Anterior insula activations in perceptual paradigms: often observed but barely understood

Anterior insular cortex is among the non-sensory brain regions most commonly found activated in functional brain imaging studies on visual and auditory perception. However, most of these studies do not explicitly address the functional role of this specific brain region in perception, but rather report its activation as a by-product. Here, we attempt to characterize the involvement of anterior insular cortex in various perceptual paradigms, including studies of visual awareness, perceptual decision making, cross-modal sensory processes and the role of spontaneous neural activity fluctuations in perception. We conclude that anterior insular cortex may be associated with perception in that it underpins heightened alertness of either stimulus- or task-driven origin, or both. Such a mechanism could integrate endogenous and exogenous functional demands under the joint criterion of whether they challenge an individual’s homeostasis.     

Longitudinal manganese-enhanced magnetic resonance imaging of neural projections and activity

Manganese-enhanced magnetic resonance imaging (MEMRI) holds exceptional promise for preclinical studies of brain-wide physiology in awake-behaving animals. The objectives of this review are to update the current information regarding MEMRI and to inform new investigators as to its potential. Mn(II) is a powerful contrast agent for two main reasons: (1) high signal intensity at low doses; and (2) biological interactions, such as projection tracing and neural activity mapping via entry into electrically active neurons in the living brain. High-spin Mn(II) reduces the relaxation time of water protons: at Mn(II) concentrations typically encountered in MEMRI, robust hyperintensity is obtained without adverse effects. By selectively entering neurons through voltage-gated calcium channels, Mn(II) highlights active neurons. Safe doses may be repeated over weeks to allow for longitudinal imaging of brain-wide dynamics in the same individual across time. When delivered by stereotactic intracerebral injection, Mn(II) enters active neurons at the injection site and then travels inside axons for long distances, tracing neuronal projection anatomy. Rates of axonal transport within the brain were measured for the first time in “time-lapse” MEMRI. When delivered systemically, Mn(II) enters active neurons throughout the brain via voltage-sensitive calcium channels and clears slowly. Thus behavior can be monitored during Mn(II) uptake and hyperintense signals due to Mn(II) uptake captured retrospectively, allowing pairing of behavior with neural activity maps for the first time. Here we review critical information gained from MEMRI projection mapping about human neuropsychological disorders. We then discuss results from neural activity mapping from systemic Mn(II) imaged longitudinally that have illuminated development of the tonotopic map in the inferior colliculus as well as brain-wide responses to acute threat and how it evolves over time. MEMRI posed specific challenges for image data analysis that have recently been transcended. We predict a bright future for longitudinal MEMRI in pursuit of solutions to the brain-behavior mystery.     

Conscious and nonconscious processes: An ERP index of an anticipatory response in a conditioning paradigm using visually masked stimuli

This study investigates the nonconscious elicitation of a previously conditioned response by using a differential conditioning paradigm with visually masked affectively valent facial schematics. Electrodermal (skin conductance response [SCR]) and brain (event-related potential [ERP]) activity were main dependent measures. Following a preconditioning phase in which subjects viewed energy masked pleasant and unpleasant facial schematics, conditioning with an aversive shock was established to unmasked presentations of an unpleasant face in a partial factorial design. A postconditioning phase of masked presentations, when compared with the preconditioning phase, revealed how the conditional effect within awareness might affect the same stimuli when presented outside awareness. An adaptive staircase technique was used to establish individual threshold levels, which represented a methodological advance over procedures typically used in visual masking research. The results revealed that responses to the CS+ (unpleasant face) changed significantly in predicted directions from preconditioning to postconditioning phase when compared with responses to the CS? (pleasant face). The SCR results systematically replicated recent Ohman, Dimberg, and Esteves (1988) findings, with the pattern of responses resembling a resistance to extinction effect. A new finding emerged for the brain responses. For the CS+, distinct slow wave activity occurred just before the point at which the shock had been delivered in the conditioning phase; no such activity was found for the CS?. This slow wave activity is similar to what has been described by others as an expectancy wave. The results indicate that an anticipatory process, as indexed by different physiological systems, can be elicited entirely outside awareness. Implications are discussed in regard to the nature of conscious and nonconscious processes.     

Reflections on extraordinary knowing: Insight into the nature of the mind

Scientists have spent considerable time and effort studying and mapping the geography of the brain, with the expectation that this understanding will lead to insights related to the nature of the mind. This article discusses evidence that, while the mind utilizes sensory information processed by the brain, awareness is not limited to these structures. Research studies give evidence supporting the mind's ability to expand awareness to include perception of objects and events not available to the five senses. This awareness also extends to moments in the future, including the mind's ability to access information seconds or even days in advance of the occurrence. A major brain filter that limits this capacity for expanded awareness is the Default Mode Network (DMN). We summarize research showing that when the DMN activity is reduced, e.g., through meditation, ingestion of neuromodulatory drugs, or NDEs, filtering within the brain is reduced, there is a concomitant development of new connectivity, and these neural changes are correlated with access to expanded awareness.     

基于低频振幅的吸烟成瘾者戒烟2周后脑功能活动变化的研究

探讨吸烟成瘾者戒烟前后的脑功能活动差异,使用3.0T磁共振扫描仪采集14名吸烟成瘾者戒烟前和戒烟后的静息态MRI数据,采用低频振幅(amplitude of low-frequency fluctuation, ALFF)的方法来比较分析吸烟成瘾者在戒烟前和戒烟两周后的脑功能活动情况.与戒烟前相比,吸烟成瘾者戒烟两周后静息状态下的右侧楔前叶、右侧后扣带回、左侧缘上回、左侧背外侧额上回和左侧额中回的ALFF活动降低;双侧距状裂周围皮层、双侧楔叶、左侧中央后回和左侧中央旁小叶的ALFF活动增加.研究结果表明:吸烟成瘾者在戒烟两周后额叶、边缘叶、顶叶和枕叶脑区的脑功能活动发生了改变,提示ALFF可作为监测或评价戒烟效果的潜在生理指标.     

Sleep-wave activity of a delta sleep-inducing peptide analog correlates with its penetrance of the blood-brain barrier

Delta sleep-inducing peptide (DSIP) significantly increases delta wave electrical activity in the brain of rats after intraperitoneal (i.p.) injection. Rats (n = 10) were peripherally injected with DSIP and [D-Ala4]DSIP-NH2 during the dark portion of a 12-h light/dark cycle prior to recording of epidural encephalographic (EEG) wave forms. Administration of [D-Ala4]DSIP-NH2, an analog that enters the brain after peripheral administration more readily than the parent DSIP molecule, resulted in significantly more delta waves than DSIP together with a highly significant amount of theta activity. DSIP was found to significantly increase EEG output in the delta range when compared with controls. In addition, the DSIP analog significantly decreased locomotor activity, whereas DSIP itself was without effect. These findings strongly support the controversial concepts that peripherally injected peptides can reach the brain and that DSIP compounds can increase sleep activity.     

Therapeutic antibodies for brain disorders

The enzyme β-secretase (BACE1) remains an important potential disease-modifying target for developing drugs to treat Alzheimer's disease. However, finding selective BACE1 inhibitors that can penetrate the brain has proved challenging. In this issue of Science Translational Medicine, a pair of studies describes a new approach to inhibiting BACE1 using a human monoclonal antibody that uses receptor-mediated transcytosis to cross the blood brain barrier (Atwal et al. and Yu et al.). The authors engineer a low-affinity bispecific monoclonal antibody targeting both BACE1 and the transferrin receptor and show that this antibody enters the brain more readily and inhibits BACE1 activity more efficiently than does a monospecific antibody against BACE1 alone. These findings should stimulate attempts to use receptor-mediated transcytosis to increase brain uptake of therapeutic antibodies for a variety of brain disorders.     

Simultaneous encoding of multiple potential reach directions in dorsal premotor cortex

We present evidence that the primate brain can simultaneously generate discrete directional signals related to multiple alternative reaching actions before making a decision between them. A monkey performed a task in which the correct target for a reaching movement was specified during two consecutive instructed-delay periods. First, two potential targets were presented; and second, a nonspatial cue identified one of them as the correct movement target. During the first period, two directional signals coexisted in the activity of cells in dorsal premotor cortex (PMd), oriented toward the two potential targets. During the second period, one of these disappeared and the remaining signal predicted the monkey's response choice. These results suggest that, when faced with multiple salient opportunities for reaching, the primate brain performs sensorimotor transformations in parallel to begin planning several reaching movements simultaneously before selecting one for overt execution.     

Neural, electrodermal and behavioral response patterns in contingency aware and unaware subjects during a picture-picture conditioning paradigm

One way of investigating affective learning is the use of aversive pictures as unconditioned stimuli (UCS) in conditioning paradigms. In the last decades, there has been a heated debate on the influence of contingency awareness on conditioned responses (CRs). Only a few studies found CRs in contingency unaware subjects whereas other studies only reported conditioned reactions in contingency aware participants. However, as a shortcoming, most studies employing picture-picture paradigms only investigated one response level (e.g. changes in subjective ratings). Further, changes in brain activity have so far been neglected in this field of research. The aim of the present study was to investigate different response levels with respect to contingency awareness: brain activity measured by functional magnetic resonance imaging (fMRI), skin conductance responses (SCRs) and valence ratings. A neutral geometric shape (conditioned stimulus, CS+) was followed by aversive pictures, whereas another shape (CS-) preceded neutral pictures. Unaware participants showed CRs in brain activity (e.g. the insula). Generally more activity was observed in the fear network (e.g. the amygdala, the lateral orbitofrontal cortex) in aware participants and in the nucleus accumbens (NAcc). Investigation of SCRs and valence ratings revealed that only aware participants showed conditioned reactions. Our results point toward dissociations between response levels (e.g. brain activity) not affected by contingency awareness and more cognitive response levels (e.g. subjective ratings and SCRs) which are affected by contingency awareness. As a unique finding in human aversive conditioning, we discuss the role of the nucleus accumbens as well as practical implications for affective learning models.     

Searching for a therapy of creatine transporter deficiency: some effects of creatine ethyl ester in brain slices in vitro

Creatine, an ergogenic compound essential for brain function, is very hydrophilic and needs a transporter to cross lipid-rich cells' plasma membranes. Hereditary creatine transporter deficiency is a severe incurable neurological disease where creatine is missing from the brain. Creatine esters are more lipophylic than creatine and may not need the transporter to cross plasma membranes. Thus, they may represent a useful therapy for hereditary creatine transporter deficiency. Creatine ethyl ester (CEE) is commercially available and widely used as a nutritional supplement. It was reported that it enters the cells of patients lacking the transporter but was not useful when administered in vivo, by oral route, to affected patients. In this paper we investigated the effects of CEE in in vitro brain slices before and after biochemical block of the creatine transporter. We found that CEE is rapidly degraded in the aqueous incubation medium to creatinine, however it remains in solution long enough to cause an increase in tissue content of creatine and, more prominently, phosphocreatine. Both CEE and creatine delayed the anoxia-induced failure of synaptic transmission, and there was no difference between the two compounds. Contrary to what we expected, CEE did not increase tissue creatine content after the creatine transporter was blocked. We confirm that CEE is probably not an effective treatment for hereditary creatine transporter deficiency. Two factors seem to affect the possibility for creatine esters to be exploited in the therapy of creatine transporter deficiency. First, the size of their alcohol moiety should be increased since this would increase the lipophilicity of the compound and improve its ability to diffuse through biological membranes. Second, creatine esters should be further modified to slow their degradation to creatinine and increase their half-life in aqueous solutions. Moreover, we should not forget the possibility that they are degraded in vivo by plasma esterases.     

Neuronal activity in primate orbitofrontal cortex reflects the value of time

Neurons in monkey orbitofrontal cortex (OF) are known to respond to reward-predicting cues with a strength that depends on the value of the predicted reward as determined 1) by intrinsic attributes including size and quality and 2) by extrinsic factors including the monkey's state of satiation and awareness of what other rewards are currently available. We pose here the question whether another extrinsic factor critical to determining reward value-the delay expected to elapse before delivery-influences neuronal activity in OF. To answer this question, we recorded from OF neurons while monkeys performed a memory-guided saccade task in which a cue presented early in each trial predicted whether the delay before the monkey could respond and receive a reward of fixed size would be short or long. OF neurons tended to fire more strongly in response to a cue predicting a short delay. The tendency to fire more strongly in anticipation of a short delay was correlated across neurons with the tendency to fire more strongly before a large reward. We conclude that neuronal activity in OF represents the time-discounted value of the expected reward.     

Top-down modulation of brain activity underlying intentional action and its relationship with awareness of intention: an ERP/Laplacian analysis

Intentional actions are executed with the peculiar experience of “I decide to do that.” It has been proposed that intentional actions involve a specific brain network involving the supplementary motor areas (SMAs). Here, we manipulated the internal representation participants attended to (intention vs. movement) in order to (1) examine the activity of SMAs and of the primary motor cortex (M1) during intentional action preparation and execution, and (2) investigate the temporal relationship between activity in these structures and intention awareness. Participants performed self-paced key presses. After each key press, participants were asked to report either the time they had the first intention to press the key (W-condition) or the time they actually started the movement (M-condition). We then estimated surface Laplacians from brain electrical potentials recorded while participants were performing the task. Activity in SMAs was greater in the W-condition than in the M-condition more than 1 s before electromyographic (EMG) activation, suggesting that this region is indeed associated to the formation of conscious intention. Conversely, activity in primary motor cortex (M1) contralateral to the responding hand was larger in the M-condition than in the W-condition, revealing that this region is also modulated by top-down processes. In addition, waveforms time-locked to the W-judgement revealed that M1 as well as EMG activation preceded the time at which participants become aware of their intention by about 0.3 s. This observation argues against the possibility that the temporal delay between motor-related activation and intention awareness results from smearing artifacts.     

Conflict-related activity in the caudal anterior cingulate cortex in the absence of awareness

The caudal anterior cingulate cortex (cACC) is thought to be involved in performance monitoring, as conflict and error-related activity frequently co-localize in this area. Recent results suggest that these effects may be differentially modulated by awareness. To clarify the role of awareness in performance monitoring by the cACC, we used rapid event-related fMRI to examine the cACC activity while subjects performed a dual task: a delayed recognition task and a serial response task (SRT) with an implicit probabilistic learning rule (i.e. the stimulus location followed a probabilistic sequence of which the subjects were unaware). Task performance confirmed that the location sequence was learned implicitly. Even though we found no evidence of awareness for the presence of the sequence, imaging data revealed increased cACC activity during correct trials which violated the sequence (high-conflict), relative to trials when stimuli followed the sequence (low conflict). Errors made with awareness also activated the same brain region. These results suggest that the performance monitoring function of the cACC extends beyond detection of errors made with or without awareness, and involves detection of multiple responses even when they are outside of awareness.     

Etiopathogenesis of information disease]

On the basis of the results of animal experiments and observations of people the concept of the information disease was formulated. It is understood as a form of psychoneural pathology characterized by special causes bringing it about, as well as by a number of peculiarities of its manifestation and pathogenesis. Besides, the information diseases, as any nosological form, is characterized by distinct protection mechanisms. The methods of prophylaxis and treatment, based on the specifics of its pathogenesis, were developed in animal experiments and effectively tested on humans. The information disease (ID) is understood as various disturbances of the higher functions of the nervous system, as well as resulting from it, disturbances of the functioning of the other systems of the organisms, occurring because of the brain being for a long time in the conditions of unfavorable combinations of the three following factors, i. e. certain volume of information to be processed for an important decision to be made, the factor of time assigned for the brain work and the level of motivation determining the importance of information and necessity of its being processed. The combination of these three factors can be unfavourable if: 1) it is necessary to process a large volume of information, including the function of decision making, in the conditions of prolonged deficit of time assigned for such work of the brain with the high level of behavioral motivation, or 2) there is information deficit during a long period of time, and the behavioral motivation is also high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of rodent secondary motor cortex in value-based action selection

Despite widespread neural activity related to reward values, signals related to upcoming choice have not been clearly identified in the rodent brain. Here we examined neuronal activity in the lateral (AGl) and medial (AGm) agranular cortex, corresponding to the primary and secondary motor cortex, respectively, in rats performing a dynamic foraging task. Choice signals, before behavioral manifestation of the rat's choice, arose in the AGm earlier than in any other areas of the rat brain previously studied under free-choice conditions. The AGm also conveyed neural signals for decision value and chosen value. By contrast, upcoming choice signals arose later, and value signals were weaker, in the AGl. We also found that AGm lesions made the rats' choices less dependent on dynamically updated values. These results suggest that rodent secondary motor cortex might be uniquely involved in both representing and reading out value signals for flexible action selection.     

Regret and its avoidance: a neuroimaging study of choice behavior

Human decisions can be shaped by predictions of emotions that ensue after choosing advantageously or disadvantageously. Indeed, anticipating regret is a powerful predictor of future choices. We measured brain activity using functional magnetic resonance imaging (fMRI) while subjects selected between two gambles wherein regret was induced by providing information about the outcome of the unchosen gamble. Increasing regret enhanced activity in the medial orbitofrontal region, the anterior cingulate cortex and the hippocampus. Notably, across the experiment, subjects became increasingly regret-aversive, a cumulative effect reflected in enhanced activity within medial orbitofrontal cortex and amygdala. This pattern of activity reoccurred just before making a choice, suggesting that the same neural circuitry mediates direct experience of regret and its anticipation. These results demonstrate that medial orbitofrontal cortex modulates the gain of adaptive emotions in a manner that may provide a substrate for the influence of high-level emotions on decision making.     

Direct comparison of neural systems mediating conscious and unconscious skill learning

Procedural learning, such as perceptual-motor sequence learning, has been suggested to be an obligatory consequence of practiced performance and to reflect adaptive plasticity in the neural systems mediating performance. Prior neuroimaging studies, however, have found that sequence learning accompanied with awareness (declarative learning) of the sequence activates entirely different brain regions than learning without awareness of the sequence (procedural learning). Functional neuroimaging was used to assess whether declarative sequence learning prevents procedural learning in the brain. Awareness of the sequence was controlled by changing the color of the stimuli to match or differ from the color used for random sequences. This allowed direct comparison of brain activation associated with procedural and declarative memory for an identical sequence. Activation occurred in a common neural network whether initial learning had occurred with or without awareness of the sequence, and whether subjects were aware or not aware of the sequence during performance. There was widespread additional activation associated with awareness of the sequence. This supports the view that some types of unconscious procedural learning occurs in the brain whether or not it is accompanied by conscious declarative knowledge.     

Hyperactive external awareness against hypoactive internal awareness in disorders of consciousness using resting‐state functional MRI: highlighting the involvement of visuo‐motor modulation

Resting‐state functional MRI (fMRI) has emerged as a valuable tool to characterize the complex states encompassing disorders of consciousness (DOC). Awareness appears to comprise two coexistent, anticorrelated components named the external and internal awareness networks. The present study hypothesizes that DOC interrupts the balance between the internal and external awareness networks. To gain more understanding of this phenomenon, the present study analyzed resting‐state fMRI data from 12 patients with DOC versus 12 healthy age‐matched controls. The data were explored using independent component analysis and amplitude of low‐frequency fluctuation (ALFF) analysis. The results indicated that DOC deactivated midline areas associated with internal awareness. In addition, external awareness was strengthened in DOC because of increased activation in the insula, lingual gyrus, paracentral and supplementary motor area. The activity patterns suggested strengthened external awareness against weakened internal awareness in DOC. In particular, increased activity found in the insula, lingual gyrus, paracentral and supplementary motor area of patients with DOC implied possible involvement of augmented visuo‐motor modulation in these patients. DOC is probably related to hyperactive external awareness opposing hypoactive internal awareness. This unique pattern of brain activity may potentially be a prognostic marker for DOC. Copyright © 2014 John Wiley & Sons, Ltd.     

The neural mechanisms of percept-memory comparison in visual working memory

The perception of internal bodily signals (interoception) plays a relevant role for emotion processing and feelings. This study investigated changes of interoceptive awareness and cardiac autonomic activity induced by short-term food deprivation and its relationship to hunger and affective experience. 20 healthy women were exposed to 24 h of food deprivation in a controlled setting. Interoceptive awareness was assessed by using a heartbeat tracking task. Felt hunger, cardiac autonomic activity, mood and subjective appraisal of interoceptive sensations were assessed before and after fasting. Results show that short-term fasting intensifies interoceptive awareness, not restricted to food cues, via changes of autonomic cardiac and/or cardiodynamic activity. The increase of interoceptive awareness was positively related to felt hunger. Additionally, the results demonstrate the role of cardiac vagal activity as a potential index of emotion related self-regulation, for hunger, mood and the affective appraisal of interoceptive signals during acute fasting.     

Brain activity before an event predicts later recollection

Neural activity elicited by an event can predict whether the event is successfully encoded into memory. Here we assessed whether memory encoding relies not only on neural activity that follows an event, but also on activity that precedes it. In two experiments we found that human brain activity elicited by a cue presented just before a word could predict whether the word would be recollected in a later memory test.