Computational insights on asymmetrical D1 and D2 receptor-mediated chunking: implications for OCD and Schizophrenia.

Repetitive thoughts and motor programs including perseveration are bridge symptoms characteristic of obsessive compulsive disorder (OCD), schizophrenia and in the co-morbid overlap of these conditions. The above pathologies are sensitive to altered activation and kinetics of dopamine D1 and D2 receptors that differently influence sequence learning and recall. Recognizing start and stop elements of motor and cognitive behaviors has crucial importance. During chunking, frequent components of temporal strings are concatenated into single units. We extended a published computational model (Asabuki et al. 2018), where two populations of neurons are connected and simulated in a reservoir computing framework. These neural pools were adopted to represent D1 and D2 striatal neuronal populations. We investigated how specific neural and striatal circuit parameters can influence start/stop signaling and found that asymmetric intra-network connection probabilities, synaptic weights and differential time constants may contribute to signaling of start/stop elements within learned sequences. Asymmetric coupling between the striatal D1 and D2 neural populations was also demonstrated to be beneficial. Our modeling results predict that dynamical differences between the two dopaminergic striatal populations and the interaction between them may play complementary roles in chunk boundary signaling. Start and stop dichotomies can arise from the larger circuit dynamics as well, since neural and intra-striatal connections only partially support a clear division of labor.

Why Does Tardive Dyskinesia Have Oro-facial Predominance? A Network Analysis.

Tardive dyskinesia is a involuntary hyperkinetic disorder which usually occurs in older patients after long-term treatment with antipsychotic drugs. These dyskinesias are mostly irreversible and are frequently expressed in the tongue, cheeks, mandible, perioral area and other regions of the face. In this theoretical study we asked the question, why does tardive dyskinesia often have orofacial predominance? What might be the underlying neural network structure which contributes to this propensity? Graph analysis of high-level cortico-striato-thalamo-cortical network structure suggests a connectivity bottleneck. The number of walks of different lengths from the substantia nigra pars reticulata (SNr) to other vertices, as well as the returning cycles are the lowest in the network, which may indicate a higher damage susceptibility of this node. Analysis was also performed on published data from a recent high resolution histological study on cortico-striato-thalamo-cortical networks in rodents. Finer network partitioning and adjacency matrices demonstrated that the SNr has a heterogeneous connectivity structure and the number of local walks from nodes neighboring orofacial neural representation is higher, indicating possible early compensatory escape routes. However, with more extensive SNr damage the larger circuit compensation might be limited. This area of inquiry is important for future research, because identifying key vulnerable structures may provide more targeted therapeutical interventions.

Erectile dysfunction in hypertensive males in Kenya: a tertiary referral hospital experience.

Erectile dysfunction (ED) in males can be organic or/and psychological. Objective: To determine the burden of ED among adult hypertensive men attending ambulatory clinic at Kenyatta National Hospital, Nairobi, Kenya. Methods: Descriptive cross-sectional study on patients on antihypertensive medications, followed for ≥ one month. The tools used were five-item International Index of Erectile Function (IIEF-5) for ED and Alcohol Use Disorders Identification Test for alcohol use. Results: Among 385 patients, the mean age was 56.2 ±11.3 years, median follow up in medical clinic was 5 years. The mean body mass index was 26.3 ± 4.6 kg/m2, 209(54.3%) were pre-obese/obese. Current smokers were 76(19.7%) while 133(34.5%) were former smokers. Alcohol use in the past year was reported by 256(68.5%), while hazardous alcohol intake was in 54(14%). Prescribed antihypertensives in various combinations included angiotensin converting enzyme inhibitors/angiotensin receptor blockers to 292(75.8%), calcium channel blockers to 238(61.8%), beta blockerso 129(33.5%) and thiazide diuretics on 77(20%). Using IIEF-5 tool, the prevalence of ED was 364(94.5%) (95%CI 92.2-96.6) distributed as mild in 255(70%), moderate 76(21.9%) and 33(9.1%) severe. Conclusion: The burden of ED is high among hypertensive males. Precipitants of ED like cigarette smoking and alcohol use and use of antihypertensives which can cause ED are prevalent too.

Computational Predictions for OCD Pathophysiology and Treatment: A Review.

Obsessive compulsive disorder (OCD) can manifest as a debilitating disease with high degrees of co-morbidity as well as clinical and etiological heterogenity. However, the underlying pathophysiology is not clearly understood. Computational psychiatry is an emerging field in which behavior and its neural correlates are quantitatively analyzed and computational models are developed to improve understanding of disorders by comparing model predictions to observations. The aim is to more precisely understand psychiatric illnesses. Such computational and theoretical approaches may also enable more personalized treatments. Yet, these methodological approaches are not self-evident for clinicians with a traditional medical background. In this mini-review, we summarize a selection of computational OCD models and computational analysis frameworks, while also considering the model predictions from a perspective of possible personalized treatment. The reviewed computational approaches used dynamical systems frameworks or machine learning methods for modeling, analyzing and classifying patient data. Bayesian interpretations of probability for model selection were also included. The computational dissection of the underlying pathology is expected to narrow the explanatory gap between the phenomenological nosology and the neuropathophysiological background of this heterogeneous disorder. It may also contribute to develop biologically grounded and more informed dimensional taxonomies of psychopathology.

Analyzing the Efficacy of Isotretinoin in Treating Dissecting Cellulitis: A Literature Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Dissecting cellulitis of the scalp is a primary scarring alopecia. Isotretinoin is commonly referenced in the literature as a treatment for dissecting cellulitis. The objective of this article was to conduct a review and meta-analysis to assess the efficacy of isotretinoin for treating dissecting cellulitis of the scalp. METHODS: The following databases were searched for articles prior to 23 June, 2019: PubMed, Embase, Cochrane Central, CINAHL, and Web of Science. Multi-patient studies (more than three) that reported on the administration of isotretinoin for dissecting cellulitis were included. A pooled meta-analysis for improvement of disease burden after isotretinoin administration in patients with dissecting cellulitis of the scalp was performed. A fixed-effects model was used. RESULTS: Five articles were ultimately used for the quantitative meta-analysis. The overall efficacy rate of isotretinoin in treating dissecting cellulitis of the scalp was estimated to be 0.9 with a 95% confidence interval (0.81-0.97). The sensitivity analysis suggested that the overall efficacy is still very high, with a range of 0.83-0.94. Recurrence was seen in 24% (6/25) of patients. Common associated diseases amongst patients with dissecting cellulitis of the scalp were acne conglobata 20% (30/151) and hidradenitis suppurativa 19% (11/72). CONCLUSIONS: Isotretinoin is an effective treatment for improving symptoms of dissecting cellulitis of the scalp. Disease recurrence is a common finding for those who undergo successful treatment.

Neural dynamics in co-morbid schizophrenia and OCD: A computational approach.

The co-morbidity of obsessive-compulsive disorder (OCD) and schizophrenia is higher than what would be expected by chance and the common underlying neuropathophysiology is not well understood. Repetitive stereotypes and routines can be caused by perseverative thoughts and motor sequences in both of these disorders. We extended a previously published computational model to investigate cortico-striatal network dynamics. Given the considerable overlap in symptom phenomenology and the high degree of co-morbidity between OCD and schizophrenia, we examined the dynamical consequences of functional connectivity variations in the overlapping network. This was achieved by focusing on the emergence of network oscillatory activity and examining parameter sensitivity. Opposing activity levels are present in orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) in schizophrenia and OCD. We found that with over-compensation of the primary pathology, emergence of the other disorder can occur. The oscillatory behavior is delicately modulated by connections between the OFC/ACC to the ventral and dorsal striatum and by the coupling between the ACC and dorsolateral prefrontal cortex (DLPFC). Modulation on cortical self-inhibition (e.g. serotonin reuptake inhibitor treatment) together with dopaminergic input to the striatum (e.g. anti-dopaminergic medication) has non-trivial complex effects on the network oscillatory behavior, with an optimal modulatory window. Additionally, there are several disruption mechanisms and compensatory processes in the cortico-striato-thalamic network which may contribute to the underlying neuropathophysiology and clinical heterogeneity in schizo-obsessive spectrum disorders. Our mechanistic model predicts that dynamic over-compensation of the primarily occuring neuropathophysiology can lead to the secondary co-morbid disease.

An ingestible self-orienting system for oral delivery of macromolecules.

Biomacromolecules have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limit their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. Inspired by the leopard tortoise's ability to passively reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that autonomously positions itself to engage with GI tissue. It then deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. We conducted in vivo studies in rats and swine that support the applicator's safety and, using insulin as a model drug, demonstrated that the SOMA delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration.

Nodules on the Nasal Tip: Think Before You Laser

Cosmetic consultations are routinely part of a dermatologist's day. Often, patients present after consultation from another dermatologist or other physician with an established diagnosis and would like a particular treatment to resolve their condition. However, it is imperative to take a full history and physical exam prior to rendering treatment in the event of a missed or new diagnosis.

Cortico-striatal language pathways dynamically adjust for syntactic complexity: A computational study.

A growing body of literature supports a key role of fronto-striatal circuits in language perception. It is now known that the striatum plays a role in engaging attentional resources and linguistic rule computation while also serving phonological short-term memory capabilities. The ventral semantic and the dorsal phonological stream dichotomy assumed for spoken language processing also seems to play a role in cortico-striatal perception. Based on recent studies that correlate deep Broca-striatal pathways with complex syntax performance, we used a previously developed computational model of frontal-striatal syntax circuits and hypothesized that different parallel language pathways may contribute to canonical and non-canonical sentence comprehension separately. We modified and further analyzed a thematic role assignment task and corresponding reservoir computing model of language circuits, as previously developed by Dominey and coworkers. We examined the models performance under various parameter regimes, by influencing how fast the presented language input decays and altering the temporal dynamics of activated word representations. This enabled us to quantify canonical and non-canonical sentence comprehension abilities. The modeling results suggest that separate cortico-cortical and cortico-striatal circuits may be recruited differently for processing syntactically more difficult and less complicated sentences. Alternatively, a single circuit would need to dynamically and adaptively adjust to syntactic complexity.

Clinical resolution of pemphigus vulgaris on rituximab.

Although significant progress has been made for the treatment of pemphigus vulgaris (PV) with rituximab (RTX), a consensus remains to be determined for standard treatment protocol, regarding optimal dosing, infusion regimen, and use of concomitant immunotherapy to achieve safe, effective, and rapid clinical response. We describe a patient with pemphigus vulgaris treated with high dose rituximab with the rheumatoid arthritis protocol along with intravenous immunoglobulin therapy. This case provides evidence towards the growing body of research needed to modify and improve treatment for pemphigus using rituximab.

Dermatology consultations in a tertiary care hospital: A retrospective study of 243 cases.

BACKGROUND: The practice of dermatology remains mainly outpatient, although dermatologic consultations often have a large impact on inpatient care. OBJECTIVE: To analyze the reasons for dermatologic consultation and the impact of dermatologic evaluation at a major teaching hospital. METHODS: Retrospective chart review of 243 consecutive dermatologic consultations from primary ward teams between July 2012, and August 2013. RESULTS: Sixty-seven percent of the dermatologic consults were requested by the internal medicine, intensive care units, and hematology/oncology departments. Common skin conditions accounted for a large majority of consultations including: infectious (24.0%), drug-related (22.3%), and inflammatory skin conditions (21.0%). Most consultations required only one visit for resolution (60.9%). The primary team submitted a correct dermatologic diagnosis in 48.9% of cases. Dermatology consultation resulted in a change in or addition to treatment in 72.4% of patients. LIMITATIONS: Our analysis was limited by the data capture of the consulting physicians and the reliability of the patient historian. CONCLUSIONS: Our results revealed that common dermatoses account for a majority of dermatologic consultations. Modern ward teams continue to struggle with promptly recognizing and appropriately managing common skin conditions. Further training of ward physicians on common dermatologic conditions will improve recognition and treatment of skin conditions in hospitalized patients.

A multi-pathway hypothesis for human visual fear signaling.

A hypothesis is proposed for five visual fear signaling pathways in humans, based on an analysis of anatomical connectivity from primate studies and human functional connectvity and tractography from brain imaging studies. Earlier work has identified possible subcortical and cortical fear pathways known as the "low road" and "high road," which arrive at the amygdala independently. In addition to a subcortical pathway, we propose four cortical signaling pathways in humans along the visual ventral stream. All four of these traverse through the LGN to the visual cortex (VC) and branching off at the inferior temporal area, with one projection directly to the amygdala; another traversing the orbitofrontal cortex; and two others passing through the parietal and then prefrontal cortex, one excitatory pathway via the ventral-medial area and one regulatory pathway via the ventral-lateral area. These pathways have progressively longer propagation latencies and may have progressively evolved with brain development to take advantage of higher-level processing. Using the anatomical path lengths and latency estimates for each of these five pathways, predictions are made for the relative processing times at selective ROIs and arrival at the amygdala, based on the presentation of a fear-relevant visual stimulus. Partial verification of the temporal dynamics of this hypothesis might be accomplished using experimental MEG analysis. Possible experimental protocols are suggested.

A computational investigation of feedforward and feedback processing in metacontrast backward masking.

In human perception studies, visual backward masking has been used to understand the temporal dynamics of subliminal vs. conscious perception. When a brief target stimulus is followed by a masking stimulus after a short interval of <100 ms, performance on the target is impaired when the target and mask are in close spatial proximity. While the psychophysical properties of backward masking have been studied extensively, there is still debate on the underlying cortical dynamics. One prevailing theory suggests that the impairment of target performance due to the mask is the result of lateral inhibition between the target and mask in feedforward processing. Another prevailing theory suggests that this impairment is due to the interruption of feedback processing of the target by the mask. This computational study demonstrates that both aspects of these theories may be correct. Using a biophysical model of V1 and V2, visual processing was modeled as interacting neocortical attractors, which must propagate up the visual stream. If an activating target attractor in V1 is quiesced enough with lateral inhibition from a mask, or not reinforced by recurrent feedback, it is more likely to burn out before becoming fully active and progressing through V2 and beyond. Results are presented which simulate metacontrast backward masking with an increasing stimulus interval and with the presence and absence of feedback activity. This showed that recurrent feedback diminishes backward masking effects and can make conscious perception more likely. One model configuration presented a metacontrast noise mask in the same hypercolumns as the target, and produced type-A masking. A second model configuration presented a target line with two parallel adjacent masking lines, and produced type-B masking. Future work should examine how the model extends to more complex spatial mask configurations.