Age Patterns of HSV-2 Incidence and Prevalence in Two Ugandan Communities: A Catalytic Incidence Model Applied to Population-Based Seroprevalence Data.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) is an incurable sexually transmitted infection associated with increased risk of acquiring and transmitting human immunodeficiency virus (HIV). HSV-2 is highly prevalent in sub-Saharan Africa, but population-level estimates of incidence are sparse. METHODS: We measured HSV-2 prevalence from cross-sectional serological data among adults aged 18-49 years in 2 south-central Uganda communities (fishing, inland). We identified risk factors for seropositivity, then inferred age patterns of HSV-2 with a Bayesian catalytic model. RESULTS: HSV-2 prevalence was 53.6% (n = 975/1819; 95% confidence interval, 51.3%-55.9%). Prevalence increased with age, was higher in the fishing community, and among women, reaching 93.6% (95% credible interval, 90.2%-96.6%) by age 49 years. Factors associated with HSV-2 seropositivity included more lifetime sexual partners, HIV positive status, and lower education. HSV-2 incidence peakied at age 18 years for women and 19-20 years for men. HIV prevalence was up to 10-fold higher in HSV-2-positive individuals. CONCLUSIONS: HSV-2 prevalence and incidence were extremely high, with most infections occurring in late adolescence. Interventions against HSV-2, such as future vaccines or therapeutics, must target young populations. Remarkably higher HIV prevalence among HSV-2-positive individuals underscores this population as a priority for HIV prevention.

The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey.

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between 'pressure-only' and 'pressure + cold' stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of the LF-HRVnu-CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi-modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. KEY POINTS: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.

Qualitative Assessment of Barriers and Facilitators of PrEP Use Before and After Rollout of a PrEP Program for Priority Populations in South-central Uganda.

Uganda piloted HIV pre-exposure prophylaxis (PrEP) for priority populations (sex workers, fishermen, truck drivers, discordant couples) in 2017. To assess facilitators and barriers to PrEP uptake and adherence, we explored perceptions of PrEP before and experiences after rollout among community members and providers in south-central Uganda. We conducted 75 in-depth interviews and 12 focus group discussions. We analyzed transcripts using a team-based thematic framework approach. Partners, family, peers, and experienced PrEP users provided adherence support. Occupational factors hindered adherence for sex workers and fishermen, particularly related to mobility. Pre-rollout concerns about unskilled/untrained volunteers distributing PrEP and price-gouging were mitigated. After rollout, awareness of high community HIV risk and trust in PrEP effectiveness facilitated uptake. PrEP stigma and unexpected migration persisted as barriers. Community-initiated, tailored communication with successful PrEP users may optimize future engagement by addressing fears and rumors, while flexible delivery and refill models may facilitate PrEP continuation and adherence.

RESUMEN: En 2017, Uganda introdujo profilaxis pre-exposición (PrEP), dirigida a las populaciones con alto riesgo de contraer al VIH (trabajadoras sexuales, pescadores, camioneros, parejas sero-discordantes). Para investigar facilitadores y barreras para la adopción y la adherencia a la PrEP, exploramos percepciones de PrEP antes y después de su introducción en Uganda. Realizamos 75 entrevistas y 12 grupos focales con miembros de la comunidad y trabajadores de salud. Analizamos las transcripciones temáticamente usando un marco de referencia. Parejas, familias, compañeros, y clientes usando PrEP apoyaron a los demás mantener adherencia. Movilidad fue una barrera para la adherencia a la PrEP para trabajadoras sexuales y pescadores. Preocupaciones sobre el entrenamiento de los distribuidores de PrEP y la especulación de precios no fueron realizadas. Percepciones del riesgo del VIH y confianza en la eficacia de PrEP facilitaron su adopción. Estigma y migración inesperada persistieron como barreras para la adopción de PrEP. Comunicaciones manejadas por clientes usando PrEP pueden motivar interés en PrEP y abordar rumores. Sistemas flexibles del entrego y la recarga de medicinas pueden permitir continuación de, y adherencia a, la PrEP.

Noxious pressure stimulation demonstrates robust, reliable estimates of brain activity and self-reported pain.

Functional neuroimaging techniques have provided great insight in the field of pain. Utilising these techniques, we have characterised pain-induced responses in the brain and improved our understanding of key pain-related phenomena. Despite the utility of these methods, there remains a need to assess the test retest reliability of pain modulated blood-oxygen-level-dependant (BOLD) MR signal across repeated sessions. This is especially the case for more novel yet increasingly implemented stimulation modalities, such as noxious pressure, and it is acutely important for multi-session studies considering treatment efficacy. In the present investigation, BOLD signal responses were estimated for noxious-pressure stimulation in a group of healthy participants, across two separate sessions. Test retest reliability of functional magnetic resonance imaging (fMRI) data and self-reported visual analogue scale measures were determined by the intra-class correlation coefficient. High levels of reliability were observed in several key brain regions known to underpin the pain experience, including in the thalamus, insula, somatosensory cortices, and inferior frontal regions, alongside "excellent" reliability of self-reported pain measures. These data demonstrate that BOLD-fMRI derived signals are a valuable tool for quantifying noxious responses pertaining to pressure stimulation. We further recommend the implementation of pressure as a stimulation modality in experimental applications.

Feature-selective Attention in Frontoparietal Cortex: Multivoxel Codes Adjust to Prioritize Task-relevant Information.

Human cognition is characterized by astounding flexibility, enabling us to select appropriate information according to the objectives of our current task. A circuit of frontal and parietal brain regions, often referred to as the frontoparietal attention network or multiple-demand (MD) regions, are believed to play a fundamental role in this flexibility. There is evidence that these regions dynamically adjust their responses to selectively process information that is currently relevant for behavior, as proposed by the "adaptive coding hypothesis" [Duncan, J. An adaptive coding model of neural function in prefrontal cortex. Nature Reviews Neuroscience, 2, 820-829, 2001]. Could this provide a neural mechanism for feature-selective attention, the process by which we preferentially process one feature of a stimulus over another? We used multivariate pattern analysis of fMRI data during a perceptually challenging categorization task to investigate whether the representation of visual object features in the MD regions flexibly adjusts according to task relevance. Participants were trained to categorize visually similar novel objects along two orthogonal stimulus dimensions (length/orientation) and performed short alternating blocks in which only one of these dimensions was relevant. We found that multivoxel patterns of activation in the MD regions encoded the task-relevant distinctions more strongly than the task-irrelevant distinctions: The MD regions discriminated between stimuli of different lengths when length was relevant and between the same objects according to orientation when orientation was relevant. The data suggest a flexible neural system that adjusts its representation of visual objects to preferentially encode stimulus features that are currently relevant for behavior, providing a neural mechanism for feature-selective attention.

Spatial scale and distribution of neurovascular signals underlying decoding of orientation and eye of origin from fMRI data.

Multivariate pattern analysis of functional magnetic resonance imaging (fMRI) data is widely used, yet the spatial scales and origin of neurovascular signals underlying such analyses remain unclear. We compared decoding performance for stimulus orientation and eye of origin from fMRI measurements in human visual cortex with predictions based on the columnar organization of each feature and estimated the spatial scales of patterns driving decoding. Both orientation and eye of origin could be decoded significantly above chance in early visual areas (V1-V3). Contrary to predictions based on a columnar origin of response biases, decoding performance for eye of origin in V2 and V3 was not significantly lower than that in V1, nor did decoding performance for orientation and eye of origin differ significantly. Instead, response biases for both features showed large-scale organization, evident as a radial bias for orientation, and a nasotemporal bias for eye preference. To determine whether these patterns could drive classification, we quantified the effect on classification performance of binning voxels according to visual field position. Consistent with large-scale biases driving classification, binning by polar angle yielded significantly better decoding performance for orientation than random binning in V1-V3. Similarly, binning by hemifield significantly improved decoding performance for eye of origin. Patterns of orientation and eye preference bias in V2 and V3 showed a substantial degree of spatial correlation with the corresponding patterns in V1, suggesting that response biases in these areas originate in V1. Together, these findings indicate that multivariate classification results need not reflect the underlying columnar organization of neuronal response selectivities in early visual areas.NEW & NOTEWORTHY Large-scale response biases can account for decoding of orientation and eye of origin in human early visual areas V1-V3. For eye of origin this pattern is a nasotemporal bias; for orientation it is a radial bias. Differences in decoding performance across areas and stimulus features are not well predicted by differences in columnar-scale organization of each feature. Large-scale biases in extrastriate areas are spatially correlated with those in V1, suggesting biases originate in primary visual cortex.

Coding of Visual, Auditory, Rule, and Response Information in the Brain: 10 Years of Multivoxel Pattern Analysis.

How is the processing of task information organized in the brain? Many views of brain function emphasize modularity, with different regions specialized for processing different types of information. However, recent accounts also highlight flexibility, pointing especially to the highly consistent pattern of frontoparietal activation across many tasks. Although early insights from functional imaging were based on overall activation levels during different cognitive operations, in the last decade many researchers have used multivoxel pattern analyses to interrogate the representational content of activations, mapping out the brain regions that make particular stimulus, rule, or response distinctions. Here, we drew on 100 searchlight decoding analyses from 57 published papers to characterize the information coded in different brain networks. The outcome was highly structured. Visual, auditory, and motor networks predominantly (but not exclusively) coded visual, auditory, and motor information, respectively. By contrast, the frontoparietal multiple-demand network was characterized by domain generality, coding visual, auditory, motor, and rule information. The contribution of the default mode network and voxels elsewhere was minor. The data suggest a balanced picture of brain organization in which sensory and motor networks are relatively specialized for information in their own domain, whereas a specific frontoparietal network acts as a domain-general "core" with the capacity to code many different aspects of a task.

Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda.

HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years. As new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance of 38,749 participants in the Rakai Community Cohort Study and longitudinal deep-sequence viral phylogenetics to assess how HIV incidence and population groups driving transmission have changed from 2003 to 2018 in Uganda. We observed 1,117 individuals in the incidence cohort and 1,978 individuals in the transmission cohort. HIV viral suppression increased more rapidly in women than men, however incidence declined more slowly in women than men. We found that age-specific transmission flows shifted: whereas HIV transmission to girls and women (aged 15-24 years) from older men declined by about one-third, transmission to women (aged 25-34 years) from men that were 0-6 years older increased by half in 2003 to 2018. Based on changes in transmission flows, we estimated that closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018. This study suggests that HIV programmes to increase HIV suppression in men are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa.

Diabetes mellitus is not associated with major morbidity following open abdominal aortic aneurysm repair.

BACKGROUND: It has been suggested that there is an increased morbidity and mortality risk for diabetics undergoing elective aortic surgery. This, however, is not universally accepted. In this study, we utilize a national database to determine if diabetes is associated with adverse outcomes following open, elective, infrarenal abdominal aortic aneurysm (AAA) repair. METHODS: The American College of Surgeons' National Surgical Quality Improvement Program database was queried to identify all patients who underwent an open, elective, nonruptured AAA repair from January 1, 2005 to December 31, 2007. Patient demographics, comorbidities, and outcomes were compared by diabetes status. Multivariate analysis was performed adjusting for demographics and comorbidities. RESULTS: There were 2110 American College of Surgeons' National Surgical Quality Improvement Program patients who underwent an open, elective, nonruptured AAA repair during this time period. Of these patients, 245 (11.6%) had diabetes mellitus. The overall mortality rate was 3.7% (5.3% for diabetics and 3.5% for nondiabetics, P = 0.171). On bivariate analysis, diabetics were more likely to present preoperatively with cardiovascular and renal comorbidities. Postoperatively, there was no significant difference in mortality or in cardiac, pulmonary, or renal complications. Diabetics were more likely to develop superficial surgical site infections (SSIs) (4.5% versus 1.6%, P = 0.002). On multivariate regression, there was no difference in mortality or major complications between diabetics and nondiabetics (OR 1.4, 95% CI 0.68-2.71). Diabetics, however, were almost three times more likely to develop superficial SSIs (OR 2.8, 95% CI 1.29-6.00). CONCLUSIONS: Diabetes mellitus is not associated with significantly worse major outcomes following open, elective, infrarenal AAA repair. Diabetics, however, are more likely to develop superficial SSIs.

Understanding the drivers of preferential migration of people living with HIV to fishing communities of Lake Victoria in Uganda.

Fishing communities around Lake Victoria have among the highest burdens of HIV globally. Growing evidence suggests that high HIV prevalence is partially due to selective migration of people living with HIV to fishing communities. However, the reasons for this preferential migration are unclear. We recruited 60 men and women for qualitative in-depth interviews (30% living with HIV; 70% recent migrants of unknown HIV status) from seven Ugandan fishing communities. Interviews discussed mobility histories and the social context surrounding migration. Interviews were audio-recorded, transcribed, and translated. A version of the 'Push-Pull' theory of migration helped structure a conceptual thematic framework for data analysis. Unfavourable conditions related primarily to stigma, social discrimination, humiliation, rejection or HIV labelling, and violence, induced individuals to leave their home communities. Factors which eventually resulted in migration to fishing communities included anticipating less HIV-related stigma and a safe, friendly environment that accommodates all people. Access to healthy food (fish) and the perceived availability of community-based HIV care services were also attractions. We found that stigma is the major social phenomenon shaping preferential migration to fishing communities in Uganda.

Nearly half of adults with symptoms of sexually transmitted infections (STIs) did not seek clinical care: A population-based study of treatment-seeking behavior among adults in Rakai, Uganda.

Understanding treatment-seeking behavior is critical to the treatment and control of sexually transmitted infections (STIs), yet current data on STI treatment seeking in low-resource settings is rare. This population-based study aimed to describe STI treatment-seeking behavior and identify factors associated with seeking treatment at a clinic among adults with STI-related symptoms in rural Uganda. The STI prevalence study (STIPS) conducted a survey and STI testing among all consenting adults aged 18-49 in two communities in rural south-central Uganda. Of 1,825 participants, 962 individuals self-reported STI symptoms in the past six months; we present descriptive data on treatment seeking and STI prevalence among these individuals. We used multivariable Poisson regressions with robust variance to determine the sociodemographic and symptom-related factors independently associated with seeking STI treatment at a clinic and assessed the association with previous clinic treatment seeking and current STI diagnosis. Forty-three percent of adults who reported STI-related symptoms in the past six months said they did not seek any treatment. Among those who did, 58% sought treatment at a private clinic, 28% at a government clinic, 9% at a pharmacy/drug store, 3% at a traditional healer, 2% at a market/shop, and 5% at another location. Among both males and females, having multiple STI related symptoms was positively associated with clinic treatment seeking (males = PRR: 1.73, 95%CI: 1.36-2.21; females = PR: 1.41, 95%CI: 1.12-1.78). Approximately one-third of males and females who reported previously seeking clinic treatment for their symptoms were diagnosed with a curable STI at the time of the survey. In this setting, nearly half of adults with STI-related symptoms are not seeking clinical care and many who report having sought treatment for recent STI symptoms have curable STIs. Future studies should explore barriers to care-seeking and strategies to improve STI services.

High Acceptability and Perceived Feasibility of Long-Acting Injectable Antiretroviral Treatment Among People Living with HIV Who Are Viremic and Health Workers in Uganda.

Long-acting injectable antiretroviral treatment (LAI ART), such as a bimonthly injection of cabotegravir/rilpivirine, is a promising HIV treatment option. LAI ART may particularly benefit people who are reluctant to initiate or are poorly adherent to daily oral pills and not virally suppressed. However, the acceptability and feasibility of LAI ART among individuals with viremia in Africa has not been well studied. We conducted qualitative in-depth interviews with 38 people living with HIV with viral load ≥1000 copies/mL and 15 medical and nursing staff, and 6 focus group discussions with peer health workers, to examine acceptability and feasibility of LAI ART in south-central Uganda. Transcripts were thematically analyzed through a team-based framework approach. Most people living with HIV reacted positively toward LAI ART and endorsed interest in taking it themselves. Most felt LAI ART would make adherence easier by reducing the challenge with remembering daily pills, particularly in the context of busy schedules, travel, alcohol use, and dietary requirements. Participants also appreciated the privacy of injections, reducing the likelihood of stigma or inadvertent HIV serostatus disclosure with pill possession. Concerns about LAI ART included side effects, perceived medication effectiveness, fear of injection, and medical mistrust and conspiracy beliefs. Health workers and participants with viremia also noted health system challenges, such as stockouts and monitoring treatment failure. However, they felt the health system could overcome these challenges. Implementation complexities must be addressed as LAI ART is introduced and expanded in Africa to best support viral suppression and address HIV care continuum gaps.

Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda.

HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years. As new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance of 38,749 participants in the Rakai Community Cohort Study and longitudinal deep sequence viral phylogenetics to assess how HIV incidence and population groups driving transmission have changed from 2003 to 2018 in Uganda. We observed 1,117 individuals in the incidence cohort and 1,978 individuals in the transmission cohort. HIV viral suppression increased more rapidly in women than men, however incidence declined more slowly in women than men. We found that age-specific transmission flows shifted, while HIV transmission to girls and women (aged 15-24 years) from older men declined by about one third, transmission to women (aged 25-34 years) from men that were 0-6 years older increased by half in 2003 to 2018. Based on changes in transmission flows, we estimated that closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018. This study suggests that HIV programs to increase HIV suppression in men are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa.

The HIV and sexually transmitted infection syndemic following mass scale-up of combination HIV interventions in two communities in southern Uganda: a population-based cross-sectional study.

BACKGROUND: Combination HIV prevention and treatment interventions (CHIs) have led to substantial declines in HIV incidence in sub-Saharan Africa; however, population-level data on non-HIV sexually transmitted infections (STIs) in the context of CHIs are rare. We aimed to assess STI burden following scale-up of CHIs in Uganda. METHODS: The Sexually Transmitted Infection Prevalence Study (STIPS) was a cross-sectional study nested within a population-based cohort among inland agrarian and Lake Victoria fishing populations in southern Uganda. STIPS enrolled consenting residents aged 18-49 years in two communities (one inland and one fishing) between May and October, 2019, and measured the prevalence of chlamydia, gonorrhoea, trichomonas, syphilis, and herpes simplex virus 2 (HSV-2). FINDINGS: Between May 27, 2019 and Oct 25, 2019, STIPS enrolled 1825 participants. HIV prevalence was 14·0% among the inland population and 39·8% among the fishing population, with about 90% HIV viral load suppression in both communities. Among inland and fishing populations, chlamydia prevalence was 9·6% (95% CI 7·9-11·7) and 9·9% (8·1-12·0), gonorrhoea prevalence 5·0% (3·8-6·7) and 8·4% (6·8-10·5), trichomonas prevalence 9·4% (7·7-11·5) and 12·2% (10·2-14·5), and HSV-2 prevalence 43·0% (39·9-46·3) and 64·4% (61·3-67·6), respectively. In the fishing population, syphilis seropositivity was 24·2% (21·5-27·2) with 9·4% (7·7-11·5) having high-titre (rapid plasma reagin ≥1:8) infection, including 16·9% (11·9-24·0%) of men living with HIV. Prevalence of at least one curable STI (chlamydia, gonorrhoea, trichomonas, or high-titre syphilis) was 51% higher among people living with HIV (vs HIV negative; adjusted prevalence risk ratio [PRR] 1·51; 95% CI 1·27-1·78), including among pregnant women (adjusted PRR 1·87, 1·11-3·17), with no differences by HIV suppression status. INTERPRETATION: Despite near universal HIV treatment, STI burden remains extremely high in southern Uganda, particularly among people living with HIV. There is an urgent need to integrate STI care with HIV services in African settings. FUNDING: National Institutes of Health.

Concurrent neuroimaging and neurostimulation reveals a causal role for dlPFC in coding of task-relevant information.

Dorsolateral prefrontal cortex (dlPFC) is proposed to drive brain-wide focus by biasing processing in favour of task-relevant information. A longstanding debate concerns whether this is achieved through enhancing processing of relevant information and/or by inhibiting irrelevant information. To address this, we applied transcranial magnetic stimulation (TMS) during fMRI, and tested for causal changes in information coding. Participants attended to one feature, whilst ignoring another feature, of a visual object. If dlPFC is necessary for facilitation, disruptive TMS should decrease coding of attended features. Conversely, if dlPFC is crucial for inhibition, TMS should increase coding of ignored features. Here, we show that TMS decreases coding of relevant information across frontoparietal cortex, and the impact is significantly stronger than any effect on irrelevant information, which is not statistically detectable. This provides causal evidence for a specific role of dlPFC in enhancing task-relevant representations and demonstrates the cognitive-neural insights possible with concurrent TMS-fMRI-MVPA.

Imaging Brain Glx Dynamics in Response to Pressure Pain Stimulation: A 1H-fMRS Study.

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (1H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION (p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies.

Sustained perturbation in functional connectivity induced by cold pain.

BACKGROUND: Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes varies between cohorts and may relate to the consequences of living with chronic-pain related comorbidities, such as anxiety and depression. Healthy volunteer studies provide opportunities to study the effects of tonic noxious stimulation independently of these sequelae. Connectivity changes in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how these and other connectivity networks, for example, those governing descending pain control are affected by the presence of tonic, noxious stimulation in healthy, pain-free individuals, remains unknown. METHOD: In 20 healthy volunteers, we assessed FC prior to, during, and following tonic cold painful stimulation in the ventromedial prefrontal cortex (vmPFC), rostral anterior insula (rAI), subgenual anterior cingulate cortex (ACC) and periaqueductal grey (PAG). We also recorded subjectively reported pain using a computerised visual analogue scale. RESULTS: We saw DMN FC changes during painful stimulation and that inter-network connectivity between the rAI with the vmPFC increased during pain, whereas PAG-precuneus FC decreased. Pain-induced FC alterations persisted following noxious stimulation. FC changes related to the magnitude of individuals' subjectively reported pain. CONCLUSIONS: We demonstrate FC changes during and following tonic cold-pain in healthy participants. Similarities between our findings and reports of patients with chronic pain suggest that some FC changes observed in these patients may relate to the presence of an ongoing afferent nociceptive drive. SIGNIFICANCE: How pain-related resting state networks are affected by tonic cold-pain remains unknown. We investigated functional connectivity alterations during and following tonic cold pain in healthy volunteers. Cold pain perturbed the functional connectivity of the ventro-medial prefrontal cortex, anterior insula, and the periacquaductal grey area. These connectivity changes were associated with the magnitude of individuals' reported pain. We suggest that some connectivity changes described in chronic pain patients may be due to an ongoing afferent peripheral drive.

Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks.

There are bi-directional interactions between the autonomic nervous system (ANS) and pain. This is likely underpinned by a substantial overlap between brain areas of the central autonomic network and areas involved in pain processing and modulation. To date, however, relatively little is known about the neuronal substrates of the ANS-pain association. Here, we acquired resting state fMRI scans in 21 healthy subjects at rest and during tonic noxious cold stimulation. As indicators of autonomic function, we examined how heart rate variability (HRV) frequency measures were influenced by tonic noxious stimulation and how these variables related to participants' pain perception and to brain functional connectivity in regions known to play a role in both ANS regulation and pain perception, namely the right dorsal anterior cingulate cortex (dACC) and periaqueductal gray (PAG). Our findings support a role of the cardiac ANS in brain connectivity during pain, linking functional connections of the dACC and PAG with measurements of low frequency (LF)-HRV. In particular, we identified a three-way relationship between the ANS, cortical brain networks known to underpin pain processing, and participants' subjectively reported pain experiences. LF-HRV both at rest and during pain correlated with functional connectivity between the seed regions and other cortical areas including the right dorsolateral prefrontal cortex (dlPFC), left anterior insula (AI), and the precuneus. Our findings link cardiovascular autonomic parameters to brain activity changes involved in the elaboration of nociceptive information, thus beginning to elucidate underlying brain mechanisms associated with the reciprocal relationship between autonomic and pain-related systems.

Adaptive coding in the human brain: Distinct object features are encoded by overlapping voxels in frontoparietal cortex.

Our ability to flexibly switch between different tasks is a key component of cognitive control. Non-human primate (NHP) studies (e.g., Freedman, Riesenhuber, Poggio, & Miller, 2001) have shown that prefrontal neurons are re-used across tasks, re-configuring their responses to code currently relevant information. In a similar vein, in the human brain, the "multiple demand" (MD) system is suggested to exert control by adjusting its responses, selectively processing information in line with our current goals (Duncan, 2010). However, whether the same or different resources (underlying neural populations) in the human brain are recruited to solve different tasks remains elusive. In the present study, we aimed to bridge the gap between the NHP and human literature by examining human functional imaging data at an intermediate level of resolution: quantifying the extent to which single voxels contributed to multiple neural codes. Participants alternated between two tasks requiring the selection of feature information from two distinct sets of objects. We examined whether neural codes for the relevant stimulus features in the two different tasks depended on the same or different voxels. In line with the electrophysiological literature, MD voxels were more likely to contribute to multiple neural codes than we predicted based on permutation tests. Comparatively, in the visual system the neural codes depended on distinct sets of voxels. Our data emphasise the flexibility of the MD regions to re-configure their responses and adaptively code relevant information across different tasks.

Activity-driven relaxation of the cortical actomyosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking.

In neurosecretory cells, secretory vesicles (SVs) undergo Ca(2+)-dependent fusion with the plasma membrane to release neurotransmitters. How SVs cross the dense mesh of the cortical actin network to reach the plasma membrane remains unclear. Here we reveal that, in bovine chromaffin cells, SVs embedded in the cortical actin network undergo a highly synchronized transition towards the plasma membrane and Munc18-1-dependent docking in response to secretagogues. This movement coincides with a translocation of the cortical actin network in the same direction. Both effects are abolished by the knockdown or the pharmacological inhibition of myosin II, suggesting changes in actomyosin-generated forces across the cell cortex. Indeed, we report a reduction in cortical actin network tension elicited on secretagogue stimulation that is sensitive to myosin II inhibition. We reveal that the cortical actin network acts as a 'casting net' that undergoes activity-dependent relaxation, thereby driving tethered SVs towards the plasma membrane where they undergo Munc18-1-dependent docking.