Motor performance and learning have distinct behavioral and neural signatures and can be uniquely modulated by various informational and motivational factors. Contemporary frameworks describe four different motor learning mechanisms mapped onto specific neural regions which are key for motor skill acquisition: error-based learning (cerebellum), reinforcement learning , cognitive strategies , and use-dependent learning (motor cortex). However, little is known about the neural circuits engaged during skill acquisition that are modulated specifically by practice-based performance improvement and those that predict recall performance. Based on previous work, we hypothesize that brain activity during practice in primary motor cortex and basal ganglia (1) is associated with trial-by-trial practice performance and (2) is predictive of immediate recall performance. Leveraging the contemporary framework, we use a well-known task paradigm that primarily relies upon cognitive strategy, reinforcement, and use-based learning mechanisms to test our hypotheses. Forty neurotypical young adults were asked to practice a pinch force tracking task. Participants received performance feedback after each trial during practice. We used whole brain analysis of functional magnetic resonance imaging (fMRI) and behavioral performance measures  during the practice phase to determine which brain activation patterns are (1) associated with trial-by-trial tracking performance and (2) predictive of immediate no-feedback retention performance. We observed brain activations in the frontal orbital cortex, putamen, amygdala, and insula correlated with tracking performance improvement during practice. In contrast, a different set of performance-related activated regions were observed that were associated with immediate retention performance that included the primary motor cortex, superior frontal gyrus, somatosensory cortex, angular gyrus, and parietal gyrus. Our findings demonstrate that improved practice performance and recall of a sensorimotor skill are correlated with distinct neural activity patterns during acquisition, drawing on different motor learning mechanisms during encoding. While motor performance improvements depend on both cortical and subcortical regions, motor skill recall depends primarily on prefrontal and motor cortices. We discuss possible interpretations for why our hypothesis regarding basal ganglia activity and retention performance was not supported. Understanding the different neural mechanisms engaged in motor performance and learning may inform novel interventions to enhance motor skill learning. The ability to acquire and retain motor skills is important in various developmental, occupational, and rehabilitative settings. The neural substrates that mediate this ability are thought to depend primarily on specific learning mechanisms . ContempFor example, there is a body of work indicating the role of the cerebellum in early stages of motor acquisition, that accounts for systematic changes in error reduction on a trial-by-trial basis (error-based learning) . In addiWhile there have been many investigations of brain activation associated with processes and stages of learning during acquisition (encoding), less attention has been given to examining brain areas activated during practice that specifically correlate with task practice performance and recall performance during retention tests.Neuroimaging investigations have begun to shed light on brain activity during acquisition that is correlated with practice and retention performance. Specifically, non-invasive brain stimulation studies in humans have recently revealed that primary motor cortex (M1) excitability during practice is proportional to skill retention performance the next day in a sequential visual isometric pinch task . A combiMotivation, classified as either extrinsic or intrinsic can exert a powerful influence on learning and memory behavior. Extrinsic motivation refers to being driven to do something because it leads to an independent outcome, such as working for monetary reward or studying for a good score. Intrinsic motivation, on the other hand refers to an intrinsic source, to being moved to doing something because it is inherently interesting and perhaps satisfies fundamental psychological needs for competence, autonomy, and social relatedness .Recent studies are beginning to examine the behavioral impact and mechanistic processes of monetary reward (extrinsic motivation)  in combiThis experiment was designed to fill three related gaps in knowledge described above. We devised a study whereby all participants receive knowledge of results (KR) performance feedback (information) after every trial while half the participants also receive motivational statements  during practice of a well-known pinch force tracking task . We chosHere, we use whole brain analysis of fMRI during practice to address the following two primary aims: to identify neural correlates of motor practice that: (1) are associated with performance improvement during acquisition (encoding) of a sensorimotor tracking task, and (2) predict immediate retention performance (without feedback). The third aim is to explore the impact of intrinsic motivational statements on behavioral and neural correlates of motor skill learning.Based on the task demands for skill acquisition, our hypotheses for the two primary aims are that: engagement of prefrontal cortex, basal ganglia, and motor cortex will be associated with greater performance improvement during the acquisition phase and specifically we expect that motor cortex and basal ganglia activity during acquisition will be predictive of recall performance at immediate retention. To address our third aim, we curated our motivation statements, which were based on previous behavioral studies and were designed around three criteria: to enhance self-efficacy expectations, induce a positive  concept of ability mindset (the notion that abilities can be developed through effort and persistence)  and suppForty-three participants were sequentially recruited into the study. Three individuals were excluded from all analyses because of incomplete behavioral and fMRI data. All three exclusions were due to scheduling conflicts for the neuroimaging scan. 40 subjects  participated . All parWe used a single group design to determine the neural correlates of motor performance improvement during practice and those that were predictive of retention performance. For the exploratory analysis, we used a between-group design to examine effects of motivational statements plus informational performance feedback  compared to performance feedback alone on brain activity and concurrent motor performance.Participants lay supine in the MRI tube and held a pressure sensor  between the thumb and index finger of the right dominant hand. The pressure sensor was connected to an air tube, which led to the MRI control room, where it was connected to a transducer converting air pressure to voltage. Pinching of the pad resulted in generation of a differential voltage signal. The recorded signal was used to provide participants with real time visual feedback of the cursor movement. The cursor movement and moving target presentation were instantaneously displayed on a projector screen, which participants were able to see through a mirror positioned above their eyes.The study consisted of five phases , as illustrated in Prior to the fMRI session, participants were familiarized with the task inside a mock scanner (Familiarization), which was not part of the blocks performed in the real MRI scanner and not used in the imaging analysis . The firThree different spatiotemporal tracking patterns of equivalent difficulty were used to optimize comparability of tracking pattern and to dissociate non-pattern specific learning  for the three phases; Familiarization: pattern A, Baseline period: pattern B, and Practice period: pattern C . All traThe goal of the tracking task was to keep the cursor (blue box) inside a target box (white box), which was moving vertically across (up and down) the screen, for as long as possible in a 12-s trial period. Participants controlled the cursor movement by varying the isometric pinch force applied to an instrumented pneumatic pad (squeezing between the thumb and index finger). Performance information, specifically KR feedback, was presented for 1 s after each trial followed by a 12-s rest before the next trial began. All participants received the following instructions about the task: “In this task, there is a white target box that is moving in a specific pattern. The goal is to keep the blue box inside the white box for as long as possible. After every trial, you will see a number which is the amount of time the blue box was in the white box. Each trial is 12 s long. We will begin the trials now.”Task performance was assessed separately for acquisition and retention sessions in 2 ways. Time on target was used as one primary measure, which was part of the explicit task goal, and provided as information feedback (both KR and KP) during practice. For a second primary measure, we decomposed the participant’s cursor trajectory into spatial and temporal accuracy components using time-series analysis; the participant’s cursor trajectory was iteratively shifted in time toward the target onset until a maximum correlation between participant trajectory and target trajectory was achieved; this was done for each 12 s trial. The resulting correlation coefficient  represents the spatial accuracy of tracking performance. The number of milliseconds that the participant’s cursor trajectory was shifted to achieve the highest correlation coefficient (between the target and the cursor trajectory) represents the time lag or temporal accuracy of tracking.The time that the cursor was entirely inside the target box was calculated for each trial. Average time on target was calculated separately for each trial block. If the participant kept the cursor in the target box for the entire length of the trial, a perfect score of 12 s would be displayed.r = 1.The maximum correlation coefficient between the target trajectory and the participant’s cursor trajectory, after adjusting for time lag, was calculated for each trial. Average correlation was calculated separately for each block. Perfect spatial accuracy would be reflected by The shift in time that was associated with the maximum correlation between the target trajectory and participant’s cursor trajectory was calculated for each trial to determine temporal accuracy. Average time lag was calculated separately for each trial block. Perfect temporal accuracy reflected by anticipatory tracking would yield a time lag = 0. In practice, the shorter the time lag, the better the learner is anticipating the target pattern.To assess performance, time on target, maximum correlation of cursor and target trajectory  and the time lag that was used to achieve the maximum correlation  was evaluated for each block. Data were then corrected for outlier trials .Keep in mind that at the beginning it is common to undershoot or overshoot the target, but this is the type of task that you get better at with practice; prior to block (2) Alright! Your improvement across the past trials is reflecting your learning and getting the hang of it; prior to block (3) Very good! Based on your performance so far, it looks like you are going to continue to improve across the coming trials; prior to block (4) Alright! Nice work!; prior to block (5) Great job! followed by ‘Well done’ at the end of the acquisition session. These motivational statements were modified from previous behavioral studies and were designed around three criteria: to enhance self-efficacy expectation, induce a positive (growth) concept of ability mindset and support perceived competence.In addition to the basic task-related instructions, half the participants were given additional motivational statements (instructions and feedback) after the baseline block in the scanner. The motivation plus feedback group received the following oral motivational statements prior to each of the 5 practice blocks: prior to block (1) A 6-item questionnaire assessed task-specific self-efficacy on a Likert scale. All participants were asked to rate how confident they were to keep the blue box (cursor) in the white target box for 2, 4, 6, 8, 10, and 12 s. The scale ranged from 0  to 10 (extremely confident). The self-efficacy questionnaire was given after the familiarization block, before and after the practice phase, and before delayed retention trials on day 2. See Supplementary Material for questionnaire items.Neutral statements  were provided to all participants between each of the 5 practice block runs to ensure that social contact and communication between the groups was comparable.An adapted version of the perceived competence, effort/importance and task interest/enjoyment subscale of the Intrinsic Motivation Inventory was administered after delayed retention trials on day 2. Participants rated their interest/enjoyment, perceived competence, and the effort/importance they attributed to the task on a Likert scale. Items on the questionnaire were shuffled in order of presentation for participants.All statistical tests, with the exception of normal distribution tests, linear regressions, and linear mixed effects modeling, were conducted using SPSS. We checked for normal distribution using the Lilliefors test for normality. Time lag and self-efficacy data were normally distributed. Time on target and cross correlation were not normally distributed. For data that was not normally distributed (Time on target and cross correlation), we used linear mixed effects modeling. We used Matlab R2020b  and its Statistical Toolbox for all regression analyses.U test.Levene’s test for equality of variance was used to check for verification of assumptions of homogeneity of variances. The time lag data with the exception of the practice 3 timepoint passed the test of homogeneity of variance. Time on target data for immediate and delayed retention tests did not show homogeneity of variance; thus, we used the Mann–Whitney To assess task improvement across practice for the time lag measure, performance during practice was analyzed in separate one-way repeated measures analysis of variance (rmANOVA) with practice block as the repeated measures factor. For the exploratory analysis (Aim 3), time lag performance during practice was analyzed in a 2 (groups: motivation plus feedback and feedback only) × 5 (practice blocks) ANOVA with repeated measures on the practice block factor, controlling for baseline performance.To assess task improvement across practice and to compare task performance measures between the groups (Aim 3) for time on target and cross correlation, we used linear mixed effects modeling, with time points and groups as fixed effect variables and the baseline performance as a random effect variable. In this modeling, the time points and groups were set as categorical variables, and the baseline performance was set as a continuous variable. Specifically, we generated the linear mixed effects model using ‘fitlme’ function, then we used ‘anova’ function for the linear mixed effects model ANOVA marginal tests.U test was used.To compare groups on the time lag measure for immediate and delayed retention tests, two separate independent t-tests were used. To compare groups on the time on target and cross correlation measure, Mann–Whitney Post hoc tests were performed with a Bonferroni correction applied, resulting in a significance level set at p < 0.01 to adjust for multiple comparisons.Self-efficacy was analyzed in a 2 (groups: motivation plus feedback and feedback only) × 4  repeated measures ANOVA to compare ratings between groups. We used a linear regression to examine the relationship between self-efficacy changes (before to after practice period) and time on target improvement (start to end of practice). We also used linear regression to test the linear relationship between self-efficacy changes (before to after practice period) and time on target, assessed at immediate and delayed retention, respectively.t-test was used to compare ratings between the groups for each subscale of the Intrinsic Motivation Inventory.An independent For all analyses, significance level was set at 0.05.We acquired T2-weighted echo spiral images with blood oxygen level dependent (BOLD) contrast using a 3 Tesla scanner (GE Signa Excite) with an 8-channel head coil. Each volume comprised 37, 3 mm thick axial slices, using the following parameters: TR = 2.5 s, TE = 34.5 flip angle = 90; FOV = 22, 64 × 64 matrix. For each participant, a total number of 131 volumes were obtained. Additionally, we acquired a T1-weighted structural image at the start of the scan session, before tracking task performance.RRID:SCR_002823)]. The fMRI data for each participant were preprocessed using the FMRIB  Expert Analysis Tool (FEAT1). Preprocessing included skull extraction with the FSL brain extraction tool (BET), motion correction and spatial smoothing using a Gaussian kernel with full-width half-maximum of 5 mm.Analysis of fMRI data were conducted using FSL , (not shown).Across the groups, there was a significant linear relationship between change in self-efficacy (pre to post training) and gain in time on target performance during practice (gain = difference between baseline and last training block), R2 = 0.25, F = 6.07, p = 0.02, feedback only: R2 = 0.04, F = 0.75, p = 0.40; Delayed retention, motivation plus feedback: R2 = 0.28, F = 6.24, p = 0.02, feedback only: R2 = 0.03, F = 0.56, p = 0.47].Importantly and illustrated in We observed no group differences in brain activity during the task practice period. Moreover, there were no brain activity differences related to Performance-specific task activity nor brain activity during task practice that were related to immediate retention performance.While recent contemporary frameworks have identified neural regions involved with specific mechanisms of sensorimotor encoding and recall, this is still a new frontier in behavioral neuroscience seeking a better understanding of the “neural implementation of behavior” that allows for motor skill learning . We desiIn particular, we examined how task performance modulates brain activation during motor skill acquisition . Additionally, we aimed to examine the neural implementation during the dynamic process of encoding and memory formation that are reflected through retention performance . Finally, we explored the influence of carefully crafted motivational statements during motor skill acquisition on brain and behavior mechanisms of motor learning.This study adds to the literature by demonstrating that the neural implementation of practice improvement during encoding is associated with primarily cortical and subcortical brain regions, while activity in cortical regions is specifically correlated with immediate retention performance. The unique contribution of our approach allowed us to isolate the neural activity patterns associated with the performance-specific analysis from the typical task-specific analysis thereby revealing the distinct nature of performance modulated neural activity that allows for motor learning. We highlight this revelation in the next two sections.The neural activation we identified through our Task-related practice activity analysis aligns with the four learning mechanisms we expect with our visuomotor tracking task paradigm: cognitive strategy learning , reinforcement learning , use dependent learning (motor cortex) and error-based learning (cerebellum) mechanisms. Moreover, these findings are consistent with previous studies that have examined the learning of implicit motor skills such as visuomotor tracking and isometric force production .Our findings for the activation correlated specifically with performance during task practice supported our hypothesis for engagement of the prefrontal cortex and striatal regions . ConsideFurthermore, our task paradigm involves the provision of performance feedback (KR) after each trial in addition to visual feedback of the cursor and target position (KP), both engaging reinforcement learning processes. Reinforcement learning is defined by the process of selecting appropriate motor actions based on feedback about the success or failure of a movement to maximize reward  . Animal The brain region associated with error-based learning, also termed sensorimotor adaptation, notably the cerebellum, is not represented in our analysis of Performance specific task activity. One reason for this may be that there is ample practice  with 2 other tracking patterns before the pattern-specific practice period begins. For the Performance specific task analysis, we specifically examined brain activity associated with trial-by-trial task performance during the acquisition phase. We suspect that much of the non-specific learning of how to perform the task, which engages error-based processes, such as calibration of one’s force with the grip of the pad to control the cursor, may have occurred in those early familiarization trials prior to the task acquisition phase. This finding is different from our analysis of task-related activity (without performance modulation), where we do see cerebellar activity. Thus, one viable interpretation is that cerebellar activity is relevant to execution of the task throughout practice as seen in our task related activity analysis, reflecting non-specific learning processes  for these kinds of continuous tracking tasks.Our findings showing cortical activity, including the primary motor cortex, supports our hypothesis for the role of the motor cortex in predicting immediate retention performance. The regions engaged, including primary motor cortex, superior frontal gyrus, somatosensory cortex and angular and parietal gyrus are consistent with work that has begun to investigate neural activity associated with next day motor retention. Recent studies in humans that use non-invasive brain stimulation reveal that M1 excitability during practice is proportional to retention performance the next day . As noteTogether, these studies emphasize the relevance of cortical region activity during acquisition that is correlated with retention performance. These cortical regions are all relevant for motor planning, preparation, and controlled sequencing of movements important for learning the track pattern and reflected by retention performance. Such learning processes are critical in acquiring the skills during practice that lead to and can predict successful recall performance during retention tests. Specifically, the feedforward nature of learning to anticipate the target trajectory that allows one to maximize the time on target during each trial (quantified by a reduction in time lag across practice) is consistent with prefrontal and motor cortical activity that we found to be critical to the prediction of immediate retention performance.Furthermore, neuroimaging studies demonstrate that the angular gyrus has an important role in perceptual learning and spatial action awareness, specifically in identifying discrepancies between an intended action and movement consequences . There iWe speculate that a greater understanding of the brain regions active during encoding, that predict greater recall performance, may show promise toward the development of a diagnostic biomarker that can be used for individuals approaching neurorehabilitation. An assessment of the degree of existing neural substrates engaged during task acquisition, that are important for effective motor learning , may inform the potential success of a given treatment plan.Finally, the absence of basal ganglia activity in the brain regions found to be associated with immediate retention performance is supported by research that highlights the significant and necessary contribution of the dopaminergic system to the motor cortex specifically for skill acquisition during the encoding phase. Animal studies have revealed that while dopaminergic projections to the motor cortex are necessary for skill acquisition, these connections are not necessary for recall performance after the acquisition period is complete .These results underscore the importance of cortical activation during skill acquisition of visuomotor tasks for long term retention of motor skills and its potential for interventions that may capitalize on these regions to maximize motor skill learning and immediate retention. Our Performance specific activation analysis corroborates the crucial role of basal ganglia for encoding processes and its unique role in performance improvements during acquisition. This emphasizes the nature of motor learning processes such as reinforcement learning  in promoting cognitive strategies and use-dependent practice mechanisms, dependent on key neural nodes required for learning the task-specific skills . Translating these findings suggests that primary attention to conditions during learning, including strategy based, explicit instructive feedback and practice schedules  that support engagement of the prefrontal and motor cortices during practice can foster greater retention of motor skills, while reinforcement-based interventions, such as motivational statements and feedback, can boost and support those principal motor learning processes.This understanding may be crucial for the development of interventions to promote motor recovery in populations with neurological disorders. Given that recovery-supportive neuroplasticity, motor learning and task practice are fundamental to neurorehabilitation  understaOur behavioral findings from the between group  analyses show that statements to enhance intrinsic motivation and supplement performance feedback improve motor performance and learning of a visuomotor tracking task. This is evidenced by improved temporal accuracy and time-on-target measures . The sigThe actual time lag during immediate and delayed retention was ∼90 ms for the motivation plus feedback group compared to ∼130 ms for the feedback only group, which is nearly 40 ms shorter. This is a clear indication that the motivational statements enlisted enhanced anticipatory processes, and importantly supported better memory development for the tracking pattern than achieved with KR/KP feedback alone. The skill to anticipate the upcoming position of the target and then to coordinate grip pressure accordingly demonstrates an elegant motor planning and execution capability.Our behavioral findings are consistent with previous studies reporting greater automatic movement control provided through instructions that enhanced learners’ sense of competence . PreviouOur self-efficacy findings provide further evidence that the motivational statements did indeed have the intended impact on performance and especially retention performance. The significant linear relationship between self-efficacy enhancement and immediate retention performance for the motivation plus feedback group, but not the feedback only group, may suggest the nature of the impact of KR/KP feedback on retention performance when motivational statements are provided. While both groups received performance feedback, the motivation plus feedback group may apply more salience to the feedback, making it a stronger reinforcement compared to feedback alone and thereby influence encoding processes which are also reflected by performance gains at immediate and delayed retention . We speculate that this could be likened to the beneficial learning effects seen when an extrinsic motivator  is coupled with performance feedback . ExploraThe lack of brain activation correlates for the robust behavioral findings was surprising. However, in retrospect, there are several reasons for why we may not have seen group differences in the fMRI signal between those who received motivational statements plus performance feedback and those who received feedback alone. Firstly, both groups show task performance improvements and self-efficacy rating increases throughout practice and retention test time points. We controlled many of the variables amongst the participants to examine neural correlates of practice and retention performance across all individuals, including a common task, comparable informational performance feedback, consistent practice structure, and the same number of trials. Most relevant to interpretation of the neural effects of motivational statements is that all participants received KR and KP  which as we have discussed earlier can also act as a source of reinforcement and motivation (success of movement) and thus may have engaged neural circuitry that overlaps and thus limits the sensitivity to pick up additional motivation-related engagement of those same neural circuits through our fMRI study design. Moreover, the results from the direct measure of intrinsic motivation  suggest that the differences in intrinsic motivation may not have been robust enough to see between-group differences in fMRI activation. Using the three subscales of the intrinsic motivation inventory , we observed a trend for greater effort/importance ratings reported in the motivation plus feedback group compared to the feedback only group. However, we did not see statistically significant between-group differences in IMI ratings for any of the three subscales. Results from our first level fMRI analysis that identified the neural correlates of performance improvements supports the possibility of performance feedback acting on motivational processes that are inherent to reinforcement learning. Specifically, the striatal regions involved with encoding task components are correlated with better practice performance. Such brain activation findings are aligned with human studies that have investigated the role of motivational circuits in motor skill learning  and receFurther, it is possible that other motor tasks and populations  different task demands, and/or experimental paradigms may enable a more robust neural activation response to instructions of enhanced intrinsic motivation . For exaFinally, we utilized an fMRI block design, which comes with the disadvantage of potential habituation, anticipation, and other strategy effects across the scanning period. While we tried to address the possibility for habituation and anticipation during the scanning period to influence the between-group comparisons by having a feedback only group, further studies could better address this limitation using event-related neuroimaging paradigms. Additionally, other neuroscientific methods such as EEG, PET, or TMS or a combination e.g.,  may be mOur findings provide evidence that performance during skill acquisition  and retention  are associated with distinct neural components of the four major motor learning mechanisms engaged with practice of a visuospatial pinch force tracking task. While cortical activity, including motor and prefrontal cortices (cognitive strategies) was correlated with retention performance, both cortical and subcortical area activity, namely prefrontal (cognitive strategies) and striatal regions (reinforcement learning), were associated with task performance improvement during practice. Results from our exploratory analysis of the influence of intrinsic motivational enhancements on motor learning mechanisms demonstrate enhanced anticipatory performance implemented through more precise timing of movements during acquisition and retention performance. These behavioral findings are comparable to studies utilizing extrinsic motivational manipulations  during motor learning.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by University of Southern California (USC) Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.DB-K: conception and design of the study, fMRI data analysis, statistical data analysis, writing—original draft preparation, and data visualization. BK: fMRI data analysis, statistical data analysis, data visualization, and editing. JM: conceptualization, supervision, fMRI analysis, and writing—review and editing. RL and CW: conceptualization, supervision, and writing—review and editing. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cancer patients need multimodal therapies to treat their disease increasingly. In particular, drug treatment, as chemotherapy, immunotherapy, or various associations between them are commonly used to increase efficacy. However, the use of drugs predisposes a percentage of patients to develop toxicity in multiple organs and systems. Principle chemotherapy drugs mechanism of action is cell replication inhibition, rapidly proliferating cells especially. Immunotherapy is another tumor therapy strategy based on antitumor immunity activation trough agents as CTLA4 inhibitors (ipilimumab) or PD-1/PD-L1 inhibitors as nivolumab. If, on the one hand, all these agents inhibit tumor growth, on the other, they can cause various degrees toxicity in several organs, due to their specific mechanism of action. Particularly interesting are bowel toxicity, which can be clinically heterogeneous , up to severe consequences, such as ischemia, a rare occurrence. However, this event can occur both in vessels that supply intestine and in submucosa microvessels. We report drug-related intestinal vascular damage main characteristics, showing the radiological aspect of these alterations. Interpretation of imaging in oncologic patients has become progressively more complicated in the context of “target therapy” and thanks to the increasing number and types of therapies provided. Radiologists should know this variety of antiangiogenic treatments and immunotherapy regimens first because they can determine atypical features of tumor response and then also because of their eventual bowel toxicity. Cancer patients need multimodal therapies to treat their disease increasingly. In particular, drug treatment, as chemotherapy, immunotherapy, or various associations between them are commonly used to increase efficacy. However, the use of drugs predisposes a percentage of patients to develop toxicity in multiple organs and systems . They caCommon side effects during chemotherapy are observed in gastrointestinal system and consists of mucosal damage mainly, which can manifest itself with various symptoms . At the Many anticancer drugs can induce vascular toxicity, venous, and more rarely arterial system. Great and microvessels may be affected by thrombosis and thromboembolism; if bowel vessels are involved, they can give rise to critical ischemic events, which lead to necrosis and perforation. Thrombotic and thromboembolism events pathogenesis is induced by drug-related endothelial damage, with consequent basement membrane exposure and abnormal coagulation cascade activation , 32. PlaClinical features of acute ischemic bowel is very changeable: acute abdominal pain could be determined by many different causes  and the ‘classic triad’ of chronic mesenteric ischemia  is rarely found in clinical practice .Radiological imaging is crucial in the emergency setting. It is very difficult to make differential diagnosis only through physical examination; as explained by Terlouw et al., at least upper gastrointestinal endoscopy and abdominal imaging (computed tomography/magnetic resonance imaging) must be executed if there is a suspicious of chronic mesenteric ischemia. Colonoscopy should be performed in patients with diarrhea.In the emergency setting the baseline of radiological examination in patient with acute abdominal pain include abdominal ultrasonography (US) and/or abdominal plain radiography. US allows to detect some differential diagnosis of acute abdominal pain such as cholecystitis, pancreatitis, hernias. Colour and Power Doppler imaging therefore could be useful to study bowel’s vascularity: an increase of vascularity of the bowel wall and adjacent mesentery is a sign of hyperemia and inflammatory bowel disease. On the contrary, a reduction of vascularity is a specific sign of ischemia . Duplex According to Mazzei et al., MRI could play an important role not only for follow up but also for the diagnosis of acute ischemic colitis without using contrast medium through combined T2-weighted steady state free procession sequences on coronal plane and T2W fast-recovery fast-spin echo sequences both in coronal and axial plane. For example, colonic wall thickening is typical both on CT and MR in case of severe colonic: especially when this sign has segmental distribution is quite specific for ischemic colitis compared to inflammatory colitis . MRI is Currently, computed tomography (CT) represents the primary imaging technique in imaging bowel injuries with numerous advantages in comparison with other diagnostic modalities . In partMainly, multidetector CT represents the gold standard for the intestinal study because, in few minutes, it can provide a complete study of the abdomen also in non-cooperating patients and can avoid angiography through a multiphase study using contrast agents.First, we know that oncologic patients are almost exclusively examined by CT to detect their “tumor burden” so it is possible to discover intestinal pathological features in asymptomatic patients during the planned follow-up; it is known that 70.8% of cancer patients with pneumatosis and/or bowel perforation are asymptomatic . If sympFree intraperitoneal gas means perforation of an infarcted bowel segment . In the Radiologists must take in count that bowel ischemia can also exist in malignant conditions, such as in proximity to a colonic carcinoma or a metastatic intestinal lesion .Moreover, some chemotherapy agents may determine spontaneous gastrointestinal necrosis and even perforation , 64. At Side effects from molecular target therapy include enterocolitis, pneumatosis, micro-perforations of the bowel, fistula formation, and wound dehiscence, especially in rectal carcinoma , 65, 66.These features, however, are not specific because they can also occur after radiation that induces small-vessel occlusions and could determine ischemia anywhere in the digestive tract, especially in patients with prior abdominal surgery with adhesive changes, previous peritonitis before radiation therapy and in patients that have cardiovascular factors or risk . ImmunotWe report the case of a 35 years old male patient diagnosed in February 2017 with squamous non-small-cell lung cancer (sqNSCLC). From June 2017, he received a second-line treatment with nivolumab for advanced disease achieving a major partial response. After 23 drug administrations, he presented with symptoms of moderate left lower quadrant pain without fever. Abdominal CT with IV iodinated contrast showed sigmoid diverticulitis with colonic wall thickening and pericolic fat stranding  –80. It iWe believe that CT is the primary imaging technique with a high temporal resolution that can provide a specific diagnosis of chemotherapy-induced bowel ischemia. CT could reveal also a fearsome complication that might occur in the bowel ischemia pathological process represented by bowel perforation. A hole through the wall of the intestines can develop; this results in the contents of the intestine leaking into the abdominal cavity, causing peritonitis. An interesting study conducted by Bagdwell and his group examined the management of perforation and the associated outcomes in patients with bevacizumab-associated bowel perforation. A bevacizumab-associated perforation on CT . Bowel pNivolumab determined small bowel obstruction and perforation in a patient that was on long-term therapy for metastatic non-small cell lung cancer that was confirmed after surgery . This paTherefore, it seems to be very important for radiologists to be aware as much as possible of the various chemotherapy treatment and pathological mechanisms that can promote bowel ischemia and perforation in the oncologic setting. Radiologists should talk to oncologists in multidisciplinary teams to manage together the clinical-therapeutic pathway of these patients; according to us, the knowledge of medical history in the oncologic setting is mandatory because, for example, patients could also be subjected to radiation before our observation so in this case the intestinal illness maybe not related to the therapeutic regimen. Patients with risk factors that could develop bowel perforation  should be detected before therapy –87. The Interpretation of imaging in oncologic patients has become progressively more complicated in the context of “target therapy” and thanks to the increasing number and types of therapies provided. Radiologists should know this variety of antiangiogenic treatments and immunotherapy regimens first because they can determine atypical features of tumor response and then also because of their eventual bowel toxicity. To avoid emergency surgery and significant risk of mortality among chemotherapy-induced bowel ischemia, it is necessary to give prompt diagnoses detecting drug toxicities; the dialogue with the clinician could be helpful for radiologists for this issue. After all the recognition of risk factors for chemotherapy-associated bowel ischemia and perforation will depend on the assessment of large clinical trials and observational studies.


In the DSM-5, psychiatric diagnoses are made based on self-reported symptoms and clinician-identified signs. Though helpful in choosing potential interventions based on the available regimens, this conceptualization of psychiatric diseases can limit basic science investigation into their underlying causes. The reward prediction error (RPE) hypothesis of dopamine neuron function posits that phasic dopamine signals encode the difference between the rewards a person expects and experiences. The computational framework from which this hypothesis was derived, temporal difference reinforcement learning (TDRL), is largely focused on reward processing rather than punishment learning. Many psychiatric disorders are characterized by aberrant behaviors, expectations, reward processing, and hypothesized dopaminergic signaling, but also characterized by suffering and the inability to change one's behavior despite negative consequences. In this review, we provide an overview of the RPE theory of phasic dopamine neuron activity and review the gains that have been made through the use of computational reinforcement learning theory as a framework for understanding changes in reward processing. The relative dearth of explicit accounts of punishment learning in computational reinforcement learning theory and its application in neuroscience is highlighted as a significant gap in current computational psychiatric research. Four disorders comprise the main focus of this review: two disorders of traditionally hypothesized hyperdopaminergic function, addiction and schizophrenia, followed by two disorders of traditionally hypothesized hypodopaminergic function, depression and post-traumatic stress disorder (PTSD). Insights gained from a reward processing based reinforcement learning framework about underlying dopaminergic mechanisms and the role of punishment learning (when available) are explored in each disorder. Concluding remarks focus on the future directions required to characterize neuropsychiatric disorders with a hypothesized cause of underlying dopaminergic transmission. Psychiatric conditions diagnosed within DSM-5  criteriaComputational reinforcement learning (RL) theory , 6 descrBox 1Temporal difference reinforcement learning provides a computational framework to investigate how an agent might learn directly from experience. The goal of TDRL algorithms are to estimate the value of a particular state or of an action paired with a state  in order to maximize the rewards that can be obtained. At the core of this family of algorithms is a teaching signal called a temporal difference reward prediction error (TD-RPE), Equation 1:t is the TD-RPE quantity at time t, which is determined by evaluating the outcome magnitude  observed at time t added to the expected future value, V(St+1), of being in the present state. V(St+1) is discounted by the term γ. All of this is compared to the overall value expected at time V(St). This amounts generally to the idea of reward received vs. reward expected. However, the time indices cause the agent to evaluate not only what is received in the present state, but also consider how being in the present state increases or decreases the overall value of future states. It can be shown that the agent only needs to estimate one step into the future (t) is then used to update the estimated value of the current state following Equation 2:Here, δe future , 6 to haV(St) to a new estimate where α is a fractional multiplier that controls how much the current reward prediction error updates the (apparently wrong) estimate of the value of the current state t = 80 is consistent with there being a TD-RPE equal to zero – the reward received is exactly as expected. If, however, the reward is omitted  a negative reward prediction error is emitted signaling that things are worse than expected.Using these computations, one can simulate simple Pavlovian conditioning paradigms  reward prediction errors  in response to better-than-expected or worse-than-expected outcomes  , 11. HowRecent work suggests that dopaminergic signals in the human brain also encode reward prediction errors , 11, 13,via the dopamine system. However, empirical and theoretical studies in psychology and neuroscience indicate that this assumption might not accurately reflect the nature of reward and punishment learning and associated behavioral responses in humans and other animals  are handled by a negatively valenced system. Both systems are hypothesized, here, to learn optimally from experience and hence use the TDRL-prediction error, but for partitioned valence specific receptive fields (Equations 3 and 4):One hypothesized solution to the limitations of TDRL  is to paAs in TDRL, the prediction errors update representations of the appetitive (Positive system) and aversive (Negative system) values The estimated appetitive (positive system) and aversive (negative system) values This approach maintains the optimal learning algorithm from TDRL reward processing and it is expected that the results of experiments that only vary reward will result in the same predictions when comparing traditional TDRL  and this2/3 receptors in the striatum  . IndividA special class of BAs, Impulse Control Disorder (ICD), has furthered the investigation of addiction and the role reinforcement learning mechanisms may play. Impulse control disorders (ICDs) are identified as rapid changes in risky behavior that arise secondary to dopaminergic therapies for the treatment of Parkinson's disease (PD), particularly dopamine receptor agonists . The cur11C] raclopride positron emission tomography (PET) measurements during a gambling task have revealed increases in ventral striatal dopamine release in patients with Parkinson's disease with ICD compared to patients with Parkinson's disease without ICD  and the dopaminergic dysfunction in Sz has led research into the relationship between schizophrenia and altered adaptive decision-making behavior. Findings based on PET and SPECT research, human neuroimaging studies, and computational models suggest that RPE signaling in the striatum is impaired in Sz compared to controls , 109–111Patients with Sz who display negative symptoms show alterations in reward learning that lead to a tendency to fail to appropriately estimate and use future rewards to guide decision-making behavior , 111. ThIn addition to reward learning, patients with Sz show differences in punishment learning, though results in the literature are mixed. For example, patients with Sz have been shown to maintain sensitivity to rewarding stimuli but undervalue potential losses . AnotherSchizophrenia is a severe psychiatric disorder characterized by alterations in dopaminergic activity eventuating in positive, negative, and cognitive symptoms . AlteratMajor depressive disorder is a leading cause of global disability, affecting over 300 million people worldwide . DespiteTemporal difference reinforcement learning models , 6 of huMultiple treatment modalities are suggested to improve reward learning impairments experienced by patients with MDD, including antidepressant medications, psychotherapies, and brain stimulation techniques , 139. ThDepression is also treated with cognitive behavioral therapy (CBT), an efficacious psychotherapy theorized to reduce symptoms in part through changing learning . A recenCertain brain regions are posited to integrate reward and punishment information encoded by separate, opponent, neural systems relevant to depression. This opponent systems theory hypothesizes that neural systems that track negative reward prediction errors may include serotoninergic or a subset of dopaminergic neurons distinct from those that encode RPEs , 17, 23.There has also been investigation into the structural abnormalities associated with reward and punishment learning systems in depression. These structural foundations for which functional (reward and punishment) prediction error signals are carried are an important aspect to consider as decreases in the integrity of physical connections within reward and punishment valuation networks may underlie loss of reward and punishment efficacy in depression . At thisCurrent TDRL research investigating depression also suggests altered punishment learning within certain brain regions  , 124. ThThere has been much less focus linking punishment learning and white matter differences associated with depression. One study did report a significant decrease in mean FA within the VTA-lOFC  connection tract of the MFB associated with punishment processing in depressed individuals compared to non-depressed controls . HoweverOverall, reward learning has been widely investigated in depression, but future research may use computational frameworks to explicitly parse reward and punishment learning processes to identify and delineate hypothesized reward and punishment learning neural circuits. In turn, this may help pinpoint reward and punishment system pathways in the human brain and better capture how humans—and especially patients with MDD—may react differently from complicated interactions of appetitive and aversive outcomes in natural experience. While computational formulations that better account for these systems will help, it is important to note that factors such as clinical heterogeneity, different subtypes of depression, and variability in study methodology likely also contribute to discrepancies in the current literature. Still, more detailed computational characterizations of patient behavior, charateristics, and patient populations may provide an approach to better stratify patient subtypes for more effective targeting of individualized therapeutic strategies. The precision gained through a computational lens may provide hypotheses about how distinct learning processes and associated circuits are altered in depression. These data, paired with white matter abnormalities in individual patients with depression, including MDD, may provide important behavioral, functional, and structural measures to advance our current understanding and treatment of depression.A diagnosis of post-traumatic stress disorder (PTSD) by DSM-5 criteria must involve exposure to actual or threatened death, serious injury, or sexual violence; after such an event, the following must be present: 1) the presence of intrusion symptoms associated with the traumatic event; (2) persistent avoidance of stimuli associated with the traumatic event; (3) negative alterations in cognition or mood beginning or worsening after event; (4) marked alteration in arousal and reactivity associated with the traumatic event; and (5) symptoms lasting longer than a month  the pres. Though It is known that PTSD patients are unable to inhibit fear response in the presence of environmental cues that indicate that an environment associated with punishment will not result in punishment . For exaIn humans the safety signal phenotype of PTSD is seen in the startle response, where startle is attenuated by the presence of the safety signal. Startle responses of PTSD patients are not attenuated by the presence of a safety signal compared to controls . AdminisTemporal difference reinforcement learning theory and the calculation of reward prediction errors therein has been instrumental in providing insight into the information that dopamine neurons encode. The idea that dopamine neurons encode “reward prediction errors” that are important for updating expectations and guiding choice behavior has been a critical one for understanding motivated mammalian behavior and has led computational psychiatric investigations into a number of psychiatric conditions where subjective suffering and aberrant decision-making are hallmark features.The gains that have been made using TDRL, and computational reinforcement learning theory more generally, to guide computational psychiatric investigations are undeniable. Future computational psychiatric investigations may utilize VPRL as it is described here or some other explicit approach to hypothesize about how the brain may learn to adapt in the face of punishing outcomes. The best approach is to be determined, but we hope to have made the case that some way of accounting for this fundamental aspect of human behavior and psychiatric illness ought be accounted for and investigated further.We hope to provide those interested in computational psychiatry a clear picture of the importance of extending the widely successfully computational reinforcement learning framework to include punishment learning. The mathematical explication of reward learning mechanisms has allowed rigorous testing of hypothesized processes including the role dopamine neuron activity and dopamine release in the brain may play in human cognition generally, but specifically how these processes may be altered in psychiatric illness . We hopeBL and KK conceived of and planned the layout and content of this review. BL, RJ, ED, JT, JH, LS, KS, CJ, EF, AJ, and KK contributed to the literature review and drafting of individual sections of this work. All authors reviewed and edited this manuscript in its entirety for intellectual content, provided final approval of the version to be submitted for review and publication, and agree to be accountable for all aspects of the work including ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.https://www.ninds.nih.gov/funding/training-career-development/institutional-grants/jointly-sponsored-institutional-predoctoral-training-program-jsptpn).The authors would like to acknowledge the following funding sources that supported this work: National Institutes of Mental Health (KK: R01MH121099 and R01MH124115), National Institutes of Drug Abuse , the National Center for Advancing Translational Sciences (KK: UL1TR001420 and KL2TR001421), and KS is funded by T32NS115704 from National Institute of Neurological Disorders and Stroke and National Institutes of Mental Health (The program, JSPTPN, is jointly sponsored by the NINDS and NIMH - The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Dental student training in clinical communication skills and behavioral aspects of treatment are lauded as clinically meaningful in the dental education literature. However, many dental school curricula still only provide didactic, one-time coursework with multiple choice examination assessment and little or no student skill-activating activities. This article aims to review literature relevant to optimizing clinical communication and behavioral skills in dental education. The review summarizes findings of several relevant reviews and usable models to focus on four themes: (1) special characteristics of dentistry relevant to communication skill needs, (2) essential components of dental student learning of communications skills, (3) clinical consultation guides or styles and (4) optimal curricular structure for communication learning effectiveness. Contexts of communications in the dental chair differ from medical and other allied health professions, given the current mostly dentist-dominant and patient-passive relationships. Patient-centered communication should be trained. Dental students need more practical learning in active listening and patient-centered skills including using role-play, videotaping and ultimately, real patient training. Medical consultation guides are often unwieldy and impractical in many dental contexts, so a shortened guide is proposed. Communication skills need to be learned and taught with the same rigor as other core dental skills over the entire course of the dental curriculum.  Effective communication skills, that is, accurate listening or observation and focused verbal or non-verbal response, enhances efficiency of diagnoses, ethical clinical decision making, positive clinical outcomes, promotes patient use of services, and patient–clinician satisfaction ,2,3. It Most of the literature about student learning of clinical communication skills appears in allied health, especially for medical and nursing students. This literature is vast compared with similar dental educational literature ,8. The rFinally, dental communication skills have traditionally been taught as one time didactic coursework, with little or no practical components prior to 2010 . AlthougThe following review attempts to synthesize knowledge gained from the literature specifically related to dental student learning of clinical communication skills in order to make recommendations towards optimization. Knowledge synthesis is important in health care research and practice because it can help contextualize and make sense of evidence that might not be obvious for some, yet can be influential for, as in this case, educational policy and practice. This review placed relatively few restrictions on inclusion criteria in order to sample essential or underemphasized points in the literature that speak to the unique nature and expected quality of teaching dental clinical communication skills. As described in the paragraph above, several reviews about dental school communication skills training, among others referred to below, seemed to share several conceptual agreements over the time between their respective publications. These temporal reiterations appeared important to their respective authors, but sometimes lacked depth of description contextualized to the daily needs of dental students. Four themes appeared to provide important contexts for optimizing learning of communication skills of dental students. The following review research agenda and search aimed to improve understanding of (1) special characteristics of dentistry relevant to communication skills needs, (2) essential components of dental student learning of communications skills, (3) clinical consultation guides or styles used in communication skills learning and (4) optimal curricular structure for clinical communication learning effectiveness. The hope of this review is to bring into focus these important themes of dental communications skills training that could improve educational policy and practice for optimizing dental student learning in the clinic. In order to make a list of considerations that would be helpful for optimizing communication skills training (CST) in dental education, the review especially focused on including (1) review studies, (2) 2010 or later and (3) English language articles that examined CST components in dental education. The initial search query was run in PubMed. Text terms used in the blanket query were “communication skills +/in dental education”. The search retrieved 369 articles. A Cochrane Library search contributed 7 more articles after duplicates were culled out. Since most of the review articles in that batch were before or included 2019, Google Scholar was used to repeat the same blanket query search for updates from 2020 to November 2021 to supplement previous searches. Google Scholar also has another convenient feature with its selection choice for “reviews”, which was helpful to refine the overall search for the most up-to-date review articles. The Google Scholar search found 10 more potentially relevant articles after duplicates were culled. Thirteen articles were identified as bona fide review articles related to learning or teaching of communication skills in dental education. The reason review articles were the focus of selection from the initial search was in order to explore themes from an overview perspective and in context, rather than search out of context for “uniqueness of dental communications”, “essential components of dental communication skills training”, “clinical consultation guides in communication skills training” or “optimal dental curricular structure for communication skills training”. Thus, presently selected review articles and their references were used to sample the literature that contained contextual information about any of the four themes. Seven of the studies were systematic reviews, one was a systematic scoping review and five were narrative reviews. Since review articles would report on content of CST components at the time of their publication, all articles before 2010 were considered outdated, which eliminated one of the systematic reviews . The remFindings in the present review are summarized and tabled in Sociolinguists Coleman and Burton  originalOn the other hand, one crucial difference is that there is actual administration of hands-on dental treatment in nearly all phases of dentist–patient interaction, including initial consultations ,18,19,20Furthermore, all dental patients are recalled for periodical check-ups and preventive treatments, unlike most medical patients. This also affects the context of dentist–patient communication compared with the context of medical consultations. In a 2019 major systematic review of communication coursework in dental education, Khalifah and Celenza  also poiKhalifah and Celenza  identifiKhalifah and Celenza also tabled each of the 50 relevant studies for type of communication skills taught, teaching method  and assessment method and outcomes . From thPeople tend to overestimate their listening comprehension, suggesting that they may not perceive listening as a skill requiring development in the same way that speaking, reading, writing or manual techniques are skills acquired through instruction, effort and time . Active Patient-centered care (PCC) has grown out of observations that active listening and empathy maximize clinical communication and health outcomes and was first officially espoused by the Institute of Medicine in 2001 . King anIn a systematic review of PCC in dentistry, Scambler et al.,  concludeThe model does not assume that all patients would want, or be happy with a Level 4 approach, that is, may not be their hierarchical endpoint.Another systematic review by Mills et al.  revealedIn summary, unlike the medical literature, the dental literature on patient-centered care and communication is scant. This possibly reflects values of dental education and of the profession as a whole in the reluctance to adopt what has proven to be in the medical profession and in society in general, a developmental paradigm shift. In their seminal review of teaching dental students communication skills, Khalifah and Celenza expressed disappointment that CST was still being taught using passive lecture techniques and that assessment was by written examination . It is gHowever, the Carey et al., review of dental communication skills training  indicateBurkert’s review  reportedThe literature on structural checklists or guides for health care personnel for making consultations is in agreement with a central premise to facilitate patient-centered communication. However, from the start, there is some controversy, since the overwhelming amount of literature about structural guides for clinical student learning is mainly in health science education literature other than dentistry. There is not nearly this amount of literature for dental consultation formats and styles. The descriptions in the first theme at the beginning of this review regarding special characteristics of the dental clinical environment and special clinical communication conditions fundamentally refers to a difference between medical and dental consultations and that important emphasis is also needed on intra-operative communication in dentistry. The intention with the descriptions below is to provide dental students with a helpful, relevant guide in learning the case wise temporal structure of longer patient consultations. Hopefully, the following narrative will provide some needed synthesis about this theme and can clarify directions for teaching dental students these skills. According to the literature, there are two main types of models of patient-centered consultation strategies that have been developed as guidelines for interviewing patients for diagnostics and/or health promotion: motivational interviewing (MI) ,35,36 anOpen-ended questions, providing Affirmations (positive feedback), use of Reflective listening, and discussion of Summaries. These are described in detail by Miller and others [Motivational interviewing (MI) was perhaps the earliest consultation model strategy. It came about from a desire of health professionals to support patients to achieve desired behavior change in special needs  ,34,39. Md others  as the fOpen-ended questioning—In contrast to closed questions, which generally require a simple yes/no or numeric answer, open questions do not direct a patient to respond in a particular manner. Instead, they enable a patient to think through and provide richer, fuller responses. The conversation should be started with words such as how or what or describe so that the patient does most of the talking.Affirmations—Sincere affirmations can help build a stronger relationship with a patient. These are the statements and gestures of health care workers that help the patient to recognize strength and acknowledge behaviors that lead to positive change, regardless of how big or small.Reflective listening—Akin to active listening, this demonstrates that the clinician has accurately heard and understood a patient’s communication. This relational empathy encourages further exploration of problems and feelings and encourages “change talk”.Summaries reinforce what has been said. Summary statements include trying to obtain the full picture of a patient’s behavior and checking with the patient to make sure that they feel the health care professional has reflected their situation accurately. Summarizing helps in integrating the communication that has occurred between the patient and provider.The Macy Foundation model identifies seven parts of the medical encounter  and focuses on relationship-building skills and interview-managing skills . The ManThe Calgary–Cambridge Guide  has ofteThere is also a dental version inspired by the C–CG, the Dental Consultation Communications Checklist (DCCC) ,42,43. TTorper et al.  present Given the need described above to find a concise yet flexible guide for training dental student consultations, the following suggestion is made, given special communication needs in the dental clinic. In Khalifah and Celenza’s systematic review, they differentiated generic skills from case- or time-specific skills. However, all of the models or guides above described a mix of skill sets as if they are from the same dimension. Logically, generic skills such as active listening, empathy, professionalism and patient-centered communication should be precursors to learning the structure and timing of communications for initial consultations. Generic skills are relevant to both initial consultations as well as more sporadic intra-operative communication. In other words, use of case- and time-specific guides that help students structure their communications with patients in a simplified manner should follow after they have some competency in the basic generic skills that apply to all forms of clinical communication. Generic skills often require the most time to learn, given their qualitative nature . If learIn summary, clinical consultation guidance schemes for dental students need to fit with the assumptions for dental clinical situations. Based on analysis of the consultation guide literature, recommendations described above are (1) two phase learning in CST for dental students, with focus on learning patient-centered generic skills in the first phase and (2) an efficient and effective guidance and structural plan for the chronological order of longer consultations in dentistry in the second phase.Longitudinal learning is almost taken for granted in educating dental students about caries/restorative dentistry, periodontology, prosthodontics and oral physiology. However, in dental educational programs for communication, there is limited progressive development during the curriculum in most cases ,15. The A curricular example of teaching communication skills was developed by Ayn et al.  after thStudies on German-speaking dental schools ,48 have It was apparent in the literature that there is a need to assess dental students’ skills in a longitudinal communication skills curricula. Although this review does not focus on assessment as a theme, the importance of competence assessment begs the question: “Did dental students learn what they needed to learn to improve their clinical communication skills?” Two of the tabled reviews ,33 citedThe following conclusions and recommendations can be drawn from this study:(1) The work environment for dentists is unique in that communication occurs most often while the patient is sitting passively in the dental chair, which for some, can be symbolic for vulnerability. Often the patient cannot talk since they are opening their mouths for dental treatment. It is important that regardless of whether there is an initial consultation or whether treatment needs to be interrupted for a consultation, the basis for patient communication and at dental teaching clinics should be a patient-centered approach. It should emphasize high-quality dialogue based on the generic skills of active listening, empathy and mirroring of patient perceptions.(2) Differentiation of skill sets required in the dental clinical environment and appropriate adjustment to needs for generic skills, case-specific skills, time-specific skills and emerging or advanced skills would be best fine-tuned with the aid of video clip supervision both in dentist–patient role-play in pre-clinical years and with patients in clinical years.(3) Motivational interviewing as a consultation guide is optimally useful in health promotion and appreciative inquiry approaches to oral health behavioral change interventions.(4) The basic protocol for systematic initial anamnestic dental consultations should start with a modified Calgary–Cambridge–like Guide, such as the Dental Consultation Communication Checklist. However, learning in dental communication skills should not be limited to initial anamnestic consultations, which also requires rethinking consultations during the treatment phase much as the Four-plus-one Habit model suggests. A DCCC short form was proposed for learning initial consultation structure and timing in dental educational CST. The short form assumes prior learning and competence in generic skills such as active listening, empathy, rapport building and motivation.(5) Longitudinal learning should be a strategic goal in communication skills education, in which learning with time and experience progress over the curriculum along with general clinical experience levels of students. Communication skills need to be taught and learned with the same rigor as other core dental skills.


This review article provides a framework for the use of deoxyribonucleic acid (DNA) methylation (DNAm) biomarkers to study the biological embedding of socioeconomic position (SEP) and summarizes the latest developments in the area. It presents the emerging literature showing associations between individual- and neighborhood-level SEP exposures and DNAm across the life course. In contrast to questionnaire-based methods of assessing SEP, we suggest that DNAm biomarkers may offer an accessible metric to study questions about SEP and health outcomes, acting as a personal dosimeter of exposure. However, further work remains in standardizing SEP measures across studies and evaluating consistency across domains, tissue types, and time periods. Meta-analyses of epigenetic associations with SEP are offered as one approach to confirm the replication of DNAm loci across studies. The development of DNAm biomarkers of SEP would provide a method for examining its impact on health outcomes in a more robust way, increasing the rigor of epidemiological studies. The term epigenetics is used to describe the study of mitotically heritable cellular material above the level of the DNA sequence that helps to regulate organismal development, gene expression, gene imprinting, genome stability, and other biological processes. Because of these functions, the amount and patterns of epigenetic material differ across cell types and across developmental and life course windows and may change in response to the environment. The most studied types of epigenetic material include DNA methylation (DNAm), histone tail modifications, and chromatin structure. DNAm involves the covalent addition of a methyl or hydroxymethyl group to cytosine nucleotides in DNA at CpG dinucleotides. DNAm is commonly used in epidemiologic studies because it is practical to obtain biosamples, it is stable when collected and stored at various conditions due to the covalent bond, and we understand the biological and inheritance properties well . BecauseThe use of DNAm profiles as biomarkers of environmental exposures can provide opportunities to assess environmental influences on health outcomes that may otherwise not be possible when there are challenges with measures of exposure. For example, an epigenetic biomarker may serve as a surrogate for unmeasured prior exposure in cases where exposure information was not collected. DNAm patterns have been shown to reflect past exposures to prenatal smoking, prenatal alcohol, exposure to pesticides and toxins, maternal diet, and other health metrics . DNAm siOne potential application of DNAm biomarkers is in capturing how social determinants of health become embodied . SocioecA large body of literature suggests that SEP is strongly associated with mortality and morbidity in multiple health domains . Lower SSEP is hypothesized to act via multiple mechanisms in manifesting biological risk for disease. For instance, the material hypothesis suggests that access to resources such as health care, health education, housing, and food quality translates to better health outcomes . Others SEP can be measured in different ways and at various levels, from individual to neighborhood. Some studies have used individual proxy factors, such as education, income, occupation, or subjective social ranking, while others have used composite scores . There iEducation is one of the most widely used factors to measure SEP; higher levels of education are associated with better jobs, income, and material resources . In chilNeighborhood-level composite scores can also be summarized at a geographic level, such as the median income of a census tract or the percentage of those with high school education in a county. Neighborhood factors such as infrastructure deprivation, stress, and lack of social support can have significant impacts on morbidity and mortality .et al. (2021) concluded that this may not be the case with little overlap in DNAm across SEP indicators [Each of the individual- and neighborhood-level SEP indicators may have varied effects on health outcomes. While some have suggested that DNAm may be a harmonizable accessible metric to study the many ways in which SEP is embodied, a recent review by Cerruti dicators . HoweverIncreasing evidence shows that SEP is associated with DNAm patterns in genes involved in stress and inflammation , 28 and et al. (2021) published a recent scoping review of 37 studies capturing global DNA, candidate gene studies, and epigenome-scale association studies (EWAS) to examine the association between SEP and DNAm in humans across the life course [Cerruti e course . The maie course , 35. Anoe course .et al. (2021) provided a comprehensive scoping review of articles showing evidence of the association between DNAm and SEP, we provide references that demonstrate aspects of SEP that have been examined in EWAS, candidate genes, and global methylation studies and may be of potential use for biomarker development [SEP-related factors are associated with specific DNAm patterns in EWAS , candidaelopment . Howeveret al., 2021) [et al. (2021) reported summary statistics compiled from nine EWAS showing 14 of 113 unique CpG sites associated with SEP domains across more than one study with 12 CpG sites in the education domain, one CpG site in the income domain, and one CpG site within the composite domain [Karlsson Linnér (2017) and van Dongen (2018) both assessed the same SEP domain, namely educational attainment, in adult blood with overlapping DNAm signatures  , 37, 38.e domain . Studieset al. (2019) and Laubach et al. (2019) examined the relationship between a composite measure of SEP and methylation in placental and cord blood, respectively, but did not find any overlap in CpG sites that were significantly associated with DNAm at birth [Another question is whether CpG sites for the same SEP domain are consistent across tissues within the same domain and tissue type. Santos at birth , 40. Theet al. (2018) found two relevant CpG sites within the SULF1 gene that were significantly associated with maternal education at birth in cord blood as well as in adolescence [Finally, the consistency of findings can also be examined over time. lescence . HoweverDNAm signatures have several characteristics that make them ideal biomarkers to capture SEP as a measure of risk for health outcomes. First, DNAm is practical to collect in large samples across multiple collection sites and can be modified by changing environmental influences and across time . Second,As illustrated, the traditional model uses self-report questionnaires and other sources of information such as neighborhood census reports to delineate SEP. When such traditional exposure information is not available, or to complement traditional exposure measures, methylation-based models can be used as a surrogate.We describe the steps for creating these methylation-based models briefly and specifically in the context of an SEP biomarker, although there is an extensive literature detailing the considerations for building prediction models in the broader context of epidemiological research , 43. NotThe first step to creating methylation-based models is to select CpG sites and their association statistics with SEP in a “training” population. This “training” population may consist of previous studies of SEP-related methylation changes, as delineated in If the investigator deems the predictive ability of the biomarker sufficient to act as a surrogate of SEP, the biomarker scores can be assessed as a single exposure for the SEP-related health outcome of interest along with covariates as delineated in the bottom portion of the conceptual Once replicable and generalizable SEP DNAm signatures are developed across studies, these biomarkers can be adjusted for in analyses to help disentangle the differential effects of other environmental factors  on health and development outcomes. Ultimately, these individual factors can also be added to the exposure biomarker model to examine the cumulative and interactive effects in conferring increased risk for poor health outcomes.Research is needed to elucidate epigenetic signatures that can capture SEP, at specific life stages, to provide a complementary measure of SEP for use in studies to examine the effects of SEP on health outcomes. Further work remains in developing harmonizable composite measures of SEP at both the individual and neighborhood levels that can be used across studies to help disentangle the complex relationship between SEP and other related environmental exposures. Research is also needed to elucidate the best tissue types for sampling DNAm changes related to socioeconomic exposures. In light of organismal research showing intergenerational and transgenerational transmission of epigenetic changes related to social disadvantage , 54, it A crucial step to generating valid and precise epigenetic biomarkers is a meta-analysis of epigenetic associations with SEP . Except To facilitate meta-analyses, EWAS for SEP must report comprehensive summary statistics beyond their statistically significant sites. Gathering comprehensive information across studies of epigenetic associations with SEP will improve the performance of the biomarkers by increasing confidence in the measurements of methylation and expanding the number of sites represented in the biomarker.The heterogeneity of studies reporting relationships between SEP constructs and DNAm is cited as a barrier to meta-analyses . HoweverEpigenome-scale studies that offer an unbiased capture of biomarkers of SEP and can be measured in accessible tissues would provide a valuable tool for early detection and intervention toward mitigating SEP-based health disparities.


Since this pH-inhibition could be deeply hard-wired in their metabolic make-up, it may be difficult for malignant cells in NMRs to acquire the WE-phenotype that facilitates cancer growth in other mammals. In the present commentary, we discuss this idea and propose experimental tests of our hypothesis.Metabolic flexibility in mammals enables stressed tissues to generate additional ATP by converting large amounts of glucose into lactic acid; however, this process can cause transient local or systemic acidosis. Certain mammals are adapted to extreme environments and are capable of enhanced metabolic flexibility as a specialized adaptation to challenging habitat niches. For example, naked mole-rats (NMRs) are a fossorial and hypoxia-tolerant mammal whose metabolic responses to environmental stressors markedly differ from most other mammals. When exposed to hypoxia, NMRs exhibit robust hypometabolism but develop minimal acidosis. Furthermore, and despite a very long lifespan relative to other rodents, NMRs have a remarkably low cancer incidence. Most advanced cancers in mammals display increased production of lactic acid from glucose, irrespective of oxygen availability. This hallmark of cancer is known as the Warburg effect (WE). Most malignancies acquire this metabolic phenotype during their somatic evolution, as the WE benefits tumor growth in several ways. We propose that the peculiar metabolism of the NMR makes development of the WE inherently difficult, which might contribute to the extraordinarily low cancer rate in NMRs. Such an adaptation of NMRs to their subterranean environment may have been facilitated by modified biochemical responses with a stronger inhibition of the production of CO Heterocephalus glaber), in which experimental data and metabolic logic both suggest that lactic acidosis occurs only to a very limited extent. NMRs also have a very low incidence of cancer, a disease in which extracellular lactic acidosis in the tumor microenvironment is a common hallmark.In this commentary we address the interplay between glycolysis and oxidative phosphorylation (OxPhos) in humans and most adult mammals, with a particular focus on the physiological flexibility that is enabled by extensive exchange of lactic acid. Of particular interest is the metabolism of naked mole-rats  lactic acid production by NMR tissues is strongly inhibited by extracellular acidosis, and (2) this sensitivity of NMR cells to acidosis is retained by cancerous cells after malignant transformation. As a result, the Warburg effect (WE), which is central to malignant cancer progression and underlies excessive lactic acidosis in tumors, may be strongly inhibited in this species.2 and H2O.Glycolysis is a ubiquitous metabolic pathway and its constituent enzymes are relatively conserved throughout evolution . Glycoly2 at the mitochondrial level, the rate of pyruvate production can be far greater than the ability of OxPhos to metabolize it (−), with the concomitant oxidation of NADH to restore NAD+. This near equilibrium reaction is catalyzed by lactate dehydrogenase (LDH). Together with H+, La− can be exported to the extracellular space via monocarboxylate transporters (MCTs)   . Essentie by LDH . Importaid (HLa) . Thus, w through (2e) can occur simultaneously in different tissues or sequentially in the same tissue . It is eAccordingly, 2 will generate both a systemic catecholamine-mediated stress response as well as stress at the cellular level resulting from decreasing ATP levels. Both usually induce an immediate increase of anaerobic glycolysis  to restore the nominal situation, so the “oxygen debt” that developed during hypoxia is “repaid” during recovery , impact reactive oxygen species (ROS) generation, or damage mitochondrial components, among other effects  stable, bicarbonate must have increased  . Since pNonetheless, all species must use glycolytic throughput to at least partially compensate for a drastically reduced ability to produce ATP in severe hypoxia and thus many hypoxia-tolerant species have developed elegant strategies to ameliorate the impact of lactic acidosis arising from sustained reliance on anaerobic metabolism. For example, the production of alternative end-products reduces or prevents backlogs of metabolic pathways and cellular acidification in some species , while o2), NMRs rapidly decrease their 2 by up to 85%  (2/2) rises towards 1.0, pointing to a switch from lipid to carbohydrate metabolism, which is metabolically advantageous under limited oxygen supply. Furthermore, the characteristic increase in 2 to repay oxygen debt is not observed in NMRs after reoxygenation. Although lactate levels have not been measured in hypoxic NMRs, these results strongly suggest that a major systemic rise in lactate is absent. In addition, expression of glucose transporter 4 , glycogen synthase (a key regulatory enzyme of glycolysis), and the phosphorylated form of AMP kinase   . Under tcolysis) , all dec hypoxia , changesin vivo evidence supports reliance on glycolytic metabolism in the hypoxic NMR, at least to some degree and in certain tissues. For example, in hypoxia we observe mobilization of liver glycogen stores and increase in blood glucose levels. The increase in blood glucose levels may also partly be explained by decreased glucose consumption during hypometabolic states  protein expression increases, and the expression of SREP2, a key regulator of fatty acid synthesis, decreases  in the NMR (or in most NMR tissues), glycolysis and OxPhos are strongly coupled (b) since it is important that this inhibition should hold across tissues and organs, the higher pH-setpoint for inhibition of glycolysis could be deeply hardwired in the NMR’s biochemistry. Thus, even malignant cells cannot circumvent this inhibition to develop the WE.Therefore, we hypothesize that:2 conditions  but NMRs appear to possess numerous defenses against cancer progression, which may explain low incidence rates of brain cancer in this organism, even if the WE were not inhibited in this tissue.Several clear implications of the strong inhibition of glycolysis by acidosis could be verified through comparisons of NMRs with other animals.in vivo blood sampling is far more difficult in the NMR than in mice due to anatomical differences. Once this technical challenge is addressed, our hypothesis predicts lower lactate levels in NMRs than in mice under hypoxia and other comparable stress conditions such as heavy exertion. Alternatively, artificially induced metabolic acidosis  should decrease glycolysis and induce hypometabolism. Likewise, administration of lactate to NMRs in the form of HLa or as sodium lactate (NaLa) could be used to compare the ability of NMRs to clear lactate with that of other animals. Labelling with stable isotopes of important substrates may help define how metabolic fluxes differ and how they are affected by pH changes.At the whole animal level, the most straightforward test would be to perform blood gas analyses, including lactate measurements, in NMRs under hypoxia. Although hyperlactatemia has been abundantly demonstrated in many mammalian models, this has unfortunately not been assessed in NMRs, since in vitro under various conditions, including under varying oxygen, glucose and lactate concentrations, and for different extracellular pH levels, all of which are relatively easy to manipulate in these ex vivo systems. It would also be instructive to determine the pH sensitivity of the enzymes of glycolysis  in the NMR. Likewise, the general expression of LDH or MCT’s may be lower, leading to lower generation of HLa. Alternatively, post-translational changes in LDH might result in lower enzyme activity (Alternatively, at the tissue or cellular levels, the coupling of glycolysis and OxPhos could be compared activity .Beyond these “baseline” measures, several cancer-targeted investigations could help test our hypothesis. Only a few cases of cancer in NMRs have been reported and described in detail postmortem . SamplesIt is not unreasonable to assume that the NMR’s unique metabolism, which suits its underground habitat, is in some way related to its remarkable resistance to cancer. The ability of NMRs to tolerate and exercise in hypoxic environments without significant acidosis is a striking metabolic characteristic of this mammal. Thus, we hypothesize that the low cancer incidence in the NMR may be related to a hard-wired coupling of glycolysis with OxPhos leading to the inability to express the Warburg effect, a phenotype that characterizes most cancers in other mammals.