Ventrolateral prefrontal cortex in macaques guides decisions in different learning contexts.

Flexibly adjusting our behavioral strategies based on the environmental context is critical to maximize rewards. Ventrolateral prefrontal cortex (vlPFC) has been implicated in both learning and decision-making for probabilistic rewards, although how context influences these processes remains unclear. We collected functional neuroimaging data while rhesus macaques performed a probabilistic learning task in two contexts: one with novel and another with familiar visual stimuli. We found that activity in vlPFC encoded rewards irrespective of the context but encoded behavioral strategies that depend on reward outcome (win-stay/lose-shift) preferentially in novel contexts. Functional connectivity between vlPFC and anterior cingulate cortex varied with behavioral strategy in novel learning blocks. By contrast, connectivity between vlPFC and mediodorsal thalamus was highest when subjects repeated a prior choice. Furthermore, pharmacological D2-receptor blockade altered behavioral strategies during learning and resting-state vlPFC activity. Taken together, our results suggest that multiple vlPFC-linked circuits contribute to adaptive decision-making in different contexts.

What can neuroimaging of neuromodulation reveal about the basis of circuit therapies for psychiatry?

Neuromodulation is increasingly becoming a therapeutic option for treatment resistant psychiatric disorders. These non-invasive and invasive therapies are still being refined but are clinically effective and, in some cases, provide sustained symptom reduction. Neuromodulation relies on changing activity within a specific brain region or circuit, but the precise mechanisms of action of these therapies, is unclear. Here we review work in both humans and animals that has provided insight into how therapies such as deep brain and transcranial magnetic stimulation alter neural activity across the brain. We focus on studies that have combined neuromodulation with neuroimaging such as PET and MRI as these measures provide detailed information about the distributed networks that are modulated and thus insight into both the mechanisms of action of neuromodulation but also potentially the basis of psychiatric disorders. Further we highlight work in nonhuman primates that has revealed how neuromodulation changes neural activity at different scales from single neuron activity to functional connectivity, providing key insight into how neuromodulation influences the brain. Ultimately, these studies highlight the value of combining neuromodulation with neuroimaging to reveal the mechanisms through which these treatments influence the brain, knowledge vital for refining targeted neuromodulation therapies for psychiatric disorders.

Distinct roles of monkey OFC-subcortical pathways in adaptive behavior.

Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.

Deep brain stimulation induces white matter remodeling and functional changes to brain-wide networks.

Deep brain stimulation (DBS) is an emerging therapeutic option for treatment resistant neurological and psychiatric disorders, most notably depression. Despite this, little is known about the anatomical and functional mechanisms that underlie this therapy. Here we targeted stimulation to the white matter adjacent to the subcallosal anterior cingulate cortex (SCC-DBS) in macaques, modeling the location in the brain proven effective for depression. We demonstrate that SCC-DBS has a selective effect on white matter macro- and micro-structure in the cingulum bundle distant to where stimulation was delivered. SCC-DBS also decreased functional connectivity between subcallosal and posterior cingulate cortex, two areas linked by the cingulum bundle and implicated in depression. Our data reveal that white matter remodeling as well as functional effects contribute to DBS's therapeutic efficacy.

The neural basis of resting-state fMRI functional connectivity in fronto-limbic circuits revealed by chemogenetic manipulation.

Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and the underlying patterns of neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the amygdala of two male macaques. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5 Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-modal approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.

Can dermatologists reach their full potential in teledermatology? A validation study of diagnostic performance of skin diseases in live video conferencing teledermatology.

The diagnostic accuracy rate of live videoconferencing (LVC) teledermatology, by board-certified dermatologists compared to non-dermatologists has not yet been fully investigated. The aim of this study was to compare the diagnostic accuracy of board-certified dermatologists, dermatology specialty trainees, and board-certified internists in LVC teledermatology. We examined the diagnostic accuracy of clinicians from different specialties in diagnosing the same group of patients. The clinicians were isolated from each other during the diagnosis process. We enrolled 18 volunteer physicians (six board-certified dermatologists, six dermatology specialty trainees, and six board-certified internists) who reviewed the skin conditions of 18 patients via LVC teledermatology. The diagnostic accuracy of the participating physicians was evaluated using the final diagnosis as the reference standard. The diagnostic accuracy averages were compared according to the physicians' specialties and disease categories. The mean ± standard deviation diagnostic accuracy of the most detailed level diagnosis was 83.3% ± 3.5% (range, 77.8%-89.0%) for board-certified dermatologists, 53.7 ± 20.7% (range 27.8%-77.8%) for dermatology specialty trainees, and 27.8 ± 5.0% (range, 22.2%-33.3%) for board-certified internists. Board-certified dermatologists showed significantly higher diagnostic accuracy, not only against board-certified internists (p < 0.0001) but also against dermatology specialty trainees (p < 0.05). Disease categories with high accuracy rates (≥80%) only by board-certified dermatologists were inflammatory papulosquamous dermatoses (87.5%), compared to 58.3%, and 20.8% for dermatology specialty trainees and board-certified internists respectively). For inflammatory erythemas and other reactive inflammatory dermatoses the accuracy rates for board-certified dermatologists, dermatology specialty trainees, and board-certified internists were 83.3%, 33.3%, 8.3% respectively; for melanoma in situ neoplasms, 83.3%, 50.0%, 66.7% respectively), and for genetic disorders of keratinization 83.3%, 33.3%, and 0% respectively). Our findings showed that board-certified dermatologists may have high diagnostic accuracy with practical safety and effectiveness in LVC teledermatology.

Sublingual immunotherapy for cedar pollinosis possibly triggers eosinophilic esophagitis.

Sublingual immunotherapy (SLIT) is an effective and popular treatment for cedar pollinosis. Although SLIT can cause allergic side effects, eosinophilic esophagitis (EoE) is a lesser-known side effect of SLIT. A 26-year-old male with cedar pollinosis, wheat-dependent exercise-induced anaphylaxis, and food allergies to bananas and avocados presented with persistent throat itching, difficulty swallowing, heartburn, and anterior chest pain 8 days after starting SLIT for cedar pollinosis. Laboratory examination showed remarkably elevated eosinophils, and esophagogastroduodenoscopy revealed linear furrows in the entire esophagus. Histological examination of an esophageal biopsy specimen revealed high eosinophil levels. The patient was strongly suspected with EoE triggered by SLIT. The patient was advised to switch from the swallow to the spit method for SLIT, and the symptoms associated with SLIT-triggered EoE were reduced after switching to the spit method. This case highlights the importance of recognizing SLIT-triggered EoE as a potential side effect of SLIT for cedar pollinosis, especially with the increasing use of SLIT in clinical practice. EoE can occur within a month after initiating SLIT in patients with multiple allergic conditions, as observed in our case. Furthermore, the spit method should be recommended for patients who experience SLIT-triggered EoE before discontinuing SLIT.

Distinct roles of monkey OFC-subcortical pathways in adaptive behavior.

To be the most successful, primates must adapt to changing environments and optimize their behavior by making the most beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate a dissociable contribution of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.

Single basolateral amygdala neurons in macaques exhibit distinct connectional motifs with frontal cortex.

Basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for appropriate emotional responding and decision making. While it is appreciated that single BLA neurons branch and project to multiple areas in frontal cortex, the organization and frequency of this branching has yet to be fully characterized. Here, we determined the projection patterns of more than 3,000 macaque BLA neurons. We found that one-third of BLA neurons had two or more distinct projection targets in frontal cortex and subcortical structures. The patterns of single BLA neuron projections to multiple areas were organized into repeating motifs that targeted distinct sets of areas in medial and ventral frontal cortex, indicative of separable BLA networks. Our findings begin to reveal the rich structure of single-neuron connections in the non-human primate brain, providing a neuroanatomical basis for the role of BLA in coordinating brain-wide responses to valent stimuli.

The neural basis of resting-state fMRI functional connectivity in fronto-limbic circuits revealed by chemogenetic manipulation.

Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the macaque amygdala and activated them with a highly selective and potent DREADD agonist, deschloroclozapine. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Interestingly, activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-disciplinary approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.

High-throughput sequencing of macaque basolateral amygdala projections reveals dissociable connectional motifs with frontal cortex.

The basolateral amygdala (BLA) projects widely across the macaque frontal cortex1-4, and amygdalo-frontal projections are critical for optimal emotional responding5 and decision-making6. Yet, little is known about the single-neuron architecture of these projections: namely, whether single BLA neurons project to multiple parts of the frontal cortex. Here, we use MAPseq7 to determine the projection patterns of over 3000 macaque BLA neurons. We found that one-third of BLA neurons have two or more distinct targets in parts of frontal cortex and of subcortical structures. Further, we reveal non-random structure within these branching patterns such that neurons with four targets are more frequently observed than those with two or three, indicative of widespread networks. Consequently, these multi-target single neurons form distinct networks within medial and ventral frontal cortex consistent with their known functions in regulating mood and decision-making. Additionally, we show that branching patterns of single neurons shape functional networks in the brain as assessed by fMRI-based functional connectivity. These results provide a neuroanatomical basis for the role of the BLA in coordinating brain-wide responses to valent stimuli8 and highlight the importance of high-resolution neuroanatomical data for understanding functional networks in the brain.

Pharmacological modulation of dopamine D1 and D2 receptors reveals distinct neural networks related to probabilistic learning in non-human primates.

The neurotransmitter dopamine (DA) has a multifaceted role in healthy and disordered brains through its action on multiple subtypes of dopaminergic receptors. How modulation of these receptors controls behavior by altering connectivity across intrinsic brain-wide networks remains elusive. Here we performed parallel behavioral and resting-state functional MRI experiments after administration of two different DA receptor antagonists in macaque monkeys. Systemic administration of SCH-23390 (D1 antagonist) disrupted probabilistic learning when subjects had to learn new stimulus-reward associations and diminished functional connectivity (FC) in cortico-cortical and fronto-striatal connections. By contrast, haloperidol (D2 antagonist) improved learning and broadly enhanced FC in cortical connections. Further comparison between the effect of SCH-23390/haloperidol on behavioral and resting-state FC revealed specific cortical and subcortical networks associated with the cognitive and motivational effects of DA, respectively. Thus, we reveal the distinct brain-wide networks that are associated with the dopaminergic control of learning and motivation via DA receptors.

Current approaches and questions yet to be resolved for the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis.

Prophylaxis is important for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), which is the most common and serious complication of ERCP. Although the current guidelines include independent patient- and procedure-related risk factors for PEP and available PEP prophylactic measures, the synergistic effect of these risk factors on PEP should also be considered, given that patients often harbor multiple risk factors. Furthermore, a combination of prophylactic measures is often selected in clinical practice. However, established methods estimating the synergistic effect of independent risk factors on PEP incidence are lacking, and evidence on the impact of combining prophylactic measures on PEP should be discussed. Selection of appropriate candidate patients for ERCP is also important to reduce the incidence of PEP associated with unnecessary ERCP. ERCP indications in patients with asymptomatic common bile duct stones (CBDSs) and in those with suspected CBDSs with no imaging-based evidence of stones are controversial. Further studies are warranted to predict the synergistic effect of independent risk factors on PEP, determine the best prophylactic PEP measures, and identify appropriate candidates for ERCP in patients with asymptomatic CBDSs and those with suspected CBDSs.

Resting-State fMRI-Based Screening of Deschloroclozapine in Rhesus Macaques Predicts Dosage-Dependent Behavioral Effects.

Chemogenetic techniques, such as designer receptors exclusively activated by designer drugs (DREADDs), enable transient, reversible, and minimally invasive manipulation of neural activity in vivo Their development in nonhuman primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we use resting-state fMRI, a noninvasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brainwide resting-state functional connectivity in 7 rhesus macaques (6 males and 1 female) without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Additional behavioral tests confirmed a negligible impact of 0.1 mg/kg DCZ on socio-emotional behaviors as well as on reaction time in a probabilistic learning task; 0.3 mg/kg DCZ did, however, slow responses in the probabilistic learning task, suggesting attentional or motivational deficits associated with hyperconnectivity in fronto-temporo-parietal networks. Our study highlights both the excellent selectivity of DCZ as a DREADD actuator, and the side effects of its excess dosage. The results demonstrate the translational value of resting-state fMRI as a drug-screening tool to accelerate the development of chemogenetics in primates.SIGNIFICANCE STATEMENT Chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), can afford control over neural activity with unprecedented spatiotemporal resolution. Accelerating the translation of chemogenetic neuromodulation from rodents to primates requires an approach to screen novel DREADD actuators in vivo Here, we assessed brainwide activity in response to a DREADD actuator deschloroclozapine (DCZ) using resting-state fMRI in macaque monkeys. We demonstrated that low-dose DCZ (0.1 mg/kg) did not change whole-brain functional connectivity or affective behaviors, while a higher dose (0.3 mg/kg) altered frontal functional connectivity and slowed response in a learning task. Our study highlights the excellent selectivity of DCZ at proper dosing, and demonstrates the utility of resting-state fMRI to screen novel chemogenetic actuators in primates.

Deep Neural Network for Early Image Diagnosis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

BACKGROUND: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction (cADR). Distinguishing SJS/TEN from nonsevere cADRs is difficult, especially in the early stages of the disease. OBJECTIVE: To overcome this limitation, we developed a computer-aided diagnosis system for the early diagnosis of SJS/TEN, powered by a deep convolutional neural network (DCNN). METHODS: We trained a DCNN using a dataset of 26,661 individual lesion images obtained from 123 patients with a diagnosis of SJS/TEN or nonsevere cADRs. The DCNN's accuracy of classification was compared with that of 10 board-certified dermatologists and 24 trainee dermatologists. RESULTS: The DCNN achieved 84.6% sensitivity (95% confidence interval [CI], 80.6-88.6), whereas the sensitivities of the board-certified dermatologists and trainee dermatologists were 31.3 % (95% CI, 20.9-41.8; P < .0001) and 27.8% (95% CI, 22.6-32.5; P < .0001), respectively. The negative predictive value was 94.6% (95% CI, 93.2-96.0) for the DCNN, 68.1% (95% CI, 66.1-70.0; P < .0001) for the board-certified dermatologists, and 67.4% (95% CI, 66.1-68.7; P < .0001) for the trainee dermatologists. The area under the receiver operating characteristic curve of the DCNN for a SJS/TEN diagnosis was 0.873, which was significantly higher than that for all board-certified dermatologists and trainee dermatologists. CONCLUSIONS: We developed a DCNN to classify SJS/TEN and nonsevere cADRs based on individual lesion images of erythema. The DCNN performed significantly better than did dermatologists in classifying SJS/TEN from skin images.

Interaction between decision-making and interoceptive representations of bodily arousal in frontal cortex.

Decision-making and representations of arousal are intimately linked. Behavioral investigations have classically shown that either too little or too much bodily arousal is detrimental to decision-making, indicating that there is an inverted "U" relationship between bodily arousal and performance. How these processes interact at the level of single neurons as well as the neural circuits involved are unclear. Here we recorded neural activity from orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaque monkeys while they made reward-guided decisions. Heart rate (HR) was also recorded and used as a proxy for bodily arousal. Recordings were made both before and after subjects received excitotoxic lesions of the bilateral amygdala. In intact monkeys, higher HR facilitated reaction times (RTs). Concurrently, a set of neurons in OFC and dACC selectively encoded trial-by-trial variations in HR independent of reward value. After amygdala lesions, HR increased, and the relationship between HR and RTs was altered. Concurrent with this change, there was an increase in the proportion of dACC neurons encoding HR. Applying a population-coding analysis, we show that after bilateral amygdala lesions, the balance of encoding in dACC is skewed away from signaling either reward value or choice direction toward HR coding around the time that choices are made. Taken together, the present results provide insight into how bodily arousal and decision-making are signaled in frontal cortex.

Single caudate neurons encode temporally discounted value for formulating motivation for action.

The term 'temporal discounting' describes both choice preferences and motivation for delayed rewards. Here we show that neuronal activity in the dorsal part of the primate caudate head (dCDh) signals the temporally discounted value needed to compute the motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which visual cues indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animal's physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh markedly distorted the normal task performance based on the integration of reward size and delay, but did not affect the task performance for different reward sizes without delay. These results suggest that dCDh is involved in encoding the integrated multi-dimensional information critical for motivation.