animals. Seven days after the training, persistent but reorganized networks toward the cortex were observed. Data from the 1-day trained rats, on the contrary, showed connectivity similar to the swim control and less persistent. The connectivity in several regions was highly correlated with the behavioral performance in these animals. The data demonstrates that longitudinal changes following learning-induced plasticity can be detected and tracked with resting state connectivity.

Amphetamine induced sensitization in acoustic startle: lack of blockade by adrenalectomy and alpha-helical CRF9-41.

The present study utilized the acoustic startle response to evaluate the sensitization effect of repeated administration of amphetamine (AMPH). Intraperitoneal injections of AMPH induced a dose-dependent enhancement of startle: 5.0 mg/kg caused a robust effect, 1.0 or 3.0 mg/kg caused a negligible effect. Sensitization was generated by repeated administration of 5.0 mg/kg AMPH for 7 consecutive days and tested on the 8th and 9th days with challenge of saline and 3 mg/kg AMPH. The results showed that rats receiving chronic injections of AMPH, but not saline, showed significant enhancement of startle to 3.0 mg/kg AMPH, and this effect lasted at least for a month. To explore the role of the hypothalamo-pituitary-adrenal axis in this sensitization effect, rats received adrenalectomy, adrenal demedullation, or sham adrenal operation, and then were subjected to acute or chronic injections of 5.0 mg/kg AMPH. Removal of the whole adrenal gland or only the medulla abolished neither the startle enhancing effect of AMPH injected acutely nor the sensitization effect of AMPH injected chronically. In addition, intracerebroventricular infusion of a CRF antagonist, alpha-helical CRF9-41, prior to the challenge test failed to alter the sensitization effect of AMPH. These findings suggest that neither adrenal hormones nor CRF was indispensable for induction/expression of AMPH-induced sensitization in acoustic startle.

Pre- and post-training infusion of prazosin into the bed nucleus of the stria terminalis impaired acquisition and retention in a Morris water maze task.

The bed nucleus of the stria terminalis (BNST) is interconnected with the amygdala that is implicated in memory modulation. In view of the innervation of this structure by the hippocampus and brain stem noradrenergic nuclei, this study examined the role of BNST noradrenergic activity in acquisition, formation and expression of spatial memory. Male Wistar rats with indwelling cannulae in the BNST were trained on a spatial navigation task in the Morris water maze. Groups of rats received intra-BNST infusion of vehicle, norepinephrine, prazosin or both drugs shortly before or after each daily training session, or shortly before retention tests. Results showed that pre- or posttraining infusion of 1.0 microg prazosin impaired acquisition and retention, but the treatment had no effect on a cued response task. Posttraining infusion of 1.0 microg norepinephrine enhanced acquisition and retention, and this enhancing effect was blocked by simultaneous infusion of 0.3 microg prazosin. Pretest intra-BNST of prazosin or norepinephrine at a dose of 1.0 microg did not impair expression of the spatial navigation memory. These findings suggest that the BNST noradrengergic function is involved in modulating acquisition and formation of spatial memory that engage the hippocampus.

Self-organized Mn2+-Block Copolymer Complexes and Their Use for In Vivo MR Imaging of Biological Processes.

Manganese-block copolymer complexes (MnBCs) that contain paramagnetic Mn ions complexed with ionic-nonionic poly(ethylene oxide-b-poly(methacrylate) have been developed for use as a T1-weighted MRI contrast agent. By encasing Mn ion within ionized polymer matrices, r1 values could be increased by 250-350 % in comparison with free Mn ion at relative high fields of 4.7 to 11.7 T. MnBCs were further manipulated by treatment with NaOH to achieve more stable complexes (iMnBCs). iMnBCs delayed release of Mn2+ which could be accelerated by low pH, indeed by cellular uptake via endocytosis into acidic compartments. Both complexes exhibited good T1 contrast signal enhancement in liver following intravenous infusion. The contrast was observed in gallbladder due to the clearance of Mn ion from liver to biliary process. iMnBCs, notably, showed a delayed contrast enhancement profile in gallbladder, which was interpreted to be due to degradation and excretion of Mn2+ ions into the gallbladder. Intracortical injection of iMnBCs into the rat brain also led to delayed neuronal transport to thalamus. The delayed enhancement feature may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be internalized by endocytosis.

Comparison of fMRI BOLD response patterns by electrical stimulation of the ventroposterior complex and medial thalamus of the rat.

The objective of this study was to compare the functional connectivity of the lateral and medial thalamocortical pain pathways by investigating the blood oxygen level-dependent (BOLD) activation patterns in the forebrain elicited by direct electrical stimulation of the ventroposterior (VP) and medial (MT) thalamus. An MRI-compatible stimulation electrode was implanted in the VP or MT of α-chloralose-anesthetized rats. Electrical stimulation was applied to the VP or MT at various intensities (50 µA to 300 µA) and frequencies (1 Hz to 12 Hz). BOLD responses were analyzed in the ipsilateral forelimb region of the primary somatosensory cortex (iS1FL) after VP stimulation and in the ipsilateral cingulate cortex (iCC) after MT stimulation. When stimulating the VP, the strongest activation occurred at 3 Hz. The stimulation intensity threshold was 50 µA and the response rapidly peaked at 100 µA. When stimulating the MT, The optimal frequency for stimulation was 9 Hz or 12 Hz, the stimulation intensity threshold was 100 µA and we observed a graded increase in the BOLD response following the application of higher intensity stimuli. We also evaluated c-Fos expression following the application of a 200-µA stimulus. Ventroposterior thalamic stimulation elicited c-Fos-positivity in few cells in the iS1FL and caudate putamen (iCPu). Medial thalamic stimulation, however, produced numerous c-Fos-positive cells in the iCC and iCPu. The differential BOLD responses and c-Fos expressions elicited by VP and MT stimulation indicate differences in stimulus-response properties of the medial and lateral thalamic pain pathways.

Thalamocortical inputs show post-critical-period plasticity.

Experience-dependent plasticity in the adult brain has clinical potential for functional rehabilitation following central and peripheral nerve injuries. Here, plasticity induced by unilateral infraorbital (IO) nerve resection in 4-week-old rats was mapped using MRI and synaptic mechanisms were elucidated by slice electrophysiology. Functional MRI demonstrates a cortical potentiation compared to thalamus 2 weeks after IO nerve resection. Tracing thalamocortical (TC) projections with manganese-enhanced MRI revealed circuit changes in the spared layer 4 (L4) barrel cortex. Brain slice electrophysiology revealed TC input strengthening onto L4 stellate cells due to an increase in postsynaptic strength and the number of functional synapses. This work shows that the TC input is a site for robust plasticity after the end of the previously defined critical period for this input. Thus, TC inputs may represent a major site for adult plasticity in contrast to the consensus that adult plasticity mainly occurs at cortico-cortical connections.

The use of silica coated MnO nanoparticles to control MRI relaxivity in response to specific physiological changes.

MnO nanoparticles have been tested to engineer a delayed increase in MRI T(1) relaxivity caused by cellular uptake via endocytosis into acidic compartments. Various coatings on core-shell structured MnO nanoparticles were tested for those that had the lowest T(1) relaxivity at pH 7.4, a pH where MnO does not dissolve into Mn(2+) ions. The rate of dissolution and release of Mn(2+) of the different coated MnO particles as well as changes in T(1) relaxivity were measured at pH 5, a pH routinely obtained in the endosomal-lysosomal pathway. Of a number of coatings, silica coated MnO (MnO@SiO(2)) had the lowest relaxivity at pH 7.4 (0.29 mm(-1) sec(-1)). About one third of the MnO dissolved within 20 min and the T(1) relaxivity increased to that of free Mn(2+) (6.10 mm(-1) sec(-1)) after three days at pH 5. MRI of MnO@SiO(2) particles injected into the rat brain showed time-dependent signal changes consistent with the in vitro rates. Thalamocortical tract-tracing could be observed due to the released Mn(2+). Intravenous infusion of MnO@SiO(2) particles showed little enhancement in any tissue except gallbladder. The gallbladder enhancement was interpreted to be due to endocytosis by liver cells and excretion of Mn(2+) ions into the gallbladder. The MnO@SiO(2) core-shell nanoparticles show the best potential for delaying the release of MRI contrast until endocytosis into low pH compartments activate MRI contrast. The delayed enhancement may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be recycled by endocytosis.