Cortico-thalamocortical interactions for learning, memory and decision-making.

The thalamus and cortex are interconnected both functionally and anatomically and share a common developmental trajectory. Interactions between the mediodorsal thalamus (MD) and different parts of the prefrontal cortex are essential in cognitive processes, such as learning and adaptive decision-making. Cortico-thalamocortical interactions involving other dorsal thalamic nuclei, including the anterior thalamus and pulvinar, also influence these cognitive processes. Our work, and that of others, indicates a crucial influence of these interdependent cortico-thalamocortical neural networks that contributes actively to the processing of information within the cortex. Each of these thalamic nuclei also receives potent subcortical inputs that are likely to provide additional influences on their regulation of cortical activity. Here, we highlight our current neuroscientific research aimed at establishing when cortico-MD thalamocortical neural network communication is vital within the context of a rapid learning and memory discrimination task. We are collecting evidence of MD-prefrontal cortex neural network communication in awake, behaving male rhesus macaques. Given the prevailing evidence, further studies are needed to identify both broad and specific mechanisms that govern how the MD, anterior thalamus and pulvinar cortico-thalamocortical interactions support learning, memory and decision-making. Current evidence shows that the MD (and the anterior thalamus) are crucial for frontotemporal communication, and the pulvinar is crucial for frontoparietal communication. Such work is crucial to advance our understanding of the neuroanatomical and physiological bases of these brain functions in humans. In turn, this might offer avenues to develop effective treatment strategies to improve the cognitive deficits often observed in many debilitating neurological disorders and diseases and in neurodegeneration.

Sensorimotor neural dynamics during isochronous tapping in the medial premotor cortex of the macaque.

We determined the response properties of neurons in the primate medial premotor cortex that were classified as sensory or motor during isochronous tapping to a visual or auditory metronome, using different target intervals and three sequential elements in the task. The cell classification was based on a warping transformation, which determined whether the cell activity was statistically aligned to sensory or motor events, finding a large proportion of cells classified as sensory or motor. Two distinctive clusters of sensory cells were observed, i.e. one cell population with short response-onset latencies to the previous stimulus, and another that was probably predicting the occurrence of the next stimuli. These cells were called sensory-driven and stimulus-predicting neurons, respectively. Sensory-driven neurons showed a clear bias towards the visual modality and were more responsive to the first stimulus, with a decrease in activity for the following sequential elements of the metronome. In contrast, stimulus-predicting neurons were bimodal and showed similar response profiles across serial-order elements. Motor cells showed a consecutive activity onset across discrete neural ensembles, generating a rapid succession of activation patterns between the two taps defining a produced interval. The cyclical configuration in activation profiles engaged more motor cells as the serial-order elements progressed across the task, and the rate of cell recruitment over time decreased as a function of the target interval. Our findings support the idea that motor cells were responsible for the rhythmic progression of taps in the task, gaining more importance as the trial advanced, while, simultaneously, the sensory-driven cells lost their functional impact.

Neurophysiology of timing in the hundreds of milliseconds: multiple layers of neuronal clocks in the medial premotor areas.

The precise quantification of time in the subsecond scale is critical for many complex behaviors including music and dance appreciation/execution, speech comprehension/articulation, and the performance of many sports. Nevertheless, its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the cell activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing during a synchronization-continuation tapping task (SCT). In this task the rhythmic behavior of monkeys was synchronized to a metronome of isochronous stimuli in the hundreds of milliseconds range (synchronization phase), followed by a period where animals internally temporalized their movements (continuation phase). Overall, we found that the time-keeping mechanism in MPC is governed by different layers of neural clocks. Close to the temporal control of movements are two separate populations of ramping cells that code for elapsed or remaining time for a tapping movement during the SCT. Thus, the sensorimotor loops engaged during the task may depend on the cyclic interplay between two neuronal chronometers that quantify in their instantaneous discharge rate the time passed and the remaining time for an action. In addition, we found MPC neurons that are tuned to the duration of produced intervals during the rhythmic task, showing an orderly variation in the average discharge rate as a function of duration. All the tested durations in the subsecond scale were represented in the preferred intervals of the cell population. Most of the interval-tuned cells were also tuned to the ordinal structure of the six intervals produced sequentially in the SCT. Hence, this next level of temporal processing may work as the notes of a musical score, providing information to the timing network about what duration and ordinal element of the sequence are being executed. Finally, we describe how the timing circuit can use a dynamic neural representation of the passage of time and the context in which the intervals are executed by integrating the time-varying activity of populations of cells. These neural population clocks can be defined as distinct trajectories in the multidimensional cell response-space. We provide a hypothesis of how these different levels of neural clocks can interact to constitute a coherent timing machine that controls the rhythmic behavior during the SCT.

Cholangioscopy-based convoluted neuronal network vs. confocal laser endomicroscopy in identification of neoplastic biliary strictures.

Background and study aims Artificial intelligence (AI) models have demonstrated high diagnostic performance identifying neoplasia during digital single-operator cholangioscopy (DSOC). To date, there are no studies directly comparing AI vs. DSOC-guided probe-base confocal laser endomicroscopy (DSOC-pCLE). Thus, we aimed to compare the diagnostic accuracy of a DSOC-based AI model with DSOC-pCLE for identifying neoplasia in patients with indeterminate biliary strictures. Patients and methods This retrospective cohort-based diagnostic accuracy study included patients ≥ 18 years old who underwent DSOC and DSOC-pCLE (June 2014 to May 2022). Four methods were used to diagnose each patient's biliary structure, including DSOC direct visualization, DSOC-pCLE, an offline DSOC-based AI model analysis performed in DSOC recordings, and DSOC/pCLE-guided biopsies. The reference standard for neoplasia was a diagnosis based on further clinical evolution, imaging, or surgical specimen findings during a 12-month follow-up period. Results A total of 90 patients were included in the study. Eighty-six of 90 (95.5%) had neoplastic lesions including cholangiocarcinoma (98.8%) and tubulopapillary adenoma (1.2%). Four cases were inflammatory including two cases with chronic inflammation and two cases of primary sclerosing cholangitis. Compared with DSOC-AI, which obtained an area under the receiver operator curve (AUC) of 0.79, DSOC direct visualization had an AUC of 0.74 ( P = 0.763), DSOC-pCLE had an AUC of 0.72 ( P = 0.634), and DSOC- and pCLE-guided biopsy had an AUC of 0.83 ( P = 0.809). Conclusions The DSOC-AI model demonstrated an offline diagnostic performance similar to that of DSOC-pCLE, DSOC alone, and DSOC/pCLE-guided biopsies. Larger multicenter, prospective, head-to-head trials with a proportional sample among neoplastic and nonneoplastic cases are advisable to confirm the obtained results.

Variable cardiac responses in rhesus macaque monkeys after discrete mediodorsal thalamus manipulations.

The control of some physiological parameters, such as the heart rate, is known to have a role in cognitive and emotional processes. Cardiac changes are also linked to mental health issues and neurodegeneration. Thus, it is not surprising that many of the brain structures typically associated with cognition and emotion also comprise a circuit-the central automatic network-responsible for the modulation of cardiovascular output. The mediodorsal thalamus (MD) is involved in higher cognitive processes and is also known to be connected to some of the key neural structures that regulate cardiovascular function. However, it is unclear whether the MD has any role in this circuitry. Here, we show that discrete manipulations (microstimulation during anaesthetized functional neuroimaging or localized cytotoxin infusions) to either the magnocellular or the parvocellular MD subdivisions led to observable and variable changes in the heart rate of female and male rhesus macaque monkeys. Considering the central positions that these two MD subdivisions have in frontal cortico-thalamocortical circuits, our findings suggest that MD contributions to autonomic regulation may interact with its identified role in higher cognitive processes, representing an important physiological link between cognition and emotion.

Distinct beta frequencies reflect categorical decisions.

Based on prior findings of content-specific beta synchronization in working memory and decision making, we hypothesized that beta oscillations support the (re-)activation of cortical representations by mediating neural ensemble formation. We found that beta activity in monkey dorsolateral prefrontal cortex (dlPFC) and pre-supplementary motor area (preSMA) reflects the content of a stimulus in relation to the task context, regardless of its objective properties. In duration- and distance-categorization tasks, we changed the boundary between categories from one block of trials to the next. We found that two distinct beta-band frequencies were consistently associated with the two relative categories, with activity in these bands predicting the animals' responses. We characterized beta at these frequencies as transient bursts, and showed that dlPFC and preSMA are connected via these distinct frequency channels. These results support the role of beta in forming neural ensembles, and further show that such ensembles synchronize at different beta frequencies.

Subsecond timing in primates: comparison of interval production between human subjects and rhesus monkeys.

This study describes the psychometric similarities and differences in motor timing performance between 20 human subjects and three rhesus monkeys during two timing production tasks. These tasks involved tapping on a push-button to produce the same set of intervals (range of 450 to 1,000 ms), but they differed in the number of intervals produced (single vs. multiple) and the modality of the stimuli (auditory vs. visual) used to define the time intervals. The data showed that for both primate species, variability increased as a function of the length of the produced target interval across tasks, a result in accordance with the scalar property. Interestingly, the temporal performance of rhesus monkeys was equivalent to that of human subjects during both the production of single intervals and the tapping synchronization to a metronome. Overall, however, human subjects were more accurate than monkeys and showed less timing variability. This was especially true during the self-pacing phase of the multiple interval production task, a behavior that may be related to complex temporal cognition, such as speech and music execution. In addition, the well-known human bias toward auditory as opposed to visual cues for the accurate execution of time intervals was not evident in rhesus monkeys. These findings validate the rhesus monkey as an appropriate model for the study of the neural basis of time production, but also suggest that the exquisite temporal abilities of humans, which peak in speech and music performance, are not all shared with macaques.

[Evaluation of benign paroxysmal positional vertigo in primary health-care and first level specialist care]. / Valoración del conocimiento del vértigo posicional paroxístico benigno en la atención primaria y especializada de primer nivel.

INTRODUCTION: Benign paroxysmal positional vertigo (BPPV) is the most common cause of vestibular vertigo, but it is not well known in routine clinical practice. OBJECTIVE: To determine the awareness of BPPV outside the ENT clinic. PATIENTS AND METHOD: Retrospective study of sixty-nine patients treated for BPPV between June 2005 and December 2006 at the specialist clinic. We analyzed the routes and details for their referral and the time elapsed since the start of the symptoms. RESULTS: 42 patients (61 %) were referred through the conventional route (primary health-care or non-hospital ENT); 17 patients (25 %) came from the emergency room (one third of them were admitted); the remainder were patients hospitalized for some other problem (5 %) or informal consultations (9 %). Only one patient had been referred with a specific diagnosis of BPPV. The onset of vertigo symptoms before treatment was, on average, 20 weeks (SD, 32 weeks) and was significantly longer among patients coming from primary care (28 weeks) as compared with the other groups (P < .01, Kruskall-Wallis test). The mean time to referral was shorter among patients with idiopathic BPPV or with BPPV secondary to recurrent vestibulopathy whereas it was more prolonged among patients with a concomitant pathology capable of justifying the presence of positional symptoms, such as vestibular neuritis or post-traumatic BPPV (P < .01, Kruskall-Wallis test). The medical cost of treating BPPV prior to referral has been calculated at euro364 per individual (mostly for non-specific medical treatments) instead of the euro136 needed for effective positional treatment. CONCLUSIONS: BPPV continues to be a poorly understood pathology outside specialist neuro-otologic clinics, leading to delays in diagnosis and treatment, as well as the unnecessary consumption of resources.

Neural basis for categorical boundaries in the primate pre-SMA during relative categorization of time intervals.

Perceptual categorization depends on the assignment of different stimuli to specific groups based, in principle, on the notion of flexible categorical boundaries. To determine the neural basis of categorical boundaries, we record the activity of pre-SMA neurons of monkeys executing an interval categorization task in which the limit between short and long categories changes between blocks of trials within a session. A large population of cells encodes this boundary by reaching a constant peak of activity close to the corresponding subjective limit. Notably, the time at which this peak is reached changes according to the categorical boundary of the current block, predicting the monkeys' categorical decision on a trial-by-trial basis. In addition, pre-SMA cells also represent the category selected by the monkeys and the outcome of the decision. These results suggest that the pre-SMA adaptively encodes subjective duration boundaries between short and long durations and contains crucial neural information to categorize intervals and evaluate the outcome of such perceptual decisions.

Lichen planus pigmentosus and its variants: review and update.

Lichen planus pigmentosus (LPP) is considered a rare variant of lichen planus (LP). It is characterized by acquired dark brown to gray macular pigmentation located on sun-exposed areas of the face, neck, and flexures, commonly found in dark-skinned patients. In patients with LPP, an inflammatory lichenoid response results in marked pigmentary incontinence. It has been associated with hepatitis C virus, sun exposure, and contactants such as mustard oil and nickel. LPP-inversus affects fair and dark skin, predominantly involving flexural and intertriginous areas, while sun-exposed areas are spared; friction is an associated trigger. LPP along Blaschko's lines has been associated with susceptibility to genetic mosaicisms. LPP can present concomitantly with other variants of LP such as frontal fibrosing alopecia, as well as endocrinopathies, and autoimmune diseases. Treatment is difficult and consists of avoidance of triggers and topical and systemic medications in order to stop the inflammatory reaction and reduce pigmentation, improving aesthetic appearance and quality of life.

Bioeconomic modeling for a small-scale sea cucumber fishery in Yucatan, Mexico.

Due to the heavy exploitation of holothurians over the last few decades, it is necessary to implement fishing regulations aimed at reversing this situation. Holothurians require specific regulations that take into account their biology and ecology. Their behavior to group and form patches as a strategy for feeding, defense and reproduction, makes them vulnerable to overfishing. The higher the population density, the higher the catchability coefficient, and because they are sedentary organisms, the catchability does not change significantly until the density is very low. Hence, the stock assessment of holothurians can be improved by analyzing their spatial distribution. This paper proposes a stock assessment technique that considers the spatial distribution pattern of the sea cucumber Isostichopus badionotus from Yucatan, Mexico. A bioeconomic spatial model was developed to explain the interactions between fishing effort allocation, quasi-profits and the population in the short term. Because of the high price of the species and the low production costs, artisanal fishers preferred to maximize short-term quasi-profits, rather than the long-term benefits they could gain with low fishing mortality rates.

Probing the timing network: A continuous theta burst stimulation study of temporal categorization.

Time perception in the millisecond and second ranges is thought to be processed by different neural mechanisms. However, whether there is a sharp boundary between these ranges and whether they are implemented in the same, overlapped or separate brain areas is still not certain. To probe the role of the right dorsolateral prefrontal cortex (dlPFC), the right supplementary motor area (SMA), and the cerebellum on time perception, we temporarily altered their activity on healthy volunteers on separate sessions using transcranial magnetic stimulation with the continuous Theta Burst Stimulation (cTBS) protocol. A control session was reserved for the stimulation of the primary somatosensory cortex (S1). Before and after stimulation, participants were tested on a temporal categorization task using intervals in the hundreds and thousands of milliseconds ranges, as well as on a pitch categorization task which was used as a further control. We then looked for changes in the Relative Threshold and the Constant Error, which, respectively, reflect participants' sensitivity to interval duration and their accuracy at setting an interval that acts as a boundary between categories. We found that after cTBS in all of the studied regions, the Relative Threshold, but not the Constant Error, was affected and only when hundreds of milliseconds intervals were being categorized. Categorization of thousands of milliseconds intervals and of pitch was not affected. These results suggest that the fronto-cerebellar circuit is particularly involved in the estimation of intervals in the hundreds of milliseconds range.

Exploring entrepreneurial intentions in Latin American university students.

The aim of this study was to determine if entrepreneurial intention, based on Ajzen's model of planned behavior (1991), can be predicted by risk propensity, internal locus of control and leadership skills. Six standardized and reliable instruments were applied to 1493 undergraduate university business students in Latin American countries, selected through non-random quota sampling in accordance with their formation level in each of the five participating universities. Using structural equation techniques, the research model was validated and intention estimated and analyzed in relation to a set of socio-demographic variables. According to the results, entrepreneurial intention can be significantly predicted by the psychological variables under consideration and, contrary to what has been reported in other research, no gender differences were found in the intention of entrepreneurship. These findings are discussed.

El propósito de este estudio fue determinar si la intención de emprendimiento, basada en el modelo de comportamiento planeado de Ajzen (1991), puede predecirse a partir de la propensión al riesgo, el locus de control interno y las habilidades de liderazgo. Se aplicaron seis instrumentos estandarizados y confiables a 1493 estudiantes latinoamericanos de áreas empresariales, utilizando un muestreo no probabilístico por cuota según año de formación en cada universidad. A través de ecuaciones estructurales se validó el modelo de investigación propuesto y se estimó y analizo la intención en relación con las variables sociodemográficas. De acuerdo con los resultados, la intención de emprendimiento puede predecirse significativamente con las variables psicológicas estudiadas y contrario a lo hallado en otros estudios no se encontraron diferencias por género. Se discuten estos hallazgos.

Linking perception, cognition, and action: psychophysical observations and neural network modelling.

It has been argued that perception, decision making, and movement planning are in reality tightly interwoven brain processes. However, how they are implemented in neural circuits is still a matter of debate. We tested human subjects in a temporal categorization task in which intervals had to be categorized as short or long. Subjects communicated their decision by moving a cursor into one of two possible targets, which appeared separated by different angles from trial to trial. Even though there was a 1 second-long delay between interval presentation and decision communication, categorization difficulty affected subjects' performance, reaction (RT) and movement time (MT). In addition, reaction and movement times were also influenced by the distance between the targets. This implies that not only perceptual, but also movement-related considerations were incorporated into the decision process. Therefore, we searched for a model that could use categorization difficulty and target separation to describe subjects' performance, RT, and MT. We developed a network consisting of two mutually inhibiting neural populations, each tuned to one of the possible categories and composed of an accumulation and a memory node. This network sequentially acquired interval information, maintained it in working memory and was then attracted to one of two possible states, corresponding to a categorical decision. It faithfully replicated subjects' RT and MT as a function of categorization difficulty and target distance; it also replicated performance as a function of categorization difficulty. Furthermore, this model was used to make new predictions about the effect of untested durations, target distances and delay durations. To our knowledge, this is the first biologically plausible model that has been proposed to account for decision making and communication by integrating both sensory and motor planning information.

Gemcitabine and capecitabine as third- or later-line therapy for refractory advanced colorectal cancer: a retrospective study.

AIM: To evaluate gemcitabine plus capecitabine as third-line or later-line therapy in patients with refractory advanced colorectal cancer (CRC) who maintain a good performance status (PS). PATIENTS AND METHODS: We retrospectively evaluated patients who had failed at least two lines of therapy or had contraindication to standard therapy and received gemcitabine (1,000 mg/m(2), d1 biweekly) plus capecitabine (1,700 mg/m(2)/day, d1-7 every two weeks) in a compassionate use program. RESULTS: Thirty-nine patients were enrolled. The majority (85%) had ECOG PS 1. Gemcitabine plus capecitabine was administered as third- and fourth-line in 49% and 23% of patients, respectively; and as fifth-line or later-line in 28%. A clinical benefit of 21% was found. The median progression-free survival and overall survival were 3.0 and 7.3 months, respectively. Toxicity was mild to moderate, with no reported grade 4 toxicities. CONCLUSION: Gemcitabine plus capecitabine was safe and well-tolerated. While the efficacy of this regimen was modest in terms of response, the survival data were acceptable and consistent with previous publications on this setting.