General mechanisms of task engagement in the primate frontal cortex.

Staying engaged is necessary to maintain goal-directed behaviors. Despite this, engagement exhibits continuous, intrinsic fluctuations. Even in experimental settings, animals, unlike most humans, repeatedly and spontaneously move between periods of complete task engagement and disengagement. We, therefore, looked at behavior in male macaques (macaca mulatta) in four tasks while recording fMRI signals. We identified consistent autocorrelation in task disengagement. This made it possible to build models capturing task-independent engagement. We identified task general patterns of neural activity linked to impending sudden task disengagement in mid-cingulate gyrus. By contrast, activity centered in perigenual anterior cingulate cortex (pgACC) was associated with maintenance of performance across tasks. Importantly, we carefully controlled for task-specific factors such as the reward history and other motivational effects, such as response vigor, in our analyses. Moreover, we showed pgACC activity had a causal link to task engagement: transcranial ultrasound stimulation of pgACC changed task engagement patterns.

A frontopolar-temporal circuit determines the impact of social information in macaque decision making.

When choosing, primates are guided not only by personal experience of objects but also by social information such as others' attitudes toward the objects. Crucially, both sources of information-personal and socially derived-vary in reliability. To choose optimally, one must sometimes override choice guidance by personal experience and follow social cues instead, and sometimes one must do the opposite. The dorsomedial frontopolar cortex (dmFPC) tracks reliability of social information and determines whether it will be attended to guide behavior. To do this, dmFPC activity enters specific patterns of interaction with a region in the mid-superior temporal sulcus (mSTS). Reversible disruption of dmFPC activity with transcranial ultrasound stimulation (TUS) led macaques to fail to be guided by social information when it was reliable but to be more likely to use it when it was unreliable. By contrast, mSTS disruption uniformly downregulated the impact of social information on behavior.

Complementary roles of serotonergic and cholinergic systems in decisions about when to act.

Decision-making not only involves deciding about which action to choose but when and whether to initiate an action in the first place. Macaque monkeys tracked number of dots on a screen and could choose when to make a response. The longer the animals waited before responding, the more dots appeared on the screen and the higher the probability of reward. Monkeys waited longer before making a response when a trial's value was less than the environment's average value. Recordings of brain activity with fMRI revealed that activity in dorsal raphe nucleus (DRN)-a key source of serotonin (5-HT)-tracked average value of the environment. By contrast, activity in the basal forebrain (BF)-an important source of acetylcholine (ACh)-was related to decision time to act as a function of immediate and recent past context. Interactions between DRN and BF and the anterior cingulate cortex (ACC), another region with action initiation-related activity, occurred as a function of the decision time to act. Next, we performed two psychopharmacological studies. Manipulating systemic 5-HT by citalopram prolonged the time macaques waited to respond for a given opportunity. This effect was more evident during blocks with long inter-trial intervals (ITIs) where good opportunities were sparse. Manipulating systemic acetylcholine (ACh) by rivastigmine reduced the time macaques waited to respond given the immediate and recent past context, a pattern opposite to the effect observed with 5-HT. These findings suggest complementary roles for serotonin/DRN and acetylcholine/BF in decisions about when to initiate an action.

A habenula-insular circuit encodes the willingness to act.

The decision that it is worth doing something rather than nothing is a core yet understudied feature of voluntary behaviour. Here we study "willingness to act", the probability of making a response given the context. Human volunteers encountered opportunities to make effortful actions in order to receive rewards, while watching a movie inside a 7 T MRI scanner. Reward and other context features determined willingness-to-act. Activity in the habenula tracked trial-by-trial variation in participants' willingness-to-act. The anterior insula encoded individual environment features that determined this willingness. We identify a multi-layered network in which contextual information is encoded in the anterior insula, converges on the habenula, and is then transmitted to the supplementary motor area, where the decision is made to either act or refrain from acting via the nigrostriatal pathway.

Differential functional connectivity underlying asymmetric reward-related activity in human and nonhuman primates.

The orbitofrontal cortex (OFC) is a key brain region involved in complex cognitive functions such as reward processing and decision making. Neuroimaging studies have reported unilateral OFC response to reward-related variables; however, those studies rarely discussed this observation. Nevertheless, some lesion studies suggest that the left and right OFC contribute differently to cognitive processes. We hypothesized that the OFC asymmetrical response to reward could reflect underlying hemispherical difference in OFC functional connectivity. Using resting-state and reward-related functional MRI data from humans and from rhesus macaques, we first identified an asymmetrical response of the lateral OFC to reward in both species. Crucially, the subregion showing the highest reward-related asymmetry (RRA) overlapped with the region showing the highest functional connectivity asymmetry (FCA). Furthermore, the two types of asymmetries were found to be significantly correlated across individuals. In both species, the right lateral OFC was more connected to the default mode network compared to the left lateral OFC. Altogether, our results suggest a functional specialization of the left and right lateral OFC in primates.

Human decisions about when to act originate within a basal forebrain-nigral circuit.

Decisions about when to act are critical for survival in humans as in animals, but how a desire is translated into the decision that an action is worth taking at any particular point in time is incompletely understood. Here we show that a simple model developed to explain when animals decide it is worth taking an action also explains a significant portion of the variance in timing observed when humans take voluntary actions. The model focuses on the current environment's potential for reward, the timing of the individual's own recent actions, and the outcomes of those actions. We show, by using ultrahigh-field MRI scanning, that in addition to anterior cingulate cortex within medial frontal cortex, a group of subcortical structures including striatum, substantia nigra, basal forebrain (BF), pedunculopontine nucleus (PPN), and habenula (HB) encode trial-by-trial variation in action time. Further analysis of the activity patterns found in each area together with psychophysiological interaction analysis and structural equation modeling suggested a model in which BF integrates contextual information that will influence the decision about when to act and communicates this information, in parallel with PPN and HB influences, to nigrostriatal circuits. It is then in the nigrostriatal circuit that action initiation per se begins.

Do readiness potentials happen all the time?

The Readiness Potential (RP) is a slow negative EEG potential found in the seconds preceding voluntary actions. Here, we explore whether the RP is found only at this time, or if it also occurs when no action is produced. Recent theories suggest the RP reflects the average of accumulated stochastic fluctuations in neural activity, rather than a specific signal related to self-initiated action: RP-like events should then be widely present, even in the absence of actions. We investigated this hypothesis by searching for RP-like events in background EEG of an appropriate dataset for which the action-locked EEG had previously been analysed to test other hypotheses [Khalighinejad, N., Brann, E., Dorgham, A., Haggard, P. Dissociating cognitive and motoric precursors of human self-initiated action. Journal of Cognitive Neuroscience. 2019, 1-14]. We used the actual mean RP as a template, and searched the entire epoch for similar neural signals, using similarity metrics that capture the temporal or spatial properties of the RP. Most EEG epochs contained a number of events that were similar to the true RP, but did not lead directly to any voluntary action. However, these RP-like events were equally common in epochs that eventually terminated in voluntary actions as in those where voluntary actions were not permitted. Events matching the temporal profile of the RP were also a poor match for the spatial profile, and vice versa. We conclude that these events are false positives, and do not reflect the same mechanism as the RP itself. Finally, applying the same template-search algorithm to simulated EEG data synthesized from different noise distributions showed that RP-like events will occur in any dataset containing the 1/f noise ubiquitous in EEG recordings. To summarise, we found no evidence of genuinely RP-like events at any time other than immediately prior to self-initiated actions. Our findings do not support a purely stochastic model of RP generation, and suggest that the RP may be a specific precursor of self-initiated voluntary actions.

A Basal Forebrain-Cingulate Circuit in Macaques Decides It Is Time to Act.

The medial frontal cortex has been linked to voluntary action, but an explanation of why decisions to act emerge at particular points in time has been lacking. We show that, in macaques, decisions about whether and when to act are predicted by a set of features defining the animal's current and past context; for example, respectively, cues indicating the current average rate of reward and recent previous voluntary action decisions. We show that activity in two brain areas-the anterior cingulate cortex and basal forebrain-tracks these contextual factors and mediates their effects on behavior in distinct ways. We use focused transcranial ultrasound to selectively and effectively stimulate deep in the brain, even as deep as the basal forebrain, and demonstrate that alteration of activity in the two areas changes decisions about when to act.

Dissociating Cognitive and Motoric Precursors of Human Self-Initiated Action.

Across-trial variability of EEG decreases more markedly before self-initiated than before externally triggered actions, providing a novel neural precursor for volitional action. However, it remains unclear whether this neural convergence is an early, deliberative stage or a late, execution-related stage in the chain of cognitive processes that transform intentions to actions. We report two experiments addressing these questions. Participants viewed randomly moving dots on a screen. At a random time, all dots started moving coherently to the left or right side of the screen. Participants were rewarded for correctly responding to the direction of coherent dot movement. However, the waiting time before coherent dot motion onset could be extremely long. Participants had the option to skip waiting by pressing a "skip" key. These self-initiated "skips" were compared with blocks where participants were instructed to skip. EEG variability decreased more markedly before self-initiated compared with externally triggered "skip" actions, replicating previous findings. Importantly, this EEG convergence was stronger at frontomidline electrodes than at either the electrode contralateral or ipsilateral to the hand assigned to the "skip" action in each block (Experiment 1). Furthermore, convergence was stronger when availability of skip responses was "rationed," encouraging deliberate planning before skipping (Experiment 2). This suggests that the initiation of voluntary actions involves a bilaterally distributed, effector-independent process related to deliberation. A consistent process of volition is detectable during early, deliberative planning and not only during late, execution-related time windows.

Precursor processes of human self-initiated action.

A gradual buildup of electrical potential over motor areas precedes self-initiated movements. Recently, such "readiness potentials" (RPs) were attributed to stochastic fluctuations in neural activity. We developed a new experimental paradigm that operationalized self-initiated actions as endogenous 'skip' responses while waiting for target stimuli in a perceptual decision task. We compared these to a block of trials where participants could not choose when to skip, but were instead instructed to skip. Frequency and timing of motor action were therefore balanced across blocks, so that conditions differed only in how the timing of skip decisions was generated. We reasoned that across-trial variability of EEG could carry as much information about the source of skip decisions as the mean RP. EEG variability decreased more markedly prior to self-initiated compared to externally-triggered skip actions. This convergence suggests a consistent preparatory process prior to self-initiated action. A leaky stochastic accumulator model could reproduce this convergence given the additional assumption of a systematic decrease in input noise prior to self-initiated actions. Our results may provide a novel neurophysiological perspective on the topical debate regarding whether self-initiated actions arise from a deterministic neurocognitive process, or from neural stochasticity. We suggest that the key precursor of self-initiated action may manifest as a reduction in neural noise.

I could have done otherwise: Availability of counterfactual comparisons informs the sense of agency.

Personal control and agency are closely associated with the counterfactual notion that a person could have done otherwise (CDO). In both philosophy and law, this counterfactual evaluation determines responsibility and punishment, yet little is known about its influence on agents' experience during action. We used a risky decision-making task to study how counterfactual evaluations influenced participants' sense of agency. Two factors were manipulated independently: the presence/absence of counterfactual comparisons between actions and the presence/absence of counterfactual comparisons between outcomes of these actions. Perceived agency was highest when both counterfactual comparisons were available. Interestingly, this pattern persisted even when counterfactual information was only revealed after action, suggesting a purely reconstructive evaluation effect. These findings allow a more precise phrasing of the CDO element of personal agency: a person feels most control when she could have performed another action, thereby obtaining another outcome.

Social Transmission of Experience of Agency: An Experimental Study.

The sense of controlling one's own actions is fundamental to normal human mental function, and also underlies concepts of social responsibility for action. However, it remains unclear how the wider social context of human action influences sense of agency. Using a simple experimental design, we investigated, for the first time, how observing the action of another person or a robot could potentially influence one's own sense of agency. We assessed how observing another's action might change the perceived temporal relationship between one's own voluntary actions and their outcomes, which has been proposed as an implicit measure of sense of agency. Working in pairs, participants chose between two action alternatives, one rewarded more frequently than the other, while watching a rotating clock hand. They judged, in separate blocks, either the time of their own action, or the time of a tone that followed the action. These were compared to baseline judgements of actions alone, or tones alone, to calculate the perceptual shift of action toward outcome and vice versa. Our design focused on how these two dependent variables, which jointly provide an implicit measure of sense of agency, might be influenced by observing another's action. In the observational group, each participant could see the other's actions. Multivariate analysis showed that the perceived time of action and tone shifted progressively toward the actual time of outcome with repeated experience of this social situation. No such progressive change occurred in other groups for whom a barrier hid participants' actions from each other. However, a similar effect was observed in the group that viewed movements of a human-like robotic hand, rather than actions of another person. This finding suggests that observing the actions of others increases the salience of the external outcomes of action and this effect is not unique to observing human agents. Social contexts in which we see others controlling external events may play an important role in mentally representing the impact of our own actions on the external world.

Extending experiences of voluntary action by association.

"Sense of agency" refers to the experience that links one's voluntary actions to their external outcomes. It remains unclear whether this ubiquitous experience is hardwired, arising from specific signals within the brain's motor systems, or rather depends on associative learning, through repeated cooccurrence of voluntary movements and their outcomes. To distinguish these two models, we asked participants to trigger a tone by a voluntary keypress action. The voluntary action was always associated with an involuntary movement of the other hand. We then tested whether the combination of the involuntary movement and tone alone might now suffice to produce a sense of agency, even when the voluntary action was omitted. Sense of agency was measured using an implicit marker based on time perception, namely a shift in the perceived time of the outcome toward the action that caused it. Across two experiments, repeatedly pairing an involuntary movement with a voluntary action induced key temporal features of agency, with the outcome now perceived as shifted toward the involuntary movement. This shift required involuntary movements to have been previously associated with voluntary actions. We show that some key aspects of agency may be transferred from voluntary actions to involuntary movements. An internal volitional signal is required for the primary acquisition of agency but, with repeated association, the involuntary movement in itself comes to produce some key temporal features of agency over the subsequent outcome. This finding may explain how humans can develop an enduring sense of agency in nonnatural cases, like brain-machine interfaces.

Endogenous Action Selection Processes in Dorsolateral Prefrontal Cortex Contribute to Sense of Agency: A Meta-Analysis of tDCS Studies of 'Intentional Binding'.

BACKGROUND: Sense of agency is the experience of being in control of one's own actions and their consequences. The role of frontal cortex in this aspect of action control and awareness remains unclear. OBJECTIVE/HYPOTHESIS: Given the role of dorsolateral prefrontal cortex (DLPFC) in action selection, we predicted that DLPFC may contribute to sense of agency when participants select between multiple actions. METHODS: We performed a series of experiments by manipulating a range of task parameters related to action selection and action outcomes while participants were exposed to tDCS stimulation of the left DLPFC. We measured the temporal association between a voluntary action and its outcome using the intentional binding effect, as an implicit measure of sense of agency. RESULTS: Fixed-effect meta-analysis of our primary data showed a trend towards a frontal tDCS, together with considerable heterogeneity between our experiments. Classifying the experiments into subsets of studies, according to whether participants endogenously selected between alternative actions or not, explained 71% of this heterogeneity. Anodal stimulation of DLPFC increased the temporal binding of actions towards tones in the subset of studies involving endogenous action selection, but not in the other studies. CONCLUSIONS: DLPFC may contribute to sense of agency when participants selected between multiple actions. This enhanced feeling of control over voluntary actions could be related to the observed therapeutic effects of frontal tDCS in depression.

Slow oscillating transcranial direct current stimulation during sleep has a sleep-stabilizing effect in chronic insomnia: a pilot study.

Recent evidence suggests that lack of slow-wave activity may play a fundamental role in the pathogenesis of insomnia. Pharmacological approaches and brain stimulation techniques have recently offered solutions for increasing slow-wave activity during sleep. We used slow (0.75 Hz) oscillatory transcranial direct current stimulation during stage 2 of non-rapid eye movement sleeping insomnia patients for resonating their brain waves to the frequency of sleep slow-wave. Six patients diagnosed with either sleep maintenance or non-restorative sleep insomnia entered the study. After 1 night of adaptation and 1 night of baseline polysomnography, patients randomly received sham or real stimulation on the third and fourth night of the experiment. Our preliminary results show that after termination of stimulations (sham or real), slow oscillatory transcranial direct current stimulation increased the duration of stage 3 of non-rapid eye movement sleep by 33 ± 26 min (P = 0.026), and decreased stage 1 of non-rapid eye movement sleep duration by 22 ± 17.7 min (P = 0.028), compared with sham. Slow oscillatory transcranial direct current stimulation decreased stage 1 of non-rapid eye movement sleep and wake time after sleep-onset durations, together, by 55.4 ± 51 min (P = 0.045). Slow oscillatory transcranial direct current stimulation also increased sleep efficiency by 9 ± 7% (P = 0.026), and probability of transition from stage 2 to stage 3 of non-rapid eye movement sleep by 20 ± 17.8% (P = 0.04). Meanwhile, slow oscillatory transcranial direct current stimulation decreased transitions from stage 2 of non-rapid eye movement sleep to wake by 12 ± 6.7% (P = 0.007). Our preliminary results suggest a sleep-stabilizing role for the intervention, which may mimic the effect of sleep slow-wave-enhancing drugs.

Modulating human sense of agency with non-invasive brain stimulation.

Human voluntary actions are accompanied by a distinctive subjective experience termed "sense of agency". We performed three experiments using transcranial direct current stimulation (tDCS) to modulate brain circuits involved in control of action, while measuring stimulation-induced changes in one implicit measure of sense of agency, namely the perceived temporal relationship between a voluntary action and tone triggered by the action. Participants perceived such tones as shifted towards the action that caused them, relative to baseline conditions with tones but no actions. Actions that caused tones were perceived as shifted towards the tone, relative to baseline actions without tones. This 'intentional binding' was diminished by anodal stimulation of the left parietal cortex [targeting the angular gyrus (AG)], and, to a lesser extent, by stimulation targeting the left dorsolateral prefrontal cortex (DLPFC), (Experiment 1). Cathodal AG stimulation had no effect (Experiment 2). Experiment 3 replicated the effect of left anodal AG stimulation for actions made with either the left or the right hand, and showed no effect of right anodal AG stimulation. The angular gyrus has been identified as a key area for explicit agency judgements in previous neuroimaging and lesion studies. Our study provides new causal evidence that the left angular gyrus plays a key role in the perceptual experience of agency.

A 12-year epidemiologic study on primary spinal cord tumors in Isfahan, Iran.

BACKGROUND: Although primary spinal cord tumors (PSCTs) comprise a minority of primary central nervous system tumors, they often impose a great deal of morbidity on their victims. Few epidemiologic studies have addressed PSCTs in Iran. MATERIALS AND METHODS: We analyzed the demographic/clinical features of all primary intraspinal tumors (with a specific focus on primary intradural spinal cord tumors) identified between 1992 and 2004 in three of the major related hospitals in Isfahan, Iran. We also tracked the malignant cases until 2012. RESULTS: 102 patients with primary intraspinal tumors were found; 82 tumors were Intradural (36 intramedullary and 46 extramedullary) and 20 extradural. The principal intradural histological subtypes were nerve sheath tumor (33%), ependymoma (22%), astrocytoma (16%), and meningioma (15%). 20 (19%) of the tumors were malignant. Local pain (43%) and motor disabilities (36%) were the most common first-presenting symptoms in the patients. Male-to-female ratio was significant only in ependymoma (male:female ratio = 3.6, P < 0.05). The mean age in meningioma (57 years, standard error [SE]: 15.7) was significantly higher than other types (one-way ANOVA, P < 0.05). CONCLUSION: Our results reflect analogous frequency of distribution for PSCTs compared with most of the previous counterpart studies worldwide. The only notable exception was the comparatively fewer frequency of spinal cord meningioma in our study.

Analysing the effect of early acetazolamide administration on patients with a high risk of permanent cerebrospinal fluid leakage.

In this study, we examined the role of early acetazolamide administration in reducing the risk of cerebrospinal fluid (CSF) leakage in patients with a high risk of permanent CSF leakage. In a randomised clinical trial, 57 patients with a high risk of permanent CSF leakage (rhinorrhea, otorrhea, pneumatocele or imaging-based evidence of severe skull-base fracture) were analysed. In the experimental group, acetazolamide, at 25 mg/kg/day, was started in the first 48 hours after admission. In the control group, acetazolamide was administered after the first 48 hours at the same dose administered to the patients in the experimental group. The following factors were compared between the two groups: duration of CSF leakage, duration of hospital stay, incidence of meningitis, need for surgical intervention and need for lumbar puncture (LP) and lumbar drainage (LD). All of the patients in the experimental group stopped having CSF leakage less than 14 days after the first day of admission, but 6 out of 21 patients (22%) in the control group continued having CSF leakage after 14 days of admission, which was a significant difference (P=0.01). This study showed that early acetazolamide administration can prevent CSF leakage in patients with a high risk of permanent CSF leak.

Converting three general-cognitive function scales into persian and assessment of their validity and reliability.

OBJECTIVES: Glasgow Outcome Scale Extended (GOSE), Galveston Amnesia and orientation Test (GOAT) and Disability Rating Scale (DRS) are three popular outcome measure tools used principally in traumatic brain injury (TBI) patients. We conducted this study to provide a Farsi version of these outcome scales for use in Iran. METHODS: Following a comprehensive literature review, Farsi transcripts were prepared by "forward-backward" translation and reviewed by subject experts. After a pretest on a few patients, the final versions were obtained. 38 patients with closed head injury were interviewed simultaneously by two interviewers. Main statistics used to assess validity and reliability included "Factor analysis" for construct validity, Cronbach's alpha for internal consistency, and Pearson Correlation and Kappa Coefficient for inter-rater agreement. RESULTS: Factor analysis for Farsi-GOAT (FGOAT) revealed 5 independent factors with a total distribution variance of 80.2%. For Farsi-DRS (FDRS), 3 independent factors were found with a 92.3% variance. The Cronbach's alpha (95% confidence interval) was 0.84 (0.763- 0.919) and 0.91 (0.901-0.919) for FGOAT and FDRS, respectively. Pearson Correlation between total scores of two raters was 0.98 and 0.97 for FGOAT and FDRS, in order. Kappa coefficient (95% CI) between outcome rankings of raters was 0.73 (0.618-0.852) and 0.68 (0.594-0.770) for FGOAT and FDRS, respectively. As for Farsi-GOSE scale, Kappa value was 0.4 (0.285-0.507) for 8-level outcome ranking and improved to 0.7 (0.585-0.817) for 5-level scale. We found a good correlation between FDRS and FGOSE predicted prognoses (Spearman's rho= 0.74, 95% CI: 0.676-0.802). CONCLUSIONS: FDRS and FGOAT had appropriate validity and reliability. The 8-level outcome FGOSE scale disclosed a low inter-rater agreement, but a suitable observer agreement was achieved when the 5-level outcome was applied.

Adenoviral gene therapy in gastric cancer: a review.

Gastric cancer is one of the most common malignancies worldwide. With current therapeutic approaches the prognosis of gastric cancer is very poor, as gastric cancer accounts for the second most common cause of death in cancer related deaths. Gastric cancer like almost all other cancers has a molecular genetic basis which relies on disruption in normal cellular regulatory mechanisms regarding cell growth, apoptosis and cell division. Thus novel therapeutic approaches such as gene therapy promise to become the alternative choice of treatment in gastric cancer. In gene therapy, suicide genes, tumor suppressor genes and anti-angiogenesis genes among many others are introduced to cancer cells via vectors. Some of the vectors widely used in gene therapy are Adenoviral vectors. This review provides an update of the new developments in adenoviral cancer gene therapy including strategies for inducing apoptosis, inhibiting metastasis and targeting the cancer cells.