Long-term antibody response following SPUTNIK V primary vaccination in healthcare workers with and without history of SARS-CoV-2 infection: Prospective cohort study from a hospital in Argentina.

Background: In December 2020, Sputnik V was incorporated to the National COVID-19 Immunization Plan in Argentina. Studies had shown 98% of antibody response rate. To date, data on immunogenicity and antibody persistence in Argentina are scarce.The objective was to assess humoral immune response after two doses of Sputnik V in Health Care Workers (HCWs) at the Ricardo Gutierrez Children's Hospital (RGCH). Methods: A prospective, cohort study in HCWs immunized with two doses of Sputnik V between February and March 2021. The following variables were assessed: age, gender, risk factors for severe COVID-19 or mortality, immunosuppressive therapy and history of SARS-CoV-2. Blood samples were drawn on the day of the first dose, 28 days and 180 days after the second. Anti-Spike IgG was measured using an ELISA assay. Differences in immune response were evaluated according to study variables. Comparison analyses between groups with or without history of infection were performed, with T-test and ANOVA or Mann-Whitney tests. For each subject, we compared baseline values with 28 days and 180 days after the second vaccine.STATA version 14 and R Sofware were used for data analyses. Results: We included 528 individuals, mean age 41.5 years, 82.9% female, 14.4% (76/528) reported previous SARS-CoV-2 infection.All subjects developed antibodies post-vaccination. At day 28, concentrations were significantly higher in previously infected than naïve subjects (p < 0.001) with no differences according to age, gender and comorbidities.At day 180, 17% (95% CI 13.17-21.53) of naïve subjects were negative. Antibody concentrations decreased significantly in all subjects except in those who reported SARS-CoV-2 infection after vaccination (n = 31). This last group had significantly higher antibody concentrations. Conclusion: This study assessed immune response to a new COVID-19 vaccine in real life in a cohort of subjects. Antibody concentrations varied according to history of SARS-COV-2 infection and decreased over time.

Assessment of stigma related to visible skin diseases: a systematic review and evaluation of patient-reported outcome measures.

Misconceptions about visible skin diseases are widespread, and patients often face discrimination and stigmatization due to their condition. The associated negative health and psychosocial consequences of stigmatization in skin diseases have prompted an increase in research activity in recent times, resulting in a wide variety of assessment measures. This study aimed at aggregating and evaluating evidence of psychometric properties and methodological quality of published measures to assess stigma in visible skin diseases. Studies assessing stigmatization in visible skin diseases were searched in four databases (Medline, PsycINFO, Web of Science and Embase) until February 2021. The review followed PRISMA guidelines. Papers regarding development and/or validation of measures were identified by two independent researchers. Inclusion criteria were defined as follows: (i) quantitative studies in (ii) populations with skin diseases using (iii) questionnaires explicitly assessing (iv) perceived or public stigmatization or discrimination available in (iv) English or German language. The COnsensus-based Standards of health Measurement INstruments (COSMIN) checklist was used to evaluate their psychometric properties and risk of bias. 35 studies using 21 instruments were identified. Twenty instruments focused on assessing the perceived reality of those affected by visible skin diseases, while public stigma was only assessed by two instruments. Twelve scales could be recommended for use, while nine instruments had the potential to be recommended after further studies have assessed their quality. Some limitations are to be noted. Only studies in English and German were included. Research on self-constructed instruments can lead to new validated instruments, but they were not included in the review at this point. Several validated instruments could be recommended for use. Future research is needed regarding the assessment of stigma across different visible skin diseases, in children and adolescents, and in the general public.

Strategies to reduce stigma related to visible chronic skin diseases: a systematic review.

Many patients with a visible chronic skin disease experience discrimination and stigmatization. This results in psychosocial impairments in addition to the burden of disease and emphasizes the urgency to implement effective stigma-reduction strategies. To synthesize what is known globally about effective interventions to reduce stigma associated with visible chronic skin diseases, a systematic review was conducted. Four electronic databases were searched until May 2018. Studies evaluating interventions to reduce stigmatization in patients with visible chronic skin diseases and applying at least one stigma-related outcome measure were included. Data were extracted on study design, country, study population, outcome measures and main findings. Results were subsequently synthesized in a narrative review. Critical Appraisal Skills Programme tools were used to assess study quality. Nineteen studies were included in the review. Study design was very heterogeneous and study quality rather poor. Thirteen studies addresses patients with leprosy in low- and middle-income countries, and one study each targeted patients with onychomycosis, leg ulcer, facial disfigurement, atopic dermatitis, vitiligo and alopecia. Evaluated interventions were mainly multi-faceted incorporating more than one type of intervention. While 10 studies focused on the reduction in self-stigma and 4 on the reduction in public stigma, another 5 studies aimed at reducing both. The present review revealed a lack of high-quality studies on effective approaches to reduce stigmatization of patients with visible chronic skin diseases. Development and evaluation of intervention formats to adequately address stigma is essential to promote patients' health and well-being.

Remodeling sensory cortical maps implants specific behavioral memory.

Neural mechanisms underlying the capacity of memory to be rich in sensory detail are largely unknown. A candidate mechanism is learning-induced plasticity that remodels the adult sensory cortex. Here, expansion in the primary auditory cortical (A1) tonotopic map of rats was induced by pairing a 3.66-kHz tone with activation of the nucleus basalis, mimicking the effects of natural associative learning. Remodeling of A1 produced de novo specific behavioral memory, but neither memory nor plasticity was consistently at the frequency of the paired tone, which typically decreased in A1 representation. Rather, there was a specific match between individual subjects' area of expansion and the tone that was strongest in each animal's memory, as determined by post-training frequency generalization gradients. These findings provide the first demonstration of a match between the artificial induction of specific neural representational plasticity and artificial induction of behavioral memory. As such, together with prior and present findings for detection, correlation and mimicry of plasticity with the acquisition of memory, they satisfy a key criterion for neural substrates of memory. This demonstrates that directly remodeling sensory cortical maps is sufficient for the specificity of memory formation.

The brain decade in debate: VI. Sensory and motor maps: dynamics and plasticity

This article is an edited transcription of a virtual symposium promoted by the Brazilian Society of Neuroscience and Behavior (SBNeC). Although the dynamics of sensory and motor representations have been one of the most studied features of the central nervous system, the actual mechanisms of brain plasticity that underlie the dynamic nature of sensory and motor maps are not entirely unraveled. Our discussion began with the notion that the processing of sensory information depends on many different cortical areas. Some of them are arranged topographically and others have non-topographic (analytical) properties. Besides a sensory component, every cortical area has an efferent output that can be mapped and can influence motor behavior. Although new behaviors might be related to modifications of the sensory or motor representations in a given cortical area, they can also be the result of the acquired ability to make new associations between specific sensory cues and certain movements, a type of learning known as conditioning motor learning. Many types of learning are directly related to the emotional or cognitive context in which a new behavior is acquired. This has been demonstrated by paradigms in which the receptive field properties of cortical neurons are modified when an animal is engaged in a given discrimination task or when a triggering feature is paired with an aversive stimulus. The role of the cholinergic input from the nucleus basalis to the neocortex was also highlighted as one important component of the circuits responsible for the context-dependent changes that can be induced in cortical maps

The brain decade in debate: VI. Sensory and motor maps: dynamics and plasticity.

This article is an edited transcription of a virtual symposium promoted by the Brazilian Society of Neuroscience and Behavior (SBNeC). Although the dynamics of sensory and motor representations have been one of the most studied features of the central nervous system, the actual mechanisms of brain plasticity that underlie the dynamic nature of sensory and motor maps are not entirely unraveled. Our discussion began with the notion that the processing of sensory information depends on many different cortical areas. Some of them are arranged topographically and others have non-topographic (analytical) properties. Besides a sensory component, every cortical area has an efferent output that can be mapped and can influence motor behavior. Although new behaviors might be related to modifications of the sensory or motor representations in a given cortical area, they can also be the result of the acquired ability to make new associations between specific sensory cues and certain movements, a type of learning known as conditioning motor learning. Many types of learning are directly related to the emotional or cognitive context in which a new behavior is acquired. This has been demonstrated by paradigms in which the receptive field properties of cortical neurons are modified when an animal is engaged in a given discrimination task or when a triggering feature is paired with an aversive stimulus. The role of the cholinergic input from the nucleus basalis to the neocortex was also highlighted as one important component of the circuits responsible for the context-dependent changes that can be induced in cortical maps.

Long-term frequency tuning of local field potentials in the auditory cortex of the waking guinea pig.

The goal of our study was to determine the extent of changes in frequency tuning in the auditory cortex over weeks. The subjects were awake adult male guinea pigs (n = 8) bearing electrodes chronically implanted in layers IV-VI of primary auditory cortex. Tuning was determined by presenting sequences of pure tone bursts (approximately 0.97-41.97 kHz, -20 to 80 dB, 100-ms tone duration, 5-ms rise-fall, 800-ms intertone intervals, 1.5-s intersequence interval) either in 0.5-octave steps (n = 5, 14 probes) or 0.25-octave steps (n = 3, 9 probes) delivered to the ear contralateral to recording sites. Tuning curves were determined for local field potentials (LFPs), which were tuned to frequency (negative potential, latency to peak 15-20 ms), repeatedly for up to 27 days (0.5 octave) or 12 days (0.25 octave). Characteristic frequency (CF), best frequency at 10 and 30 dB above absolute threshold (BF10, BF30), threshold (TH), and bandwidth (10 dB above threshold; BW) were measured. Absolute amplitude often decreased across weeks, necessitating normalization of amplitude. However, there were no significant trends in tuning over days for CF, BF10, or BF30 for either the half- or the quarter-octave group. Both groups exhibited random daily variations in frequency tuning, the quarter-octave group revealing larger variations averaging 0.228, 0.211, and 0.250 octave for CF, BF10, and BF30, respectively. Therefore, frequency tuning in waking animals does not exhibit directional drift over very long periods of time. However, daily tuning variations on the order of 0.20-0.25 octave indicate that the peaks of tuning curves (CF, BF) represent a preferred frequency range rather than a fixed frequency.

The neurobiology of learning and memory: some reminders to remember.

We have learned much about the neurobiology of learning and memory in the past 100 years. We have also learned much about how we should, and should not, investigate these complex processes. However, with the rapid recent growth in the field and the influx of investigators not familiar with this past, these crucial lessons too often fail to guide the research of today. Here we highlight some major lessons gleaned from this wealth of experience. These include the need to carefully attend to the learning/performance distinction, to rely equally on synthetic as well as reductionistic thinking, and to avoid the seduction of simplicity. Examples in which the lessons of history are, and are not, educating current research are also given.

Muscarinic dependence of nucleus basalis induced conditioned receptive field plasticity.

Receptive field (RF) plasticity in primary auditory cortex of adult animals, specifically selective increased response to a tonal conditioned stimulus (CS) relative to other frequencies, can be induced both by behavioral conditioning and by pairing a tone with stimulation of the nucleus basalis (NB). This study determined whether cortical muscarinic receptors are necessary for NB-induced RF plasticity. Single units in layers II-IV were studied in Urethane anesthetized adult rats. The cortex was perfused with saline or saline+atropine sulfate. Conditioning, 30 trials of pairing a tone with NB stimulation, produced a significant CS-specific response increase (n=8). Local atropine blocked NB-induced RF plasticity, actually resulting in CS-specific response decrease (n=6). Therefore, NB-induced RF plasticity requires engagement of muscarinic receptors in auditory cortex.

In vivo Hebbian and basal forebrain stimulation treatment in morphologically identified auditory cortical cells.

The present study concerns the interactions of local pre/postsynaptic covariance and activity of the cortically-projecting cholinergic basal forebrain, in physiological plasticity of auditory cortex. Specifically, a tone that activated presynaptic inputs to a recorded auditory cortical neuron was repeatedly paired with a combination of two stimuli: (1) local juxtacellular current that excited the recorded cell and (2) basal forebrain stimulation which desynchronized the cortical EEG. In addition, the recorded neurons were filled with biocytin for morphological examination. The hypothesis tested was that the combined treatment would cause increased potentiation of responses to the paired tone, relative to similar conditioning treatments involving either postsynaptic excitation alone or basal forebrain stimulation alone. In contrast, there was no net increase in plasticity and indeed the combined treatment appears to have decreased plasticity below that previously found for either treatment alone. Several alternate interpretations of these results are discussed.

Differentially responsive adjacent auditory cortical cells maintained coordinated firing.

Temporal relationships between adjacent single cells were studied in the auditory cortex of the waking guinea pig during silence and pure tone stimulation. One cell of each pair was responsive while the other was completely unresponsive Coordinated discharge was found for spontaneous activity in 14/17 (82%) pairs, generally at and near the origin of cross correlation histograms (CCHs, 5 ms bins). These relationships, involving the same temporal intervals, were also maintained during tone driven discharges of the responsive cell. Thus, responsive neurons may participate simultaneously in specific sensory processing tasks while also responding to a presumptive common modulatory influence within a local network, without the two processes necessarily being linked. Therefore, responsive cells may have greater information processing capacity than realized.

Basal forebrain stimulation induces discriminative receptive field plasticity in the auditory cortex.

Learning alters receptive field (RF) tuning in the primary auditory cortex (ACx) to emphasize the frequency of a tonal conditioned stimulus. RF plasticity is a candidate substrate of memory, as it is associative, specific, discriminative, rapidly induced, and enduring. The authors hypothesized that it is produced by the release of acetylcholine in the ACx from the basal forebrain (BasF), caused by presentation of reinforced but not nonreinforced conditioned stimuli. Waking adult male Hartley guinea pigs (n = 16) received 1 of 2 tones followed by BasF stimulation, in a single session of 30 pseudo-random order trials each. RFs from neuronal discharges before and after differential pairing revealed the induction of predicted plasticity, as well as increased responses to the paired tone and decreased responses to the unpaired tone. Thus, highly specific, learning-induced RF plasticity in the ACx may be produced by activation of the BasF by a reinforced conditioned stimulus.

Physiological memory in primary auditory cortex: characteristics and mechanisms.

"Physiological memory" is enduring neuronal change sufficiently specific to represent learned information. It transcends both sensory traces that are detailed but transient and long-term physiological plasticities that are insufficiently specific to actually represent cardinal details of an experience. The specificity of most physiological plasticities has not been comprehensively studied. We adopted receptive field analysis from sensory physiology to seek physiological memory in the primary auditory cortex of adult guinea pigs. Receptive fields for acoustic frequency were determined before and at various retention intervals after a learning experience, typified by single-tone delay classical conditioning, e.g., 30 trials of tone-shock pairing. Subjects rapidly (5-10 trials) acquire behavioral fear conditioned responses, indexing acquisition of an association between the conditioned and the unconditioned stimuli. Such stimulus-stimulus association produces receptive field plasticity in which responses to the conditioned stimulus frequency are increased in contrast to responses to other frequencies which are decreased, resulting in a shift of tuning toward or to the frequency of the conditioned stimulus. This receptive field plasticity is associative, highly specific, acquired within a few trials, and retained indefinitely (tested to 8 weeks). It thus meets criteria for "physiological memory." The acquired importance of the conditioned stimulus is thought to be represented by the increase in tuning to this stimulus during learning, both within cells and across the primary auditory cortex. Further, receptive field plasticity develops in several tasks, one-tone and two-tone discriminative classical and instrumental conditioning (habituation produces a frequency-specific decrease in the receptive field), suggesting it as a general process for representing the acquired meaning of a signal stimulus. We have proposed a two-stage model involving convergence of the conditioned and unconditioned stimuli in the magnocellular medial geniculate of the thalamus followed by activation of the nucleus basalis, which in turn releases acetylcholine that engages muscarinic receptors in the auditory cortex. This model is supported by several recent findings. For example, tone paired with NB stimulation induces associative, specific receptive field plasticity of at least a 24-h duration. We propose that physiological memory in auditory cortex is not "procedural" memory, i.e., is not tied to any behavioral conditioned response, but can be used flexibly.

Induction of long-term receptive field plasticity in the auditory cortex of the waking guinea pig by stimulation of the nucleus basalis.

Learning induces neuronal receptive field (RF) plasticity in primary auditory cortex. This plasticity constitutes physiological memory as it is associative, highly specific, discriminative, develops rapidly, and is retained indefinitely. This study examined whether pairing a tone with activation of the nucleus basalis could induce RF plasticity in the waking guinea pig and, if so, whether it could be retained for 24 hr. Subjects received 40 trials of a single frequency paired with electrical stimulation of the nucleus basalis (NB) at tone offset. The physiological effectiveness of NB stimulation was assessed later while subjects were anesthetized with urethane by noting whether stimulation produced cortical desynchronization. Subjects in which NB stimulation was effective did develop RF plasticity and this was retained for 24 hr. Thus, activation of the NB during normal learning may be sufficient to induce enduring physiological memory in auditory cortex.

Acoustic frequency tuning of neurons in the basal forebrain of the waking guinea pig.

The acoustic responses of cells in the basal forebrain were studied in the adult waking guinea pig. Frequency receptive fields were obtained across wide frequency (0.094-45.0 kHz) and intensity (0-90 dB) ranges. A total of 326 recordings were obtained in 26 electrode penetrations from five subjects; 205 from the globus pallidus (GP), 98 from the caudate-putamen (CPu) and 23 from the central nucleus of the amygdala (ACE). Twenty-nine recordings exhibited acoustic responses (GP=20 (9.8%); CPu=9 (9.2%); ACE=0). Cells in the regions of the GP that project to the primary auditory cortex (ACx) exhibited frequency tuning that was dominantly suppressive. Responses in the CPu were excitatory, but poorly tuned. The spontaneous rate of discharge of GP cells that yielded complete tuning data was positively correlated with power in the beta bands (12-25 and 25-50 Hz) and negatively correlated with power in the delta band (1-4 Hz) of the EEG of the ACx. These findings suggest that acoustically tuned neurons in the GP that are inhibited by tones are involved in the regulation of auditory cortical state, possibly promoting deactivation to unimportant sounds, and may be cholinergic in nature.

Learning-induced physiological memory in adult primary auditory cortex: receptive fields plasticity, model, and mechanisms.

It is well established that the functional organization of adult sensory cortices, including the auditory cortex, can be modified by deafferentation, sensory deprivation, or selective sensory stimulation. This paper reviews evidence establishing that the adult primary auditory cortex develops physiological plasticity during learning. Determination of frequency receptive fields before and at various times following aversive classical conditioning and instrumental avoidance learning in the guinea pig reveals increased neuronal responses to the pure tone frequency used as a conditioned stimulus (CS). In contrast, responses to the pretraining best frequency and other non-CS frequencies are decreased. These opposite changes are often sufficient to shift cellular tuning toward or even to the frequency of the CS. Learning-induced receptive field (RF) plasticity (i) is associative (requires pairing tone and shock), (ii) highly specific to the CS frequency (e.g., limited to this frequency +/- a small fraction of an octave), (iii) discriminative (specific increased response to a reinforced CS+ frequency but decreased response to a nonreinforced CS- frequency), (iv) develops extremely rapidly (within 5 trials, the fewest trials tested), and (v) is retained indefinitely (tested to 8 weeks). Moreover, RF plasticity is robust and not due to arousal, but can be expressed in the deeply anesthetized subject. Because learning- induced RF plasticity has the major characteristics of associative memory, it is therefore referred to as "physiological memory". We developed a model of RF plasticity based on convergence in the auditory cortex of nucleus basalis cholinergic effects acting at muscarinic receptors, with lemniscal and nonlemniscal frequency information from the ventral and magnocellular divisions of the medial geniculate nucleus, respectively. In the model, the specificity of RF plasticity is dependent on Hebbian rules of covariance. This aspect was confirmed in vivo using microstimulation techniques. Further, the model predicts that pairing a tone with activation of the nucleus basalis is sufficient to induce RF plasticity similar to that obtained in behavioral learning. This prediction has been confirmed. Additional tests of the model are described. RF plasticity is thought to translate the acquired significance of sound into an increased frequency representation of behaviorally important stimuli.

Tuning the brain by learning and by stimulation of the nucleus basalis.

Although it is well-established that the cerebral cortex is a substrate for learning, memory and higher cognitive functions, rather less is known about the mechanisms by which experiences are acquired and stored in the cortex. The role of the basal forebrain cholinergic system (BFCS) in learning-induced plasticity is underlined by a recent report by Kilgard and Merzenich[1]. In this article I will discuss the findings of Kilgard and Merzenich in the context of other developments in our understanding of the BFCS and its role in learning-induced plasticity. However, before the discussion I would like to provide some essential background information.

Evidence for the Hebbian hypothesis in experience-dependent physiological plasticity of neocortex: a critical review.

Over the past decade, the number of experimental papers reporting physiological plasticity in primary neocortical regions, following certain types of controlled sensory experience, have increased greatly. These reports have been characterized by specific changes in receptive fields of individual neurons and/or the distributions of receptive fields across cortical maps. There is a widespread belief these types of plasticities have underlying Hebbian/covariance induction mechanisms. This belief appears to be based mainly on: (a) indirect evidence, largely from experiments on the kitten visual cortex, indicating that Hebbian induction mechanisms could be involved in neocortical plasticity; (b) the observation that some types of plasticity in systems other than neocortex follow Hebbian rules of induction; and (c) the adaptability of Hebbian induction mechanisms to models of neural plasticity. In addition, some experiments have directly tested the role of Hebbian induction mechanisms in experience-dependent neocortical plasticity. The present review critically analyzes these (and related) experiments, in order to evaluate the evidence for the Hebbian Hypothesis in experience-dependent physiological plasticity of neocortex. First, we present a set of criteria to show the involvement of a Hebbian process in any form of plasticity. Next, we compare evidence from each primary neocortical region to these criteria. Finally, we examine unresolved issues. While selected developmental studies are included, emphasis is placed on plasticity in the adult neocortex. It is concluded that there is some evidence meeting the criteria for the Hebbian hypothesis in neocortical plasticity. However, this evidence is quite limited considering the popular belief in the validity of the Hebbian hypothesis.